Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][C:5]=2[O:4][CH:3]=1.CO[CH:27](OC)[N:28]([CH3:30])[CH3:29]>>[CH3:27][N:28]([CH:30]=[N:1][C:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:11]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][C:5]=2[O:4][CH:3]=1)[CH3:29]
Reactant: COC(OC)N(C)C
Reactant: CS(=O)(=O)Nc1cc2occ(N)c(=O)c2cc1Oc1ccccc1
Product: CN(C)C=Nc1coc2cc(NS(C)(=O)=O)c(Oc3ccccc3)cc2c1=O

Procedure:
3-Amino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one was reacted with N,N-dimethylformamide dimethylacetal to obtain 3-(N,N-dimethylamino)methyleneamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][CH2:15][CH2:16][CH2:17]O)([O-:3])=[O:2].S(Cl)([Cl:21])=O>ClC(Cl)Cl>[Cl:21][CH2:17][CH2:16][CH2:15][NH:14][C:5]1[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCCCl
Reaction time: 8 h

Procedure:
To a stirred mixture of 26 parts of 3-{[2-nitro-4-(trifluoromethyl)phenyl]amino}-1-propanol and 150 parts of trichloromethane are added dropwise 40 parts of sulfinyl chloride. Upon completion, stirring is continued overnight at reflux temperature. The reaction mixture is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5) as eluent. The pure fractions are collected and the eluent is evaporated, yielding N-(3-chloropropyl)-2-nitro-4-(trifluoromethyl)benzenamine as a residue.
Reaction SMILES: [O:1]=[C:2]1[C:6]([CH2:7][C:8]([OH:10])=[O:9])=[CH:5][C:4](=O)[O:3]1.S(O)(O)(=O)=O.[NH2:17][NH2:18]>O>[O:1]=[C:2]1[C:6]([CH2:7][C:8]([OH:10])=[O:9])=[CH:5][C:4](=[O:3])[NH:18][NH:17]1
Reactant: O=C(O)CC1=CC(=O)OC1=O
Reactant: NN
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1cc(=O)[nH][nH]c1=O
Temperature: 25 °C
Yield: 85.4 %

Procedure:
A mixture of (2,5-dioxo-2,5-dihydro-3-furanyl)acetic acid (9 g) and hydrazine sulphate (7.2 g) in water was heated to reflux for 4 hours then allowed to cool to ambient temperature. The precipitate was filtered, washing with water then acetone. Drying in vacuo afforded a white solid (8.04 g, 82%).
Reaction SMILES: [BH4-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([CH:35]=[O:36])=[CH:32][CH:33]=4)[N:28]([CH3:37])[CH:27]=3)[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[O:14])=[CH:11][C:6]=2[O:5][CH2:4]1>C(O)C>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([CH2:35][OH:36])=[CH:32][CH:33]=4)[N:28]([CH3:37])[CH:27]=3)[C:13]([NH:15][S:16]([C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)(=[O:18])=[O:17])=[O:14])=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: Cc1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(C=O)ccc23)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(CO)ccc23)cc1
Yield: 70.8 %

Procedure:
Sodium borohydride (51 mg, 1.33 mmol) was added to a stirred solution of 3-{1-(1,3-benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-6-bromo-1-methyl-1H-indole (from Example 94, 305 mg, 0.66 mmol) in ethanol (10 ml) at room temperature under a nitrogen atmosphere. After 1 h the ethanol was removed in vacuo and the product was extracted from 0.5 N hydrochloric acid (50 ml) with dichloromethane (2×50 ml). The organic layers were dried (MgSO4) and concentrated. Flash column chromatography (elution with 95% dichloromethane/5% methanol) gave the product (230 mg) as a white foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[C:12](OC(=O)C)(=[O:14])[CH3:13].[H][H]>[Pt](=O)=O.C(OCC)(=O)C>[C:12]([NH:8][C:7]1[CH:6]=[CH:5][C:4]([OH:11])=[CH:3][C:2]=1[F:1])(=[O:14])[CH3:13]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: CC(=O)OC(C)=O
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(O)cc1F
Reaction time: 6 h
Yield: 83 %

