Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH:11]([N:14]1[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23](OCC)=[O:24])[CH:16]=[N:15]1)([CH3:13])[CH3:12].Cl>C1(C)C=CC=CC=1>[CH:11]([N:14]1[C:18]([C:19]([F:21])([F:20])[F:22])=[C:17]([CH2:23][OH:24])[CH:16]=[N:15]1)([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1cnn(C(C)C)c1C(F)(F)F
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)n1ncc(CO)c1C(F)(F)F
Temperature: -78 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Diisobutylaluminium hydride (99 mL, 120 mmol, 1.2 M solution in toluene) was added to ethyl 1-isopropyl-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (WO 2007071900, 12 g, 48 mmol) in toluene (220 mL) at −78° C. The reaction mixture was stirred at −78° C. for 2 hours then poured into aqueous HCl (100 mL, 2 M). The mixture was stirred for 4 hours at room temperature then extracted with EtOAc (400 mL). The organic phase was washed with water (200 mL), brine (200 mL) and dried over sodium sulphate. The filtrate was evaporated in vacuo to afford the title compound as a colourless oil in 100% yield, 10.5 g.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:20]=C)[CH:18]=3)[N:13]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[C:12]=2[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:37].[Na+].O>O1CCCC1.[Os](=O)(=O)(=O)=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:20]=[O:37])[CH:18]=3)[N:13]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[C:12]=2[C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1ccc2c(c1)c(-c1ccc(C(C)(C)C)cc1)c(C(=O)OCC)n2Cc1cccc(OC)c1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(C=O)ccc2n1Cc1cccc(OC)c1
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
Ethyl 3-(4-tert-butylphenyl)-1-(3-methoxybenzyl)-5-vinyl-1H-indole-2-carboxylate (Example 129, 2.28 g, 4.9 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL), and osmium tetroxide (2.5 weight % solution in 2-methyl-2-propanol, 1.5 mL, 0.15 mmol) was added. After ten minutes, the reaction mixture was cooled with an ice bath. Sodium periodate (2.10 g, 9.8 mmol) was added followed by a minimum volume of water to dissolve the solids. The reaction was allowed to return to room temperature, and after 30 minutes, the reaction was partitioned between water and diethyl ether. The organic layer was separated, dried over anhydrous magnesium sulfate, and concentrated. The resulting crude oil was passed through a pad of silica gel with 20% ethyl acetate/hexane. The filtrate was concentrated in vacuo without heat to provide the title compound as a brown oil (1.70 g, 75%). The product had: 1H NMR (300 MHz, acetone-d6) 10.01 (s, 1 H), 8.15 (d, 1 H), 7.88 (d, 1 H), 7.75 (d, 1 H), 7.54 (d, 2 H), 7.44 (d, 2 H), 7.21-7.19 (m, 1 H), 6.81-6.79 (m, 1 H), 6.72-6.69 (m, 2 H), 5.92 (s, 2 H), 4.12 (q, 2 H), 3.71 (s, 3 H), 1.39 (s, 9 H), 0.78 (t, 3 H).
Reaction SMILES: C([O:4][C:5]1[CH:17]=[CH:16][C:8]([O:9][C@H:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)(=O)C.Cl>CO>[OH:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][C@H:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:16][CH:17]=1
Reactant: COC(=O)[C@@H](C)Oc1ccc(OC(C)=O)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H](C)Oc1ccc(O)cc1
Yield: 96 %

Procedure:
A mixture of 45 g (189 mmol) of methyl (R)-2-(4-acetoxyphenoxy)propionate (enantiomeric excess 94-95%), 135 ml of methanol and 2.5 ml of methanol saturated with gaseous hydrogen chloride was refluxed for 5 h and subsequently concentrated. The crude product was purified by distillation at 140° C. under 0.1 mbar. Yield: 96% (94-95% enantiomeric excess).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1.Cl[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[N:26]1[CH:27]=[CH:28][CH:29]=[N:30][C:25]=1[NH:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][NH:7][C:8]1[C:17]2[C:12](=[C:13]([C:18]([NH2:20])=[O:19])[CH:14]=[CH:15][CH:16]=2)[N:11]=[CH:10][N:9]=1
Reactant: NC(=O)c1cccc2c(NCc3cccc(N)c3)ncnc12
Reactant: Clc1ncccn1
Agent: Cl
Product: NC(=O)c1cccc2c(NCc3cccc(Nc4ncccn4)c3)ncnc12

