Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3](I)=[CH:4][C:5]([CH3:15])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)[CH:7]=1.[Cl-].[C:18]([O:22][C:23](=[O:26])[CH2:24][Zn+])([CH3:21])([CH3:20])[CH3:19]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2].C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)[C:5]([CH3:15])=[CH:4][C:3]=1[CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:26]
Reactant: Cc1cc(-c2cc(F)c(I)cc2C)ccn1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Product: Cc1cc(-c2cc(F)c(CC(=O)OC(C)(C)C)cc2C)ccn1
Temperature: 70 °C

Procedure:
To a seal tube charged with 4-(5-fluoro-4-iodo-2-methylphenyl)-2-methylpyridine 191-4 (200 mg, 0.6 mmol), Pd2(dba)3 (28 mg, 0.03 mmol), and Q-Phos (21 mg, 0.03 mmol) was added anhydrous THF (2.5 mL). The reaction vessel was flushed with nitrogen and (2-tert-butoxy-2-oxoethyl)zinc(II) chloride (0.5 M in ether, 1.34 mL, 0.67 mmol) was added subsequently. The reaction was heated to 70° C. for 12 hours. The solvent was removed by rotary evaporation and the residue was purified by silica gel flash chromatography, eluted with 50% ethyl acetate in hexane to give tert-butyl 2-(2-fluoro-5-methyl-4-(2-methylpyridin-4-yl)phenyl)acetate 191-5. MS m/z 316.10 (M+1).
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13][CH3:14])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:2][C:3]#[N:4])=[C:8]([CH2:13][CH3:14])[CH:7]=1
Reactant: CCc1cc(Br)ccc1O
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cc(Br)ccc1OCC#N
Reaction time: 12 h
Yield: 83.8 %

Procedure:
Bromoacetonitrile (1.19 ml, 9.94 mmol) was added to a solution of 4-bromo-2-ethylphenol (2.0 g, 9.94 mmol) and potassium carbonate (1.35 g, 9.94 mmol) in DMF (50 ml). The reaction was stirred for 12 hours and then partitioned between diethyl ether (200 ml) and water (200 ml). The organics were separated, dried over magnesium sulfate, filtered and concentrated in vacuuo to afford the title compound as a yellow oil (2.0 g). 1H NMR (CDCl3): δ 1.13 (t, J=12.07 Hz, 3H), 2.45 (m, 2H), 4.84 (s, 2H), 7.03-7.10 (m, 2H), 7.21 (m, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:47][C:48]([F:78])([F:77])[C:49]1[CH:50]=[C:51]([C:59]([CH3:76])([CH3:75])[C:60]([N:62]([CH3:74])[C@H:63]2[C@H:67]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[CH2:66][NH:65][CH2:64]2)=[O:61])[CH:52]=[C:53]([C:55]([F:58])([F:57])[F:56])[CH:54]=1>C1COCC1>[F:77][C:48]([F:47])([F:78])[C:49]1[CH:50]=[C:51]([C:59]([CH3:75])([CH3:76])[C:60]([N:62]([C@H:63]2[C@H:67]([C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)[CH2:66][N:65]([C:10]([CH:7]3[CH2:6][CH2:5][CH:4]([CH2:3][O:2][CH3:1])[CH2:9][CH2:8]3)=[O:12])[CH2:64]2)[CH3:74])=[O:61])[CH:52]=[C:53]([C:55]([F:56])([F:57])[F:58])[CH:54]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CNC[C@H]1c1ccccc1
Reactant: COCC1CCC(C(=O)O)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC1CCC(C(=O)N2C[C@@H](N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](c3ccccc3)C2)CC1
Reaction time: 48 h
Yield: 48.2 %

