Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([OH:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[CH:12]([N:14]1C(=O)C2C(=CC=CC=2)C1=O)[CH3:13].O.NN>CO>[NH2:14][CH:12]([C:3]1[CH:4]=[CH:5][C:6]([C:8]([OH:11])([CH3:9])[CH3:10])=[CH:7][C:2]=1[F:1])[CH3:13]
Reactant: CC(c1ccc(C(C)(C)O)cc1F)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: CC(N)c1ccc(C(C)(C)O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.2 %

Procedure:
A mixture of 158 mg (0.48 mmol) (±)-2-[1-[2-fluoro-4-[1-hydroxy-1-methyl-ethyl]-phenyl]-ethyl]-isoindole-1,3-dione and 0.08 ml (2.4 mmol) hydrazine hydrate in 10 ml methanol was stirred at room temperature overnight. The resulting precipitate was filtered and the filtrate concentrated to give a solid. The solid was triturated with chloroform, filtered and the filtrate was then concentrated to give 110 mg (100%) oil.
Reaction SMILES: [CH3:1][C:2]([CH3:58])([CH3:57])[C@H:3]([N:43]1[CH2:47][CH2:46][N:45]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[N:50]=2)[C:44]1=[O:56])[C:4]([NH:6][C@@H:7]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:8][C@H:9]([OH:35])[C@@H:10]([NH:24]C(=O)OCC1C=CC=CC=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)=[O:5].Cl>CO.[OH-].[OH-].[Pd+2]>[NH2:24][C@@H:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[C@@H:9]([OH:35])[CH2:8][C@@H:7]([NH:6][C:4](=[O:5])[C@@H:3]([N:43]1[CH2:47][CH2:46][N:45]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([CH3:55])[N:50]=2)[C:44]1=[O:56])[C:2]([CH3:57])([CH3:1])[CH3:58])[CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: Cc1cccc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccccc3)C[C@H](O)[C@H](Cc3ccc(-c4ccncc4)cc3)NC(=O)OCc3ccccc3)C(C)(C)C)C2=O)n1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(CN2CCN([C@H](C(=O)N[C@@H](Cc3ccccc3)C[C@H](O)[C@@H](N)Cc3ccc(-c4ccncc4)cc3)C(C)(C)C)C2=O)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 73C (0.095 g, 0.121 mmol) in methanol (1.5 mL) was treated with Pd(OH)2 on carbon (0.075 g, 20% Pd by wt.) and HCl solution (0.090 mL, 4N in dioxane), stirred under a hydrogen atmosphere (balloon pressure) at 25° C. for 16 hours, filtered through a bed of celite® and rinsed with methanol. The solvent was concentrated to give the title compound as the hydrochloride salt, which was used without further purification.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[NH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].C1(C)C=CC=CC=1.P(Cl)(Cl)(Cl)=O>O.CN(C=O)C>[C:1]([CH2:3][C:4]([NH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: CCOC(N)=O
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)NC(=O)CC#N
Reaction time: 2 h
Yield: 66.6 %

Procedure:
2-cyanoacetic acid (85 g, 1 mol) and ethyl aminoformate (89 g, 1 mol) were added to toluene (500 mL). To the mixture was slowly added phosphorus oxychloride (45 mL, 0.5 mol), and then added DMF (5 mL). The reaction was conducted at 70° C. for 2 h. After cooling, water (500 mL) was added to the reaction solution to quench phosphorus oxychloride. The reaction is filtered by suction. The filtered cake was washed with ethyl ether and dried to produce a white solid (104 g) in a yield of 67%.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([O:7][C:8](=[O:12])[C:9]([CH3:11])=[CH2:10])[C:4]([OH:6])=[O:5].C1CCC(N=C=NC2CCCCC2)CC1.[F:30][C:31]([F:35])([F:34])[CH2:32]O.Cl>CN(C1C=CN=CC=1)C.ClCCl.C(OCC)(=O)C>[C:8]([O:7][CH:3]([C:4](=[O:6])[O:5][CH2:32][C:31]([F:35])([F:34])[F:30])[C:2]([F:13])([F:14])[F:1])(=[O:12])[C:9]([CH3:11])=[CH2:10]
Reactant: OCC(F)(F)F
Reactant: C=C(C)C(=O)OC(C(=O)O)C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=C(C)C(=O)OC(C(=O)OCC(F)(F)F)C(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 60.1 %

