Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([N:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:4]([Cl:27])[CH:3]=1.[CH3:28][NH:29][CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:35]([O:34][C:33]([NH:32][CH2:31][CH2:30][N:29]([CH3:28])[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([N:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:4]([Cl:27])[CH:3]=1)=[O:39])([CH3:38])([CH3:37])[CH3:36]
Reactant: CNCCNC(=O)OC(C)(C)C
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(C#N)c(Br)cc2Cl)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(C#N)c(N(C)CCNC(=O)OC(C)(C)C)cc2Cl)cc1
Temperature: 100 °C
Yield: 90.7 %

Procedure:
A mixture of tert-butyl (4-bromo-2-chloro-5-cyanophenyl)(4-methoxybenzyl)carbamate (363 mg, 0.803 mmol), tert-butyl (2-(methylamino)ethyl)carbamate (182 mg, 1.05 mmol), Pd2(dba)3 (51.5 mg, 0.056 mmol), BINAP (105 mg, 0.169 mmol), and Cs2CO3 (524 mg, 1.61 mmol) in a dry microwave vial was flushed with nitrogen. Toluene (5 mL) was added and the vial was sealed and heated at 100° C. overnight. The reaction was diluted with EtOAc and filtered through celite. The solvent was removed from the filtrate and silica gel radial chromatography eluting with hexane containing 5 to 30% EtOAc afforded tert-butyl (4-((2-((tert-butoxycarbonyl)amino)ethyl)(methyl)amino)-2-chloro-5-cyanophenyl)(4-methoxybenzyl)carbamate (397 mg) as an oil.
Reaction SMILES: [H+].[B-](F)(F)(F)F.[CH3:7][N:8]1[CH:12]([CH3:13])[CH2:11][CH2:10][C:9]1=[NH:14].[Cl:15][C:16]1[CH:17]=[C:18]([N:22]=[C:23]=[O:24])[CH:19]=[CH:20][CH:21]=1>C1C=CC=CC=1>[Cl:15][C:16]1[CH:17]=[C:18]([NH:22][C:23]([N:14]=[C:9]2[CH2:10][CH2:11][CH:12]([CH3:13])[N:8]2[CH3:7])=[O:24])[CH:19]=[CH:20][CH:21]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: CC1CCC(=N)N1C
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: c1ccccc1
Product: CC1CCC(=NC(=O)Nc2cccc(Cl)c2)N1C
Reaction time: 2 h

Procedure:
The HBF4 salt of 1,5-dimethyl-2-iminopyrrolidine (6.75 g.; 0.0337 mole) is converted to free base in benzene in the usual manner. Then 5.16 g. (0.0337 mole) of m-chlorophenylisocyanate, dissolved in anhydrous benzene, is added. The reaction mixture is stirred for 2 hours and then the solvent is evaporated in vacuo leaving a solid residue of 1-m-chlorophenyl-3-(1,5-dimethyl-2-pyrrolidylidene)urea, m.p. = 129°-130° C. After recrystallization from ethyl acetate, the m.p. is still 129°-130° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:8]([CH3:9])[N:7]=[CH:6][C:5]=1[CH2:10][CH2:11][NH2:12].[CH3:13][O-:14].[Na+]>CO>[NH2:3][C:4]1[N:8]([CH3:9])[N:7]=[CH:6][C:5]=1[CH2:10][CH2:11][NH:12][CH:13]=[O:14]
Reactant: C[O-]
Reactant: Cn1ncc(CCN)c1N
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cn1ncc(CCNC=O)c1N

Procedure:
To a solution of 2-(5-amino-1-methylpyrazol-4-yl)ethylamine dihydrochloride (2.98 g, 14 mmol) in methanol (50 ml) was added 28% sodium methoxide solution in methanol (5.4 ml, 28 mmol). The mixture was filtered through Celite, and the filtrate was concentrated in vacuo. A mixture of the residue and ethyl formate (80 ml) was stirred under reflux for 16 hours. To the reaction mixture was added chloroform, and the mixture was filtered through Celite. The filtrate was concentrated in vacuo to give N-[2-(5-amino-1-methylpyrazol-4-yl)ethyl]formamide (2.7 g) as a brown oil. 1H-NMR(CDCl3) δ2.57 (2H, t, J=6.9 Hz), 3.40–3.44 (2H, m), 3.67(3H, s), 5.77 (1H, br), 7.15 (1H, s), 8.16 (1H, s)
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])[NH2:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+]>O.CO>[CH2:19]([NH:13][C@H:12]([C:14]([OH:16])=[O:15])[CH2:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](N)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCC[C@H](NCc1ccccc1)C(=O)O
Reaction time: 1 h