Procedure:
To a stirred solution of 4-methoxymethyl-cyclohexanecarboxylic acid (described in JP60258141) (7.4 mg, 0.043 mmol) in THF (2 ml) at RT were added Et3N (12 μl, 0.086 mmol), BOP (25 mg, 0.057 mmol) and rac-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-((3S,4R)-4-phenyl-pyrrolidin-3-yl)-isobutyramide (Intermediate VII-1) (20 mg, 0.043 mmol). Stirring was continued at 40° C. for 48 hours. Concentration and purification by preparative HPLC afforded 12.7 mg (48%) of the title compound.
Reaction SMILES: C12BC(CCC1)CCC2.[CH3:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=[CH2:27])[C:21]1=[O:28].[OH-].[Na+].OO.S(OS([O-])=O)([O-])=[O:34].[Na+].[Na+]>O1CCCC1.O>[OH:34][CH2:27][CH2:26][C:22]1[C:21](=[O:28])[N:20]([C:12]2[CH:13]=[CH:14][C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:11]=2[CH3:10])[CH:25]=[CH:24][CH:23]=1
Reactant: O=S([O-])OS(=O)[O-]
Reactant: C=Cc1cccn(-c2ccc([N+](=O)[O-])cc2C)c1=O
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])ccc1-n1cccc(CCO)c1=O
Reaction time: 0.5 h

Procedure:
With ice-cooling, a solution of 40 g (326 mmol) of 9-borabicyclo[3.3.1]nonane in 650 ml of tetrahydrofuran is added over a period of 45 min to 38 g (148 mmol) of the compound from Example 13A. The mixture is stirred at this temperature for another hour, and a solution of 30 g (747 mmol) of sodium hydroxide in 740 ml of water is then added over a period of 15 min. 151 ml of a 30% strength hydrogen peroxide solution are added such that the temperature does not exceed 30° C. After the addition has ended, the cooling is removed and stirring is continued for a further 30 min. The mixture is repeatedly extracted with ethyl acetate, the combined organic phases are washed with a solution of 780 g (1.63 mol) of sodium disulphite, the organic phase is separated off and the aqueous phase is again extracted with ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated to dryness under reduced pressure. The residue is applied to silica gel and chromatographed using a gradient of cyclohexane and ethyl acetate. The product-containing fractions are combined and concentrated to dryness under reduced pressure. This gives 38 mg (93% of theory) of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][CH2:14][CH:15]=O)=[CH:11][C:10]([CH2:17][CH2:18][CH2:19][CH3:20])=[N:9]2)=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:15][CH2:14][CH2:13][C:12]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[C:10]([CH2:17][CH2:18][CH2:19][CH3:20])[CH:11]=2)[CH2:30][CH2:29]1
Reactant: CCCCc1cc(CCC=O)n(-c2ccc(F)cc2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCCCc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccc(F)cc2)n1

Procedure:
218 mg (87.5%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-(4-fluorophenyl)-3-butyl-1H-pyrazol-5-yl)propanal (155.9 mg, 0.568 mmol), 1-(2-fluorophenyl)piperazine (106 mL, 0.852 mmol), and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]([CH3:13])([CH3:12])[C:10]2[CH:9]=[C:8]([C:14]([NH2:16])=[O:15])[CH:7]=[CH:6][C:5]=2[CH2:4][C@H:3]1[O:17][CH3:18].[CH3:19][C:20]([CH3:30])([CH3:29])[CH2:21][C:22]([NH:24][CH2:25][CH2:26][CH:27]=O)=[O:23].C(O)(C(F)(F)F)=O>>[CH3:19][C:20]([CH3:29])([CH3:30])[CH2:21][C:22]([NH:24][CH2:25][CH2:26][CH2:27][NH:1][C@@H:2]1[C:11]([CH3:13])([CH3:12])[C:10]2[CH:9]=[C:8]([C:14]([NH2:16])=[O:15])[CH:7]=[CH:6][C:5]=2[CH2:4][C@H:3]1[O:17][CH3:18])=[O:23]
Reactant: CC(C)(C)CC(=O)NCCC=O
Reactant: CO[C@@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@H]1N
Solvent: O=C(O)C(F)(F)F
Product: CO[C@@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@H]1NCCCNC(=O)CC(C)(C)C

