Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[N:7]=[C:8]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11]2.[CH2:38]([O:40][C:41]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)=[O:42])[CH3:39].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:32]([O:31][C:30]([NH:29][C:8]1[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:46]3[CH:47]=[CH:48][C:43]([C:41]([O:40][CH2:38][CH3:39])=[O:42])=[CH:44][CH:45]=3)=[CH:37][C:6]=2[N:7]=1)=[O:36])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(C(=O)OCC)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Temperature: 100 °C

Procedure:
tert-butyl (1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate, 4-(ethoxycarbonyl)phenylboronic acid (1.5 equiv), tetrakis(triphenylphosphine)palladium(0), 2M aqueous potassium carbonate (3 equiv) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) afforded ethyl 4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]CCC(OCC)=O)=[CH:10][CH:9]=2)=[CH:4][N:3]=1.CC([O-])(C)C.[K+].CO>C1COCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]3[C:16]([SH:21])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: CCOC(=O)CCSc1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ncc(-c2ccc(-c3ccccc3S)cc2F)cn1
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of ethyl 3-(4′-(2-aminopyrimidin-5-yl)-5′-fluorobiphenyl-2-ylthio)propanoate (6.5 g, 16 mmol) in THF (70 mL) was added t-BuOK (3.68 g, 32.8 mmol) under a N2 atmosphere. After stirring for 10 min, methanol (5 mL) was added and the resulting mixture purified by FCC to give the title compound (4.8 g, 16 mmol, 98%). MS (ESI): mass calcd. for C16H12FN3S, 297.07; m/z found, 298.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:16][C:4]2([CH2:7][CH:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:5]2)[CH2:3]1.[CH3:17][Li]>C1COCC1>[OH:1][C:2]1([CH3:17])[CH2:3][C:4]2([CH2:7][CH:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:5]2)[CH2:16]1
Reactant: [Li]C
Reactant: CC(C)(C)OC(=O)NC1CC2(CC(=O)C2)C1
Solvent: C1CCOC1
Product: CC1(O)CC2(CC(NC(=O)OC(C)(C)C)C2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (6-oxospiro[3.3]heptan-2-yl)carbamate (800 mg, 3.55 mmol) in anhydrous THF (15 mL) was added a solution of methyl lithium in THF (2.36 mL, 3 mol/L, 7.50 mmol) at −78° C. under nitrogen. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to afford the title compound (760 mg, crude) as a brown solid, which was which was used to next step without further purification. MS (ESI) m/z 242.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](O)=[O:6].B.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: O=C(O)c1cc(Cl)cc(Br)c1
Agent: B
Solvent: C1CCOC1
Product: OCc1cc(Cl)cc(Br)c1
Reaction time: 16 h

Procedure:
To a solution of 3-bromo-5-chlorobenzoic acid (1.0 g, 4.3 mmol) in THF (30 mL) was added borane-THF solution (13 mL, 1.0 M) at 0° C. The mixture was allowed to stir for 16 hours. TLC showed clean conversion. The reaction was quenched with methanol, diluted with EtOAc (100 mL), washed with 0.5 N HCl, 0.5 N NaOH, and brine, dried over sodium sulfate, filtered and concentrated to give rise to (3-bromo-5-chlorophenyl)methanol as a waxy solid (680 mg, 72% yield). To the above solid (680 mg, 3.1 mmol) was added thallium trifluoroacetate (1.8 g, 3.4 mmol) and TFA (4 mL). The mixture was allowed to stir at RT for 16 hours. The volatiles were removed under reduced pressure. The residue was pumped under high vacuum for 15 minutes before palladium (II) chloride (0.054 g, 0.31 mmol), magnesium oxide (0.25 g, 6.1 mmol), lithium chloride (0.13 g, 0.31 mmol), and methanol (30 mL) were added. The mixture was stirred under an atmosphere of carbon mono-oxide until the reaction turned black. The reaction was diluted with DCM (50 mL), filtered through a pad of Celite®, adsorbed onto silica gel, and purified by MPLC. Removal of solvent gave rise to a mixture of 5-bromo-7-chloro-2-benzofuran-1(3H)-one and 7-bromo-5-chloro-2-benzofuran-1(3H)-one. LC/MS: (IE, m/z) (M+1)+=249.0;
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[F:19][C:20]([F:37])([F:36])[O:21][C:22]1[CH:23]=[C:24]([C:28]2[O:32][CH:31]=[N:30][C:29]=2[C:33](O)=[O:34])[CH:25]=[CH:26][CH:27]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:33]([C:29]3[N:30]=[CH:31][O:32][C:28]=3[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:36])([F:19])[F:37])[CH:23]=3)=[O:34])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Reactant: O=C(O)c1ncoc1-c1cccc(OC(F)(F)F)c1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(OC(F)(F)F)c3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: Cl.O.[C:3]([O:9][C:10]1[CH:15]=[C:14]([CH:16]([CH3:18])[CH3:17])[CH:13]=[CH:12][C:11]=1[C:19]1([NH:33][C:34](=[O:39])[CH2:35][CH2:36][CH2:37][CH3:38])[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[N+:29]([O-])=O)[C:20]1=[O:32])(=[O:8])[CH2:4][CH2:5][CH2:6][CH3:7]>C(O)C.[Fe]>[C:3]([O:9][C:10]1[CH:15]=[C:14]([CH:16]([CH3:17])[CH3:18])[CH:13]=[CH:12][C:11]=1[C:19]1([NH:33][C:34](=[O:39])[CH2:35][CH2:36][CH2:37][CH3:38])[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[NH2:29])[C:20]1=[O:32])(=[O:8])[CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)CCCC)C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)CCCC)C(=O)c2cccc(N)c2C1=O
Yield: 57.5 %

