Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].[CH:11](Cl)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)c1cnn(C(c2ccccc2)c2ccccc2)c1
Temperature: 100 °C

Procedure:
A suspension of 1H-pyrazole-4-carboxylic acid ethyl ester (1.0 g), benzhydryl chloride (1.9 ml) and potassium carbonate (1.48 g) in anhydrous 1-methyl-2-pyrrolidinone (10 ml) was heated at 100° C. under nitrogen for 6 h. It was diluted with water and extracted with ethyl acetate, the organic extracts washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica, eluting with i-hexane/ethyl acetate (4:1) followed by i-hexane/ethyl acetate (2:1) to give the sub-title compound (2.18 g).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]1([CH3:22])[CH3:21])C1C=CC=CC=1>C(O)C.[Pd]>[OH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]1([CH3:22])[CH3:21]
Reactant: CC1(C)NC(C)(C)N(CCCCOCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: CC1(C)NC(C)(C)N(CCCCO)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 26.2 %

Procedure:
3-(4-(benzyloxy)butyl)-2,2,5,5-tetramethylimidazolidin-4-one (3.40 g, 11.2 mmol), was dissolved in ethanol (100 ml), and palladium (10% on carbon, 410 mg, 0.4 mmol) was added to the solution. The flask was purged several times with nitrogen, and then several times with hydrogen. The reaction was stirred at room temperature for 18 hours under hydrogen. The mixture was filtered and purified by silica gel column chromatography (0 to 20% methanol in dichloromethane) to give 628 mg (26%) the title compound. 1H NMR (400 MHz, D2O) δ 3.72 (t, 6.0 Hz, 2H), 3.49 (s, 1H), 3.28-3.20 (m, 2H), 1.76-1.66 (m, 4H), 1.64-1.56 (m, 2H), 1.40 (s, 6H), 1.32 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH2:12])=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH3:26][CH:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28].Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH:12][S:29]([CH:27]([CH3:28])[CH3:26])(=[O:31])=[O:30])=[CH:4][CH:3]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: N[C@@H]1CCC[C@@H]1Oc1ccc(Br)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1Oc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a slurry of cis-2-(4-bromophenoxy)cyclopentanamine (1.43 g, 5.58 mmol) in methylene chloride (38.5 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.40 mL, 9.36 mmol), then 4-(dimethylamino)pyridine (915 mg, 7.49 mmol). The reaction mixture was cooled to 0° C. and propane-2-sulfonyl chloride (0.937 mL, 8.38 mmol) was added drop-wise. The mixture was then allowed to warm to room temperature and stir for 18 hours. The reaction was treated with 1N aqueous hydrochloric acid, and the organic layer was washed with saturated aqueous sodium chloride solution, dried over calcium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (Gradient: 0% to 15% ethyl acetate in heptane) to provide product as a colorless gum. Yield: 1.586 g, 4.38 mmol, 78%.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].[O:6]1[CH2:9][CH:8](N)[CH2:7]1>O>[S:1]([NH:5][CH:8]1[CH2:9][O:6][CH2:7]1)(=[O:3])(=[O:2])[NH2:4]
Reactant: NC1COC1
Reactant: NS(N)(=O)=O
Solvent: O
Product: NS(=O)(=O)NC1COC1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Sulfamide (15.6 mmol) was dissolved in H2O (8 mL), added oxetan-3-amine (6.85 mmol) and stirred at 70° C. for 16 h and then at 100° C. for another 16 h. The obtained reaction mixture was cooled to rt and freezedried affording the title compound as white solid. Used without further purification.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]([OH:15])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:8][C:9]#[CH:10])([CH3:4])[CH3:3].N1C=CN=C1.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23].CCCCCC>CN(C)C=O>[CH3:23][Si:22]([O:15][C:7]([C:6]#[C:5][Si:2]([CH3:3])([CH3:1])[CH3:4])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:8][C:9]#[CH:10])([CH3:25])[CH3:24]
Reactant: C#CCC(O)(C#C[Si](C)(C)C)CCCC
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C#CCC(C#C[Si](C)(C)C)(CCCC)O[Si](C)(C)C
Reaction time: 1 h

