Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]([CH:6]=[O:7])=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:14](I)[CH3:15].O>CN(C)C=O.C(OCC)(=O)C>[CH2:14]([N:1]1[C:5]([CH:6]=[O:7])=[CH:4][N:3]=[CH:2]1)[CH3:15].[CH2:14]([N:3]1[CH:4]=[C:5]([CH:6]=[O:7])[N:1]=[CH:2]1)[CH3:15]
Reactant: CCI
Reactant: O=Cc1cnc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cnc(C=O)c1
Product: CCn1cncc1C=O
Reaction time: 1.5 h
Yield: 9 %
Yield: 30 %

Procedure:
1H-Imidazole-5-carbaldehyde (300 mg, 3.12 mmol) was dissolved in N,N-dimethylformamide (4 mL). To this, potassium carbonate (862 mg, 6.24 mmol) and ethyl iodide (0.275 mL, 3.43 mmol) were added at room temperature and the mixture was stirred at the same temperature for 1.5 hours. After water was added to the reaction mixture, extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by preparative thin-layer chromatography (chloroform/methanol=20/1) to give 1-ethyl-1H-imidazole-5-carbaldehyde (115 mg, yield: 30%) and 1-ethyl-1H-imidazole-4-carbaldehyde (36 mg, yield: 9%). 1-ethyl-1H-imidazole-5-carbaldehyde
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+].C(O)(=O)C>O.C(OCC)(=O)C>[N+:17](/[CH:20]=[CH:13]/[C:12]1[CH:15]=[CH:16][C:9]([CH2:8][O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:10][CH:11]=1)([O-:19])=[O:18]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(COc2ccccn2)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])/C=C/c1ccc(COc2ccccn2)cc1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-(pyridin-2-yloxymethyl)-benzaldehyde described in Manufacturing Example 230-1-2 (26.8 g, 126 mmol), nitromethane (34 mL, 630 mmol), ammonium acetate (19 g, 252 mmol) and acetic acid (90 mL) was stirred for 1 hour and 30 minutes at 100° C. Ethyl acetate and water were added to the reaction solution, and liquid separation was carried out. This organic layer was separated, washed with water (5 times) and saturated aqueous sodium bicarbonate solution (once), dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (31 g) as a crude product.
Reaction SMILES: [C:1]1([N:7]2[C:11]([NH:12][C:13](=[O:21])OC3C=CC=CC=3)=[CH:10][C:9]([C:22]([F:25])([F:24])[F:23])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH2:39][CH2:40][O:41][CH3:42])[N:34]=[CH:33][N:32]=[C:31]2[O:43][C:44]1[CH:45]=[C:46]([CH:48]=[CH:49][CH:50]=1)[NH2:47].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH2:39][CH2:40][O:41][CH3:42])[N:34]=[CH:33][N:32]=[C:31]2[O:43][C:44]1[CH:45]=[C:46]([NH:47][C:13]([NH:12][C:11]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[C:9]([C:22]([F:23])([F:24])[F:25])[CH:10]=2)=[O:21])[CH:48]=[CH:49][CH:50]=1
Reactant: O=C(Nc1cc(C(F)(F)F)nn1-c1ccccc1)Oc1ccccc1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)nn4-c4ccccc4)c3)c2cc1OC
Yield: 48.4 %

