Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])=[N:13][C:12]=1[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1>>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH2:20][CH2:19][CH:18]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=3)[C:17]2=[O:21])=[N:13][C:12]=1[CH3:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCCC2=O)sc1C(=O)NCc1ccccc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: Cc1nc(N2CCC(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)NCc1ccccc1
Yield: 27 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use N-benzyl-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide in place of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide to react with 1-(bromomethyl)-4-(trifluoromethyl)benzene, the title compound was obtained as a white solid in 27% yield: mp 174-175° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J=8.0 Hz, 2H), 7.39-7.20 (m, 7H), 6.01 (t, J=5.6 Hz, 1H), 4.57 (d, J=5.6 Hz, 2H), 4.14-4.02 (m, 1H), 3.93-3.79 (m, 1H), 3.35-3.24 (m, 1H), 3.09-2.96 (m 1H), 2.90-2.80 (m, 1H), 2.61 (s, 3H), 2.34-2.19 (m, 1H), 1.95-1.81 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 174.4, 162.3, 155.3, 152.6, 142.4, 137.8, 129.3, 128.8, 127.9, 127.7, 125.7, 125.6, 125.5, 118.8, 45.9, 44.2, 44.1, 36.2, 24.4, 17.2; MS (ES+) m/z 474.1 (M+1).
Reaction SMILES: IC.CN([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH2:17][S:18]([N:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH:14]=2)[NH:9][CH:8]=1)C.[C-:24]#[N:25].[K+]>CS(C)=O>[C:24]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][CH2:17][S:18]([N:21]([CH3:22])[CH3:23])(=[O:19])=[O:20])[CH:14]=2)[NH:9][CH:8]=1)#[N:25]
Reactant: CN(C)Cc1c[nH]c2ccc(CCS(=O)(=O)N(C)C)cc12
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: CI
Product: CN(C)S(=O)(=O)CCc1ccc2[nH]cc(CC#N)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
Iodomethane (1.1 ml) was added to a stirred solution of the product of Stage (iii) (2.7 g) in dry dimethylsulphoxide (30 ml) and the resulting solution stirred at room temperature for 10 min. Potassium cyanide (2.7 g) was added, and the resulting mixture stirred at room temperature overnight. The mixture was partitioned between sodium carbonate, (2N, 300 ml) and ethyl acetate (2×100 ml). The combined extracts were dried (Na2SO4) and evaporated in vacuo to give an oil which was purified by `flash` chromatography (J, 5 cm col.) to give the title compound as a solid (1.3 g) m.p. 105°-107°.
Reaction SMILES: NCCC(O)=O.[C:7]1([CH2:13][CH2:14][O:15][CH2:16][CH:17]=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:19](#[N:23])[CH2:20][C:21]#[N:22]>C(O)C>[C:7]1([CH2:13][CH2:14][O:15][CH2:16][CH:17]=[C:20]([C:19]#[N:23])[C:21]#[N:22])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#CCC#N
Reactant: O=CCOCCc1ccccc1
Agent: NCCC(=O)O
Solvent: CCO
Product: N#CC(C#N)=CCOCCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.6 %

