Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1.CCN(CC)CC.[C:23]1([CH2:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:30](=[O:31])[CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:10]=1
Reactant: COc1ccccc1-c1cc(N)ncn1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1-c1cc(NC(=O)Cc2ccccc2)ncn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(2-methoxy-phenyl)-pyrimidin-4-ylamine (XXIV) (0.15 g, 0.74 mmol) in THF (10 ml) was added NEt3 (0.210 ml, 1.49 mmol) under an atmosphere of nitrogen at ice bath temperature, followed by phenyl acetyl chloride (XLVI) (0.819 mmol) at the same temperature. The reaction mixture was stirred for 1 hour at 0° C. and then brought to room temperature and stirred for another hour. Usual work up as described above followed by column chromatographic purification over silica gel (30% ethyl acetate/hexane) yielded N-[6-(2-methoxy-phenyl)-pyrimidin-4-yl]-2-phenyl-acetamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:46])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26](OS(C(F)(F)F)(=O)=O)[CH:25]=[C:24]([C:36](=[O:38])[CH3:37])[CH:23]=2)[C:10]=1[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH3:2].[F:47][C:48]1([F:60])[O:52][C:51]2[CH:53]=[CH:54][C:55](B(O)O)=[CH:56][C:50]=2[O:49]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:46])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:55]3[CH:54]=[CH:53][C:51]4[O:52][C:48]([F:60])([F:47])[O:49][C:50]=4[CH:56]=3)[CH:25]=[C:24]([C:36](=[O:38])[CH3:37])[CH:23]=2)[C:10]=1[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OS(=O)(=O)C(F)(F)F)cc(C(C)=O)c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccc2c(c1)OC(F)(F)O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(C)=O)cc(-c3ccc4c(c3)OC(F)(F)O4)c2)c1CCC(=O)OCC
Temperature: 90 °C
Reaction time: 3 h
Yield: 59.3 %

Procedure:
To a solution of 4-[3-[6-(3-acetyl-5-trifluoromethanesulfonyloxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (500 mg) in 1,2-dimethoxyethane (5 mL) were added 2,2-difluoro-benzo[1,3]dioxole-5-boronic acid (273 mg), 2 M aq. sodium carbonate solution (1.0 mL) and Pd(PPh3)4 (8 mg) and the resulting mixture was stirred at 90° C. for 3 h. Then the reaction mixture was diluted with ethyl acetate, filtered through Celite and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 300 mg of the title compound (59% yield). HRMS calcd for C38H44O9F2 [M+Na]+ 705.2845, observed 705.2843.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[F:12][C:13]([F:20])([CH:17]([F:19])[F:18])[C:14](Cl)=[O:15]>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:8][C:14](=[O:15])[C:13]([F:20])([F:12])[CH:17]([F:19])[F:18])=[N:6][CH:7]=1
Reactant: Nc1ncc(Cl)cc1[N+](=O)[O-]
Reactant: O=C(Cl)C(F)(F)C(F)F
Product: O=C(Nc1ncc(Cl)cc1[N+](=O)[O-])C(F)(F)C(F)F