Procedure:
Using the procedure described in Example 159B, using phenyl 1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-ylcarbamate from Example 161C (0.139 g, 0.4 mmol), 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (0.137 g, 0.4 mmol), and N,N-diisopropylethylamine (0.3 mL) in THF (6 mL) at 50° C. for 6 hours, to afford 1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-[1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]urea as solid (0.115 g, 48%). 1H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.81 (s, 1H), 8.54 (s, 1H), 7.49-7.62 (m, 7H), 7.38 (m, 2H), 7.20 (d, 1H), 6.95 (d, 1H), 6.87 (s, 1H), 4.38 (m, 2H), 3.98 (s, 3H), 3.78 (m, 2H), 3.35 (s, 3H); LC-MS (ESI) m/z 595 (M+H)+.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl[CH2:26][CH2:27][C:28]([OH:30])=O.CCN(C(C)C)C(C)C.[Cl:40][C:41]1[C:42]([NH:62][C:63]2[CH:67]=[C:66]([CH3:68])[NH:65][N:64]=2)=[N:43][C:44]([NH:47][C:48]2[CH:53]=[C:52]([CH3:54])[C:51]([CH:55]3[CH2:60][CH2:59][NH:58][CH2:57][CH2:56]3)=[CH:50][C:49]=2[CH3:61])=[N:45][CH:46]=1>CN(C=O)C>[Cl:40][C:41]1[C:42]([NH:62][C:63]2[CH:67]=[C:66]([CH3:68])[NH:65][N:64]=2)=[N:43][C:44]([NH:47][C:48]2[C:49]([CH3:61])=[CH:50][C:51]([CH:55]3[CH2:60][CH2:59][N:58]([C:28](=[O:30])[CH:27]=[CH2:26])[CH2:57][CH2:56]3)=[C:52]([CH3:54])[CH:53]=2)=[N:45][CH:46]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCNCC4)cc3C)ncc2Cl)n[nH]1
Reactant: O=C(O)CCCl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C=CC(=O)N1CCC(c2cc(C)c(Nc3ncc(Cl)c(Nc4cc(C)[nH]n4)n3)cc2C)CC1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
A solution of HATU (108 mg, 0.28 mmol), 3-chloropropanoic acid (30 mg, 0.28 mmol) and DIEA (0.1 mL) in DMF (1 mL) was stirred at rt. After 3 min, this solution was transferred to a solution of 5-chloro-N2-(2,5-dimethyl-4-(piperidin-4-yl)phenyl)-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine solution (111 mg, 0.27 mmol) in DMF (10 mL). The resulting mixture was stirred at rt overnight. The reaction was quenched with water (20 mL) and extracted with EtOAc (3×30 mL). The combined EtOAc layers were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica chromatography (0-10% MeOH in DCM gradient with 1% NH3 additive) to give 1-(4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)piperidin-1-yl)prop-2-en-1-one as a light brown oil; ESMS m/z 466.1 (M+H+).
Reaction SMILES: [H-].[Na+].[C:3]([O:12][CH2:13][CH:14]=[CH2:15])(=[O:11])[CH2:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].[H][H].Cl[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.Cl>O1CCOCC1.C1COCC1.O>[CH3:27][O:26][C:24]([C:23]1[CH:28]=[CH:29][C:20]([CH2:19][CH:4]([C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])[C:3]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])=[CH:21][CH:22]=1)=[O:25]
Reactant: COC(=O)c1ccc(CCl)cc1
Reactant: [H][H]
Reactant: C=CCOC(=O)CC(=O)OCC=C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)C(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
14.42 g (0.36 mol) of sodium hydride are added in portions to a solution of 56.7 g (0.3 mol) of diallyl malonate in 375 ml of dioxane and 75 ml of THF at 0° C. (caution: evolution of hydrogen). After warming to room temperature, the mixture is stirred at 40° C. for 1 hour. Subsequently, 111.88 g (0.6 mol) of methyl 4-chloromethylbenzoate, dissolved in 375 ml of dioxane, are slowly added dropwise at 40° C., and the reaction solution is stirred at 110° C. overnight. After cooling to room temperature, the reaction mixture is added to 1200 ml of water. Care must be taken during this that the pH is <7 (where appropriate, a few ml of 1 M hydrochloric acid are metered in to about pH 2). The mixture is then extracted three times with ethyl acetate, and the combined organic phases are washed with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is concentrated to dryness in vacuo. The resulting crude product is purified by flash chromatography (mobile phase: petroleum ether/ethyl acetate 10:1; 3 kg of silica gel). 85.4 g (0.26 mol, 85% of theory) of a colorless solid are obtained.
Reaction SMILES: [C:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3]Cl.[Na+].[I-].[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([F:42])=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:36][C@@H:37]([OH:41])[C:38]([OH:40])=[O:39])[NH:26][C:27]([C:29]3[O:33][N:32]=[C:31]([O:34][CH3:35])[CH:30]=3)=[O:28])=[CH:20][CH:19]=2)[CH:17]=1.CCN(C(C)C)C(C)C>CC(C)=O.C(O)(=O)C>[CH2:6]([O:5][C:1]([O:2][CH2:3][O:40][C:38](=[O:39])[C@H:37]([OH:41])[CH2:36][N:25]([CH2:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[CH:17]=[C:12]([Cl:11])[CH:13]=[CH:14][C:15]=2[F:42])=[CH:23][CH:22]=1)[NH:26][C:27]([C:29]1[O:33][N:32]=[C:31]([O:34][CH3:35])[CH:30]=1)=[O:28])=[O:8])[CH3:7]
Reactant: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)on1
Reactant: CCOC(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)OCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(OC)no1
Temperature: 65 °C
Reaction time: 1 h
Yield: 23.8 %

