Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH2:5][C:4](=[O:13])[CH:3]=1.[OH-].[K+]>C(O)C.C1(C)C=CC=CC=1>[CH3:4][C:3]1[C:3]2[C:4](=[O:13])[CH2:5][CH:6]([C:8]3[CH:12]=[CH:11][S:10][CH:9]=3)[CH2:7][C:2]=2[N:1]=[CH:7][CH:2]=1
Reactant: NC1=CC(=O)CC(c2ccsc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccnc2c1C(=O)CC(c1ccsc1)C2
Temperature: 115 °C
Yield: 103.3 %

Procedure:
In a mixture of ethanol (200 ml) and toluene (600 ml) was dissolved 1-amino-5-(3-thienyl)cyclohexen-3-one (10 g), and to the solution were added 3-oxobutylaldehydedimethylacetal (17.4 g) and granulated potassium hydroxide (2.87 g). The mixture was stirred at 115° C. (bath temperature), and to the reaction solution were added granulated potassium hydroxide (590 mg), 30 minutes later; 1 hour later; and 1.5 hours later; respectively. The reaction solution was stirred at the same temperature for 1 hour and cooled. Under reduced pressure, the solvent was evaporated, and to the residue were added ethyl acetate (250 ml) and water (70 ml). The mixture was shaken, and the separated ethyl acetate layer was washed with water (40 ml, thrice) and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane) and eluted with ethyl acetate/hexane to give 4-methyl-7-(3-thienyl)-5,6,7,8-tetrahydroquinolin-5-one (6.5 g) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]([F:17])([CH2:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.O.[OH-].[Li+].[C:21]([O:24][C@@H:25]1[C@H:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[C@@H:28]([CH:40]=O)[C@H:27]([O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[CH2:26]1)(=[O:23])[CH3:22]>COC(C)(C)C.O>[C:21]([O:24][C@@H:25]1[C@H:29]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[C@@H:28](/[CH:40]=[CH:4]/[C:3](=[O:11])[C:2]([F:1])([F:17])[CH2:12][C@@H:13]([CH3:16])[CH2:14][CH3:15])[C@H:27]([O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[CH2:26]1)(=[O:23])[CH3:22]
Reactant: CC[C@H](C)CC(F)(F)C(=O)CP(=O)(OC)OC
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Product: CC[C@H](C)CC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To a solution of dimethyl ((5S)-3,3-difluoro-5-methyl-2-oxoheptyl)phosphonate (A) (74.7 g, 274 mmol) in t-butyl methyl ether (1120 ml), lithium hydroxide monohydrate (11.5 g, 273 mmol) was added and the mixture was stirred for one hour at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyl-oxy)cyclopentyl]heptanate (B) (64.02 g, 160.6=1) in t-butyl methyl ether (278 ml) and water (21.7 ml) were added thereto, and the mixed solution was heat refluxed for approximately 31 hours (internal temperature: approximately 53° C.). After cooling to room temperature, water (351 ml) was added to the solution and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate (234 ml). The organic layers were combined, washed twice with saturated aqueous sodium chloride (351 ml), and dried with anhydrous magnesium sulfate (55 g). After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300: 2110 g; ethyl acetate:hexane=1:4 to 1:2). The fractions containing impurities were re-purified by silica gel column chromatography (Fuji Silysia BW-300: 850 g; ethyl acetate:hexane=1:4 to 1:2) to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-(6S)-4,4-difluoro-6-methyl-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (C) (75.03 g; 137.8 mmol; yield: 85.8%) as a pale yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH3:12])[CH:4]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>S(=O)(=O)(O)O>[C:13]([NH:1][CH2:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][CH3:12])[CH:4]=1)(=[O:15])[CH3:14]
Reactant: COc1cc(CN)nc(OC)n1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: COc1cc(CNC(C)=O)nc(OC)n1

