Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH:3]([OH:30])[CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][N:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][C@@H:18]3[C:22]3[C:23](=[O:29])[NH:24][CH:25]=[C:26]([F:28])[CH:27]=3)=[N:13][C:12]=12)=[O:7].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:28][C:26]1[CH:27]=[C:22]2[C:23](=[N:24][CH:25]=1)[O:29][CH2:2][CH:3]([OH:30])[CH2:4][NH:5][C:6](=[O:7])[C:8]1=[C:12]3[N:13]=[C:14]([CH:15]=[CH:16][N:11]3[N:10]=[CH:9]1)[N:17]1[C@@H:18]2[CH2:19][CH2:20][CH2:21]1
Reactant: O=C(NCC(O)CCl)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1NCC(O)COc2ncc(F)cc2[C@H]2CCCN2c2ccn3ncc1c3n2
Temperature: 85 °C

Procedure:
A suspension of N-(3-chloro-2-hydroxypropyl)-5-((R)-2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (100 mg, 0.23 mmol) and Cs2CO3 (375 mg, 1.15 mmol) in DMF (3 mL) was heated at 85° C. for 2 hours. The reaction mixture was filtered through a GF/F paper and directly purified on reverse phase column chromatography (Biotage SP4 system C-18 25+M column, 5 to 50% acetonitrile/water), to provide the title product as a white solid. MS (apci) m/z=399.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23])([O-:15])=[O:14].N1C=CC=CC=1>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])(=[O:23])=[O:24])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1ccc(Cl)c2cccnc12
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1ccc(Cl)c2cccnc12
Yield: 78.7 %

Procedure:
In a similar fashion using route 14 general procedure 26, 5-chloro-quinolin-8-ylamine (Intermediate 27) (380 mg, 2.13 mmol), 2-nitrobenzene-1-sulfonyl chloride (566 mg, 2.56 mmol), pyridine (0.34 ml, 4.26 mmol) and DCM (12 ml) gave the title compound (610 mg, 79%) after purification by column chromatography with n-hexane/DCM (1:1) as the eluent.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH:8]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C1(C)C=CC=CC=1>[CH:8]1([NH:14][C:1](=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=C1C=CC(=O)O1
Reactant: NC1CCCCC1
Solvent: Cc1ccccc1
Product: O=C(O)/C=C\C(=O)NC1CCCCC1

Procedure:
To a solution of 98 g of maleic anhydride in 500 g of toluene, 99.2 g of cyclohexylamine was added dropwise at a temperature in the range of 50° to 70° C. while in a stirred state. After the dropwise addition, the resultant mixture was stirred for two hours. Consequently N-cyclohexyl maleinamic acid was obtained. Then, the reaction solution and 14 g of methanesulfonic acid, 8.7 g of methanesulfonic acid-N-cyclohexyl maleinamate, and 15 g of N-methyl pyrrolidone added thereto were left reacting at 115° C. for 3.5 hours in a refluxed state, with the formed water continuously expelled from the reaction system through azeotropic distillation with toluene.
Reaction SMILES: [C:1]1([N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:19][CH:18]=2)[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][I:39]>>[I-:39].[CH3:38][N+:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:8]([N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:21][CH:22]=2)=[O:9])[CH:11]=1
Reactant: CI
Reactant: CCCCCCCCCCCCCCOc1ccc(CN(C(=O)c2cccnc2)c2ccccc2)cc1
Product: CCCCCCCCCCCCCCOc1ccc(CN(C(=O)c2ccc[n+](C)c2)c2ccccc2)cc1
Product: [I-]
Temperature: 100 °C
Yield: 99.3 %