Procedure:
5.0 Grams of 3-fluoro-4-nitrophenol, 3.57 g of acetic anhydride, 0.72 g of platinum dioxide and 50 ml of ethyl acetate were added to a reactor, and the atmosphere in the reactor was replaced by a hydrogen stream with stirring. Stirring was then continued at room temperature for 6 hours while introducing a hydrogen gas. Thereafter, the reaction solution was filtered off, and the filtrate was washed with two 50-ml portions of a 5% aqueous sodium hydrogencarbonate solution, dried and concentrated. The residue was subjected to chromatography on silica gel to obtain 4.47 g of 4-acetylamino-3-fluorophenol.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:11]=1.C(O)=O.[N:21]([O-])=O.[Na+].[CH:25]1[C:38]2[CH:37]=[C:36]([OH:39])[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]=2[CH:28]=[CH:27][CH:26]=1>O.C(O)C>[C:12]1([C:10]2[N:11]=[C:7]([N:6]=[N:21][C:37]3[C:38]4[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=4[C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:36]=3[OH:39])[S:8][CH:9]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1cc2ccccc2c2ccccc12
Reactant: Nc1nc(-c2ccccc2)cs1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: O=CO
Solvent: CCO
Product: Oc1c(N=Nc2nc(-c3ccccc3)cs2)c2ccccc2c2ccccc12
Temperature: 0 °C

Procedure:
A reaction flask was loaded with water (3.4 ml), a 98% aqueous solution of sulfuric acid (7.2 ml), 2-amino-4-phenylthiazol (1.66 g) and formic acid (1.6 ml) successively, followed by stirring to dissolve 2-amino-4-phenylthiazol. The liquid was cooled to 0° C., followed by dropwise addition of a solution in which sodium nitrite (0.47 g) was dissolved in water (2 ml) to the mixture in 10 minutes. After stirring at or below 5° C. for one hour, a solution in which 9-phenanthrol (3.2 g) was dissolved in ethanol (30 ml) was dropwise added to the mixture in one hour. The cooling was stopped and the reaction mixture at room temperature was filtrated to give crystals. The crystals were recrystallized with dioxane-methanol to give intended crystals (1.7 g).
Reaction SMILES: Cl.[CH:2](=[O:4])[CH3:3].[CH2:5]([CH:7]1[O:11][C:10](=[O:12])[NH:9][CH2:8]1)[CH3:6].C[O-].[Na+].[CH2:16](O)[CH3:17]>>[CH2:2]([O:4][CH:16]([N:9]1[CH2:8][CH:7]([CH2:5][CH3:6])[O:11][C:10]1=[O:12])[CH3:17])[CH3:3]
Reactant: CCO
Reactant: CC=O
Reactant: CCC1CNC(=O)O1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CCOC(C)N1CC(CC)OC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a three-necked flask equipped with a mechanical stirrer and reflux condenser, ethanol is acidified to a pH of 0.5-1.5 with 8 percent methanolic HCl. To the cooled alcohol is added acetaldehyde. The addition is so conducted that the temperature of the mixture stays under 40° C. The solution is stirred at room temperature for 2 hours after the completion of addition. The mole ratio of alcohol to acetaldehyde is about 1.5:1. 5-Ethyl-2-oxazolidinone (mole ratio of acetaldehyde to 2-oxazolidinone is 3:1) is added dropwise to the solution. The mixture is then stirred for 24 hours at 45° C. The mixture is then neutralized to a pH of 6.5-8 with a solution of sodium methoxide. After removing the unconsumed hemiacetal and alcohol under vacuum, the liquid 3-(1-ethoxyethyl)-5-ethyl-2-oxazolidinone is obtained.
Reaction SMILES: [CH3:1][S:2][CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH:11]=[N:12][C:13]([C:14]3[O:15][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:17][N:18]=3)=[C:7]2[N:6]=[N:5]1.S([O-])(O[O-])(=O)=[O:26].[K+].[K+].OOS([O-])=O.[K+]>CN(C=O)C.O>[CH3:1][S:2]([CH2:3][N:4]1[C:9](=[O:10])[N:8]2[CH:11]=[N:12][C:13]([C:14]3[O:15][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:17][N:18]=3)=[C:7]2[N:6]=[N:5]1)=[O:26]
Reactant: CSCn1nnc2c(-c3nnc(-c4ccccc4)o3)ncn2c1=O
Reactant: O=S(=O)([O-])O[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)Cn1nnc2c(-c3nnc(-c4ccccc4)o3)ncn2c1=O
Temperature: 0 °C
Yield: 90 %

