Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:16](Cl)([CH3:18])=[O:17].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:11][CH2:12][N:13]([C:16](=[O:17])[CH3:18])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 110 %

Procedure:
To a solution of 4-(4-Nitro-phenyl)-piperidin (206 mg, 1 mmol) in CH2Cl2 (3 mL) is added AcCl (0.106 mL, 1.5 mmol) at 0° C. Then Et3N (0.253 mL, 1.8 mmol) is added slowly. The mixture is stirred at 0° C. for 10 minutes. Then saturated NaHCO3 aqueous solution is added. The aqueous layer is extracted with CH2Cl2, and the organic extracts are dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product is purified by column chromatography (SiO2, MeOH:CH2Cl2=0.7:99.3 to 6:93) to give 273 mg of the title compound as yellow solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=O)=[CH:9][CH:8]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[NH2:30][C:31]1[C:39]([NH2:40])=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([NH2:35])=[O:34]>N1C=CC=CC=1.CN(C)C=O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]2[NH:40][C:39]3[CH:38]=[CH:37][CH:36]=[C:32]([C:33]([NH2:35])=[O:34])[C:31]=3[N:30]=2)=[CH:9][CH:8]=1
Reactant: O=C(O)c1ccc(CC2OCCO2)cc1
Reactant: NC(=O)c1cccc(N)c1N
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2[nH]c(-c3ccc(CC4OCCO4)cc3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(1,3-dioxolan-2-ylmethyl)benzoic acid (1.0 g, 4.80 mmol) in pyridine (5 mL) and N,N-dimethylformamide (5 mL) was treated with 1,1′-carbonyldiimidazole (0.856 g, 5.28 mmol) at 45° C. for 2 hours. 2,3-Diaminobenzamide dihydrochloride (synthesized as described in U.S. Pat. No. 6,737,421, column 11, EXAMPLE 2, step (e), 1.08 g, 4.80 mmol) was added and the mixture stirred at ambient temperature overnight. The mixture was concentrated and the residue heated in acetic acid (30 mL) at 80° C. for 3 hours. After cooling, the mixture was concentrated and the residue partitioned between ethyl acetate and sodium bicarbonate solution. After filtering, the filtrate was concentrated and the residue purified by flash chromatography on silica gel (0-15% methanol in 2:1 ethyl acetate/hexane) to give 1.14 g of the title compound. MS (DCI) m/z 324 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)=[O:4].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CS(C)=O>[CH2:15]([NH:22][CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2)=[O:4])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCc1ccccc1
Reactant: O=C(CCl)Nc1cccc2[nH]ccc12
Solvent: O
Solvent: CS(C)=O
Product: O=C(CNCc1ccccc1)Nc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.5 %