Procedure:
5-Chloro-3-nitro-2-aminopyridine is reacted with 2,2,3,3-tetrafluoropropionyl chloride to yield 5-chloro-3-nitro-2-(2,2,3,3-tetrafluoropropionamido)pyridine, which when hydrogenated yields 6-chloro-1-hydroxy-2-(1,1,2,2-tetrafluoroethyl)-1H-imidazo-(4,5-b)pyridine. This compound is reacted with trimethylamine to prepare 6-chloro-1-hydroxy-2-(1,1,2,2-tetrafluoroethyl)-1H-imidazo-(4,5-b)pyridine trimethylamine salt.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=2)[C:10]([C:20](=[O:31])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[C:9]1[CH:32]([CH3:34])[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH2:71][CH2:72][C:73]([CH3:76])([OH:75])[CH3:74]>CN(C=O)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH:71][CH2:72][C:73]([OH:75])([CH3:76])[CH3:74])=[O:19])[CH:15]=2)[C:10]([C:20]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=2)=[O:31])=[C:9]1[CH:32]([CH3:33])[CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)O)cc2n1Cc1ccccc1
Reactant: CC(C)(O)CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(C(=O)NCC(C)(C)O)cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Following General Procedure G, 1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indole-6-carboxylic acid (Compound 56, 35 mg, 0.080 mmol) in DMF (4 ml) was added BOP (40 mg, 0.10 mmol) and DIPEA (20 mg, 0.11 mmol), followed by 1-amino-2-methylpropan-2-ol (10 mg, 0.10 mmol). The reaction was stirred at room temperature for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (5:95 MeOH—CH2Cl2) to yield the title compound as yellow oil.
Reaction SMILES: [CH2:1]([CH:8]([NH:32][C:33]([C:35]1[CH:44]=[N:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=1)=[O:34])[CH:9]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH2:10][CH:11]([C:18](=O)[NH:19][CH2:20][CH2:21][OH:22])[CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([CH:8]([NH:32][C:33]([C:35]1[CH:44]=[N:43][C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:36]=1)=[O:34])[CH:9]([O:24][Si:25]([C:28]([CH3:29])([CH3:31])[CH3:30])([CH3:26])[CH3:27])[CH2:10][CH:11]([C:18]1[O:22][CH2:21][CH2:20][N:19]=1)[CH2:12][CH2:13][C:14]([F:17])([CH3:16])[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(F)CCC(CC(O[Si](C)(C)C(C)(C)C)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=O)NCCO
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(F)CCC(CC(O[Si](C)(C)C(C)(C)C)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C1=NCCO1
Reaction time: 2 h
Yield: 74.7 %

Procedure:
To a solution of quinoxaline-2-carboxylic acid [1-benzyl-2-(tert-butyl-dimethyl-silanyloxy)-7-fluoro-4-(2-hydroxy-ethylcarbamoyl)-7-methyl-octyl]-amide (100 mg, 0.160 mmol) in methylene chloride (1.5 mL) was added triphenylphosphine (63 mg, 0.240 mmol), hexachloroethane (57 mg, 0.240 mmol), and triethylamine (0.045 mL, 0.320 mmol). The reaction was stirred for 2 hours than chromatographed directly on silica gel to give the title compound (72.5 mg, 75%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[CH:13][C:12]=1[OH:21].I[CH2:23][CH2:24][CH3:25]>CN(C)C=O>[CH3:7][O:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([O:17][CH2:18][O:19][CH3:20])[CH:14]=[CH:13][C:12]=1[O:21][CH2:23][CH2:24][CH3:25]
Reactant: COCOc1ccc(O)c(OCOC)c1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1ccc(OCOC)cc1OCOC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
Potassium carbonate (322 mg, 2.33 mmol) was added to 3b (50 mg, 0.233 mmol) in N,N-dimethylformamide (2.33 mL) at room temperature. After 10 minutes, iodopropane (226 μL, 2.33 mmol) was added and the solution was heated to reflux for 12 hours. Upon cooling to room temperature, the solution was extracted with EtOAc (3×10 mL); combined organic fractions were washed with saturated aqueous NaCl, dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (SiO2, 5:1 Hexane:EtOAc) to afford 4b as a yellow oil (36.4 mg, 61%): 1H NMR (CD2Cl2, 400 MHz) δ 6.87 (s, 1H), 6.84 (d, J=2.9 Hz, 1H), 6.68 (dd, J=11.7, 2.8 Hz, 1H), 5.19 (s, 2H), 5.12 (s, 2H), 3.93 (t, J=6.6 Hz, 2H), 3.53 (s, 3H), 3.49 (s, 3H), 1.86-1.78 (m, 2H), 1.06 (t, J=7.5 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 150.6, 146.5, 143.8, 113.7, 108.5, 106.6, 94.7, 94.2, 70.3, 55.2, 54.9, 21.6, 9.5; IR (film) νmax 2961, 2826, 1595, 1506, 1400, 1261, 1154, 1013, 1076, 924, 800 cm−1; HRMS (ESI+) m/z: [M+H]+ calcd for C13H20O5, 257.1389. found, 257.1410; [M Na]+ calcd for C13H20O5, 279.1208. found, 279.1165.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.C(N(CC)CC)C.[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[OH-].[Na+]>CN(C=O)C.O>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:4][C:3]=2[O:2]1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)NCC3
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: c1ccc(CN2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the 1-(3,4-methylenedioxyphenyl)-2,3,4,9-tetrahydro-1H-β-carboline (prepared according to the process as disclosed in WO97/43287, Intermediate 7, page 24) (7.37 g, 25 mmol) in dry DMF (25 mL) was added triethylamine (3.52 mL, 25 mmol) and benzyl bromide (3.00 mL, 25 mmol). The mixture was stirred at ambient temperature overnight and added dropwise to a solution of sodium hydroxide (25 mmol) in water (200 mL). A precipitate was formed, collected by vacuum filtration, washed with water (2×50 mL), and dried in vacuo overnight to yield the product as a freely flowing pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:24][CH3:25])[C:11]=1[CH:12]([CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:13]([O:15]CC)=[O:14])[N:8]([CH2:26][C:27]([F:30])([F:29])[F:28])[CH:7]=[C:6]([C:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:37][C:36]=1[CH3:46])=[O:32])[C:5]2=[O:47].[Li+].[OH-].Cl>O1CCOCC1.O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:24][CH3:25])[C:11]=1[CH:12]([CH:18]1[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]1)[C:13]([OH:15])=[O:14])[N:8]([CH2:26][C:27]([F:30])([F:28])[F:29])[CH:7]=[C:6]([C:31]([NH:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][C:42]([F:43])([F:44])[F:45])=[CH:37][C:36]=1[CH3:46])=[O:32])[C:5]2=[O:47]
Reactant: CCOC(=O)C(c1c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3C)cn(CC(F)(F)F)c2c1OC)C1CCNCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(C(C(=O)O)C2CCNCC2)c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3C)cn(CC(F)(F)F)c12
Yield: 98.9 %

