Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[N:12]=2)[C:7](=[O:21])[C:6]([C:22]([O:24]CC)=[O:23])=[CH:5]1.[OH-].[Na+]>C(O)(=O)C>[O:21]=[C:7]1[C:8]2[C:13](=[N:12][C:11]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[N:4]([CH:3]=[CH2:2])[CH:5]=[C:6]1[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)c1cn(CCCl)c2nc(N3CCN(C)CC3)ccc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: C=Cn1cc(C(=O)O)c(=O)c2ccc(N3CCN(C)CC3)nc21
Yield: 84.4 %

Procedure:
To 0.80 g of ethyl 1-(2-chloroethyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-1,8-naphthyridine-3-carboxylate was added 10 ml of a 10% aqueous solution of sodium hydroxide. The mixture was heated at 90° - 95° C for 30 minutes and neutralized with acetic acid under cooling. The resulting mixture was extracted with chloroform. The extract was washed with water and concentrated to leave a yellow solid which was collected and recrystallized from ethanol to give 0.56 g of the product as pale yellow needles, m.p. 238° - 239° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N:11]([C@@H:14]1[C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[C@H:18]([OH:25])[CH2:17][CH2:16][C@H:15]1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[F:33])=[N+:12]=[N-:13].C(N(CC)CC)C>ClCCl>[N:11]([C@@H:14]1[C:24]2[C:19](=[N:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:25])[CH2:17][CH2:16][C@H:15]1[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[F:33])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=N[C@@H]1c2cccnc2[C@H](O)CC[C@H]1c1cccc(F)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=N[C@@H]1c2cccnc2C(=O)CC[C@H]1c1cccc(F)c1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of oxalyl chloride (0.22 mL, 2.6 mmol) in dichloromethane (20 mL) at −15° C. was added DMSO (0.24 mL, 3.4 mmol). The reaction mixture was cooled to −78° C. and a solution of (5S,6S,9R)-5-azido-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ol (prepared according to the procedures described in WO2011/046997, 270 mg, 0.85 mmol) in dichloromethane (5 mL) was added and the resulting solution was stirred at −78° C. for 2 h. Triethylamine (0.71 mL, 5.1 mmol) was added and the reaction mixture was allowed to warm to ambient temperature and then washed with water (15 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc 100:0 to 0:100, to give the title compound. MS: m/z=315.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH2:6]1)=[O:4].[BH4-].[Na+].O.CCOC(C)=O>CO>[OH:11][CH:7]1[CH2:8][CH2:9][CH2:10][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1
Reactant: COC(=O)C1CCCC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C1CCCC(O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-oxo-1-cyclohexanecarboxylic acid methyl ester (1.1 g, 7.04 mmol) was dissolved in methanol (25 ml) and cooled to 0° C. under N2. Sodium borohydride (0.550 g, 14.54 mmol) was added in portions and the resulting solution stirred at 0° C. for 2 h. The solution was then diluted by the dropwise addition of water, followed by EtOAc (100 mL). The aqueous phase was separated and extracted with EtOAc (2×50 ml). The combined organic layers were washed with brine, dried over sodium sulphate, and concentrated in vacuo to give the title compound. TLC: 40% EtOAc/hexanes, high Rf: 0.4, low Rf: 0.3.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH2:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O1CCCC1>[CH2:42]([NH:49][C:8]([C:4]1[S:3][C:2]([Br:1])=[N:6][C:5]=1[CH3:7])=[O:10])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Cc1nc(Br)sc1C(=O)O
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of of 2-bromo-4-methylthiazole-5-carboxylic acid (9.00 g, 40.0 mmol) in anhydrous tetrahydrofuran (140 mL) was added N,N-diisopropylethylamine (20.76 mL, 121.0 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (10.87 g, 56.0 mmol). The reaction mixture was stirred at ambient temperature for 0.5 hours and 1-hydroxybenzotriazole (7.60 g, 56.0 mmol) and benzyl amine (6.00 g, 56.0 mmol) were added. The resulting mixture was stirred at ambient temperature for 18 hours, then concentrated to half volume in vacuo, diluted with dichloromethane (400 mL), and washed with water (400 mL) and brine (150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate/hexane (1/1) to afford the title compound as a colorless solid in 70% yield (8.89 g): mp 92-94° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.41-7.23 (m, 5H), 5.94 (br s, 1H), 4.57 (d, J=5.6 Hz, 2H), 2.64 (s, 3H); MS (ES+) m/z 311.0 (M+1), 313.1 (M+3).
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C@@:17]1([CH2:34][F:35])[CH2:21][CH2:20][N:19]([C:22]2[C:30]([F:31])=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:32])[C:23]=2[F:33])[CH2:18]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:38])=O>ClCCCl.CN(C)C=O>[ClH:38].[CH2:1]([N:8]([CH2:16][C@@:17]1([CH2:34][F:35])[CH2:21][CH2:20][N:19]([C:22]2[C:30]([F:31])=[CH:29][C:25]([C:26]([Cl:38])=[O:27])=[C:24]([F:32])[C:23]=2[F:33])[CH2:18]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(F)c(N2CC[C@](CF)(CN(Cc3ccccc3)Cc3ccccc3)C2)c(F)c1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cl
Product: O=C(Cl)c1cc(F)c(N2CC[C@](CF)(CN(Cc3ccccc3)Cc3ccccc3)C2)c(F)c1F