Procedure:
A mixture of chloromethyl ethyl carbonate (17.9 mg, 129 μmol) and NaI (19.4 mg, 129 μmol) in acetone (0.7 mL, 10 mmol) was heated at 65° C. for 1 hour. The mixture was then cooled to room temperature and a mixture of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid (20.0 mg) and DIPEA (15.0 μL, 0.1 mmol) in acetone (0.3 mL) was added. The resulting mixture was stirred at room temperature for 1 hour then concentrated. The residue was dissolved in AcOH (2.0 mL), filtered, and purified by reverse phase preparative HPLC. The desired fractions were combined and freeze dried to yield a white solid. The solid was dissolved in acetic acid (1.5 mL), filtered and purified by reverse phase preparative HPLC to yield the title compound (5.8 mg, purity 94%). MS m/z [M+H]+ calc'd for C25H25ClFN3O9, 566.13. found 566.
Reaction SMILES: [NH2:1][CH:2]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[CH2:3][NH:4][C:5](=[O:16])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15].C(N(C(C)C)CC)(C)C.[Br:36][CH2:37][C:38](Br)=[O:39].C(OCC)(=O)C>O1CCCC1>[Br:36][CH2:37][C:38]([NH:1][CH:2]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[CH2:3][NH:4][C:5](=[O:16])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])=[O:39]
Reactant: O=C(Br)CBr
Reactant: COc1ccccc1CCC(=O)NCC(N)Cc1c[nH]c2ccccc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1CCC(=O)NCC(Cc1c[nH]c2ccccc12)NC(=O)CBr
Reaction time: 2 h

Procedure:
To a stirring solution of 2-amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane (7.51 g, 21.369 mmoles) in anhydrous tetrahydrofuran (100 ml) under a nitrogen atmosphere at 0° C. was added diisopropylethylamine (4.1 ml, 23.537 mmoles) and bromoacetyl bromide (2.05 ml, 23.530 mmoles). After 2 hours, ethyl acetate was added and the reaction mixture washed with water twice, 1.0 N hydrochloric acid (2×), saturated sodium bicarbonate solution (2×), and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to a tan foam on a rotary evaporator. In this manner the 2-[(2-bromo)acetyl]amino-3-(1H-indol-3-yl)-1-[N-(2-methoxybenzyl)acetylamino]propane was obtained in quantitative yield. No further purification was necessary.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:9]=[CH:8][C:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)[NH:12][C:6]=2[CH:5]=1.Br[CH2:20][CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>CN(C=O)C.O.CCOC(C)=O>[Br:3][C:4]1[N:9]=[CH:8][C:7]2[CH:10]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=3)[N:12]([CH2:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:6]=2[CH:5]=1
Reactant: BrCC1CCCC1
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc3cnc(Br)cc3n2CC2CCCC2)cn1
Temperature: 60 °C
Reaction time: 24 h
Yield: 69.6 %

