Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][S:17][C:16]3=[O:21])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:22](=O)[CH2:23][CH2:24][CH3:25].N1CCCCC1>C(O)C>[CH:22](=[C:18]1[S:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:19]1=[O:20])[CH2:23][CH2:24][CH3:25]
Reactant: CCCC=O
Reactant: O=C1CSC(=O)N1CCCCSc1cccc2nccn12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1SC(=O)N(CCCCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.61 g (5.0 mmol) of 3-[4-(imidazo[1,2-a]pyridin-5-ylthio)butyl]thiazolidine-2,4-dione and 0.45 ml (5.0 mmol) of n-butyraldehyde in 50 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, ethyl acetate) to yield 1.89 g (quant, light yellow oily substance) of the desired product.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]=[C:16]([NH:50]C(OC(C)(C)C)=O)[NH:17][C@@H:18]([CH2:22][S:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([C:37]3[C:42]4[O:43][C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=5[C:41]=4[CH:40]=[CH:39][CH:38]=3)=[CH:33][CH:32]=2)=[CH:27][CH:26]=1)[C:19]([OH:21])=[O:20])=O)(C)(C)C>ClCCl>[CH:40]1[C:41]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[O:43][C:42]=2[C:37]([C:34]2[CH:33]=[CH:32][C:31]([C:28]3[CH:29]=[CH:30][C:25]([CH2:24][S:23][CH2:22][C@H:18]([NH:17][C:16]([NH2:50])=[NH:15])[C:19]([OH:21])=[O:20])=[CH:26][CH:27]=3)=[CH:36][CH:35]=2)=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N[C@@H](CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)N[C@@H](CSCc1ccc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cc1)C(=O)O
Reaction time: 4 h
Yield: 98.1 %

Procedure:
Trifluoroacetic acid (2 mL) was added to a stirred solution of (2R)-2-[2,3-bis-(tert-butoxycarbonyl)guanidino]-3-(4′-dibenzofuran-4-yl-biphenyl-4-ylmethylsulfanyl)-propionic acid (250 mg, 0.36 mmol) in anhydrous dichloromethane (10 mL). The reaction was stirred for 4 hours (HPLC control) and then concentrated in vacuo. The resultant brown oil was reconstituted and concentrated from methanol (3×10 mL) and then from dichloromethane (2×10 mL) to give the title compound as an off-white solid (175 mg, 99%): Rf=0.20 (10% methanol in dichloromethane). 1H NMR (DMSO-d6, 300 MHz): δ 8.19 (1H, d, J=8 Hz, Ar—H), 8.13 (1H, d, J=9 Hz, Ar—H), 8.02 (2H, d, J=9 Hz, Ar—H), 7.84 (3H, m, Ar—H), 7.74 (4H, m, 2×Ar—H, 2×NH), 7.53 (3H, m, Ar—H), 7.42 (3H, m, Ar—H), 7.26 (1H, d, J=9 Hz, NH), 7.10 (1H, br s, NH), 4.58 (1H, m, CHN), 3.86 (2H, s, PhCH2S), 2.92 (1H, dd, J=15, 5 Hz, CHHCHN), 2.75 (1H, dd, J=15, 7 Hz, CHHCHN); ESI-LCMS e/z calcd for C29H25N3O3S 495.600, found 496 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[C:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:25])[C@@H:15]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:16][CH3:17]>C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.CN(C)C=O>[NH:1]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:8]=[C:9]1[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:25])[C@@H:15]([NH:18][C:19](=[O:24])[C:20]([F:21])([F:22])[F:23])[CH2:16][CH3:17]
Reactant: CC[C@H](NC(=O)C(F)(F)F)C(=O)NCCCC#Cc1ccccc1N
Agent: Cl[Pd]Cl
Solvent: N#Cc1ccccc1
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)C(F)(F)F)C(=O)NCCCc1cc2ccccc2[nH]1
Temperature: 80 °C

Procedure:
A 50 mL round bottom flask was charged with N-[5-(2-aminophenyl)pent-4-ynyl]-2-(S)-(2,2,2-trifluoroacetylamino)butyramide (130 mg, 0.37 mmol), dichlorobis(benzonitrile)palladium (II) (38.0 mg, 0.099 mmol), and dimethylformamide (4.1 mL) and the resulting mixture heated to 80° C. for 22 h. The resulting mixture was then concentrated in-vacuo and the resulting residue purified via flash silica gel chromatography (Analogix IF-280, SF25-40 g column, gradient 90:10-50:50 Heptane:EtOAc) to yield (S)—N-(3-(1H-indol-2-yl)propyl)-2-(2,2,2-trifluoroacetamido)butanamide. 1H NMR (300 MHz, CDCl3) δ 7.48-7.53 (m, 1H), 7.32 (d, J=7.9 Hz, 1H), 7.04-7.15 (m, 2H), 6.23 (s, 1H), 4.32-4.39 (m, 1H), 3.31-3.38 (m, 2H), 2.71-2.75 (m, 2H), 1.82-1.95 (m, 3H), 1.63-1.77 (m, 1H), and 0.90-0.95 (m, 3H); MS (ES+) 356 (M+1).
