Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[N+:14]([O-])([OH:16])=[O:15]>>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[C:8]([N+:14]([O-:16])=[O:15])[CH:9]=2)[NH:4][C:3]1=[O:12]
Reactant: O=[N+]([O-])O
Reactant: CC1(C)C(=O)Nc2cc(O)ccc21
Product: CC1(C)C(=O)Nc2cc(O)c([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4.5 g. 1,3-Dihydro-3,3-dimethyl-6-hydroxy-2H-indol-2-one were added portionwise, with vigorous stirring, to 35 ml. 65% nitric acid which was cooled with a mixture of ice and salt. The reaction mixture was further stirred in the cold for 10 minutes, diluted with ice/water to 150 ml. and the crystalline precipitate filtered off with suction and subsequently washed with water to give 4.1 g. (73% of theory) of the title compound in the form of yellow crystals; m.p. 244°-247° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Br:9])[CH:6]=[CH:7][CH:8]=1.[C:10](Cl)(=[O:14])[C:11]([CH3:13])=[CH2:12].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Br:9][C:5]1[CH:6]=[CH:7][C:8]([C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: C=C(C)C(=O)Cl
Reactant: COc1cccc(Br)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=C(C)C(=O)c1ccc(Br)cc1OC
Yield: 44.7 %

Procedure:
3-methoxybromobenzene (238 mg), methacryloyl chloride (110 mg), and aluminium chloride (160 mg) were reacted in dichloromethane (1.5 mL) at from 0° C. to room temperature for 4 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (120 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:17](=[O:33])[CH2:18][C:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:21]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:15][C:11]1[C:12]([F:14])=[CH:13][C:8]2[N:7]=[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=4)[CH:21]=3)[CH2:18][C:17](=[O:33])[NH:16][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccccn3)c2)=Nc2cc(F)c(Cl)cc2N1

Procedure:
The title compound was prepared from {4-chloro-5-fluoro-2-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert-butyl ester (Example M48) (270 mg, 0.54 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (174 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:28])[C@@H:15]([N+:25]([O-])=O)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C:10]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO.[Ni](Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([C@@H:14]([OH:28])[C@@H:15]([NH2:25])[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)[CH2:12][O:11][C:10]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(c2ccccc2)(c2ccccc2)OC[C@@H]1[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)[N+](=O)[O-]
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(c2ccccc2)(c2ccccc2)OC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Reaction time: 0.25 h

Procedure:
Dissolve (R)-5-[(1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-2-nitropropyl]-2,2-diphenylmorpholine-4-carboxylic acid tert-butyl ester (0.172 g, 0.31 mmol) in dry methanol (8 mL), add nickel chloride (0.060 g, 0.46 mmol) then sodium borohydride (0.059 g, 1.55 mmol). Stir 15 minutes, add water (˜2 mL) and concentrate. Add ethyl acetate (˜70 mL), filter (Celite®), wash with water and saturated aqueous sodium chloride. Dry (magnesium sulfate), filter and concentrate to give the desired compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH2:29])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>O1CCCC1.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH:29][C:37](=[O:39])[CH3:38])[C:25]([F:26])([F:27])[F:28])=[CH:4][CH:3]=1
Reactant: CC(=O)Cl
Reactant: NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Yield: 94.5 %

Procedure:
To a mixture of 1-[9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanamine (80.0 mg, 0.165 mmol) and triethylamine (0.0460 mL, 0.330 mmol) in tetrahydrofuran (2 mL) was added acetyl chloride (0.0141 mL, 0.198 mmol) at 0° C. The resultant mixture was stirred at room temperature for 30 min and diluted with aqueous sodium bicarbonate. The resultant mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (82.2 mg, 0.156 mmol, 95%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([C:18]([F:21])([F:20])[F:19])[CH:13]=[C:14]([Cl:17])[C:15]=1F.O>C1C=CC=CC=1.C([Li])CCC.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:15]2[C:14]([Cl:17])=[CH:13][C:12]([C:18]([F:19])([F:21])[F:20])=[CH:11][C:10]=2[Cl:9])[CH:3]=1
Reactant: Clc1cccc(I)c1
Reactant: Fc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: c1ccccc1
Product: FC(F)(F)c1cc(Cl)c(-c2cccc(Cl)c2)c(Cl)c1
Yield: 36.7 %