Procedure:
To a 0° C. solution of 3-(methylthiomethyl)-8-(5-phenyl-1,3,4-oxadiazol-2-yl)imidazo[5,1-d][1,2,3,5]tetrazin-4(3H)-one (0.337 mmol, 115 mg, 1 eq.) in DMF (6 mL) was added potassium peroxymonosulfate (Oxone™) (0.37 mmol, 114 mg, 1.1 eq.) dissolved in water (1.2 mL) drop wise. The formed suspension was stirred at 0° C. and stepwise additions of Oxone™ in water were made until reaction completion. The reaction mixture was filtered and the obtained solid was washed with water, acetonitrile and ether, and dried under vacuum to give the title compound. Yield 90%. δH (DMSO-d6) 9.15 (1H, s), 8.13 (2H, dd, J: 7.96, 2.25), 7.70 (3H, m), 5.67 (1H, d, J: 13.06), 5.52 (1H, d, J: 13.06), 2.81 (3H, s).
Reaction SMILES: Cl[CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[C:3](=O)[CH3:4].[C:16]([CH2:19][NH:20][C:21]([NH2:23])=[S:22])([OH:18])=[O:17].[CH2:24](O)[CH3:25]>>[CH3:4][C:3]1[N:23]=[C:21]([NH:20][CH2:19][C:16]([O:18][CH2:24][CH3:25])=[O:17])[S:22][C:2]=1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1
Reactant: NC(=S)NCC(=O)O
Reactant: CC(=O)C(Cl)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCO
Product: CCOC(=O)CNc1nc(C)c(Cc2ccc([N+](=O)[O-])cc2)s1

Procedure:
7.6 g of 3-chloro-4-(4-nitrophenyl)butan-2-one and 4.5 g of N-carboxymethylthiourea (NH2CSNHCH2COOH) are dissolved in 100 ml of ethanol and refluxed for 12 hours. The reaction medium is concentrated and the residue is recrystallized from isopropanol to give 9.5 g of ethyl (4-methyl-5-(4-nitrobenzyl)thiazol-2-yl)aminoacetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:17]([C:18]4[CH:19]=[N:20][N:21]([CH2:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH:22]=4)=[CH:16][N:15](S(C4C=CC(C)=CC=4)(=O)=O)[C:12]3=[N:13][CH:14]=2)=[CH:5][C:4]=1[NH:41][S:42]([CH3:45])(=[O:44])=[O:43].[OH-].[Li+]>C1COCC1.CO.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:17]([C:18]4[CH:19]=[N:20][N:21]([CH2:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH:22]=4)=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)=[CH:5][C:4]=1[NH:41][S:42]([CH3:45])(=[O:44])=[O:43]
Reactant: COc1ccc(-c2cnc3c(c2)c(-c2cnn(CCc4ccccc4)c2)cn3S(=O)(=O)c2ccc(C)cc2)cc1NS(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(-c2cnc3[nH]cc(-c4cnn(CCc5ccccc5)c4)c3c2)cc1NS(C)(=O)=O
Yield: 17.2 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(2-methoxy-5-(3-(1-phenethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methanesulfonamide (100 mg, 0.155 mmol) was hydrolyzed by lithium hydroxide (13 mg, 0.311 mmol) in THF/methanol/water (5/1/2 mL) to afford 13 mg of the titled compound. 1H NMR (DMSO-d6, 400 MHz): δ 9.07 (s, 1H), 8.45-8.44 (d, 1H), 8.186-8.182 (d, 1H), 8.13, s 1H), 7.89 (s, 1H), 7.716-7.710 (d, 1H), 7.60-7.59 (m, 2H), 7.31-7.28 (m, 2H), 7.24-7.19 (m, 4H), 4.43-4.39 (t, 2H), 3.91 (s, 3H), 3.20-3.16 (t, 2H), 3.02 (s, 3H). MS: m/z=487.8 (M+1), HPLC: 95.48% in method A.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([CH3:18])([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:10]=2)[N:7]=1.[Cl:19]N1C(=O)CCC1=O.O>C(OCC)(=O)C>[Cl:19][C:8]1[N:6]2[N:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[N:10][C:9]=1[C:11]([CH3:17])([CH3:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)c1nc2ccc(Cl)nn2c1Cl
Yield: 97.5 %