Procedure:
Sodium hydride (60% in mineral oil, 10.8 mg, 0.271 mmol) was added to a solution of 6-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 50 mg, 0.180 mmol) in DMF (780 mL). The reaction mixture was then stirred for 15 minutes at room temperature before the addition of (bromomethyl)cyclopentane (44 mg, 0.271 mmol). The reaction mixture was then stirred overnight at room temperature and for 24 hours at 60° C. Sodium hydride (60% in mineral oil, 5 mg, 0.125 mmol) was added and the reaction was stirred for another 7 hours at 60° C. The reaction mixture was then diluted with water and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude was purified via Biotage silica gel column chromatography eluting with (DCM/EtOAc 99/1 to 80/20) to afford the title product as a colourless oil (45 mg, 69%). 1H NMR (500 MHz, CDCl3) d 1.10-1.19 (m, 2H), 1.46-1.64 (m, 6H), 2.24-2.33 (m, 1H), 4.03 (s, 3H), 4.09 (d, J=7.6 Hz, 2H), 6.53 (d, J=0.9 Hz, 1H), 7.45 (t, J=0.9 Hz, 1H), 7.59 (s, 1H), 7.68 (s, 1H), 8.60 (d, J=0.9 Hz, 1H). LC (Method B)-MS (ESI, m/z) tR 3.03 min, 359 [(M+H+), 100%].
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][N:7]=[N:8][C:4]=2[CH:3]=1.[OH:11][C:12]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:15]=[C:14]([CH3:23])[C:13]=1[N:24]=[N:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.CN(C)C1C=CC=CC=1.O>O1CCCC1>[NH:6]1[C:5]2[CH:9]=[CH:10][C:2]([NH:1][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([N:25]=[N:24][C:13]4[C:14]([CH3:23])=[N:15][N:16]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[C:12]=4[OH:11])=[CH:27][CH:28]=3)=[CH:3][C:4]=2[N:8]=[N:7]1
Reactant: Nc1ccc2[nH]nnc2c1
Reactant: Cc1nn(-c2ccccc2)c(O)c1N=Nc1ccc(C(=O)Cl)cc1
Solvent: CN(C)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(-c2ccccc2)c(O)c1N=Nc1ccc(C(=O)Nc2ccc3[nH]nnc3c2)cc1
Reaction time: 8 h

Procedure:
A mixture of 5-aminobenzotriazole (0.78 g), 4-(5-hydroxy-3-methyl-1-phenylpyrazol-4-ylazo)benzoyl chloride (2.0 g) and N,N-dimethylaniline (0.71 g) in dry tetrahydrofuran (15 ml) was stirred overnight and water (50 ml) was added. The precipitate was filtered and crystallized in aqueous pyridine (1.9 g), m.p. 285° decomp., λmax (methanol) = 396 nm.
Reaction SMILES: [NH:1]1[C:14]2[C:5](=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[CH:11][CH:10]=[CH:9]3)[CH2:4][CH2:3][CH2:2]1.C([C:17]1[C:23](=[O:24])[C:22](Cl)=[C:21](Cl)[C:19](=O)[C:18]=1[C:27]#N)#N.[CH2:29]1[CH2:33]OC[CH2:30]1>>[CH3:30][C:29]([C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[C:14]3[C:5](=[CH:6][CH:7]=2)[CH:4]=[CH:3][CH:2]=[N:1]3)[N:12]=1)([CH:22]1[CH2:21][CH2:19][C@@H:18]([CH3:27])[CH2:17][C:23]1=[O:24])[CH3:33]
Reactant: c1cnc2c3c(ccc2c1)CCCN3
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: C1CCOC1
Product: C[C@@H]1CCC(C(C)(C)c2ccc3ccc4cccnc4c3n2)C(=O)C1

Procedure:
The title compound is prepared by reacting in THF the tetrahydrophenanthroline, obtained as described by Example 24, with DDQ.
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].C(O)=O.[NH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]2[S:21][C:20]3[N:22]=[CH:23][CH:24]=[N:25][C:19]=3[NH:18][C:17]=2[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)(=O)C>[N:25]1[C:19]2[NH:18][C:17]3[CH:26]=[C:13]([CH2:12][NH:11][S:2]([NH2:5])(=[O:4])=[O:3])[CH:14]=[CH:15][C:16]=3[S:21][C:20]=2[N:22]=[CH:23][CH:24]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: NCc1ccc2c(c1)Nc1nccnc1S2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O=CO
Product: NS(=O)(=O)NCc1ccc2c(c1)Nc1nccnc1S2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 12.1 %