Procedure:
A solution of Nδ-Boc-ornithine (7.0 g), 2M sodium hydroxide (20 ml), benzaldehyde (3.2 ml) and methanol (10 ml) was cooled to 0° C. and sodium borohydride (2.7 g) was added. After 1 hr at 0° C., the mixture was kept at 25° C. for 12 h. Water (100 ml) was added and the mixture extracted with ether (2×60 ml). The combined organic extract was washed with sat. sodium bicarbonate (ca. 150 ml) and water, and dried over anhydrous sodium sulfate. After concentration in vacuo, the desired product (4.5 g) was obtained as a white solid: 1H NMR (400 MHz, CD3OD) δ1.42 (s, 9H), 1.60 (m, 2H), 1.84 (m, 2H), 3.03 (m, 2H), 3.50 (t, J=7.4 Hz, 1H), 4.11 (d, J=11.9 Hz, 1H), 4.21 (d, J=11.9 Hz, 1H), 7.41 (m, 3H), and 7.49 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:28]([C:29]5[CH:30]=[N:31][N:32]([CH2:34][CH2:35][C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)[CH:33]=5)=[CH:27][N:26](C(OC(C)(C)C)=O)[C:23]4=[N:24][CH:25]=3)=[CH:16][C:15]=2[NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH2:10][CH2:9]1)=O)(C)(C)C.CO.[ClH:56]>C(OCC)C>[ClH:56].[CH2:34]([N:32]1[CH:33]=[C:29]([C:28]2[C:22]3[C:23](=[N:24][CH:25]=[C:20]([C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[C:15]([NH:49][S:50]([CH3:53])(=[O:52])=[O:51])[CH:16]=4)[CH:21]=3)[NH:26][CH:27]=2)[CH:30]=[N:31]1)[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4c(c3)c(-c3cnn(CCc5ccccc5)c3)cn4C(=O)OC(C)(C)C)cc2NS(C)(=O)=O)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CS(=O)(=O)Nc1cc(-c2cnc3[nH]cc(-c4cnn(CCc5ccccc5)c4)c3c2)ccc1N1CCNCC1
Yield: 68 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-3-(methylsulfonamido)phenyl)-3-(1-phenethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (21 mg, mmol) was deprotected in methanol/HCl in diethyl ether (2/1 ml) to afford 11 mg (68% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.859-8.853 (d, 1H), 8.736-8.73 (d, 1H), 8.37 (s, 1H), 8.33 (s, 1H), 8.00 (s, 1H), 7.867-7.861 (d, 1H), 7.66-7.63 (dd, 1H), 7.53-7.50 (d, 1H), 7.27-7.12 (m, 5H), 4.63-4.61 (t, 2H), 3.51-3.47 (t, 4H), 3.50-3.24 (m, 9H). MS: m/z=542.3 (M+1), HPLC: 98.49% in method B.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][OH:19])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH:18]=[O:19])[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3CO)CC2)nc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3C=O)CC2)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of the product of step A (5 g, 19.6 mmol), powdered 4 Å activated molecular sieves (10 g) and N-methylmorpholine oxide (3.5 g, 29.4 mmol) was stirred in DCM (100 mL) for 15 min at RT. Then the mixture was cooled to 0° C. and tetrapropylammonium perruthenate (0.69 g, 0.196 mmol) was added in one portion. The cold bath was removed and the mixture was stirred at RT for 1 h. The reaction was diluted with Et2O and stirred for 15 min at RT. The mixture was filtered through a plug of silica gel which was washed thoroughly with 2:1 hexane: ethyl acetate. The filtrate was concentrated to get a residue which was purified by column chromatography on silica (elution with 2:1 hexane:ethyl acetate) to yield the desired aldehyde. MS (ESI) m/z 260 [M+H]+.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[NH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=2)=[CH:25][C:24]=1[Cl:36]>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=3)=[CH:25][C:24]=2[Cl:36])=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)COCCc1ccc(OCC2CO2)cc1
Reactant: NCCOc1ccc(C2=NNC(=O)CC2)cc1Cl
Product: CC(C)COCCc1ccc(OCC(O)CNCCOc2ccc(C3=NNC(=O)CC3)cc2Cl)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isobutoxy-ethyl)-phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: C(N(CC)CC)C.[OH:8][N:9]=[C:10](Cl)[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20]>C(O)C>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:10]2[CH2:20][CH:19]([C:18]([O:22][CH3:23])=[O:21])[O:8][N:9]=2)[CH:12]=1
Reactant: C=CC(=O)OC
Reactant: ON=C(Cl)c1cccnc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)C1CC(c2cccnc2)=NO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.5 %