Procedure:
A sample of 6-aminomethyl-2,4-dimethoxypyrimidine (from Example 11) was stirred at 20° C. with excess acetic anhydride and a few drops of sulfuric acid for about 20 hours. Evaporation, extraction into chloroform and reisolation provided 6-acetylaminomethyl-2,4-dimethoxypyrimidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][C:25]4[CH2:26][NH:27][CH:28]([CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])[CH2:29][C:30]=4[N:31]=3)=[O:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>C(Cl)Cl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][C:25]4[CH2:26][NH:27][CH:28]([CH2:32][C:33]([OH:35])=[O:34])[CH2:29][C:30]=4[N:31]=3)=[O:22])[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)sc2CN1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)sc2CN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In methylene chloride (1 ml) was dissolved tert-butyl [2-[[4-[(6-chloronaphthalen-2-yl)sulfonyl]piperazin-1-yl]carbonyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-6-yl)acetate (200 mg), followed by the addition of trifluoroacetic acid (2 ml). The resulting mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, diethyl ether was added to the residue. The precipitate so formed was collected by filtration, whereby the title compound (193 mg) was obtained as a colorless foam.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5](=[O:17])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[N+:18]([C:21]1[CH:32]=[CH:31][C:24]([O:25][CH:26]([CH3:30])[C:27](O)=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]([O:4][CH2:3][CH2:2][O:1][C:27](=[O:28])[CH:26]([O:25][C:24]2[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:32][CH:31]=2)[CH3:30])=[O:17])=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: O=C(COc1ccc([N+](=O)[O-])cc1)OCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)OCCOC(=O)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 29.8 %

Procedure:
To a mixture of [4-nitrophenoxy]-acetic acid-2-hydroxyethyl ester 23 (100 grams, 410 mmol) and 2-(4-nitrophenoxy)-propionic acid 29 (95 g, 450 mmol ) in anhydrous dichloromethane (1000 ml) under nitrogen atmosphere was added dropwise a solution of 1,3-dicyclohexyl carbodiimide (240 g, 1160 mmol) in anhydrous dichloromethane (600 ml). The reaction mixture was stirred at room temperature for 12 hrs. The solids were filtered off and dichloromethane distilled off to get crude 38. The crude 38 was purified by column chromatography on silica gel using benzene as eluant to give pure 38 (53 grams, 29%) as a yellow low melting solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:36]=[CH:35][C:22]3[NH:23][C:24]([S:26][CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])=[N:25][C:21]=3[CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:36]=[CH:35][C:22]3[NH:23][C:24]([S:26][CH2:27][C:28]([OH:30])=[O:29])=[N:25][C:21]=3[CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CSc1nc2cc(C(=O)N3CCN(c4ccccc4C(C)(C)C)CC3)ccc2[nH]1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc3[nH]c(SCC(=O)O)nc3c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
A mixture of tert-butyl [(5-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}-1H-benzimidazol-2-yl)sulfanyl]acetate obtained in Example 29 (763 mg) and trifluoroacetic acid (3 mL) was stirred at room temperature for 3 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to provide the title compound (475 mg, 70%) as crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])[OH:12])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1C(O)c1cnc2c(F)cccc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)c1ccccc1C(=O)c1cnc2c(F)cccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.1 %

Procedure:
After 0.32 g of (2-t-butyl-phenyl)-(8-fluoro-quinolin-3-yl)-methanol was dissolved in 3 ml of dichloromethane, 0.51 g of Dess-Martin reagent was added and the mixture was stirred for 1 hour at room temperature. After water was added and then the liquid was separated with ethyl acetate, the organic layer was concentrated and purified by silica gel column chromatography to obtain 0.21 g of (2-t-butyl-phenyl)-(8-fluoro-quinolin-3-yl)-methanone (Compound Number 57).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH3:14][NH:15][CH3:16].C(N(CC)CC)C>C(Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:15]([CH3:16])[CH3:14])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-nitrobenzoyl chloride (7.20 g, 38.8 mmol) and dimethylamine hydrochloride (3.20 g, 39.2 mmol) in 100 mL DCM is added triethyl amine (14.0 mL, 99.6 mmol) at 0° C. The cooling bath is removed and the reaction mixture is stirred overnight at RT. Then 300 mL DCM is added and the reaction mixture is washed with 50% saturated aqueous ammonium chloride, water, 50% saturated aqueous sodium hydrogen carbonate and 0.1 M aqueous NaOH. The organic phase is dried over MgSO4 and concentrated in vacuo. Yield: 5.37 g.
Reaction SMILES: [CH2:1]1[O:5][CH2:4][O:3][CH:2]1[CH2:6][OH:7].N1C=CC=CC=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:7][CH:6]1[CH2:2][O:3][CH2:4][O:5][CH2:1]1)(=[O:16])[CH3:15]
Reactant: OCC1COCO1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1COCOC1
Temperature: 25 °C
Yield: 37 %

