Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([OH:18])[C@@H:16]([OH:19])[C@@H:15]([CH3:20])[O:14][C@H:10]1[S:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:28]([O:18][C@H:17]1[C@@H:16]([OH:19])[C@@H:15]([CH3:20])[O:14][C@@H:10]([S:11][CH2:12][CH3:13])[C@@H:9]1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCS[C@@H]1O[C@H](C)[C@H](O)[C@H](O)[C@H]1OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS[C@@H]1O[C@H](C)[C@H](O)[C@H](OC(=O)c2ccccc2)[C@H]1OCc1ccccc1
Temperature: -30 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
To a solution of ethyl 2-O-benzyl-6-deoxy-1-thio-β-D-galactopyranoside (1.03 g, 3.45 mmol) and DMAP (126 mg, 1.0 mmol) in 10 mL of dry CH2Cl2 at −30° C. was added Et3N (1.92 mL, 13.8 mmol). Benzoyl chloride (0.4 mL, 3.45 mmol) was added to this mixture in a dropwise fashion, and the stirred at −30° C. for 3 hr. The reaction was then quenched by the addition of MeOH (2 mL) and the mixture was gradually warmed to room temperature after which the resulting mixture was diluted with EtOAc (250 mL). The solution was washed with saturated NaHCO3 solution (2×20 mL), water (30 mL), dried over Na2SO4, concentrated and purified by flash chromatography (3:1 to 1:1 hexane/EtOAc) to give 1.12 g (80%) of the title product. [α]D=96.9° (c=1, CHCl3); 1H NMR (CDCl3) 8.09–8.03 (m, 2H), 7.56 (t, 1H, J=7.4 Hz), 7.49 (m, 2H), 7.22 (m, 2H), 7.18 (m, 3H), 5.28 (dd, 1H, J=3.0, 9.6 Hz), 4.87 (d, 1H, J=10.6 Hz), 4.67 (d, 1H, J=10.6 Hz), 4.56 (d, 1H, J=9.7 Hz), 4.12 (m, 1H), 3.85 (t, 1H, J=9.8 Hz), 3.80 (m, 1H), 2.81 (m, 2H), 1.93 (d, 1H, J=6.7 Hz), 1.36 (m, 6H); 13C NMR (CDCl3) 166.2, 138.0, 133.7, 130.2, 130.1, 128.9, 128.7, 128.6, 128.2, 85.7, 78.1, 77.6, 76.5, 76.0, 74.7, 70.9, 25.6, 16.9, 15.4; MS: calcd for C22H26O5SNa 425.1, found m/z 425.2 (M+Na).
Reaction SMILES: [C:1]1([C:7]2[C:14]3[S:13][C:12]([NH2:15])=[N:11][C:10]=3[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.Cl.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[OH-].[Na+].Cl>C1COCC1.CO>[C:1]1([C:7]2[C:14]3[S:13][C:12]([NH:15][C:23](=[O:30])[C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)=[N:11][C:10]=3[NH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1nc2[nH]nc(-c3ccccc3)c2s1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: c1ccncc1
Product: O=C(Nc1nc2[nH]nc(-c3ccccc3)c2s1)c1ccncc1
Temperature: 70 °C
Reaction time: 22 h
Yield: 42.3 %

Procedure:
To a stirring solution of 3-phenyl-1H-pyrazolo[3,4-d]thiazol-5-ylamine (20 mg, 0.092 mmol) and pyridine (52 μL, 0.65 mmol) in THF (0.5 mL) was added isonicotinoyl chloride hydrochloride (82 mg, 0.46 mmol). The reaction mixture was stirred at 70° C. for 22 h, then cooled to room temperature and treated with MeOH (1 mL) and a 4N aqueous solution of NaOH (0.25 mL). The reaction mixture was further stirred at room temperature for 4 h, then a 1N aqueous solution of HCl was added to adjust the pH to 7, and the mixture was extracted with 10% MeOH in CH2Cl2 (3×). Purification on silica gel with 0-10% MeOH in CH2Cl2 as eluent provided 12.5 mg (42%) of N-(3-phenyl-1H-pyrazolo[3,4-d]thiazol-5-yl)-isonicotinamide as a beige solid. 1H-NMR (d6-DMSO) δ: 13.5 and 13.7 (2 broad s, 1H, NH+tautomer), 13.2 (broad s, 1H, NH), 8.83 (d, 2H), 7.99 (d, 2H), 7.80 (m, 2H, tautomers), 7.55 (m, 2H, tautomers), 7.40 (m, 1H, tautomers; HPLC/MS m/z: 322 [MH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(Cl)c2)CC1