Procedure:
4.07 g of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate was suspended in 60 ml of ethyl acetate; 2.13 g of N-chlorosuccinimide was added, followed by thermal refluxing for 4 hours. After cooling, water was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (5:1). The desired fraction was collected and concentrated under reduced pressure to yield 4.48 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])[CH:7]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: C1CNCCN1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1S(=O)(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71.1 %

Procedure:
5-Fluoro-2-methylbenzenesulfonyl chloride (35.1 g, 168.5 mmol) in diethyl ether (50 mL) was added drop-wise to a suspension of piperazine (28.8 g, 337.0 mmol) in diethyl ether (500 mL) and triethylamine (47 mL, 337.0 mmol). The white suspension was stirred at room temp for 1.5 h. The mixture was washed with saturated aqueous sodium carbonate. The organic phase was washed with water and brine and dried (Na2SO4). Concentration gave a white solid that was triturated with diethyl ether to give the title compound as a white solid (30.95 g, 36% yield). 1H NMR (300 MHz, CDCl3) δ: 7.57 (1H, dd, J=8.6, 2.7 Hz), 7.25 (1H, dd, J=8.4, 5.1 Hz), 7.12 (1H, td, J=8.1, 2.8 Hz), 3.13-3.10 (4H, m), 2.98-2.85 (4H, m), 2.55 (3H, s), 1.69 (1H, bs). LCMS (M+H) calcd for C11H16FN2O2S: 259.09; found: 259.18.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][C:19]1=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:32][C:33]1[S:37][C:36]([CH:38]=[CH:39][S:40](Cl)(=[O:42])=[O:41])=[CH:35][CH:34]=1>CC#N>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][N:13]=[CH:12][C:11]=2[CH:10]=[C:9]1[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([S:40]([CH:39]=[CH:38][C:36]2[S:37][C:33]([Cl:32])=[CH:34][CH:35]=2)(=[O:42])=[O:41])[CH2:20][C:19]1=[O:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1c(CN2CCNCC2=O)cc2cnccc21
Reactant: O=S(=O)(Cl)C=Cc1ccc(Cl)s1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(CN2CCN(S(=O)(=O)C=Cc3ccc(Cl)s3)CC2=O)cc2cnccc21
Reaction time: 8 h

Procedure:
To a solution of 2-(2-oxopiperazin-1-ylmethyl)pyrrolo[3,2-c]pyridin-1-carboxylic acid tert-butyl ester (0.71 g, 2.1 mmol), EXAMPLE 69, in CH3CN (7 mL) is added triethylamine (0.60 mL, 4.3 mmol) followed by 2-(5-chloro-thiophen-2-yl)-ethenesulfonyl chloride, EXAMPLE 3, (0.57 g, 2.1 mmol). The mixture is stirred overnight, then concentrated to dryness. The residue is diluted with CH2Cl2 and washed with saturated sodium bicarbonate and brine. The organic layer is dried over MgSO4, filtered and concentrated in vacuo to give the title compound (1.2 g, 2.1 mmol) as a light yellow solid. The crude material can be used in the subsequent step without further purification. 1H NMR (CDCl3, 300 MHz) δ8.80 (s, 1H), 8.42 (d, 1H), 7.88 (d, 1H), 7.55 (d, 1H), 7.14 (d, 1H), 6.98 (d, 1H), 6.41 (s, 1H), 6.36 (d, 1H), 5.00 (s, 2H), 3.98 (s, 2H), 3.61 (m, 4H), 1.71 (s, 9H). Ion spray MS, [M+H]+=537, 539, Cl pattern.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](O)=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[SH:20]>>[S:20]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:10]1[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=1
Reactant: Nc1ccccc1S
Reactant: O=C(O)Cc1ccc(CO)cc1
Product: OCc1ccc(Cc2nc3ccccc3s2)cc1
Temperature: 160 °C
Yield: 13.7 %