Procedure:
Iron powder (0.03 g, 0.6 mmol), conc. HCl (0.05 ml), and water (0.5 ml) were added in that order to a solution of 5-isopropyl-2-(4-nitro-1,3-dioxo-2-pentanamido-2,3-dihydro-1H-inden-2-yl)phenyl pentanoate (43 mg, 0.08 mmol) in ethanol (5 ml). The reaction mixture was heated for 1 hrs under reflux. The reaction mixture was hot filtered off, the filtrate was concentrated in a vacuum and purified by column chromatography (ethylacetate:hexane=1:4 to 1:2) to afford the title compound (22 mg, 55%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7](Cl)=[N:6][S:5][N:4]=1.CS(C)=O.[S:13]([NH2:23])(=[O:22])([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+].Cl>O>[CH3:1][O:2][C:3]1[C:7]([NH:23][S:13]([C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)(=[O:14])=[O:22])=[N:6][S:5][N:4]=1
Reactant: COc1nsnc1Cl
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1nsnc1NS(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.7 %

Procedure:
150.6 g of 3-methoxy-4-chloro-1,2,5-thiadiazole (1 mole) were suspended in 156.26 g of dimethyl sulfoxide (2 mole) and 258.31 g of sulfanilamide (1.5 mole) and 414.63 g of potassium carbonate (3 mole) were then added. The mixture was kept at 70° C. for 48 hours while stirring. 600 ml of water were then added, the mixture was cooled to ambient temperature and adjusted to pH 1.5 with concentrated hydrochloric acid. The precipitated crystallized material was filtered off, washed with water and dried. A yield of 271.1 g of crude 3-methoxy-4-(4'-aminobenzenesulfonamido)-1,2,5-thiadiazole (94.67% of theory), melting point 138°-146° C., was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](C)[CH:10]=1)[C:5]([NH2:7])=[O:6].[F:12]C1C=C(C=C([N+]([O-])=O)C=1)C(O)=O.N>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:12])[CH:10]=1)[C:5]([NH2:7])=[O:6]
Reactant: O=C(O)c1cc(F)cc([N+](=O)[O-])c1
Reactant: Cc1cc(N)cc(C(N)=O)c1
Agent: N
Product: NC(=O)c1cc(N)cc(F)c1

Procedure:
Using a procedure analogous to that described for preparation of 89C, 3-fluoro-5-nitrobenzoic acid was converted to an acid chloride, reacted with aqueous ammonia, and hydrogenated to give 91A. 1H NMR (400 MHz, CD3OD) δ ppm 6.55 (dt, J=10.99, 2.20 Hz, 1H) 6.79 (m, 1H) 6.95 (t, J=1.54 Hz, 1H); LC/MS 155 (M+H).
Reaction SMILES: [CH:1]([C:3]1[C:4](=[O:13])[NH:5][C:6]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=O.[C:14]1([NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20].S(=O)(O)[O-].[Na+]>C(O)C.O>[N:20]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[NH:21][C:1]=1[C:3]1[C:4](=[O:13])[NH:5][C:6]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: Nc1ccccc1N
Reactant: O=Cc1c2cccccc-2[nH]c1=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=c1[nH]c2cccccc-2c1-c1nc2ccccc2[nH]1
Yield: 32.9 %