Procedure:
60 mg (0.089 mmol) of the compound of Example 5 are stirred in 2.2 ml of dioxane and 444 μl of LiOH 1M (5 eq.) in water at RT overnight. The mixture is acidified with 1N HCl and diluted with ethyl acetate. It is extracted by shaking twice with water and once with a saturated NaCl solution. The organic phase is dried over magnesium sulfate and freed from the solvent on a rotary evaporator. The residue is dried under HV. 57 mg of the title compound (94% of theory) are obtained.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.F[C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][N:18]=1)[C:13]([OH:15])=[O:14]>>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:16]2[CH:17]=[N:18][CH:10]=[CH:11][C:12]=2[C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)cc1
Reactant: O=C(O)c1ccnc(F)c1
Product: O=C(O)c1ccncc1Nc1ccc(I)cc1

Procedure:
3-(4-iodo-phenylamino)-isonicotinic acid was synthesized according to the procedure for General Method 1 and as Intermediate 1 by reacting 1.4 mmol of 4-iodoaniline with 2.8 mmol of 2-fluoro-isonicotinic acid LC/MS [6.29 min; 341 (M+1)].
Reaction SMILES: C[O:2][C:3]1[C:4]([Cl:16])=[C:5]([Cl:15])[C:6]2[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:14]=1.Cl.N1C=CC=CC=1.C1C2CCCCC(=O)C=2C=CC=1>O>[OH:2][C:3]1[C:4]([Cl:16])=[C:5]([Cl:15])[C:6]2[C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[CH:14]=1
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)CCCC2
Agent: Cl
Agent: O=C1CCCCc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: O=C1CCCCc2cc(O)c(Cl)c(Cl)c21
Temperature: 180 °C