Procedure:
(S)-4-(3-(N,N-Dibenzylaminomethyl)-3-fluoromethylpyrrolidin-1-yl)-2,3,5-trifluorobenzoic acid (12.6 g) was dissolved in dry 1,2-dichloroethane (63 ml), and two drops of dry dimethylformamide were added. Thionyl chloride (2.3 ml) was added at room temperature and the mixture was refluxed for 2 hours. The reaction mixture was concentrated to give the object compound as pale-gray crystals, melting point 170°-173° C. (decomposition).
Reaction SMILES: [CH3:1][O:2][CH:3]1[O:7][C@@H:6]([CH2:8][O:9][Si](C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:5][CH2:4]1.C(O)=O.CCOC(C)=O>CO>[CH3:1][O:2][CH:3]1[O:7][C@@H:6]([CH2:8][OH:9])[CH2:5][CH2:4]1
Reactant: COC1CC[C@H](CO[Si](C)(c2ccccc2)c2ccccc2)O1
Solvent: CO
Solvent: O=CO
Solvent: CCOC(C)=O
Product: COC1CC[C@H](CO)O1
Yield: 100 %

Procedure:
((R)-5-Methoxy-tetrahydro-furan-2-ylmethoxy)-methyl-diphenylsilane (Pilli, R. A.; Riatto, V. B. Tet. Asymm. (2000)), 11, 3675) (0.80 g, 2.25 mmol) was dissolved in 35 mL of anhydrous MeOH and 5 mL of formic acid was added to the mixture. The mixture was stirred at room temperature for 30 minutes at which point TLC (9:1 hexanes:EtOAc) indicated complete conversion to the product. Volatiles were removed in vacuo and 0.83 g, 100% of the title compound was obtained as clear oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[C:6]([CH:9]=1)[CH2:7]O.[BrH:23].[C:24]1([P:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[Br-:23].[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[C:6]([CH:9]=1)[CH2:7][P+:30]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Br
Reactant: OCc1cc(F)ccc1OCCc1ccc(C(F)(F)F)cc1
Solvent: CC#N
Product: Fc1ccc(OCCc2ccc(C(F)(F)F)cc2)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]

