Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=S(Cl)Cl.[CH3:5][O:6][C:7]1[C:8]([N+:18]([O-:20])=[O:19])=[C:9]([CH:13]=[C:14]([O:16][CH3:17])[CH:15]=1)[C:10]([OH:12])=O.[NH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:23]1.C(N(CC)CC)C>C(Cl)(Cl)Cl.C1COCC1.CN(C=O)C>[CH3:5][O:6][C:7]1[C:8]([N+:18]([O-:20])=[O:19])=[C:9]([CH:13]=[C:14]([O:16][CH3:17])[CH:15]=1)[C:10]([NH:21][CH:22]1[CH2:27][CH2:26][N:25]([CH:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:24][CH2:23]1)=[O:12]
Reactant: NC1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: COc1cc(OC)c([N+](=O)[O-])c(C(=O)O)c1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(OC)c([N+](=O)[O-])c(C(=O)NC2CCN(C(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Step 1): A solution of SOCl2 (0.5 ml, 6.6 mmol) in chloroform (10 ml) was added dropwise to a solution of 3,5-dimethoxy-2-nitrobenzoic acid [Bull. Soc. Chim. Fr., 127, 258 (1990)] (1.0 g, 4.4 mmol) and a catalytic amount of DMF in chloroform (20 ml) at room temperature. The reaction mixture was refluxed for 1 hour and then concentrated. The residue was dissolved in THF (10 ml). The THF solution was added dropwise to a solution of 4-amino-1-diphenylmethylpiperidine (1.2 g, 4.4 mmol) and triethylamine (0.5 ml, 6.6 mmol) in THF (20 ml) at 5° C. The mixture was stirred at room temperature for 1 hour and then concentrated. The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel (10% ethyl acetate in dichloromethane) to give 3,5-dimethoxy-2-nitro-N-(1-diphenylmethylpiperidin-4-yl)benzamide (81.0%): mp 148°-150° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH3:15][NH:16][CH3:17].C(N(C(C)C)C)(C)C>ClCCl>[CH3:15][N:16]([CH3:17])[S:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNC
Agent: CC(C)N(C)C(C)C
Agent: Cl
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4.43 g (20 mmol) of 4-nitrobenzenesulphonic acid chloride are added dropwise at 0° C. to a solution of 2.45 g (30 mmol) of dimethylamine-hydrochloride and 6.46 g (50 mmol) of N,N-diisopropyl-N-methylamine in 30 ml of dichloromethane. The mixture is stirred for 18 hours at ambient temperature. Then the reaction solution is washed with water and dilute hydrochloric acid, dried over magnesium sulphate and evaporated to dryness.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:24][O:23][CH2:22][CH2:21][O:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)C=CC=CC=1.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[O:20]1[CH2:21][CH2:22][O:23][CH2:24][CH:19]1[C:18]1[C:12]2[S:11][C:10]([NH:9][C:8]([N:32]3[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]3)=[O:27])=[N:14][C:13]=2[C:15]([O:25][CH3:26])=[CH:16][CH:17]=1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)Oc3ccccc3)nc12
Reactant: OC1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)N3CCC(O)CC3)nc12

Procedure:
From (+)-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-carbamic acid phenyl ester with 4-hydroxypiperidine and pyridine in chloroform. [α]D20=+29.4° (c=1.01, CHCl3), ES-MS m/e (%): 394 (M+H+, 100).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][C:13]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)=[N:12][N:11]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:29](O)[CH3:30]>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:14][C:13]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([O:21][CH2:29][CH3:30])=[O:20])=[CH:17][CH:16]=2)=[N:12][N:11]=1)([O-:3])=[O:2]
Reactant: CCO
Reactant: O=C(O)c1ccc(-c2nnc(-c3ccccc3[N+](=O)[O-])o2)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(-c2nnc(-c3ccccc3[N+](=O)[O-])o2)cc1
Yield: 24 %