Procedure:
The title compound was prepared according to Example 684 starting 4-(3-Amino-benzylamino)-quinazoline-8-carboxylic acid amide hydrochloride and 2-Chloro-pyrimidine at 120° C.:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22](=[O:32])[NH:23][CH2:24][C@H:25]([CH3:31])[CH2:26][C:27]([F:30])([F:29])[F:28])[CH:20]=2)[N:15]([CH3:33])[CH:14]=1)[C:6]([OH:8])=O.Cl.CN(C)CCCN=C=NCC.[CH3:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[S:53]([NH2:56])(=[O:55])=[O:54]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22](=[O:32])[NH:23][CH2:24][C@H:25]([CH3:31])[CH2:26][C:27]([F:28])([F:30])[F:29])[CH:20]=2)[N:15]([CH3:33])[CH:14]=1)[C:6]([NH:56][S:53]([C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][C:47]=1[CH3:46])(=[O:54])=[O:55])=[O:8]
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(C)c2ccc(C(=O)NC[C@H](C)CC(F)(F)F)cc12
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(C)c2ccc(C(=O)NC[C@H](C)CC(F)(F)F)cc12
Reaction time: 48 h
Yield: 87.8 %

Procedure:
A mixture of (R)-3-methoxy-4-[1-methyl-5-(2-methyl-4,4,4-trifluorobutylcarbamoyl)indol-3-yl-methyl]benzoic acid (14.28 g), 4-dimethylaminopyridine (4.39 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.34 g) and 2-methylbenzenesulfonamide (5.85 g) was dissolved in dry methylene chloride (270 mL) and the solution was stirred under an inert atmosphere for 48 h. The mixture was diluted with methylene chloride (300 mL) and washed three times with 1N hydrochloric acid. The combined hydrochloric washes were back washed with methylene chloride. The combined organic extracts were washed twice with water and evaporated. The residue was dissolved in a small volume of methanol and 1N sodium hydroxide and this solution was purified by flash chromatography over octadecylsilyl bonded silica gel ("Regis PREP-40-ODS"--irregularly shaped 32-74μ diameter particles, 72% silanol coverage, 21% carbon load) (450 g) eluting with 50:50 methanol:water, pH 7.1. The appropriate fractions (TLC, Rf =0.73, octadecylisilyl bonded silica gel, 200μ layer, 12% carbon load, 80:20 methanol:water, pH 6.1, 0.1% ammonium acetate buffer) were combined, the methanol evaporated, and the residual aqueous solution acidified to pH 1 with 1N hydrochloric acid. The resultant precipitate was filtered, washed (water), and dried under vacuum to give the title compound (16.7 g, 88%) as a white solid; mp 117°-120° C.; ee at least 99%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[NH3:20]>>[NH2:20][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: N
Reactant: CCOC(=O)c1cnc2ccc(OCC)cc2c1Cl
Product: CCOC(=O)c1cnc2ccc(OCC)cc2c1N