Procedure:
1.7 g (5.41 mmol) of 5-fluoro-2-[2-(4-trifluoromethylphenyl)ethoxy]benzyl alcohol and 1.76 g (5.14 mmol) of triphenylphosphine hydrobromide are heated under reflux in 20 ml of acetonitrile for three hours. A first product fraction is crystallized at −20° C. The mother liquor is concentrated, the residue is dissolved in dichloromethane, and a second fraction is crystallized with diethyl ether. A total of 2.71 g (76% of theory) of the title compound is obtained.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1)[C:3]#N.Cl.CC[O:22][CH2:23]C.C[OH:26]>>[NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=1)[C:3]([O:22][CH3:23])=[O:26]
Reactant: CO
Reactant: CCOCC
Reactant: N#CC(N)c1cccc(OCc2ccccc2)c1
Agent: Cl
Product: COC(=O)C(N)c1cccc(OCc2ccccc2)c1
Yield: 70 %

Procedure:
To a stirred solution of 2-amino-2-(3-(benzyloxy)phenyl)acetonitrile (1.22 g, 5.3 mmol) in methanol (10 mL) at room temperature was added 2 N HCl in ether (10 mL, 20 mmol). The resulting mixture was heated under reflux for 18 h and concentrated to dryness. The crude material was taken up in ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate (100 mL). The layers were separated and the organic phase dried over magnesium sulfate, filtered and the solvent was removed in vacuo. The residue was loaded onto a SCX cartridge eluting with dichloromethane/methanol followed by 7N ammonia in methanol to afford the title compound (1.0 g, 70%) as a thick orange oil.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH2:10])=[C:5]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:4]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[N-:31]=[C:32]=[O:33].N[C:35]1[C:40]2[O:41][CH2:42][C:43](=[O:45])[NH:44][C:39]=2[CH:38]=[CH:37][CH:36]=1>CCOC(C)=O.CN(C=O)C>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:32]([NH:31][C:35]2[C:40]3[O:41][CH2:42][C:43](=[O:45])[NH:44][C:39]=3[CH:38]=[CH:37][CH:36]=2)=[O:33])=[C:5]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:4]=1
Reactant: Nc1cccc2c1OCC(=O)N2
Reactant: [N-]=C=O
Reactant: NCc1ccc(C(F)(F)F)cc1N1CCCCC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1COc2c(cccc2NC(=O)NCc2ccc(C(F)(F)F)cc2N2CCCCC2)N1
Temperature: 80 °C
Yield: 32 %

Procedure:
Amine 2c (420 mg, 1.6 mmol) (Scheme 7) was dissolved in 20 ml of AcOEt and at 0° C. triphosgene (475 mg, 1.6 mmol) was added to the solution. The mixture was warmed at 80° C. for 4 hours then evaporated and dissolved in 5 ml of DMF. The solution of the isocyanate was added drop wise to a solution in DMF (10 ml) of compound 1f (180 mg, 1.1 mmol) and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt 1/petroleum ether 1). The solvent was evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column gave 160 mg of a white solid. Yield=32% 1HNMR (DMSO, 200 MHz) δ 1.57 (2H, bs), 1.68 (4H, bs), 2.85 (4H, m), 4.39 (2H, d, J=5.6 Hz), 4.62 (2H, s), 6.47 (1H, dd, J=7.8 Hz, J′=1.2 Hz), 6.81 (1H, t, J=8 Hz), 7.31 (2H, m), 7.43 (2H, m), 7.74 (1H, dd, J=8.4 Hz, J′=1.2 Hz), 8.18 (1H, bs), 10.65 (1H, bs); [M+1] 449.2 (C22H23F3N4O3 requires 448.4).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=O)C.CO.C1COCC1.CO.[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:44][C:45]2[N:46]=[C:47]([N+:50]([O-])=O)[NH:48][CH:49]=2)[CH2:40][CH2:39]1>[Ni].C(Cl)Cl.CO>[CH3:37][N:38]1[CH2:43][CH2:42][N:41]([CH2:44][C:45]2[N:46]=[C:47]([NH:50][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=4[Cl:27])=[CH:14][CH:15]=3)=[O:3])[NH:48][CH:49]=2)[CH2:40][CH2:39]1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Reactant: CN1CCN(Cc2c[nH]c([N+](=O)[O-])n2)CC1
Agent: [Ni]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3nc(CN4CCN(C)CC4)c[nH]3)c3nccnc23)c1F