Procedure:
Following the process of Example 11(c) using (6R,7R)-7-amino-6-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid amide and 3,3-dimethyl-N-(3-oxo-propyl)-butyramide the TFA salt of the title compound was prepared. (m/z): [M+H]+ calcd for C23H37N3O3, 404.28; found, 404.8.
Reaction SMILES: [NH3:1].[C:2]([C:4]1[CH:35]=[CH:34][C:7]([C:8]([NH:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([C:18]([F:30])([C:26]([F:29])([F:28])[F:27])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[CH:13][C:12]=2[CH2:31][O:32][CH3:33])=[O:9])=[CH:6][C:5]=1F)#[N:3]>CS(C)=O>[NH2:1][C:5]1[CH:6]=[C:7]([CH:34]=[CH:35][C:4]=1[C:2]#[N:3])[C:8]([NH:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([C:18]([F:30])([C:26]([F:29])([F:28])[F:27])[C:19]([F:24])([F:25])[C:20]([F:23])([F:22])[F:21])=[CH:13][C:12]=1[CH2:31][O:32][CH3:33])=[O:9]
Reactant: COCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C#N)c(F)c1
Reactant: N
Solvent: CS(C)=O
Product: COCc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(C)c1NC(=O)c1ccc(C#N)c(N)c1
Temperature: 100 °C
Yield: 66 %

Procedure:
Ammonia gas was added for 30 minutes to a solution of 4-cyano-3-fluoro-N-[2-methoxymethyl-6-methyl-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethyl-propyl)-phenyl]-benzamide (0.981 g, 1.90 mmol) (Example I1) in dimethylsulfoxide (20 ml). The reaction mixture was heated to 100° C. for 16 hours. The reaction mixture was allowed to cool to ambient temperature and more ammonia gas was added. The reaction mixture was heated to 100° C. for a further 16 hours. The reaction mixture was allowed to cool to ambient temperature and then partitioned between water and ethyl acetate. The aqueous phase was extracted 3 times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 3:1) to give 3-amino-4-cyano-N-[2-methoxymethyl-6-methyl-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethyl-propyl)-phenyl]-benzamide (640 mg, 66% yield). 1H-NMR (400 MHz, CDCl3): 8.77 (s, 1H), 7.51 (m, 2H), 7.37 (m, 2H), 7.18 (d, 1H), 4.63 (s, 2H), 4.49 (s, 2H), 3.37 (s, 3H), 2.36 (s, 3H) ppm.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])C.[Cl:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][NH2:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[Cl:20][C:21]1[CH:22]=[C:23]([CH2:29][CH2:30][NH:31][C:8]2[C:9](=[O:10])[N:5]([CH:1]([CH3:3])[CH3:4])[S:6](=[O:18])(=[O:19])[C:7]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: COc1ccc(CCN)cc1Cl
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Product: COc1ccc(CCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)C)C2=O)cc1Cl

Procedure:
The title compound was prepared from 2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide and [2-(3-chloro-4-methoxyphenyl)ethyl]amine in a similar manner as described for Example 24. 1H NMR (500 MHz DMSO-d6): δ 7.55-7.47 (m, 5H), 7.34 (t, 1H), 6.94 (d, 1H), 6.65 (dd, 1H), 6.61 (d, 1H), 4.32 (qt, 1H), 3.78 (s, 3H), 3.03-2.96 (m, 2H), 2.43-2.37 (m, 2H), 1.46 (d, 6H); 13C NMR (125 MHz DMSO-d6): δ 158.7, 153.7, 136.1, 132.4, 131.9, 130.3, 129.4, 128.8, 126.1, 121.3, 113.3, 105.0, 56.7, 47.3, 45.0, 34.4, 20.5; Mass spectrum M+H+ 435
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:11]=[C:5]2[CH:4]=1)=O.Cl.[NH2:28][OH:29].C(N(CC)CC)C.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:29][N:28]=[CH:1][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:11]=[C:5]2[CH:4]=1
Reactant: O=Cc1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Reactant: NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(C=NO)ccn23)c1
Reaction time: 18 h
Yield: 43.5 %

