Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19](O)=[O:20])[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[CH2:43]([O:50][C:51]([N:53]1[CH2:62][CH2:61][C:60]2[C:55](=[CH:56][C:57]([NH2:63])=[CH:58][CH:59]=2)[CH2:54]1)=[O:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C=O)C.CCOC(C)=O>[CH2:43]([O:50][C:51]([N:53]1[CH2:62][CH2:61][C:60]2[C:55](=[CH:56][C:57]([NH:63][C:19](=[O:20])[C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([CH:9]4[CH2:10][CH2:11][CH2:12][N:8]4[C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH:14]=3)=[CH:58][CH:59]=2)[CH2:54]1)=[O:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1cccc(C(=O)O)c1
Reactant: Nc1ccc2c(c1)CN(C(=O)OCc1ccccc1)CC2
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1c1cccc(C(=O)Nc2ccc3c(c2)CN(C(=O)OCc2ccccc2)CC3)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.5 %

Procedure:
To a solution of 2-(3-carboxy-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 1.682 mmol), EDC (346 mg, 1.766 mmol), and HOBt (240 mg, 1.682 mmol) in DMF (5 mL) add Et3N (0.355 mL, 2.523 mmol) and stir the solution at room temperature for 15 min. To this add a solution of the 7-amino-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (500 mg, 1.682 mmol) as a solution in DMF (5 mL) and stir the solution at 65° C. for 24 h. Dilute the reaction with EtOAc (250 mL) and wash with sat. NH4Cl (250 mL), sat. NaHCO3 (250 mL), then water (250 mL). Extract the aqueous layers with more EtOAc (250 mL) and dry the combined organics (Na2SO4), and concentrate in vacuo to give 902 mg of 7-[3-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-benzoylamino]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester as a solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]([C:16]([F:19])([F:18])[F:17])[CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[CH:12]2.CN([CH:23]=[O:24])C>>[Br:6][C:7]1[CH:8]=[C:9]([C:16]([F:19])([F:17])[F:18])[CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH:23]=[O:24]
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cc(Br)c2[nH]ccc2c1
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2c(Br)cc(C(F)(F)F)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
Phosphorus oxychloride (1.029 ml, 11.04 mmol) was added dropwise to DMF (8 ml) at 0° C. The mixture was stirred 30 min at 0° C. and 7-bromo-5-(trifluoromethyl)-1H-indole (2.65 g, 10.04 mmol) in DMF (2 mL) was added dropwise. The cooling bath was removed and the reaction was stirred at ambient temperature for 3 hours. The reaction was quenched with ice (5 g) and aqueous sodium hydroxide (1N, 20 mL). The reaction was extracted with ethyl acetate (2×30 mL) and the organic phase was dried with MgSO4 and evaporated. The residue was purified by chromatography on SiO2 with a 5%-60% gradient of ethyl acetate/hexanes. The product 7-bromo-5-(trifluoromethyl)-1H-indole-3-carbaldehyde (2.17 g, 7.43 mmol, 74.0% yield) was obtained as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 10.09 (s, 1H), 9.06 (s, 1H), 8.59 (s, 1H), 8.00 (d, J=3.2 Hz, 1H), 7.72 (d, J=3.0 Hz, 1H). LC/MS (HPLC method 4): tR=3.29 min, 292.06(MH)+.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1[OH:22]>C(OCC)C.N1C=CC=CC=1>[C:1]([O:22][C:15]1[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=1[Cl:13])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: CCCCCCCCCC(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Oc1cc(Cl)c(Cl)cc1Cl