Procedure:
A solution containing 2-chloro-N-(1H-indol-4-yl)-acetamide (3.0 g, 14.4 mmol), benzylamine (4.76 g, 43.1 mmol) in DMSO (60 mL) was stirred at ambient temperature for 16 hours. The mixture was poured into water (700 mL) and the crude product crystallized as a solid. After filtration, the solids were dissolved in ethyl acetate (600 mL), washed with water (200 mL) and brine (200 mL), dried over anhydrous magnesium sulfate and filtered. Concentration of the ethyl acetate gave the title compound as a white solid, (3.36 g, 83.6%), mp 158-161° C.; MS EI m/e 279 (M+).
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]1(O)[CH:16]2[CH2:17][N:13]([CH2:14][CH2:15]2)[CH2:12]1.O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:3][C:11]1([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][N:5]=2)[CH:16]2[CH2:17][N:13]([CH2:14][CH2:15]2)[CH2:12]1
Reactant: OC1(c2cnccn2)CN2CCC1C2
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: ClC1(c2cnccn2)CN2CCC1C2
Temperature: 60 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
Thionyl chloride (1.5 g, 12.6 mmol) was added to a rapidly stirred solution of 3-(2-pyrazinyl)-1-azabicyclo[ 2.2.1]heptan-3-ol (0.5 g, 2.6 mmol) in dichloromethane (30 ml) at room temperature. The solution was stirred for 1 h, heated at 60° C. for 0.5 h, and then cooled to room temperature, before adding water (20 ml) and basifying with potassium carbonate. Extraction into dichloromethane (3×75 mls), drying (Na2SO4) and chromatography of the residue remaining after removal of solvent through alumina, using ethyl acetate as eluant, gave 3-chloro-3-(2-pyrazinyl)-1-azabicyclo[2.2.1]heptane as a pale yellow oil (0.18 g); m/e 209 (M+ of free base); δ (360 MHz,CDCl3) 0.84-0.92(1H,m,CH of CH2); 1.58-1.67(1H,m,CH of CH2); 2.42-2.48(1H,m,CH of CH2 --N); 2.69-2.72(1H,m,CH of CH2 --N); 2.78-2.86(1H,m,CH of CH2 --N); 3.22-3.24(1H,d, J=4.5 Hz, CH-bridgehead); 3.42-3.49(2H,m,2×CH of CH2 --N); 4.13(1H,dd J=3 and 14 Hz, CH of CH2); 8.48(2H,s,pyrazine-H); 8.91(1H,s,pyrazine-H).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:13][C:12]3[C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O-:20])=[O:19])=[CH:10][CH:9]=[CH:8][C:7]=3[C:5]=2[N:6]=1.[C:21]1([CH:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:28][CH2:29]I)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([CH:27]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:28][CH2:29][S:1][C:2]2[S:3][C:4]3[CH2:13][C:12]4[C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:10][CH:9]=[CH:8][C:7]=4[C:5]=3[N:6]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ICCC(c1ccccc1)c1ccccc1
Reactant: O=C([O-])CCCOc1cccc2c1Cc1sc(S)nc1-2
Product: O=C(O)CCCOc1cccc2c1Cc1sc(SCCC(c3ccccc3)c3ccccc3)nc1-2
Yield: 27 %

Procedure:
Using 4-[(2-mercapto-8H-indeno[1,2-d]thiazol-7-yl]oxy]butyrate and 3,3-diphenylpropyl iodide, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 27%.
Reaction SMILES: [CH2:1]([C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:8][CH2:7][CH:6]1[OH:10])[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.[CH3:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:1]([C:5]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:8][CH2:7][CH:6]1[O:10][C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:23]([CH3:22])=[CH:24][CH:25]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(C(=O)OCC)CCCC1O
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCC1(C(=O)OCC)CCCC1OC(=O)c1ccc(C)cc1

Procedure:
6.42 grams of ethyl 1-n-butyl-2-hydroxy-cyclopentane carboxylate obtained in Example 16 were diluted with 60 ml of methylene chloride. At room temperature and with magnetic stirring, 3.66 ml of pyridine was slowly added, then 6.12 ml of 4-methyl-benzoyl chloride was dropwise added. Then the procedure as described in Example 23 was followed, to give 11.77 g of brown liquid. MS: m/e 332(M+′), 287(M+—OCH2CH3), 213(M+—CH3C6H4CO), 197(M+—CH3C6H4CO2), 119 (base), 91.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:20]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])=[CH:4][CH:3]=1.[C:28]([O:31][CH2:32][CH2:33]O)(=[O:30])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[C:28]([O:31][CH2:32][CH2:33][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[NH:12][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:9]([C:20]([NH:22][C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[O:21])[N:10]=2)=[CH:14][CH:15]=1)(=[O:30])[CH3:29]
Reactant: O=C(Nc1nccs1)c1nc(-c2ccc(O)cc2)[nH]c1-c1ccc(Cl)cc1
Reactant: CC(=O)OCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=O)OCCOc1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(Cl)cc3)[nH]2)cc1