Procedure:
To 10.0 g (41.9 mmol) of 1-chloro-3-iodobenzene in 50 ml of dry benzene, 32.0 ml of a n-butyllithium solution in hexane (1.56 mol/l) was added dropwise in a nitrogen stream at room temperature with stirring. After another 2 hours of stirring at room temperature, 9.9 g (42.5 mmol) of 3,5-dichloro-4-fluorobenzotrifluoride was added dropwise at 10° C. After another 12 hours of stirring at room temperature, the reaction mixture was poured into 500 ml of water for separation. The organic layer was washed with 200 ml of water twice and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Purification of the residue by silica gel column chromatography afforded 5.0 g of 1-chloro-3-(2,6-dichloro-4-trifluoromethylphenyl)benzene (yield 35.0%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].C(N(CC)CC)C.[C:18]([CH2:22][CH2:23][C:24](Cl)=[O:25])([O:20][CH3:21])=[O:19]>C(Cl)Cl>[CH3:21][O:20][C:18](=[O:19])[CH2:22][CH2:23][C:24](=[O:25])[NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10]
Reactant: COC(=O)CCC(=O)Cl
Reactant: NCCCN1CCCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCC(=O)NCCCN1CCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To a solution of 1-(3-aminopropyl)-2-oxopyrrolidine (570 mg) in methylene chloride (10 ml) were added triethylamine (0.67 ml) and 3-carbomethoxy propionylchloride (600 mg) in sequence under ice-cooling and the mixture was stirred for 0.5 hour. After 3.5 hours' stirring at room temperature, the reaction mixture was poured into ice water and extracted with chloroform. The organic layer was washed with 1N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate and saturated brine in sequence, and dried over magnesium sulfate, followed by concentration. The residue was purified by silica gel column chromatography (chloroform-methanol) to give 902 mg of 4-oxo-4-[3-(2-oxo-1-pyrrolidinyl)propylamino]butyric acid methyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:13][CH:12]2[N:14](CC3C=CC=CC=3)[CH:8]([CH2:9][C:10](=[O:22])[CH2:11]2)[CH2:7]1)=[O:5])[CH3:2].[H][H]>CO.[OH-].[Pd+2].[OH-]>[CH2:1]([O:3][C:4]([CH:6]1[CH2:13][CH:12]2[NH:14][CH:8]([CH2:9][C:10](=[O:22])[CH2:11]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C1CC2CC(=O)CC(C1)N2Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)C1CC2CC(=O)CC(C1)N2
Reaction time: 12 h
Yield: 100.5 %

Procedure:
9-Benzyl-7-oxo-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid ethyl ester (11.1 g, 36.8 mmol) was dissolved in methanol (30 mL) and added to a suspension of palladium hydroxide (1 g) in methanol (10 mL) in a Parr bottle. The Parr bottle was filled with hydrogen (30 psi) and evacuated three times. The Parr bottle was refilled with hydrogen (30 psi) and shook for 12 h. The suspension was filtered through Celite and concentrated under vacuum to give 7.81 g (quantitative yield) of 7-oxo-9-aza-bicyclo[3.3.1]nonane-3-carboxylic acid ethyl ester as a yellow oil. Retention time (min)=0.369, method [1], MS(ESI) 212.1 (M+H).
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][NH:24][CH2:25]2)[CH2:21][CH2:20]1)=[O:17].C1(C(C2CCCCC2)C(N[C@@H]2[C@H]3[C@H](CNC3)CC2)=O)CCCCC1>>[CH3:13][CH:14]([CH3:33])[CH:15]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:16]([NH:18][C@@H:19]1[C@@H:26]2[C@@H:22]([CH2:23][N:24]([CH2:6][C:5]3[CH:8]=[CH:9][CH:10]=[C:3]([CH3:2])[CH:4]=3)[CH2:25]2)[CH2:21][CH2:20]1)=[O:17]
Reactant: CC(C)C(C(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21)c1ccccc1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Agent: O=C(N[C@H]1CC[C@H]2CNC[C@H]21)C(C1CCCCC1)C1CCCCC1
Product: Cc1cccc(CN2C[C@H]3CC[C@H](NC(=O)C(c4ccccc4)C(C)C)[C@H]3C2)c1

Procedure:
The title compound was prepared by substituting 3-methylbenzaldehyde for 3-(trifluoromethyl)benzaldehyde and 3-methyl-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl]-2-phenylbutanamide from Example 83 Step A for 2,2-dicyclohexyl-N-[(3aS,4S,6aR)-octahydrocyclopenta[c]pyrrol-4-yl]acetamide in the procedure described for Example 54: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.62-8.50 (m, 1H), 7.64 (d, J=7.5, 2H), 7.33 (td, J=3.7, 7.5, 2H), 7.29-7.23 (m, J=5.5, 11.0, 3H), 7.18 (s, 1H), 7.07 (d, J=7.0, 1H), 4.42-4.29 (m, 1H), 3.60 (d, J=13.1, 0.5H), 3.51 (d, J=13.0, 0.5H), 3.45 (d, J=13.1, 0.5H), 3.33 (d, J=13.0, 0.5H), 3.22 (d, J=10.4, 1H), 2.90 (dd, J=2.9, 8.9, 0.5H), 2.64 (tt, J=6.8, 13.6, 1H), 2.59-2.46 (m, J=5.3, 12.0, 23.8, 2H), 2.44-2.34 (m, 1H), 2.30 (d, J=5.3, 1H), 2.28-2.23 (m, J=8.0, 4H), 2.13 (dt, J=6.3, 12.4, 1H), 1.94-1.78 (m, 1H), 1.78-1.64 (m, 1H), 1.48-1.25 (m, 1.5H), 1.20 (t, J=6.1, 3H), 0.70 (dd, J=1.9, 6.7, 3H); MS (ESI+) m/z 391 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:17][N:18]([CH3:23])[S:19](Cl)(=[O:21])=[O:20].Cl>N1C=CC=CC=1>[CH3:17][N:18]([CH3:23])[S:19]([NH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1)(=[O:21])=[O:20]
Reactant: Nc1ccc(C(=O)Nc2ccccc2)cc1
Reactant: CN(C)S(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)Nc1ccc(C(=O)Nc2ccccc2)cc1
Temperature: 0 °C
Yield: 57.4 %

Procedure:
To a solution of 1.0 g of 4-aminobenzanilide 4 dissolved in 10 ml of dried pyridine is added 1.01 g of dimethylaminosulfonyl chloride 5 at room temperature, and the mixture is stirred over-night. The reaction mixture is poured into ice-water, acidified with 6N hydrochloric acid, and extracted with a mixture of methylene chloride-methanol. The organic layer is extracted again with 10% sodium hydroxide solution. The alkaline layer is acidified with 6N hydrochloric acid; the precipitate is collected by filtration and recrystallized from methanol to give 864 mg of 4-[(dimethylaminosulfonyl)amino]benzanilide 6 as crystals, m.p. 213°-215° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH3:14].[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27](O)=O)=[CH:25][C:24]([CH:30]([F:32])[F:31])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>C(#N)C>[Cl:15][C:16]1[C:17]([N:22]2[C:26]([C:27]3[O:12][C:11](=[O:13])[C:10]4[C:2](=[C:3]([CH3:14])[CH:4]=[C:5]5[CH:6]=[N:7][NH:8][C:9]5=4)[N:1]=3)=[CH:25][C:24]([CH:30]([F:32])[F:31])=[N:23]2)=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cc2cn[nH]c2c(C(=O)O)c1N
Reactant: O=C(O)c1cc(C(F)F)nn1-c1ncccc1Cl
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1cc2cn[nH]c2c2c(=O)oc(-c3cc(C(F)F)nn3-c3ncccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 540 mg (2.82 mmol) of 6-amino-5-methyl-1H-indazole-7-carboxylic acid in 20 mL of anhydrous acetonitrile is added 771 mg (2.82 mmol) of 2-(3-chloro-pyridin-2-yl)-5-difluoromethyl-2H-pyrazole-3-carboxylic acid followed by 1.02 mL (12.7 mmol) of pyridine. The mixture is stirred at ambient temperature during 30 minutes. Then the suspension is cooled to 0° C. and 766 μL (9.9 mmol) of methanesulfonyl chloride is added dropwise. The mixture is stirred at 50° C. for 16 hours. Then the solvent is evaporated and the residue is triturated with a minimum of cold water. The precipitate, which is formed is filtrated, washed with cold water and dried. The pale yellowish product obtained is engaged in the next step; LC/MS:429/431 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[OH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:2]2[N:3]=[CH:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:17][CH2:16]1
Reactant: OCCN1CCNCC1
Reactant: Clc1cc2ccccc2cn1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: OCCN1CCN(c2cc3ccccc3cn2)CC1

Procedure:
Prepared analogously to Example 1 from 3-chloroisoquinoline and N-(2-hydroxyethyl)-piperazine. Melting point of base 134°-136° C.; melting point of dihydrochloride 282°-283° C.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH:4]([CH3:32])[CH2:5][C:6]1[S:7][C:8]([S:11]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[C:27]([F:30])([F:29])[F:28])[CH2:16][C@H:15]2[CH3:31])(=[O:13])=[O:12])=[CH:9][CH:10]=1.[Li+].[OH-].O.Cl>C1COCC1>[F:26][C:23]1[CH:24]=[CH:25][C:20]([N:17]2[CH2:18][CH2:19][N:14]([S:11]([C:8]3[S:7][C:6]([CH2:5][CH:4]([CH3:32])[C:3]([OH:33])=[O:2])=[CH:10][CH:9]=3)(=[O:12])=[O:13])[C@H:15]([CH3:31])[CH2:16]2)=[C:21]([C:27]([F:30])([F:28])[F:29])[CH:22]=1
Reactant: COC(=O)C(C)Cc1ccc(S(=O)(=O)N2CCN(c3ccc(F)cc3C(F)(F)F)C[C@H]2C)s1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(Cc1ccc(S(=O)(=O)N2CCN(c3ccc(F)cc3C(F)(F)F)C[C@H]2C)s1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 3-[5-({(2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methylpiperazin-1-yl}sulfonyl)-2-thienyl]-2-methylpropanoic acid methyl ester (115 mg, 0.2 mmol) in THF (3 mL) was added LiOH (excess) and water (3 mL). The reaction mixture was stirred at rt overnight and acidified with 1N aq. HCl, then extracted with EtOAc. The organic layer was dried over Na2SO4. The crude product was purified on SiO2 column eluted with hexanes/EtOAc to give the titled compounds as a light yellow solid (94 mg, 95%). HRMS: calcd for C20H22F4N2O4S2+H+, 495.10299. found (ESI-FTMS, [M+H]1+), 495.10293.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[CH3:13][O:14][NH2:15]>C1(C)C=CC=CC=1.C(O)C.C(N(CC)CC)C.CO>[N:1]([CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]([NH:15][O:14][CH3:13])=[NH:10])=[CH:7][CH:6]=1)=[N+:2]=[N-:3]
Reactant: N#Cc1ccc(CN=[N+]=[N-])cc1
Reactant: CON
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CO
Product: CONC(=N)c1ccc(CN=[N+]=[N-])cc1
Temperature: -10 °C
Reaction time: 48 h

Procedure:
4-Azidomethylbenzonitrile (17.3 g, 0.109 mol; Nishiyama et al; Chem. Lett. (1982) 1477) was dissolved in 500 mL of toluene and 200 mL of absolute ethanol. The solution was cooled to −10° C. and HCl(g) was bubbled through until saturation. The mixture was kept in the refrigerator for 2 days when most of the solvents were evaporated. Diethyl ether was added and was decanted off. The product was re-dissolved in a solution of O-methylhydroxylamine (10.5 g, 0.125 mol) and triethyl amine (56 mL) in 200 mL of methanol. The mixture was allowed to stand for 3 days whence the methanol was evaporated with addition of EtOAc. The organic phase was washed with water, dilute HOAc and aqueous sodium bicarbonate, dried (Na2SO4) and diluted with more EtOAc to a total volume of 500 mL. A sample of 25 mL was evaporated to dryness. The remainder was 932 mg. Total yield: 18.6 g (83%).
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[C:10]([O:12]C)=[O:11].O[Li].O.Cl>CO.O>[S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1cc2cnccc2s1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2cnccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl thieno[3,2-c]pyridine-2-carboxylate (D-2) (12 g, 62.1 mmol) in MeOH (150 mL) and H2O (15 mL) was added LiOH.H2O (5.2 g, 124.2 mmol). The solution was stirred at room temperature overnight, and then acidified with 1N aqueous HCl. The resulting white precipitate was collected by filtration and air-dried to afford the title compound. MS (m/z): 179 (M)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9])(=O)=O.C[NH2:17]>C1COCC1.CCOCC>[C:10]1([C@H:8]([OH:9])[CH2:7][CH2:6][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CS(=O)(=O)OCC[C@@H](O)c1ccccc1
Reactant: CN
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCC[C@@H](O)c1ccccc1

Procedure:
A solution of (R)-3-phenyl-3-(hydroxy)-propyl methanesulfonate (3 mmol) and methylamine (10 mL, 40% in water) in THF (10 mL) is heated at 65° C. for 3 h. After cooling, the solution is diluted with ether, washed with saturated aqueous sodium bicarbonate and brine, and dried with anhydrous potassium carbonate. Concentration of extract provides (R)-3-phenyl-3-(hydroxy)-propyl amine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].Cl[CH2:22][CH2:23][N:24]([CH2:32][CH2:33]Cl)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]#[C:18][CH3:19])=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:22][CH2:23][N:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:32][CH2:33]1)=[O:20])[CH3:2]
Reactant: CC#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Reactant: ClCCN(CCCl)Cc1ccccc1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccccc3)CC2)cc1