Procedure:
A solution of decanoyl chloride (Pfaltz and Bauer, 5.6 ml), and 2,4,5-trichlorophenol (5.6 g) in diethyl ether (1 L ) and pyridine (120 ml) is stirred for 4 hours. The reaction mixture is filtered and dried in vacuo. The 2,4,5-trichlorophenyl n-decanoate is purified on a silica-gel column (Woelm), using toluene as the eluent. Fractions are monitored by TLC, using short-wave UV for detection. Appropriate fractions are pooled and dried in vacuo to give 10.4 g of 2,4,5-trichlorophenyl n-decanoate.
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[F:31][C:32]1[CH:37]=[CH:36]C(CCN)=[CH:34][CH:33]=1>>[F:31][C:32]1[CH:37]=[CH:36][C:12]([CH2:11][CH2:10][NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])=[CH:34][CH:33]=1
Reactant: NCCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: O=C(NCCc1ccc(F)cc1)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-(4-fluorophenyl)ethylamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 381 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 12.19 (1H, br. s.) 10.45 (1H, s) 8.21 (1H, t, J=5.76 Hz) 8.07 (1H, d, J=6.64 Hz) 7.86 (1H, d, J=5.27 Hz) 7.42 (1H, dd, J=3.12, 1.76 Hz) 7.36 (1H, d, J=5.27 Hz) 7.18 (2H, dd, J=8.79, 5.66 Hz) 7.00 (2H, t, J=8.98 Hz) 6.73 (1H, d, J=6.44 Hz) 6.63 (1H, d, J=3.32 Hz) 3.39-3.47 (2H, m) 2.75 (2H, t, J=7.22 Hz)
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH2:12][C:13]3[CH:14]=[N:15][C:16]([O:20][CH2:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])=[C:17]([CH3:19])[CH:18]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:28]([O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:29]>>[CH3:19][C:17]1[CH:18]=[C:13]([CH2:12][N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:28]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:29])[C:7]=3[CH2:8]2)[CH:14]=[N:15][C:16]=1[O:20][CH2:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24]
Reactant: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)C(F)F
Reactant: O=COc1ccccc1
Product: Cc1cc(CN2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)cnc1OCC(F)(F)C(F)F
Yield: 71 %

Procedure:
The title compound is prepared in 71% yield (220 mg, yellow oil) from 4-chloro-2-((5-methyl-6-(2,2,3,3-tetrafluoropropoxy)pyridin-3-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (250 mg, 0.62 mmol, Intermediate-68) and phenyl formate (150 mg, 1.2 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][C:15]#[N:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:24]COCC.F[B-](F)(F)F.C[O+](C)C.[BH4-].[Na+]>C(Cl)Cl.CO>[CH3:24][NH:16][CH2:15][CH2:14][CH2:13][N:10]1[CH2:9][CH2:8][C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][CH2:11]1
Reactant: CCOCC
Reactant: N#CCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Agent: C[O+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CNCCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
To a stirred solution of 3-(4,4-diphenylpiperidin-1-yl)propionitrile (5.00 g, 17.2 mmol, 1.00 equiv) in CH2Cl2 (40 mL) was added HCl in ether (1.0 M, 22.4 mL, 22 mmol, 1.3 equiv). After removal of the solvents, the residue and trimethyloxonium tetrafluoroborate (9.67 g, 65.4 mmol, 3.80 equiv) were stirred in refluxing anhydrous CH2Cl2 (80 mL) under argon for 44 hours. The mixture was cooled to 0° C., anhydrous MeOH (5 mL) was added, and stirring was continued for 1 hour at 0° C. The solvents were removed and the residue was dissolved in anhydrous MeOH (30 mL). Sodium borohydride (5.20 g, 138 mmol, 8.00 equiv) was added at 0° C., and stirring was continued at this temperature under argon for 2 hours. The solution was acidified to pH 1 by slow addition of 6 N aqueous HCl (40 mL) at 0° C. and stirred for 3 hours at room temperature. After removal of the solvents, water (30 mL) was added and the mixture was basified to pH 9 by addition of 6 N aqueous NaOH. The mixture was extracted with CH2Cl2 (3×100 mL), and the combined organic solutions were dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2, EtOAc-MeOH-isopropylamine 9:1:0 to 5:1:0.2) to give 2.18 g (41%) of yellow solid, which was characterized spectroscopically.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[O:12][C:11]([CH3:14])=[N:10][C:9]=2[C:8]([C:15]2[CH2:19][C:18]([C:24]3[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=3)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[Na+].CO>O1CCCC1.Cl.C(OCC)(=O)C>[Cl:30][C:28]1[CH:29]=[C:24]([C:18]2([C:20]([F:22])([F:21])[F:23])[O:17][N:16]=[C:15]([C:8]3[C:9]4[N:10]=[C:11]([CH3:14])[O:12][C:13]=4[C:5]([C:3]([OH:4])=[O:2])=[CH:6][CH:7]=3)[CH2:19]2)[CH:25]=[C:26]([Cl:31])[CH:27]=1
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2nc(C)oc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2c(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)ccc(C(=O)O)c2o1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.4 %