Procedure:
Under a nitrogen atmosphere, 3.18 g (15 mmol) of 3,3,3-trifluoro-2-(methacryloyloxy)propionic acid was added to 60 mL of a solution of 6.8 g (16.5 mmol) of DCC and 0.37 g (0.003 mol) of DMAP in dichloromethane, and 1.78 g (18 mmol) of 2,2,2-trifluoroethanol was added thereto at 0° C. The temperature of the mixture was equilibrated to the room temperature, and the mixture was stirred for 3 hrs. After disappearance of the raw material was confirmed by TLC, the reaction liquid was cooled to 0° C., and the reaction was stopped by adding 1 N hydrochloric acid. Thereafter, ethyl acetate was added to the reaction liquid and extraction was carried out three times, and the organic layer thus obtained was washed with water twice. Thereafter, purification by column chromatography gave 2.65 g of intended 1,1,1-trifluoro-3-oxo-3-(2,2,2-trifluoroethoxy)propan-2-yl methacrylate (M-6) (yield: 60%).
Reaction SMILES: [O:1]=[C:2]([C:6]1[C:7]([CH3:13])=[N:8][N:9]([CH3:12])[C:10]=1[CH3:11])[C:3]([OH:5])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[CH:41]1([CH2:44][N:45]2[C:53]3[N:52]=[C:51]([CH2:54][C:55]4[CH:60]=[CH:59][C:58]([NH:61][CH3:62])=[CH:57][CH:56]=4)[NH:50][C:49]=3[C:48](=[O:63])[N:47]([CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=3[F:71])[C:46]2=[O:72])[CH2:43][CH2:42]1.C(N(CC)CC)C>ClCCl>[CH:41]1([CH2:44][N:45]2[C:53]3[N:52]=[C:51]([CH2:54][C:55]4[CH:56]=[CH:57][C:58]([N:61]([CH3:62])[C:3](=[O:5])[C:2](=[O:1])[C:6]5[C:7]([CH3:13])=[N:8][N:9]([CH3:12])[C:10]=5[CH3:11])=[CH:59][CH:60]=4)[NH:50][C:49]=3[C:48](=[O:63])[N:47]([CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][C:66]=3[F:71])[C:46]2=[O:72])[CH2:43][CH2:42]1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: Cc1nn(C)c(C)c1C(=O)C(=O)O
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nn(C)c(C)c1C(=O)C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
A mixture of oxo-(1,3,5-trimethyl-1H-pyrazol-4-yl)-acetic acid (134 mg, 0.87 mmol) in dichloromethane (4.0 mL) at 25° C. was treated with triphenylphosphine (145 mg, 0.55 mmol). The reaction was cooled to 0° C. and was treated with N-chlorosuccinimide (74 mg, 0.55 mmol). This mixture was stirred at 0° C. for 30 min and then was warmed to 25° C. for 20 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione (290 mg, 0.69 mmol) and triethylamine (0.23 mL, 1.67 mmol). The reaction was stirred at 25° C. for 24 h. At this time, the reaction was diluted with dichloromethane and then was washed with a 1N aqueous hydrochloric acid solution (2×50 mL) followed by a saturated aqueous sodium bicarbonate solution (2×50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 2:98 methanol/dichloromethane) afforded impure product. The resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (50 mL) and was washed with a saturated aqueous sodium bicarbonate solution (50 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dried in vacuo for 24 h to afford N-{4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-N-methyl-2-oxo-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)-acetamide (183 mg, 45.8%) as a white solid: (ES)+-HRMS m/e calcd for C32H32N7O4F (M+H)+ 598.2573, found 598.2578.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.Cl[C:11]1[N:16]=[C:15]([Cl:17])[N:14]=[C:13]2[N:18]([CH3:21])[N:19]=[CH:20][C:12]=12.C(N(CC)CC)C.CCOCC>C(O)C>[Cl:17][C:15]1[N:14]=[C:13]2[N:18]([CH3:21])[N:19]=[CH:20][C:12]2=[C:11]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:16]=1
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Reactant: COc1cccc(N)c1
Solvent: CCO
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1cccc(Nc2nc(Cl)nc3c2cnn3C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
m-Anisidine (1.1 eq) was added to a solution of 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 5 (1 eq.) and triethylamine (NEt3, 1.5 eq) in ethanol. The mixture was stirred at room temperature for 2 hr and then ether was added. The solid was filtered off and the filtrate concentrated in vacuo to give 6-chloro-N-(3-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 6.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([CH:12]1[CH2:17][CH2:16][C:15]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=2[F:33])([C:18]2(C=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH2:10][CH3:11].[C:34](OCC)(=[O:36])C.N>C1COCC1>[OH:36][CH2:34][CH:21]1[CH2:22][CH2:23][CH:18]([C:15]2([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=3[F:33])[CH2:16][CH2:17][CH:12]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:13][CH2:14]2)[CH2:19][CH2:20]1
Reactant: CCOC(C)=O
Reactant: CCCCCC1CCC(c2cccc(F)c2F)(C2(C=O)CCCCC2)CC1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCCC1CCC(c2cccc(F)c2F)(C2CCC(CO)CC2)CC1
Reaction time: 2 h