Procedure:
5-(4-Chlorophenyl)-2-(4-hydroxyphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide, 2-hydroxyethyl acetate, triphenylphosphine and diethyl azodicarboxylate are reacted and treated in the same manner as in Example 24 to give 2-(4-(2-acetoxyethyloxy)phenyl)-5-(4-chlorophenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH2:14])[N:11]=[C:10]([NH2:15])[N:9]=2)=[CH:4][CH:3]=1.[C:16]1([S:22](Cl)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[NH2:14][C:12]1[N:11]=[C:10]([NH2:15])[N:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:22]([C:16]3[CH:21]=[CH:20][C:19]4[C:18](=[CH:7][CH:2]=[CH:3][CH:4]=4)[CH:17]=3)(=[O:24])=[O:23])=[CH:7][CH:6]=2)[N:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(-c2nc(N)nc(N)n2)cc1
Product: Nc1nc(N)nc(-c2ccc(NS(=O)(=O)c3ccc4ccccc4c3)cc2)n1

Procedure:
6-(4-Aminophenyl)-1,3,5-triazine-2,4-diamine was processed as in Example 23 but substituting 2-naphthalenesulfonyl chloride for benzenesulfonyl chloride to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:29]=[N:30][C:31](F)=[CH:32][CH:33]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[CH3:35][NH:36][CH3:37].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]5[CH:33]=[CH:32][C:31]([N:36]([CH3:37])[CH3:35])=[N:30][CH:29]=5)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: CNC
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(-c4ccc(F)nc4)ccc2OCC3)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(C)c1ccc(-c2ccc3c(n2)-c2sc(-c4ncnn4-c4ccc(F)cc4F)cc2CCO3)cn1
Temperature: 150 °C
Yield: 12.2 %

Procedure:
2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-9-(6-fluoro-pyridin-3-yl)-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene (470 mg, 1.0 mmol), from the procedure for 249, Dimethyl-amine (98 mg, 1.2 mmol), DIPEA (340 mg, 3 mmol) and NMP (4 mL) were added in a 10 mL of sealed tube, and the mixture was heated by microwave at 150° C. for 120 min under N2. The reaction mixture was filtered to gather the solution and water was added. The mixture was extracted by DCM (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by preparative HPLC to give 339 (61.4 mg, yield: 12%). 1HNMR (DMSO-d6, 400 MHz): δ8.74 (s, 1H), 8.31 (s, 1H), 8.06 (d, J=9.2 Hz, 1H), 7.91-7.87 (m, 1H), 7.73-7.71 (m, 2H), 7.42-7.40 (m, 2H), 7.19 (d, J=4.4 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.77 (d, J=8.8 Hz, 1H), 4.31 (s, 2H), 3.16-3.11 (m, 8H). ESI-MS: m/z=503 [M+H+]
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]3[O:16][C:15]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[N:14][C:13]=3[CH:30]=2)O1.Br[C:33]1[CH:38]=[CH:37][C:36]([N:39]2[CH:43]=[N:42][N:41]=[N:40]2)=[CH:35][C:34]=1[F:44]>>[F:44][C:34]1[CH:35]=[C:36]([N:39]2[CH:43]=[N:42][N:41]=[N:40]2)[CH:37]=[CH:38][C:33]=1[C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]3[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:21][CH2:22]3)=[N:14][C:13]=2[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc3cc(B4OC(C)(C)C(C)(C)O4)ccc3o2)CC1
Reactant: Fc1cc(-n2cnnn2)ccc1Br
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(-c4ccc(-n5cnnn5)cc4F)ccc3o2)CC1
Yield: 4.8 %