Procedure:
To a solution of 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl)-2-methyl-benzo[d]oxazole-7-carboxylic acid methyl ester (2.75 g) in tetrahydrofuran (50 ml) was added aqueous sodium hydroxide (1M) (8.7 ml) and methanol (5 ml). The reaction mixture was stirred at ambient temperature for 2.5 hours. The reaction mixture was diluted with aqueous hydrochloric acid (1M) (150 ml) and ethyl acetate (200 ml) and the phases separated. The organic phase was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: 1-6% v/v methanol in dichloromethane) to give 4-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl)-2-methyl-benzo[d]oxazole-7-carboxylic acid (2.12 g) as yellow solid. 1H-NMR (400 MHz, CDCl3): 8.05-7.43 (m, 5H), 4.57 (d, 1H), 4.13 (d, 1H), 2.79 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]2[C:5]([C:6]([OH:20])=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:8]=[N:9]2)=[CH:4][C:3]=1[F:21]>C(O)(=O)C.[Fe]>[NH2:12][C:11]1[C:2]([Cl:1])=[C:3]([F:21])[CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:6]2[OH:20]
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])c(Cl)c(F)cc2c1O
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)c1cnc2c(N)c(Cl)c(F)cc2c1O
Temperature: 110 °C

Procedure:
9.4 g of the product from Example 5 and 19.2 g of iron turnings are warmed at 80° C. for 1 hour in 190 ml of acetic acid. The mixture is then heated briefly to 110° C. and filtered while hot. Ice-water is then added to the filtrate, and the precipitated solid is isolated. After drying at 110° C., the product is recrystallized from glycol monomethyl ether. Yield: 7.8 g, melting point: 268°-70° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][S:9][C:8]2[CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=[CH:15][C:7]1=2)[CH3:2].O.NN>CO.[Ni]>[CH2:19]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][S:9][C:8]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:7]1=2)[CH3:20]
Reactant: CCN(CC)CCN1CCSc2cc([N+](=O)[O-])ccc21
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CCN(CC)CCN1CCSc2cc(N)ccc21
Temperature: 25 °C
Yield: 107.2 %

Procedure:
To a stirred solution of N,N-diethyl-2-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)ethanamine (1.109 g, 3.76 mmol) in MeOH (30 mL) was added Raney-Nickel (slurry in water; ˜0.1 g, 3.76 mmol) followed by hydrazine hydrate (1.828 mL, 37.6 mmol). The mixture was immersed in a preheated oil bath and refluxed for 30 minutes. The solution was cooled to room temperature, filtered through Celite, and washed with MeOH. The crude material was filtered through a silica plug (3.5% (2M NH3 in MeOH):CH2Cl2). The solvent was evaporated to give the product as dark brown oil (1.07 g, quantitative). 1H NMR (CDCl3) δ 6.58 (d, J=8.7 Hz, 1H), 6.45 (d, J=2.7 Hz, 1H), 6.40 (dd, J=2.7, 8.7 Hz, 1H), 3.53-3.50 (m, 2H), 3.30 (m, 4H), 3.03-2.99 (m, 2H), 1.03 (t, J=7.2 Hz, 6H); ESI-MS (m/z, %): 268, 266 (MH+, 100), 100 (52).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[CH:17]([N:20]=[C:21]=[S:22])([CH3:19])[CH3:18]>>[CH:17]([NH:20][C:21](=[S:22])[NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])([CH3:19])[CH3:18]
Reactant: CC(C)N=C=S
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CC(C)NC(=S)Nc1cccc(C(=O)C2CCN(C)CC2)c1
Yield: 42.5 %