Procedure:
) A solution of N,N-diethylethanamine (0.544 mol) in ethanol (600 ml) was added dropwise to a stirred suspension of N-hydroxy-3-pyridinecarboximidoyl chloride (0.259 mol) and methyl 2-propenoate (1.295 mol) in ethanol (1500 ml) over a period of 1 hour. The reaction mixture was stirred for 1 hour at RT. The reaction mixture was evaporated. The residue was mixed with diethyl ether and filtered. The organic layer was separated, washed three times with water, separated again, dried (MgSO4), filtered and left overnight. Partial crystallization occurred on overnight standing. The crystals were filtered and dried and the filtrate was evaporated, yielding 52.6 g (98%) of (±)-methyl 4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxylate (interm. 1).
Reaction SMILES: [NH2:1][C@H:2]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[CH2:3][C:4](O)=[O:5].CO>C1COCC1>[NH2:1][C@H:2]([C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)[CH2:3][CH2:4][OH:5]
Reactant: N[C@@H](CC(=O)O)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CO
Product: N[C@@H](CCO)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
Borane-tetrahydrofuran complex (71.7 mL, 71.70 mmol) was added dropwise to a stirred suspension of (S)-3-amino-3-(4-bromophenyl)propanoic acid (3.5 g, 14.34 mmol) in THF (80 mL) at 0° C. over a period of 30 minutes under nitrogen. The resulting suspension was stirred at 0° C. for 30 minutes then at 22° C. for 5 hours. The reaction mixture was added portionwise to methanol (250 mL). The solution was stirred at room temperature for 24 hours. The mixture was concentrated, redissolved in methanol (250 mL) and reconcentrated (this process was repeated three times). The residue was dissolved in DCM (75 mL) and washed with 1N NaOH (50 mL). The aqueous layer was extracted with DCM (3×100 mL) and the extracts combined with the organic layer. The combined organics were washed with saturated brine (50 mL), dried over MgSO4 and concentrated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 2 to 6% MeOH/ammonia in DCM. Pure fractions were evaporated to dryness to afford (S)-3-amino-3-(4-bromophenyl)propan-1-ol (2.160 g, 65.5%) as a colourless gum.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([C:5]1[N:6]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:7]2[C:12]([C:13](=[O:26])[C:14]=1[CH2:15][NH:16][C:17]([C:19]1[CH:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1)=[O:18])=[CH:11][CH:10]=[C:9]([Cl:27])[CH:8]=2)=[O:4].[NH:35]1[CH2:40][CH2:39][CH:38]([CH2:41][OH:42])[CH2:37][CH2:36]1>CN1C(=O)CCC1>[Cl:27][C:9]1[CH:8]=[C:7]2[C:12]([C:13](=[O:26])[C:14]([CH2:15][NH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:35]4[CH2:40][CH2:39][CH:38]([CH2:41][OH:42])[CH2:37][CH2:36]4)=[N:21][CH:20]=3)=[O:18])=[C:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:34])[N:6]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:11][CH:10]=1
Reactant: OCC1CCNCC1
Reactant: CN(C)C(=O)c1c(CNC(=O)c2ccc(Cl)nc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Solvent: CN1CCCC1=O
Product: CN(C)C(=O)c1c(CNC(=O)c2ccc(N3CCC(CO)CC3)nc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Temperature: 125 °C