Procedure:
2-chloro-4-fluoronitrobenzene (1.0 eq, 1 g, 5.7 mmol), N-methyl piperazine (1.2 eq, 1.18 g, 6.84 mmol), potassium carbonate (2.0 eq, 1.6 g, 11.6 mmol) were stirred at 100° C. in DMF for 3 hours. The mixture was cooled down and diluted with water. The material was extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and the solvent evaporated in vacuo. After trituration in diethylether and filtration, 1-(3-chloro-4-nitrophenyl)-4-methylpiperazine was isolated as a solid (0.9 g, 62%). LCMS (ES): m/z 256 [M+1]+. This material was suspended in MeOH (20 ml) with Raney Nickel (0.2 g) and stirred under hydrogen atmosphere overnight. The catalyst was filtered off through celite. Evaporation of the solvents provided 2-chloro-4-(4-methylpiperazin-1-yl)aniline as a dark brown oil (0.68 g, 86%). LCMS (ES): m/z 226 [M+1]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][S:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][S:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[CH2:8][NH2:10]
Reactant: COCCSc1ccccc1C(N)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCSc1ccccc1CN
Temperature: 0 °C
Yield: 142.8 %

Procedure:
(Step 1) To a suspension of 2-[(2-methoxyethyl)sulfanyl]benzamide (12.0 g) in tetrahydrofuran (122 ml) was added lithium aluminum hydride (13.4 g) at 0° C. under a nitrogen atmosphere. The reaction mixture was heated under reflux for 5 hr, cooled to 0° C., and quenched successively with water (15 ml) and 15% aqueous sodium hydroxide solution (15 ml). The mixture was filtered through celite, and washed with dichloromethane. The filtrate was washed with saturated brine, and the organic layer was dried over sodium sulfate, and filtered. The solvent was evaporated under reduced pressure to give 1-{2-[(2-methoxyethyl)sulfanyl]phenyl}methanamine (16.0 g) as an oil.
Reaction SMILES: BrBr.[Cl:3][C:4]1[CH:5]=[C:6]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[C:7](C(N)C#N)=[O:8].[CH2:17]([OH:21])[C:18]#[C:19][CH3:20].Br.C([N:25](CC)[CH2:26][CH3:27])C.C([N:32](CC)CC)C>C(OCC)(=O)C.O.O1CCCC1>[CH2:17]([O:21][CH:27]([NH:32][C:7](=[O:8])[C:6]1[CH:13]=[C:14]([Cl:16])[CH:15]=[C:4]([Cl:3])[CH:5]=1)[C:26]#[N:25])[C:18]#[C:19][CH3:20]
Reactant: N#CC(N)C(=O)c1cc(Cl)cc(Cl)c1
Reactant: CC#CCO
Reactant: CCN(CC)CC
Agent: Br
Agent: BrBr
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC#CCOC(C#N)NC(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
Bromine (2.8 g) was added at a time to a solution of 4.0 g of 3,5-dichlorobenzoyl aminoacetonitrile in 100 ml of ethyl acetate at room temperature. The mixture was stirred until the color of bromine in the reaction solution disappeared. The reaction solution was then cooled to 0° to 5° C. A mixture of 1.5 g of 2-butyn-1-ol, 3.5 g of triethylamine and 30 ml of tetrahydrofuran was cooled to 0° to 5° C. on an ice bath, and with stirring, the ethyl acetate solution of the bromine compound prepared above was added dropwise. After the addition, the reaction was continued for 30 minutes under cooling. Water (100 ml) was added to dissolve the precipitated triethylamine hydrobromide. The oil layer was separated, washed with water, and dried. The solvent was then distilled off under reduced pressure. The residual solid was suspended in ethyl ether, filtered, washed and dried to give 4.2 g of the desired alpha-(2-butynyloxy)-3,5-dichlorobenzoylaminoacetonitrile as a white solid. The yield was 79.9%, and the melting point of the product was 124° to 128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([OH:17])=O)=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:49][CH:50]1[NH:54][CH2:53][C:52]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)([OH:55])[CH2:51]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]([N:54]3[CH:50]([CH3:49])[CH2:51][C:52]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)([OH:55])[CH2:53]3)=[O:17])=[CH:13][O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(-c2nocc2C(=O)O)cc1Cl
Reactant: CC1CC(O)(c2ccccc2)CN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2nocc2C(=O)N2CC(O)(c3ccccc3)CC2C)cc1Cl
Yield: 72.7 %

