Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@:2]1([OH:20])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[C:14]2[N:15]=[CH:16][N:17]=[C:18]([NH2:19])[C:13]=2[CH:12]=[CH:11]1.C1C2=C(N)N=CN=C2N([C@@H]2[O:35][C@H:34](CO)[C@@H](O)[C@H]2O)C=1>>[CH3:1][C@@:2]1([OH:20])[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[C:14]2[N:15]=[CH:16][N:17]=[C:18]([NH2:19])[C:13]=2[C:12]([CH:34]=[O:35])=[CH:11]1
Reactant: Nc1ncnc2c1ccn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1ccc2c(N)ncnc21
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(C=O)c2c(N)ncnc21

Procedure:
7-(2′-C-methyl-β-D-ribofuranosyl)-4-amino-5-(formyl)-pyrrolo[2,3-d]pyrimidine was synthesized according to the procedure described by Shin-ichi Watanabe and Tohru Ueda in Nucleosides and Nucleotides (1983) 2(2), 113–125. In the synthesis of the title compound however, 7-(2′-C-methyl-β-D-ribofuranosyl)-4-amino-pyrrolo[2,3-d]pyrimidine (See Carroll, et al.,11,12) was substituted in place of tubercidin.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=1.[Li]CCCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:27]=[N:26][N:25]([CH3:28])[C:24]=2[CH:29]=[O:30])=[CH:19][CH:18]=1>C1COCC1>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[N:27]=[N:26][N:25]([CH3:28])[C:24]=2[CH:29]([OH:30])[CH2:1][C:2]2[S:3][C:4]([C:8]([OH:10])=[O:9])=[C:5]([CH3:7])[N:6]=2)=[CH:21][CH:22]=1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1C=O
Reactant: Cc1nc(C)c(C(=O)O)s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nc(CC(O)c2c(-c3ccc(F)cc3)nnn2C)sc1C(=O)O
Temperature: -75 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
To a suspension of 2,4-dimethylthiazole-5-carboxylic acid (236 mg, 1.5 mmol) in THF (12 mL) was added dropwise n-BuLi (1.6 M in hexanes, 1.88 mL, 3.0 mmol) under Ar at −75° C. The brown suspension was stirred at −75° C. for 2 h and then a solution of 5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazole-4-carbaldehyde (308 mg, 1.50 mmol) in THF (4.5 mL) was added at −75° C. and the brown suspension was stirred at −75° C. for 2 h. The mixture was then quenched with an aqueous solution of citric acid (5%, 15 mL), allowed to warm to room temperature. The mixture was then poured into saturated ammonium chloride solution and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated. Purification by chromatography (silica, 0 to 30% methanol in dichloromethane) afforded 2-{2-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-yl]-2-hydroxy-ethyl}-4-methyl-thiazole-5-carboxylic acid (417 mg, 77%) as a yellow foam. The acid was then dissolved in methanol (4 mL) and diethylether (2 mL) and trimethylsilyldiazomethane (2M in diethylether, 5×0.38 mL, 3.75 mmol) added dropwise. The reaction was quenched with a few drops of AcOH and evaporated. To the brown oil was added sodium hydroxide (1 N, 20 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, 0 to 30% methanol in dichloromethane) afforded the title compound (214 mg, 38%) as a light brown foam.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][C:21]1[CH:22]=[C:23]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:24]=[C:25]([CH3:27])[CH:26]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:31]1[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[C:25]([CH3:27])[CH:26]=[C:21]([CH3:20])[CH:22]=3)[CH2:29][CH2:30]1)=[O:19])=[N:5]2
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2cc(C)cc(C)c2)CC1
Yield: 79 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 79%). 1H NMR (300 MHz, CDCl3): δ 2.29 (s, 6H), 3.27 (s, 4H), 3.88 (s, 3H), 4.14 (s, 4H), 6.59 (s, 3H), 7.01-7.10 (s, 1H), 7.24-7.36 (m, 2H), 7.47-7.71 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].[CH2:23](O)[CH3:24].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:13][CH:12]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)CCCc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Reactant: CCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCCc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 4-[4-(5-nitropyridin-2-yloxy)phenyl]butanoic acid (9.98 g, 33.01 mmol) in dichloromethane were added ethanol (5.59 mL, 99.01 mmol), 4-dimethylaminopyridine (400 mg, 3.27 mmol), triethylamine (13.81 mL, 99.08 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.6 g, 39.65 mmol) under ice cooling, and the resulting solution was stirred for 20 minutes under ice cooling and then for 1 hour at room temperature. The reaction solution was concentrated under reduced pressure. Water was added to the residue, and extracted with ethyl acetate, and the ethyl acetate layer was washed with 1 N hydrochloric acid, a saturated sodium bicarbonate solution and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), to thereby yield 6.77 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([OH:31])=O)=[CH:23][CH:22]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CCOC(C)=O>[CH3:1][O:2][C:3]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:4]=1[CH2:5][N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:29](=[O:31])[CH2:28][CH2:27][C:24]1[CH:23]=[CH:22][C:21]([OH:20])=[CH:26][CH:25]=1
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: CCCCCCCNCc1cccc(OC)c1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCCCCCN(Cc1cccc(OC)c1OC)C(=O)CCc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
N-(2,3-Dimethoxybenzyl)-N-heptylamine (0.70 g, 2.65 mmol) was dissolved in DM (10 ml), 3-(4-hydroxyphenyl)propanoic acid (0.4 g, 2.41 mmol), was added and the mixture was cooled to 0° C. N-[(1H-1,2,3-benzotriazol-1-yloxy)(dimethylamino)methylene]-N-methylmethanaminium tetrafluoroborate (0.85 g, 2.65 mmol) and diisopropylethylamine (0.65 g, 5.05 mmol) was added. The mixture was allowed to warm to room temperature and stirred overnight. EtOAc (15 ml) was added and the organic phase was washed with two portions of sodium hydrogencarbonate (aq, 10 ml). EtOAc was removed by evaporation and the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). The solvent was removed by evaporation and gave 0.98 gram N-(2,3-dimethoxybenzyl)-N-heptyl-3-(4-hydroxyphenyl)propanamide (yield 70%).
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:6][C:7]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)=[O:8])[CH2:5][CH2:4]1.[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34](Cl)(=[O:36])=[O:35])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:16])[CH3:15]>C1COCC1.CN(C=O)C>[C:14]([C:18]1[N:22]([CH2:23][CH:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[C:21]2[CH:30]=[CH:31][C:32]([S:34]([N:11]3[CH:10]=[C:9]([C:7]([NH:6][CH:3]4[CH2:4][CH2:5]4)=[O:8])[CH:13]=[N:12]3)(=[O:35])=[O:36])=[CH:33][C:20]=2[N:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: O=C(NC1CC1)c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)NC4CC4)cn3)ccc2n1CC1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.8 %