Procedure:
A mixture of 0.80 g of product from Example 146 and 11.34 g of methyl iodide is heated, in a sealed tube, at 100° C. for 10 hours. The reaction is concentrated in vacuo to give 1.02 g of the desired product as light yellow crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]2[CH2:19][CH2:18][CH:17]([CH2:20][C:21]([N:23]([CH3:25])[CH3:24])=O)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][N:23]([CH3:24])[CH3:25])[CH2:16][CH2:15]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C(=O)CC1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)CCC1CCC(N2CCN(Cc3ccccc3)CC2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
2-(4-(4-benzylpiperazin-1-yl)cyclohexyl)-N,N-dimethylacetamide (800 mg) is dissolved in THF (20 ml) and cooled to 0° C. 2 M LiAlH4 in THF (2.3 ml) is added. The reaction mixture is warmed to room temperature and stirred for 1 hour. The reaction is quenched by slow addition of satd. aqueous K2CO3 (50 ml), then a potassium sodium tartrate solution (20 ml) is added. The mixture is diluted with EtOAc and the layers are separated. The aqueous layer is extracted with EtOAc (2×). The combined organic layers are dried (Na2SO4), filtered, and the solvent is removed under reduced pressure to give 2-(4-(4-benzylpiperazin-1-yl)cyclohexyl)-N,N-dimethylethanamine (660 mg). m/z(+) 330 (M+H+).
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH3:18][O:19][C:20]1[C:25]2[O:26][C@H:27]([CH2:30]C3C=C(C)C=CC=3S([O-])(=O)=O)[CH2:28][O:29][C:24]=2[CH:23]=[CH:22][CH:21]=1>CN(C)C=O.O1CCCC1.C(=O)(O)[O-].[Na+]>[CH3:18][O:19][C:20]1[C:25]2[O:26][CH:27]([CH2:30][N:1]3[CH2:2][CH:3]=[C:4]([C:7]4[C:15]5[C:10](=[CH:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=5)[NH:9][CH:8]=4)[CH2:5][CH2:6]3)[CH2:28][O:29][C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: COc1cccc2c1O[C@H](Cc1cc(C)ccc1S(=O)(=O)[O-])CO2
Reactant: N#Cc1ccc2[nH]cc(C3=CCNCC3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cccc2c1OC(CN1CC=C(c3c[nH]c4ccc(C#N)cc34)CC1)CO2
Yield: 56.6 %

Procedure:
3-(1,2,3,6-Tetrahydro-4-pyridinyl)1H-indole-5-carbonitrile (0.70 g, 3.1 mmole) and [(2R)-8-methoxy-2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl-4-methylbenzenesulfonate (040 g, 1.1 mmole) were dissolved in a mixture of dimethylformamide/tetrahydrofuran (1:1 v/v, 50 mL) and sodium bicarbonate (1.0 g) added. The reaction mixture was refluxed under nitrogen for 18 hours. The solvent was evaporated in vacuum and the residue partitioned between 400 mL each of methylene chloride and water. The organic phase was separated, washed with water and saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuum to give a solid which was purified by column chromatography on silica gel. Elution with 2% methanol in chloroform, concentration of the product fractions in vacuum and treatment of an ethereal solution of the residue with 4 N isopropanolic HCl gave the (S)-enantiomer of the title compound (250 mg, 54%) as a yellow solid hydrochloride, one-quarter hydrate, m.p. 235–238° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+].[CH3:29][N:30]1[C:34](=[O:35])[CH2:33][S:32][C:31]1=[S:36]>C(O)(=O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[C:33]3[S:32][C:31](=[S:36])[N:30]([CH3:29])[C:34]3=[O:35])=[CH:14][CH:13]=2)=[C:6]([CH2:20][CH2:21][CH3:22])[C:5]=1[OH:23])(=[O:3])[CH3:2]
Reactant: CCCc1c(COc2ccc(C=O)cc2)ccc(C(C)=O)c1O
Reactant: CN1C(=O)CSC1=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCCc1c(COc2ccc(C=C3SC(=S)N(C)C3=O)cc2)ccc(C(C)=O)c1O
Temperature: 100 °C

Procedure:
Under a nitrogen atmosphere in a three-neck round bottom flask 4-[(4-acetyl-3-hydroxy-2-propylphenyl)methoxy]benzaldehyde (90.0 mg, 0.29 mmol) was dissolved in acetic acid (1.5 ml) with stirring. To this solution was added sodium acetate (82.8 mg, 1.00 mmol) and N-methylrhodanine (42.5 mg, 0.29 mmol). The reaction mixture was then heated to 100° C. and maintained at this temperature for about two hours at which time the reaction mixture was raised to the reflux temperature and allowed to reflux for about 28 hours. The reaction progress was monitored by thin layer chromatography.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CN1CCC(C(=O)NCc2nccnc2Cl)CC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CN1CCC(c2ncc3c(Cl)nccn23)CC1
Temperature: 80 °C
Yield: 91.9 %