Procedure:
3-Formyl-1-azaazulen-2-one (0.1 mmol) was dissolved in a mixture of 10 mL ethanol and 5 mL water. o-Phenylenediamine (0.15 mmol) and sodium bisulfite (0.2 mmol) were then added and heat to reflux for 1 day. After working up, the residue was then purified by column chromatography to give 8.6 mg of A1, yield 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH:13]3[CH2:15][CH2:14]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([OH:20])=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:21][C:22]([F:32])([F:31])[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([CH:13]3[CH2:14][CH2:15]3)[C:11](=[O:16])[N:10]([CH2:17][C:18]([NH:27][CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([C:22]([F:21])([F:31])[F:32])[CH:24]=3)=[O:20])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: O=C(O)Cn1nc(-c2cccc(Cl)c2)n(C2CC2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cn1nc(-c2cccc(Cl)c2)n(C2CC2)c1=O)NCc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
30.0 mg (0.102 mmol) of [3-(3-chlorophenyl)-4-cyclopropyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 104A, 19.7 mg (0.112 mmol) of 3-trifluoromethylbenzylamine and 16.6 mg (0.123 mmol) of HOBt are placed in 0.75 ml of dimethylformamide and treated with 25.5 mg (0.133 mmol) of EDC hydrochloride. This is stirred overnight at room temperature and the reaction solution is purified directly by preparative HPLC [Method 9]. 20 mg (43% of theory) of the target compound are thus obtained.
Reaction SMILES: C(O[C:4]([N:6]=[C:7]=[S:8])=[O:5])C.[CH3:9][O:10][C:11]([CH3:23])([CH3:22])[CH2:12][NH:13][C:14]1[N:15]=[CH:16][NH:17][C:18]=1C(N)=O>C(Cl)Cl>[CH3:9][O:10][C:11]([CH3:23])([CH3:22])[CH2:12][N:13]1[C:14]2[N:15]=[CH:16][NH:17][C:18]=2[C:4](=[O:5])[NH:6][C:7]1=[S:8]
Reactant: COC(C)(C)CNc1nc[nH]c1C(N)=O
Reactant: CCOC(=O)N=C=S
Solvent: ClCCl
Product: COC(C)(C)Cn1c(=S)[nH]c(=O)c2[nH]cnc21
Temperature: 50 °C
Yield: 32 %

Procedure:
Ethoxycarbonyl isothiocyanate (0.144 g, 1.1 mmol) was added to a stirred solution of 4-[(2-methoxy-2-methylpropyl)amino]-1H-imidazole-5-carboxamide (0.155 g, 0.73 mmol), which was obtained from Example 3(b), in CH2Cl2 (2.5 mL) at r.t. for 16 h. The solvent was evaporated and the residue was then dissolved in 2% aqueous sodium hydroxide (NaOH) solution (10 mL) and heated at 50° C. for 3 h. The pH was adjusted to neutral with 2 M HCl and the resulted precipitates were collected by filtration followed by prep-HPLC purification. The title compound was obtained as a white solid in 32% yield (60 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[N:13]=[C:12]([OH:14])[CH:11]=[N+:10]2[O-:15])[CH:5]=[CH:6][C:7]=1[CH3:8].[OH-].[K+].S(OC)(O[CH3:22])(=O)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[N:13]=[C:12]([O:14][CH3:22])[CH:11]=[N+:10]2[O-:15])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-n2nc(O)c[n+]2[O-])cc1Cl
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1c[n+]([O-])n(-c2ccc(C)c(Cl)c2)n1
Temperature: 25 °C
Yield: 25 %