Procedure:
To a stirred mixture of 8.5 g of 4-trimethylsilylethynyl-1-octyn-4-ol and 6.2 g of imidazole in 24 ml of dry dimethylformamide is added, under nitrogen, 5.7 ml of chlorotrimethylsilane, in a slow stream, via a syringe. The mixture is stirred in an ice bath for one hour and then at room temperature overnight. The mixture is poured into hexane, washed with saturated sodium bicarbonate solution, water and then brine and dried over sodium sulfate. The solvents are evaporated to dryness giving 11.1 g of the desired product.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:5][CH:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:22]>C(Cl)Cl>[F:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:22])=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1ccc(SCc2ccccn2)cc1
Agent: Cl
Solvent: ClCCl
Product: O=S(Cc1ccccn1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.3 %

Procedure:
A stirred suspension of 2-(((4-fluorophenyl)thio)methyl)pyridine, hydrochloride (2 g) in methylene chloride (50 ml) at 0° C. was treated portionwise with m-chloroperoxybenzoic acid (1.8 g) over 1/2 hour. The mixture was allowed to warm to ambient temperature and the mixture was stirred for a further 4 hours. The solution was washed with saturated Na2CO3 solution and water, dried (MgSO4) and evaporated. The residue was recrystallised from diisopropyl ether to give the title compound (1.0 g) mp 92°-4° C. (Found: C,60.9; H,4.6; N,5.6 C12H10FNOS requires C,61.3; H,4.3; N,5.95%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][C@@H:14]3[CH2:18][CH2:17][CH2:16][O:15]3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[C@H:19]1[CH2:28][CH2:27][C:26]2[CH:25]=[C:24]([CH:29]=O)[CH:23]=[CH:22][C:21]=2[CH2:20]1.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([CH2:29][C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[CH2:20][C@@H:19]([N:3]2[CH2:4][CH2:5][C:6]4[C:11](=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C@@H:14]5[CH2:18][CH2:17][CH2:16][O:15]5)[CH:7]=4)[C:2]2=[O:1])[CH2:28][CH2:27]3)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=Cc1ccc2c(c1)CC[C@H](N1CCc3cc(OC[C@@H]4CCCO4)ccc3C1=O)C2
Reactant: C1CCNC1
Product: O=C1c2ccc(OC[C@@H]3CCCO3)cc2CCN1[C@H]1CCc2cc(CN3CCCC3)ccc2C1

Procedure:
According to method H-1, (S)-6-{1-oxo-6-[(S)-1-(tetrahydrofuran-2-yl)methoxy]-3,4-dihydro-1H-isoquinolin-2-yl}-5,6,7,8-tetrahydronaphthalene-2-carbaldehyde was reacted with pyrrolidine. The product was thus obtained with the molecular weight of 460.62 (C29H36N2O3); MS (ESI): 461 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:12]([O:14][C:15](=[O:29])[CH:16]([C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:17][C:18](=O)[CH3:19])[CH3:13].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:17]=[C:18]([CH3:19])[N:1]([C:2]2[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)[C:21]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:29])[CH3:13]
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Reactant: COC(=O)c1cccc(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2cccc(C(=O)OC)c2)c1-c1ccccc1