Procedure:
A mixture of 4-[5-(2-nitrophenyl)-1,3,4-oxadiazol-2-yl]benzoic acid (2.00 g), conc. sulfuric acid (0.5 ml) and ethanol (50 ml) was heated under reflux for 6 hrs. After cooling, the reaction mixture was concentrated, and the residue was diluted with ethyl acetate. This solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-2:1, volume ratio) to give ethyl 4-[5-(2-nitrophenyl)-1,3,4-oxadiazol-2-yl]benzoate (0.51 g, yield 24%). Recrystallization from hexane-ethyl acetate gave pale-yellow prism crystals. melting point: 127–128° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C@@H:29]2[CH2:31][O:30]2)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C@@H:29]([OH:30])[CH2:31][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)=[CH:25][CH:24]=1
Reactant: Clc1ccc(OC[C@@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C[C@H](O)COc3ccc(Cl)cc3)CC1)O2

Procedure:
Compound 182 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-chlorophenoxy)methyl]oxirane and conditions outlined in procedure Y. M.p.=138-140° C.; 400 MHz 1H NMR (CDCl3) δ: 8.06 (dd, J=7.7, 1.5 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.67 (td, J=7.7, 1.1 Hz, 1H), 7.49 (td, J=7.5, 1.1 Hz, 1H), 7.28-7.21 (m, 2H), 6.88-6.82 (m, 2H), 4.17-4.08 (m, 1H), 4.02-3.94 (m, 2H), 3.02-2.92 (m, 1H), 2.95 (s, 2H), 2.84-2.76 (m, 2H), 2.71-2.61 (m, 2H), 2.54 (td, J=11.5, 2.4 Hz, 1H), 2.17 (br. d, J=13.9 Hz, 2H), 1.98-1.82 (m, 2H); LCMS: 486 [M+H]; enantiomeric excess determined from chiral HPLC: 98%; Chiral HPLC Rt=62.95 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C1C=CC2N(O)N=NC=2C=1.[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:30]1.N=C=N.C(O)C(N)(CO)CO>C(Cl)Cl>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[N:10]=[CH:11][C:12]([C:13]([NH:28][CH:29]3[CH2:30][CH2:31][N:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:33][CH2:34]3)=[O:15])=[CH:16][CH:17]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1ccc(-c2cc(F)cc(F)c2)nc1
Agent: N=C=N
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOC(=O)N1CCC(NC(=O)c2ccc(-c3cc(F)cc(F)c3)nc2)CC1
Yield: 16.4 %

Procedure:
6-(3,5-difluoro-phenyl)-nicotinic acid (55 mg, 0.23 mmol), HOBt (40 mg, 0.29 mmol), ethyl 4-aminopiperidine-1-carboxylate (23 mg, 0.13 mmol), and PS-carbodimide (350 mg) in DCM (5 ml) was shaken 12 h. After shaking, PS-trisamine (3 mg) was added and the reaction shaken for 4 h, then filtered and washed with 15% MeOH/DCM. The organic was concentrated and purified by reversed phase automatic chromatography to provide 8.3 mg (9%) of the title compound. 1H NMR (400 MHz, DMSO-d6) □ ppm 9.08 (1H, d, J=1.5 Hz), 8.51 (1H, d, J=7.3 Hz), 8.31 (1H, dd, J=8.2, 2.4 Hz), 8.19 (1 h, d, J=8.8 Hz), 7.89 (2H, br. s.), 4.03 (2H, br. s.), 4.05 (4H, d, J=7.3 Hz), 2.94 (2H, br. s.), 1.85 (2H, d, J=13.5 Hz), 1.48 (2H, br. s.), 1.20 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[CH:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14])[CH3:3].C(N(CC)CC)C.[CH3:25][O:26][C:27]([S:29]Cl)=[O:28]>C1C=CC=CC=1>[CH3:25][O:26][C:27]([S:29][C:5]([C:6](=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]([F:16])([F:15])[F:14])=[CH:4][N:2]([CH3:3])[CH3:1])=[O:28]
Reactant: CN(C)C=CC(=O)c1ccccc1C(F)(F)F
Reactant: COC(=O)SCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COC(=O)SC(=CN(C)C)C(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
4.2 g of 1-(N,N-dimethylamino)-2-(2-trifluoromethylbenzoyl)ethene and 2.6 g of triethylamine were added to 50 ml of benzene. 2.4 g of methoxycarbonylsulfenyl chloride dissolved in 10 ml of benzene was added dropwise to the solution obtained above under cooling in an ice-bath. After completion of the addition, the reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the solvent was distilled away under reduced pressure. After adding an aqueous solution of sodium hydrogencarbonate, the mixture was extracted with ether. Thus 5.0 g of 1-methoxycarbonylthio-1-(2-trifluoromethylbenzoyl)-2-(N,N-dimethylamino)ethene was obtained (Compound 209).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:9]1[C:13]([S-:14])=[CH:12][N:11]=[N:10]1.[Na+]>C(O)C.C(OCC)(=O)C>[CH2:1]([S:14][C:13]1[N:9]=[N:10][NH:11][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: [S-]c1cnn[nH]1
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: c1ccc(CSc2c[nH]nn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.3 %