Reaction SMILES: O[CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:20].C(N(S(F)(F)[F:27])CC)C.C(=O)=O.CC(C)=O>C(Cl)Cl>[F:27][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:20]
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1O
Reactant: CCN(CC)S(F)(F)F
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1F

Procedure:
A well stirred suspension of 10 g (0.03 mol) of 3-hydroxy-1,3-dihydro-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one and 500 ml of methylene chloride was cooled to -70°. Diethylaminosulfur trifluoride (25 ml, 0.2 mol) was then added dropwise with exclusion of moisture and air. On completion of the addition the dry-ice acetone bath was removed, the contents of the flask were allowed to warm up in about 25 minutes to -10° and the reaction then immediately quenched by pouring into a beaker containing 400-500 ml of ice water. (If the reaction mixture is allowed to warm to 25°, none of the desired product is obtained.) Vigorous stirring of the ice water mixture continued for 7 to 10 minutes. The organic layer was separated, dried over MgSO4 and evaporated under reduced pressure to give a light orange powder. The product was dissolved in hot benzene, treated with decolorizing charcoal and filtered hot. On addition of heptane to the benzene solution, followed by cooling in ice, 3-fluoro-1,3-dihydro-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one crystallized out as a white powder, 8.19 g (82%): mp 190°-192° (decom.); 19F nmr (DMSO-d6) δ -161.5 ppm (d, d, J = 56, 4 Hz, 1H), 1H nmr (DMSO-d6) δ 7.2-7.8 (m, 8H), δ 5.72 (d, J = 56 Hz, 1H), δ 11.0 ppm (N-H).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[F:11][C:12]1[CH:13]=[CH:14][C:15]2[N:19]=[C:18]([CH:20]([NH2:22])[CH3:21])[N:17]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:16]=2[CH:30]=1.CCN(C(C)C)C(C)C>C(O)CCC>[F:11][C:12]1[CH:13]=[CH:14][C:15]2[N:19]=[C:18]([CH:20]([NH:22][C:2]3[N:10]=[CH:9][N:8]=[C:7]4[C:3]=3[N:4]=[CH:5][NH:6]4)[CH3:21])[N:17]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[C:16]=2[CH:30]=1
Reactant: CC(N)c1nc2ccc(F)cc2n1-c1cccc(F)c1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1cccc(F)c1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a microwave vessel was added 6-chloropurine (0.113 g, 0.732 mmol), 1-(6-fluoro-1-(3-fluorophenyl)-1H-benzo[d]imidazol-2-yl)ethanamine (Prepared in Example 22, 0.200 g, 0.732 mmol), and DIEA (0.256 mL, 1.46 mmol) in n-butanol (3.66 mL). The solution was stirred at 120° C. for 3 h, filtered and the resulting precipitate was washed with EtOAc:hexane (1:4) to give an off-white solid. The solid was purified by column chromatography on a silica gel column using 10 to 90% gradient of DCM:MeOH:NH4OH (90:10:1) in DCM as eluent to give an off-white solid. This material was triturated in EtOAc:hexane (1:3) and the suspension was filtered to give N-(1-(6-fluoro-1-(3-fluorophenyl)-1H-benzo[d]imidazol-2-yl)ethyl)-9H-purin-6-amine as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.60 (d, J=6.65 Hz, 3H) 5.57 (br. s., 1H) 6.94 (dd, J=8.90, 2.25 Hz, 1H) 7.11 (td, J=9.39, 2.35 Hz, 1H) 7.29 (t, J=7.04 Hz, 1H) 7.40-7.47 (m, 1H) 7.47-7.63 (m, 2H) 7.70 (dd, J=8.80, 4.89 Hz, 1H) 7.94 (s, 1H) 8.07 (s, 1H) 8.12 (s, 1H) 12.78 (br. s., 1H); LC-MS (ESI) m/z 392.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH:3]1[C:13]2[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[NH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[C@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:20]1>CS(C)=O>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][N:21]2[CH2:22][CH2:23][CH2:24][C@@H:20]2[CH2:19][N:8]2[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:13]=3[CH2:12][O:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]2=3)=[CH:32][CH:31]=1
Reactant: c1ccc2c(c1)COc1ccccc1N2