Procedure:
Methyl 3-aminobenzoate (10 mmol, 1.4 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (10 mmol, 2.5 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The named product was purified over silica gel and crystallized upon standing, 1H-NMR (CDCl3, ppm) 1.15 t (3H), 2.08 s (3H), 3.88 s (3H), 4.05 q (2H), 6.56 s (1H), 7.15-7.33 bm (7H), 7.79-7.97 bm (2H).
Reaction SMILES: [CH:1]1([CH3:34])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([O:10][C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[N:15]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:26]=3[F:32])[C:14]2=[O:33])=[O:12])[CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].O>CN(C=O)C>[CH3:47][C:46]([O:45][C:43](=[O:44])[CH2:42][C:13]1([C:11]([O:10][CH:3]2[CH:4]([CH:7]([CH3:8])[CH3:9])[CH2:5][CH2:6][CH:1]([CH3:34])[CH2:2]2)=[O:12])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[N:15]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:26]=2[F:32])[C:14]1=[O:33])([CH3:49])[CH3:48]
Reactant: CC1CCC(C(C)C)C(OC(=O)C2C(=O)N(Cc3ccc(Br)cc3F)C(=O)c3ccccc32)C1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCC(C(C)C)C(OC(=O)C2(CC(=O)OC(C)(C)C)C(=O)N(Cc3ccc(Br)cc3F)C(=O)c3ccccc32)C1
Temperature: 85 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
To a mixture of 2-[(4-bromo-2-fluorophenyl)methyl]-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinoline carboxylic acid menthyl ester (7.62 g, 14.37 mmol), K2CO3 (3.96 g, 28.74 mmol) in DMF (100 mL) was added tert-butyl bromoacetate (4.64 mL, 28.74 mmol). The mixture was stirred at 85° C. for 2 hours, poured into H2O (1000 mL) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexane/EtOAc:4/1) gave a clear oil (6.9 g, diastereomeric mixture). The two diastereomers were separated by preparative HPLC on prep. Pac silica column, (μ poraSi/125 Å, 15-20 μsilica) by elution with hexane/CH2Cl2 to give the less polar A-diastereomer as a white solid (2.4 g) and the more polar diastereomer B as a clear oil (2.2 g). The diastereomeric purity was determined by analytical HPLC, on Dynamax silica 25 cmx4.1 mm and was found to be greater than 99% for both diastereomers.
Reaction SMILES: [OH:1][CH:2]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[CH3:26])[C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:5][C:4]=1[CH3:14].N1C=CC=CC=1.[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH:43][C@@H:44]([CH3:48])[C:45](Cl)=[O:46])(=[O:42])=[O:41])=[CH:36][CH:35]=1>ClC(Cl)C>[N:9]1([C:7]2[CH:6]=[CH:5][C:4]([CH3:14])=[C:3]([CH:8]=2)[CH:2]([C:15]2[C:16]([CH3:26])=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][C:24]=2[CH3:25])[O:1][C:45](=[O:46])[C@@H:44]([NH:43][S:40]([C:37]2[CH:38]=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=2)(=[O:42])=[O:41])[CH3:48])[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: COC(=O)c1cc(C)c(C(O)c2cc(-n3ccnc3)ccc2C)c(C)c1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CC(Cl)Cl
Product: COC(=O)c1cc(C)c(C(OC(=O)[C@H](C)NS(=O)(=O)c2ccc(C)cc2)c2cc(-n3ccnc3)ccc2C)c(C)c1
Yield: 100.9 %

Procedure:
Methyl (±)-4-[α-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoate (35 g) was suspended in dichloroethane (350 ml) and pyridine (12 ml) and a solution of (S)-2-(4-methylbenzenesulfonylamino)propionyl chloride (31.4 g) in dichloroethane (70 ml) was added dropwise to the suspension over 10 minutes with stirring under ice-cooling. The mixture was stirred at room temperature for 4 hours, and the reaction mixture was washed successively with water, 5% citric acid, 5% potassium carbonate and water. The organic layer was separated and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 58 g of methyl (±)-4-[5-(1-imidazolyl)-2-methyl-α-{(S)-2-(4-methylbenzenesulfonylamino)propionyloxy}benzyl]-3,5-dimethylbenzoate as a pale-yellow oil. This was crystallized from ethyl acetate (120 ml) and isopropyl ether (480 ml), and the obtained crystals were recrystallized from ethyl acetate (50 ml) and isopropyl ether (100 ml) to give 20 g of methyl (S)-4-[5-(1-imidazolyl)-2-methyl-α-{(S)-2-(4-methylbenzenesulfonylamino)propionyloxy}benzyl]-3,5-dimethylbenzoate as white crystals, melting point 103-105° C.
Reaction SMILES: O[C:2]([C:5]1[N:6]([CH3:14])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([CH3:4])[CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:2]([C:5]1[N:6]([CH3:14])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([CH3:4])=[CH2:3]
Reactant: Cn1c(C(C)(C)O)cc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)c1cc2ccccc2n1C
Temperature: 25 °C
Yield: 23.5 %

Procedure:
4.0 g of 2-(1-hydroxy-1-methylethyl)-1-methylindole was dissolved in 80 ml of toluene. Thereto was added 200 mg of p-toluenesulfonic acid monohydrate. The mixture was azeotropically refluxed for 2 hours. The reaction mixture was cooled to room temperature, washed with an aqueous saturated sodium hydrogencarbonate solution and an aqueous saturated sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: n-hexane/toluene=1/0 to 20/1) to obtain 850 mg (yield: 24%) of 2-isopropenyl-1-methylindole as a light yellow oily material.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C1C=CC=CN=1)C.C(N=C=NCCCN(C)C)C.[F:28][CH:29]([F:55])[C:30]1[CH:34]=[C:33]([CH:35]([F:37])[F:36])[N:32]([CH2:38][C:39]([N:41]2[CH2:46][CH2:45][CH:44]([C:47]3[S:48][CH:49]=[C:50]([C:52](O)=[O:53])[N:51]=3)[CH2:43][CH2:42]2)=[O:40])[N:31]=1>ClCCl.O>[F:55][CH:29]([F:28])[C:30]1[CH:34]=[C:33]([CH:35]([F:36])[F:37])[N:32]([CH2:38][C:39]([N:41]2[CH2:42][CH2:43][CH:44]([C:47]3[S:48][CH:49]=[C:50]([C:52]([O:7][CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:53])[N:51]=3)[CH2:45][CH2:46]2)=[O:40])[N:31]=1
Reactant: O=C(O)c1csc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Reactant: OC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: O
Product: O=C(OC1CCCCC1)c1csc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Reaction time: 8 h