Procedure:
Following the example above and beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and isopropyl isothiocyanate (133 μL, 1.401 mmol), 15.6 mg (43%) of the title compound were recovered.
Reaction SMILES: F[C:2]1[C:3]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([CH3:19])[C:5]([C:17]#[N:18])=[C:6]2[C:10]=1[O:9][C:8]([C:11]([CH3:16])([CH3:15])[CH2:12][O:13][CH3:14])=[N:7]2.C(N(CC)CC)C.[CH3:33][N:34]([CH3:40])[C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1.C(OCC)(=O)C>CS(C)=O.O>[CH3:33][N:34]([CH3:40])[C@H:35]1[CH2:39][CH2:38][N:37]([C:2]2[C:3]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[C:4]([CH3:19])[C:5]([C:17]#[N:18])=[C:6]3[C:10]=2[O:9][C:8]([C:11]([CH3:16])([CH3:15])[CH2:12][O:13][CH3:14])=[N:7]3)[CH2:36]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: COCC(C)(C)c1nc2c(C#N)c(C)c(-c3ccccc3)c(F)c2o1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COCC(C)(C)c1nc2c(C#N)c(C)c(-c3ccccc3)c(N3CC[C@H](N(C)C)C3)c2o1
Temperature: 90 °C
Reaction time: 3 h
Yield: 34.7 %

Procedure:
7-Fluoro-2-(2-methoxy-1,1-dimethylethyl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-100) (40 mg, 0.12 mmol) was dissolved in dimethyl sulfoxide (0.8 ml), triethylamine (23 μl, 0.17 mmol) and (3S)-3-(dimethylamino)pyrrolidine (18 μl, 0.14 mmol) were added, followed by stirring at 90° C. for 3 hours under nitrogen atmosphere. After cooling to room temperature, ethyl acetate was added, followed by fractionation with water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated away and the resulting residue was subjected to preparative thin-layer silica gel column chromatography, eluted with a mixed solvent of chloroform/methanol (10:1, v/v), and washed with n-hexane and ethyl acetate to obtain the entitled compound (18 mg, 35%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]([NH2:11])=[O:10])=[N:5][CH:4]=1)#[CH:2].[CH3:12][N:13]([CH3:41])[C@@H:14]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:36])[C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[C:30](I)[CH:29]=3)=[CH:22][C:21]=2[C:37]([F:40])([F:39])[F:38])[CH2:15]1>>[CH3:41][N:13]([CH3:12])[C@@H:14]1[CH2:18][CH2:17][N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([C:28]3[CH:29]=[CH:30][C:31]([CH3:34])=[C:32]([C:2]#[C:1][C:3]4[N:7]([CH3:8])[C:6]([C:9]([NH2:11])=[O:10])=[N:5][CH:4]=4)[CH:33]=3)=[O:36])=[CH:22][C:21]=2[C:37]([F:40])([F:39])[F:38])[CH2:15]1
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CC[C@@H](N(C)C)C3)c(C(F)(F)F)c2)cc1I
Reactant: C#Cc1cnc(C(N)=O)n1C
Product: Cc1ccc(C(=O)Nc2ccc(CN3CC[C@@H](N(C)C)C3)c(C(F)(F)F)c2)cc1C#Cc1cnc(C(N)=O)n1C