Procedure:
The intermediate 7-chloro-3-{[(6-chloro-pyridine-3-carbonyl)-amino]-methyl}-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide (70 mg, 0.141 mmol) was combined with piperidin-4-ylmethanol (40 mg, 0.346 mmol) and NMP (2 mL). The reaction mixture was heated at 125° C. for 2 hr. After this time, the crude product was subjected to preparative reverse-phase HPLC purification. The product, 4-hydroxymethyl-3,4,5,6-tetrahydro-2H[1,2′]bipyridinyl-5′-carboxylic acid (7-chloro-2-dimethylcarbamoyl-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was obtained as 30 mg (37%) of a white solid. MS calcd. for C31H32ClN5O4 [(M+H)+] 574.2, obsd. 574.3.
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:28]1([C:31]2[C:32]([O:41][CH2:42][CH:43]3[CH2:49][CH2:48][CH:47]4[CH:45]([C:46]4([F:51])[F:50])[CH2:44]3)=[CH:33][C:34]([F:40])=[C:35]([CH:39]=2)[C:36](O)=[O:37])[CH2:30][CH2:29]1.CS(N)(=O)=O.[CH:57]1([S:60]([NH2:63])(=[O:62])=[O:61])[CH2:59][CH2:58]1>>[CH:28]1([C:31]2[C:32]([O:41][CH2:42][CH:43]3[CH2:49][CH2:48][CH:47]4[CH:45]([C:46]4([F:50])[F:51])[CH2:44]3)=[CH:33][C:34]([F:40])=[C:35]([CH:39]=2)[C:36]([NH:63][S:60]([CH:57]2[CH2:59][CH2:58]2)(=[O:62])=[O:61])=[O:37])[CH2:30][CH2:29]1
Reactant: NS(=O)(=O)C1CC1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CCC3C(C2)C3(F)F)cc1F
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: O=C(NS(=O)(=O)C1CC1)c1cc(C2CC2)c(OCC2CCC3C(C2)C3(F)F)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-4-((7,7-difluorobicyclo[4.1.0]heptan-3-yl)methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with cyclopropanesulfonamide, the title compound was obtained as a colorless solid (0.012 g, 11%): 1H NMR (300 MHz, CDCl3) δ11.80 (br s, 1H), 7.10 (d, J=8.2 Hz, 1H), 7.02-6.87 (m, 1H), 4.14-3.78 (m, 2H), 3.12-2.50 (m, 2H), 2.42-2.05 (m, 2H), 2.05-1.27 (m, 5H), 1.28-1.14 (m, 2H), 1.15-0.95 (m, 4H), 0.95-0.74 (m, 2H), 0.70-0.54 (m, 2H); MS (ES+) m/z 444.1 (M+1).
Reaction SMILES: [CH2:1]([S:3]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([F:19])=[C:11]([CH:18]=1)[NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])(=[O:5])=[O:4])[CH3:2].[Cl:20]Cl>O1CCOCC1.O>[Cl:20][C:8]1[C:7]([NH:6][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])=[CH:18][C:11]([NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])=[C:10]([F:19])[CH:9]=1
Reactant: ClCl
Reactant: CCOC(=O)Nc1cc(NS(=O)(=O)CC)ccc1F
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Nc1cc(NS(=O)(=O)CC)c(Cl)cc1F
Yield: 86 %

