Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[CH3:3][N:4]([CH3:13])[CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:14][C:15]1[CH:16]=[C:17]([O:21][CH2:22][CH2:23]Br)[CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C>CN(C=O)C>[ClH:14].[ClH:1].[Cl:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[O:21][CH2:22][CH2:23][N:10]1[CH2:11][CH2:12][CH:7]([CH2:6][CH2:5][N:4]([CH3:3])[CH3:13])[CH2:8][CH2:9]1
Reactant: CN(C)CCC1CCNCC1
Reactant: Clc1cccc(OCCBr)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CCC1CCN(CCOc2cccc(Cl)c2)CC1

Procedure:
A mixture of 4-(2-dimethylaminoethyl)piperidine dihydrochloride (7.0 g), 2-bromoethyl 3-chlorophenyl ether (7.2 g), triethylamine (12.75 ml) and DMF (50 ml) was heated on a steam bath for 16 hours then worked up as described in Example 16 to give 1-[2-(3-chlorophenoxy)ethyl]-4-(2-dimethylaminoethyl)piperidine dihydrochloride, m.p. 260°-264° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([O:20][C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:19][C:14]=3[O:13][CH:12]([C:25]([OH:27])=[O:26])[CH2:11]2)=[CH:5][CH:4]=1.[Li+].[CH3:29]C([N-]C(C)C)C.IC.Cl>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([O:20][C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:19][C:14]=3[O:13][C:12]([CH3:29])([C:25]([OH:27])=[O:26])[CH2:11]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CN2CC(C(=O)O)Oc3ccc(OC(F)(F)F)cc32)cc1
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: COc1ccc(CN2CC(C)(C(=O)O)Oc3ccc(OC(F)(F)F)cc32)cc1
Temperature: -50 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
To a solution of 4[(4-methoxyphenyl)methyl]-6-(trifluoromethoxy)-2,3-dihydro-1,4-benzoxazine-2-carboxylic acid (290 mg, 0.76 mmol) in tetrahydrofuran (7 mL), under N2 atmosphere and cooled to −50° C., was added LDA (1.5 mL of 2 M, 3.03 mmol). The mixture was stirred for 2 h at −50° C. then treated with iodomethane (430 mg, 188 μL, 3.03 mmol). The mixture was allowed to warm to room temperature and stirred for 16 h. 30 mL water was added and the solution acidified to ˜pH 3 with 1 N HCl. The solution was extracted with ethyl acetate (3×10 mL) and the organic layer washed with brine, dried over Na2SO4, filtered and dried down to provide 4-[(4-methoxyphenyl)methyl]-2-methyl-6-(trifluoromethoxy)-3H-1,4-benzoxazine-2-carboxylic acid as an orange oil (300 mg, quantitative yield). LC/MS m/z 398.0 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 13.11 (s, 1H), 7.21 (d, J=8.6 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 6.80 (d, J=8.6 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H), 6.51 (d, J=8.7 Hz, 1H), 4.45 (d, J=15.7 Hz, 1H), 4.30 (d, J=15.7 Hz, 1H), 3.73 (s, 3H), 3.67 (d, J=11.8 Hz, 1H), 3.15 (d, J=11.8 Hz, 1H), 1.48 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[C:13]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[N:14][C:15]3[C:20]([N:21]=1)=[CH:19][C:18]([C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=3)[CH2:7][CH2:6][CH2:5]2.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[C:13]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[N:14][C:15]3[C:20]([N:21]=1)=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][CH:16]=3)[CH2:7][CH2:6][CH2:5]2
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(Cl)ccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(Cl)ccc43)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a solution of methyl 3-(6-chloro-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (125 mg, 0.28 mmol) in methanol (30 ml) and water (1.0 ml) was added sodium hydroxide (44.6 mg, 1.11 mmol). The reaction was stirred overnight at room temperature. Then the reaction mixture was concentrated in vacuo, dissolved in water (30 ml), adjusted to pH 5 with aqueous hydrochloric acid (3 N) to give a precipitate, which was collected by filtration to afford 3-(6-chloro-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a light yellow solid (90 mg, 74%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[C:6]([N:13]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[F:32][C:33]1[CH:34]=[C:35]([CH:47]=[C:48]([F:50])[CH:49]=1)[CH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][N:41]=[C:40]2[NH2:46]>C(Cl)Cl.N1C=CC=CC=1>[F:32][C:33]1[CH:34]=[C:35]([CH:47]=[C:48]([F:50])[CH:49]=1)[CH2:36][C:37]1[CH:38]=[C:39]2[C:43](=[CH:44][CH:45]=1)[NH:42][N:41]=[C:40]2[NH:46][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[N:13]([CH:20]1[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1)[C:14](=[O:19])[C:15]([F:16])([F:17])[F:18]
Reactant: Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1N(C(=O)C(F)(F)F)C1CCOCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12)c1ccc([N+](=O)[O-])cc1N(C(=O)C(F)(F)F)C1CCOCC1
Yield: 83.7 %