Procedure:
Sodium hydride (0.98 g, 60%, 25 mmol) was added to a solution of N-cyclopropyl-1H-pyrazole-4-carboxamide (0.49 g, 3.5 mmol) (see following steps B and C for preparation) in 40 mL of THF-DMF (3:1) at 0° C. Stirring for 1 h at 0° C. and 0.5 h at room temperature, 2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (1.30 g, 3.5 mmol) was added. The reaction mixture was stirred for 2 h at 0° C., quenched with NaHCO3 (10 mL) and extracted with EtOAc (3×50 mL). The combined organic phases were washed with NaCl (20 mL) and dried over Na2SO4. The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 0.54 g (33%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.52-0.59 (m, 2 H), 0.71-0.79 (m, 2 H), 1.39-1.57 (m, 4 H), 1.60 (s, 9 H), 2.22-2.37 (m, 1 H), 2.71-2.79 (m, 1 H), 3.26-3.34 (m, 2 H), 3.86-3.93 (m, 2 H), 4.43 (d, J=7.62 Hz, 2 H), 7.91-7.95 (m, 1 H), 7.97-8.01 (m, 1 H), 8.03 (d, J=0.78 Hz, 1 H), 8.34 (d, J=1.37 Hz, 1 H), 8.74 (d, J=0.59 Hz, 1 H); MS (ESI) (M+H)+=485.8.
Reaction SMILES: C(OC([N:8]1[CH:17]([CH3:18])[CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:19]([CH3:21])[CH3:20])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(N1C(C2C=CC(C)=CC=2)=C2C(CCNC(C)C2)=N1)(C)C>>[CH:19]([N:13]1[C:12]([C:34]2[CH:35]=[CH:36][C:31]([CH3:30])=[CH:32][CH:33]=2)=[C:11]2[C:15]([CH2:16][CH:17]([CH3:18])[NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:20])[CH3:21]
Reactant: CC1Cc2nn(C(C)C)c(OS(=O)(=O)C(F)(F)F)c2CCN1C(=O)OC(C)(C)C
Reactant: Cc1ccc(B(O)O)cc1
Agent: Cc1ccc(-c2c3c(nn2C(C)C)CCNC(C)C3)cc1
Product: Cc1ccc(-c2c3c(nn2C(C)C)CC(C)NCC3)cc1
Yield: 76.1 %

