Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([N:13]3[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]3=[O:25])=[C:11]([F:26])[CH:10]=[C:9]([Cl:27])[C:7]=2[CH:8]=1)(=O)[CH3:2].C([O-])(=O)C.[K+].Cl.[CH3:34][O:35][NH2:36]>CO>[Cl:27][C:9]1[C:7]2[CH:8]=[C:4]([C:1](=[N:36][O:35][CH3:34])[CH3:2])[O:5][C:6]=2[C:12]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[C:11]([F:26])[CH:10]=1
Reactant: CON
Reactant: CC(=O)c1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CON=C(C)c1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 25 °C
Reaction time: 12 h
Yield: 64.6 %

Procedure:
20 ml of methanol was added to 0.4 g (1 mmol) of 3-(2-acetyl-4-chloro-6-fluorobenzofuran-7-yl) -1-methyl-6-trifluoromethyluracil, 0.4 g (4 mmol) of potassium acetate and 0.33 g (4 mmol) of methoxyamine hydrochloride, followed by stirring at room temperature for 12 hours. After completion of the reaction, the solvent was distilled off under reduced pressure. The obtained residue was purified directly by silica gel column chromatography to obtain 0.28 g (yield: 64.6%) of the desired product as white powder. Melting point: 176-178° C.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:12])[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[O:13]([CH2:20][CH:21]([OH:30])[CH2:22][NH:23][CH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][NH2:27])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1.O>C(Cl)Cl>[O:13]([CH2:20][CH:21]([OH:30])[CH2:22][NH:23][CH2:24][C:25]([CH3:28])([CH3:29])[CH2:26][NH:27][C:2]1[N:3]([CH3:12])[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(CN)CNCC(O)COc1ccccc1
Reactant: Cc1c(Cl)n(C)c(=O)n(C)c1=O
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1c(NCC(C)(C)CNCC(O)COc2ccccc2)n(C)c(=O)n(C)c1=O

Procedure:
4.5 g. 4-Chloro-1,3,5-trimethylpyrimidine-2,6(1H,3H)-dione and 6.1 g. 1-phenoxy-3-(3-amino-2,2-dimethylpropylamino)-propan-2-ol (b.p. 159°-161° C./0.01 mm.Hg; obtained from phenyl glycidyl ether and 2,2-dimethyl-1,3-diaminopropane) are stirred for 50 hours at 80° C. in 8 ml. pyridine. The reaction mixture is taken up in methylene chloride, shaken with water, dried, evaporated and the residue obtained chromatographed on silica gel in the manner described in Example 29 to give 2.3 g. (24% of theory) of the desired product in the form of colorless crystals; m.p. 111°-112° C., after recrystallization from ethyl acetate.
Reaction SMILES: C[O-].[Na+].C([S:7][CH:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)(=O)C.C(O)(=O)C>CO>[SH:7][CH:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1
Reactant: CC(=O)SC1CN2CCC1CC2
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: SC1CN2CCC1CC2
Yield: 25 %

Procedure:
Sodium methylate (0.5 g) is added to a solution of 3-(acetylthio)quinuclidine (14.5 g) in methanol (150 cc). The reaction mixture is then heated under reflux for 1 hour. Sodium methylate (0.5 g) is added again and the mixture is then heated under reflux for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. Distilled water (40 cc) is added to the residue obtained, followed by acetic acid (approximately 1 cc) to obtain a pH in the region of 8. The mixture obtained is extracted with methylene chloride (3×20 cc). The combined organic phases are dried over sodium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 30° C. The brown oil obtained is distilled under reduced pressure (920 Pa); the fraction distilling at about 94° C. is collected. 3-Mercaptoquinuclidine (2.8 g) is thereby obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][C:13]([N+:21]([O-])=O)=[C:12]2[NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[F:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.O.C(OCC)(=O)C>C(O)C>[NH2:21][C:13]1[CH:14]=[N:15][C:16]2[C:11]([C:12]=1[NH:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[F:33])=[CH:10][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[C:18]([O:19][CH3:20])[CH:17]=2
Reactant: COc1cc2ncc([N+](=O)[O-])c(Nc3ccc(C#N)cc3F)c2cc1OCc1ccccc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc2ncc(N)c(Nc3ccc(C#N)cc3F)c2cc1OCc1ccccc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 56.1 %

Procedure:
4-(6-Benzyloxy-7-methoxy-3-nitroquinolin-4-ylamino)-3-fluorobenzonitrile (6.50 g, 14.62 mmol) and tin(II) chloride dihydrate (14.70 g, 65.15 mmol) were dissolved in ethanol (780 ml). The reaction solution was subsequently stirred at 70° C. for 30 min. When the reaction was complete (TLC, LC-MS), water (2 l) and ethyl acetate (1.5 l) was added, and the mixture was stirred vigorously for a further 30 min. The suspension obtained was filtered through kieselguhr. The aqueous phase was extracted again with ethyl acetate (1 l), and the combined organic phases were washed with water (500 ml). After the organic phase had been dried over Na2SO4, the solid material was filtered off with suction, and the filtrate was evaporated to dryness in vacuo, giving 4-(3-amino-6-benzyloxy-7-methoxyquinolin-4-ylamino)-3-fluorobenzonitrile (3.40 g, 8.2 mmol) as solid. MS: 415.1 (M+H+), TLC (HPTLC): Rf=0.47 (ethyl acetate).
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[C:24]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[N:23][C:22]([Cl:31])=[N:21][C:20]=4[N:32]=3)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.N1CCC(N2C[CH2:43][O:42][CH2:41][CH2:40]2)CC1>>[Cl:31][C:22]1[N:23]=[C:24]([N:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[C:19]2[S:18][C:17]([CH2:16][N:12]3[CH2:13][CH2:14][CH:9]([N:8]4[CH2:40][CH2:41][O:42][CH2:43][CH2:15]4)[CH2:10][CH2:11]3)=[N:32][C:20]=2[N:21]=1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Reactant: C1CC(N2CCOCC2)CCN1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCC(N4CCOCC4)CC3)nc2n1

Procedure:
Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-yl-thiazolo[4,5-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 4-piperidin-4-yl-morpholine in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a cream solid (28 mg, 80%).
Reaction SMILES: [CH3:1][C:2]1[C:10]([NH:11][C:12]([C:14]2[CH:15]=[N:16][N:17]3[CH:22]=[C:21](C4C=NN(C)C=4)[CH:20]=[CH:19][C:18]=23)=[O:13])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.BrC1C=CN2[C:36]([C:39]([NH:41]C3C(C)=NC=C(C=3)C(OC)=O)=O)=[CH:37][N:38]=[C:32]2C=1.CN1C(B2OC(C)(C)C(C)(C)O2)=CC=N1.[OH-].[Na+]>>[CH3:1][C:2]1[C:10]([NH:11][C:12]([C:14]2[CH:15]=[N:16][N:17]3[CH:22]=[C:21]([C:37]4[N:38]([CH3:32])[N:41]=[CH:39][CH:36]=4)[CH:20]=[CH:19][C:18]=23)=[O:13])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: Cc1ncc(C(=O)O)cc1NC(=O)c1cnn2cc(-c3cnn(C)c3)ccc12
Reactant: COC(=O)c1cnc(C)c(NC(=O)c2cnc3cc(Br)ccn23)c1
Agent: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ncc(C(=O)O)cc1NC(=O)c1cnn2cc(-c3ccnn3C)ccc12

Procedure:
The title compound was prepared analogously to 6-methyl-5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carboxamido)nicotinic acid (Example 9.0 step 2) from Intermediate 1C and 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole followed hydrolysis of the resulting methyl ester using sodium hydroxide;
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH2:19][CH2:20][CH:21]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]1[CH2:32][CH2:33][N:34]([CH2:21][CH2:20][CH2:19][C:9]2[CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:35][CH2:36]1
Reactant: Cc1ccc(-c2cc(CCC=O)nn2-c2ccccc2)cc1
Reactant: Cc1cccc(N2CCNCC2)c1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(CCCN3CCN(c4cccc(C)c4C)CC3)nn2-c2ccccc2)cc1

Procedure:
104 mg (75%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (80 mg, 0.276 mmol), 1-(2,3-dimethylphenyl)piperazine (53 mg, 0.276 mmol), DIPEA (0.072 mL, 0.414 mmol) and NaBH(OAc)3 (175 mg, 0.828 mmol).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Br[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[C:13]([O:12][C:10](=[O:11])[CH2:9][NH:1][N:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: NN1CCOCC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
A mixture of N-aminomorpholine (4 g), t-butyl bromoacetate (7.6 g) and sodium carbonate (2.1 g) in 20 ml of DMF was stirred at room temperature overnight. After concentration in vacuo, the residue was taken up in ethyl acetate. The organic solution was washed with water, dried, filtered and concentrated in vacuo to give 2.5 g of crude N-(morpholino)glycine t-butyl ester (compound III-A). This crude compound was used without further purification. To a solution of 5 g of the product (I-D) in 10 ml of methylene chloride was added a solution of 2.5 g of compound (III-A) and 5 ml of pyridine in 5 ml of methylene chloride over a period of 10 minutes. After 16 hours the reaction mixture was washed successively with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and once with brine. The organic solution was dried, filtered, concentrated in vacuo, and purified by dry column chromatography to give 3.5 g of oily product (III-B), N-(morpholino)-N-[N-[(1S)-1-ethoxycarbonyl-3-phenylpropyl]-N-(2,2,2-trichloroethoxycarbonyl)-L-alanyl]glycine t-butyl ester: ##STR21## To a solution of 0.6 g of product (III-B) in 10 ml of glacial acetic acid was added 2 g of zinc dust. After three hours the mixture was filtered through celite and concentrated in vacuo. The residue was taken up in ethyl acetate and washed with water. The organic solution was dried, filtered, concentrated in vacuo, and chromatographed to give 0.4 g of product (III-C), N-(morpholine)-N-[N-[(1S)-1-ethoxycarbonyl-3-phenylpropyl]L-alanyl]glycine t-butyl ester: ##STR22## The dihydrochloric acid salt of the free acid was formed by bubbling dry hydrogen chloride gas into an ethereal solution containing 0.5 g of product (III-C) at 0° C. for 2.5 hours. Concentration in vacuo gave 0.4 g of solid product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:10].[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[O:10])(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccn1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccn2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-pyridin-2-yl-methanone and 116 mg of 4-tert-Butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.24 (s, 9H), 7.34-7.38 (m, 2H), 7.47(dd, 1H, J=8.8 Hz, 2.4 Hz), 7.60 (m, 1H), 7.65-7.68 (m, 4H), 7.85 (d, 1H, J=8Hz), 8.00 (td, 1H, J=7.6 Hz, 2 Hz), 8.71 (bd, 1H, J=4.8 Hz). MS: m/z 429.9 (M++1).
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]CC)=O)[CH:5]=[N:4][C:3]1=2.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1>>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:18][CH2:19][CH2:20][CH2:21][N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Reactant: NCCCn1ccnc1
Product: O=C(CCn1cnc2c(=O)[nH]cnc21)NCCCn1ccnc1
Yield: 59.8 %

Procedure:
250 mg (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl) propionic acid, ethyl ester (AIT-0027) was heated with 500 mg (3.99 mmol) of 1-(3-aminopropyl)-imidazole in a 10 ml round bottom flask at 120° C. for two hours with stirring. The resulting viscous yellow oil was chromatographed on 15 g of silica gel, eluting with 60% methanol/40% ethyl acetate, which yielded a highly viscous colorless oil after evaporation of the solvent. The oil was dissolved in approximately 50 ml of ethyl ether and then methanol was added slowly until a white precipitate formed. The precipitate was collected by vacuum filtration and washed with ethyl ether. The material was dried to yield 200 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-[3-(1-imidazolyl)propyl]propanamide (AIT-0037) as a white solid. Yield 66%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][C:10](=[O:15])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[CH3:17][Mg+].[Br-].OS([O-])(=O)=O.[K+]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][CH2:9][C:10](=[O:15])[CH3:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[Mg+]
Reactant: CON(C)C(=O)CCNC(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of BOC-beta-alanine (20 g, 105 mmol), 10-2 (10.3 g, 105 mmol), BOP reagent (46.5 g, 105 mmol), and N-methylmorpholine (46 mL, 420 mmol) in acetonitrile (500 mL) was stirred for 15 h. The reaction was diluted with EtOAc, washed with H2O, 10% KHSO4 (aq.), sat. NaHCO3, dried (MgSO4) and concentrated to give crude [2-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester 10-3 as a yellow oil. TLC Rf =0.42 (silica, 20% EtOAc/hexanes). To a solution of this crude amide in THF (500 mL) at 0° C. was added CH3MgBr (100 mL of 3M in ether, 300 mmol) over 30 minutes. After 2 h, 10% KHSO4 (aq.) was added, the mixture warmed to 25° C., and diluted with EtOAc. The organics were washed with sat. NaHCO3, dried (MgSO4) and concentrated. Flash chromatography (silica, 20% EtOAc/hexanes) gave 10-4 as a yellow oil.
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([Cl:14])=[CH:6][C:5]=1[CH2:15]Br.[CH2:18]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1)[CH3:19].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:14][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([C:10]([F:11])([F:12])[F:13])[CH:8]=1)[C:3](=[O:17])[N:25]([CH2:24][C:23]1[CH:26]=[CH:27][C:20]([CH2:18][CH3:19])=[CH:21][CH:22]=1)[CH2:15]2
Reactant: COC(=O)c1c(CBr)cc(Cl)cc1C(F)(F)F
Reactant: CCc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCc1ccc(CN2Cc3cc(Cl)cc(C(F)(F)F)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 28.3 %

Procedure:
A mixture of 4-chloro-2-bromomethyl-6-trifluoromethyl-benzoic acid methyl ester (0.995 g, 3.0 mmol), 4-ethyl-benzylamine (0.520 mL, 3.6 mmol), and K2CO3 (0.621 g, 4.5 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-chloro-2-(4-ethyl-benzyl)-7-trifluoromethyl-2,3-dihydro-isoindol-1-one (0.30 g, 28%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.24 (t, 3H), 2.63 (q, 2H), 4.27 (s, 2H), 4.76 (s, 2H) 7.20 (m, 4H), 7.59 (s, 1H), 7.78 (s, 1H). GC-MS: m/z 353 (M)+, 338 (M−15)+, 324 (M−29)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([C:19]#[N:20])(C)C>C(OCC)C.[I-].[Zn+2].[I-]>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([OH:14])([CH2:19][NH2:20])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: CCOCC
Product: NCC1(O)CCN(Cc2ccccc2)CC1
Reaction time: 6 h

Procedure:
To neat 1-benzyl-4-piperidone (2.22 mL, 12 mmol) was added trimethylsilyl cyanide (1.95 mL, ˜15 mmol) and zinc iodide (˜5 mg). The solution was stirred for 6 hours or until reaction was completed as indicated by tlc. This oil was dissolved in diethyl ether (30 mL), filtered to remove some solid and added dropwise to a solution of diethyl ether (15 mL) containing 1M lithium aluminium hydride/diethyl ether (30 mL). After stirring at ambient temp. for 2 hours, the reaction was carefully quenched with aqueous sat'd sodium sulfate. This suspension was diluted with more diethyl ether, filtered to remove solids, and the solvent evaporated under partial vacuum to give the crude title compound as an oil.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.[CH3:14][C:15]([Si:18]([CH3:68])([CH3:67])[O:19][C:20]([C:23]#[C:24][CH:25](OC(=S)NC1C=CC=CC=1)[C@H:26]([C:28]1[C@:45]2([CH3:46])[C@H:31]([C:32]3[C@H:42]([CH2:43][CH2:44]2)[C@:40]2([CH3:41])[C:35]([CH2:36][C@@H:37]([O:47][Si:48]([CH3:56])([CH3:55])[C:49]([CH3:54])([CH3:53])[CH:50]([CH3:52])[CH3:51])[CH2:38][CH2:39]2)=[CH:34][CH:33]=3)[CH2:30][CH:29]=1)[CH3:27])([CH3:22])[CH3:21])([CH3:17])[CH3:16]>CCCCCC.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:14][C:15]([Si:18]([CH3:67])([CH3:68])[O:19][C:20]([C:23]#[C:24][CH2:25][C@H:26]([C:28]1[C@:45]2([CH3:46])[C@H:31]([C:32]3[C@H:42]([CH2:43][CH2:44]2)[C@:40]2([CH3:41])[C:35]([CH2:36][C@@H:37]([O:47][Si:48]([CH3:55])([CH3:56])[C:49]([CH3:54])([CH3:53])[CH:50]([CH3:51])[CH3:52])[CH2:38][CH2:39]2)=[CH:34][CH:33]=3)[CH2:30][CH:29]=1)[CH3:27])([CH3:21])[CH3:22])([CH3:17])[CH3:16]
Reactant: CC(C)C(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(=CC=C3[C@@H]2CC[C@]2(C)C([C@H](C)C(C#CC(C)(C)O[Si](C)(C)C(C)(C)C)OC(=S)Nc4ccccc4)=CC[C@@H]32)C1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCCCCC
Product: CC(C)C(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(=CC=C3[C@@H]2CC[C@]2(C)C([C@H](C)CC#CC(C)(C)O[Si](C)(C)C(C)(C)C)=CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 133.6 %

Procedure:
To a mixture of 70.5 mL (262 mmol) tributyltin hydride and 1.08 g (6.55 mmol) 2,2'-azobis(2-methylpropionitrile) (AIBN) in 50 mL of hexane at 80° C. was added a solution of 117 g (131 mmol) crude phenyl-carbamothioic acid O-[(3β)-25-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-3-[[dimethyl(1,1,2-trimethylpropyl)silyl]oxy]cholesta-5,7,16-trien-23-yn-22-yl] ester in 1.5 L of hexane over 45 min. After refluxing for 1 hr, additional tributyltin hydride (35 mL, 131 mmol) and AIBN (1.07 g, 6.52 mmol) were added. After 30 min. of refluxing, the mixture was cooled to room temperature and stirred for 1 hr. The precipitate was filtered, and the filtrate was concentrated. The residue was dissolved in 200 mL of hexane and purified by filtration through 425 g of silica gel. The column was eluted with hexane and then with 20% toluene in hexane. The fractions containing the product were combined and concentrated to give 114 g (overweight) of crude [[(3β)-25-[[(1,1-dimethylethyl)dimethylsilyl]oxy]cholesta-5,7,16-trien-23-yn-3-yl]oxy]dimethyl(1,1,2-trimethylpropyl)silane as a light yellow oil. This crude material was used in the next step. An analytical sample was obtained by chromatographic purification followed by crystallization from ethyl acetate/methanol (1:1): mp 62°-66° C.; Anal Calcd. for C41H70O2Si2 : C, 75.62, H, 10.84; Si, 8.63. Found C, 75.12; H, 10.77; Si, 8.55.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([N:16]=[C:17]=S)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:22]=[C:23]([NH2:37])[C:24]([NH2:36])=[CH:25][C:26]=1[N:27]1[CH2:31][CH2:30][CH2:29][CH:28]1[CH2:32][N:33]([CH3:35])[CH3:34]>CN(C=O)C>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17]2[NH:36][C:24]3[CH:25]=[C:26]([N:27]4[CH2:31][CH2:30][CH2:29][CH:28]4[CH2:32][N:33]([CH3:35])[CH3:34])[C:21]([Cl:20])=[CH:22][C:23]=3[N:37]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(N=C=S)c1
Reactant: CN(C)CC1CCCN1c1cc(N)c(N)cc1Cl
Solvent: CN(C)C=O
Product: CN(C)CC1CCCN1c1cc2[nH]c(Nc3cc(CNC(=O)OC(C)(C)C)ccc3Cl)nc2cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(4-Chloro-3-isothiocyanato-benzyl)-carbamic acid tert-butyl ester (68 mg, 0.2 mmol) followed by TEA (160 μL, 1.2 mmol) were added to 4-chloro-5-(2-dimethylaminomethyl-pyrrolidin-1-yl)-benzene-1,2-diamine (95 mg) in DMF (3 mL). The mixture was stirred at rt for 4 h and then purified by chromatography to give the sub-title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([S:17]Cl)[CH:14]=[CH:15][CH:16]=1>>[Cl:10][C:11]1[CH:12]=[C:13]([S:17][C:5]2[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: ClSc1cccc(Cl)c1
Reactant: COC(=O)c1cc[nH]c1
Product: COC(=O)c1c[nH]c(Sc2cccc(Cl)c2)c1

Procedure:
By the procedure of Example 14, methyl pyrrole-3-carboxylate (2.5 g., 20 mmoles) was reacted with m-chlorobenzenesulfenyl chloride to yield crude product as an oil (5.0 g.). The crude was chromatographed on 250 g. of silica gel, with 100 ml. fractions of the methylene chloride eluant collected. Fractions 17 to 30 were combined and evaporated to yield purified methyl 5-(3-chlorophenylthio)pyrrole-3-carboxylate (1.8 g., m.p. 90°-95° C., m/e 267) which crystallized on standing.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:13])[C:8]=2[NH2:12])[CH:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:25][C@@H:24]([CH3:26])[CH2:23][C@H:22]1[C:27](O)=[O:28])=[O:20])([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:14]([O:18][C:19]([N:21]1[CH2:25][C@@H:24]([CH3:26])[CH2:23][C@H:22]1[C:27](=[O:28])[NH:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:13])=[O:20])([CH3:16])([CH3:17])[CH3:15]
Reactant: C[C@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Nc1ccc2cc(Br)ccc2c1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1C[C@@H](C(=O)Nc2c(N)ccc3cc(Br)ccc23)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of 6-bromo-naphthalene-1,2-diamine (2.0 g, 8.5 mmol) in DMF (150 mL) was added (2S,4S)-4-methyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2.14 g, 10.2 mmol), DIPEA (3.29 g, 25.5 mmol), and HATU (4.84 g, 12.7 mmol). The reaction mixture was stirred at RT overnight and extracted with EtOAc/H2O (150 mL). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by silica gel chromatography (2:1 EtOAc:petroleum ether) to provide the title intermediate (1.6 g)