Procedure:
β-Alanine (0.6 g) was added to a solution of [2-phenylethoxy]acetaldehyde (8.0 g) and malononitrile (3.5 g) in ethanol (100 ml). The mixture was stirred at room temperature for 3 hours. The solid was filtered off, washed with fresh ethanol and dried to yield the subtitled compound (5.85 g, 54%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:7]=1[CH3:21].Cl[C:36]1[N:41]=[CH:40][C:39]([CH2:42][CH3:43])=[CH:38][N:37]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH2:42]([C:39]1[CH:38]=[N:37][C:36]([C:9]2[CH:10]=[CH:11][C:6]([CH:5]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=3)[CH2:4][CH2:3][C:2]([F:33])([F:34])[F:1])=[C:7]([CH3:21])[CH:8]=2)=[N:41][CH:40]=1)[CH3:43]
Reactant: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2C)cc1
Reactant: CCc1cnc(Cl)nc1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCc1cnc(-c2ccc(C(CCC(F)(F)F)Nc3ccc(C(=O)OC)cc3)c(C)c2)nc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A reaction mixture of methyl 4-((4,4,4-trifluoro-1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butyl)amino)benzoate (14.3 g) obtained in Example 1, step F, 2-chloro-5-ethylpyrimidine (4.00 mL), tetrakistriphenylphosphinepalladium (3.46 g), 2M aqueous sodium carbonate solution (44.9 mL) and DME (135 mL) was stirred at 100° C. overnight under a nitrogen atmosphere. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was solidified with diisopropyl ether to give the title compound (12.6 g).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([C:14]#[C:15][CH2:16][CH2:17][OH:18])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([C:14]#[C:15][CH2:16][CH2:17][O:18][S:27]([CH3:26])(=[O:29])=[O:28])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: OCCC#Cc1cccc(CN2CCOCC2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC#Cc1cccc(CN2CCOCC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
A 500-mL 1-necked round-bottom flask was equipped with a magnetic stirring bar and rubber septum with a nitrogen inlet. The vessel was charged with the product of Example 6 (13.6 g), dichloromethane (100 mL) and triethylamine (8.43 mL). The reaction mixture was cooled to 0° C. in an ice bath, and a solution of methanesulfonyl chloride (6.93 g) in dichloromethane (10 mL) was added in drops over 30 min. The cooling was removed and the reaction mixture was allowed to warm up to room temperature. After 1 h when TLC indicated complete conversion, 50 mL ice water was added, and the reaction mixture was transferred to a 500-mL separatory funnel. The organic extract was separated and washed with aqueous NaHCO3, brine, and dried over MgSO4. After filtration, the solvents were evaporated under reduced pressure (rotary evaporator, 30° C.) to obtain the title compound as pale yellow gum (17.5 g).
Reaction SMILES: COB(OC)OC.C1([C@]2(CO)CCCN2C2C=CC=CC=2)C=CC=CC=1.CSC.B.[Cl:31][CH2:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=1)=[O:34]>C1(C)C=CC=CC=1.CO>[Cl:31][CH2:32][C@H:33]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=1)[OH:34]
Reactant: O=C(CCl)c1ccc(F)c(F)c1
Agent: B
Agent: COB(OC)OC
Agent: OC[C@@]1(c2ccccc2)CCCN1c1ccccc1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CSC
Product: O[C@H](CCl)c1ccc(F)c(F)c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 94.2 %

Procedure:
Trimethoxy borane (2.0 g) was added at room temperature to a stirred solution of (S)-diphenylprolinol (3.5 g) in toluene (100 mL). After stirring this mixture for 90 minutes at about 65-75° C., borane dimethylsulfide (2M THF solution, 105 mL) was added over a period of 50 minutes maintaining the temperature between 65 and 75° C. This mixture was stirred for another 90 minutes at 75° C., then a solution of 2-chloro-1-(3,4-difluorophenyl)ethanone (50.0 g) in toluene (150 mL) was dosed over a period of 25 minutes maintaining the temperature between 65 and 75° C. After the completion of the addition the reaction mixture was stirred for another 100 minutes at 75° C. at which point the completion of reaction was monitored by TLC. Then mixture was cooled to 0-5° C. and methanol (50 mL) was added over a period of 30 minutes controlling the gas formation and the temperature to a maximum of 5° C. After the addition is complete, the obtained solution was subjected to distillation under reduced pressure at below 60° C., followed by sequential addition of 10% aqueous acetic acid solution (250 mL) and toluene (500 mL) to the residue. The layers were separated and obtained water layer was back extracted with toluene (250 mL). Both organic layers were combined and washed with water (500 mL). The resulting organic layer was subjected to complete distillation under vacuum to afford the title compound in 94.2% yield having chiral HPLC purity of 99.62%.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[C:12]2[O:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:11]=2[CH:10]=[CH:9][CH:8]=1.[CH3:19]O>>[CH3:5][O:6][C:7]1[C:12]2[O:13][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CO
Reactant: COc1cccc2cc(C(=O)O)oc12
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2cccc(OC)c2o1