Procedure:
The title compound (127 mg) was prepared as in Example 311 using 260 mg of 2-isopropyl-7-methyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester and 112 mg of 4-methylphenylboronic acid. The reaction sequence also yielded 2-isopropyl-5-methyl-3-p-tolyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene. MS (ESI): exact mass calculated for C18H25N3, 283.20; found, m/z 284.5 [M+H]+. 1H NMR (600 MHz, CD3OD): 7.38-7.36 (m, 2H), 7.22-7.20 (m, 2H), 4.41 (m, 1H), 3.60-3.56 (m, 1H), 3.50-3.45 (m, 1H), 3.21-3.06 (m, 3H), 2.84-2.70 (m, 2H), 1.46 (d, J=6.6 Hz, 3H), 1.42-1.37 (m, 6H).
Reaction SMILES: I[CH2:2][CH3:3].[OH:4][C@@H:5]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[Cl:21])[CH:13]=2)=[O:11])[CH2:6]1>>[Cl:21][C:18]1[CH:17]=[CH:16][N:15]=[C:14]2[CH:13]=[C:12]([C:10]([N:7]3[CH2:8][CH2:9][C@@H:5]([O:4][CH2:2][CH3:3])[CH2:6]3)=[O:11])[S:20][C:19]=12
Reactant: CCI
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Product: CCO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1

Procedure:
The title compound was prepared from iodoethane and (3R)-(3-hydroxy-pyrrolidin-1-yl)-[7-chloro-thieno[3,2-b]pyridin-2-yl]-methanone by a procedure analogous to Example 67B. MS: 311.2/313.2 (MH+); HPLC Rf: 4.697 min.; HPLC purity: 98%.
Reaction SMILES: NC1C=C2C(=CC=1)N=CC=C2.[OH:12][N:13]=[CH:14][C:15]([NH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2)=[O:16].S(=O)(=O)(O)[OH:29]>>[OH:12][N:13]=[CH:14][C:15]([NH:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[CH:23][CH:22]=[CH:21]2)=[O:16].[C:14]1(=[O:29])[C:19]2=[C:20]3[C:25](=[CH:26][CH:27]=[C:18]2[NH:17][C:15]1=[O:16])[N:24]=[CH:23][CH:22]=[CH:21]3
Reactant: O=S(=O)(O)O
Agent: Nc1ccc2ncccc2c1
Agent: O=C(C=NO)Nc1ccc2ncccc2c1
Product: O=C1Nc2ccc3ncccc3c2C1=O
Reaction time: 1 h
Yield: 31 %