Procedure:
0.50 g (1.72 mmol) of ethyl 5-ethylsulfonylamino-2-fluorocarbanilate was dissolved in a mixture of 5 ml of dioxane and 1 ml of water, and chlorine gas was added to the resultant solution at a temperature of not higher than 25° C. until the starting material disappeared. After the reaction was completed, the surplus chlorine gas was removed by blowing nitrogen gas thereinto, and water was added. The precipitates crystals were filtered out and dried to obtain 0.48 g of the objective product (yield: 86%) in the form of light brown crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([OH:11])=[C:7]([CH:10]=1)[CH:8]=O.C(=O)([O-])[O-].[K+].[K+].[CH:18]([CH:20]=[CH2:21])=[O:19]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:21][C:20]([CH:18]=[O:19])=[CH:8][C:7]=2[CH:10]=1
Reactant: COc1ccc(O)c(C=O)c1
Reactant: C=CC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2c(c1)C=C(C=O)CO2
Temperature: 100 °C

Procedure:
The starting material is prepared as follows: 5-Methoxy-2-hydroxybenzaldehyde (25 g, 0.16 mol) and potassium carbonate (22.7 g, 0.16 mol) are taken up in 300 ml of 1,4-dioxane and treated with acrolein (13.8 g, 0.25 mol). The mixture is heated at 100° C. for 1 hour, and allowed to cool. The mixture is diluted with water and extracted three times with ether. The combined ether extracts are dried (MgSO4) and evaporated. The residual oil is dissolved in a minimal amount of ethyl acetate (approx. 40 ml) and passed through 40 g of silica gel. The gel is successively washed with several portions of a hexane/ether mixture (3:1) until no further fluorescent material is eluted. The organic phase is evaporated and the residue is crystallized from ethyl acetate/hexane to give 6-methoxy-2H-1-benzopyran-3-carboxaldehyde as a yellow solid, m.p. 49°-50° C.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=[CH2:2].[OH:12][CH:13]([C:21]([F:24])([F:23])[F:22])[C:14]([F:20])([F:19])[S:15]([O-:18])(=[O:17])=[O:16].[C:25]1([S+:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[F:20][C:14]([F:19])([S:15]([O-:18])(=[O:17])=[O:16])[CH:13]([O:12][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=1)[C:21]([F:24])([F:22])[F:23].[C:38]1([S+:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: C=Cc1ccc(C(=O)Cl)cc1
Reactant: O=S(=O)([O-])C(F)(F)C(O)C(F)(F)F
Agent: Cl
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=Cc1ccc(C(=O)OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under ice cooling, 2.0 g (12 mmol) of the resulting 4-vinylbenzoyl chloride in methylene chloride was added dropwise to a mixture of 4.9 g (10 mmol) of triphenylsulfonium 2-hydroxy-1,1,3,3,3-pentafluoropropane-1-sulfonate in Synthesis Example 1-11, 1.21 g (12 mmol) of triethylamine, 0.24 g (2 mmol) of N,N-dimethylaminopyridine, and 20 g of methylene chloride. The reaction mixture was stirred at room temperature for 2 hours. Thereafter, 11 g of 5% dilute hydrochloric acid was added. The organic layer was separated and washed with water whereupon methylene chloride was distilled off under vacuum. The residue was combined with 30 g of methyl isobutyl ketone and washed with dilute aqueous ammonia and then with water, whereupon the methyl isobutyl ketone was distilled off under vacuum. Diisopropyl ether was added to the residue, followed by decantation. The target compound, triphenylsulfonium 1,1,3,3,3-pentafluoro-2-(4-vinyl-benzoyloxy)-propane-1-sulfonate was obtained as colorless oil (5.3 g, yield 85%). The compound has the following structure.
Reaction SMILES: Br[C:2]1[C:3]([C:24]#[N:25])=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[C:11]([CH3:16])([CH3:15])[C:10]3[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:9]=3[C:8](=[O:23])[C:7]2=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[OH-:60].[Na+].C(Cl)(Cl)Cl.Cl>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[OH:60][C:2]1[C:3]([C:24]#[N:25])=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[C:11]([CH3:16])([CH3:15])[C:10]3[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:9]=3[C:8](=[O:23])[C:7]2=1
Reactant: COc1ccc2c(c1)C(C)(C)c1[nH]c3c(Br)c(C#N)ccc3c1C2=O
Reactant: [OH-]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc2c(c1)C(C)(C)c1[nH]c3c(O)c(C#N)ccc3c1C2=O
Yield: 64.2 %

