Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](OC)=[O:26].O>ClCCl>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[CH:19]=[CH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]
Reactant: COC(=O)CCCCC=Cc1ccc(Cl)cc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: ClCCl
Product: OCCCCCC=Cc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.4 %

Procedure:
Di-isobutylaluminium hydride (1.0M in dichloromethane, 308 ml, 308 mmol) was injected into a stirred solution of methyl 7-(2,4-dichlorophenyl)-6-heptenoate (40.2 g, 140 mmol) in dichloromethane (200 ml) at -78° C. under argon. After 5 min, the solution was warmed to 0° C., stirred for 0.5 h, then cooled again to -78° C. Water (102 ml) was injected slowly, while allowing the mixture to warm to room temperature. When solid had precipitated, ethyl acetate (400 ml) was added, then excess NaHCO3, and the mixture stirred vigorously for 0.25 h. The solids were filtered off, the solvent removed under vacuum, and the residue purified by chromatography on silica gel (30-70% ether/petroleum ether 40°-60° C.) to give the title compound (31.7 g, 85%) as an oil, comprising a mixture of E and Z isomers.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH:4]([NH2:8])[C:5](=O)[CH3:6].[O:10]([C:12]#[N:13])[K].Cl>C(O)C>[CH3:1][O:2][C:3]([C:4]1[NH:8][C:12](=[O:10])[NH:13][C:5]=1[CH3:6])=[O:9]
Reactant: COC(=O)C(N)C(C)=O
Reactant: N#CO[K]
Agent: Cl
Solvent: CCO
Product: COC(=O)c1[nH]c(=O)[nH]c1C
Temperature: 80 °C
Yield: 96.1 %

Procedure:
To a solution of 2-amino-3-oxo-butyric acid methyl ester (100 mmol) (Lida, H. et al. Synthetic Communication, 1973, 3, 225–230) in 150 mL of ethanol was added KOCN (16.2 g, 200 mmol). The mixture was heated at 80° C. for 2 h. The solution was acidified with 2 N HCl and concentrated to half of the volume in vacuo. The product precipitated out upon cooling. Filtration, followed by washing with water, provided 5-methyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid methyl ester 4a (15 g, >95%). MS (ESI+) (M+1)=157.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[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.[N+:20]([C:23]1[CH:43]=[CH:42][C:26]([CH2:27][O:28][C:29](=[O:41])[CH:30]([N:32]2[C@H:35]([S:36][C:37](=[O:39])[CH3:38])[CH2:34][C:33]2=[O:40])Cl)=[CH:25][CH:24]=1)([O-:22])=[O:21]>O1CCOCC1>[N+:20]([C:23]1[CH:24]=[CH:25][C:26]([CH2:27][O:28][C:29](=[O:41])[C:30]([N:32]2[C@H:35]([S:36][C:37](=[O:39])[CH3:38])[CH2:34][C:33]2=[O:40])=[P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:42][CH:43]=1)([O-:22])=[O:21]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC(=O)S[C@@H]1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1COCCO1
Product: CC(=O)S[C@@H]1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 17 h