Procedure:
5 ml of a solution of 283 mg of chlorosulfonyl isocyanate in tetrahydrofuran was ice-cooled and 92 mg of formic acid was added thereto. After stirring at room temperature for 30 minutes, the mixture was added to a solution of 276 mg of 8-aminomethyl-10H-pyrazino[2,3-b][1,4]benzothiazine in tetrahydrofuran (5 ml) and the resulting mixture was stirred at room temperature for 20 minutes. Next, it was distributed into an aqueous solution of potassium carbonate and ethyl acetate and the aqueous layer was extracted. The aqueous layer was well washed with ethyl acetate and the organic solvent contained therein was distilled off under reduced pressure. The residual aqueous solution was purified by High-porous gel chromatography (CHP20P mfd. by Mitsubishi Chemical Industries, Ltd., 75-150 μ) (eluted with water/methanol) to thereby give 45 mg of the title compound as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[O:7][CH2:6][N:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)[C:4](=[O:14])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44].C(N(CC)CC)C>ClC(Cl)(Cl)Cl.ClCCl>[Cl:40][C:41]1[CH:42]=[C:43]([NH:44][C:9](=[O:11])[C:8]([N:5]2[C:4](=[O:14])[C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:2]([CH3:1])[O:7][CH2:6]2)([CH3:13])[CH3:12])[CH:45]=[CH:46][CH:47]=1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)O)CO1
Reactant: Nc1cccc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)Nc2cccc(Cl)c2)CO1
Yield: 74.9 %

Procedure:
A mixture of 2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanoic acid (27.5 g) and triphenylphosphine (34.5 g) in tetrachloromethane (173 ml) and dichloromethane was heated at reflux for 45 minutes. The reaction mixture was cooled in an ice bath and 3-chloroaniline (12.8 g) and then triethylamine (14.0 ml) were added dropwise with stirring. The mixture was stirred at ambient temperature for 2 hours and evaporated under reduced pressure. The residue was suspended in ethyl acetate and the insoluble material removed by filtration. The filtrate was evaporated under reduced pressure and the residue purified by chromatography on silica gel, eluting with ethyl acetate/hexane to give N-(3-chlorophenyl)-2-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (28.8 g) as a white solid, m.p. 146.5-149.9° C.
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[CH:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@:9]1([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:10](=[O:23])[CH:11]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OCC)(=O)C.CO>[Pd].ClCCl>[CH2:1]([N:8]1[C@@H:13]2[CH:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@:9]1([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:10](=[O:23])[CH2:11][CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C1C[C@@]2(c3ccccc3)C(=O)C=C[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)C1C[C@@]2(c3ccccc3)C(=O)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.6 %

Procedure:
A mixture of (1R*,5S*,6RS)-8-benzyl-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicylco[3.2.1]oct-3-en-2-one (Description 18; 26 g, 66 mmol), 10% palladium on charcoal (3.5 g, 3.3 mmol), ethyl acetate (50 ml) and methanol (100 ml) was stirred under hydrogen atmosphere (1 atm) at room temperature for 1 hour. The reaction mixture was treated with dichloromethane (500 ml), filtered through a pad of Celite™. The filter cake was well washed with dichloromethane and the filtrate was concentrated to give the title compound as a solid (26 g, 100%). The isomers were separated on silica gel (isohexane:ethyl acetate) and crystallised from acetone:isohexane yielding pure ketones as a colourless crystals.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[C:12]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:13][NH:14][CH:15]=2)C=CC=CC=1.BrCCC=C.N1C=CC=C(C2C(O)=CN(COCC[Si](C)(C)C)N=2)C=1>C(OCC)C>[CH2:9]([O:10][C:11]1[C:12]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:13][NH:14][CH:15]=1)[CH2:8][CH:7]=[CH2:1]
Reactant: c1ccc(CCCOc2c[nH]nc2-c2cccnc2)cc1
Agent: C=CCCBr
Agent: C[Si](C)(C)CCOCn1cc(O)c(-c2cccnc2)n1
Solvent: CCOCC
Product: C=CCCOc1c[nH]nc1-c1cccnc1
Yield: 43 %