Procedure:
Prepared as in Example 1a from ethyl 4-chloro-6-ethoxyquinoline-3-carboxylate (Example 13b) and ammonia as an off white solid (77%). 1H NMR (400 MHz, DMSO-d6) δ 1.31-1.40 (m, 6H), 4.15 (q, J=7.2 Hz, 2H), 4.31 (q, J=6.8 Hz, 2H), 7.34 (q, J=6.4 Hz, 1H), 7.69-7.74 (m, 2H), 8.21 (bs, 2H), 8.77 (s, 1H). MS 261 (MH+).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]([CH3:8])([CH3:7])[CH2:5][OH:6].Br[CH2:10][C:11]([CH3:13])=[CH2:12]>CN(C=O)C>[CH3:7][C:4]([NH2:3])([CH3:8])[CH2:5][O:6][CH2:12][C:11]([CH3:13])=[CH2:10]
Reactant: C=C(C)CBr
Reactant: CC(C)(N)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)COCC(C)(C)N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of NaH (60% dispersion in mineral oil, 2.0 g, 50 mmol, 1 equiv) in DMF at 0° C. was added 2-amino-2-methyl-1-propanol (4.8 ml, 50 mmol, 1 equiv) and after 1 h 3-bromo-2-methyl-1-propene (5.5 ml, 55 mmol, 1.1 equiv). The resulting solution was stirred at room temperature for 15 h then partitioned between AcOEt and H2O. The two layers were separated and the organic phase was washed with H2O and brine, dried over MgSO4 and distillated (45° C., P=150 mbar) to give 2-methyl-1-[(2-methyl-2-propen-1-yl)oxy]-2-propanamine (F71) as a light pink solid.
Reaction SMILES: N([O-])=[O:2].[Na+].N[C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O.S(=O)(=O)(O)O>[C:8]1([CH2:7][CH:6]([OH:2])[C:14]([OH:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=N[O-]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)C(O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
A solution of 0.829 g of sodium nitrite in 4.2 ml of water is added dropwise at 0° C. to a suspension of 1.6 g of phenylalanine in 5.3 ml of sulfuric acid (2.5N). The reaction mixture is stirred for 2 hours at 0° C. and then for 17 hours at room temperature. The reaction mixture is extracted with twice 100 ml of ethyl acetate. The pooled organic phases are washed with 100 ml of a saturated sodium chloride solution in water. 1.2 g of yellow crystals are obtained after drying.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:22][CH:21]=2)[CH2:17][CH2:18][CH3:19])[C:9]([O:11]C(C)(C)C)=[O:10])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:16]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:27])=[CH:22][CH:21]=2)[CH2:17][CH2:18][CH3:19])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1
Reactant: CCCC(c1ccc(C(=O)NCCC(=O)OCC)cc1)C(C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(c1ccc(C(=O)NCCC(=O)OCC)cc1)C(C(=O)O)c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a solution of the slower-eluting diastereomer of tert-butyl 2-(4-chlorophenyl)-3-(4-{[(3-ethoxy-3-oxopropyl)amino]carbonyl}phenyl)hexanoate (1.9 g, 3.8 mmol) in DCM (20 mL) at 0° C. was added TFA (20 mL) over 1 min. After being stirred for 30 minutes, the solution was concentrated to afford the title compound. After being dried on high vacuum overnight, the material was used directly for the next step. LC1 2.09 min. (M+H)+ 446.
Reaction SMILES: CS([O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[O:17][N:16]=[C:15]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:9][CH2:8]1)(=O)=O.Cl.[F:22][C:23]1[CH:28]=[C:27]([S:29][CH3:30])[CH:26]=[CH:25][C:24]=1[C:31]1[N:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:22][C:23]1[CH:28]=[C:27]([S:29][CH3:30])[CH:26]=[CH:25][C:24]=1[C:31]1[CH:32]=[CH:33][C:34]([O:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13]3[O:17][N:16]=[C:15]([CH:18]([CH3:19])[CH3:20])[N:14]=3)[CH2:11][CH2:12]2)=[CH:35][N:36]=1
Reactant: CSc1ccc(-c2ccc(O)cn2)c(F)c1
Reactant: CC(C)c1noc(N2CCC(COS(C)(=O)=O)CC2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ccc(-c2ccc(OCC3CCN(c4nc(C(C)C)no4)CC3)cn2)c(F)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 91.9 %