Procedure:
A solution of 3-(3-chloro-4-methoxyphenyl)-isoxazole-4-carboxylic acid (10 mg, 0.04 mmol), N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.08 mmol, 2 equ.) and TBTU (15 mg, 0.046 mmol, 1.2 equ.) in DMF (0.3 mL) was added to 5-methyl-3-phenylpyrrolidin-3-ol (7 mg, 0.04 mmol). After 1 h at rt the crude product was purified by RP-HPLC, evaporated and dried in vacuum to yield the title compound (12 mg). MS (ESI, pos. ion) m/z: calcd for C22H21ClN2O4: 412.1190, found 412.1189.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[N:10][CH:11]=[C:12]([N+:15]([O-])=O)[C:13]=2[NH2:14])[CH2:4][CH2:3]1>CO.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[C:13]([NH2:14])=[C:12]([NH2:15])[CH:11]=[N:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2cncc([N+](=O)[O-])c2N)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(c2cncc(N)c2N)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.8 %

Procedure:
To a solution of 3-(4-methylpiperazin-1-yl)-5-nitropyridin-4-amine (LXX) (382 mg, 1.61 mmol) in MeOH (11 mL) was added 10% Pd/C. The solution was purged with hydrogen and stirred at room temperature under hydrogen for 4 h. The suspension was filtered through Celite® and the concentrated under vacuum to produce 5-(4-methylpiperazin-1-yl)pyridine-3,4-diamine (LXXI) as purple solid (330 mg, 1.59 mmol, 99% yield). 1H NMR (DMSO-d6, 500 MHz,): δ 2.18 (s, 3H), 2.34-2.36 (m, 4H), 3.13-3.16 (m, 4H), 3.89 (s, 2H), 5.20 (s, 2H), 5.94 (s, 1H), 7.31 (s, 1H); ESIMS found C10H17N5 m/z 208 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[K].[CH3:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>>[CH3:16][N:17]([CH3:21])[C:18]([C:10]1[C:2]([CH3:1])=[N:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12)=[O:19]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1cc2ccccn2n1
Agent: [Al+3]
Agent: [Cl-]
Agent: [K]
Product: Cc1nn2ccccc2c1C(=O)N(C)C
Temperature: 0 °C
Yield: 32.5 %

Procedure:
2-Methylpyrazolo[1,5-a]pyridine (3.6g) was dissolved in N,N-dimethylcarbamoyl chloride (10.8g). Aluminum chloride (8.0g) was added to the resulting solution and the mixture was heated at 130° for 3 hr and poured into ice water. The solution was made basic with potassium hydroxied solution and extracted with chloroform. The chloroform solution was dried over sodium sulfate and concentrated. The residue was distilled to give 1.8g of the objective product, bp 149°-150° (2 mmHg). Yield 32%.
Reaction SMILES: [F:1][C:2]1([F:22])[CH2:6][NH:5][C@@H:4]([C:7]([NH:9][C@H:10]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[CH3:11])=[O:8])[CH2:3]1.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>>[F:22][C:2]1([F:1])[CH2:6][N:5]([CH2:29][C:28]2[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:33])[F:34])=[CH:32][CH:31]=2)[C@@H:4]([C:7]([NH:9][C@H:10]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)[CH3:11])=[O:8])[CH2:3]1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(F)(F)CN2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(F)(F)CN2Cc2ccc(C(F)(F)F)cc2)cc1
Yield: 36.5 %