Procedure:
Following the General Procedure-1, the titled compound (10 mg) was prepared from Intermediate 8 (200 mg, 0.47 mmol) and 1-(4-bromo-3-fluorophenyl)-1H-tetrazole (110 mg, 0.45 mmol) as a brown solid. M.P.: 203-207° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 9.04 (s, 1H), 7.88 (s, 1H), 7.71-7.58 (m, 4H), 7.52 (td, 1.6, 8.4, 1H), 4.16 (d, J 10.8, 2H), 3.21-3.12 (m, 1H), 3.00 (t, J 12.2, 2H), 2.21-2.13 (m, 2H), 2.00-1.85 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:16]=[C:15]([C:17]([OH:19])=O)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[N:3][CH:2]=1.Cl.[CH3:21][O:22][C:23]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:16]=[C:15]([C:17]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:23]=4[O:22][CH3:21])[CH2:28]3)=[O:19])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)=[N:3][CH:2]=1
Reactant: O=C(O)c1nc(-c2ccncn2)nc2ccccc12
Reactant: COc1ccc2c(c1OC)CCNC2
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3ccncn3)nc3ccccc13)C2
Yield: 17 %

Procedure:
Reaction of 2-(4-pyrimidinyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 72 (17% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 2.86 and 3.13 (2t, 2H), 3.54 and 4.17 (2t, 2H), 3.81-3.90 (m, 6H), 4.43 and 5.06 (2s, 2H), 6.51 and 6.91 (2d, 1H), 6.71 and 7.01 (2d, 1H), 7.74-7.81 (m, 2H), 8.04-8.13 (m, 2H), 8.39-8.41 (2s, 1H), 8.65-8.70 (m, 1H), 9.04-9.06 (m, 1H), 9.57 (s, 1H); MS (ESI) m/z 428 ([M+H]+).
Reaction SMILES: CO.[NH3:3].Cl[C:5]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]>[Cu]Cl.O>[NH2:3][C:5]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: N
Reactant: O=C(O)c1cccc(Cl)c1Cl
Agent: Cl[Cu]
Solvent: CO
Solvent: O
Product: Nc1c(Cl)cccc1C(=O)O
Temperature: -70 °C
Reaction time: 20 h
Yield: 80.9 %

Procedure:
70 ml of methanol was added to an autoclave, and cooled to −70° C., and 16 g (942 mmol) of a generated ammonia gas was added. 30 g (157 mmol) of 2,3-dichlorobenzoic acid and 0.78 g (7.85 mmol) of copper(I) chloride were added. The autoclave was sealed, and heated in an oil bath at 130° C. and 30 atmospheres for 20 hours. After the completion of the reaction, the autoclave was cooled to room temperature, and the reaction mixture was transferred into a reaction flask. 100 ml of water was added to the reaction solution, and the reaction solution was heated in an oil bath to 100° C. to remove the ammonia and the methanol. Then, the reaction solution was cooled to room temperature, and hydrochloric acid was added to adjust the pH value to 3. The precipitated crystals were filtered and dried to obtain 21.8 g of 2-amino-3-chlorobenzoic acid as white crystals with a yield of 81%.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](Cl)=O)=[CH:3][CH:2]=1.[C:16](#[N:19])[CH:17]=C>>[C:10]1([C:1]2[CH:6]=[CH:5][C:4]([CH:7]=[CH:17][C:16]#[N:19])=[CH:3][CH:2]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: C=CC#N
Product: N#CC=Cc1ccc(-c2ccccc2)cc1
Reaction time: 2 h

Procedure:
This compound is prepared from 10.83 g (50 millimols) of biphenyl-4-carboxylic acid chloride and 3.31 g (62.5 millimols) of acrylonitrile, the mixture being stirredfor 2 hours at 120° C. The crude product is extracted, in a Soxhlet extractor, with 100 ml of n-hexane, and is recrystallised from methanol. 3.83 g (37% of theory) of yellow crystals, melting point 43.7° C., are obtained. Analysis for C15H11N: calculated C 87.77%, H 5.40%, N 6.82%; found C 87.64%, H 5.34%, N 6.76%.
Reaction SMILES: CO[C:3](=[O:16])[C@H:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[NH:5][C:6](=[O:8])[CH3:7].[CH:17]([Mg]Cl)([CH3:19])[CH3:18].[Cl-].[NH4+].Cl>O1CCCC1>[C:6]([NH:5][CH:4]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:3](=[O:16])[CH:17]([CH3:19])[CH3:18])(=[O:8])[CH3:7]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(C)=O
Reactant: CC(C)[Mg]Cl
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)NC(Cc1ccccc1)C(=O)C(C)C
Reaction time: 0.25 h