Procedure:
113 g of 2-(3-chloro-4-methylphenyl)-4-hydroxy-2H-1,2,3-triazole-1-oxide (m.p. 166°-170° with decomp., prepared in accordance with Synthesis 1974 (March), pp. 189-199) are added at room temperature to a solution of 43 g of 85% potassium hydroxide in 750 ml of water. With efficient stirring, 79 g of dimethyl sulphate and simultaneously 55 ml of 30% potassium hydroxide solution are added to the reaction mixture in the course of 15 minutes while maintaining an internal temperature of 25°-35° C. by cooling. The batch is subsequently heated for 1 hour to 45°-50° C., and cooled to room temperature. The solid is then collected with suction, washed with water and dried. One crystallisation from isopropanol yields 30 g of 2-(3-chloro-4-methylphenyl)-4-methoxy-2H-1,2,3-triazole-1-oxide in the form of colourless crystals. Melting point: 106°-108° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][NH:27]2>C(O)(=O)C>[F:14][C:13]([F:15])([F:16])[C:10]([CH:11]=[N:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[N:26][NH:27]2)([OH:17])[CH2:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[O:20][CH3:21])([CH3:19])[CH3:18]
Reactant: COc1c(Cl)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Nc1cccc2[nH]ncc12
Solvent: CC(=O)O
Product: COc1c(Cl)cccc1C(C)(C)CC(O)(C=Nc1cccc2[nH]ncc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
125 mg (0.385 mmol) of 4-(3-chloro-2-methoxy-phenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)-pentanal is mixed in 0.7 ml of glacial acetic acid with 51.3 mg (0.385 mmol) of 4-aminoindazole, and it is stirred overnight at room temperature. After concentration by evaporation until a dry state is reached, it is chromatographed on a Flashmaster. 11.9 mg (74.1%) of the desired compound is isolated.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.Br[C:12]#N.CC#N>CO.O>[F:8][C:7]1[CH:2]=[CH:3][C:4]2[N:10]=[CH:12][NH:9][C:5]=2[CH:6]=1
Reactant: N#CBr
Reactant: Nc1cc(F)c(Cl)cc1N
Solvent: CC#N
Solvent: CO
Solvent: O
Product: Fc1ccc2nc[nH]c2c1
Reaction time: 3 h

Procedure:
4-Chloro-5-fluoro-1,2-phenylenediamine (12a, 3.212 g, 20 mmol) was dissolved in 40 mL of MeOH and then added dropwise to a stirred solution of 4.4 mL of 5M BrCN/MeCN in 40 mL of H2O over 30 min. After the addition, stirring was continued at room temperature for 3 hr. The reaction mixture was concentrated to ~40 mL and then was washed with EtOAc (100 mL). The EtOAc phase was extracted with H2O (60 mL). The combined H2O phase was neutralized with sat. NaHCO3 solution to ~pH 8 and the resulting suspension was extracted with EtOAc (200 mL). The EtOAc phase was washed with a mixture of sat. NaHCO3 /sat. NaCl solution (20 mL/180 mL), dried (Na2SO4), and evaporated. The residue was coevaporated with CHCl3 (20 mL×2) and then was suspended in 50 mL of CHCl3. The suspension was filtered to give 3.340 g of 12b as a grey solid. The filtrate was evaporated and coevaporated with CHCl3. The resulting solid was again suspended in a small amount of CHCl3 and the suspension was filtered to give an additional 0.235 g of 12b. The total yield of 12b was 3.575 g (96%). This product showed a single spot on TLC. MP: 194°-196° C. MS: (El) m/e 185.0156 (100%, M+ =185.0156). 1H NMR (DMSO-d6): d 10.85, (br s, 1, 1-NH), 7.16 (d, 1, 4-H, 4JF-H =7.0 Hz), 7.06 (d, 1, 7-H, 3JF-H =10.0 Hz), 6.43 (br s, 2, 2-NH2). Anal. Calcd. for C7H5ClFN3 ; C, 45.30; H, 2.72; N, 22.64. Found: C, 45.14; H, 2.67; N, 22.44.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21]([OH:23])=O)=[CH:4][C:5]([NH:8][C:9]2[N:13]([CH:14]([CH3:16])[CH3:15])[N:12]=[C:11]([CH3:17])[CH:10]=2)=[N:6][CH:7]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.[CH3:50][O:51][NH2:52].C(N(C(C)C)CC)(C)C>CN(C)C=O.C(O)(=O)C.O>[Cl:1][C:2]1[C:3]([NH:18][C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21]([NH:52][O:51][CH3:50])=[O:23])=[CH:4][C:5]([NH:8][C:9]2[N:13]([CH:14]([CH3:15])[CH3:16])[N:12]=[C:11]([CH3:17])[CH:10]=2)=[N:6][CH:7]=1
Reactant: CON
Reactant: Cc1cc(Nc2cc(Nc3ccccc3C(=O)O)c(Cl)cn2)n(C(C)C)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CONC(=O)c1ccccc1Nc1cc(Nc2cc(C)nn2C(C)C)ncc1Cl
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a solution of 2-[(5-chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzoic acid (67 g, 174 mmol) and 1-hydroxybenzotriazole (29.3 g, 191 mmol) in N,N-dimethylformamide (700 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (36.6 g, 191 mmol) and the solution was stirred for 30 minutes. O-Methylhydroxylamine hydrochloride (15.95 g, 191 mmol) was added and the solution stirred for additional 15 minutes, the cooled down to the 0° C. and diisopropylethlyamine (91 mL, 521 mmol) was added dropwise. The reaction mixture was stirred overnight tat the room temperature. Water (4000 mL) was added and the solution was acidified with acetic acid (20 mL). The solution was extracted 2×2 L of ethyl acetate. The organic was washed with water (1 L), brine, and dried over MgSO4, filtered and evaporated. 2-[(5-Chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]-N-(methyloxy)benzamide (74 g, 164 mmol, 94% yield, 92% pure) was isolated as a yellow foam. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (d, J=6.57 Hz, 6H) 2.10 (s, 3H) 3.71 (s, 3H) 4.39 (quin, J=6.51 Hz, 1H) 5.93 (s, 1H) 6.66 (s, 1H) 7.08-7.19 (m, 1H) 7.49-7.64 (m, 3H) 7.98 (s, 1H) 8.50 (s, 1H) 9.50 (s, 1H) 11.93 (s, 1H).; HPLC Rt=2.13 min, MS (ESI): [M+H]+=415.1.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[O:21][CH3:22].[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=[O:28].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Br:13][C:14]1[C:15]([O:21][CH3:22])=[C:16]([CH:27]([C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([F:23])[CH:25]=2)[OH:28])[C:17]([F:20])=[CH:18][CH:19]=1
Reactant: COc1cc(F)ccc1Br
Reactant: O=Cc1cccc(F)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: COc1c(Br)ccc(F)c1C(O)c1cccc(F)c1
Temperature: -60 °C