Procedure:
To a suspension of 1-[3-(7-Formyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (50 mg, 0.14 mmol) in toluene (5 ml) was added hydroxylamine hydrochloride (11 mg, 0.15 mmol) and triethylamine (21 μl, 0.15 mmol). The reaction mixture was stirred for 10 min before tosic acid (3 mg, 0.014 mmol) was added and then stirred for a further 18 h. The resulting precipitate was filtered off and washed with Et2O to give the product (23 mg). MS: [M+H]+ 378.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][N:4]1[CH:8]=[C:7]([C:9](Cl)=[O:10])[C:6]([N+:12]([O-:14])=[O:13])=[N:5]1>O>[CH3:1][NH:2][C:9]([C:7]1[C:6]([N+:12]([O-:14])=[O:13])=[N:5][N:4]([CH3:3])[CH:8]=1)=[O:10]
Reactant: CN
Reactant: Cn1cc(C(=O)Cl)c([N+](=O)[O-])n1
Solvent: O
Product: CNC(=O)c1cn(C)nc1[N+](=O)[O-]

Procedure:
Fifty ml. of water was cooled in an ice bath and saturated with monomethylamine. To the solution was added 2 gm. of 1-methyl-3-nitro-4-pyrazolecarbonyl chloride in portions, and the mixture was heated until the solid dissolved. Upon cooling a solid precipitated which was recrystallized from water and identified as 1.3 gm. of N,1-dimethyl-3-nitro-4-pyrazolecarboxamide, m.p. 163°-165° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([OH:27])=O)=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH:29]1[CH2:32][CH2:31][CH2:30]1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([N:29]4[CH2:32][CH2:31][CH2:30]4)=[O:27])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccc(F)c3)nc2c1
Reactant: C1CNC1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(-c3cccc(F)c3)nc2c1
Yield: 90.7 %

Procedure:
The product was prepared in the same manner as described in example 3 using 5-(2-(3-fluorophenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (70 mg, 184 μmol) and azetidine (12.5 μl, 184 μmol) as starting materials. The reaction affords 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid [2-(3-fluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (70 mg, 90.7%) as white solid. mp.: 232-236° C., MS: m/z=420.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][CH:15]([O:18][C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=2[F:27])[CH2:14][CH2:13]1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[CH2:28]([N:9]1[CH2:10][CH2:11][C:5]2[C:6](=[N:7][C:2]([Cl:1])=[C:3]([N:12]3[CH2:13][CH2:14][CH:15]([O:18][C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][C:20]=4[F:27])[CH2:16][CH2:17]3)[N:4]=2)[CH2:8]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N#Cc1ccc(OC2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Reactant: BrCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC#N
Product: N#Cc1ccc(OC2CCN(c3nc4c(nc3Cl)CN(Cc3ccccc3)CC4)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzyl bromide was purified by filtration through a plug of basic alumina prior to use. A solution of 4-((1-(3-chloropyrido[3,4-b]pyrazin-2-yl)piperidin-4-yl)oxy)-3-fluorobenzonitrile (200 mg, 0.521 mmol) and benzyl bromide (0.062 mL, 0.521 mmol) in ACN (2.60 mL) was heated at 80° C. for 3 h. The reaction mixture was allowed to cool to room temperature and sodium triacetoxyborohydride (331 mg, 1.563 mmol) was added. After stirring for 1 h at room temperature, the reaction mixture was quenched with saturated aqueous NaCl (1 mL). After bubbling ceased, the reaction mixture was purified by HPLC Method B, with the exception that a Waters SunFire™ C18, 5 μm, ID 30×75 mm column was used, using a 35% to 70% ACN gradient to give the title compound, as a TFA salt, as a yellow oil (117.9 mg, 38.2%). ESI-MS m/z [M+H]+ 478.5.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:20])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:6]=[N:7][CH:8]=1)=O.[F:21][C:22]([F:28])([F:27])[S:23]([NH2:26])(=[O:25])=[O:24]>>[C:18]([C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:20])[C:9]=1[C:5]1[CH:4]=[C:3]([CH2:1][NH:26][S:23]([C:22]([F:28])([F:27])[F:21])(=[O:25])=[O:24])[CH:8]=[N:7][CH:6]=1)#[N:19]
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: Cn1c(-c2cncc(C=O)c2)c(C#N)c2ccccc21
Product: Cn1c(-c2cncc(CNS(=O)(=O)C(F)(F)F)c2)c(C#N)c2ccccc21