Procedure:
Thionyl chloride (10 ml) was added dropwise to methanol (100 ml) with stirring under ice-cooling. 7-Methoxybenzo(b)furan-2-carboxylic acid (10 g) was successively added, and the mixture was refluxed under heating for 1 hr. After cooling, the solvent was evaporated under reduced pressure and the precipitated yellow crystals were collected by filtration to give methyl 7-methoxybenzo(b)furan-2-carboxylate (11.2 g). This was used in the next reaction without purification. Acetone oxime (4.8 g) was dissolved in tetrahydrofuran (100 ml), and butyllithium (1.6M hexane solution) (80 ml) was added dropwise to this solution at −5° C. with stirring. Thereafter, the mixture was stirred under ice-cooling for 1 hr, and a solution (50 ml) of methyl 7-methoxybenzo(b)furan-2-carboxylate (11.2 g) in tetrahydrofuran was added. The mixture was stirred at room temperature for 20 hr. A solution of sulfuric acid (28 g) dissolved in tetrahydrofuran (120 ml)-water (30 ml) was prepared, into which the reaction mixture was poured. The mixture was refluxed under heating for 2 hr. After cooling, the reaction mixture was poured into ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.1 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2(O)[CH2:14][CH2:13][N:12]([S:15]([CH3:18])(=[O:17])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[OH:8].O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH2:14][CH2:13][N:12]([S:15]([CH3:18])(=[O:16])=[O:17])[CH2:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: CS(=O)(=O)N1CCC(O)(c2ccc(O)c(F)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CS(=O)(=O)N1CC=C(c2ccc(O)c(F)c2)CC1
Temperature: 60 °C
Yield: 104.8 %

Procedure:
4-(3-Fluoro-4-hydroxy-phenyl)-1-methanesulfonyl-piperidin-4-ol (726.00 mg, 2.51 mmol) is dissolved in 1,4-dioxane (10.36 g, 10.04 mL, 117.57 mmol). p-Toluenesulfonic acid (43.65 mg, 250.93 μmol) is added and the mixture is heated at 60° C. Solid sodium carbonate is added and the reaction is concentrated. The residue is partitioned between water and ethyl acetate, the pH adjusted to 7 with 1 M hydrogen chloride and extracted with ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate, filtered, and concentrated to dryness to provide 714 mg of the title compound as a white solid. MS (m/z) 272 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])C(=O)C(F)(F)F)=[CH:6][CH:5]=1.[OH-].[K+]>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[N+:25]([O-:27])=[O:26])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CN(C(=O)C(F)(F)F)c2ccc(C)cc2[N+](=O)[O-])cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)c1ccc(CNc2ccc(C)cc2[N+](=O)[O-])cc1
Temperature: 38 °C
Yield: 90 %

Procedure:
A stirred solution of 4{[(4-methyl-2-nitrophenyl)(2,2,2-trifluoroacetyl)-amino]methyl}benzoic acid methyl ester (14.0 g, 35 mmol) in CH2Cl2, was treated with tetrabutylammonium bromide (1.13 g, 3.5 mmol) and 20% aq. KOH (100 mL). The reaction mixture was heated to 38° C. for 3 h and cooled to room temperature. The phases were separated, the aqueous phase was extracted with CH2Cl2. The combined extracts and organic phase were washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to afford 4-[(4-methyl-2-nitrophenylamino)methyl]-benzoic acid methyl ester as an orange solid. Yield: 90%. 1H NMR (400 MHz, CDCl3): 8.37 (bs, 1H); 8.02 (m, 3H); 7.40 (d, J=8 Hz, 2H); 7.19 (d, J=8 Hz, 1H); 6.63(d, J=8 Hz, 1H); 4.60(d, J=8 Hz, 2H); 3.91(s,3H); 2.35 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([NH:18][C:19]([N:21]3[CH:25]=[CH:24]N=C3)=[O:20])=[N:15][C:14]=2[CH3:26])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2].[CH2:27]([C:29]1[O:33][C:32](CCN)=[N:31][CH:30]=1)[CH3:28].C(N(CC)CC)C>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[S:17][C:16]([NH:18][C:19]([NH:21][CH2:25][CH2:24][C:32]3[O:33][C:29]([CH2:27][CH3:28])=[CH:30][N:31]=3)=[O:20])=[N:15][C:14]=2[CH3:26])[CH:6]=[CH:7][C:8]=1[S:9]([CH3:12])(=[O:11])=[O:10])#[N:2]
Reactant: CCc1cnc(CCN)o1
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccc(S(C)(=O)=O)c(C#N)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cnc(CCNC(=O)Nc2nc(C)c(-c3ccc(S(C)(=O)=O)c(C#N)c3)s2)o1
Temperature: 70 °C

Procedure:
To a stirred solution of imidazole-1-carboxylic acid [5-(3-cyano-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide (Intermediate BD) (0.05 g, 1.29 mmol) in DMF (1.5 ml) under an inert atmosphere is added 2-(5-ethyl-oxazol-2-yl)-ethylamine (Amine) (0.018 g, 1.29 mmol) followed by triethylamine (0.02 ml, 0.14 mmol). The reaction mixture is heated to 70° C. for 2.5 hours and then allowed to cool to room temperature. The solvent is removed in vacuo and the resulting crude residue is dissolved in THF and passed through a 0.5 g polymer supported isocyanate resin (pre-washed with THE). The solution is concentrated in vacuo and the crude residue is dissolved in DCM and washed with water, brine, dried over MgSO4 and concentrated in vacuo again. Triturating with ether affords the titled compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1C=CC=CC=1C(O)=O.[NH2:29][C:30]1[C:35]([C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=2)=[CH:34][C:33]([Cl:43])=[CH:32][N:31]=1>CS(C)=O.[Cu]I>[Cl:43][C:33]1[CH:34]=[C:35]([C:36]2[CH:41]=[CH:40][C:39]([O:42][C:2]3[CH:7]=[CH:6][N:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:3]=3)=[CH:38][CH:37]=2)[CH:30]([NH2:29])[NH:31][CH:32]=1
Reactant: Nc1ncc(Cl)cc1-c1ccc(O)cc1
Reactant: FC(F)(F)c1cc(Br)ccn1
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: NC1NC=C(Cl)C=C1c1ccc(Oc2ccnc(C(F)(F)F)c2)cc1
Temperature: 140 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
A mixture of 4-bromo-2-(trifluoromethyl)pyridine (282 mg), tripotassium phosphate (481 mg), picolinic acid (27.9 mg), copper(I) iodide (21.58 mg) and 4-(2-amino-5-chloropyridin-3-yl)phenol (250 mg) in DMSO (5 mL) was stirred at 140° C. under N2 overnight. The mixture was poured into sat.NH4Cl aq. and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (230 mg) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.Cl.Cl.[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](/[CH:18]=[CH:19]/[C:20]2[CH:33]=[CH:32][C:23]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])=[C:22]([CH3:34])[CH:21]=2)=[N:10]1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][C:4]([N:29]1[CH2:30][CH2:31][N:26]([C:24](=[O:25])[C:23]2[CH:32]=[CH:33][C:20](/[CH:19]=[CH:18]/[C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[NH:9][N:10]=3)=[CH:21][C:22]=2[CH3:34])[CH2:27][CH2:28]1)=[O:6]
Reactant: COCC(=O)O
Reactant: Cc1cc(/C=C/c2n[nH]c3ccccc23)ccc1C(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COCC(=O)N1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2C)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
A solution of methoxyacetic acid (0.019 mL, 0.24 mmol) in THF (5.0 mL) was added with Compound 95 (0.10 g, 0.29 mmol), 1-hydroxybenzotriazole monohydrate (52 mg, 0.337 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (69 mg, 0.36 mmol), followed by stirring at 60° C. for 1 hour. The reaction mixture was added with ethyl acetate and saturated aqueous sodium hydrogencarbonate solution (4.0 mL) and was extracted. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=10/1), and the product was added with ethyl acetate, then precipitate was collected by filtration to obtain Compound 100 (39 mg, 39%).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1.[C:23]([S:27]([N:29]=[CH:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[O:28])([CH3:26])([CH3:25])[CH3:24].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[CH3:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([O:21][CH3:22])[C:20]=1[CH:30]([NH:29][S:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[O:28])[CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35]
Reactant: COC(=O)CCCC=NS(=O)C(C)(C)C
Reactant: COc1cncc(OC)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCCC(NS(=O)C(C)(C)C)c1c(OC)cncc1OC
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
A cooled (−78° C.) slightly yellow solution of diisopropylamine (1.946 g; 19.23 mmol) in anh. THF (85 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (12.0 ml; 19.23 mmol). The resulting slightly yellow solution was further stirred at −78° C. for 20 min. A slightly yellow solution of 3,5-dimethoxypyridine (2.433 g; 17.48 mmol) in anh. THF (7 ml) was then added dropwise. The resulting yellow heterogeneous mixture was further stirred at −78° C. for 30 min. A yellow solution of methyl 5-((tert-butylsulfinyl)imino)pentanoate (4.080 g; 17.48 mmol) in anh. THF (8 ml) was then added to the cooled reaction mixture, and stirring at −78° C. was continued for 90 min. The resulting orange reaction mixture was treated successively with aq. sat. NH4Cl (29 ml), Et2O (100 ml) and water (25 ml). The separated yellow organic layer was then washed with brine (30 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=20/1) afforded methyl 5-(3,5-dimethoxypyridin-4-yl)-5-(1,1-dimethylethylsulfinamido)pentanoate as a yellow oil. LC-MS (conditions B): tR=0.59 min.; [M+H]+: 373.00 g/mol.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33]N)=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:29][CH:28]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Reactant: NNc1ccc(Cl)cc1
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1ccc(Cl)cc1