Procedure:
Lithium aluminum hydride (0.45 g) was suspended in THF (100 ml). The compound (40) (7.5 g) dissolved in THF (100 ml) was added dropwise to this suspension in the temperature range of −20° C. to −10° C., and the mixture was stirred in this temperature range for another 2 hours. After the termination of the reaction had been confirmed by GC analysis, ethyl acetate and a saturated aqueous solution of ammonia were sequentially added to the reaction mixture under ice-cooling, and deposits were removed by filtration through Celite. The filtrate was extracted in ethyl acetate. The organic phase obtained was washed sequentially with water and saturated brine, and then dried over anhydrous magnesium sulfate. Then, the product was purified by means of recrystallization from heptane, dried and concentrated under reduced pressure, giving 7.4 g of 4-hydroxymethyl-[4-pentyl-(2,3-difluorophenyl)cyclohexyl]-cyclohexane (41). The yield based on the compound (40) was 98.1%.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH2:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>C(Cl)Cl.N1C=CC=CC=1.C(OCC)(=O)C>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)Cl
Reactant: NCCc1ccc(Oc2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)NCCc1ccc(Oc2ccccc2)cc1
Reaction time: 6 h

Procedure:
To the solution of crude amine resulting from Example 67E in methylene chloride (20 mL) and pyridine (5 mL) was added propionyl chloride (3.0 mL, 34 mmol). After 6 hours, the reaction was diluted with ethyl acetate (80 mL), washed with water (20 mL), 10% aqueous hydrochloric acid (20 mL), water (20 mL), saturated copper sulfate (20 mL) and brine (20 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography eluting with 50% ethyl acetate in hexane to give the desired product (1.23 g, 27% for the last 4 steps). 1H NMR (300 MHz, CDCl3) δ 7.36-6.95 (m, 9 H), 5.46 (bs, 1 H), 3.51 (q, 2 H), 2.80 (t, 2 H), 2.19 (q, 2 H), 1.15 (t, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[C:8](=[O:15])[N:7]([C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[CH3:22])[CH2:6][CH2:5]2.C(O)(=O)C>C1COCC1.[Fe]>[NH2:12][C:11]1[CH:10]=[C:9]2[C:4]([CH2:5][CH2:6][N:7]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[CH3:22])[C:8]2=[O:15])=[CH:3][C:2]=1[F:1]
Reactant: Cc1ccncc1N1CCc2cc(F)c([N+](=O)[O-])cc2C1=O
Agent: [Fe]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1ccncc1N1CCc2cc(F)c(N)cc2C1=O
Yield: 96.2 %