Procedure:
2-Methoxy-3,4-dichloro-6,7,8,9-tetrahydro-5H- benzocyclohepten-5-one (25.9 g., 0.1 mole) intimately mixed with pyridine hydrochloride (250 g.) is heated at 180° C. for 1 hour. The hot mixture is poured into water whereupon 2-hydroxy-3,4-dichloro-,6,7,8,9-tetrahydro-5H-benzocyclohepten- 5-one separates and is isolated in the usual way.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][CH:26]=[C:25](Br)[C:24]=2[CH:29]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].[CH:31]#[C:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>>[CH2:1]([O:3][C:4](=[O:30])[C:5]([N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]2[O:27][CH:26]=[C:25]([C:31]#[C:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:24]=2[CH:29]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)N(Cc1ccc(C(F)(F)F)cc1)Cc1ccc2occ(Br)c2c1
Reactant: C#CCCCCCCCCCC
Product: CCCCCCCCCCC#Cc1coc2ccc(CN(Cc3ccc(C(F)(F)F)cc3)C(=O)C(=O)OCC)cc12
Yield: 34 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step c) but using ethyl{[(3-bromo-1-benzofuran-5-yl)methyl][4-(trifluoromethyl)benzyl]amino}(oxo)acetate and 1-dodecyne gave the title compound as a yellow oil (34%). HPLC (Condition A), Rt: 6.39 min (HPLC purity: 99.2%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:15][C:16]([CH:18]1[CH2:23][CH:22]2[CH:20]([CH2:21]2)[N:19]1[C:24](=[O:39])[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([OH:35])=[CH:32][CH:33]=2)[C:28]([C:36](=[O:38])[CH3:37])=[N:27]1)=[O:17].Br[CH2:41][CH2:42][O:43][CH3:44]>CN(C=O)C>[F:3][C:4]1[C:9]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=[CH:6][C:5]=1[NH:15][C:16]([C@@H:18]1[CH2:23][C@@H:22]2[C@@H:20]([CH2:21]2)[N:19]1[C:24](=[O:39])[CH2:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([O:35][CH2:41][CH2:42][O:43][CH3:44])=[CH:32][CH:33]=2)[C:28]([C:36](=[O:38])[CH3:37])=[N:27]1)=[O:17]
Reactant: COCCBr
Reactant: CC(=O)c1nn(CC(=O)N2C(C(=O)Nc3cccc(OC(F)(F)F)c3F)CC3CC32)c2ccc(O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1ccc2c(c1)c(C(C)=O)nn2CC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)Nc1cccc(OC(F)(F)F)c1F
Reaction time: 0.08 h

Procedure:
To a suspension of sodium hydride (60% in Mineral oil, 4.8 mg, 0.121 mmol) in DMF (5 mL) at 0° C. was added 1R,3S,5R)-2-[2-(3-acetyl-5-hydroxy-indazol-1-yl)-acetyl]-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid (2-fluoro-3-trifluoromethoxy-phenyl)-amide (60 mg, 0.115 mmol). After stirring for 5 min, 1-bromo-2-methoxyethane (0.016 mL, 0.173 mmol) was added and the reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by preparative HPLC (Waters Sunfire C18-ODB, 5 um, 30×100 mm, flow: 40 mL/min, gradient: 0-18.5 min 5% to 100% CH3CN, 18.5-20 min 100% CH3CN, H2O and CH3CN containing 0.1% TFA). Further purification by flash chromatography on silica gel (c-hexane/EtOAc 1:0 to 0:1) afforded the title compound. MS (UPLC-MS): 579.3. tR (HPLC conditions f): 2.07 min.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C@@H:9]2[CH2:13][C@H:12]([S:14][C:15]3[C@H:21]([CH3:22])[C@H:20]4[N:17]([C:18](=[O:26])[C@@H:19]4[C@H:23]([OH:25])[CH3:24])[C:16]=3[C:27]([O:29]CC3C=CC([N+]([O-])=O)=CC=3)=[O:28])[CH2:11][N:10]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)=[N:5][N:4]=[N:3]1.P([O-])([O-])([O-])=O.[H][H]>[OH-].[OH-].[Pd+2].O1CCCC1>[OH:25][C@@H:23]([C@H:19]1[C:18](=[O:26])[N:17]2[C@@H:20]1[C@@H:21]([CH3:22])[C:15]([S:14][C@@H:12]1[CH2:11][NH:10][C@H:9]([CH2:8][S:7][C:6]3[N:2]([CH3:1])[N:3]=[N:4][N:5]=3)[CH2:13]1)=[C:16]2[C:27]([OH:29])=[O:28])[CH3:24]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](CSc4nnnn4C)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reactant: [H][H]
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](CSc4nnnn4C)C3)[C@H](C)[C@H]12
Yield: 49.3 %