Procedure:
2-Hydroxyimino-N-quinolin-6-yl-acetamide was prepared in 61% yield from 6-aminoquinoline according to Procedure A: 1H NMR (DMSO-d6): δ 12.4 (s, 1H), 10.8 (s, 1H), 9.0 (d, 1H), 8.8 (d, 1H), 8.7 (s, 1H), 8.2 (s, 2H), 7.81 (m, 1H), 7.78 (s, 1H); C11H9N3O2: APCI−MS m/z 216 (M+H)+. To a 1-L 3-neck round bottom flask was placed a magnetic stir bar and 110 mL of concentrated sulfuric acid. The flask was fitted with a thermometer to monitor the temperature of the reaction. The sulfuric acid was heated to 100° C. followed by slow addition of 2-hydroxyimino-N-quinolin-6-yl-acetamide (26.0 g, 0.121 mol). Heat to the reaction was maintained for approximately 1 h. The flask was removed from the heat source, and the reaction was poured slowly and carefully onto a mixture of 1 Kg of ice and 200 g of sodium carbonate. The residual reaction mixture in the reaction vessel was washed out with an additional 40 mL of cold water. The resulting aqueous slurry was stirred for about 1 h and filtered. The solid was washed thoroughly with water, filtered, and air dried to yield 7.31 g (31 %) of 3-H-pyrrolo[3,2-f]quinoline-1,2-dione: 1H NMR (DMSO-d6): δ 11.1 (s, 1H), 8.8 (d, 1H), 8.7 (d, 1H), 8.2 (d, 1H), 7.6 (m, 1H), 7.4 (d, 1H); APCI−MS m/z 197 (M−H)−. The title compound was prepared in 77% yield from 3-H-pyrrolo[3,2-f]quinoline-1,2-dione and 4-hydrazinophenylmethane sulfonamide according to Procedure G: 1H NMR (DMSO-d6): δ 13.1 (s, 1H), 11.5 (s, 1H), 9.3 (d, 1H), 8.9 (d, 1H), 8.0 (d, 1H), 7.9 (m, 1H), 7.6 (d, 1H), 7.6 (d, 2H), 7.4 (d, 2H), 6.9(d, 1H), 4.3 (s, 2H), 2.55 (d, 3H); APCI−MS m/z 396 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.Cl[CH2:15][CH:16]1[CH2:18][O:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:12][O:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][CH2:6][C:7]2=[O:13])=[CH:3][C:2]=1[O:1][CH2:15][CH:16]1[CH2:18][O:17]1
Reactant: ClCC1CO1
Reactant: COc1cc2c(cc1O)CCC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1OCC1CO1)CCC2=O

Procedure:
A mixture of 5-Hydroxy-6-methoxy-indan-1-one (Intermediate H, 5.0 g, 0.028 mole), 2-chloromethyl-oxirane (4.4 mL, 0.056 mole), and potassium carbonate (11.6 g, 0.084 mole) was stirred in 50 mL of DMF at 70° C. overnight under Argon. The reaction was then diluted with 200 mL of ethyl acetate and washed 3 times with water. The ethyl acetate solution was dried over sodium sulfate and the solvent removed in vacuo to yield the title compound (Intermediate M). MS m/z 236 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][NH2:25].CCOC(C)=O>CS(C)=O>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][NH:25][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc2ncc(Cl)nc2c1
Reactant: COc1ccc(CN)c(OC)c1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(CNc2cnc3ccc(OC)cc3n2)c(OC)c1
Yield: 93.2 %