Procedure:
A mixture of 10.0 g (96 mmole) of glycerol formal, 8.35 g (105 mmole) of pyridine, and 20 ml of acetic anhydride was stirred at ambient temperature under protection from moisture. After a period ranging from a few hours to 5 days, the solution was fractionally distilled under vacuum. The early fractions consisted primarily of pyridine, acetic acid, and acetic anhydride. The bulk of the product distilled at 56°-57° (1.1 mm). The product fractions (10.8 g) were separated into the 5- and 6-membered ring isomers by preparative HPLC on silica gel in 3:1 hexane-ethyl acetate with recycling. Fractions were identified and checked for purity by analytical HPLC. In total 3.19 g (23%) of 1,3-dioxolane-4-methyl acetate (shorter retention time) and 5.23 g (37%) of 1,3-dioxan-5-yl acetate (longer retention time) were obtained. The structures were confirmed by NMR.
Reaction SMILES: F[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:21]([NH2:24])[CH:22]=[CH2:23].CC(N(C)C)=O>C(OCC)(=O)C>[CH2:21]([NH:24][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])[CH:22]=[CH2:23]
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1F
Reactant: C=CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: C=CCNc1cc(C(F)(F)F)ccc1C(N)=O
Temperature: 140 °C
Yield: 98.4 %

Procedure:
A mixture of 2-fluoro-4-trifluoromethylbenzamide (5.60 g, 27.05 mmol.), K2CO3 (11.2 g, 81.16 mmol), allylamine (7.71 g, 135.26 mmol) and dimethylacetamide (50 mL) was heated at 140° C. for 18 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL) and washed with a solution of aqueous saturated sodium bicarbonate (3×100 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated to give the title compound (6.5 g, 98% yield) as a brown solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[N:18]=[CH:17][C:16]2[N:15]([CH3:19])[C:14](=[O:20])[C@@H:13]([CH2:21][CH3:22])[N:12]([CH:23]([CH3:25])[CH3:24])[C:11]=2[N:10]=1.[C:26](O)([C:28](F)(F)F)=[O:27]>C(O)(=O)C>[CH2:21]([C@H:13]1[N:12]([CH:23]([CH3:24])[CH3:25])[C:11]2[N:10]=[C:9]([C:8]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[CH2:2][NH:1][C:26](=[O:27])[CH3:28])[N:18]=[CH:17][C:16]=2[N:15]([CH3:19])[C:14]1=[O:20])[CH3:22]
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CN)nc2N1C(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CC[C@@H]1C(=O)N(C)c2cnc(-c3ccncc3CNC(C)=O)nc2N1C(C)C

Procedure:
The title compound was prepared similarly to the methods described in Example 102, with (R)-2-(3-(aminomethyl)pyridin-4-yl)-7-ethyl-8-isopropyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 126) instead of (R)-2-(3-aminopyridin-4-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 91), and with acetic acid instead of benzoic acid. LCMS (0.05% TFA): 383.2 m/z (M+H)+; 1H-NMR (MeOD, 500 MHz): δ: 8.51 (s, 1H), 8.46 (d, 1H, J=5.0 Hz), 8.04 (s, 1H), 7.84 (d, 1H, J=5.0 Hz), 4.70 (d, 2H, 10.5 Hz), 4.61 (m, 1H), 4.33 (m, 1H), 3.31 (s, 3H), 1.85 (s, 3H), 1.83 (m, 1H), 1.69 (m, 1H), 1.35 (d, 3H, J=6.5 Hz), 1.32 (d, 3H, J=6.5 Hz), 0.77 (t, 3H, J=7.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([NH:12][C:13]2[C:14]3[CH:39]=[CH:38][N:37](S(C4C=CC(C)=CC=4)(=O)=O)[C:15]=3[N:16]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]4)=[CH:22][C:21]=3[O:35][CH3:36])[N:18]=2)[C:3]=1[C:4]([NH2:6])=[O:5].[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([NH:12][C:13]2[N:18]=[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([N:26]4[CH2:27][CH2:28][N:29]([CH:32]([CH3:33])[CH3:34])[CH2:30][CH2:31]4)=[CH:22][C:21]=3[O:35][CH3:36])[NH:16][C:15]3=[N:37][CH:38]=[CH:39][C:14]=23)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: COc1cc(N2CCN(C(C)C)CC2)ccc1Nc1nc(Nc2cc(F)cc(F)c2C(N)=O)c2ccn(S(=O)(=O)c3ccc(C)cc3)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc(N2CCN(C(C)C)CC2)ccc1Nc1nc(Nc2cc(F)cc(F)c2C(N)=O)c2ccnc-2[nH]1
Temperature: 120 °C
Yield: 62.4 %