Procedure:
To a solution of N-((3-chloropyrazin-2-yl)methyl)-1-methylpiperidine-4-carboxamide (6.51 mmol, 1.75 g) in acetonitrile (10 ml) was added phosphorus oxychloride (65.1 mmol, 6.36 ml) and this solution was heated at 80° C. for four hours. The reaction mixture was concentrated in vacuo and coevaporated with toluene. The residue was cooled in an ice bath and quenched with 7N ammonia in methanol (50 ml) and dichloromethane (50 ml). The solids were removed by filtration and the filtrate was concentrated. To the residue dichloromethane (50 ml) and of 7N ammonia in methanol (1 ml) was added. After 10 minutes at room temperature the solids were removed by filtration and the filtrate was concentrated. To the residue dichloromethane (50 ml) was added. After 10 minutes at room temperature the solids were removed by filtration and the filtrate was concentrated to give 8-chloro-3-(1-methylpiperidin-4-yl)imidazo[1,5-a]pyrazine (1.5 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]=O)=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.Cl.NO.C([N:24](CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[N:24])=[CH:14][CH:15]=3)[CH2:10][O:9]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=Cc1ccc2c(c1)COC2c1ccc(F)cc1
Agent: Cl
Agent: NO
Solvent: Cc1ccccc1
Product: N#Cc1ccc2c(c1)COC2c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
1-(4′-Fluorophenyl)-1,3-dihydroisobenzofuran-5-carbaldehyde (17.00 g) was dissolved in toluene (200 ml) and hydroxylamine hydrochloride (5.5 g) and triethylamine (8.0 g) were added. The mixture was stirred at 80-100° C. for 2 hr. The obtained triethylamine hydrochloride was filtered and the solvent was evaporated. Thereto was added acetic anhydride (36.5 g) and the mixture was stirred at 125-130° C. for 5 hr. The reaction mixture was poured into 10% aqueous sodium hydroxide solution (300 ml) and extracted twice with toluene (200 ml). The toluene layer was washed successively with 5% aqueous sodium hydroxide solution, water and saturated brine and dried over magnesium sulfate. Silica gel (5 g) was added and the mixture was thoroughly stirred and filtered. The solvent was evaporated to give crude 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (14.2 g). This was recrystallized from a mixed solvent of ethanol/hexane to give 1-(4′-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (9.52 g, 59.8%).
Reaction SMILES: N[C:2]1[S:3][C:4]2[C:9]([N:10]([CH3:17])[C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])=[N:8][C:7]([SH:18])=[N:6][C:5]=2[N:19]=1.[ClH:20].N([O-])=O.[Na+]>C(#N)C.O>[Cl:20][C:2]1[S:3][C:4]2[C:9]([N:10]([C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])[CH3:17])=[N:8][C:7]([S:18][S:18][C:7]3[N:8]=[C:9]([N:10]([C@H:11]([CH2:14][CH2:15][CH3:16])[CH2:12][OH:13])[CH3:17])[C:4]4[S:3][C:2]([Cl:20])=[N:19][C:5]=4[N:6]=3)=[N:6][C:5]=2[N:19]=1
Reactant: Cl
Reactant: CCC[C@H](CO)N(C)c1nc(S)nc2nc(N)sc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCC[C@H](CO)N(C)c1nc(SSc2nc(N(C)[C@@H](CO)CCC)c3sc(Cl)nc3n2)nc2nc(Cl)sc12
Reaction time: 72 h
Yield: 75 %

Procedure:
(2R)-2-[(2-Amino-5-mercapto[1,3]thiazolo[4,5-d]pyrimidin-7-yl)(methyl)amino]pentan-1-ol (1.0 g, 3.34 mmol) was dissolved in acetonitrile (25 ml) and concentrated hydrochloric acid (40 mL). Sodium nitrite (461 mg, 6.67 mmol) was dissolved in water (2 mL) and added at 0° C. The reaction mixture was kept at 0° C. for three days. The reaction mixture was poured onto ice and the precipitated product was collected by filtration and washed with water. Drying in vacuo gave the title compound 800 mg (75% yield).
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.[CH:30](=O)[CH2:31][CH2:32]/[CH:33]=[CH:34]/[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C1COCC1>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]=[CH:30][CH2:31][CH2:32]/[CH:33]=[CH:34]/[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:8][CH:9]=1
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCC/C=C/CCC=O
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCC/C=C/CCC=Cc1ccc(OC)cc1
Yield: 71.6 %