Procedure:
Compound 32D was prepared following the procedure as described for the synthesis of compound 32A (see Scheme 5) using 4-bromo-but-1-ene as the alkyl halogenide and 3-pyridin-3-yl-1-(2-trimethylsilanyl-1-ethoxymethyl)-1H-pyrazol-4-ol (30). Work-up and flash chromatography (diethyl ether) afforded compound 31D. Yield 43% (oil, TLC diethyl ether Rf 0.37), which was subsequently deprotected (TBAF/THF) to afford 3-(4-but-3-enyloxy-1H-pyrazol-3-yl)-pyridine (32D).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:20]([OH:22])=O)=[CH:11][C:12]3[N:16]([CH3:17])[CH:15]=[N:14][C:13]=3[C:18]=2[Cl:19])=[C:4]([Cl:23])[CH:3]=1.[CH:24]([O:26][CH2:27][CH2:28][O:29][NH2:30])=[CH2:25].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C>CCOC(C)=O.CN(C)C=O>[CH:24]([O:26][CH2:27][CH2:28][O:29][NH:30][C:20]([C:10]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[Cl:23])=[C:18]([Cl:19])[C:13]2[N:14]=[CH:15][N:16]([CH3:17])[C:12]=2[CH:11]=1)=[O:22])=[CH2:25]
Reactant: Cn1cnc2c(Cl)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cc21
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=COCCONC(=O)c1cc2c(ncn2C)c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-chloro-3-methyl-3H-benzoimidazole-5-carboxylic acid 10ff (32 mg, 0.077 mmol), O-(2-vinyloxy-ethyl)-hydroxylamine (0.010 mL, 0.092 mmol), HOBt (13 mg, 0.093 mmol), triethylamine (0.011 mL, 0.077 mmol), and EDCI (19 mg, 0.10 mmol) are dissolved into dimethylformamide (1.0 mL) and allowed to stir under a nitrogen atmosphere at room temperature for 24 hours. The reaction mixture is diluted with EtOAc, washed with water (3×), 10% potassium carbonate (2×), saturated ammonium chloride, brine, dried (Na2SO4), and concentrated under reduced pressure to give 39 mg of 85% pure material. MS APCI (−) m/z 497, 501 (M−, Br pattern) detected.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[C:10](=[CH:11][CH:12]=[C:13]4[C:21]=3[NH:20][C:19]3[C:14]4=[CH:15][C:16](Br)=[CH:17][CH:18]=3)[C:4]=2[CH:3]=1.[C:23]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].[CH3:44][CH2:45]O>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.C1(C)C=CC=CC=1>[C:23]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[C:10](=[CH:11][CH:12]=[C:13]4[C:21]=3[NH:20][C:19]3[C:14]4=[CH:15][C:16]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=4[C:44]4[CH:45]=[CH:13][CH:21]=[CH:9][CH:10]=4)=[CH:17][CH:18]=3)[C:4]=2[CH:3]=1
Reactant: OB(O)c1ccccc1-c1ccccc1
Reactant: CCO
Reactant: Brc1ccc2[nH]c3c(ccc4c5cc(Br)ccc5[nH]c43)c2c1
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: Cc1ccccc1
Product: c1ccc(-c2ccccc2-c2ccc3[nH]c4c(ccc5c6cc(-c7ccccc7-c7ccccc7)ccc6[nH]c54)c3c2)cc1
Temperature: 100 °C
Yield: 59 %

Procedure:
A mixture of 15.3 g (37 mmol) of 3,8-dibromo-11,12-dihydroindolo[2,3-a]carbazole, 18.3 g (92.4 mmol) of biphenyl-2-ylboronic acid, 0.86 g (0.8 mmol) of Pd(PPh3)4, 55 ml of 2M Na2CO3, 100 ml of EtOH and 200 ml toluene was degassed and placed under nitrogen, and then heated at 100° C. for 24 h. After finishing the reaction, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified by column chromatography on silica to give product (12.2 g, 21.8 mmol, 59%).