Procedure:
6-Fluoro-7-nitro-2-(4-methyl-pyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-84a: 150 mg, 0.498 mmol) was reduced with iron powder (139 mg, 2.4 mmol) and acetic acid (5 mL) in THF (5 mL) at 70° C. for 4 hours to afford 130 mg of the product (96.2% yield).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([S:7]([N:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[CH3:11])(=[O:9])=[O:8])[N:3]=1.[CH3:20][N:21]=[C:22]=[O:23].C(N(CC)CC)C>O1CCCC1>[NH2:1][C:2]1[N:6]([C:22](=[O:23])[NH:21][CH3:20])[N:5]=[C:4]([S:7]([N:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])[CH3:11])(=[O:9])=[O:8])[N:3]=1
Reactant: CN(c1c(Cl)cccc1Cl)S(=O)(=O)c1n[nH]c(N)n1
Reactant: CN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)n1nc(S(=O)(=O)N(C)c2c(Cl)cccc2Cl)nc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.0 g (6.2 mmol) 5-Amino-N-(2,6-dichlorophenyl)-N-methyl-1,2,4-triazole-3-sulphonamide was suspended in 30 ml tetrahydrofuran and treated with 0.5 ml (8.5 mmol) methyl isocyanate and 0.9 ml (6.5 mmol) triethylamine. The mixture was stirred for 3 hours at room temperature and allowed to stand overnight. The solution was concentrated and the residue chromatographed on silica gel using a mixture of hexane and ethyl acetate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C@@H:5]1[CH2:9][S:8][C:7]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[N+:20]([O-])=O)=[N:6]1.[C:24]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C@@H:5]1[CH2:9][S:8][C:7]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([Cl:19])=[CH:14][C:13]=3[NH:20][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:6]1
Reactant: COC(=O)C[C@@H]1CSC(c2cc3cc(Cl)cc([N+](=O)[O-])c3[nH]2)=N1
Reactant: O=C1CCCC1
Product: COC(=O)C[C@@H]1CSC(c2cc3cc(Cl)cc(NC4CCCC4)c3[nH]2)=N1

Procedure:
[(R)-2-(5-chloro-7-nitro-1H-indol-2-yl)-4,5-dihydro-thiazol-4-yl]-acetic acid methyl ester prepared in Preparation 67 and cyclopentanone were reacted according to the same procedures as Steps A and B of Example 1 to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.Cl.[CH3:14][OH:15]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:5][CH:14]([OH:15])[CH2:7][CH2:8]1
Reactant: O=c1ccc2ccc(Br)cc2[nH]1
Reactant: CO
Agent: Cl
Product: O=C1CCc2cc(N3CCC(O)CC3)c(Br)cc2N1

Procedure:
This 7-bromocarbostyril was dissolved in 2.5 ml of hydrogen chloride-methanol solution, and mixture was refluxed for 1 hr. The reaction mixture was concentrated and purified by a silica gel column chromatography to give 56 mg of 7-bromo-6-(4-hydroxypiperidino)-3,4-dihydrocarbostyril.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=2)[C:10]=1[CH3:26])=O)(C)(C)C>CCOC(C)=O.Cl>[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=2)[C:10]=1[CH3:26]
Reactant: Cc1c(NC(=O)OC(C)(C)C)cccc1OCCc1ccc(C#N)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(N)cccc1OCCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.8 %