Procedure:
A total of 1.64 ml of diisopropylamine was dissolved in 27 ml of tetrahydrofuran, 6.8 ml of a 1.57 M solution of n-butyllithium in hexane was added at −50° C. under stirring, and the mixture was stirred at −30° C. for 30 minutes. After cooling to −60° C., 2 g of 1-bromo-4-fluoro-2-methoxy-benzene obtained in Production Example II-1-a was added and the mixture was stirred at −60° C. for 1 hour. Then, 1.55 ml of 3-fluoro-benzaldehyde was added, followed by stirring for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The resulting organic layer was washed with brine, dried over magnesium sulfate and the solvent was evaporated, to give 2.4 g of the title compound as a yellow-brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11]C)=[O:10])=[C:4]([F:15])[CH:3]=1.[OH-].[K+]>CCO.C(OCC)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:14])[C:9]([OH:11])=[O:10])=[C:4]([F:15])[CH:3]=1
Reactant: COC(=O)C(C)(C)c1ccc(Cl)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: CC(C)(C(=O)O)c1ccc(Cl)cc1F
Temperature: 120 °C
Yield: 84.7 %

Procedure:
Methyl 2-(4-chloro-2-fluorophenyl)-2-methylpropanoate (8.11 g, 35.2 mmol) was dissolved in EtOH (70.3 mL) in a vial. KOH (3.95 g, 70.3 mmol) was added, and the sealed vial was heated at 120° C. for 2 hours. The reaction mixture was then diluted with 75 mL of diethyl ether, added to a separatory funnel, partitioned with water, washed with 75 mL of water, and separated. The aqueous layer was acidified to pH=3 with 3N HCl and extracted 2 times with 100 mL of diethyl ether. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (6.46 g) as a light yellow solid. MS (m/z)=217 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]1=2.[Cl:22][S:23](O)(=[O:25])=[O:24]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:23]([Cl:22])(=[O:25])=[O:24])[CH:20]=[CH:21][C:13]1=2
Reactant: O=S(=O)(O)Cl
Reactant: FC(F)(F)c1ccc(N2CCOc3ccccc32)c(Br)c1
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br

Procedure:
A solution of INTERMEDIATE B (1.325 g, 3.70 mmol) in DCM (7.40 mL) was cooled to 0° C. in an ice-water bath, and chlorosulfonic acid (1.230 mL, 18.50 mmol) was added dropwise. The resulting solution was stirred at RT for 4 hours until complete conversion to the desired product occurred. The reaction mixture was then slowly added dropwise to well-stirred ice water and subsequently neutralized to a pH of about 7 with saturated aqueous sodium bicarbonate solution. After extraction with EtOAc (×3), the combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated to provide INTERMEDIATE C. The material was taken forward without further purification. m/z (ESI) 477.8 (M+Na)+.