Procedure:
The title compound can be synthesized from 5-ethynyl-1-methyl-1H-imidazole-2-carboxylic acid amide and (R)-N-(4-((3-(Dimethylamino)pyrrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide in a manner similar to that described for Example 2. 5-ethynyl-1-methyl-1H-imidazole-2-carboxylic acid amide is prepared as in Example 2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:10]=[C:11]([CH3:13])[CH3:12])[C:5]([CH2:8][CH3:9])=[N:6][CH:7]=1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][CH:11]([CH3:12])[CH3:13])[C:5]([CH2:8][CH3:9])=[N:6][CH:7]=1
Reactant: CCc1ncc(Br)cc1N=C(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1ncc(Br)cc1NC(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To solution of (5-bromo-2-ethyl-pyridin-3-yl)-isopropylidene-amine (Stage 162.1.2, 1.17 mmol) in dichloromethane (25 ml) was added AcOH (0.25 ml) and sodium triacetoxyborohydride (3.51 mmol). The reaction mixture was stirred for 4 h at rt. The RM was quenched with aqueous NaHCO3 and extracted with dichloromethane (2×). The combined organic layers were washed with saturated aqueous NaHCO3, with brine, dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and eluted (CH2Cl2/MeOH 0% to 3%). The fractions containing the product were purified by preparative HPLC. The fractions containing pure product were basified with NaHCO3, concentrated and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and evaporated to the title compound as an oil (HPLC: tR 2.40 min (Method A); M+H=243, 245 MS-ES).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)C.C(O)(=O)C>O>[CH3:14][O:13][C:9]1[CH:8]=[C:7]([S:6][CH2:5][CH:4]=[O:3])[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(CSc1cccc(OC)c1)OCC
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc(SCC=O)c1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
1-(2,2-Diethoxyethylsulphanyl)-3-methoxybenzene (18 g, 70.21 mmol), glacial acetic acid (26 mL) and water (18 mL) were stirred at reflux temperature under nitrogen for 45 min. The reaction mixture was cooled to ambient temperature, diluted with water (180 mL) and extracted with tert-butyl methyl ether (3×40 mL). The combined extracts were cooled to <5° C. and washed with 5% aqueous sodium carbonate solution, water, and brine. The organic phase was dried (MgSO4) and concentrated in vacuo to yield the title compound (11.8 g, 92%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[C:12]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:15]([C:18](Cl)=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>C1COCC1>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:13][CH:14]=3)=[O:19])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc2c(c1)CCC2=O
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(c1)CCC2=O)c1ccc(-c2ccccc2)cc1
Yield: 60 %

Procedure:
5-amino-indan-1-one (73 mg, 0.50 mmol) in THF (6 mL) with 4-biphenylcarbonyl chloride (140 mg, 0.65 mmol) in presence of triethylamine (90 μL, 0.65 mmol) according to method A gave biphenyl-4-carboxylic acid (1-oxo-indan-5-yl)-amide (100 mg, 0.30 mmol, 60% yield) as a brown powder after purification by washing the crude product with ethyl acetate.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1.[CH2:8]([NH2:10])[CH3:9]>C1COCC1>[CH2:8]([NH:10][CH2:2][C:3]1[N:4]=[CH:5][S:6][CH:7]=1)[CH3:9]
Reactant: ClCc1cscn1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1cscn1

Procedure:
prepared by reaction of the commercially available 4-chloromethyl-thiazole with 2M ethylamine in THF.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13]CC)=[O:12])=[CH:7]2.CO.[OH-].[K+]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:18]=[N:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)nc3)cc(C)c2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(=O)O)[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.5 %