Procedure:
The title compound was prepared in analogy to the procedures described in Example 14 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), Raney nickel and MeOH/THF (1:1) instead of palladium on carbon and MeOH in Step 14.2, and 1-methyl-4-(2-nitro-1H-imidazol-4-ylmethyl)-piperazine (Step 20.1) instead of 2-nitroimidazole in Step 14.3. Title compound: ESI-MS: 540.0 [M+H]+; tR=3.07 min (System 1); TLC: Rf=0.23 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([OH:14])[CH:8]=[CH:7]2.[CH2:15](I)[CH3:16].O>CN(C=O)C>[Br:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH2:15][CH3:16])[CH:10]=2)[CH:5]=1
Reactant: CCI
Reactant: Oc1ccc2cc(Br)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc2cc(Br)ccc2c1
Yield: 60 %

Procedure:
To a suspension of sodium hydride (800 mg, 60% oil dispersion) in DMF (20 ml) was added a solution of 6-Bromo-2-naphthol dropwise with stirring at 0°. After gas evolution had ceased, neat ethyl iodide (1.6 ml) was added dropwise to the stirred solution. The reaction was stirred overnight at rt. The reaction mixture was poured into water and extracted several times with tert-butyl methyl ether. The combined organic extracts were washed with water and brine, then dried over MgSO4, filtered and evaporated under reduced pressure to give tan solid. This was recrystallized from MeOH and dried under high vacuum to a constant wt. giving a white solid (3.11 g, 60%). 1H NMR(400 MHz, CDCl3) δ 7.92 (d, J=1.7 Hz, 1H), 7.65(d, J=8.9 Hz, 1H), 7.59 (d, J=8.7 Hz, 2H), 7.16 (dd, J=8.9 Hz, 2.48, 1H), 7.09 (d, J=2.4 Hz, 1H), 4.15 (q, 2H), 1.49 (t, 3H).
Reaction SMILES: [OH-].[Na+].[N:3]1([CH:8]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:7]=[CH:6][N:5]=[CH:4]1>CO.O>[N:3]1([CH:8]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: CCCCCCCCCCCCC(CCCCC(=O)OC)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCC(CCCCC(=O)O)n1ccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
Sodium hydroxide (0.11 g, 2.75 mmol) was added to a stirred solution of methyl 6-(1H-imidazol-1-yl)octadecanoate (0.5 g, 1.37 mmol) in a mixture of methanol (9 ml) and water (3 ml) at 0° C., warmed to room temperature, and stirring continued for another 3 hours. Methanol was removed from the mixture by evaporation. The aqueous layer was acidified with 1N HCl up to pH 4, extracted with dichloromethane (3×15 ml), and the combined organic layers were washed with brine solution, dried on anhydrous MgSO4, and concentrated. Crude product was purified on silica gel column (5% methanol in dichloromethane) to obtain a gummy liquid (370 mg, 77%).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:11]1[CH:15]=[CH:14][N:13]=[N:12]1.[C:16]([O-])([O-])=O.[Cs+].[Cs+].CN[C@@H]1CCCC[C@H]1NC>CN(C=O)C.CCOC(C)=O.[Cu]I>[CH3:16][C:8]1[CH:9]=[CH:10][C:2]([N:12]2[N:13]=[CH:14][CH:15]=[N:11]2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: c1c[nH]nn1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccccc1I
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Temperature: 120 °C

