Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([O:23][C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31](=[O:35])[CH2:32][O:33][CH3:34])[CH:25]=3)=[CH:15][CH:14]=2)[N:7]([C:37]2[CH:42]=[CH:41][C:40]([N+:43]([O-])=O)=[CH:39][CH:38]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.CC(O)=O.[Pt]>[NH2:43][C:40]1[CH:39]=[CH:38][C:37]([N:7]2[C:8]([NH:10][C:11](=[O:36])[NH:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][C:31](=[O:35])[CH2:32][O:33][CH3:34])[CH:25]=4)=[CH:15][CH:14]=3)=[CH:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6]2)=[CH:42][CH:41]=1
Reactant: [H][H]
Reactant: COCC(=O)Nc1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc([N+](=O)[O-])cc3)c3ccccc23)ccn1
Agent: [Pt]
Solvent: CC(=O)O
Solvent: CO
Product: COCC(=O)Nc1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(N)cc3)c3ccccc23)ccn1

Procedure:
A solution of N-(4-(4-(3-(3-tert-butyl-1-(4-nitrophenyl)-1H-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-methoxyacetamide (270 mg, 0.443 mmol) in a mixture of MeOH (20 mL) and AcOH (1.0 mL) was subjected to hydrogenation by passage through a Thales H-cube (1.0 mL min−1, 40° C., 55 mm, 10% Pt—C Cat-Cart, full hydrogen mode). The reaction mixture was evaporated in vacuo and the residue was partitioned between EtOAc (15 mL) and saturated aq. NaHCO3 (15 mL). The organic layer was separated and was washed with brine (15 mL) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, EtOAc in isohexane, 20-100%, gradient elution) to afford the title compound, Example 1, as a pale brown solid (115 mg, 43%); Rt 4.87 min (Method 1 basic); m/z 580 (M+H)+ (ES+); 1H NMR (400 MHz, DMSO-d6) δ: 1.25 (9H, s), 3.30 (3H, s), 3.98 (2H, s), 5.41 (2H, s), 6.34 (1H, s), 6.68-6.71 (3H, overlapping m), 7.14 (2H, d), 7.33 (1H, d), 7.57 (1H, m), 7.63-7.67 (2H, overlapping m), 7.83 (1H, d), 7.98 (1H, dd), 8.09 (1H, d), 8.18 (1H, d), 8.65 (1H, s), 9.18 (1H, s), 10.04 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][CH2:14][C:15]([OH:17])=O)=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.Cl.[OH:19][CH:20]1[CH2:23][NH:22][CH2:21]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[OH:19][CH:20]1[CH2:23][N:22]([C:15](=[O:17])[CH2:14][NH:13][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:12])[CH2:21]1
Reactant: O=C(O)CNC(=O)c1cc2cc(Cl)ncc2[nH]1
Reactant: OC1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CC(O)C1)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
[(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]acetic acid (30 mg, 0.12 mmol), 3-hydroxyazetidine hydrochloride (13 mg, 0.12 mmol) and HOBt (16 mg, 0.12 mmol) were dissolved in DMF (3 ml) and DIPEA (4311, 0.25 mmol). After 5 min, EDCI (30 mg, 0.15 mmol) was added and the reaction mixture stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (20 ml) and DCM (3×20 ml). The combined organics were dried (MgSO4), concentrated in vacuo and the residue purified by chromatography on silica gel eluting with methanol:dichloromethane (1:24) to give the title compound as a white solid. δH (CD3OD): 4.06-4.15 (3H, m), 4.40-4.46 (1H, m), 4.55-4.63 (1H, m), 4.77-4.94 (2H, m), 7.14 (1H, s), 7.71 (1H, s), 8.62 (1H, s); RT=2.82 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=2)[C:15]([OH:17])=[O:16])[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>O>[OH:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:28][CH:27]=2)[C:9]([OH:11])=[O:10])[C:15]([OH:17])=[O:16])=[CH:24][CH:23]=1