Procedure:
To a solution of ethyl 7-methyl-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carboxylate (3.9 g), methanol (30 mL), and tetrahydrofuran (50 mL) was added aqueous solution (20 mL) of potassium hydroxide (2.0 g), and the mixture was stirred at room temperature for 15 hr. The reaction solution was concentrated, acidified with aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained pale-yellow crystals were washed with ethyl acetate-hexane to give the title compound (3.30 g, yield 92%) as pale-yellow crystals.
Reaction SMILES: C([O:8][C:9]1[C:14]2[N:15]([CH3:18])[CH:16]=[N:17][C:13]=2[CH:12]=[C:11]([Br:19])[CH:10]=1)C1C=CC=CC=1.B(Br)(Br)Br.C1COCC1>C(Cl)Cl>[Br:19][C:11]1[CH:10]=[C:9]([OH:8])[C:14]2[N:15]([CH3:18])[CH:16]=[N:17][C:13]=2[CH:12]=1
Reactant: Cn1cnc2cc(Br)cc(OCc3ccccc3)c21
Agent: BrB(Br)Br
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1cnc2cc(Br)cc(O)c21
Reaction time: 1 h

Procedure:
To a solution of 7-(benzyloxy)-5-bromo-1-methyl-1H-benzo[d]imidazole 2.51 (157 mg, 0.495 mmol) in DCM (3 mL) at 0° C. was added a solution of 1.0M BBr3 in THF (1.1 equiv). After 1 h at 0° C., the reaction mixture was diluted with DCM and washed with sat'd NaHCO3 and then the aqueous layer was then extracted with EtOAc (3×). Combined organic layers were washed successively with water and brine and dried over anhydrous magnesium sulfate. The residue was purified by flash column chromatography (SiO2, 0% MeOH/EtOAc→10% MeOH/EtOAc) to give of 5-bromo-1-methyl-1H-benzo[d]imidazol-7-ol 2.56.
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=[C:6]([F:16])[CH:5]=1.[OH-].[Na+]>CO>[F:16][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=1)[C:3]([OH:17])=[O:2]
Reactant: COC(=O)c1cc(F)cc(-c2cccnc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(F)cc(-c2cccnc2)c1
Temperature: 25 °C
Yield: 117.2 %

Procedure:
In a 100 ml round bottom flask equipped with stir bar added Methyl-3-fluoro-5-(3-pyridyl)benzoate (0.92 g, 3.93 mmol), methanol (10 ml) and sodium hydroxide (5.89 ml, 5.89 mmol, 1N aqueous). Stirred the resulting mixture at 50° C. for 2 h. The reaction mixture was cooled to room temperature, concentrated in-vacuo and the residue was dissolved in methanol (20 ml). To this mixture added hydrochloric acid (1N diethyl ether) dropwise and stirred at room temperature for 10 min. The reaction mixture was concentrated in-vacuo and the residue was triturated with diethyl ether to provide the crude hydrochloride salt of title compound (1.00 g) as an off white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:27][CH:28]([CH3:30])[CH3:29].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9]([N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH2:27][CH:28]([CH3:30])[CH3:29])(=[O:10])=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)CI
Reactant: O=S(=O)(Cc1ccc(Br)cc1)Nc1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CN(c1cccc(Cl)c1)S(=O)(=O)Cc1ccc(Br)cc1
Temperature: 100 °C
Yield: 59.5 %

Procedure:
To a mixture of C-(4-bromo-phenyl)-N-(3-chloro-phenyl)-methanesulfonamide (0.61 g, 1.68 mmol) and K2CO3 (464 mg, 3.4 mmol) in dimethylformamide (5 mL) was added 1-iodo-2-methylpropane (584 μL, 5.0 mmol). The mixture was heated at 100° C. in microwave reactor for 3 hours. Water was added and the reaction extracted with EtOAc, washed with brine, dried with Na2SO4, concentrated and purified by silica gel column chromatography (0-50% DCM in cyclohexane) to give C-(4-bromo-phenyl)-N-(3-chloro-phenyl)-N-isobutyl-methanesulfonamide (423 mg, 1.0 mmol, 60%). LCMS (m/z, Method A) ES+ 415.8 [M+1]+.