Procedure:
A mixture of {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl methanesulfonate (prepared as in Example 100, Step 4, 50.4 g, 166 mmol), 6-[2-fluoro-4-(methylthio)phenyl]-3-pyridinol hydrochloride (47.6 g, 175 mmol), powdered potassium carbonate (72.6 g, 525 mmol) and N,N-dimethylformamide (450 mL) was mechanically stirred and heated at 80° C. under nitrogen for 48 h. The reaction was cooled to ambient temperature, poured onto ice water (2.5 L) and allowed to stand for 30 min. The resulting solid was filtered, rinsed with water (500 mL), heptane (500 mL) and air-dried to afford 2-[2-fluoro-4-(methylthio)phenyl]-5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]pyridine (67.5 g, 92%) as a light tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][C:13](Cl)=[C:12]([N+:17]([O-:19])=[O:18])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:21][C:22]1[CH:23]=[C:24]([SH:28])[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[NH2:21][C:22]1[CH:23]=[C:24]([S:28][C:13]2[CH:14]=[CH:15][C:10]([C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)=[O:20])=[CH:11][C:12]=2[N+:17]([O-:19])=[O:18])[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1cccc(S)c1
Reactant: O=C(Nc1cccc(Br)c1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1cccc(Sc2ccc(C(=O)Nc3cccc(Br)c3)cc2[N+](=O)[O-])c1
Temperature: 25 °C
Yield: 107.7 %

Procedure:
A solution of N-(3-Bromo-phenyl)-4-chloro-3-nitro-benzamide (from Example 26A) (2.13 g, 6.0 mmol), 3-aminothiophenol (0.75 g, 6.0 mmol) and cesium carbonate (4.0 g, 12.0 mmol) in N,N-dimethylformamide (20 mL) was heated to 95° C. for 3 hours. After cooling to room temperature the mixture was poured into ice water (100 mL) and the resultant solution adjusted to pH 6 with 1N aqueous hydrochloric acid. The solution was then extracted with ethyl acetate (3×50 mL), the combined extracts dried over sodium sulfate, filtered and concentrated under vacuum to provide the title compound (2.87 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[NH2:12][C:13]1[S:14][CH:15]=[C:16]([CH3:18])[N:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:12][C:13]2[S:14][CH:15]=[C:16]([CH3:18])[N:17]=2)=[S:10])[CH:7]=1
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: Cc1csc(N)n1
Product: Cc1csc(NC(=S)Nc2cc(Cl)ccc2C)n1
Yield: 65.8 %

Procedure:
Prepared using Method B from 4.5 g (24.5 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 2.8 g (24.5 mmol) of 2-amino-4-methylthiazole to give 4.8 g of title compound as an off-white solid (95% yield, m.p. 188° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][N:10]=2)=[CH:5][C:3]=1[NH2:4].[C:16]([O:20][C:21]([NH:23][C:24]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=S)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl>[C:30]([O:29][C:27]([NH:26][C:24]([NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])=[N:4][C:3]1[CH:5]=[C:6]([C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][N:10]=2)[CH:7]=[CH:8][C:2]=1[CH3:1])=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: Cc1ccnc(-c2ccc(C)c(N)c2)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccnc(-c2ccc(C)c(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Reaction time: 2 h
Yield: 83.2 %

Procedure:
To a suspension of 2-methyl-5-(4-methylpyridin-2-yl)aniline (285 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (475 mg) and diisopropylethylamine (0.577 ml) in dichloromethane (15 ml) was added 1-methyl-2-chloropyridinium iodide (478 mg), and the mixture was stirred for 2 hours. The mixture was diluted with dichloromethane, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. To the residue was added 2-propanol, and the mixture was stirred. The precipitate was collected by filtration and dried to give N,N′-bis(tert-butoxycarbonyl)-N″-(2-methyl-5-(4-methylpyridin-2-yl)phenyl)guanidine (527 mg).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16]>>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1S
Reactant: Ic1ccccc1
Product: COc1ccccc1Sc1ccccc1