Reactant: COc1ccc(CCN2CCC[C@H](Cl)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(CCN2CCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 70 %

Procedure:
Sixty-percent sodium hydride (520 mg, 13 mmols) was washed with petroleum ether, and then suspended in 55 ml of dimethyl sulfoxide. To the suspension were added 2.0 g (10 mmols) of 5,11-dihydrodibenzo[b,e][1,4]oxazepine. The mixture was stirred in a nitrogen atmosphere at room temperature for 40 minutes. To this reaction solution was added dropwise a solution of 3.1 g (12 mmols) of (S)-(+)-3-chloro-1-(4-methoxyphenethyl)piperidine [[α]D25 =+10.1° (c=1.2, ethanol)] in 10 ml of dimethyl sulfoxide, and the mixed solution was stirred at room temperature for 14 hours and at 40° C. for 6 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and with a saturated aqueous solution of sodium chloride in this order, and dried. Subsequently, the solvent was distilled off under reduced pressure. The resulting residue was subjected to column chromatography, and eluted with a mixed solvent of ethyl acetate and hexane at a ratio of 1:2. This mixed solvent was distilled off under reduced pressure to give 2.9 g of (R)-(+)-5,11-dihydro-5-[1-(4-methoxyphenethyl)-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine as a pale yellow oil in a yield of 70%.
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])(OCC)=O>O>[C:24]1(=[O:33])[N:1]([CH:2]([CH2:3][C:4]2[N:8]=[CH:7][NH:6][CH:5]=2)[C:9]([OH:11])=[O:10])[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]12
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(Cc1c[nH]cn1)N1C(=O)c2ccccc2C1=O
Reaction time: 1.5 h
Yield: 64 %

Procedure:
To a stirred solution of histidine (3.17 g, 20.0 mmol) and sodium carbonate (2.23 g, 21 mmol) in 50 mL of water is added N-carboethoxyphthalimide (4.52 g, 20.0 mmol). After 1.5 hour, the reaction slurry is filtered. The filtrate is stirred and the pH adjusted to 1-2 with 4N hydrochloric acid. The resulting slurry is filtered and the solid washed with water and dried in vacuo (60 C, <1 mm) to afford 3.65 g (64%) of 2-phthalimido-3-(imidazol-4-yl)propionic acid as a white powder: mp 280°-285° C.; 1H NMR (DMSO-d6, 250 M Hz) δ 12.5 (br s, 1H), 7.90-7.60 (m, 6H), 6.80 (s, 1H), 4.94 (t, 1H, J=7.8), 3.36 (d, 2H, J=7.8); 13C NMR (DMSO-d6) δ 170.1, 167.1, 134.8, 134.6, 133.2, 131.1, 123.2, 116.3, 52.4, 25.8; Anal. Calculated for C14H11N3O4. Theoretical: C, 58.95; H, 3.89; N, 14.73. Found: C, 58.80; H, 3.88; N, 14.66.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[C:21]([C:23]([OH:25])=O)[CH:20]=[N:19]2)=[CH:14][CH:13]=1.O.O[N:28]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N.C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[CH3:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH:22]=[C:21]([C:23]([NH2:28])=[O:25])[CH:20]=[N:19]2)=[CH:14][CH:13]=1
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)O)cn2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(N)=O)cn2)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of 1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazole-4-carboxylic acid hydrochloride obtained in Example 2-(1) (1.08 g) in N,N-dimethylformamide (11 mL), 1-hydroxybenzotriazole monohydrate (0.539 g) was added at room temperature and stirred for 5 minutes. To the reaction mixture, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.679 g) was added and stirred at room temperature for 30 minutes, followed by addition of aqueous ammonia (25%, 0.702 g) and stirring overnight at room temperature. After addition of water and saturated aqueous sodium bicarbonate, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: chloroform:methanol=20:1) to give the titled compound (0.504 g) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][C:11](=[O:17])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C.Br[CH2:28][CH2:29][O:30][CH2:31][CH2:32]Br.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Br:8][C:6]1[CH:7]=[C:2]([N:1]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[C:3]([NH:10][C:11](=[O:17])[CH2:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[C:4]([CH3:9])[CH:5]=1