Procedure:
t-Butoxycarbonylamino-3-[2-(4-cyanophenyl)ethoxy]-2-methylbenzene (2.69 g, 7.64 mmol; from step (ii) above) were dissolved in EtOAc, pre-saturated with HCl(g), (150 mL) under nitrogen and stirred at room temperature overnight. After evaporation of the solvent the residue was partitioned between 10% aqueous HCl and EtOAc. The aqueous phase was washed with EtOAc, basified with NaOH (2M, aq.) and extracted with EtOAc. The combined organic phases were washed with brine, dried (MgSO4) and the solvent evaporated to afford 0.42 g (19%) of the sub-title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:11]=[C:10]([C:18]2[CH:22]=[C:21]([CH:23]3[CH2:25][CH2:24]3)[NH:20][N:19]=2)[CH:9]=1)(C)(C)C>Cl.O1CCOCC1>[CH:23]1([C:21]2[NH:20][N:19]=[C:18]([C:10]3[CH:9]=[C:8]([CH:13]=[C:12]([S:14]([CH3:17])(=[O:15])=[O:16])[CH:11]=3)[NH2:7])[CH:22]=2)[CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2cc(C3CC3)[nH]n2)cc(S(C)(=O)=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cc(N)cc(-c2cc(C3CC3)[nH]n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
[3-(5-Cyclopropyl-1H-pyrazol-3-yl)-5-(methylsulfonyl)-phenyl]-carbamic acid tert butyl ester (250 mg; 0.662 mmol) was suspended in 0.5 ml of 4 M HCl solution in 1,4-dioxane. The reaction mixture was stirred at room temperature for 1 h then it was concentrated in vacuo. 200 mg (0.638 mmol; 96% yield) of the desired aniline were obtained as hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([N:22]4[CH2:25][CH:24]([N:26]([CH3:28])[CH3:27])[CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[F:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]([N:41]=[C:42]=[O:43])=[O:40])=[CH:34][CH:33]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)C.CCCCCC>[F:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:38][C:39]([NH:41][C:42](=[O:43])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]4[CH2:17][CH2:18][CH:19]([N:22]5[CH2:23][CH:24]([N:26]([CH3:28])[CH3:27])[CH2:25]5)[CH2:20][CH2:21]4)=[O:15])[CH:8]=3)=[CH:29][CH:30]=2)=[O:40])=[CH:36][CH:37]=1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4)ccn3)CC2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: CN(C)C1CN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)Cc5ccc(F)cc5)cc4)ccn3)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a solution of 4-(3-dimethylaminoazetidin-1-yl)piperidine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (60 mg) in tetrahydrofuran (5.0 ml) was added a solution of 2-(4-fluorophenyl)acetyl isocyanate in tetrahydrofuran (0.25 M, 1.75 ml) at room temperature, followed by stirring at room temperature for 0.5 hr. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, followed by stirring at room temperature for 0.5 hr. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=10:1). Fractions containing a target compound were concentrated to give a solid, which was suspended in diethyl ether (1 ml) and hexane (2 ml). The solid was filtered off, washed with diethyl ether:hexane=1:2, and dried under aeration to provide the titled compound (23.2 mg, 27%) as white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[C:9]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[F:24][C:21]([F:22])([F:23])[C:18]1[CH:19]=[CH:20][C:15]([O:14][C:9]2[C:10]3[CH:11]=[CH:12][CH:13]=[C:4]([NH2:1])[C:5]=3[CH:6]=[CH:7][N:8]=2)=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1cccc2c(Oc3ccc(C(F)(F)F)cc3)nccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cccc2c(Oc3ccc(C(F)(F)F)cc3)nccc12
Yield: 19.3 %

Procedure:
The title compound was prepared following the procedure described in Step 3 of Intermediate-1 using 5-nitro-1-(4-(trifluoromethyl)phenoxy)isoquinoline (800 mg, 2.39 mmol), iron powder (1.34 g, 23.9 mmol), and NH4Cl (1.02 g, 19.1 mmol) in EtOH (5 mL) and water (1 mL) to afford 140 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 7.81 (m, 3H), 7.72 (d, 1H), 7.46-7.40 (m, 4H), 6.94 (d, J=6.9 Hz, 1H), 6.03 (s, 2H); MS (m/z): 305.17 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([CH:12]=[O:13])[CH:5]=[C:6]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:7]=1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24]>ClCCl>[C:23]([NH:11][S:8]([C:6]1[CH:7]=[C:2]([Br:1])[C:3]([O:14][CH3:15])=[C:4]([CH:12]=[O:13])[CH:5]=1)(=[O:10])=[O:9])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(Br)cc(S(N)(=O)=O)cc1C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(Br)cc(S(=O)(=O)NC(C)=O)cc1C=O
Reaction time: 1 h
Yield: 91.6 %