Reactant: COc1ccc(C[C@@H](CC[C@H](Cc2ccc(OC)cc2)C(=O)O)C(=O)O)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(C[C@@H](CC[C@H](Cc2ccc(O)cc2)C(=O)O)C(=O)O)cc1
Temperature: 160 °C
Reaction time: 0.33 h
Yield: 30.8 %

Procedure:
To a round bottom flask was added (2R,5R)-2,5-bis(4-methoxybenzyl)hexanedioic acid (124 mg, 0.321 mmol) and pyridine hydrochloride (371 mg, 3.21 mmol). The reaction was stirred at 160° C. for 20 min. After cooling to rt, the reaction was diluted with water and extracted with EtOAc (2×15 mL). The combined EtOAc extracts were concentrated in vacuum. The resulting residue was purified using RP prep-HPLC (Method B) to give (2R,5R)-2-(4-hydroxybenzyl)-5-(4-methoxybenzyl)hexanedioic acid (37 mg, 0.099 mmol, 31% yield) as white solid.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li:13])CCC>CCCCCC.O1CCCC1>[C:1]1([S:7][CH2:8][Li:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1ccccc1
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Li]CSc1ccccc1

Procedure:
To a solution of 1.17 ml. of thioanisole in 20 ml. of dry tetrahydrofuran were added 8.4 ml. of a 1.2M solution of n-butyllithium in n-hexane at -20° C. and the mixture was stirred at the same temperature of 1.5 hours to give a 0.28M solution of phenylthiomethyllithium in tetrahydrofuran.
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([CH2:8][N:9]2[C:13]([CH2:14][C:15]([OH:17])=[O:16])=[C:12]([Cl:18])[N:11]=[C:10]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[H][H].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[C:13]([CH2:14][C:15]([OH:17])=[O:16])=[C:12]([Cl:18])[N:11]=[C:10]2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:25][CH:26]=1
Reactant: [H][H]
Reactant: O=C(O)Cc1c(Cl)nc(-c2ccccc2)n1Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Cn2c(-c3ccccc3)nc(Cl)c2CC(=O)O)cc1
Yield: 76.1 %

Procedure:
In 100 ml of ethanol was dissolved 2 g of 1-(p-nitrobenzyl)-2-phenyl-4-chloroimidazole-5-acetic acid, and following addition of 300 mg of 10% palladium-on-carbon, the solution was shaken in hydrogen streams for 2 hours. The catalyst was filtered off and the filtrate was concentrated to dryness under reduced pressure and recrystallized from ethanol-hexane. By the above procedure was obtained 1.4 g of 1-(p-aminobenzyl)-2-phenyl-4-chloroimidazole-5-acetic acid as colorless needles, m.p. 141°-145° C. (decomp.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH2:30])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1.[H-].[Na+].[C:33]1([N:39]=[C:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:29]([NH:30][C:40]([NH:39][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:41])=[N:28][C:12]2[N:13]=[C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: O=C=Nc1ccccc1
Reactant: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(N)nc3n2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(CCCNc2ncc3cc(-c4c(Cl)cccc4Cl)c(NC(=O)Nc4ccccc4)nc3n2)CC1
Yield: 65.5 %

Procedure:
6-(2,6-Dichlorophenyl)-N2 -[3-(4-methyl-piperazin-1-yl)-propyl]-pyrido[2,3-d]pyrimidine-2,7-diamine (13.0 g) from Example 36 in DMF (160 mL) was reacted with 60% sodium hydride suspension (1.16 g) and phenyl isocyanate (3.47 g) according to the general procedure of Example 37. Recrystallization of the chromatographed product from ethyl acetate gave 10.78 g of the title compound 1-{6-(2,6-dichlorophenyl)-2-[3-(4-methyl-piperazin-1-yl)-propylamino]-pyrido[2,3-d]-pyrimidin-7-yl}-3-phenyl-urea, ESMS (20/80 MeOH/CH3CN+0.1% AcOH): M+ +H=565;