Procedure:
2-(5-Formyl-pyridin-3-yl)-1-methyl-1H-indole-3-carbonitrile (Example 127) and trifluoromethanesulfonamide are processed according to the method described in Example 170 to give trifluoromethanesulfonic acid [5-(3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]amide. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.79 (s, 3H), 4.58 (s, 2H), 7.34-7.39 (m, 1H), 7.42-7.47 (m, 1H), 7.72 (d, J=7.7 Hz, 1H), 7.77 (d, J=8.3 Hz, 1H), 8.10 (t, J=2.1 Hz, 1H), 8.78 (d, J=2.1 Hz, 1H), 8.85 (d, J=2.1 Hz, 1H), 10.19 (br. s, 1H). HRMS (ESI) m/z 395.0779 [(M+H)+ Calcd for C17H14F3N4O2S: 395.0790].
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH:27]=2)O1>>[C:9]([NH:8][C:6]1[N:7]=[C:2]([C:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH:23]=2)[CH:3]=[CH:4][CH:5]=1)(=[O:13])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)C(=O)Nc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: CC(C)C(=O)Nc1cccc(C2=CCN(C(=O)OC(C)(C)C)CC2)n1

Procedure:
Prepared by Procedure W and Scheme AF using N-(6-bromo-2-pyridinyl)-2-methylpropanamide and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate: ESMS m/e: 245.8 (M−100)+.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:15][CH2:14][C:13]2[N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[C:11]3[CH:10]=[CH:9][C:8]([C:24]#[N:25])=[CH:7][C:6]=3[C:5]=2[CH2:4]1.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)=[O:28]>>[N+:36]([C:33]1[CH:32]=[CH:31][C:30]([O:29][C:27](=[O:28])[NH:2][CH:3]2[CH2:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[C:8]([C:24]#[N:25])[CH:7]=4)[N:12]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[C:13]=3[CH2:14][CH2:15]2)=[CH:35][CH:34]=1)([O-:38])=[O:37]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CCC(N)C1
Agent: Cl
Product: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CCC(NC(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Yield: 33 %

Procedure:
Prepare the title compound by essentially following the procedures as described in Example 162, using 6-amino-9-(3-fluoro-benzyl)-6,7,8,9-tetrahydro-5H-carbazole-3-carbonitrile hydrochloride (Preparation 51) and 4-nitrophenyl chloroformate. Purify by silica gel chromatography (50% (4% (2M NH3/MeOH)/CH2Cl2)/hexanes) to give the title compound in 33% yield as a white solid. MS (ES): m/z 346 (M-p-nitrophenolate); HPLC (Method B): Rt=2.23 min (86%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][N:17](C(OCC3C=CC=CC=3)=O)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)=O>CO.[Pd]>[N:14]1([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CC(C)(C)OC(=O)N1CCC(N2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 3.01 g (7.46 mmol) of benzyl 4-(1-tert-butoxycarbonylpiperidin-4-yl)piperazine-1-carboxylate and 300 mg of Pd—C (5%) in 100 ml of methanol was mixed with 4 ml of formic acid and stirred under a hydrogen atmosphere (1 bar) at room temperature overnight. The reaction mixture was filtered through Celite, the residue on the filter was washed with methanol, and the solvent was then removed in vacuo. The residue was used without further purification in the next reaction step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:22][C:23](=[O:29])[CH2:24][C:25]([O:27]C)=[O:26])[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]([CH3:20])[CH3:19].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:22][C:23](=[O:29])[CH2:24][C:25]([OH:27])=[O:26])[CH:5]=[C:6]([Cl:21])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH:18]([CH3:20])[CH3:19]
Reactant: COC(=O)CC(=O)Nc1cc(Cl)c(Oc2ccc3[nH]cc(C(C)C)c3c2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1c[nH]c2ccc(Oc3c(Cl)cc(NC(=O)CC(=O)O)cc3Cl)cc12