Procedure:
To (4-hydroxymethyl-phenyl)-acetic acid (2 g, 12 mmol) was added 2-amino-benzenethiol (13.2 g, 12 mmol) and the mixture was heated at 160° C. for 48 h. The crude residue was then partitioned between EtOAc (200 mL) and 1 N NaOH (200 mL). The organic layer was separated, washed with satd. aq. NaCl (200 mL), dried (MgSO4), filtered and concentrated. Purification by silica gel flash chromatography (0% to 80% EtOAc in hexanes) afforded the title compound as a colorless oil (0.42 g, 14%). MS (ESI): mass calcd. for C15H13NOS, 255.34; m/z found, 456.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.00 (d, J=8.1 Hz, 1H), 7.80 (d, J=8.1 Hz, 1H), 7.48-7.45 (m, 1H), 7.39-7.28 (m, 5H), 4.71 (s, 2H), 4.44 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:27])[C:13]1[CH:18]=[CH:17][C:16]([O:19]COC)=[C:15]([O:23]COC)[CH:14]=1.[C:28](Cl)(=[O:30])[CH3:29].O>N1C=CC=CC=1.ClCCl>[C:28]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:27])[C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([OH:23])[CH:14]=1)(=[O:30])[CH3:29]
Reactant: COCOc1ccc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)cc1OCOC
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1c(C(=O)c2ccc(O)c(O)c2)[nH]c2cc(Cl)ccc12
Reaction time: 1 h
Yield: 17.9 %

Procedure:
To a solution of 3-amino-6-chloro-2-[[3,4-bis(methoxymethyloxy)]benzoyl]indole (step 3, 0.50 g, 1.3 mmol) in pyridine (1.0 ml) and dichloromethane (20 ml) cooled to 0° C. was added acetyl chloride (0.10 ml, 1.40 mmol). After stiiring for 1 h at room temperature, the reaction mixture was poured into water (20 ml) and extracted with dichloromethane (30 ml×2). The organic extracts were dried (MgSO4) and solvent removed by evaporation. The residue was dissolved in dichloromethane (30 ml), trifluoroacetic acid (0.50 ml) added and the mixture heated at reflux for 5 h. The mixture was cooled, poured into water and extracted with ethyl acetate (80 ml×2). The organic extracts were dried (MgSO4) and solvent removed by evaporation. The residual oil was purified by flash column chromatography eluting with hexane/ethyl acetate (1/3) to give 80 mg (20%) of the title compound. Recrystallization from ethyl acetate/hexane afforded the title compound as a yellow solid. m.p.: 193-200° C. 1H-NMR (CDCl3) δ: 11.64 (1H, br s), 9.66 (1H, br s), 7.58 (1H, d, J=8.4 Hz), 7.41 (1H, J=1.5 Hz), 7.24 (1H, d, J=2.2 Hz), 7.15 (1H, dd, J=8.8, 1.8 Hz), 7.08 (1H, dd, J=8.8, 1.5 Hz), 6.80 (1H, d, J=8.4 Hz), 1.98 (3H, s)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([CH:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:22]([NH:24][N:25]1[C:29](=[O:30])[C:28]2([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[NH:27][C:26]1=[O:36])=[O:23])[CH2:12][CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].[H][H]>CO.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:22]([NH:24][N:25]1[C:29](=[O:30])[C:28]2([CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[NH:27][C:26]1=[O:36])=[O:23])[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)CC(C(=O)NN1C(=O)NC2(CCCCC2)C1=O)[C@H](CC=Cc1ccccc1)C(=O)NOC1CCCCO1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN1C(=O)NC2(CCCCC2)C1=O)[C@H](CCCc1ccccc1)C(=O)NOC1CCCCO1