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]([CH2:19][CH3:20])[CH3:18])=[O:16])[CH2:10]2)=[N:6][C:7]=1[NH2:8].[CH:21]1([C:24]2[N:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][N:25]=2)[CH2:23][CH2:22]1.[S].C(O)(=O)C>C(O)C>[CH:21]1([C:24]2[N:29]=[C:28]([C:30]3[NH:8][C:7]4=[N:6][C:5]([N:9]5[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([N:17]([CH2:19][CH3:20])[CH3:18])=[O:16])[CH2:10]5)=[CH:4][CH:3]=[C:2]4[N:1]=3)[CH:27]=[CH:26][N:25]=2)[CH2:23][CH2:22]1
Reactant: CCN(C)C(=O)[C@@H]1CCCN(c2ccc(N)c(N)n2)C1
Reactant: O=Cc1ccnc(C2CC2)n1
Agent: [S]
Solvent: CCO
Solvent: CC(=O)O
Product: CCN(C)C(=O)[C@@H]1CCCN(c2ccc3nc(-c4ccnc(C5CC5)n4)[nH]c3n2)C1
Temperature: 80 °C
Yield: 13.7 %

Procedure:
To a solution of (R)-1-(5,6-diaminopyridin-2-yl)-N-ethyl-N-methylpiperidine-3-carboxamide (200 mg, 0.722 mmol) in ethanol (10 mL) was added 2-cyclopropylpyrimidine-4-carbaldehyde (106 mg, 0.722 mmol), sulfur powder (69 mg, 2.16 mmol), and acetic acid (0.2 mL). The reaction mixture was heated to 80° C. for 18 h. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was concentrated under reduced pressure. The crude material was purified via preparative HPLC to afford the title compound (40 mg, 13.5%). 1H NMR (300 MHz, CDCl3) δ 1.09-1.18 (m, 3H), 1.19-1.31 (m, 4H), 1.65-1.73 (m, 1H), 1.84 (d, 1H), 1.88-1.98 (m, 2H), 2.31 (d, 1H), 2.69-2.87 (m, 1H), 2.99 (br s, 1H), 3.03 (br s, 1H), 3.11 (br s, 1H), 3.14-3.27 (m, 1H), 3.37-3.57 (m, 2H), 4.37 (d, 1H), 4.45-4.59 (m, 1H), 6.76 (d, 1H), 7.79-7.96 (m, 1H), 8.67 (d, 1H), 10.25 (br s, 1H). MS (ES+APCI) (M+H) 406.3; LCMS retention time 3.055 min (Method U1).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][CH:29]([OH:37])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:27]([CH2:28][CH:29]([OH:37])[CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH3:26])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Reactant: CNCC(O)Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(CN(C)CC(O)Cc2ccccc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.7 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 1-(methylamino)-3-phenylpropan-2-ol (Eur. J Med. Chem.—Chim. Ther. 1979, 14, 165-70)(63 mg, 0.38 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5.0 mL) was stirred for 24 hours at room temperature. The solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (94 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8](Cl)[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:17][NH2:18]>CCO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:18][CH3:17])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: Cl[C@@H](CN1CCOCC1)c1ccc(Br)cc1
Reactant: CN
Solvent: CCO
Product: CN[C@@H](CN1CCOCC1)c1ccc(Br)cc1
Temperature: 0 °C
Yield: 93 %

Procedure:
Crude 4-[(2R)-2-(4-Bromophenyl)-2-chloroethyl]morpholine (34.5 g) was dissolved in 200 mL of EtOH at room temperature with magnetic stirring. The resulting solution was cooled to 0° C. and treated with 71 ml of MeNH2 (33 wt % in EtOH) under N2. The reaction flask was capped by a rubber septum, and the reaction mixture was maintained at room temperature for 48 h. The reaction mixture was concentrated, and the residue was partitioned between EtOAc and sat NaHCO3(aq). The organic layer was washed by brine, dried over MgSO4, and filtered. The filtrate was concentrated to yield the title compound as a yellow solid (31.6 g, 93%). MS (ES) m/e 300, 301 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:13][SH:14])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[CH2:16]([C:23]1[O:24][C:25]2[CH:45]=[CH:44][CH:43]=[CH:42][C:26]=2[C:27]=1[C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=2)=[CH:30][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:15])[C@@H:4]([NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])[CH2:13][S:14][CH2:40][C:37]1[CH:36]=[CH:35][C:34]([C:31]2[CH:30]=[CH:29][C:28]([C:27]3[C:26]4[CH:42]=[CH:43][CH:44]=[CH:45][C:25]=4[O:24][C:23]=3[CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:33][CH:32]=2)=[CH:39][CH:38]=1
Reactant: BrCc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Reactant: COC(=O)[C@H](CS)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CSCc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.7 %

Procedure:
N-Boc-L-Cysteine methyl ester (260 mg, 0.23 mL, 1.1 mmol) was added dropwise to a stirred suspension of 2-Benzyl-3-(4′-bromomethylbiphen-4-yl)benzofuran (500 mg, 1.1 mmol) and cesium carbonate (720 mg, 2.21 mmol) in anhydrous dimethylformamide (20 mL). The reaction was stirred at room temperature for 2 hrs (TLC control) and then poured into water (100 mL) and extracted with diethyl ether (3×100 mL). The combined extract was washed with water, brine (3×), dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification using 30% ethyl acetate in heptane as eluent afforded the title compound as a white solid (620 mg, 92%): 1H NMR (CDCl3, 300 MHz): δ 7.70 (2H, m, Ar—H), 7.64 (2H, m, Ar—H), 7.60 (3H, m, Ar—H), 7.48 (1H, m, Ar—H), 7.42 (2H, m, Ar—H), 7.26-7.36 (7H, m, Ar—H), 5.32 (1H, d, J=8 Hz, NH), 4.58 (1H, m, CHN), 4.26 (2H, PhCH2), 3.79 (2H, s, PhCH2S), 3.76 (3H, s, OMe), 2.95 (1H, dd, J=13, 5 Hz, CHHCHN), 2.84 (1H, dd, J=13, 7 Hz, CHHCHN), 1.46 (9H, s, CMe3); ESI-LCMS e/z calcd for C37H37NO5S 607.760, found 608 (M+H)+, 630 (M+Na)+.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][C:11]([O:13][CH3:14])=[O:12].Cl[CH:16](Cl)[O:17]C.Cl>ClCCl.O>[CH:16]([C:9]1[S:5][C:6]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:8]=1)=[O:17]
Reactant: COC(=O)Cc1cccs1
Reactant: COC(Cl)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COC(=O)Cc1ccc(C=O)s1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
To a suspension of aluminium trichloride (853 mg, 6.4 mmol) in dichloromethane (4 mL) at −10° C. was added a solution of methyl 2-(2-thienyl)acetate (500 mg, 3.2 mmol) in dichloromethane (3 mL). The resulting solution was stirred at −10° C. for 10 minutes. A solution of dichloro(methoxy)methane (434 μL, 4.8 mmol) in dichloromethane (3 mL) was then added dropwise over 30 minutes. The reaction mixture was stirred at −10° C. for 1 h. The resulting solution was poured into a flask containing water (20 mL), crushed ice and concentrated HCl (1 mL) and stirred vigorously for 30 minutes. The solution was washed with dichloromethane (3×20 mL) and the combined organic phases washed with aqueous saturated sodium bicarbonate (30 mL) followed by brine (30 mL). The phases were separated over a hydrophobic frit and concentrated in vacuo to give the title compound as a red oil (533 mg, 91%) which was used in the next step without further purification.