Procedure:
The general procedure was used to convert iodobenzene and 2-methoxybenzenethiol to the title product. Purification by flash chromatography (hexane/CH2Cl2 [3:1] as the eluent) gave the analytically pure product as a clear oil (406 mg, 94% yield). 1H NMR (300 MHz, CDCl3) δ 7.43–7.25 (m, 6H; Hc, He, He′, HfHf′, Hg), 7.14 (dd, 1H; Ha), 6.96–6.89 (m, 2H; Hb, Hd), 3.90 (s, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 157.20 (C6), 134.38 (C8), 131.88 (C2), 131.35 (C9, C13), 129.15 (C10, C12), 128.25 (C4), 127.40 (C11), 123.93 (C1), 121.14 (C3), 110.75 (C5), 55.76 (C7). Anal. Calcd. for C13H12OS: C, 72.19; H, 5.59; S, 14.82; Found C, 72.22; H, 5.70; S, 14.63.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:20](=[O:23])(=[O:22])[NH2:21])[C:10]=1[NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]([OH:7])=[O:6].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[CH2:24]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:20](=[O:23])(=[O:22])[NH2:21])[C:10]=1[NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:5]([OH:7])=[O:6])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: Nc1cc(C(=O)O)cc(S(N)(=O)=O)c1NCCc1ccccc1
Solvent: CCO
Product: NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccccc2)c1NCCc1ccccc1

Procedure:
A mixture of 3-amino-4-(β-phenylethylamino)-5-sulphamyl-benzoic acid (3.35 g), benzyl bromide (5.3 g), and anhydrous ethanol (30 ml) was refluxed for 48 hours. After cooling, the precipitated ethyl ester was collected by suction, recrystallized from ethanol and saponified by heating in 1N sodium hydroxide (30 ml) for 1 hour. The 3-benzylamino-4-(β-phenylethylamino)-5-sulphamyl-benzoic acid was precipitated at room temperature by addition of 4N hydrochloric acid until the pH was 2.5. After recrystallization from aqueous ethanol, the compound was obtained with a melting point of 203°C.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:14]>ClCCCl>[Br:1][C:2]1[C:3]([Cl:8])=[N+:4]([O-:14])[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncccc1Br
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCCl
Product: [O-][n+]1cccc(Br)c1Cl

Procedure:
A solution of 3-bromo-2-chloropyridine (50 g, 0.26 mol) and 3-chloroperoxybenzoic acid (70-75% wet with water; 67.3 g, 0.39 mol) in 1,2-dichloroethane (600 mL) was heated under reflux for 7 hours. The reaction was then concentrated under reduced pressure to an approximate volume of 200 mL and purified by chromatography on silica gel (Gradient: 80% to 100% ethyl acetate in heptane, followed by 5% to 10% methanol in ethyl acetate) to yield the title compound as a brown solid. Yield: 32.9 g, 0.158 mol, 61%. LCMS m/z 210.0 (M+1). 1H NMR (400 MHz, CDCl3) δ 7.09 (dd, J=7.8, 6.9 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), 8.33 (d, J=6.4 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:22][C:23]#[C:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[CH2:9][CH2:10][N:11]([CH:19]([CH3:21])[CH3:20])[C:12](=[O:18])[C:13]([O:15]CC)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]([CH2:22][C:23]#[C:24][C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)[CH2:9][CH2:10][N:11]([CH:19]([CH3:21])[CH3:20])[C:12](=[O:18])[C:13]([OH:15])=[O:14])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)C(=O)N(CCN(CC#Cc1cccs1)C(=O)OC(C)(C)C)C(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)N(CCN(CC#Cc1cccs1)C(=O)OC(C)(C)C)C(=O)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
A solution of 400 mg of 10h in 6 ml of dioxane was mixed with a solution of 180 mg of KOH in 1.5 ml of water and stirred for 2 hr at RT. The reaction mixture was diluted with 20 ml of water and acidified to pH3 by addition of 0.5N HCl. The product was extracted into ethyl acetate. The combined organic layers were once washed with water, dried and concentrated, to provide 320 mg of 10i as colorless oil:
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:33]=[CH:32][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]([CH3:31])=[C:15]([NH:17][C:18](=[O:30])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[CH:20]=3)[CH:16]=2)=[CH:8][CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:7]2[CH:8]=[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14]([CH3:31])=[C:15]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:26])[CH3:27])[CH:20]=4)[CH:16]=3)[CH:32]=[CH:33][C:6]=2[N:5]=1
Reactant: N#C[S-]
Reactant: Cc1ccc(Oc2ccc(N)cc2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1ccc(Oc2ccc3nc(N)sc3c2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.6 %