Procedure:
Starting from (4-methoxyphenyl)methyltriphenylphosphonium bromide (14.0 g, 30.2 mmol, 1.0 equiv.), KtBuO (34 mL, 34.0 mmol, 1.1 equiv., 1M in THF) and (E)-dec-4-enal (5.59 g, 36.3 mmol, 1.2 equiv.), 5.59 g (72%) of the title compound was obtained after purification by flash chromatography on SiO2 (cyclohexane/EtOAc 99:1) as a light yellow oil.
Reaction SMILES: [F:1][C:2]([F:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.O.[OH-].[Li+].[C:22]([O:25][C@@H:26]1[C@H:30]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C@@H:29]([CH:41]=O)[C@H:28]([O:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][O:45]2)[CH2:27]1)(=[O:24])[CH3:23]>COC(C)(C)C.O>[C:22]([O:25][C@@H:26]1[C@H:30]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[C@@H:29](/[CH:41]=[CH:4]/[C:3](=[O:11])[C:2]([F:1])([F:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:28]([O:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][O:45]2)[CH2:27]1)(=[O:24])[CH3:23]
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Reactant: COP(=O)(CC(=O)C(F)(F)c1ccccc1)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Product: COC(=O)CCCCCC[C@@H]1[C@@H](/C=C/C(=O)C(F)(F)c2ccccc2)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxo-3-phenylpropyl)phosphonate (6) (0.262 g, 0.942 mmol) in t-butyl methyl ether (7 ml), lithium hydroxide monohydrate (38.2 mg, 0.910 mmol) was added and the mixture was stirred for one hour at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyl-oxy)cyclopentyl]heptanate (2) (0.250 g, 0.627 mmol) in t-butyl methyl ether (3 ml) and water (0.3 ml) were added thereto, and the mixed solution was heat refluxed for approximately 48 hours. After cooling to room temperature, the reaction mixture was added to water, and extracted twice with t-butyl methyl ether. The organic layers were combined, sequentially washed with water, saturated sodium bicarbonate water and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Merck Art. 9385: 200 g; ethyl acetate:hexane=2:3). The fractions containing impurities were re-purified by silica gel column chromatography (Merck Art. 9385: 120 g; ethyl acetate:hexane=2:3), to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-4-phenyl-1-butenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (7) (0.257 g; 0.467 mmol; yield: 74.4%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[S:22][CH:23]=2)[N:3]=1.[CH3:31][NH2:32].CO>O1CCCC1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2[S:22][CH:23]=[C:19]([CH2:18][S:17][C:4]3[C:5]([C:15]#[N:16])=[C:6]([C:10]4[CH:14]=[CH:13][NH:12][N:11]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:32][CH3:31])[N:3]=3)[N:20]=2)=[CH:25][CH:26]=1
Reactant: CN
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1cc[nH]n1
Solvent: C1CCOC1
Solvent: CO
Product: CNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2cc[nH]n2)c1C#N
Reaction time: 0.5 h

Procedure:
300 mg (0.639 mmol) of 2-chloro-6-({[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}sulfanyl)-4-(1H-pyrazol-3-yl)pyridine-3,5-dicarbonitrile were dissolved in 2 ml of tetrahydrofuran, and 0.639 ml (1.278 mmol) of a 2 M solution of methylamine in tetrahydrofuran was added. After 30 minutes of stirring, methanol was added, the mixture was filtered and the filtrate was purified by preparative HPLC. This gave 173 mg (58% of theory) of the target compound.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH2:10][CH2:11][NH:12][CH3:13].[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15]>C(Cl)Cl>[CH3:8][O:9][CH2:10][CH2:11][N:12]([CH3:13])[S:23]([C:20]1[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:22][CH:21]=1)(=[O:24])=[O:25]
Reactant: CNCCOC
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCN(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 95.9 %