Procedure:
The title compound (D166) (16.5 mg) was prepared according to the general procedure for substituted benzylamine preparation starting from methyl 4-((S)-1-((R)-4,4-difluoropyrrolidine-2-carboxamido)ethyl)benzoate (D165) (30 mg) and 4-(Trifluoromethyl)benzyl bromide (33 mg). (Na2CO3: 2.5 eq; reaction time: 18 hrs; 68° C.)
Reaction SMILES: COC[O:4][C:5]1[C:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]3[CH2:22][CH2:23][O:24][C:25]4[CH:31]=[CH:30][C:29]([C:32]5[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=5)=[CH:28][C:26]=4[CH:27]=3)=[O:20])=[CH:14][CH:13]=2)=[N:7][CH:8]=[CH:9][CH:10]=1.Cl.C(=O)(O)[O-].[Na+]>C(O)C>[OH:4][C:5]1[C:6]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]([C:21]3[CH2:22][CH2:23][O:24][C:25]4[CH:31]=[CH:30][C:29]([C:32]5[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=5)=[CH:28][C:26]=4[CH:27]=3)=[O:20])=[CH:16][CH:17]=2)=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: COCOc1cccnc1Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(C)cc4)ccc3OCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(Cc4ncccc4O)cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 75.9 %

Procedure:
To a solution of N-[4—(3-methoxymethoxypyridin-2-ylmethyl)phenyl]-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (1.00 g) in ethanol(20 ml) was added concentrated hydrochloric acid (5.0 ml), and the mixture was stirred at room temperature for 4 days. To the mixture was added saturated sodium bicarbonate solution at 0° C. to make the solution pH 6-7, and precipitated crystal was collected by filtration to give N-[4—(3-hydroxypyridin-2-ylmethyl)phenyl]-7—(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 174) (693 mg) as pale yellow crystals.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:29]([O:36][C:37]1[CH:42]=[CH:41][C:40]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19]([NH:21][CH3:22])=[O:20])=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(C)(=O)=O)c(C3CC3)cc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(OCc4ccccc4)cc3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 25 °C
Yield: 55.6 %