Procedure:
Under nitrogen atmosphere, 4-bromo-8-methoxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound U5, 10.0 mg, 25.30 μmol), X-phos (1.07 mg, 2.530 μmol), sodium hydroxide (4.36 mg, 75.90 μmol) and Pd2dba3.CHCl3 (1.31 mg, 1.265 μmol) were dissolved in dioxane (0.50 mL) and water (0.50 mL) and the mixture was stirred at 100° C. for 1 hr. The reaction solution was poured into hydrochloric acid (1 M), extracted with ethyl acetate, washed with saturated brine, dried over sodium sulfate, and then filtered. The residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) and washed with dichloromethane to obtain the title compound (5.4 mg, 64%).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:11]=[N:10][N:9]2[CH2:12][CH2:13][NH:14][C:8]=12.C(N(C(C)C)C(C)C)C.[C:24]([O:28][C:29]([NH:31][CH2:32][C:33](ON1C(=O)CCC1=O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[C:24]([O:28][C:29]([NH:31][CH2:32][C:33]([NH:6][C:7]1[CH:11]=[N:10][N:9]2[CH2:12][CH2:13][NH:14][C:8]=12)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: Nc1cnn2c1NCC2
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cnn2c1NCC2
Temperature: 25 °C
Reaction time: 22 h
Yield: 59.5 %

Procedure:
To a solution of 7-amino-2,3-dihydro-1H-imidazo[1,2-b]pyrazole sulfuric acid salt (1.42 g) and N-ethyldiisopropylamine (2.73 g) in methylene chloride (50 ml) was added N-[2-(tert-butoxycarbonylamino)acetoxy]succinimide (1.90 g). The mixture was stirred at room temperature for 22 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The oily residue was purified by column chromatography on silica gel eluting with 5% methanol/chloroform to give 7-[2-(tert-butoxycarbonylamino)acetyl]amino-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (1.07 g) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[N:14][N:15]2[CH2:18][CH:19]([OH:21])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[C:27]([Si:31](Cl)([CH3:33])[CH3:32])([CH3:30])([CH3:29])[CH3:28].C([O-])(=O)C.[NH4+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[N:14][N:15]2[CH2:18][CH:19]([O:21][Si:31]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:33])[CH3:32])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)Cn1ncc2ccc(OCc3ccccc3)cc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(Cn1ncc2ccc(OCc3ccccc3)cc21)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.3 %

Procedure:
To a mixture of 1-(6-benzyloxyindazol-1-yl)-propan-2-ol (10 g, 35.5 mmol) in THF (100 mL) and imidazole (3.4 g, 50 mmol) was added tert-butyl-chloro-dimethyl-silane (6.42 g, 42.6 mmol) and the mixture was stirred for 15 min at ambient temperature. The reaction mixture was poured into a saturated aqueous solution of ammonium acetate (300 mL) and extracted with ethyl acetate (2×150 mL). Purification by chromatography (silica, EtOAc/hexane) gave a yellow solid (10.6 g, 76%): mp 56-58° C.; LC/MS (+APCI) m/z 397 (M+H).
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:25]1[C:26]2[S:43][C:42]([NH2:44])=[N:41][C:27]=2[N:28]=[C:29]([S:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=2[F:40])[N:30]=1>CN1C(=O)CCC1>[NH2:44][C:42]1[S:43][C:26]2[C:25]([NH:1][C@H:2]3[C@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]3)=[N:30][C:29]([S:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=3[F:40])=[N:28][C:27]=2[N:41]=1
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](O)C1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](Nc2nc(SCc3cccc(F)c3F)nc3nc(N)sc23)C1

Procedure:
(3R,4R)- 3-Amino-4-hydroxy-1-pyrrolidinecarboxylic acid, 1,1-dimethylethyl ester (0.73 g), diisopropylethylamine (1.0 ml) and the product of example 4 step b), were stirred is in NMP (10 ml) at 100° C. for 28 hrs. The cooled mixture was poured onto water and the solid produced collected, washed with water and air dried. The crude material was purified (SiO2, ethyl acetate as eluant) to give the subtitle compound as a colourless solid (0.58 g).