Procedure:
A 100 mL round-bottom flask was charged with 5-bromo-3-formyl-4-methoxy-benzenesulfonamide (586 mg, 2.0 mmol) dissolved in dichloromethane (40 mL) and the solution was stirred vigorously while triethylamine (252 mg, 2.50 mmol) was added, followed by acetic anhydride (224 mg, 2.2 mmol) and a catalytic amount of N,N-dimethylaminopyridine. The mixture was stirred for 1 hour and then concentrated by evaporation. The residue was partitioned between 5% citric acid and ethyl acetate. The organic layer was separated, washed with water and brine and dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give N-acetyl-5-bromo-3-formyl-4-methoxybenzenesulfonamide (616 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[CH:17]=[C:9]2[N:10]=[C:11]([O:15][CH3:16])[C:12]([Br:14])=[CH:13][C:8]2=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[Br:14][C:12]1[C:11]([O:15][CH3:16])=[N:10][C:9]2=[CH:17][N:6]([CH2:5][C:2]([NH:1][C:25](=[S:26])[C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=3)([C:3]#[N:4])[CH3:18])[N:7]=[C:8]2[CH:13]=1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: COc1nc2cn(CC(C)(N)C#N)nc2cc1Br
Product: COc1nc2cn(CC(C)(C#N)NC(=S)c3ccc(C(F)(F)F)cc3)nc2cc1Br

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(6-bromo-5-methoxy-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (100 mg described in Example 193) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (67.5 mg, 41%). MS (ES): M/Z [M+H]=514. 1H NMR: (400 MHz, CHLOROFORM-d): 1.93 (s, 3H), 4.05 (s, 3H), 4.76 (d, J=14.4 Hz, 1H), 4.90 (d, J=14.4 Hz, 1H), 7.78 (d, J=8.6 Hz, 2H), 7.87 (d, J=8.6 Hz, 2H), 8.12 (s, 1H) and 8.20 (s, 2H). 19F NMR (376 MHz, CHLOROFORM-d): −42.2 (s, 3F).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[O:21]([C:28]([NH:30][C:31]1[CH:32]=[C:33]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[O:34][CH2:35][CH:36]1[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]1)=O)C1C=CC=CC=1.CCN(C(C)C)C(C)C>C1COCC1>[CH:16]1([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:19]=[CH:20][C:2]([NH:1][C:28]([NH:30][C:31]4[CH:32]=[C:33]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=4)[O:34][CH2:35][CH:36]4[CH2:37][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39]4)=[O:21])=[CH:3][CH:4]=3)[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:17][CH2:18]1
Reactant: Nc1ccc(Oc2ccnc(NC(=O)C3CC3)c2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(COc2cc(NC(=O)Oc3ccccc3)cc(C(F)(F)F)c2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(COc2cc(NC(=O)Nc3ccc(Oc4ccnc(NC(=O)C5CC5)c4)cc3)cc(C(F)(F)F)c2)C1
Temperature: 70 °C
Reaction time: 12 h
Yield: 52.7 %

Procedure:
Dissolve N-[4-(4-aminophenoxy)-2-pyridyl]cyclopropanecarboxamide (200 mg, 0.74 mmol) and tert-butyl 3-[[3-(phenoxycarbonylamino)-5-(trifluoromethyl)phenoxy]methyl]-azetidine-1-carboxylate (415 mg, 0.89 mmol) in THF (10 mL), add DIEA (200 mg, 1.48 mmol), stir under N2 at 70° C. for 12 hrs. Concentrate under reduced pressure to give the crude product. Purification by chromatography (silica gel, EtOAc:PE=2:1) affords the title compound (250 mg, 52.4%). MS: (M+1): 642.3.