Reaction SMILES: [Na+].[Br:2][C:3]1[C:4]([Cl:17])=[CH:5][C:6]([N+:14]([O-])=O)=[C:7]([NH:9][CH2:10][C:11]([O-])=[O:12])[CH:8]=1.O.O.[Sn](Cl)Cl>C(O)C>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][C:4]=1[Cl:17])[NH:14][C:11](=[O:12])[CH2:10][NH:9]2
Reactant: O=C([O-])CNc1cc(Br)c(Cl)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1CNc2cc(Br)c(Cl)cc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A solution of N-(5′-bromo-4′-chloro-2′-nitrophenyl)glycine sodium salt (0.255 g, 0.824 mmol, as prepared above) and tin (II) chloride dihydrate (0.560 g, 2.48 mmol, Aldrich, used as received) in ethanol (6 mL) was refluxed for 3 h. It was then cooled to room temperature and allowed to stand overnight at room temperature. The white solid was filtered and dried to yield 0.038 g (18%) of the pure (1H NMR) title compound as white flakes; m.p. 230-232° C.; 1H NMR (DMSO-d6): δ 3.732 (s, 2H), 6.371 (s, 1H), 6.830 (s, 1H), 6.912 (s, 1H), 10.437 (s, 1H). Extraction of the filtrate with ethyl acetate (30 mL) gave 0.136 g (68%) more product for a combined yield of 86%. The product was used as such for the next reaction.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[C:4]([CH3:18])[CH:3]=1.[NH2:19][C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C@@H:9]([NH:8][C:6]2[CH:5]=[C:4]([CH3:18])[CH:3]=[C:2]([NH:19][C:20]3[CH:25]=[N:24][CH:23]=[CH:22][N:21]=3)[N:7]=2)[CH3:10])=[CH:12][CH:13]=1
Reactant: Cc1cc(Cl)nc(N[C@@H](C)c2ccc(F)cc2)c1
Reactant: Nc1cnccn1
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(Nc2cnccn2)nc(N[C@@H](C)c2ccc(F)cc2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
95 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4-methylpyridine-2-amine, 40 mg of 2-aminopyrazine, 34 mg of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, 48 mg of sodium t-butoxide and 19 mg of tris(dibenzylideneacetone)(chloroform)dipalladium were added in turn to 6 ml of degassed toluene, and the mixture was stirred at 100° C. for 1 hour under argon atmosphere. The reaction solution was purified by silica gel column chromatography to obtain 85 mg of (S)—N2-[1-(4-fluorophenyl)ethyl]-4-methyl-N6-(pyrazin-2-yl)pyridine-2,6-diamine. Furthermore, the obtained compound was subjected to hydrochlorination using a conventional method to obtain 38 mg of the objective compound as yellow powder.
Reaction SMILES: [C:1]([N:4]=[C:5](OCC)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[Cl:13])(=O)[CH3:2].Cl.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][NH2:27].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:13][C:7]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=1[C:5]1[N:4]=[C:1]([CH3:2])[N:26]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([F:18])([F:29])[F:28])[N:27]=1
Reactant: NNc1ccccc1C(F)(F)F
Reactant: CCOC(=NC(C)=O)c1ccc(F)cc1Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc(F)cc2Cl)nn1-c1ccccc1C(F)(F)F

Procedure:
A mixture of 6.1 g (22 mmol) of ethyl N-acetyl-2-chloro-4-fluorobenzimidate and 6.7 g (25 mmol) of o-trifluoromethylphenylhydrazine hydrochloride in 100 ml of toluene is treated with 3.9 ml (28 mmol) of triethylamine and the whole is heated at reflux temperature for 18 hours. Thereafter, the reaction mixture is washed once with water and extracted twice with 50 ml of concentrated hydrochloric acid. The acidic aqueous phases are neutralized with ice-cold sodium hydroxide solution and extracted twice with diethyl ether, and the combined extracts are dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue is subjected to a bulb-tube distillation, the fractions with b.p. 200° C./0.01 mmHg (9.33 Pa) being collected and finally crystallized from diisopropyl ether/n-hexane. In this manner there is obtained 3-(2-chloro-4-fluorophenyl)-5-methyl-1-(α,α,α-trifluoro-o-tolyl)-1H-1,2,4-triazole, m.p. 116° C.; 1H--NMR (CDCl3, 60 MHz): 2.37 (s,CH3); mass spectrum: 335 (48), 314(43), 159(100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[OH:15].N1C=CC=CC=1.[N+:27]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([O-:29])=[O:28]>ClCCl>[N+:27]([C:30]1[CH:31]=[CH:32][C:33]([S:36]([O:15][C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]2[O:8][CH2:7][CH2:6][C:5]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:38])=[O:37])=[CH:34][CH:35]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(CCO[C@H]2CCCC[C@H]2O)cc1OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CCO[C@H]2CCCC[C@H]2OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
A 10-mL round bottom flask under nitrogen atmosphere was charged with cis-2-(3,4-dimethoxyphenethoxy)cyclohexan-1-ol (13) (80 mg, 0.28 mmol), anhydrous dichloromethane (3 mL), and anhydrous pyridine (70 μL, 0.86 mmol). After the reaction mixture was cooled to 0° C., a solution of 4-nitro-benzenesulfonyl chloride (95 mg, 0.43 mmol) in anhydrous dichloromethane (1.5 mL) was added dropwise. The reaction was stirred at 0° C. for 30 minutes, and then at room temperature until total consumption of all starting material 13 (20 h), as revealed by TLC (1:1, v/v EtOAc:hexane). The reaction mixture was diluted with dichloromethane (10 mL) and aqueous H2SO4 (5%, 10 mL). After the aqueous layer was extracted with CH2Cl2 (2×10 mL), the organic layers were combined, washed successively with diluted aqueous H2SO4 (5%, 10 mL) and brine (10 mL), dried (anhydrous MgSO4), and concentrated in vacuo to give a yellow oil. Purification of this crude material by elution through a silica gel plug using a mixture of ethyl acetate-hexanes (1:2, v/v) afforded 14 (95 mg, 72%). Rf 0.71 (EtOAc-hexanes, 1:1, v/v); 1H-NMR (400 MHz, CDCl3) δ 1.21-1.69 (m, 8H), 2.01-2.11 (m, 1H), 2.63 (t, 2H, J 6.9 Hz), 3.36-3.38 (m, 1H), 3.43-3.57 (m, 2H), 3.83 (s, 6H, OCH3), 4.84-4.86 (m, 1H), 6.63-6.69 (m, 2H), 6.75 (d, 1H, J 8.1 Hz), 8.01-8.05 (m, 2H), 8.24-8.28 (m, 2H); 13C-NMR (100 MHz, CDCl3) δ 21.19, 21.57, 27.20, 29.00, 35.90, 55.76, 55.87, 69.93, 82.65, 111.07, 112.19, 120.63, 124.06, 128.92, 131.39, 143.45, 147.45, 148.68, 150.33.
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[N:5]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([CH:36]3[CH2:38][CH2:37]3)=[CH:28][CH:27]=2)[C:6]([S:9][CH2:10][C:11]([NH:13][CH:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([O:17]C)=[O:16])=[O:12])=[N:7][N:8]=1>C1COCC1.O>[Br:3][C:4]1[N:5]([C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([CH:36]3[CH2:38][CH2:37]3)=[CH:28][CH:27]=2)[C:6]([S:9][CH2:10][C:11]([NH:13][CH:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([OH:17])=[O:16])=[O:12])=[N:7][N:8]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=O)CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CSc1nnc(Br)n1-c1ccc(C2CC2)c2ccccc12)NC(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Aqueous lithium hydroxide solution (1M, 0.8 mL, 0.8 mmol) is added to a solution of methyl 2-(2-(5-bromo-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetamido)-3-phenylpropanoate (0.4 mmol) in 3:1, THF/H2O (1.6 mL) and the mixture stirred for 18 h at room temperature. The crude reaction mixture is concentrated and acidified with aqueous HCL (1M, 1.2 mL) and then is extracted with ethyl acetate (3×3 mL). The combined organic extracts are dried (sodium sulfate), filtered and concentrated to provide the desired product.