Procedure:
4-nitro-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzoic acid (3.62 g, 10 mmol) and oxalyl chloride (3.8 mL, 30 mmol) were stirred in DCM dry (120 mL) and a few drops of dry DMF at room temperature for 2 hours Volatiles were evaporated and the residue dissolved in dry pyridine (50 mL) at 0° C. A solution of 5-(3,5-difluoro-benzyl)-1H-indazol-3-ylamine (2 gr, 7.72 mmol) in dry pyridine (20 mL) was added to the cooled reaction mixture under nitrogen atmosphere. The resulting mixture was allowed to react overnight at room temperature, then the solvent removed under reduced pressure. The residue was taken-up with EtOAc and washed with aqueous NaHCO3 sat.sol., water and brine. Organic phase was dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel using AcOEt/Hexane 7:3 as the eluant, affording 3.9 g of the title compound.
Reaction SMILES: N[C:2]1[N:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:20]=2[NH:19][CH:18]=[C:17]3[Cl:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.N([O-])=[O:23].[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Cl:21][C:17]1[C:16]2[C:20](=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[N:7][C:2]([OH:23])=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:13]=[CH:14][CH:15]=2)[NH:19][CH:18]=1
Reactant: O=N[O-]
Reactant: Nc1ccc(S(=O)(=O)Nc2cccc3c(Cl)c[nH]c23)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=S(=O)(Nc1cccc2c(Cl)c[nH]c12)c1ccc(O)nc1
Reaction time: 1 h
Yield: 53.8 %

Procedure:
Under ice-cooling, into a solution of the compound of Example 33a (100 mg, 0.31 mmol) dissolved in 2 ml of glacial acetic acid was added dropwise 1 ml of an aqueous solution containing 32 mg (0.46 mmol) of sodium nitrite. After stirring for one hour, the mixture was adjusted to about pH 8 by adding an aqueous sodium bicarbonate and further stirred for 10 minutes. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water, dried over magnesium sulfate and concentrated. Then, the residue was purified by silica gel thin layer chromatography, to give 54 mg of the title compound.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[NH2:5][CH2:6][CH:7]1[CH2:9][CH2:8]1>>[CH:7]1([CH2:6][NH:5][CH2:3][CH2:2][C:1]#[N:4])[CH2:9][CH2:8]1
Reactant: C=CC#N
Reactant: NCC1CC1
Product: N#CCCNCC1CC1

Procedure:
With stirring and cooling in an ice-bath to maintain a temperature of 8–10° C., acrylonitrile (0.614 ml) was added to aminomethylcyclopropane (0.651 g). The resultant mixture was stirred at room temperature for 15 h to give the title compound (1.02 g) as a yellow oil.
Reaction SMILES: [Br-].[C:2]([C:5]([CH3:30])([CH3:29])[CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].[H-].[Na+].[C:33]([C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)(=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>CS(C)=O.C1(C)C=CC=CC=1>[CH3:29][C:5]([CH3:30])([CH2:6][CH2:7][CH2:8]/[CH:9]=[C:33](/[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)\[C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1)[C:2]([OH:4])=[O:3]
Reactant: O=C(c1ccccc1)c1cccnc1
Reactant: CC(C)(CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CC(C)(CCC/C=C(/c1ccccc1)c1cccnc1)C(=O)O
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
5-Carboxy-5,5-dimethylpentyltriphenylphosphonium bromide (3 g, 6 mmole) was dissolved in anhydrous dimethylsulfoxide (30 ml) under a nitrogen atmosphere, and sodium hydride (0.25 g, 64 mmole) was added to the solution at 30° to 35° C., followed by stirring at 25° to 30° C. for 30 minutes. 3-Benzoylpyridine (0.9 g, 5 mmole) was added to the solution, followed by stirring at room temperature for another 1 hour. Water (100 ml) and toluene (100 ml) were added to the reaction solution, the organic layer was separated, and the water layer was adjusted to pH 6.0 with 2N hydrochloric acid. The product was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried and concentrated under reduced pressure. The residue was chromatographed on a column of silica gel, and development was effected with ethyl acetate to yield (E+Z)-2,2-dimethyl-7-phenyl-7-(3-pyridyl)-6-heptenoic acid (2-a, 2-b) (1.36 g, 88%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[Cl:35][C:36]1[N:40]([CH2:41][CH2:42][O:43][CH3:44])[N:39]=[CH:38][C:37]=1[NH2:45].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:35][C:36]1[N:40]([CH2:41][CH2:42][O:43][CH3:44])[N:39]=[CH:38][C:37]=1[NH:45][C:2]1[N:3]=[C:4]([O:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:27])([CH3:26])[CH3:28])[C:6]=2[N:7]=1
Reactant: COCCn1ncc(N)c1Cl
Reactant: Cc1nc2ccc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCCC5)c34)cc2o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COCCn1ncc(Nc2nc(OC3CCCC3)c3c(-c4ccc5nc(C)oc5c4)cn(COCC[Si](C)(C)C)c3n2)c1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a degassed mixture of 6-(2-chloro-4-(cyclopentyloxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), 5-chloro-1-(2-methoxyethyl)-1H-pyrazol-4-amine (1.5 equiv) and cesium carbonate (3 equiv) in 1,4-dioxane (0.06 M) was added palladium acetate (0.1 equiv) and 2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (0.2 equiv). The reaction was stirred at 100° C. for 2 h. Upon completion, the reaction mixture was cooled to room temperature, and concentrated. The residue was purified by silica gel chromatography (1-2% MeOH in DCM) to afford the desired product (60% yield, crude) as a yellow solid which was used in next step without further purification. MS (ESI) m/z 638.2 [M+H]+.
Reaction SMILES: C([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:7]([CH2:17]Cl)[C:6]=1[CH2:19]Cl)(C)(C)C.[C:21]([O:24]C)(=O)[CH3:22].O>BrCCBr.C1COCC1>[C:6]([C:14]1[CH:15]=[CH:16][C:11]([C:8]2[CH:9]=[CH:10][CH:5]=[C:6]3[C:7]=2[CH2:17][C:21]([CH3:22])([OH:24])[CH2:19]3)=[CH:12][CH:13]=1)([CH3:19])([CH3:7])[CH3:5]
Reactant: COC(C)=O
Reactant: CC(C)(C)c1ccc(-c2ccccc2)c(CCl)c1CCl
Solvent: O
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC1(O)Cc2cccc(-c3ccc(C(C)(C)C)cc3)c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
633 mg (26 mmol, 4 eq.) of Mg powder (50 mesh/Aldrich) were dried under reduced pressure with the aid of a hair dryer. 10 ml of THF and 10 drops of 1,2-dibromoethane were added. The mixture was heated to reflux until gas evolution took place and the activation was complete. The solvent was removed under reduced pressure and 10 ml of fresh THF were added. A solution of 2.0 g (6.5 mmol) of tert-butyl-2,3-bis(chloromethyl)biphenyl in 120 ml of THF was added and the suspension was stirred vigorously at room temperature for 3 hours. Stirring was continued overnight and the slightly greenish turbid solution obtained was filtered to remove excess magnesium. The filtrate was cooled to −78° C. and a solution of 482 mg (6.51 mol) of methyl acetate in 60 ml of THF was added dropwise over a period of 1 hour. The reaction solution was warmed to 0° C. over a period of 2 hours. 80 ml of water were subsequently added and the solution was concentrated under reduced pressure. To dissolve the magnesium salts, 3 ml of concentrated hydrochloric acid were added and the aqueous phase was extracted with methylene chloride (3×50 ml). The combined organic phases were dried over magnesium sulfate, and the solvent was subsequently removed under reduced pressure. The product was purified by column chromatography, with the nonpolar by-products being separated off using a heptane/dichloromethane mixture and the product being eluted with pure dichloromethane, giving a yellow product. Yield: 0.64 g (2.28 mmol/35%/94.5% by GC). 1H NMR (400 MHz, CDCl3): δ=7.43–7.22 (m, 7H, aromat.), 3.08 (m, 4H, CH2), 1.48 (s, 3H, CH3), 1.35 (s, 9H, tert-butyl) ppm.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:13]([CH:14]2[O:18][N:17]=[C:16]([CH3:19])[CH2:15]2)=[C:12]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7].O.Cl.[CH3:26]O>O1CCCC1>[CH3:26][C:11]1[C:12]([S:20]([CH3:23])(=[O:22])=[O:21])=[C:13]([CH:14]2[O:18][N:17]=[C:16]([CH3:19])[CH2:15]2)[C:4]([Cl:3])=[C:5]([CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: CO
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C2CC(C)=NO2)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1=NOC(c2c(Cl)c(C(=O)O)cc(C)c2S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
69.4 g (174 mmol) of 10% strength sodium hydroxide solution were added to a solution of 38.4 g (116 mmol) of methyl 2-chloro-3-(3-methyl-4,5-dihydroisoxazol-5-yl)-4-methylsulfonylbenzoate in 400 ml of methanol and 400 ml of tetrahydrofuran. The mixture was stirred for 12 hours at room temperature, the solvent volume was reduced to half, and the mixture was poured into 1 1 of water. The pH was brought to 1 using 10% strength hydrochloric acid, and the precipitate which formed was filtered off with suction.
Reaction SMILES: [CH2:1]([NH:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:10]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:18]1(=[O:24])[O:23][C:21](=[O:22])[CH2:20][CH2:19]1>C(Cl)Cl>[CH2:1]([NH:7][C:8](=[O:17])[C:9]1[CH:14]=[C:13]([O:15][C:18](=[O:24])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH:12]=[CH:11][C:10]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNC(=O)c1cc(O)ccc1O
Reactant: O=C1CCC(=O)O1
Solvent: ClCCl
Product: CCCCCCNC(=O)c1cc(OC(=O)CCC(=O)O)ccc1O
Reaction time: 24 h