Procedure:
A stirred solution of triethylamine (2.4 ml, 17.23 mmol) and N-(2-methoxyethyl)methylamine (1.5 g, 16.85 mmol) in DCM (20 ml) was cooled in an ice/water bath. A solution of 4-nitrobenzenesulphonyl chloride (3.2 g, 14.45 mmol) in DCM (20 ml) was added dropwise. The reaction was stirred for one hour the cooling bath was removed and the mixture stirred for further 3 hours. The reaction mixture was washed with 1M hydrochloric acid (40 ml), water (30 ml) and then brine. The volatiles were evaporated to give the title compound (3.8 g). M/z: 245.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([O:15][C:16](=[O:23])[NH:17][C:18]([CH3:22])([CH3:21])[CH:19]=O)([CH3:14])([CH3:13])[CH3:12].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:11]([O:15][C:16](=[O:23])[NH:17][C:18]([CH3:22])([CH3:21])[CH:19]=[CH2:1])([CH3:14])([CH3:13])[CH3:12]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of methyl triphenylphosphonium bromide (1.9 g, 5 mmol) in THF (25 mL) at −78° C. is added dropwise KHMDS (5 mmol, 11 mL of 0.5M solution). The mixture is stirred at 0° C. for 30 min then is recooled to −78° C. To this is added dropwise a solution of (1,1-dimethyl-2-oxo-ethyl)-carbamic acid tert-butyl ester (1.0 g, 5 mmol) in THF (5 mL). The mixture is stirred at −78° C. for 10 min then is allowed to warm to RT overnight. Water is added and the mixture is extracted with EtOAc. The organic phase is dried over magnesium sulfate and the solvent removed under reduced pressure. The resulting oil is purified by flash chromatography to give the title compound.
Reaction SMILES: C([N:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:6]=[CH:5]1)(=O)C.[CH:13](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[CH:13]([N:6]1[C:7]([C:9]([O:11][CH3:12])=[O:10])=[CH:8][N:4]=[CH:5]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: ClC(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cn(C(C)=O)cn1
Solvent: CC#N
Product: COC(=O)c1cncn1C(c1ccccc1)c1ccccc1

Procedure:
1.7 g (0.01 mol) of 1-acetyl-4-methoxycarbonyl-imidazole in 5 cc of acetonitrile and 2 g of benzhydryl-chloride were refluxed for 4 hours, the solvent was removed under reduced pressure and the residue was stirred with 15 cc of 0.5 N sodium acetate solution to split off the acetyl group. The 1-benzhydryl-5-methoxycarbonyl-imidazole, m.p. 129° C., was recrystallized from chloroform.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[F-:12].[K+]>[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C>[Br:1][C:2]1[C:3]([F:12])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c(Br)c1
Reactant: [F-]
Agent: [Br-]
Agent: [K+]
Agent: c1ccc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=[N+]([O-])c1cnc(F)c(Br)c1
Yield: 56.8 %

Procedure:
3-Bromo-2-chloro-5-nitropyridine (119 g, 0.500 mol, prepared according to V. Koch and S. Schnatterer, Synthesis, 1990, 497-498), potassium fluoride (79.5 g, 1.37 mol), and tetraphenylphosphonium bromide (109 g, 0.260 mol) were combined in acetonitrile (1.5 L) and heated at reflux for 4 days until GLC indicated complete consumption of the 3-bromo-2-chloro-5-nitropyridine. The volume of the mixture was reduced to 750 mL in vacuo, then the residual liquid was diluted with 2 L of ether. The mixture was filtered and the filtrate concentrated. The residue was triturated with hot hexane, and the combined hexane extracts were concentrated to give 62.8 g (54%) of the title compound: 1H NMR (DMSO-d6 300 MHz) δ9.14 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[C:5](=[C:10]([NH:14][CH2:15][C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[K+]>CO>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[CH2:15][NH:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:21])=[O:2])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cccc(NCc2ccco2)c1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(NCc2ccco2)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of crude 3-[(furan-2-yl-methyl)-amino]-phthalic acid dimethyl ester in methanol (100 ml), was added 5N potassium hydroxide (79 ml). The mixture was stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue dissolved in water (50 ml). The water was washed with diethyl ether (2×100 ml). The aqueous portion was cooled in an ice bath and the pH was adjusted to 2-3 by dropwise addition of concentrated hydrochloric acid. The aqueous solution was then extracted into ethyl acetate (3×100 ml). The combined ethyl acetate extracts were washed with brine (150 ml), and dried over MgSO4. The solvent was evaporated in vacuo, and the residue, which contained a mixture of diacid and monomethyl esters, was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[S:33][C:34]([C:37]#[N:38])=[CH:35][CH:36]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[S:33][C:34]([C:37]#[N:38])=[CH:35][CH:36]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccc(C#N)s1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1NC(=O)CC(=O)c1ccc(C#N)s1
Yield: 94.1 %

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) (302 mg, 1.0 mmol) and 3-(5-cyano-thiophen-2-yl)-3-oxo-propionic acid tert.-butyl ester (Example H17) (276 mg, 1.1 mmol) according to the general procedure K. Obtained as a yellow solid (451 mg).