Procedure:
Benzyl bromide (11.79 ml, 99 mmol) was added dropwise to a solution of sodium 1H-1,2,3-triazole-5-thiolate (12.2 g, 99 mmol) in ethanol (100 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 20 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (100 mL), brine (100 mL) and dried (sodium sulphate). The solvent was removed to give 4-(benzylthio)-1H-1,2,3-triazole (16.9 g) as a white solid. LCMS (Method F, ES-API): RT 1.66 min, m+H=191.9; 1H NMR (400 MHz, CDCl3): δ 9.72 (1H, v br s), 7.47 (1H, s), 7.30-7.21 (5H, m), 4.12 (2H, s).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[C:3]([C:10](Cl)=[O:11])[CH:2]=1.[NH2:13][C:14]1[CH:15]=[C:16]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH:17]=[CH:18][C:19]=1[CH3:20].C(N(CC)CC)C>>[CH3:20][C:19]1[CH:18]=[CH:17][C:16]([NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=2)=[CH:15][C:14]=1[NH:13][C:10]([C:3]1[CH:2]=[N:1][N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=12)=[O:11]
Reactant: O=C(Cl)c1cnn2ccccc12
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1N
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)c1cnn2ccccc12
Temperature: 25 °C

Procedure:
Pyrazolo[1,5-a]pyridine-3-carbonylchloride (100 mg, 0.55 mmol, Maybridge Lot # 291259) and N-(3-amino-4-methyl-phenyl)-3-trifluoromethyl-benzamide (163 mg, 0.55 mmol) are dissolved in 2 ml dry methylenehloride. Triethylamine (93 μl, 0.66 mmol) is added and the reaction mixture is stirred at room temperature. After complete formation of the product, the reaction mixture is quenched with water and the product is extracted with methylenehloride. The solvent is removed under reduced pressure and the crude product is absorbed to Isolute. The product is purified by automated reversed phase column chromatography (column: Interchrom Puriflash 15/35U C18, 70 g cartouche; solvents: water+0.1% trifluoroacetic acid and acetonitrile+0.1% trifluoroacetic acid) and is dried at the high vacuum pump, yielding the title compound as a white solid.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:13][C@H:12]([OH:14])[CH2:11][CH:10]1[CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[OH:14][C@H:12]1[CH2:13][NH:9][CH:10]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=2)[CH2:11]1
Reactant: Cc1cccc(CCc2ccccc2OCC2C[C@@H](O)CN2C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cccc(CCc2ccccc2OCC2C[C@@H](O)CN2)c1
Reaction time: 3 h
Yield: 70 %