Procedure:
N-n-Hexyl 2,5-dihydroxybenzamide (1 g) is dissolved in 15 mL of methylene chloride. To the solution 0.75 g of succinic anhydride and 0.95 g of 4-N,N-dimethylaminopyridene is added. The reaction mixture is allowed to stir at ambient conditions over 24 hours. Solvent is removed and the residue is reconstituted in ethyl acetate and extracted twice with 1 N HCl to remove the catalyst. The organic layer is further extracted with saturated sodium chloride solution and dried over anhydrous sodium sulfate. Solvent is removed under reduced pressure to yield the product as an off-white powder.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1Nc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 2-chloro-3-nitropyridine (15.4 g, 97.1 mmol) in N,N-dimethylformamide (100 mL) were added 4-chloroaniline (12.4 g, 97.2 mmol) and potassium carbonate (20 g, 140 mmol). The reaction mixture was stirred at 100° C. for 18 hours, and then poured into ice-water (200 mL). The precipitate was collected via filtration and washed with water (3×30 mL) to provide the product as a black solid. Yield: 15 g, 60 mmol, 62%. 1H NMR (400 MHz, DMSO-d6) δ 9.97 (br s, 1H), 8.47-8.57 (m, 2H), 7.69 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H), 7.01 (dd, J=8.2, 4.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C@H:6]1[CH2:11][CH2:10][N:9](C)[CH2:8][C@H:7]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:29]([O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30].ClC([O-])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C@H:6]1[CH2:11][CH2:10][N:9]([C:29]([O:31][CH2:32][C:33]([Cl:36])([Cl:35])[Cl:34])=[O:30])[CH2:8][C@H:7]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CN1CC[C@H](Oc2cccc(Cl)c2)[C@H](c2ccccc2)C1
Agent: O=C([O-])Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)N1CC[C@H](Oc2cccc(Cl)c2)[C@H](c2ccccc2)C1
Temperature: 25 °C

Procedure:
A mixture of 2.48 g of the free base cis-4-(3-chlorophenoxy)-1-methyl-3-phenylpiperidine, of Example 36, 1.14 g of anhydrous potassium carbonate and 30 ml of dry benzene is treated with 1.42 ml of 2,2,2-trichloroethyl chloroformate. After 30 minutes at room temperature the mixture is refluxed 18 hours. Another 0.36 ml of chloroformate is added, and the mixture is refluxed another 4 hours. The mixture is then cooled and partitioned between 100 ml of ether and 50 ml of water. The aqueous phase is extracted with 50 ml of ether, and the combined organic extracts are washed with 2 N HCl solution, saturated aqueous NaCl solution, and dried over Na2SO4. Concentration in vacuo affords a mixture of a solid and an oil which is triturated with 25 ml of ether and then diluted with hexane to a volume of about 125 ml. After refrigeration for 18 hours the mixture is filtered, the solid is washed with hexane, and the filtrate is washed successively with 10% aqueous NaOH solution, water, and saturated aqueous NaCl solution. After drying over Na2SO4 the solution is concentrated in vacuo to a gum. Chromatography of this material on silica gel affords a colorless gum of cis-4-(3-chlorophenoxy)-3-phenyl-1-(2,2,2-trichloroethoxycabonyl) piperidine.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH2:18])=[O:5].[C:24](O)(=[O:28])[C:25]([CH3:27])=[CH2:26].ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH:18][C:24](=[O:28])[C:25]([CH3:27])=[CH2:26])=[O:5]
Reactant: C=C(C)C(=O)O
Reactant: NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(C)C(=O)NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 79.4 %