Procedure:
A mixture of 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2-(1-methyl-1H-tetrazol-5-yl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-yl]thio-4-methyl-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.80 g), 20% palladium hydroxide on carbon (0.5 g), 0.05M phosphate buffer (pH 6.3, 30 ml) and tetrahydrofuran (30 ml) was stirred for 3 hours under atmospheric pressure of hydrogen at ambient temperature. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure to remove the organic solvent. The residue was washed with ethyl acetate (30 ml×2) and evaporated in vacuo to remove the organic solvent. The residue was chromatographed on nonionic adsorption resin "Diaion HP-20" (Trademark, made by Mitsubishi Chemical Industries) (20 ml) eluting in turn with water (60 ml) and 10% aqueous acetone solution (120 ml). The fractions containing the desired compound were collected and lyophilized to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3-[(2S,4S)-2-{(1-methyl-1H-tetrazol-5-yl)thiomethyl}pyrrolidin-4-ylthio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (0.23 g).
Reaction SMILES: [CH3:1][CH:2]([C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[C:16]([CH:18]=1)[OH:17])[CH:3]([CH3:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:20]([CH:23]1[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][C:24]1=O)(=O)[CH3:21]>>[CH3:1][CH:2]([C:12]1[CH:18]=[C:16]([OH:17])[C:15]2[CH:20]([CH3:21])[C:23]3[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][C:24]=3[O:19][C:14]=2[CH:13]=1)[CH:3]([CH3:11])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCC(C)C(C)c1cc(O)cc(O)c1
Reactant: CC(=O)C1CCC(C)CC1=O
Product: CCCCCCCC(C)C(C)c1cc(O)c2c(c1)OC1=C(CCC(C)C1)C2C

Procedure:
Reaction of 5-(1,2-dimethylnonyl)resorcinol and 2-acetyl-5-methylcyclohexanone as described in Example 1 gives 3-(1,2-dimethylnonyl)-5,6,7,8-tetrahydro-1-hydroxy-6,9-dimethylxanthene.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([CH2:19][NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C@@H:14]([OH:18])[C:15]#[C:16][CH3:17])[C:9]1=[O:31])(C)(C)C.C(O)(C(F)(F)F)=O.C(N(CC)C(C)C)(C)C.[C:49]([NH:56][C:57]1[CH:65]=[CH:64][C:63]([C:66]([F:69])([F:68])[F:67])=[CH:62][C:58]=1[C:59]([OH:61])=O)([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:52]([O:51][C:49](=[O:50])[NH:56][C:57]1[CH:65]=[CH:64][C:63]([C:66]([F:69])([F:68])[F:67])=[CH:62][C:58]=1[C:59](=[O:61])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([CH2:19][NH:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[C@@H:14]([OH:18])[C:15]#[C:16][CH3:17])[C:9]1=[O:31])([CH3:53])([CH3:55])[CH3:54]
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1C(=O)O
Reactant: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)N1CC[C@H](NC(=O)OC(C)(C)C)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)N1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2NC(=O)OC(C)(C)C)C1=O
Reaction time: 3 h
Yield: 62.5 %

Procedure:
A solution of {(3S)-1-[(1S,2S)-1-(benzyloxycarbonylamino-methyl)-2-hydroxy-pent-3-ynyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (0.097 mg, 0.22 mmol, see procedure 1b above) was dissolved in CH2Cl2 (4 mL) and treated with TFA (2 mL). The solution was stirred for 3 h and then concentrated in vacuo. The residue was dissolved in CH2Cl2 and concentrated in vacuo; this procedure was repeated. The product amine was dissolved in 1:1 DMF/CH2Cl2 (4 mL). The resultant solution was charged sequentially with N, N-diisopropylethylamine (0.16 mL, 0.88 mmol), N-Boc-2-amino-5-(trifluoromethyl)-benzoic acid (S. Takagishi, et al., Synlett 1992, 360; 73 mg, 0.24 mmol), and HATU (97 mg, 0.26 mmol). The reaction was stirred for 12 h and partitioned between EtOAc and sat. NH4Cl. The organic phase was washed with sat. NaHCO3 and brine, and then dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography afforded (2-{(3S)-1-[(1S,2S)-1-(benzyloxycarbonylamino-methyl)-2-hydroxy-pent-3-ynyl]-2-oxo-pyrrolidin-3-ylcarbamoyl}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester(87 mg, 64% yield). MS found: (M+Na)+=655.5.
Reaction SMILES: [ClH:1].Cl.Cl.CNC(C1C2C=C(C3C(C)=CN=C(NCCCN4CCN(C)CC4)N=3)SC=2C=CC=1)=O.[CH:35]1([NH:38][C:39]([C:41]2[C:49]3[CH:48]=[C:47]([C:50]4[C:55]([CH3:56])=[CH:54][N:53]=[C:52]([Cl:57])[N:51]=4)[S:46][C:45]=3[CH:44]=[CH:43][CH:42]=2)=[O:40])[CH2:37][CH2:36]1.[CH3:58][N:59]1[CH2:64][CH2:63][N:62]([CH2:65][CH2:66][NH2:67])[CH2:61][CH2:60]1>>[ClH:57].[ClH:1].[ClH:57].[CH:35]1([NH:38][C:39]([C:41]2[C:49]3[CH:48]=[C:47]([C:50]4[C:55]([CH3:56])=[CH:54][N:53]=[C:52]([NH:67][CH2:66][CH2:65][N:62]5[CH2:63][CH2:64][N:59]([CH3:58])[CH2:60][CH2:61]5)[N:51]=4)[S:46][C:45]=3[CH:44]=[CH:43][CH:42]=2)=[O:40])[CH2:37][CH2:36]1
Reactant: CN1CCN(CCN)CC1
Reactant: Cc1cnc(Cl)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1
Agent: CNC(=O)c1cccc2sc(-c3nc(NCCCN4CCN(C)CC4)ncc3C)cc12
Agent: Cl
Product: Cc1cnc(NCCN2CCN(C)CC2)nc1-c1cc2c(C(=O)NC3CC3)cccc2s1

Procedure:
Using the method of 2-{5-methyl-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid methylamide tri-hydrochloride, the title compound is synthesized from [2-(2-chloro-5-methylpyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide and 2-(4-methylpiperazin-1-yl)-ethylamine and isolated as a yellow solid. ES+(m/z) 451 [M(free base)+H].
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:40]=[CH:39][C:20]3[C:21]4[N:25]([CH2:26][CH2:27][O:28][C:19]=3[CH:18]=2)[CH:24]=[C:23]([C:29]2[N:30]([CH2:34][C:35]([F:38])([F:37])[F:36])[N:31]=[CH:32][N:33]=2)[N:22]=4)[C@H:13]([C:41](=[O:43])[NH2:42])[CH2:12]1)=O)C1C=CC=CC=1>[Pd]>[F:37][C:35]([F:36])([F:38])[CH2:34][N:30]1[C:29]([C:23]2[N:22]=[C:21]3[C:20]4[CH:39]=[CH:40][C:17]([N:14]5[CH2:15][CH2:16][NH:11][CH2:12][C@H:13]5[C:41]([NH2:42])=[O:43])=[CH:18][C:19]=4[O:28][CH2:27][CH2:26][N:25]3[CH:24]=2)=[N:33][CH:32]=[N:31]1
Reactant: NC(=O)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1c1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Agent: [Pd]
Product: NC(=O)[C@@H]1CNCCN1c1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Temperature: 25 °C
Reaction time: 64 h
Yield: 21.5 %

Procedure:
A mixture of (S)-3-carbamoyl-4-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl}-piperazine-1-carboxylic acid benzyl ester (0.03 g) and 10% Pd/C (0.014 g) in IMS (5 mL) was stirred under an atmosphere of hydrogen at RT for 64 h. The reaction mixture was filtered through Celite® and the filtrate concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 20% methanol in DCM) to give 543 (0.005 g, 20%). LCMS: RT=2.49 min, [M+H]+463. 1H NMR 400 MHz (MeOD): δ 8.28 (1 H, d, J=9.03 Hz), 8.00 (1 H, s), 7.78 (1 H, s), 6.79 (1 H, dd, J=9.09, 2.63 Hz), 6.56 (1 H, d, J=2.58 Hz), 5.83 (2 H, q, J=8.50 Hz), 4.50-4.43 (3 H, m), 4.30 (1 H, t, J=3.89 Hz), 3.52-3.45 (2 H, m), 3.38 (1 H, dd, J=13.28, 3.28 Hz), 3.34 (1 H, s), 3.13-3.10 (2 H, m), 2.96-2.88 (1 H, m)