Procedure:
A solution of 2.30 g of N-acetylphenylalanine methyl ester (10.40 mmol) in 15 ml of tetrahydrofuran is chilled at -60° C. with dry ice/acetone bath. To the mixture is added dropwise 10.40 ml of 2M solution of isopropylmagnesium chloride in tetrahydrofuran (20.8 mmol) with stirring and the mixture allowed to stand for 15 minutes and returned to room temperature. The mixture was stirred for 3 hours. To the mixture is added saturated aqueous ammonium chloride under ice cooling, followed by the addition of 5% hydrochloric acid and the mixture extracted with ethyl acetate. The extract is washed with saturated brine, dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. The resulting crude product is chromatographed on a column of silica gel, eluting with methylene chloride and ethyl acetate (4:1) to give 1.40 g of the objective 4-acetylamino-2-methyl-5-phenyl-3-pentanone 5. Yield, 57.7%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([OH:12])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=[O:8].[CH3:13]O>>[Cl:2][C:3]1[CH:4]=[C:5]([OH:12])[C:6](=[CH:10][CH:11]=1)[C:7]([O:9][CH3:13])=[O:8]
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)cc1O
Agent: Cl
Product: COC(=O)c1ccc(Cl)cc1O
Temperature: 25 °C

Procedure:
Hydrogen chloride gas is bubbled into a mixture of 4-chlorosalicylic acid (100 g, 0.579 mol) in methanol while maintaining the temperature at 45°-50° C. The reaction mixture is then stirred at room temperature for several hours, concentrated in vacuo and extracted with ether. The combined organic extracts are washed sequentially with brine, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain an amber oil. The oil is distilled under reduced pressure to give the title product as a colorless oil which is identified by NMR spectral analyses.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[O:16][C:15]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])=[N:14][C:13]=2[CH2:23][CH2:24][CH2:25][CH2:26][OH:27])=[CH:4][CH:3]=1.[CH3:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[O:16][C:15]([N:17]3[CH:21]=[CH:20][N:19]=[C:18]3[CH3:22])=[N:14][C:13]=2[CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=2[CH3:28])=[CH:4][CH:3]=1
Reactant: Cc1nccn1-c1nc(CCCCO)c(-c2ccc(F)c3ccccc23)o1
Reactant: Cc1ccccc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccccc1OCCCCc1nc(-n2ccnc2C)oc1-c1ccc(F)c2ccccc12
Reaction time: 1 h

Procedure:
To a mixture of 5-(4-fluoro-1-naphthyl)-2-(2-methyl-1-imidazolyl)-4-oxazolebutanol (180 mg), 2-methylphenol (108 mg), tributylphosphine (202 mg) and tetrahydrofuran (5 ml) was added 1,1′-(azodicarbonyl)dipiperidine (252 mg) at room temperature, and the resulting mixture was stirred for 1 hour. After the reaction mixture was concentrated, the residue was subjected to silica gel column chromatography, and 5-(4-fluoro-1-naphthyl)-2-(2-methyl-1-imidazolyl)-4-[4-(2-methylphenoxy)butyl]oxazole was obtained as an oil (180 mg, 80%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]#[N:12])[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]#[N:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCC#N)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#CCCc1cccc(O)c1
Reaction time: 2 h