Procedure:
Reaction of 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (4-chloro-phenyl)-hydrazine according to example 43 gave the desired product. MS: M=432.9 (M+H)+
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:25]=[CH:24][C:9]([O:10][C:11]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:8][CH:7]=1.[PH2](O)=O.[OH-].[Na+]>O.Cl>[CH3:17][N:14]1[CH2:15][CH2:16][C:11]([O:10][C:9]2[CH:24]=[CH:25][CH:6]=[CH:7][CH:8]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12][CH2:13]1
Reactant: CN1CCC(Oc2ccc(N)cc2)(c2ccccc2)CC1
Agent: Cl
Agent: O=N[O-]
Agent: O=[PH2]O
Solvent: O
Product: CN1CCC(Oc2ccccc2)(c2ccccc2)CC1
Temperature: -5 °C
Reaction time: 0.75 h

Procedure:
A solution of 3.0 g of sodium nitrite in 18 ml of water is added dropwise to a solution of 10.0 g of 4-(4-aminophenoxy)-1-methyl-4-phenylpiperidine in 12 ml of concentrated hydrochloric acid and 30 ml of water at -10° C. The mixture is subsequently stirred at -5° C. for 45 minutes, 50 ml of 50% strength hypophosphorous acid are added dropwise at -5° C., and the reaction mixture is left to stand at 0° C. for 24 hours. It is rendered alkaline with 6 N sodium hydroxide solution, while cooling with ice, and extracted with diethyl ether. After treating the organic phase with active charcoal, it is dried over sodium sulfate and concentrated. Resulting residue yields (after recrystallization from 100 ml of n-hexane) 5.5 g of the title compound of m.p. 99° to 101° C.
Reaction SMILES: [CH:1]1([N:4]2[CH:13]=[CH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[N+:14]([O-])=O)[C:5]2=[O:17])[CH2:3][CH2:2]1.C(O)C.[Cl-].[NH4+].O>[Fe]>[NH2:14][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:12]=[CH:13][N:4]([CH:1]1[CH2:3][CH2:2]1)[C:5]2=[O:17]
Reactant: O=c1c2cccc([N+](=O)[O-])c2ccn1C1CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc2c(=O)n(C3CC3)ccc12
Temperature: 85 °C

Procedure:
To a suspension of 2-cyclopropyl-5-nitro-2H-isoquinolin-1-one (3.7 g, 0.015 mol) in Ethanol (80 mL, 1 mol) was added ammonium chloride (8 g, 0.2 mol) in Water (80 mL, 4 mol) and the reaction heated at 85° C. and then iron (4 g, 0.06 mol) was added. The reaction started turning dark and became completely brown. The reaction was heated for 1 h. LC/MS showed no starting material left and only one peak which to give the desired MW. The reaction was removed from the oil bath and 150 ml of methylene chloride was added in the flask. The mixture layers were separated and aqueous layer was extracted with CH2Cl2 (100 mL×3). The combined organic layers were washed once with brine. The organic layer was collected, dried over Na2SO4 and reduced in vacuo to produce a yellow-orange solid.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH:13]=[CH:12][C:11]([CH:15]=[O:16])=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[BH4-].[Na+].[OH-].[Na+]>C(O)C.O>[CH3:1][N:2]1[C:14]2[CH:13]=[CH:12][C:11]([CH2:15][OH:16])=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: Cn1c2ccccc2c2cc(C=O)ccc21
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1c2ccccc2c2cc(CO)ccc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a solution of 18.9 g N-methyl-3-formyl carbazole in 400 ml ethanol, a mixture of 2.5 g NaBH4 and 20 ml 0.4N NaOH in water was added dropwise. The mixture was then heated at 60° C. and stirred for one hour. Cooling at room temperature, white crystals were obtained which were filtered, washed with water, dried and recrystallized from a cyclohexane:benzene mixture (1:1), yielding 92% N-methyl-3-hydroxymethyl carbazole with m.p.=96° C. IR: 3346 cm-1 (OH), 710, 729, 747, 770, 804 cm-1 (carbazole) 1H.NMR (CDCl3): 8.13-8.03 ppm (C4, C5, multiplet) 7.43-7.29 ppm (C1, C2, C6, C7, C8, multiplet) 4.84 ppm (CH2 singlet) 3.83 ppm (CH3 singlet) 1.64 ppm (OH, singlet).