Procedure:
Potassium thiocyanate (4.80 g, 49.2 mmol) was suspended in acetic acid (80 mL) and the mixture was stirred at room temperature for 10 min. To the obtained solution was added a is solution of N-[5-(4-aminophenoxy)-2-methylphenyl]-3-(1-cyano-1-methylethyl)benzamide (5.00 g, 12.3 mmol) in acetic acid (80 mL), and the mixture was further stirred at room temperature for 20 min. To the obtained solution was added dropwise slowly a solution of bromine (2.46 g, 15.4 mmol) in acetic acid (50 mL) and, after the completion of the dropwise addition, the mixture was stirred at room temperature for 6 hr. The resulting yellow insoluble material was filtered off, and washed with acetic acid. The filtrate and the washing were combined and concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (300 mL), washed with 5% aqueous sodium hydrogencarbonate solution (300 mL) and saturated brine (300 mL), successively, and dried over anhydrous sodium sulfate. Activated carbon was added, and the mixture was stood for a while. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (3.57 g, 66%) as a pale-yellow amorphous substance.
Reaction SMILES: [C:1]1([S:7](Cl)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:10]>CCOCC>[C:1]1([S:7]([NH2:10])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)c1ccccc1
Reactant: N
Solvent: CCOCC
Product: NS(=O)c1ccccc1
Yield: 17 %

Procedure:
Benzenesulphinamide was prepared by reacting benzenesulphinyl chloride with ammonia in ether initially at -78° C. and finally at ambient temperature and was isolated in 17% yield as a solid, m.p. 112°-115° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([NH2:10])=[O:9])[N:5]([CH3:7])[CH:6]=1.[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([F:25])[CH:24]=1)[C:21](=[O:26])[N:20]([C:27]1[CH:37]=[CH:36][CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[C:28]=1[CH2:29][O:30]C(=O)C)[N:19]=[CH:18]2)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([F:25])[CH:24]=1)[C:21](=[O:26])[N:20]([C:27]1[C:28]([CH2:29][OH:30])=[C:34]([C:2]3[CH:3]=[C:4]([C:8]([NH2:10])=[O:9])[N:5]([CH3:7])[CH:6]=3)[CH:35]=[CH:36][CH:37]=1)[N:19]=[CH:18]2)([CH3:14])([CH3:12])[CH3:13]
Reactant: Cn1cc(Br)cc1C(N)=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Product: Cn1cc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc1C(N)=O
Yield: 60 %

Procedure:
This compound was prepared with the same method as described in Example 1 by using 4-bromo-1-methyl-1H-pyrrole-2-carboxylic acid amide (intermediate-3) and acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (intermediate 5). The desired compound was prepared in two steps (60% yield). 1H NMR (300 MHz, d6-DMSO) δ 8.49-8.48 (m, 1H), 7.86 (s, 1H), 7.73 (d, J=13.2 Hz, 1H), 7.44-7.42 (m, 3H), 7.25-7.23 (m, 2H), 7.06 (br s, 2H), 4.56 (s, 1H), 4.36 (s, 2H), 3.88 (s, 3H), 1.37 (s, 9H). LC-MS calcd for C25H25FN4O3 (m/e) 448.19, obsd 449.1 [M+H]+.