Procedure:
2,4-difluoro-6-({2-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)benzamide (175 mg, 0.254 mmol) was suspended in a mixture of dioxane (10 mL) and aqueous 2.0N NaOH (5 mL) and stirred rapidly under microwave heating (120° C.) for 10 minutes. After cooling, the reaction mixture was diluted with ethyl acetate and washed with saturated sodium chloride. The organic layer was dried over sodium sulfate, taken to a residue under reduced pressure, and purified by chromatography on SiO2 to afford 2,4-difluoro-6-[(2-{[4-[4-(1-methylethyl)-1-piperazinyl]-2-(methyloxy)phenyl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide as a pale yellow solid (85 mg, 63% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.00 (d, J=6.60 Hz, 6H), 2.52-2.61 (m, 4H), 2.66 (d, J=6.23 Hz, 1H), 3.08 (d, J=5.50 Hz, 4H), 3.78 (s, 3H), 6.18 (dd, J=3.67, 1.83 Hz, 1H), 6.45 (dd, J=8.80, 2.57 Hz, 1H), 6.61 (d, J=2.57 Hz, 1H), 6.89 (ddd, J=11.36, 8.80, 2.57 Hz, 1H), 6.93-6.98 (m, 1H), 7.59 (s, 1H), 7.68 (d, J=8.80 Hz, 1H), 8.01 (d, J=1.47 Hz, 1H), 8.15 (s, 1H), 8.56 (d, J=11.73 Hz, 1H), 11.08 (s, 1H), 11.32 (s, 1H). ESIMS (M+H)+=537.
Reaction SMILES: [OH:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6](=[O:27])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1.C(=O)([O-])[O-].[K+].[K+].[O:50]1[CH2:54][CH2:53]OC1=O.O>CN(C=O)C>[OH:50][CH2:54][CH2:53][O:1][C:2]1[CH:29]=[CH:28][C:5]2[C:6](=[O:27])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:25])([CH3:26])[CH3:24])[N:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1
Reactant: O=C1OCCO1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2nn(COCC[Si](C)(C)C)c4ccccc24)C3=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(OCCO)ccc3c2O/C(=C\c2nn(COCC[Si](C)(C)C)c4ccccc24)C3=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.1 %