Reactant: BrCCOCCBr
Reactant: Cc1cc(Br)cc(N)c1NC(=O)CC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Br)cc(N2CCOCC2)c1NC(=O)CC(C)(C)C
Temperature: 180 °C
Yield: 60 %

Procedure:
N-(2-Amino-4-bromo-6-methyl-phenyl)-3,3-dimethyl-butyramide (1v, 1.01 g), N,N-diisopropyl-ethylamine (1.80 mL) and bis(2-bromoethyl)ether (0.50 mL) were dissolved in dry N,N-dimethylformamide (5 mL) and heated to 180° C. for 50 minutes in a sealed microwave process vial. Saturated aqueous sodium bicarbonate (20 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL), the combined organic phases were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 0.740 g (60% yield) of the title compound as a white solid. LC-MS (m/z) 370 (MH+); tR=3.05, (UV, ELSD) 95%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.05 (s, 9H), 2.09 (s, 3H), 2.23 (s, 2H), 2.80 (t, 4H), 3.69 (t, 4H), 7.03 (d, 1H), 7.15 (d, 1H), 8.99 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:24][C:23]2[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=2)[CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CNC1CCN(C(=O)OC(C)(C)C)C1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)CN(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(methoxycarbonylmethyl-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.5 g, 2.03 mmol) in dichloroethane (5.0 mL) was added 4-chlorobenzaldehyde (0.34 g, 2.44 mmol), sodium triacetoxy borohydride (0.86 g, 4.06 mmol) and catalytic acetic acid and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in dichloromethane and washed with 10% aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using ethyl acetate. 1H-NMR (CDCl3) δ: 1.40 (9H, s), 1.80 (1H, m), 2.10 (1H, m), 3.00–3.80 (7H, m), 4.70(1H, br,s), 7.20 (4H,m). ESI-MS m/z: 383(M+1), UV retention time: 2.91 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[F:27][C:28]([F:32])([F:31])[CH2:29][NH2:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:30][CH2:29][C:28]([F:32])([F:31])[F:27])=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: NCC(F)(F)F
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(NCC(F)(F)F)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2,2,2-trifluoroethylamine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(2,2,2-trifluoroethyl)terephthalamide. MS (Q1) 469 (M)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:9]2[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=2)=[CH:4][C:3]=1[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)=[O:23].[BH4-].[Na+]>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:9]2[N:13]([CH3:14])[CH:12]=[N:11][CH:10]=2)=[CH:4][C:3]=1[CH:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)[OH:23]
Reactant: Cn1cncc1C(c1ccc(Cl)cc1)c1ccc(N)c(C(=O)c2cccc(Cl)c2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cncc1C(c1ccc(Cl)cc1)c1ccc(N)c(C(O)c2cccc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
A mixture of intermediate (16) (0.0848 mol) in methanol (400 ml) was cooled to 10° C. sodium tetrahydroborate (0.102 mol) was added portionwise. The mixture was stirred at room temperature for 2 hours, poured out into ice water and extracted with DCM. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH/NH4OH 95/5/0.1; 20–45 μm). The pure fractions were collected and the solvent was evaporated, yielding 12.3 g (33%) of 2-amino-α-(3-chlorophenyl)-5-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-benzenemethanol (intermediate 17).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][NH:10][C:9]1=[O:14])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:19].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH3:19])[C:9]1=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCCNC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCCC(NC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