Procedure:
193 mg of methyl 3-({3,5-dichloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]phenyl}-amino)-3-oxopropanoate (Example 7) are stirred in 3 ml of ethanol with 1 ml of 1N NaOH for one hour at room temperature. The solvent is removed in vacuo and the residue is taken up in dichloromethane. The mixture is shaken with water, the organic phase is dried and the solvent is removed in vacuo. By stirring with diethyl ether, 143 mg of 3-({3,5-dichloro-4-[(3-isopropyl-1H-indol-5-yl)oxy]phenyl}amino)-3-oxopropionic acid are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[N:11][C:12]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:13][CH:14]=2)[CH:5]=[CH:4][C:3]=1[NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)C(C)C)(C)C.I[CH2:47][C:48]([NH2:50])=[O:49].O>CN(C)C=O>[NH2:50][C:48](=[O:49])[CH2:47][N:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][C:3]([NH:26][C:27](=[O:36])[O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[C:2]([F:1])[CH:7]=2)[CH:14]=[CH:13]/[C:12]/1=[N:15]/[S:16]([C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)(=[O:17])=[O:18]
Reactant: NC(=O)CI
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3ccc(NC(=O)OCc4ccccc4)c(F)c3)cn2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)/N=c2/ccc(Oc3ccc(NC(=O)OCc4ccccc4)c(F)c3)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
To a solution of benzyl {2-fluoro-4-[(6-{[(4-methylphenyl)sulfonyl]amino}pyridin-3-yl)oxy]phenyl}carbamate (32.0 g, 63.1 mmol) in N,N-dimethylformamide (320 mL) were added N,N-diisopropylethylamine (14.3 mL, 82.0 mmol) and iodoacetamide (15.2 g, 82.0 mmol), and the mixture was stirred at room temperature for 24 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate/tetrahydrofuran. The combined organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was washed with hexane/ethyl acetate and collected by filtration to give the title compound (34.2 g, 96%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C=CC=CC=1>ClCCl>[Br:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1c[nH]cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Brc1cn(-c2ccccc2)cn1
Reaction time: 48 h
Yield: 26.4 %

Procedure:
4-Bromo-1H-imidazole (500 mg, 3.4 mmol, 1 eq), phenylboronic acid (830 mg, 6.8 mmol, 2 eq), anhydrous cupric acetate (926 mg, 5.1 mmol), activated 4 Å molecular sieves (2 g) and pyridine (0.3 ml) were combined in dichloromethane (20 ml) and stirred for 2 days in the presence of air. The reaction mass was then filtered through Celite, washed with methanol, and concentrated and purified by silica gel chromatography (eluent 15% ethyl acetate/hexane) to afforded yellowish sticky solid 4-bromo-1-phenyl-1H-imidazole (200 mg, 26%).
Reaction SMILES: [C:1]1([S:7](NC2SC3CCCCC=3C=2C(OCC)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:25][C:26]1[S:30][C:29]2[CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][CH2:34][C:28]=2[C:27]=1[C:37]([O:39][CH2:40][CH3:41])=[O:38].C1(S(Cl)(=O)=O)C=CC=CC=1>>[CH3:35][C:32]1([CH3:36])[CH2:31][C:29]2[S:30][C:26]([NH:25][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[C:27]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:28]=2[CH2:34][CH2:33]1
Reactant: CCOC(=O)c1c(N)sc2c1CCC(C)(C)C2
Reactant: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCCC2
Agent: O=S(=O)(Cl)c1ccccc1
Product: CCOC(=O)c1c(NS(=O)(=O)c2ccccc2)sc2c1CCC(C)(C)C2

Procedure:
Prepared by proceeding in a similar manner to Intermediate 1, starting from ethyl 2-amino-6,6-dimethyl-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (prepared according to. Pinkerton et al., Bioorg. Med. Chem. Lett., 2007, 17, 3562-3569) and benzenesulphonyl chloride.