Procedure:
2-Chloro-7-methoxyquinoxaline (0.51 g, 2.62 mmol), prepared according to J. Chem. Soc. Perk Trans. 1, 2001, 978-984, and (2,4-dimethoxyphenyl)methanamine (1.181 mL, 7.86 mmol) were microwaved in DMSO (2.5 mL) for 30 min at 150° C. This was diluted into 150 mL EtOAc and extracted three times with 100 mL brine. The crude product was purified by flash chromatography on a 90 g silica gel cartridge with 20 to 80% EtOAc in hexane, 50 min, at 40 mL/min to afford N-(2,4-dimethoxybenzyl)-7-methoxyquinoxalin-2-amine (795 mg, 2.443 mmol, 93% yield).
Reaction SMILES: N1C=CC=C(C(Cl)=O)C=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][CH:16]=[C:15]2[O:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([N:40]=[C:41]=[S:42])=[O:39])[CH:33]=1>C1(C)C=CC=CC=1.C(O)C>[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([N:40]=[C:41]=[S:42])=[O:39])[CH:33]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[O:22][CH3:23])[N:18]=[CH:17][CH:16]=[C:15]2[O:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:41]([NH:40][C:38]([C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)=[O:39])=[S:42])=[CH:27][CH:26]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1cccnc1
Agent: O=C(N=C=S)c1cccnc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccnc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
3-Pyridinecarbonyl isothiocyanate was prepared using commercially available 3-pyridinecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-pyridinecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (83 mg, yield 64%).
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH2:11])[CH2:8][CH2:9][CH2:10][C:3]1=2.[C:12](Cl)(Cl)=[O:13]>C1(C)C=CC=CC=1>[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([N:11]=[C:12]=[O:13])[CH2:8][CH2:9][CH2:10][C:3]1=2
Reactant: O=C(Cl)Cl
Reactant: NC1CCCc2sccc21
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C=NC1CCCc2sccc21

Procedure:
Alternatively, 5.7 grams of 4,5,6,7-tetrahydrobenzo[b]thien-4-amine hydrochloride is stirred in 20 ml. of toluene at 97° C., and phosgene is slowly introduced into the mixture via a capillary delivery tube. The mixture is heated to reflux temperature, and the flow of phosgene is continued until most of the amine hydrochloride disappears. The mixture is then filtered to remove unreacted amine hydrochloride, and the filtrate is evaporated to dryness under reduced pressure to give the 4,5,6,7-tetrahydrobenzo[b]thien-4-yl isocyanate.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:16][C:17]1[CH:27]=[CH:26][C:20]([CH:21]=[CH:22][C:23]([OH:25])=[O:24])=[CH:19][CH:18]=1.C(=O)([O-])O.[Na+]>O.C(OCC)C>[C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=[CH:14][C:10]([C:11]([NH:16][C:17]2[CH:18]=[CH:19][C:20](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:26][CH:27]=2)=[O:12])=[CH:9][CH:8]=1
Reactant: Nc1ccc(C=CC(=O)O)cc1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(O)/C=C/c1ccc(NC(=O)c2ccc(-c3ccccc3)cc2)cc1
Reaction time: 5 h
Yield: 42.3 %

Procedure:
4-Phenylbenzoyl chloride (2.00 g, 9.23 mmol) was added to a mixed solution of 4-aminocinnamic acid (1.51 g, 9.23 mmol) and sodium hydrogen carbonate (2.33 g, 27.7 mmol) in water and diethyl ether under ice-cooling, which was stirred for 5 hours. After the reaction mixture was separated, 5N hydrochloric acid was added to water layer, and the precipitated crude product was washed with water and ethyl acetate, to give the titled compound (1.34 g).
Reaction SMILES: [C:1]1([C@@H:7]2[NH:11][C@H:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([O:23][C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20].C1(N=C=NC2CCCCC2)CCCCC1.CO>C(#N)C>[C:19]([O:23][C:24]([NH:26][CH2:27][C:28]([N:11]1[C@@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][C@H:10]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:29])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@H](c2ccccc2)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCC(=O)N1[C@@H](c2ccccc2)CC[C@H]1C(=O)OC(C)(C)C
Yield: 80.3 %