Procedure:
1-Benzyl-4-(4-but-2-ynyloxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester was prepared according to the general method as outlined in Example 1 (Step 6). Starting from (4-but-2-ynyloxy-benzenesulfonyl)-acetic acid ethyl ester (2 g, 6.73 mmol) and bis-(2-chloro-ethyl)-benzyl amine (2.3 g, 8.8 mmol). Yield 3.33 g (99%); yellow oil; MS: 455.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6](Cl)[N:5]=[C:4]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[S:26][C:25]([C:27]4[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=4[F:34])=[N:24][CH:23]=3)[CH2:17][CH2:16]2)=[O:12])[CH:3]=1.[CH:35]1([CH2:38][OH:39])[CH2:37][CH2:36]1>>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:39][CH2:38][CH:35]2[CH2:37][CH2:36]2)[N:5]=[C:4]([C:11]([NH:13][CH2:14][CH:15]2[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[S:26][C:25]([C:27]4[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=4[F:34])=[N:24][CH:23]=3)[CH2:17][CH2:16]2)=[O:12])[CH:3]=1
Reactant: OCC1CC1
Reactant: N#Cc1c(N)cc(C(=O)NCC2CCN(Cc3cnc(-c4c(F)cccc4F)s3)CC2)nc1Cl
Product: N#Cc1c(N)cc(C(=O)NCC2CCN(Cc3cnc(-c4c(F)cccc4F)s3)CC2)nc1OCC1CC1

Procedure:
According to the same procedure described in Example 204, using the compound prepared in Example 399 instead of the compound prepared in Example 215 and cyclopropylmethanol instead of 1-cyclopropylethanol, the title compound having the following physical data was obtained.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17](O)=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]([NH:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=C1c2ccccc2C=Cc2ccccc21
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNC(=O)C=C1c2ccccc2C=Cc2ccccc21

Procedure:
173 mg (0.70 mmol) of 5H-dibenzo[a,d][7]annulen-5-ylidenacetic acid, 124 mg (0.77 mmol) of t-butyl N-(2-aminoethyl)carbamate, 143 mg (0.75 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride and 0.11 ml (0.79 mmol) of triethylamine were stirred in 5 ml of dichloromethane at room temperature overnight. The reaction mixture was washed with saturated aqueous sodium hydrogencarbonate solution and the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane:ethyl acetate=7:3) to obtain the title compound.
Reaction SMILES: O.[ClH:2].Cl.[NH:4]1[CH2:8][CH2:7][N:6]=[C:5]1[C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].[CH2:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1)[CH3:17]>CN(C)C=O>[ClH:2].[NH:6]1[CH2:7][CH2:8][N:4]=[C:5]1[C:9]1[CH:10]=[C:11]([NH:12][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:16][CH3:17])=[CH:20][CH:21]=2)=[O:27])[CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cccc(C2=NCCN2)c1
Reactant: CCOc1ccc(N=C=O)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(NC(=O)Nc2cccc(C3=NCCN3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
A mixture of 3-(4,5-dihydro-1H-imidazol-2-yl)aniline dihydrochloride monohydrate (stored with 4 A molecular sieves, 48 mg, 0.19 mmol) and 4-ethoxyphenyl isocyanate (33 mg, 0.20 mmol) in dimethylformamide (2 ml) was stirred at room temperature overnight. After removal of the solvent, water (2 ml) was added and the resulting precipitate was collected (18 mg, 64% yield) by filtration. 1H NMR (600 MHz, DMSO-d6) δ 10.5 (br s, 1H), 9.12 (br s, 1H), 8.11 (s, 1H), 7.68 (d, 1H, J=8.4 Hz), 7.52 (t, 1H, 8.4 Hz), 7.47 (d, 1H, J=7.2 Hz), 7.35 (d, 2H, J=7.2 Hz), 6.86 (d, 2H, J=7.2 Hz), 3.98 (s, 4H). MS: m/z Calcd 324.4 Found MH+ 325.5
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][C@@H:25]1[CH2:29][O:28][C:27](=[O:30])[NH:26]1>>[CH3:24][C@@H:25]1[CH2:29][O:28][C:27](=[O:30])[N:26]1[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:6][N:7]=1
Reactant: Cc1ccc(OC2CCN(C(=O)c3ccc(Br)nc3)CC2)cc1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1ccc(OC2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)nc3)CC2)cc1
Yield: 15.8 %

Procedure:
By reaction and treatment in the same manner as in Example 40 and using (6-bromopyridin-3-yl)(4-p-tolyloxypiperidin-1-yl)methanone (1.2 g) described in Preparation Example 28 and (R)-4-methyloxazolidin-2-one (364 mg) described in Preparation Example 25, the title compound (200 mg) was obtained.