Procedure:
At room temperature, cyclohexanol (2.17 g), dimethylaminopyridine (0.20 g) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (3.35 g) are added to a solution of 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-1, 7.00 g) in dichloromethane (80 ml). The mixture is stirred overnight, and water is then added. The aqueous phase is separated off and extracted with ethyl acetate. The combined organic phases are dried with sodium sulfate. The solid is filtered off and the solvent is removed by distillation. The residue is purified chromatographically. This gives cyclohexyl 2-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (2.83 g, 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([CH3:8])=[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:5][N:4]=1.C1C(=O)N([Br:21])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:21][CH2:8][C:7]1[C:3]([O:2][CH3:1])=[N:4][O:5][C:6]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1onc(OC)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1onc(OC)c1CBr
Yield: 97.4 %

Procedure:
Ethyl 3-Methoxy-4-methylisoxazole-5-carboxylate (1.3 g, 7.0 mmol), NBS (1.4 g, 7.9 mmol), dibenzoyl peroxide (catalytic amount) and tetrachloromethane (40 mL) was boiled under reflux for 10 h. The mixture was cooled, filtered and concentrated in vacuo to give crude title compound as a yellow oil (1.8 g, 97%). The crude product was used in the next step without further purification.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.Cl[C:10]1[CH:18]=[C:17]2[C:13]([C:14](=[O:20])[C:15](=[O:19])[NH:16]2)=[CH:12][CH:11]=1.S(O)(C(F)(F)F)(=O)=O>>[I:1][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:10]=1)[NH:16][C:15](=[O:19])[C:14]2=[O:20]
Reactant: O=C1Nc2cc(Cl)ccc2C1=O
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Product: O=C1Nc2ccc(I)cc2C1=O
Temperature: 25 °C
Reaction time: 19 h
Yield: 99.6 %

Procedure:
N-Iodosuccinimide (8.68 g, 38.6 mmol) was added to a stirred mixture of 6-chloro-isatin (6.98 g, 38.6 mmol) and TfOH (120 g) at 0° C. under N2. Ice-bath was removed and stirring at room temperature was continued for 19 h. The mixture was poured to ice-water. The precipitate was collected by filtration, washed with water (until pH˜7), and dried to give 6-chloro, 5-iodo-isatine (10.5 g) as a 95% pure (1H NMR, 400 MHz), orange solid: 1H NMR (DMSO-d6) 7.10 (s, 1 H), 7.96 (s, 1 H), 11.21 (s, 1 H); ms 305.9 (M−H+).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([OH:15])[C@@H:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:12]([CH2:24][OH:25])[O:11][C@H:10]1[O:26][CH2:27][C@H:28]([CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:66](Cl)(=[O:71])[C:67]([CH3:70])([CH3:69])[CH3:68]>C(OCC)(=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([OH:15])[C@@H:13]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:12]([CH2:24][O:25][C:66](=[O:71])[C:67]([CH3:70])([CH3:69])[CH3:68])[O:11][C@H:10]1[O:26][CH2:27][C@H:28]([CH2:44][O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCCCCCCCCCCCCCOC[C@@H](CO[C@@H]1O[C@H](CO)[C@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1)OCCCCCCCCCCCCCC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOC[C@@H](CO[C@@H]1O[C@H](COC(=O)C(C)(C)C)[C@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1)OCCCCCCCCCCCCCC
Temperature: -5 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
Compound 6 (687 mg, 0.831 mmol) was dissolved by addition of pyridine (12 mL). Pivaloyl chloride (130 μl, 1.08 mmol) was added to the solution, and the mixture was stirred at −5° C. for 1 hour. Pivaloyl chloride (130 μl, 1.08 mmol) was further added thereto, and the mixture was stirred at −5° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, then filtered through Celite, and washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine. The ethyl acetate layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:AcOEt=10:1) to obtain Compound 7 (716.6 mg, 94.7%).
Reaction SMILES: C([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:18][CH3:19])[C:13]([S:15]([CH3:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=O)C.[ClH:20]>>[ClH:20].[CH3:19][O:18][C:12]1[C:13]([S:15]([CH3:17])=[O:16])=[CH:14][C:7]2[CH2:6][CH2:5][NH:4][CH2:10][CH2:9][C:8]=2[CH:11]=1
Reactant: COc1cc2c(cc1S(C)=O)CCN(C(C)=O)CC2
Agent: Cl
Product: COc1cc2c(cc1S(C)=O)CCNCC2