Procedure:
3.144 g (~1.5 equivalents) of triphenylphosphine and 12 g of poly-Hunig base are added to a solution of 3.1 g of 2-[(4R)-4-acetylthio-2-oxoazetidin-1-yl]-2-chloroacetic acid p-nitrobenzyl ester in 120 ml of dioxan and the mixture is stirred for 17 hours at 50° under nitrogen. The poly-Hunig base is filtered off, washed with dioxan and the filtrate concentrated in vacuo. The residue is chromatographed twice over silica gel with toluene and toluene/ethyl acetate (4:1 and 3:2) and yields the title compound.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1.[CH3:19][C:20]1[C:21](=[O:49])[N:22]([C:37]2[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[C:39]([C:45]([F:48])([F:47])[F:46])[CH:38]=2)[C:23](=[O:36])[C:24]=1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>O1CCCC1.C(OCC)(=O)C>[F:8][C:9]1[CH:10]=[C:11]([S:15]([N:33]2[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:24]3[C:23](=[O:36])[N:22]([C:37]4[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[C:39]([C:45]([F:46])([F:47])[F:48])[CH:38]=4)[C:21](=[O:49])[C:20]=3[CH3:19])[CH2:31][CH2:32]2)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC1=C(CCCCCN2CCNCC2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC1=C(CCCCCN2CCN(S(=O)(=O)c3cccc(F)c3)CC2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.2 ml of a solution of triethylamine in tetrahydrofuran (1.5 mol/l) and 8 mg of 3-fluorophenylsulfonyl chloride in 0.4 ml of tetrahydrofuran were added to a solution of 9 mg of 4-[2,5-dihydro-3-methyl-2,5-dioxo-4-[5-(piperazin-1-yl)pentyl]-1H-pyrrol-1-yl]-2-(trifluoromethyl)benzonitrile in 0.4 ml of tetrahydrofuran, and the mixture was stirred for 8 hours at room temperature. For working-up, the reaction mixture was diluted with ethyl acetate and washed with semi-saturated sodium bicarbonate solution. After the organic phase was concentrated by evaporation, it was chromatographed with methanol/dichloromethane on silica gel, and 6 mg of the title compound was thus obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6](Cl)=[O:7].[NH2:20][C:21]1[CH:22]=[C:23]([NH:28][C:29](=[O:39])[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([N:36]([CH3:38])[CH3:37])[CH:31]=2)[CH:24]=[CH:25][C:26]=1[CH3:27]>C(Cl)Cl>[CH3:38][N:36]([CH3:37])[C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=1)[C:29]([NH:28][C:23]1[CH:24]=[CH:25][C:26]([CH3:27])=[C:21]([NH:20][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:22]=1)=[O:39]
Reactant: COc1cc(C(=O)Cl)ccc1OCc1ccccc1
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1N
Solvent: ClCCl
Product: COc1cc(C(=O)Nc2cc(NC(=O)c3cccc(N(C)C)c3)ccc2C)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 9 %

Procedure:
A solution of 3-methoxy-4-benzyloxybenzoyl chloride (3.01 g) in methylene chloride (50 ml) was added to a stirred suspension of N-(3-amino-4-methylphenyl)-3-dimethylaminobenzamide (2.69 g) in methylene chloride (30 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The organic phase was washed with water and with a saturated aqueous sodium bicarbonate solution, dried and evaporated. The solid residue was stirred in diethyl ether for 16 hours, filtered and dried to give N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3-methoxy-4-benzyloxybenzamide (0.458 g); NMR: (DMSOd6) 2.18 (s, 3H), 2.96 (s, 6H), 3.82 (s, 3H), 5.12 (s, 2H), 6.9 (m, 1H), 7.16 (t, 1H), 7.21 (d, 2H), 7.3 (t, 2H), 7.4 (m, 5H), 7.57 (m, 3H), 7.78 (d, 1H), 9.75 (s, 1H), 10.18 (s, 1H).
Reaction SMILES: [CH3:1][C:2]12[O:9][C:6]([CH3:10])([CH:7]=[CH:8]1)[C:5](=[O:11])[CH2:4][C:3]2=[O:12].[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]1[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C.CC(C)(O)C#N>C(#N)C>[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18][C:19]1[C:20]([C:21]([CH:4]2[C:3](=[O:12])[C:2]3([CH3:1])[O:9][C:6]([CH3:10])([CH:7]=[CH:8]3)[C:5]2=[O:11])=[O:22])=[CH:24][CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[N:27]=1
Reactant: COCCOCc1nc(C(F)(F)F)ccc1C(=O)O
Reactant: CC12C=CC(C)(O1)C(=O)CC2=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCCOCc1nc(C(F)(F)F)ccc1C(=O)C1C(=O)C2(C)C=CC(C)(O2)C1=O
Reaction time: 2 h

Procedure:
146 mg (0.879 mmol) of 1,5-dimethyl-8-oxa-bicyclo[3.2.1]oct-6-ene-2,4-dione and 245 mg (0.879 mmol) of 2-(2-methoxy-ethoxymethyl)-6-trifluoromethyl-nicotinic acid (preparation as described in WO 01/94339) are dissolved in 29 ml of acetonitrile and treated at ambient temperature with 199 mg (0.966 mmol) of dicyclohexylcarbodiimide. The reaction mixture is stirred for 2 hours and then 0.184 ml (1.318 mmol) of triethylamine and 0.08 ml (0.879 mmol) of acetone cyanohydrin are added. Stirring is carried out for a further 16 hours at ambient temperature, followed by concentration under reduced pressure. The residue that remains behind is chromatographed over silica gel (eluant: toluene/ethanol/dioxane/triethylamine/water 20:8:4:4:1). The product-containing fraction is concentrated. The oily residue is again dissolved in fresh ethyl acetate and washed with 10 ml of dilute hydrochloric acid (pH 1), and then with water (2×) and sodium chloride solution (2×). After the solution has been dried over sodium sulfate and concentrated by evaporation under reduced pressure, 128 mg (34%) of 3-[2-(2-methoxy-ethoxymethyl)-6-trifluoromethyl-pyridine-3-carbonyl]-1,5-dimethyl-8-oxa-bicyclo[3.2.1]oct-6-ene-2,4-dione are obtained in the form of a yellow oil.
Reaction SMILES: [ClH:1].[CH3:2][S:3]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)(=[O:5])=[O:4]>C(O)C>[ClH:1].[NH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:6][S:3]([CH3:2])(=[O:5])=[O:4]
Reactant: CC(C)(C)OC(=O)NCCCCNS(C)(=O)=O
Agent: Cl
Solvent: CCO
Product: CS(=O)(=O)NCCCCN
Temperature: 100 °C

Procedure:
A solution of hydrochloric acid in ethanol was added to a solution of tert-butyl [4-(methanesulfonylamino)butyl]carbamate (18.9 g, 71.1 mmol) in ethanol (100 mL), and the reaction was heated at 100° C. for two hours. The solvent was removed under reduced pressure. A mixture of dichloromethane:hexanes was added to the resulting oil and removed under reduced pressure; this process was repeated several times. The residue was dried for three days under vacuum to provide 14.3 g of N-(4-aminobutyl)methanesulfonamide hydrochloride as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([CH3:23])[C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17]OS(C)(=O)=O)[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[CH3:24][NH:25][CH3:26]>CO>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:8]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][N:25]([CH3:26])[CH3:24])[CH2:11][CH2:10]2)[CH3:23])=[N:6][CH:7]=1
Reactant: CN(c1ncc(Br)cn1)[C@H]1CC[C@H](CCCOS(C)(=O)=O)CC1
Reactant: CNC
Solvent: CO
Product: CN(C)CCC[C@H]1CC[C@H](N(C)c2ncc(Br)cn2)CC1
Temperature: 25 °C

Procedure:
A solution of 209 mg (corresponding to 0.50 mmol) of crude trans-Methanesulfonic acid 3-{4-[(5-bromo-pyrimidin-2-yl)-methyl-amino]-cyclohexyl}-propyl ester in 5 ml of methanol was treated with 0.89 ml (5 mmol) Dimethylamine (33% in EtOH, 5.6M) and stirred over night at RT. After the addition of 0.45 ml (2.5 mmol) Dimethylamine (33% in EtOH, 5.6M), the reaction was stirred for 66 h, then heated at 70° C. for 2 h, cooled, evaporated and the residue extracted with aqueous saturated NaHCO3/Et2O (3×). The organic phase was dried with Na2SO4, filtered and evaporated. Purification by flash column chromatography on silica gel (CH2Cl2/MeOH 97:3 to 94:6) gave 157 mg (88%) of trans-(5-Bromo-pyrimidin-2-yl)-[4-(3-dimethylamino-propyl)-cyclohexyl]-methyl-amine, MS: 355 (MH+, 1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([C:13]2[N:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:16](=[S:25])[NH:15][CH:14]=2)([CH3:12])[CH3:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([Cl:42])=[C:38]([CH:41]=1)[C:39]#[N:40]>CC(C)=O>[Cl:42][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][S:25][C:16]2[N:17]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[C:13]([C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([Cl:1])[CH:3]=3)([CH3:12])[CH3:11])=[CH:14][N:15]=2)=[CH:41][C:38]=1[C:39]#[N:40]
Reactant: N#Cc1cc(CBr)ccc1Cl
Reactant: COc1ccc(C(C)(C)c2c[nH]c(=S)n2-c2ccc(F)cc2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(C(C)(C)c2cnc(SCc3ccc(Cl)c(C#N)c3)n2-c2ccc(F)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
To a solution of 5-(2-(3-chloro-4-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2(3H)-thione (125 mg, 0.33 mmol) in acetone (2 mL) were added K2CO3 (70, mg, 0.50 mmol) and 5-(bromomethyl)-2-chlorobenzonitrile (92 mg, 0.40 mmol). The mixture was stirred at room temperature for 2 h and filtered. The mother liquor was concentrated and purified by column chromatography (silica, 0 to 30% EtOAc/Hex) to afford the title compound (105 mg, 60%) as a white solid. MS (EI) m/z 526 (MH+).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:30][S:31]([OH:34])(=[O:33])=[O:32])=C[C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[CH:9]=2)=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O.C(#[N:48])C.O>>[F:1][C:2]1[C:3]([NH:28][C@@H:29]([C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:30][S:31]([OH:34])(=[O:33])=[O:32])=[N:48][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cc(N[C@H](CS(=O)(=O)O)C(C)(C)C)c(F)cn3)c3cc(F)cnc32)cc1
Reactant: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)[C@@H](CS(=O)(=O)O)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F

Procedure:
Sulfonic acid, 11, was synthesized in a manner similar to Compound 25 described below, using compound, 57a, as the starting material: 1H NMR (400 MHz, MeOD) δ 8.44 (s, 1H), 8.34 (dd, J=9.2, 2.6 Hz, 1H), 8.22 (d, J=5.7 Hz, 1H), 8.13 (s, 1H), 5.16 (d, J=4.1 Hz, 1H), 3.46-3.33 (m, 2H), 1.10 (d, 9H); LC/MS (10-90% ACN/water 5 min with 0.9% TFA, C18) m/z 412.19 (M+H) retention time=1.91 minutes.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1.N1[C:30]2[C:21](=[CH:22][CH:23]=[C:24]3[C:29]=2N=CC=C3)[CH:20]=CC=1.[OH-].[K+]>C1(C)C(C)=CC=CC=1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([N:14]([C:24]2[CH:29]=[CH:30][C:21]([CH3:20])=[CH:22][CH:23]=2)[C:13]2[CH:15]=[CH:16][C:10]([Br:9])=[CH:11][CH:12]=2)=[CH:3][CH:4]=1
Reactant: Nc1ccc(Br)cc1
Reactant: Cc1ccc(I)cc1
Reactant: c1cnc2c(c1)ccc1cccnc12
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(Br)cc2)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 425.8 %

Procedure:
In a 500 milliliter three-necked flask equipped with a mechanical stirrer, thermometer and Dean-Stark trap, all under an argon atmosphere, were added molten p-iodotoluene (27.3 grams, 125 millimoles), 22 grams of xylene, p-bromoaniline (8.7 grams, 50 millimoles), and 1,10-phenanthroline (1.8 grams, 10 millimoles). The reaction mixture was then heated to 100° C. at which point potassium hydroxide flake (22.4 grams, 400 millimoles) and cuprous chloride (1 gram, 10 millimoles) were added. The temperature was then adjusted to 125° C., and the reaction progress monitored by high performance liquid chromatography. Analysis showed the reaction to be 94 percent complete at 2 hours and 98 percent complete at 5 hours at which point the reaction was terminated. Product isolation was accomplished by adding 24 grams of acetic acid, and partitioning the reaction mixture between 100 grams of toluene and 100 grams of deionized water. The organic phase was further washed several times with deionized water, and the solvent removed to afford 15 grams (84.5 percent) of the desired product of high purity (HPLC, 98 area percent).
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][C:8]=1[C:16](=[O:25])[CH:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:2]>C(O)C.[Pd]>[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][N:3]([CH2:26][CH3:27])[CH2:1][CH3:2])=[C:8]([C:16](=[O:25])[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:9]=1
Reactant: CCN(CC)CCOc1ccc([N+](=O)[O-])cc1C(=O)C=Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCN(CC)CCOc1ccc(N)cc1C(=O)CCc1ccccc1

Procedure:
To 5.0 g (13.6 mmol) of 1-[2-[2-(diethylamino)ethoxy]-5-nitrophenyl]-3-phenyl-2-propen-1-one in 250 mL of ethanol add 0.5 g of palladium on carbon (10%). Hydrogenate the mixture at 22 psi until the theoretical amount of hydrogen has been absorbed. Filter the reaction and remove the solvent in vacuo to provide the title compound.
Reaction SMILES: [ClH:1].N[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[O-:9].Cl.N([O-])=O.[Na+]>O>[ClH:1].[Cl:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N+:4]=1[O-:9]
Reactant: Nc1cccc[n+]1[O-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: [O-][n+]1ccccc1Cl
Reaction time: 0.12 h

Procedure:
The moist crystals of 2-aminopyridine-1-oxide hydrochloride from Example 1, with or without drying and recrystallization, or the material of Example 2 after purification, can be used in this preparation without substantial difference in the results. A solution of 2-aminopyridine-1-oxide hydrochloride (110 g. dry weight) and 146 g. of concentrated hydrochloric acid (37.5%) in 158 g. of water was cooled to about 0° C and treated dropwise, with stirring, with 51.8 g. of sodium nitrite in 110 g. of water over a period of 1 hour with the temperature being maintained between -5° C and +5° C, to give a clear, orange solution of diazotized material. The orange solution was stirred for about 5 minutes at about 0° C, and was then immediately added by a cooled funnel, over a 40-minute period with stirring, to a hot solution of 110 g. 20% hydrochloric acid with the temperature of the reaction vessel being maintained at 95°-101° C. After 1/3 of the diazotized solution was added, 58.5 g. concentrated hydrochloric acid (37.5%) was poured into the hot reaction mixture. The addition of the remaining 2/3 of diazotized solution was then continued at the same rate and temperature, and stirring was then continued until nitrogen evolution ceased, about 7 minutes. This treatment yielded an aqueous solution of 2-chloropyridine-1-oxide hydrochloride, suitable for use as the solution in Examples 4 and 5. Isolation by vacuum evaporation, extraction from inorganic salts with absolute ethanol and recrystallization from ethanol-toluene gave purified material, m.p. 135°-137° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([N:11]2[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:4][C:3]=1[N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1.[C:25]([C:27]1[O:31][C:30]([C:32](O)=[O:33])=[CH:29][CH:28]=1)#[N:26].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>[Pd].CCOC(C)=O>[F:1][C:2]1[C:3]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)=[CH:4][C:5]([N:11]2[CH2:16][CH2:15][CH:14]([CH3:17])[CH2:13][CH2:12]2)=[C:6]([NH:8][C:32]([C:30]2[O:31][C:27]([C:25]#[N:26])=[CH:28][CH:29]=2)=[O:33])[CH:7]=1
Reactant: N#Cc1ccc(C(=O)O)o1
Reactant: CC1CCN(c2cc(N3CCN(C)CC3)c(F)cc2[N+](=O)[O-])CC1
Agent: [Pd]
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN(c2cc(N3CCN(C)CC3)c(F)cc2NC(=O)c2ccc(C#N)o2)CC1
Yield: 82.1 %

Procedure:
The procedure of Example 4, step (c) was followed using 58.5 mg (0.174 mmol) of 1-[2-fluoro-5-(4-methyl-piperidin-1-yl)-4-nitro-phenyl]-4-methyl-piperazine (as prepared in the previous step), 29 mg of 10% palladium on carbon (50% by weight water), 28.6 mg (0.209 mmol) of 5-cyanofuran-2-carboxylic acid (as prepared in Example 1), 27.3 μL (0.314 mmol) of oxalyl chloride, and 72.8 μL (0.418 mmol) of DIEA except the isolated impure product was dissolved in 10 mL of EtOAc, washed with 1M K2CO3 (2×5 mL), dried (Na2SO4) and then concentrated in vacuo. Chromatography on a 5-g silica SPE column with 1-3% MeOH-dichloromethane afforded 60.8 mg (82%) of the title compound as a crystalline yellow solid: 1H-NMR (CDCl3; 400 MHz): δ 9.76 (br s, 1H), 8.19 (d, 1H, J=14.1 Hz), 7.22, 7.26 (AB q, 2H, J=3.7 Hz), 6.80 (d, 1H, J=8.5 Hz), 3.11-3.19 (m, 4H), 2.92-2.95 (m, 2H), 2.69-2.76 (m, 2H), 2.55-2.65 (br m, 4H), 2.37 (s, 3H), 1.82-1.86 (m, 2H), 1.5-1.7 (br m, 1H) and 1.42-1.53 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C23H28FN5O2, 426.2 (M+H), found 426.3.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:35])=[C:24]([N:27]3[C:31](=[O:32])[CH2:30][N:29]([CH3:33])[C:28]3=[O:34])[CH:25]=2)[NH:20][C:19](=[O:36])[C:18]=1[C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([CH3:44])[CH:38]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1.C(Cl)Cl>[Cl:35][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][CH2:15][CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[C:18]([C:37]3[CH:42]=[C:41]([CH3:43])[CH:40]=[C:39]([CH3:44])[CH:38]=3)[C:19](=[O:36])[NH:20]2)=[CH:25][C:24]=1[N:27]1[C:31](=[O:32])[CH2:30][N:29]([CH3:33])[C:28]1=[O:34]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(N4C(=O)CN(C)C4=O)c(Cl)cc3[nH]c2=O)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3)c3cc(N4C(=O)CN(C)C4=O)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C

Procedure:
To a solution of 2-{2-[7-chloro-3-(3,5-dimethylphenyl)-6-(3-methyl-2,5-dioxoimidazolidin-1-yl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester in 2.0 dry methylene chloride was added a few drops of anisole followed by 1.0 mL of trifluoroacetic acid and the mixture stirred at room temperature. After 1 hour the solvents were removed in vacuo and the resulting residue purified by flash chromatography on silica gel (methylene chloride:ammonium hydroxide:methanol, 96:1:3) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([N:21]([CH2:35][C:36]([O:38]C(C)(C)C)=[O:37])[CH:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=4)[CH2:24][CH2:23]3)[C:17](=[O:43])[CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.F[C:45](F)(F)[C:46](O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([N:21]([CH:35]([CH2:45][CH3:46])[C:36]([OH:38])=[O:37])[CH:22]3[CH2:23][CH2:24][N:25]([C:28]4[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=4)[CH2:26][CH2:27]3)[C:17](=[O:43])[CH2:16]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(N2CCC(N(CC(=O)OC(C)(C)C)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3=O)CC2)ccn1
Solvent: Cc1ccccc1
Product: CCC(C(=O)O)N(C1CCN(c2ccnc(C)c2)CC1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl {[4-(6-chloronaphthalene-2-sulfonyl)-2-oxo-1-piperazinyl][1-(2-methyl-4-pyridinyl)-4-piperidinyl]amino}acetate (135 g) obtained in Example 144 and toluene (1 ml) was combined with trifluoroacetic acid (1 ml) and stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified on a CHP-20 column (water→1% conc. aqueous ammonia-containing 25% aqueous solution of acetonitrile) to obtain the title compound (0.75 mg) as a colorless powder.
Reaction SMILES: [OH-].[Na+].C([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:18]2=[O:19])[CH2:13][CH2:12]1)(=O)C1C=CC=CC=1>C(O)C>[NH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][C:18]2=[O:19])[CH2:13][CH2:12]1
Reactant: O=C(c1ccccc1)N1CCC(n2c(=O)ccc3ccccc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=c1ccc2ccccc2n1C1CCNCC1
Yield: 84.4 %

Procedure:
Ethanol (10 ml) and 10% aqueous sodium hydroxide solution (12 ml) are added to 1-(1-benzoyl-4-piperidinyl)carbostyril (1.0 g) and the mixture is refluxed with heating for 7 hours. After concentration, water is added thereto and the mixture is extracted with dichloromethane. The dichloromethane layer is collected by filtration and water is added thereto. The mixture is acidified with diluted hydrochloric acid. The aqueous layer is basified with diluted aqueous sodium hydroxide solution, extracted with dichloromethane and then concentrated to give 1-(4piperidinyl)carbostyril (0.58 g).