Procedure:
To a stirred solution of 3-(3-methoxyphenyl)propanenitrile (Step A, 1.71 g, 10.6 mmol) in dry CH2Cl2 (20 ml) was added BBr3 (1M in CH2Cl2, 5.32 g, 21.2 mmol) at −78° C. under argon. The reaction mixture was stirred at the same temperature for 2 hours and then at 0° C. for 4 hours or until all the starting material is consumed, quenched with ice, extracted with EtOAc (30 ml×3), the combined organic layer was washed carefully with sat NaHCO3, brine and dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 2:1) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[O:17][CH3:18].[OH-].[K+].O>CS(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[O:17][CH3:18])[CH:6]=1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: Clc1c[nH]cn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc([N+](=O)[O-])ccc1-n1cnc(Cl)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
A mixture of 4-chloro-1H-imidazole (5.0 g, 48.8 mmol), 1-chloro-2-methoxy-4-nitrobenzene (9.15 g, 48.8 mmol), and potassium hydroxide flakes (2.74 g, 48.8 mmol) in anhydrous DMSO (50 mL) was heated at 80° C. for 20 h. The reaction mixture was allowed to cool to rt and was poured into 800 mL of water with vigorous stirring. The resulting yellow-orange precipitate was collected by vacuum filtration using a coarse sintered glass funnel. The crude wet solid was transferred to a 1 L Erlenmeyer flask. Absolute ethanol (250 mL) was added to the flask and the resulting suspension was heated until all of the solids dissolved. The clear solution was cooled to rt and the desired product slowly crystallized. After 2 h, the crystalline solid was collected by vacuum filtration and rinsed with 100 mL of fresh ethanol. The solid was dried under high vacuum to afford 4-chloro-1-(2-methoxy-4-nitrophenyl)-1H-imidazole (5.2 g, 42% yield) as an off-white crystalline solid. LC-MS (M+H)+=254.0. 1H NMR (500 MHz, CDCl3) δ ppm 7.94-8.01 (m, 2H) 7.76 (d, J=1.53 Hz, 1H) 7.45 (d, J=8.55 Hz, 1H) 7.21 (d, J=1.53 Hz, 1H) 4.02 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[NH2:23][CH2:24][C:25]([NH2:28])([CH3:27])[CH3:26]>CN1CCCC1=O>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:23][CH2:24][C:25]([CH3:27])([NH2:28])[CH3:26])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: CC(C)(N)CN
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)(N)CNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Temperature: 0 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
Under a nitrogen atmosphere, triethylamine (6.6 mL, 47 mmol) was added slowly to a solution of 2,4-dichloro-3-nitroquinoline (10.0 g, 41.1 mmol) in anhydrous 1-methyl-2-pyrrolidinone (40 mL). The reaction mixture was cooled to 0° C. with an ice bath. A solution of 1,2-diamino-2-methylpropane (4.1 g, 47.3 mmol) in anhydrous 1-methyl-2-pyrrolidinone (5 mL) was added dropwise over a period of 15 minutes while maintaining the temperature of the reaction mixture below 4° C. After the addition was completed the ice bath was removed and the reaction mixture was allowed to stir at ambient temperature for 4 hours. The reaction mixture was slowly poured into vigorously stirred warm water (300 mL). The resulting suspension was stirred for 1 hour and then cooled to 13° C. by adding ice. The solid was isolated by filtration and then washed with cold water until the filtrate was clear to provide 12.1 g of N1-(2-chloro-3-nitroquinolin-4-yl)-2-methylpropane-1,2-diamine as a damp yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([CH2:20]O)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS([Cl:33])(=O)=O>ClCCl>[CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([CH2:20][Cl:33])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c(CO)nn(Cc2ccccc2)c2cccc(Cl)c12
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1c(CCl)nn(Cc2ccccc2)c2cccc(Cl)c12
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.2 %

Procedure:
To 0.42 g (1.4 mmol) of 1-benzyl-5-chloro-3-hydroxymethylcinnolin-4(1H)-one in 25 mL of dichloromethane at 0° C. was added 0.97 mL (7.0 mmol) of triethylamine and 0.33 mL (4.2 mmol) of methanesulfonyl chloride. The reaction was allowed to warm to room temperature and stirred for 5 h. The reaction was concentrated by rotary evaporation and was subsequently dissolved in dichloromethane and concentrated onto silica gel. The crude material was purified by flash chromatography eluting with a 33-50% ethyl acetate/hexanes gradient mixture to give 0.26 g (59%) of the title compound as an off-white solid.