Procedure:
A solution of 0.25 g of (E)-2(R(-[1(S)-[(tetrahydro-2(RS)pyranyloxy)carbamoyl]4-phenyl-3-butenyl]-4-methyl-N-(2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)valeramide in 5 ml of methanol containing 0.025 g of 10% palladium-on-carbon catalyst was shaken in a hydrogen atmosphere for 2 hours. The catalyst was filtered off to give a solution of 0.25 g of 2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenylbutyl]-4-methyl-N-(2,4-dioxo-1,3-diazaspiro[4.5]decan-3-yl)valeramide in methanol that was used directly in the process step.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:9]=[N:10][C:11]([Cl:21])=[CH:12][C:13]=1[C:14]1[C:15]([CH3:20])=[N:16][CH:17]=[CH:18][CH:19]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25]I>CN(C=O)C>[C:1]([O:5][C:6](=[O:22])[N:7]([C:8]1[CH:9]=[N:10][C:11]([Cl:21])=[CH:12][C:13]=1[C:14]1[C:15]([CH3:20])=[N:16][CH:17]=[CH:18][CH:19]=1)[CH3:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ncccc1-c1cc(Cl)ncc1NC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ncccc1-c1cc(Cl)ncc1N(C)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a solution of 0.16 g (0.50 mmol) (6′-chloro-2-methyl-[3,4′]bipyridinyl-3′-yl)-carbamic acid tert-butyl ester in 5 ml DMF were added 25 mg (0.50 mmol) sodium hydride (50% suspension in mineral oil) under nitrogen at room temperature. After stirring for 30 min 0.034 ml (0.52 mmol) methyl iodide were added. The reaction mixture was stirred for 1 h. Quenching with water was followed by extraction with three portions of dichloromethane. The combined organic layers were washed with water. The combined aqueous layers were extracted with dichloromethane. The combined organic layers were dried with sodium sulfate and concentrated. Residual DMF was removed by Kugelrohr distillation. Flash chromatography gave 0.14 g (84%) of the title compound.
Reaction SMILES: [N:1]1([N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:25]([CH2:28][C@@H:29]([OH:33])[C:30](O)=[O:31])(=[O:27])=[O:26])[CH:19]=[CH:18]2.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([S:25]([CH2:28][C@@H:29]([OH:33])[C:30]([N:4]1[CH2:3][CH2:2][N:1]([N:7]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]3=[O:13])[CH2:6][CH2:5]1)=[O:31])(=[O:26])=[O:27])[CH:19]=[CH:18]2
Reactant: O=C(O)[C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reactant: O=C1CCCCN1N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C([C@H](O)CS(=O)(=O)c1ccc2cc(Cl)ccc2c1)N1CCN(N2CCCCC2=O)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 27.8 %

Procedure:
1-(piperazin-1-yl)piperidin-2-one (0.44 g) obtained in Example 8b), (2S)-3-[(6-chloronaphthalen-2-yl)sulfony]-2-hydroxypropionic acid (0.76 g), HOBt (0.37 g) and triethylamine (0.34 mL) were dissolved in DMF (10 mL), WSC (0.46 g) was added thereto, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with an aqueous sodium bicarbonate solution, and extracted with dichloromethane. The extract was washed with an aqueous sodium bicarbonate solution and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=10/1), and recrystallized form ethyl acetate to obtain the title compound (0.32 g, 28%) as a colorless powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:26]([O-])(=[O:28])[CH3:27].[Na+].[H][H].CO>C(OC(=O)C)(=O)C.[Ni].CCOCC>[C:26]([NH:22][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:17][CH:16]=3)[CH2:12][CH2:13]2)[CH:19]=1)(=[O:28])[CH3:27]
Reactant: N#Cc1cccc(N2CCc3cc(OCc4ccccc4)ccc32)c1
Reactant: CC(=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CC(=O)NCc1cccc(N2CCc3cc(OCc4ccccc4)ccc32)c1
Yield: 74.8 %

Procedure:
A solution of 1.52 g (4.7 mmole) of 3-(5-benzyloxy-1-indolinyl)benzonitrile of Example 18b in 60 ml acetic anhydride over 0.2 g Raney Nickel (#28 finely divided) and 0.76 g (9.3 mmole, 2 equivalents) sodium acetate was shaken at 50° C. under 50 psi of hydrogen until gas uptake had ceased and TLC analysis showed the reduction to be complete. The catalyst was filtered on a pad of celite and the filtrate was partitioned between chloroform (40 ml) and water (400 ml) and the combined organic portions were washed twice with water (600 ml), aqueous NaHCO3 (two 600 ml portions) and brine, dried over Na2SO4, and concentrated to give an oil. Chromatography on silica gel (80 g) using 1-5% methanol in ether afforded 1.31 g (86.8%) of N-Acetyl-3-(5-benzyloxy-1-indolinyl)benzenemethanamine as an oil.