Procedure:
A stirred mixture of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonamido)benzofuran-3-carboxamide (0.500 g, 1.24 mmol), (4-(benzyloxy)phenyl)boronic acid (0.567 g, 2.49 mmol), copper(II) acetate (0.451 g, 2.49 mmol), and triethylamine (1.00 mL, 7.12 mmol) in DCM (25 mL) was treated with 1.00 g of powdered 3 angstrom molecular sieves. The resulting mixture was stirred at RT under air using a drying tube to exclude moisture. After 18 hours the mixture was treated with an additional 250 mg portion of (4-(benzyloxy)phenyl)boronic acid and stirring at RT continued. After another 8 hours the mixture was filtered through Celite and the filtrate concentrated to dryness at reduced pressure. The black residue was suspended in EtOAc and the undissolved solids removed by filtration through Celite. The filtrate was concentrated to dryness at reduced pressure and the residue subjected to flash chromatography (silica gel, gradient elution from DCM to 1:1 DCM/EtOAc to give the title compound (0.403 g, 56%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.39-8.47 (m, 1H) 8.12-8.18 (m, 1H) 7.92-7.99 (m, 2H) 7.55 (d, J=8.9 Hz, 2H) 7.28-7.46 (m, 7H) 7.13 (s, 1H) 7.03 (d, J=9.0 Hz, 2H) 5.09 (s, 2H) 3.29 (s, 3H) 2.82 (d, J=4.5 Hz, 3H) 2.25-2.35 (m, 1H) 0.75-1.14 (m, 3H) 0.32-0.58 (m, 1H). LCMS (m/z, ES+)=585 (M+H+).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[C:27]([Cl:32])[CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[O:12])[CH2:7][CH2:6]1)(=[NH:3])[CH3:2].C(N(CC)CC)C.[C:40](Cl)(=[O:43])[O:41][CH3:42]>ClCCl>[CH3:42][O:41][C:40]([CH2:2][C:1]([NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[C:27]([Cl:32])[CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[O:12])[CH2:7][CH2:6]1)=[NH:3])=[O:43]
Reactant: CC(=N)N[C@H]1CC[C@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC(=N)N[C@H]1CC[C@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(trans-4-acetimidoylaminocyclohexane-1-ylcarbonyl)-4-(6-chloronaphthalene-2-sulfonyl)piperazine (300 mg) and triethylamine (199 mg) in dichloromethane (30 ml) was added methyl chlorocarbonate (192 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate) to give colorless crystals of the title compound (171 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([C:14]([OH:16])=O)[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.Cl.[CH3:18][NH:19][CH3:20].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C>C(#N)C.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH:8]([C:14]([N:19]([CH3:20])[CH3:18])=[O:16])[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1
Reactant: CNC
Reactant: COc1ccc2c(c1)NC(=O)C(C(=O)O)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc2c(c1)NC(=O)C(C(=O)N(C)C)C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 38.8 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-7-methoxy-2-oxo-3-quinolinecarboxylic acid (3.74 g), dimethylamine hydrochloride (3.44 g), 1-hydroxybenzotriazole (2.85 g), and triethylamine (8.5 g) in acetonitrile (400 ml) was added WSC (6.5 g). The reaction mixture was stirred at room temperature for 24 hr and concentrated. The residue was diluted with ethyl acetate and the organic layer was washed with 1 N aqueous hydrochloric acid, 10% aqueous potassium carbonate, and saturated aqueous sodium chloride, dried, and concentrated. The resulting crude crystals were recrystallized from ethyl acetate-hexane to obtain the titled compound (1.63 g).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:21]=[C:20]2[C:15]([CH2:16][CH2:17][CH2:18][CH:19]2[NH2:22])=[CH:14][CH:13]=1>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:22][CH:19]1[C:20]2[C:15](=[CH:14][CH:13]=[C:12]([F:11])[CH:21]=2)[CH2:16][CH2:17][CH2:18]1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: NC1CCCc2ccc(F)cc21
Product: Fc1ccc2c(c1)C(Nc1nc3ccccc3[nH]1)CCC2

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 7-fluoro-1,2,3,4-tetrahydro-1-naphthylamine (prepared by Procedure B from 7-fluoro-1 -tetralone) by Procedure A. The product was purified by column chromatography to give the title compound as the free base and as a mixture of enantiomers (white solid, mp 181° C.). MS(ES+) m/z 282 ([M+1]+, 100).
Reaction SMILES: C(O[C:4]([C:6]1[O:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[CH2:13][CH2:12]2)=[N:9][N:10]=1)=[O:5])C.[CH2:29]([NH2:34])[CH2:30][CH2:31][CH2:32][CH3:33].[C-]#N.[Na+]>>[CH2:29]([NH:34][C:4]([C:6]1[O:7][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:26])([F:27])[F:25])[CH2:13][CH2:12]2)=[N:9][N:10]=1)=[O:5])[CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCOC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)o1
Reactant: CCCCCN
Agent: [C-]#N
Agent: [Na+]
Product: CCCCCNC(=O)c1nnc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)o1
Temperature: 25 °C
Yield: 86 %

Procedure:
5-[4-(2-Trifluoromethylbenzoyl)piperazin-1-yl]-[1,3,4]oxadiazole-2-carboxylic acid ethyl ester (0.050 g, 0.126 mmol) was added to the mixture of n-pentylamine (1 mL) and sodium cyanide (0.012 g, 0.251 mmol). The reaction mixture was stirred at room temperature over night. The mixture was evaporated to dryness, then diluted with 5 mL of water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4, and then concentrated. The title compound was obtained in 86% yield (0.047 g) after column purification. 1H NMR (300 MHz, CDCl3) δ 7.74-7.71 (m, 1H), 7.64-7.52 (m, 2H), 7.33-7.31 (m, 1H), 6.91 (t, J=5.4 Hz, 1H), 4.09-3.98 (m, 1H), 3.87-3.6 (m, 3H), 3.58-3.45 (m, 2H), 3.42-3.36 (m, 2H), 3.30-3.27 (m, 2H), 1.63-1.5 (m, 2H), 1.33-1.29 (m, 4H), 0.87 (t, J=6.6 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 167.6, 164.6, 153.9, 153.5, 133.9, 132.4, 129.6, 128.97, 127.1, 126.9, 126.8, 126.7, 125.4, 121.8, 46.0, 45.7, 45.6, 40.8, 39.7, 29.0, 28.9, 22.3, 13.9. MS (ES+) m/z 440 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].[F:10][C:11]([F:23])([F:22])[C:12]1[CH:21]=[CH:20][C:15]([C:16](=[N:18]O)[NH2:17])=[CH:14][CH:13]=1.O>O1CCOCC1>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:8][N:18]=[C:16]([C:15]2[CH:14]=[CH:13][C:12]([C:11]([F:10])([F:22])[F:23])=[CH:21][CH:20]=2)[N:17]=1
Reactant: NC(=NO)c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)c1sccc1Cl
Solvent: C1COCCO1
Solvent: O
Product: FC(F)(F)c1ccc(-c2noc(-c3sccc3Cl)n2)cc1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
A solution of 3-chloro-thiophene-2-carbonyl chloride (455 mg, 2.51 mmol) and 4-trifluoromethyl-benzamidoxime (513 mg, 2.51 mmol) in 1,4-dioxane (50 mL) was refluxed for 1 h, then BF3OEt2 (0.1 mL) was added dropwise. The solution was refluxed for 5 h and cooled to room temperature. To the stirred solution was added water (100 mL) to produce precipitates. The solid was collected by filtration, washed with dioxane:water (1:1), and dried to yield 687 mg (82%) of the title compound. 1H NMR (CDCl3): 8.29 (d, J=8.1 Hz, 2H), 7.78 (d, J=8.4 Hz, 2H), 7.63 (d, J=5.1 Hz, 1H), 7.15 (d, J=5.1 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20](O)=[O:21])[C:15]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][CH:31]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:32]([OH:37])[C:33]([F:36])([F:35])[F:34].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:30][CH:31]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:32]([OH:37])[C:33]([F:34])([F:35])[F:36])=[O:21])[C:15]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:30][CH:31]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:32](=[O:37])[C:33]([F:35])([F:36])[F:34])=[O:21])[C:15]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(Cc1ccccc1)C(O)C(F)(F)F
Reactant: O=C(O)Cn1c(-c2ccc(F)cc2)ncc(NC(=O)OCc2ccccc2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cn1c(-c2ccc(F)cc2)ncc(NC(=O)OCc2ccccc2)c1=O)NC(Cc1ccccc1)C(=O)C(F)(F)F
Product: O=C(Cn1c(-c2ccc(F)cc2)ncc(NC(=O)OCc2ccccc2)c1=O)NC(Cc1ccccc1)C(O)C(F)(F)F

Procedure:
2-[5-Benzyloxycarbonylamino-2-(4-fluorophenyl)-6-oxo-1,6-dihydro-1-pyrimidyl]-N-(1-benzyl-3,3,3-trifluoro-2-hydroxypropyl)acetamide was synthesized in the same manner as in Example 1. That is, [5-benzyloxycarbonylamino-2-(4-fluorophenyl)-6-oxo-1,6-dihydro-1-pyrimidinyl]acetic acid (title compound in Reference Example 3, mixture with benzyl alcohol, 1.90 g, 4.48 mmol) was treated with 3-amino-1,1,1-trifluoro-4-phenyl-2-butanol (title compound in Reference Example 1, 1.00 g, 4.56 mmol), WSCI hydrochloride (1.03 g, 5.37 mmol) and HOBT (1.21 g, 8.95 mmol) in DMF (15 mL) to give 2.49 g (93%) of the target compound as colorless crystals.