Procedure:
A solution of tert-butyl (Z)-4-({6-hydroxy-3-oxo-2-[(N-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.416 g, 0.686 mmol) obtained in Step 2 in DMF (6 mL) was added with potassium carbonate (1.42 g, 10.3 mmol), and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was added with 1,3-dioxolan-2-one (0.725 g, 8.23 mmol), and the mixture was stirred at 100° C. for 5 hours. The reaction mixture was cooled to room temperature, and then added with water (60 mL), and the mixture was vigorously stirred at room temperature for 30 minutes. The precipitated solid was collected by filtration to obtain tert-butyl (Z)-4-{[6-(2-hydroxyethoxy)-3-oxo-2-[(N-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl]methyl}piperazine-1-carboxylate (0.331 g, 74%).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([CH2:19][C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([S:29][CH3:30])=[CH:24][CH:23]=2)([OH:18])[CH2:4][C:5]([C:8]1[C:16]2[O:15][CH2:14][CH2:13][C:12]=2[CH:11]=[C:10]([F:17])[CH:9]=1)([CH3:7])[CH3:6].I([O-])(=O)(=O)=[O:34].[Na+]>CO.[Cl-].[Na+].O>[F:32][C:2]([F:1])([F:31])[C:3]([CH2:19][C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25]([S:29]([CH3:30])=[O:34])=[CH:24][CH:23]=2)([OH:18])[CH2:4][C:5]([C:8]1[C:16]2[O:15][CH2:14][CH2:13][C:12]=2[CH:11]=[C:10]([F:17])[CH:9]=1)([CH3:7])[CH3:6]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CSc1ccc2[nH]c(CC(O)(CC(C)(C)c3cc(F)cc4c3OCC4)C(F)(F)F)cc2c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)c1ccc2[nH]c(CC(O)(CC(C)(C)c3cc(F)cc4c3OCC4)C(F)(F)F)cc2c1
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a solution of 1,1,1-trifluoro-4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-(5-methylsulfanyl-1H-indol-2-ylmethyl)pentan-2-ol (25 mg, 0.053 mmol) in 10 mL of methanol was added sodium periodate (150 mg, 0.70 mmol). After 1 hour, the mixture was diluted with brine and extracted with three 10 mL portions of ethyl acetate. The combined organic layers were washed with three 7 mL portions of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by preparative TLC on silica gel eluting with ethyl acetate to afford 19.8 mg (77% yield) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:41])[CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[CH2:34][C:33]4[CH:32]=[N:31][N:30]([CH3:35])[C:29]=4[NH:28][C:27]4[CH:36]=[CH:37][CH:38]=[CH:39][C:26]3=4)=[O:24])=[CH:19][C:18]=2[CH3:40])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1>CO>[CH3:40][C:18]1[CH:19]=[C:20]([C:23]([N:25]2[CH2:34][C:33]3[CH:32]=[N:31][N:30]([CH3:35])[C:29]=3[NH:28][C:27]3[CH:36]=[CH:37][CH:38]=[CH:39][C:26]2=3)=[O:24])[CH:21]=[CH:22][C:17]=1[CH2:16][CH2:15][C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:41]
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1CCC(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
4-{3-[2-Methyl-4-(3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-phenyl]-propionyl}-piperazine-1-carboxylic acid tert-butyl ester from Example E47.1 (1.09 g, 1.95 mmol) was dissolved in methanol (20 ml) and 4M HCl/dioxan solution (20 ml) was added. The mixture was stirred for 3 h at room temperature, concentrated in vacuo and azeotroped with toluene. The residue was dissolved in methanol (30 ml) and ammonia (5 ml) then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 0.5% 35% ammonia:4.5% methanol:95% dichloro-methane to 1% 35% ammonia:9% methanol:90% dichloro-methane) to yield the title compound (759 mg, 73%).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.C(N(CC)CC)C.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>ClCCl>[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([OH:8])=[CH:2][CH:1]=1)=[O:20]
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(O)cc1)c1ccccc1Cl
Reaction time: 1 h

Procedure:
A suspension of p-aminophenol linked to the Wang's resin from Step A (1 eq) in dichloromethane was treated with triethylamine (2 ml/mmol) and 2-chloro-benzoyl chloride (10 eq). The mixture reaction was stirred for 1 hour and then the resin was filtered, washed with MeOH/CH2Cl2 several times and dried. The resin was then treated with TEA 95% H2O 5% and stirred at room temperature for 30 minutes. Filtered and washed with dichloromethane/methanol and concentrated to dryness to afford the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][O:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:5][CH:4]=1)=O.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl.C(O)(=O)C>[N:24]1([CH2:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][O:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[CH:5][CH:4]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCC#Cc2ccc(C=O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC#Cc2ccc(CN3CCCCC3)cc2)cc1
Reaction time: 16 h

Procedure:
A solution of the product of Example 8 (2.0 g), piperidine (0.91 mL), and acetic acid (0.42 mL) in DCM (100 mL) was treated with sodium triacetoxyborohydride (1.95 g) at room temperature. After 16 h, the resulting mixture was treated with 10% aqueous sodium hydroxide (30 mL). The aqueous phase was extracted with DCM (2×300 mL). The combined organic phases were dried (magnesium sulfate) and concentrated under reduced pressure. The residue was diluted in DCM (100 mL) and passed through a pad of silica gel. The pad was washed with DCM (3×200 mL). The combined filtrate was concentrated under reduced pressure, giving the title compound as a brown oil (2.3 g).