Procedure:
3 ml of a 4N solution of hydrogen chloride in dioxane were added to a solution of 348 mg of (4R)-1-t-butoxycarbonyl-4-hydroxy-2-{2-[2-(3-methylphenyl)ethyl]phenoxymethyl}pyrrolidine [prepared as described in step (b) above] in 3 ml of dioxane, and the resulting mixture was allowed to stand at room temperature for 3 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, the resulting solid residue was dissolved in methylene chloride, and ethyl acetate was added to the solution, which was then allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo, to give 208 mg (yield 70%) of the title compound as colorless crystals, melting at 141°-143° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:45])[CH2:23][C:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:35]=[C:34]([CH2:36][O:37]C3CCCCO3)[O:33][N:32]=2)[CH:26]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:18])([F:19])[F:20])=[CH:10][C:9]2[NH:21][C:22](=[O:45])[CH2:23][C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:35]=[C:34]([CH2:36][OH:37])[O:33][N:32]=4)[CH:26]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(COC4CCCCO4)on3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cc(CO)on3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-dimethylamino-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-3-yl]-phenyl}-propionylamino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M45) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (103 mg).
Reaction SMILES: [Br-].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Zn+].[CH3:9][O:10][N:11]=[C:12]1[C:20]2[C:15](=[C:16](Br)[CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:9][O:10][N:11]=[C:12]1[C:20]2[C:15](=[C:16]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: CON=C1CCc2c(Br)cccc21
Reactant: [Zn+]c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: CON=C1CCc2c1cccc2-c1ccccn1
Temperature: 120 °C

Procedure:
2-Pyridylzinc bromide (10 mL, 5 mmol, 0.5M in THF) was added to 4-bromoindan-1-one O-methyl-oxime (600 mg, 2.5 mmol) and Pd(PPh3)4 (58 mg, 0.05 mmol) under nitrogen atmosphere. The stirred solution was heated at 120° C. for 10 minutes on the microwave. After cooling to ambient temperature, the reaction mixture was filtered through celite, then silica gel with ethyl acetate. The filtrate was concentrated to a brown oil and chromatographed on silica gel with 20-40% ethyl acetate in hexane. Obtained 4-pyridin-2-ylindan-1-one O-methyloxime (326 mg, 55%) as a yellow oil. MS (DCI/NH3) m/z: 239.09 [M+H]+. 1H NMR (DMSO-d6) δ: 2.82 (m, 2H), 3.29 (m, 2H), 3.92 (s, 3H), 7.36 & 7.38 (pair of dd, 1H), 7.43 (t, 1H), 7.64 (dd, 1H), 7.74 (dd, 1H), 7.75 (dt, 1H), 7.91 (td, 1H), 8.68 & 8.69 (pair of dd, 1H).
Reaction SMILES: Br.Cl.C[O:4][C:5]1[CH:6]=[C:7]2[O:11][CH:10]([CH3:12])[CH2:9][C:8]2=[C:13]([NH:15][CH3:16])[CH:14]=1>C(O)(=O)C>[OH:4][C:5]1[CH:6]=[C:7]2[O:11][CH:10]([CH3:12])[CH2:9][C:8]2=[C:13]([NH:15][CH3:16])[CH:14]=1
Reactant: CNc1cc(OC)cc2c1CC(C)O2
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Product: CNc1cc(O)cc2c1CC(C)O2
Yield: 77 %

Procedure:
5 cc of 48% HBr are added to a solution of 5 grams of 2,3-dihydro-6-methoxy-N,2-dimethyl-4-benzofuranamine hydrochloride in 20 cc of acetic acid and the resulting mixture is refluxed for 16 hours. At the end of this time the solvent is evaporated off and the residue, taken up with sodium bicarbonate, is thoroughly extracted with ether. Evaporation of this organic phase, previously dried over Na2SO4, gives a crude residue which crystallized from ethyl ether-petroleum ether yields 3 grams of the desired end product. Yield 77 percent of theoretical. M.p. 126°-128° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:5]=1[CH3:11].[C:13]1(/[C:19](=[C:21]2/[C:22](=[O:30])[NH:23][C:24]3[C:29]/2=[CH:28][CH:27]=[CH:26][CH:25]=3)/[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([N:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)/[C:21](=[C:19](\[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)/[CH3:20])/[C:22]2=[O:30])[CH:7]=[CH:6][C:5]=1[CH3:11]
Reactant: COC(=O)c1cc(Br)ccc1C
Reactant: C/C(=C1\C(=O)Nc2ccccc21)c1ccccc1
Product: COC(=O)c1cc(N2C(=O)/C(=C(\C)c3ccccc3)c3ccccc32)ccc1C