To a solution of tert-butyl(2-oxopiperidin-3-yl)carbamate (1714 mg) in DMF (20 mL) was added 60% sodium hydride (480 mg, containing mineral oil) under ice-cooling. The reaction mixture was stirred at room temperature for 30 min, and iodomethane (1703 mg) was added. The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (530 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C@H:11]1[CH2:16][CH2:15][C@H:14]([NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:13][CH2:12]1
Reactant: O=C1CCC(c2c[nH]c3ccc(F)cc23)CC1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Fc1ccc2[nH]cc([C@H]3CC[C@H](NCc4ccccc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4-(5-fluoro-1H-indol-3-yl)-cyclohexanone (2.31 g, mmol), benzylamine (1.1 g, 10 mmol), sodium triacetoxyborohydride (3.1 g, 14 mmol) and acetic acid (0.57 ml) in 1,2-dichloroethane (30 ml) was allowed to stir at room temperature for 4 hours. The reaction was quenched with 1N sodium hydroxide (10 ml), extracted with methylene chloride (3×60 ml) and washed with brine (3×60 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (ethyl acetate-hexanes-methanol-ammonium hydroxide: 50:50:5:0.5) afforded 0.51 g (16%) of product as a white solid: mp 131-133° C. MS EI m/e 322 (M+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[C:11](Cl)(=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][C:8]=1[C:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:20]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1cccc(OC)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(OC)cc2OC)cc1
Temperature: 25 °C

Procedure:
1,3-Dimethoxybenzene (13.8 grams, 0.1 mole) and p-anisoyl chloride (17 grams, 0.1 mole) were dissolved in 200 milliliters of methylene chloride and stirred at room temperature. Anhydrous aluminum chloride (15 grams) was added slowly to the reaction mixture over a period of 15 minutes with stirring. After stirring an additional 15 minutes, the contents of the flask were carefully poured into 200 milliliters of a mixture of ice and dilute hydrochloric acid. The organic fraction was separated and washed with water. The solvent was removed on a rotary evaporator leaving an oily product that solidified on standing. This solid was broken-up, washed with two 50 milliliter portions of pentane, and dried, yielding 2,4,4'-trimethoxybenzophenone.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:18]=[C:17](F)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:20][O:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:18]=[C:17]([NH:27][CH2:26][C:25]4[CH:28]=[CH:29][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)[N:16]=[CH:15][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cc2c(Nc3cccc(Br)c3)ncnc2cn1
Reactant: COc1ccc(CN)cc1
Solvent: CCO
Product: COc1ccc(CNc2cc3c(Nc4cccc(Br)c4)ncnc3cn2)cc1
Temperature: 100 °C
Yield: 27.4 %

Procedure:
A mixture of 4-[(3-bromophenyl)amino]-6-fluoro-pyrido[3,4-d]pyrimidine (0.48 g) and 4-methoxybenzyl-amine (10.3 g) in ethanol (50 mL) was heated to 100° C. for 5 days. The resulting product was chromatographed on silica gel, eluting with CH2Cl2:EtOAc (3:1), to give 4-[(3-bromophenyl)amino]-6-[(4-methoxyphenyl)methyl- amino]pyrido[3,4-d]pyrimidine (0.18 g,) mp (aqueous methanol), 178-179.5° C. A 0.10 g portion of this was dissolved in 5 mL trifluoroacetic acid and heated under reflux for 1 hour, and the mixture was evaporated to dryness. The residue was partitioned between EtOAc and aqueous ammonia, and the crude product was chromatographed on alumina, eluting with CH2Cl2:MeOH (97:3) to give 6-amino-4-[(3-bromophenyl)amino]pyrido-[3,4-d]pyrimidine (0.040 g,), mp (CH2Cl2) 241.5-242° C.