Procedure:
A solution of 2-iodobenzoic acid (3.0 g, 12.09 mmol) in DMF was treated with 1,2,3-triazole (1.5 g, 21.7 mmol), Cs2CO3 (7.08 g, 21.7 mmol), CuI (114 mg, 0.60 mmol), and trans-N,N′-dimethylcyclohexane-1,2-diamine (310 mg, 2.17 mmol). The mixture was heated at 120° C. for 10 min in a microwave reactor. The reaction was cooled to room temperature, diluted with EtOAc, and filtered through Celite®. The residue was purified by gradient elution on SiO2 (0 to 10% MeOH/DCM with 0.1% AcOH) to provide the faster eluting title compound as a white solid. Data for D-1: 1H NMR (500 MHz, DMSO-d6) δ 13.05 (br s, 1H), 8.12 (s, 2H), 7.81-7.52 (m, 4H). The undesired 1-(2H-1,2,3-triazol-2-yl)benzoic acid (D-2) eluted second. 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (D-3) was prepared in an analogous manner.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:23]N1C(=O)CCC1=O.O>O1CCCC1>[Br:23][C:12]1[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:9]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(-c2cccn2C(=O)OC(C)(C)C)nc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(Br)n2C(=O)OC(C)(C)C)nc1
Temperature: 0 °C
Reaction time: 19 h
Yield: 67.7 %

Procedure:
Methyl 6-[1-(t-butoxycarbonyl)-1H-pyrrol-2-yl]nicotinate (835 mg, 2.76 mmol) synthesized in Example (11a) was dissolved in tetrahydrofuran (30 mL), and cooled to 0° C. N-Bromosuccinimide (492 mg, 2.76 mmol) was added, and stirring was carried out at room temperature for 19 hours under nitrogen atmosphere. Water (30 mL) was added, and extraction was carried out with diethyl ether (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-30%) to afford the desired compound (712 mg, yield 68%) as a pale yellow oil.
Reaction SMILES: [C:1]1([NH2:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1([C:14]#[C:15][C:16](O)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1(N=C=NC2CCCCC2)CCCCC1.O>ClCCl>[C:1]1([NH:7][C:16](=[O:17])[C:15]#[C:14][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C#Cc1ccccc1
Reactant: Nc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: O
Product: O=C(C#Cc1ccccc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 61 %

Procedure:
Phenylamine (1.86 g, 20 mmol) and phenylpropiolic acid (3.22 g, 22 mmol) were dissolved in dichloromethane (50 ml) and 1,3-dicyclohexylcarbodiimide (4.8 g, 23.2 mmol) was added in one portion at 0° C. The mixture was stirred room temperature for 14 h. The mixture was poured into water and extracted with dichloromethane (3×15 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography on silica gel, eluting with hexanes-EtOAc (6:1 and then 4:1) afforded 3-phenyl-propynoic acid phenylamide 2.7 g (62%).
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[CH:4][N:3]=1.O=S(Cl)[Cl:12]>C(Cl)Cl>[Cl:12][CH2:8][C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cccnc1F
Solvent: ClCCl
Product: Fc1ncccc1CCl

Procedure:
(2-Fluoropyridin-3-yl)methanol (508 mg, 3.998 mmol) was first treated with SOCl2 (1.5 ml) in CH2Cl2 (5 ml) at rt for 3 hrs. The solvent was removed to get a crude 3-(chloromethyl)-2-fluoropyridine. Then following General Procedure A, the title compound (910 mg, 85%) was prepared from 2-amino-4-chlorobenzenethiol (957 mg, 5.995 mmol), K2CO3 (2.7 g, 19.98 mmol) in DMF (20 ml).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9].N1C=CC=CC=1.[C:16](Cl)(=[O:19])[CH:17]=[CH2:18].O>C(Cl)Cl>[C:16]([NH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[OH:9])(=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)Cl
Reactant: Cc1ccc(O)c(N)c1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(C)ccc1O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2-amino-4-methylphenol (5 g, 40.6 mmol) and pyridine (5 ml, 62 mmol) in methylene chloride (70 ml) was added dropwise a solution of acryloyl chloride (4 ml, 50 mmol) in methylene chloride (30 ml) under ice-cooling. The reaction mixture was stirred at 0° C. for 2 hours. To the reaction mixture was added water, and the mixture was stirred at room temperature for 30 minutes, extracted with methylene chloride, washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off, and thus obtained brown oil was purified by column chromatography on silica gel to give a pale yellow prismatic crystals. Yield 1.55 g (22%).
Reaction SMILES: Cl.[C:2]([O:5][CH2:6]C)(=[O:4])[CH3:3].[CH3:8][CH2:9][CH2:10][CH2:11][CH2:12]C.C(O)(=[O:21])C1C=CC=CC=1>CO>[OH:21][C:9]1[CH:8]=[C:3]([CH:12]=[CH:11][CH:10]=1)[C:2]([O:5][CH3:6])=[O:4]
Reactant: O=C(O)c1ccccc1
Reactant: CCCCCC
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CO
Product: COC(=O)c1cccc(O)c1
Yield: 61 %