Procedure:
tert-Butyl (2S,5R)-1-(2-tert-butoxycarbonylaminoacetyl)-5-phenylprolinate may be obtained as per Example 2 B, but starting from a solution containing 8 g of tert-butyl (2S,5R)-5-phenylprolinate, 5.7 g of 2-tert-butoxycarbonylaminoacetic acid and 6.7 g of N,N'-dicyclohexylcarbodiimide in 75 cm3 of anhydrous acetonitrile. 10.5 g of tert-butyl (2S,5R)-1-(2-tert-butoxycarbonylaminoacetyl)-5-phenylprolinate, melting at 136° C., [α]D20 +19.1°±0.8° (C=0.64; methanol), are thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:22][C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:8]=1)=[O:5].[Cl:32][CH2:33][C:34]1[N:39]=[C:38]([C:40](O)=[O:41])[CH:37]=[CH:36][CH:35]=1.CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1>[Cl:32][CH2:33][C:34]1[N:39]=[C:38]([C:40]([NH:1][C:2]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:22][C:3]=2[C:4](=[O:5])[NH:6][C:7]2[CH:11]=[CH:10][N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=3)[N:8]=2)=[O:41])[CH:37]=[CH:36][CH:35]=1
Reactant: O=C(O)c1cccc(CCl)n1
Reactant: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCCCC2)cc1C(=O)Nc1ccn(-c2cccc(C(F)(F)F)c2)n1)c1cccc(CCl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 126.8 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 2-amino-5-(piperidin-1-yl)-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-yl)benzamide (100 mg, 0.23 mmol, 1.00 equiv) in dichloromethane (3 mL), 6-(chloromethyl)picolinic acid (50 mg, 0.29 mmol, 1.25 equiv), EDC.HCl (67 mg, 0.35 mmol, 1.50 equiv), and 4-dimethylaminopyridine (43 mg, 0.35 mmol, 1.51 equiv). The resulting solution was stirred overnight at 25° C. in an oil bath. The mixture was concentrated under vacuum to give 170 mg (75%) of product as a
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[CH2:9]([Sn](CCCC)(CCCC)C=C)[CH2:10]CC.C(OCC)(=O)C.[F-].[K+]>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([CH:9]=[CH2:10])[CH:5]=[CH:4][N:3]=1
Reactant: Fc1cc(I)ccn1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=Cc1ccnc(F)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
A mixture of 2-fluoro-4-iodopyridine (2.23 g, 10.0 mmol), tributyl vinyl tin (3.8 g, 12 mmol), and Pd2Cl2(PPh3)2 (703 mg, 1.0 mmol) in dioxane (20 mL) was heated under nitrogen at 80° C. overnight. After cooled, ethyl acetate (40 ml) and saturated KF aqueous solution were added to the reaction mixture. The mixture was stirred for 30 min. The organic layer was separated and washed with water, dried (MgSO4), and concentrated. The resulting residue was purified by flash column chromatography eluting with hexane/ethyl acetate (20:1) to provide the title compound (463 mg, 38%). 1HNMR (500 MHz, CDCl3) δ ppm 5.55 (d, J=10.92 Hz, 1 H) 5.99 (d, J=17.47 Hz, 1 H) 6.67 (dd, J=17.47, 10.61 Hz, 1 H) 6.88 (m, 1 H) 7.17 (dt, J=5.30, 1.56 Hz, 1 H) 8.16 (d, J=5.30 Hz, 1 H).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([OH:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].CCOCC>ClCCl>[CH:12](=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCC/C=C\CCCCCCCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCCC/C=C\CCCCCCCC=O
Reaction time: 4 h
Yield: 90.1 %

Procedure:
An 18 g portion of pyridinium chlorochromate was slurried in 200 ml of dichloromethane. A solution of 15 g of oleyl alcohol in 200 ml of dichloromethane was added. This mixture was stirred for 4 hours, then poured into ether and filtered through hydrous magnesium silicate. The filtrate was evaporated, giving 13.42 g of the desired compound as a colorless liquid.