Procedure:
A mixture of 8-(2,6-dichlorobenzoylamino)-4-hydrazinoquinoline (200 mg), methacrylic acid (54.5 mg), 1-ethyl-3-(3-dimethylaminopropyl)-arbodiimide hydrochloride (133 mg) and 1-hydroxybenzotriazole (93.4 mg) in dimethylformamide (4 ml) was stirred for 4.5 hours at ambient temperature. The mixture was diluted with ethyl acetate and washed with water, saturated sodium bicarbonate solution and brine. The insoluble materials were collected by filtration and recrystallized from ethanol to give 8-(2,6-dichlorobenzoylamino)-4-(2-methacryloylhydrazino)quinoline (190 mg).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3C=[CH:22][CH:21]=[CH:20][C:16]=3[C:17](O)=O)=[O:14])[CH:10]=[CH:11][C:5]=2[N:4]=1.NC1C=CC2N=C(N(C(OC(C)(C)C)=O)[C:34]([O:36]C(C)(C)C)=[O:35])N(C(OC(C)(C)C)=O)C=2C=1>>[ClH:1].[NH2:2][C:3]1[NH:7][C:6]2[CH:8]=[C:9]([NH:12][C:13](=[O:14])[CH2:15][C:16]3([CH2:17][C:34]([OH:36])=[O:35])[CH2:20][CH2:21][CH2:22]3)[CH:10]=[CH:11][C:5]=2[N:4]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc2ccc(N)cc2n1C(=O)OC(C)(C)C
Reactant: Nc1nc2ccc(NC(=O)c3ccccc3C(=O)O)cc2[nH]1
Agent: Cl
Product: Nc1nc2ccc(NC(=O)CC3(CC(=O)O)CCC3)cc2[nH]1
Yield: 85 %

Procedure:
Following the same procedure to synthesize 2-(2-amino-1H-benzo[d]imidazol-6-ylcarbamoyl)benzoic acid hydrochloride, tert-butyl 6-amino-2-(bis(tert-butoxycarbonyl)amino)-1H-benzo[d]imidazole-1-carboxylate (0.167 g, 0.372 mmol) was reacted with (S)-7-oxaspiro[3.5]nonane-6,8-dione (0.057 g, 0.372 mmol) to give the title product (0.107 g, 85% yield) as a yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.49 (s, 1H), δ 6.95 (s, 2H), δ 2.24 (m, 4H), δ 1.32 (m, 8H) ppm; 13C NMR (75 MHz, CD3OD) δ 175.2, 173.8, 171.8, 151.9, 135.0, 129.7, 116.7, 111.3, 103.9, 44.4, 43.9, 42.0, 39.7, 37.8, 24.1 ppm; HRMS (ESI) Calcd for C15H18N4O3(M+) 302.1379. Found 302.1373.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[S:9][N:8]=2)[CH2:3][CH2:2]1.[CH:16]1([CH2:19]Cl)[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[BrH:29].CCOCC>CCOCC.O.CN(C)C=O>[BrH:29].[CH:16]1([CH2:19][N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[S:9][N:8]=3)[CH2:5][CH2:6]2)[CH2:18][CH2:17]1
Reactant: ClCC1CC1
Reactant: c1ccc2c(C3CCNCC3)nsc2c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c(C3CCN(CC4CC4)CC3)nsc2c1
Yield: 25 %

Procedure:
A stirred mixture of 5.0 g of 3-(4-piperidinyl)-1,2-benzisothiazole, 2.30 g of cyclopropylmethyl chloride, 7.95 g of potassium carbonate, 0.25 g of potassium iodide and 90 ml of dimethylformamide was heated at 90° for 20 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to yield an oil. The oil was dissolved in ether and saturated hydrogen bromide/ether solution was added dropwise to precipitate the salt. The salt was recrystallized two times from ethyl acetate/ethanol to yield 2.0 g (25%) of product, mp 214°-216°.