Procedure:
The title compound was prepared in analogy to Example 1 starting from 5-bromo-2-methyl-benzoic acid methyl ester (commercially available) and 3-[1-phenyl-eth-(E)-ylidene]-1,3-dihydro-indol-2-one. 1H NMR (400 MHz, chloroform-d) δppm 2.71 (s, 3H) 2.86 (s, 3H) 3.91 (s, 3H) 6.24 (d, J=7.83 Hz, 1H) 6.67-6.75 (m, 2H) 7.08 (t, J=7.83 Hz, 1H) 7.34-7.37 (m, 2H) 7.43-7.47 (m, 1H) 7.49-7.56 (m, 4H) 8.05 (d, J=2.27 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[CH:13][C:14]#[N:15])=[CH:5][CH:4]=1.N.C(O)C>C(O)C.[Co]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9]/[C:10]/2=[CH:13]/[C:14]#[N:15])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=CC#N)CCC2
Agent: [Co]
Agent: N
Solvent: CCO
Product: COc1ccc2c(c1)/C(=C\C#N)CCC2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 53.7 %

Procedure:
To a solution of (1,2,3,4-tetrahydro-7-methoxy-1-naphthylidene)acetonitrile (4.0 g, 20 mmol) in ethanol (10 ml) were added a saturated ammonia/ethanol solution (5 ml) and Raney cobalt (ODHT-60, 1 g). The reaction mixture was stirred for 3.5 hours at room temperature under hydrogen atmosphere (about 4 kgf/cm2). The Raney cobalt was filtered off, then the solvent was distilled off under reduced pressure. To the residue was added dilute hydrochloric acid, then the organic layer was subjected to extraction with ethyl acetate. The extract solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and water, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography to give the above-titled compound (yield 2.14 g, oil).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)(=[O:20])=[O:19])[CH2:12][C:13]([O:15]CC)=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:31][NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40](=[NH:42])[NH2:41])=[CH:36][CH:35]=1.[OH-].[Na+]>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[C:25]4[C:30]=3[N:29]=[CH:28][CH:27]=[CH:26]4)(=[O:20])=[O:19])[CH2:12][C:13]([OH:15])=[O:14])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:31][NH:32][CH2:33][C:34]1[CH:35]=[CH:36][C:37]([C:40](=[NH:41])[NH2:42])=[CH:38][CH:39]=1
Reactant: CCOC(=O)CN(c1ccc2c(c1)nc(CNCc1ccc(C(=N)N)cc1)n2C)S(=O)(=O)c1cccc2cccnc12
Agent: [Na+]
Agent: [OH-]
Product: Cn1c(CNCc2ccc(C(=N)N)cc2)nc2cc(N(CC(=O)O)S(=O)(=O)c3cccc4cccnc34)ccc21

Procedure:
Prepared analogously to Example 3 from 1-methyl-2-[N-(4-amidinobenzyl)-aminomethyl]-5-[N-(ethoxycarbonylmethyl)-quinoline-8-sulphonylamino]-benzimidazole and sodium hydroxide solution.
Reaction SMILES: [O:1]=[C:2]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:3]([CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]1[C:20]#[N:21])C(OC)=O.[OH-].[Li+].Cl>CO>[C:20]([CH:9]1[C:10]2[C:15](=[CH:14][C:13]([O:18][CH3:19])=[CH:12][CH:11]=2)[CH2:16][CH2:17][CH:8]1[CH2:3][C:2](=[O:1])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)#[N:21]
Reactant: COC(=O)C(C(=O)Cc1ccccc1)C1CCc2cc(OC)ccc2C1C#N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1)CCC(CC(=O)Cc1ccccc1)C2C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 3-oxo-4-phenyl-2-(1-cyano-6-methoxy-1,2,3,4-tetrahydronaphth-2-yl)-butyrate (4.63 g, 12 mmol), from Step 1, was dissolved in 100 mL of methanol and lithium hydroxide (77 mL of a 1.0M solution) was added. The reaction mixture was stirred overnight at ambient temperature and then acidified with 1N aqueous hydrochloric acid solution and extracted with diethyl ether. The ether extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The basic ether extract yielded 2.76 (70% yield) of the title compound; MS DCI-NH3M/Z: 337 (M+H)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([F:11])=[C:9](Cl)[N:8]=[C:7]([C:13]([O:15][CH3:16])=[O:14])[C:6]=1[Cl:17])(=[O:3])[CH3:2].NC1C(F)=C([Br:26])N=C(C(OC)=O)C=1Cl>>[C:1]([NH:4][C:5]1[C:10]([F:11])=[C:9]([Br:26])[N:8]=[C:7]([C:13]([O:15][CH3:16])=[O:14])[C:6]=1[Cl:17])(=[O:3])[CH3:2]
Reactant: COC(=O)c1nc(Br)c(F)c(N)c1Cl
Reactant: COC(=O)c1nc(Cl)c(F)c(NC(C)=O)c1Cl
Product: COC(=O)c1nc(Br)c(F)c(NC(C)=O)c1Cl

Procedure:
Methyl 4-(acetylamino)-6-bromo-3-chloro-5-fluoro-picolinate was prepared in analogous fashion to methyl 4-(acetylamino)-3,6-dichloro-5-fluoro-picolinate in Example 8 except that methyl 4-amino-6-bromo-3-chloro-5-fluoropicolinate was used in place of methyl 4-amino-3,6-dichloro-5-fluoropicolinate: mp=190-192° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.5 (s, 1H), 3.93 (s, 3H), 2.16 (s, 3H); 13C NMR (100.6 MHz, DMSO-d6) δ 168.0, 162.8, 153.1, 150.5, 143.7 (d, JF-C=24 Hz), 134.1 (d, JF-C=56 Hz), 127.3 (d, JF-C=96 Hz), 53.2, 22.5; 19F NMR (376.5 MHz, DMSO-d6) δ −108.3; MS Calcd. for C9H7BrCl2FN2O3: 323.93. Found: 289, 226.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.[Li]CCCC.CCCCCC.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28]>C1COCC1>[CH3:25][N:26]([CH3:30])[C:27]([C:11]1[N:10]([CH3:13])[N:9]=[C:8]([N:3]2[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]2[CH3:7])[CH:12]=1)=[O:28]
Reactant: CN(C)C(=O)Cl
Reactant: Cc1ccc(C)n1-c1ccn(C)n1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(C(=O)N(C)C)n(C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(2,5-dimethyl-pyrrol-1-yl)-1-methyl-1H-pyrazole (2.0 g, 11.4 mmol) in THF (100 mL) at −78° C., 2.5M nBuLi in Hexane (5.5 mL, 13.7 mmol) is added. After stirring for 1.5 hour dimethylcarbamyl chloride (1.26 mL, 13.7 mmol) is added. After 10 min the ice bath is removed and the reaction allowed to reach room temperature and stir at room temperature for 2 hour before being poured into water, separated, and the water layer extracted with DCM. The organic layers are combined and concentrated. The residue is purified by FCC to give the title compound. MS (ESI) m/z 247.2 (M+1).
Reaction SMILES: O.[OH:2][CH2:3][C:4]1([CH2:17][OH:18])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2.[CH3:19]I.[H-].[Na+]>C1COCC1>[CH3:19][O:2][CH2:3][C:4]1([CH2:17][OH:18])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2
Reactant: OCC1(CO)c2ccccc2-c2ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC1(CO)c2ccccc2-c2ccccc21
Yield: 62.1 %

Procedure:
Under nitrogen atmosphere and water-free conditions, to a reactor were added in succession 80 ml of THF, 22.6 g of 9,9-bis(hydroxymethyl)fluorene and 57 g of methyl iodide. After the reaction mixture was admixed homogeneously by stirring, 4.6 g of 52% NaH in mineral oil was added batch-wise over 2 hours at room temperature. Upon completing the addition, the reaction mixture was stirred for further 2 hours. The unreacted methyl iodide was recovered by distillation. The remainder was diluted with 100 ml of water, and extracted twice using 100 ml of diethyl ether for each time. The combined diethyl ether extract was dried over anhydrous sodium sulfate. After drying, the ether solution was evaporated to dryness to give 22.8 g of crude. The crude was purified through column chromatography to give 14.9 g of 9-methoxymethyl-9-hydroxymethyl-fluorene (yield 62%).