Procedure:
Following the general procedure of Example 4 Method B, 3-acetyl-8-methoxy-7-methylthio-2,3,4,5-tetrahydro-1H-3-benzazepine is reacted with one equivalent of 3-chloroperbenzoic acid to give 3-acetyl-8-methoxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine. Following the procedure of Example 4, 3-acetyl-8-methoxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine is reacted with 3N hydrochloric acid to give 8-methoxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride. This methoxy compound is treated with pyridine hydrochloride to give 8-hydroxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[C:13]([O-:16])(=[O:15])[CH3:14].[K+].Cl>O>[C:13]([O:16][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10])(=[O:15])[CH3:14]
Reactant: NS(=O)(=O)c1ccccc1CCl
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(=O)OCc1ccccc1S(N)(=O)=O

Procedure:
A mixture of 2-(chloromethyl)benzenesulfonamide (2.00 g), potassium acetate (6.0 g) and water (75 ml) was heated to reflux for 1.5 hour. The pH was adjusted to ca. 5.0 by addition of hydrochloric acid and the chilled mixture was filtered to give 1.05 of of shiny white solid, m.p. 131°-133°. 'H NMR δ(CD3)2CO 8.00-7.83 (M), 7.60-7.25 (M), 6.55 (brd s), 5.47 (s), 2.97 (brd s), 2.10 (s), consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[Br:12]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:12][C:10]1[C:2]([F:1])=[CH:3][C:4]([OH:11])=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(F)cc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Br)c(F)cc1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.5 %

Procedure:
To a stirring solution of 4-fluoro-2-hydroxy-benzoic acid (5.58 g, 35.7 mmol) in dimethyl formamide (72 mL, 0.5 M) was added N-bromosuccinimide (7.08 g, 39.3 mmol). The mixture was allowed to stir for 24 h at room temperature. Next, the mixture was diluted with 300 mL of ethyl acetate and washed successively with water (3×330 mL) and saturated aq LiCl (4×200 mL). The organic layer was dried over Na2SO4, filtered and concentrated to afford 5-bromo-4-fluoro-2-hydroxy-benzoic acid (8.1 g, 96%) as a beige powder. Please note, the product may contain up to 20% of a dibrominated impurity which may be separated from the desired product after coupling with a benzylamine or upon methylation (Example 50): Rf 0.32 (20% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 mHz) δ 8.00 (d, J=8.1 Hz, 1 H), 7.05 (d, J=10.5 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:15]([C:16](O)=[O:17])=[CH:14][N:13]=[C:12]2[N:19]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[N:20]=[CH:21][C:11]=12.[CH:31]([O:33][CH2:34][CH2:35][O:36][NH2:37])=[CH2:32].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:31]([O:33][CH2:34][CH2:35][O:36][NH:37][C:16]([C:15]1[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])=[C:11]2[CH:21]=[N:20][N:19]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=3)[C:12]2=[N:13][CH:14]=1)=[O:17])=[CH2:32]
Reactant: C=COCCON
Reactant: COc1ccc(Cn2ncc3c(Nc4ccc(I)cc4F)c(C(=O)O)cnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=COCCONC(=O)c1cnc2c(cnn2Cc2ccc(OC)cc2)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
4-(2-Fluoro-4-iodophenylamino)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (360 mg, 0.71 mmol), O-(2-vinyloxyethyl)-hydroxylamine (79 mg, 0.77 mmol), HOBt (103 mg, 0.77 mmol), EDCI (147 mg, 0.77 mmol) and DIPEA (130 μL, 0.77 mmol) were dissolved in DMF (10 mL). The reaction mixture was stirred at room temperature for 16 hours then concentrated in vacuo. The resultant residue was dissolved in ethyl acetate (10 mL), washed with aqueous saturated sodium bicarbonate solution (10 mL) and the aqueous fraction extracted twice with ethyl acetate (2×10 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si—SPE, gradient 0-100% ethyl acetate in cyclohexane) to yield the title compound as a yellow solid (346 mg, 81%). LCMS (Method B): RT=4.08 min, [M+H]+=604.