Procedure:
m-Hydroxybenzoic acid (10 g, 72.5 mmol) was dissolved in 100 mL of methanol and the solution refluxed with a catalytic amount of HCl. After 24 hours tlc analysis on silica with 10% ethyl acetate/hexane revealed a trace of the starting benzoic acid remaining. The solution was cooled and concentrated to dryness. The solid residue was dissolved in 200 mL of ether and washed with 100 mL of saturated aq. NaHCO3 and brine. Drying the solution over MgSO4 and evaporating the solvent left a slightly yellow solid that was purified by recrystallization from benzene/cyclohexane to give methyl 3-hydroxybenzoate as a white solid (6.74 g, 61%): 71°-73° C. ##STR39##
Reaction SMILES: [CH2:1]1[O:13][C:12]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][NH:8][C:9]3=[O:14])=[CH:4][C:3]=2[O:2]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]([CH2:32][Cl:33])[CH2:26]2)=[CH:19][CH:18]=1>>[ClH:33].[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][N:25]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]([CH2:32][N:8]3[CH2:7][CH2:6][C:5]4[C:10](=[CH:11][C:12]5[O:13][CH2:1][O:2][C:3]=5[CH:4]=4)[C:9]3=[O:14])[CH2:26]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(CCN2CCCCC(CCl)C2)cc1
Reactant: O=C1NCCc2cc3c(cc21)OCO3
Product: COc1ccc(CCN2CCCCC(CN3CCc4cc5c(cc4C3=O)OCO5)C2)cc1
Product: Cl

Procedure:
Prepared from 6,7-methylenedioxy-1-oxo-1,2,3,4-tetrahydroisoquinoline and N-[2-(4-methoxy-phenyl)-ethyl]-3-chloromethylhexahydro-azepine analogously to Example 2.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:31][CH2:30][CH2:29][CH2:28][C:5]=2[C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]2[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][CH:19]=2)=[CH:12][CH:11]=1)=[O:8].N1C=CC=CC=1.[Cl:38][CH2:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43](Cl)=[O:44]>C(Cl)Cl>[Cl:38][CH2:39][C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43]([NH:1][C:2]1[S:3][C:4]2[CH2:31][CH2:30][CH2:29][CH2:28][C:5]=2[C:6]=1[C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:26][CH:27]=2)=[CH:14][CH:15]=1)=[O:8])=[O:44]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(N)sc4c3CCCC4)cc2)cc1
Reactant: O=C(Cl)c1cccc(CCl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CCl)c4)sc4c3CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a mixture of 6.9 g of methyl 4-[2-(4-{[(2-amino-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, 1.5 mL of pyridine and 69 mL of methylene chloride was added dropwise 3.27 g of 3-(chloromethyl)benzoyl chloride, followed by stirring for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure, ethanol was added thereto, and the precipitated solid was collected by filtration, thereby obtaining 9.27 g of methyl 4-[2-(4-{[(2-{[3-(chloromethyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate.