Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:12]([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>CO>[Cl-:1].[CH2:12]([N+:19]1[CH:23]=[CH:22][N:21]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:20]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCn1ccnc1
Reactant: ClCCCCc1ccccc1
Solvent: CO
Product: CCCCCCC[n+]1ccn(CCCCc2ccccc2)c1
Product: [Cl-]

Procedure:
Combine 5.35 g (0.32 mole) of (4-chlorobutyl)benzene and 5.27 g (0.32 mole) 1-heptyl-1H-imidazole, stir the mixture at approximately 145° C. for about 30 hours. Follow the progress of the reaction by thin-layer chromatography on silica gel (acetonitrile: ammonium hydroxide 9:1). At the completion of the reaction, dissolve the resulting cooled oil in methanol and evaporate the solvent. Dissolve this product in 125 ml H2O and extract the solution with 5×100 ml hexane. Then extract the aqueous with 2×50 ml methylene chloride. Combine the methylene chloride layers and wash with 1×100 ml saturated aqueous NaCl solution. Dry the methylene chloride extracts over sodium sulfate. Evaporate the solvents to obtain 1-heptyl-3-(4-phenylbutyl)imidazolium chloride as an oil. Dissolve the oil in approximately 35 ml acetone, and to it add an equimolar amount of phthalic acid. Remove the solvents in vacuo to obtain the title compound, which may be recrystallized from acetone.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:11][C:12]1[N:17]=[CH:16][C:15]([CH2:18]Br)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][O:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:16][N:17]=1
Reactant: Clc1ccc(CBr)cn1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Product: O=[N+]([O-])c1ccc(OCc2ccc(Cl)nc2)cc1

Procedure:
The substituted aniline compounds of formula (I) wherein W is oxygen can be prepared by the reaction of nitrophenol with a substituted pyridylalkyl halide to obtain the corresponding substituted nitrobenzene which is reduced to the desired substituted aniline of formula (I). For example, the reaction of 4-nitrophenol and 6-chloro-3-pyridylmethyl bromide gives 4-(2-chloro-5-pyridylmethyloxy)nitrobenzene which is then reduced to 4-(2-chloro-5-pyridylmethyloxy)aniline of formula I. Alternatively, the compounds of formula I can be prepared by the reaction of a halo-nitrobenzene with a substituted pyridylalkyl alcohol or substituted pyridylalkyl thiol followed by reduction of the nitro group. For example, the reaction of 4-fluoronitrobenzene and 5-bromo-2-pyridine methanol gives 4-(5-bromo-2-pyridylmethyloxy)nitrobenzene which is then reduced using, for example, iron powder to give 4-(5-bromo-2-pyridylmethyloxy)aniline.
Reaction SMILES: C[NH:2][CH2:3][CH2:4][NH:5][CH3:6].[CH3:7][C:8]1[C:9]([O:11][C:12](=O)[C:13]=1[CH3:14])=[O:10].[CH3:16]O>C(Cl)(Cl)Cl>[CH3:16][N:5]([CH2:4][CH2:3][N:2]1[C:9](=[O:10])[C:8]([CH3:7])=[C:13]([CH3:14])[C:12]1=[O:11])[CH3:6]
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: CO
Reactant: CNCCNC
Solvent: ClC(Cl)Cl
Product: CC1=C(C)C(=O)N(CCN(C)C)C1=O
Temperature: 15 °C
Reaction time: 1 h

Procedure:
A solution of 17.5 g (0.2 mol.) of asym.dimethyl ethylene diamine in 100 ml of methanol is added dropwise to a solution of 25.1 g (0.2 mol.) of 2,3-dimethyl maleic acid anhydride in 100 ml of chloroform. The mixture is stirred for one hour at 15° C. The solvents are evaporated in vacuo and the residue is recrystallised from acetone. The pure product has a melting point of 9° C. and is used in the next step (c).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C@H:19]3[CH2:23][CH2:22][O:21][CH2:20]3)[N:12]=2)[C:3]=1[NH2:24].[N:25]([O-])=O.[Na+]>CCO.C(O)(=O)C.O>[Cl:1][C:2]1[C:3]2[N:24]=[N:25][N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C@H:19]4[CH2:23][CH2:22][O:21][CH2:20]4)[N:12]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: O=N[O-]
Reactant: Nc1nc(Cl)c(N)c(NCc2cccc(CO[C@H]3CCOC3)n2)n1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Nc1nc(Cl)c2nnn(Cc3cccc(CO[C@H]4CCOC4)n3)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A solution of 6-chloro-N4-{6-[(S)-(tetrahydrofuran-3-yl)oxymethyl]pyridin-2-ylmethyl}pyrimidine-2,4,5-triamine (8.09 g, 23.06 mmol) in EtOH (85 mL) and glacial acetic acid (21 mL) at 0° C., was treated with a solution of sodium nitrite (2.07 g, 29.979 mmol) in water (5.3 mL), stirred at 0° C. for 1 h and the resulting precipitate was filtered, washed with EtOH (85 mL) and dried to give the title compound (5.82 g, 70%) as an off-white solid; LC-MS retention time 1.94 min, (M+H)+ 362.
Reaction SMILES: [CH2:1]([N:11]1[C:20](=[O:21])[C:19]2[N:18]([CH3:22])[CH:17]=[N:16][C:15]=2[N:14]([CH3:23])[C:12]1=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].C[N+]1([O-])CC[O:28]CC1.[OH2:32].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(C)(C)C.CC(C)=O.[Os](=O)(=O)(=O)=O>[OH:32][CH:9]([CH2:10][OH:28])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][N:11]1[C:20](=[O:21])[C:19]2[N:18]([CH3:22])[CH:17]=[N:16][C:15]=2[N:14]([CH3:23])[C:12]1=[O:13]
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Reactant: C=CCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Product: Cn1cnc2c1c(=O)n(CCCCCCCCC(O)CO)c(=O)n2C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
A solution of 1-(9-decenyl)-3,7-dimethylxanthine (CT1563) (3.2g, 10.1 mmol), 4-methylmorpholine-N-oxide (1.41 g, 12 mmol) and 2.5% osmium tetraoxide in t-butanol (3 drops) in acetone (40 ml) and water (10 ml) was stirred for 24 hr. After the addition of saturated sodium dithionite solution (5 ml) the mixture was stirred for 15 min. The mixture was extracted with 25% ethanol-dichloromethane (4×50 ml). The combined organic layers were dried over sodium sulfate and the solvents were evaporated under vacuum to a give solid which was recrystallized (ethanol) to give 1-(9,10-dihydroxydecyl)-3,7-dimethylxanthine (CT1564) (3.30 g, 93% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH3:4].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:15])[CH2:13]Br)=[CH:8][CH:7]=1.[OH-].[Na+].Cl[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20]>C(Cl)Cl.O>[CH2:2]([N:1]([CH2:13][C:12]([C:9]1[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=1)=[O:15])[C:19]([O:21][CH2:22][C:23]([Cl:26])([Cl:25])[Cl:24])=[O:20])[CH2:3][CH3:4]
Reactant: CCCN
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCCN(CC(=O)c1ccc(Cl)cc1)C(=O)OCC(Cl)(Cl)Cl
Reaction time: 0.15 h
Yield: 68.9 %

Procedure:
To 250 ml of methylene chloride was added 180 g (3050 mmole) of 1-aminopropane. The resulting mechanically stirred mixture was cooled to +5° C. (internal) and a solution of 117 g (500 mmole) 4'-chloro-2-bromoacetophenone in 250 ml of methylene chloride was added over 6 minutes while strictly maintaining the internal temperature between +5° C. and +15° C. as a moderate exotherm occurred. Toward the end of the addition, the internal temperature was allowed to rise to +20° C. After the addition was complete, the mixture was stirred at +20° C. for 9 minutes and then rapidly cooled to -5° C. whereon 40 g (500 mmole) of 50% aqueous sodium hydroxide dissolved in 300 ml of water was added. The mixture was transferred to a separatory funnel and the organic layer was separated and thrice washed with 500 ml portions of ice cold water. The organic layer was immediately recooled to -5° C. and a solution of 40 g (500 mmole) of 50% aqueous sodium hydroxide and a solution of 100 g (450 mmole) of 2,2,2-trichloroethyl chloroformate in 100 ml of methylene chloride were simultaneously added with rapid stirring while maintaining the internal temperature between -5° C. and +5° C. After stirring an additional 15 minutes, the organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo at 20 torr. The lower boiling impurities were then removed by distillation at 0.2 torr with the bath temperature rising to 200° C. and a head temperature of up to 130° C. The undistilled pot residue was dissolved in 300 ml of diethyl ether and 300 ml of hexane, filtered through silica gel and concentrated in vacuo to yield 120 g of the desired compound, an oil. An analytical sample was isolated by column chromatography on silica gel eluting with diethyl ether and hexanes.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[Cl:11][C:12]1[CH:28]=[CH:27][C:15]([C:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)=[O:17])=[CH:14][CH:13]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[Cl:11][C:12]1[CH:28]=[CH:27][C:15]([C:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([N:8]3[CH2:9][CH2:10][C:5]4[CH:4]=[CH:3][O:2][C:6]=4[CH2:7]3)=[O:23])=[CH:20][CH:19]=2)=[O:17])=[CH:14][CH:13]=1
Reactant: c1cc2c(o1)CNCC2
Reactant: O=C(O)c1ccc(C(=O)c2ccc(Cl)cc2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)cc1)c1ccc(C(=O)N2CCc3ccoc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.287 g (1.1 mmol) of 4-(4-chlorobenzoyl)benzoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=4/1). The resulting product was recrystallized from hexane-methanol to yield the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[Br:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: Brc1cncnc1
Reactant: OB(O)c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Brc1ccccc1-c1cncnc1
Temperature: 100 °C
Yield: 54.2 %

Procedure:
A mixture of 5-bromopyrimidine (500 mg, 3.14 mmol, Aldrich), (2-bromophenyl)boronic acid (947 mg, 4.71 mmol, Aldrich), Pd(PPh3)4 (363 mg, 0.314 mmol, GLR) and potassium carbonate (2.17 g, 15.7 mmol, Qualigens) in 1,4-dioxane:water (5.8 mL:2.9 mL) was degassed for 10 min. The reaction mixture was subjected to microwave heating for 30 minutes at 100° C. After completion, the reaction mixture was diluted with water (10 mL) and ethyl acetate (25 mL). The layers were separated. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain crude material which was purified by combiflash column chromatography (column size: 12 g; elution: 15% ethyl acetate in hexane) to get 5-(2-bromophenyl)pyrimidine (400 mg, 30.5%) as yellow solid. 1H NMR (400 MHz, CDCl3) δ 9.24 (s, 1H), 8.83 (s, 2H), 7.73 (d, J=7.9 Hz, 1H), 7.48-7.42 (m, 1H), 7.33 (d, J=7.4 Hz, 2H); MS (ESI, positive ion) m/z: 234.98 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=O)[CH2:4][C:3]1=[O:9].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[C:20]([F:23])([F:22])[F:21])[CH:15]=O.[NH2:24][C:25]1[CH:29]=[CH:28][NH:27][N:26]=1>>[F:11][C:12]1[CH:13]=[C:14]([CH:15]2[C:4]3[C:3](=[O:9])[C:2]([CH3:10])([CH3:1])[CH2:7][CH2:6][C:5]=3[NH:24][C:25]3=[CH:29][CH:28]=[N:27][N:26]23)[CH:17]=[CH:18][C:19]=1[C:20]([F:23])([F:22])[F:21]
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: Nc1cc[nH]n1
Product: CC1(C)CCC2=C(C1=O)C(c1ccc(C(F)(F)F)c(F)c1)n1nccc1N2

Procedure:
4,4-Dimethyl-1,3-cyclohexanedione, 3-fluoro-4-trifluoromethylbenzaldehyde and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound.
Reaction SMILES: [CH:1]12[CH:7]([NH:8][C:9]3[CH:10]=[C:11]4[C:15](=[CH:16][CH:17]=3)[NH:14][N:13]=[CH:12]4)[CH:4]([CH2:5][CH2:6]1)[CH2:3][NH:2]2.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1>>[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:2]2[CH2:3][CH:4]3[CH:7]([NH:8][C:9]4[CH:10]=[C:11]5[C:15](=[CH:16][CH:17]=4)[NH:14][N:13]=[CH:12]5)[CH:1]2[CH2:6][CH2:5]3)=[CH:21][CH:20]=1
Reactant: c1cc2[nH]ncc2cc1NC1C2CCC1NC2
Reactant: Cc1ccc(C=O)cc1
Product: Cc1ccc(CN2CC3CCC2C3Nc2ccc3[nH]ncc3c2)cc1

Procedure:
Reaction of Intermediate 23 with 4-methylbenzaldehyde affords the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[NH:4][C@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:14])[CH:11]=2)[CH2:6]1.[CH3:16][S:17]([CH3:19])=O.N1C=CC=CC=1.[CH3:26][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([C:43](Cl)=[O:44])[C:32]=1[C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1>C(Cl)Cl>[CH3:1][O:2][C:3]([NH:4][C@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH:14][C:43]([C:31]3[C:32]([C:33]4[CH:38]=[CH:37][C:36]([C:39]([F:40])([F:42])[F:41])=[CH:35][CH:34]=4)=[C:27]([CH3:26])[CH:28]=[CH:29][CH:30]=3)=[O:44])[CH:11]=2)[CH2:6]1)=[O:15].[CH3:16][S:17][CH3:19]
Reactant: CS(C)=O
Reactant: COC(=O)N[C@@H]1Cc2ccc(N)cc2C1
Reactant: Cc1cccc(C(=O)Cl)c1-c1ccc(C(F)(F)F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)N[C@@H]1Cc2ccc(NC(=O)c3cccc(C)c3-c3ccc(C(F)(F)F)cc3)cc2C1
Product: CSC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice bath cooled solution of (R)-(5-aminoindan-2-yl)-carbamic acid methyl ester (9.5 g, 46.1 mmol), ([α]D=−26.29° (c=9.87 mg/mL, DMSO); mp 144-145° C.) and pyridine (4.48 mL, 55.5 mmol) in 200 mL of methylene chloride is added 6-methyl-4′-trifluoromethylbiphenyl-2-carboxylic acid chloride ( 80.5 mL of a 0.63 M solution in methylene chloride, 50.7 mmol). The reaction is stirred for 15 minutes at room temperature. The mixture is washed with 1N HCl, bicarbonate and brine. The organic layer is dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The product is purified by crystallization from ethyl acetate/hexanes (1:2) to give (R)-6-methyl-4′-trifluoromethylbiphenyl-2-carboxylic acid (2-methoxycarbonylaminoindan-5-yl)-amide as a crystalline solid, mp 112-114° C. [α]D=−12.85°, c=11.36 mg/mL DMS.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[N:5][NH:4][C:3]1=[O:14].[CH:15]1[CH:20]=[C:19]([C:21]([CH2:23][Br:24])=[O:22])[C:18]([Cl:25])=[CH:17][CH:16]=1>C(O)C>[Br-:24].[Cl:25][C:18]1[CH:17]=[CH:16][CH:15]=[CH:20][C:19]=1[C:21]([CH2:23][N+:11]1[CH:12]=[CH:13][C:8]([C:6]2[S:7][CH:2]([CH3:1])[C:3](=[O:14])[NH:4][N:5]=2)=[CH:9][CH:10]=1)=[O:22]
Reactant: CC1SC(c2ccncc2)=NNC1=O
Reactant: O=C(CBr)c1ccccc1Cl
Solvent: CCO
Product: CC1SC(c2cc[n+](CC(=O)c3ccccc3Cl)cc2)=NNC1=O
Product: [Br-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
6-Methyl-2-(4-pyridyl)-4H,6H-1,3,4-thiadiazin-5-one (415 mg, 2 mmol) and 2'-chlorophenacyl bromide (654 mg, 2.8 mmol) were dissolved in absolute ethanol (6 ml) and stirred at room temperature for one day. The solvent was removed under reduced pressure to obtain 1-[(2-chlorophenyl)carbonylmethyl]-4-(6-methyl-4H,6H-1,3,4-thiadiazin-5-one-2-yl)pyridinium bromide as yellow brown gum. The salt was dissolved in methanol (7 ml), gradually added with sodium borohydride (756 mg, 20 mmol) under ice cooling and stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue obtained was separated by column chromatography (dichloromethane-methanol=40:1) and purified to obtain the titled compound (621 mg) as opaline plates.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[NH2:12].N1C=CC=CC=1.Cl[S:20]([C:23]1[N:31]=[C:30]2[N:25]([C:26]([O:33][CH2:34][CH3:35])=[N:27][C:28]([F:32])=[CH:29]2)[N:24]=1)(=[O:22])=[O:21]>ClCCl>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[NH:12][S:20]([C:23]1[N:31]=[C:30]2[N:25]([C:26]([O:33][CH2:34][CH3:35])=[N:27][C:28]([F:32])=[CH:29]2)[N:24]=1)(=[O:21])=[O:22]
Reactant: CCOc1nc(F)cc2nc(S(=O)(=O)Cl)nn12
Reactant: COC(=O)c1cccc(Cl)c1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1nc(F)cc2nc(S(=O)(=O)Nc3c(Cl)cccc3C(=O)OC)nn12
Temperature: -10 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
The same product was obtained in a similar fashion using the N-(2-chloro-6-methoxycarbonylphenyl)-S,S-tetramethylenesulfilimine product mixture of Example 4 as the catalyst. A 9 mL portion of that product was diluted with 75 mL of dichloromethane, the solution was cooled to -10° C., and 9.3 g (50 mmol) of methyl 3-chloroanthranilate and then 4.8 g (60 mmol) of pyridine were added with cooling and stirring. 2-Chlorosulfonyl-7-fluoro-5-ethoxy[1,2,4]triazolo[1,5-c]pyrimidine (15.5 g of 91 percent pure, 50 mmol) was added with cooling to 0-20° C. The reaction was complete in 6 hours and a 90 percent yield of 98 percent purity title compound was obtained on recovery.
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].Cl[CH:6]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][CH:13]=1)[C:7]([OH:9])=[O:8]>C(O)C>[S:1]([CH:6]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:14][CH:13]=1)[C:7]([OH:9])=[O:8])[C:2]#[N:3]
Reactant: N#C[S-]
Reactant: O=C(O)C(Cl)CCc1ccc(-c2ccccc2Cl)cc1
Agent: [Na+]
Solvent: CCO
Product: N#CSC(CCc1ccc(-c2ccccc2Cl)cc1)C(=O)O
Reaction time: 15 h

Procedure:
To a solution of 300 ml. of anhydrous ethanol and 0.15 moles of sodium thiocyanate is added 0.12 moles of α-chloro-γ-(2'-chloro-4-biphenylyl)butyric acid and stirred for 15 hours. The reaction mixture is filtered and washed with absolute ethanol. The filtrate is evaporated to dryness, the residue is dissolved in 250 ml. of ether and washed several times with water. The ether is then dried and evaporated to dryness to obtain α-thiocyanato-γ-(2'-chloro-4-biphenylyl)butyric acid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]3[O:20][CH2:21][O:22][C:15]=13)=[CH:10][C:9]([O:23][CH3:24])=[C:8]([OH:25])[CH:7]=2)#[N:2].[Br:26][CH2:27][CH2:28]O>>[Br:26][CH2:27][CH2:28][O:25][C:8]1[CH:7]=[C:6]2[C:11]([C:12]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]4[O:20][CH2:21][O:22][C:15]=34)=[C:3]([C:1]#[N:2])[CH:4]=[N:5]2)=[CH:10][C:9]=1[O:23][CH3:24]
Reactant: OCCBr
Reactant: COc1cc2c(Nc3cccc4c3OCO4)c(C#N)cnc2cc1O
Product: COc1cc2c(Nc3cccc4c3OCO4)c(C#N)cnc2cc1OCCBr
Yield: 82 %

Procedure:
Using an analogous procedure to that described in Example 8, 3-cyano-7-hydroxy-6-methoxy-4-(2,3-methylenedioxyanilino)quinoline was reacted with 2-bromoethanol to give the title compound in 82% yield; NMR Spectrum: (DMSOd6) 3.88 (t, 2H), 3.94 (s, 3H), 4.51 (t, 2H), 5.96 (s, 2H), 6.8-6.93 (m, 3H), 7.34 (s, 1H), 7.8 (s, 1H), 8.42 (s, 1), 9.53 (s, 1H); Mass Spectrum: M+H+ 444.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([OH:8])=[O:7])[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl:22][C:23]1[N:28]=[CH:27][C:26]([CH2:29][NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([OH:8])=[O:7])[CH3:2].[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:6]([N:30]([CH2:29][C:26]1[CH:27]=[N:28][C:23]([Cl:22])=[CH:24][CH:25]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1)=[O:8])[CH3:2]
Reactant: Clc1ccc(CNc2ccccn2)cn1
Agent: CCOC(=O)C(C(=O)O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C(C(=O)N(Cc1ccc(Cl)nc1)c1ccccn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Phenylmalonic acid monoethyl ester was prepared following the procedure in Journal of Organic Chemistry 2000, 65, 5834-5836. 2-Phenylmalonic acid monoethyl ester (1.02 g, 5.0 mmol) was dissolved in anhydrous dichloromethane (10 mL), and oxalyl chloride (0.52 mL, 6.0 mmol) was added, followed by one drop of N,N-dimethylformamide. The reaction mixture was stirred for 30 min, then concentrated, redissolved in anhydrous dichloromethane (5 mL) and added to a solution of 6-chloro-N-2-pyridinyl-3-pyridinemethanamine (i.e. the product of Example 3, Step A) (1.1 g, 5.0 mmol) and triethyl amine (0.83 mL, 6.0 mmol) in anhydrous dichloromethane (5 mL) at 0° C. The stirred reaction mixture was allowed to warm to room temperature over 30 min. The reaction mixture was poured onto a silica gel cartridge (Bond Elute manufactured by Varian) and purified using a gradient of 0-50% ethyl acetate/hexanes. A mixture of desired product and starting amine was isolated (1.3 g of 33 mol % recovered amine/67 mol % desired product). 2-Phenylmalonic acid monoethyl ester (0.54 g, 2.6 mmol) was dissolved in anhydrous dichloromethane (3 mL), and oxalyl chloride (0.26 mL, 3.0 mmol) was added, followed by one drop of N,N-dimethylformamide. The reaction mixture was stirred until gas evolution ceased and then concentrated, redissolved in anhydrous dichloromethane (3 mL) and added to the mixture of recovered amine and desired product isolated previously. The reaction mixture was stirred for 30 min and then concentrated, and the crude residue was chromatographed as already described to give the title compound as a solid (0.9 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:16]([O:23][C:24](Cl)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[CH2:16]([O:23][C:24]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OCC1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(CO)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.7 %

Procedure:
4-Piperidinemethanol (5.0 g, 43 mmol) was dissolved in dichloromethane (100 ml) and triethylamine (12 ml, 86 mmol) at 0° C. Benzylchloroformate (6.8 ml, 47.3 mmol) was added and the mixture was stirred for 20 h at room temperature then solvents were removed in vacuo. The residue was redissolved in EtOAc, washed with 1M KHSO4, water then brine, dried and concentrated in vacuo to yield the title compound (8.33 g, 77%).
Reaction SMILES: ClCC(O)CO.C(N)CC.Cl.[CH2:12]([NH:15][CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH2:13][CH3:14].[Cl:21][CH2:22][CH2:23][N:24]=[C:25]=[O:26]>CO.C(N(CC)CC)C>[Cl:21][CH2:22][CH2:23][NH:24][C:25]([N:15]([CH2:12][CH2:13][CH3:14])[CH2:16][CH:17]([OH:20])[CH2:18][OH:19])=[O:26]
Reactant: CCCNCC(O)CO
Reactant: O=C=NCCCl
Agent: Cl
Agent: OCC(O)CCl
Solvent: CCCN
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCN(CC(O)CO)C(=O)NCCCl
Reaction time: 120 h
Yield: 42.6 %

Procedure:
A mixture of 3.3 g of 3-chloro-1,2-dihydroxy-n-propane and 8 g of n-propylamine is allowed to stand at room temperature for 5 days. The reaction mixture is condensed to dryness under reduced pressure, whereby 5.0 g of N-n-propyl-2,3-dihydroxy-n-propylamine hydrochloride are obtained as a crude product. 5.0 g of said crude product and 3 g of triethylamine are dissolved in 40 ml of methanol. 3.2 g of 2-chloroethyl isocyanate are added to the solution at 0° to 5° C. Then, the reaction mixture is treated in the same manner as described in Example 62-(1). 3.0 g of 1-(2-chloroethyl)-3-n-propyl-3-(2,3-dihydroxy-n-propyl)urea are obtained as a colorless oil.