Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=[CH:3][C:2]1=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C@@H:31]4[CH2:35][CH2:34][CH2:33][NH:32]4)=[CH:25][CH:24]=3)[C:19](=[O:36])[CH:18]=2)=[N:13][CH:14]=1>>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C@@H:31]4[CH2:35][CH2:34][CH2:33][N:32]4[CH2:2][CH3:3])=[CH:25][CH:24]=3)[C:19](=[O:36])[CH:18]=2)=[N:13][CH:14]=1
Reactant: O=c1cccc[nH]1
Reactant: O=c1cc(OCc2ccc(Cl)cn2)ccn1-c1ccc(OC[C@@H]2CCCN2)cc1
Product: CCN1CCC[C@H]1COc1ccc(-n2ccc(OCc3ccc(Cl)cn3)cc2=O)cc1

Procedure:
Example 123 was repeated except that 4-[(5-chloro-2-pyridinyl)methoxy]-1-4-{(3R)-3-pyrrolidinyl]oxy}phenyl)-2H-pyridin-2-one was replaced with 4-[(5-chloro-2-pyridinyl)methoxy]-1-(4-{[(2S)-2-pyrrolidinyl]methoxy}phenyl)-1H-pyridin-2-one, to provide the title compound.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([N:7]([C@@H:9]([CH3:42])[C:10]([NH:12][C:13]1[CH:14]=[C:15]([NH:19][C:20]([C:22]2[C:23]([NH:38][CH2:39][CH2:40][CH3:41])=[N:24][C:25]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([C:35](=[O:37])[NH2:36])=[CH:31][CH:30]=3)=[N:26][CH:27]=2)=[O:21])[CH:16]=[CH:17][CH:18]=1)=[O:11])[CH3:8])=[O:6].[NH:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>CN(C)C=O>[C:35]([C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:25]2[N:24]=[C:23]([NH:38][CH2:39][CH2:40][CH3:41])[C:22]([C:20]([NH:19][C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([NH:12][C:10](=[O:11])[C@@H:9]([N:7]([CH3:8])[C:5](=[O:6])/[CH:4]=[CH:3]/[CH2:2][N:43]4[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]4)[CH3:42])[CH:14]=3)=[O:21])=[CH:27][N:26]=2)=[CH:30][CH:31]=1)(=[O:37])[NH2:36]
Reactant: C1CNCCN1
Reactant: CCCNc1nc(Nc2ccc(C(N)=O)cc2)ncc1C(=O)Nc1cccc(NC(=O)[C@H](C)N(C)C(=O)/C=C/CBr)c1
Solvent: CN(C)C=O
Product: CCCNc1nc(Nc2ccc(C(N)=O)cc2)ncc1C(=O)Nc1cccc(NC(=O)[C@H](C)N(C)C(=O)/C=C/CN2CCNCC2)c1
Reaction time: 0.67 h
Yield: 56.5 %

Procedure:
To a solution of (S,E)-N-(3-(2-(4-bromo-N-methyl-2-butenamido)propanamido)phenyl)-2-((4-carbamoylphenyl)amino)-4-(propylamino)pyrimidine-5-carboxamide (3-7, 100 mg) in N,N-dimethylformamide (2 mL), piperazine (135 mg) was added at room temperature, and the mixture was stirred at the same temperature for 1 hour and 40 minutes. The solvent was evaporated under reduced pressure, and the obtained residue was purified by basic silica gel column chromatography (eluent, 85% ethyl acetate/15% methanol) to obtain (S,E)-2-((4-carbamoylphenyl)amino)-N-(3-(2-(N-methyl-4-(piperazin-1-yl)-2-butenamido)propanamido)phenyl)-4-(propylamino)pyrimidine-5-carboxamide (4-1, 57 mg) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:34]=[CH:33][C:23]([C:24]([NH:26][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:25])=[C:22]([F:35])[CH:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1)=O.Cl.[NH2:37][OH:38].C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:20]1[CH:34]=[CH:33][C:23]([C:24]([NH:26][CH:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:25])=[C:22]([F:35])[CH:21]=1)[CH2:9]/[C:10](=[N:37]\[OH:38])/[C:12]1[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=1
Reactant: NO
Reactant: Cn1cc(C(=O)CC(c2ccc(C(=O)NC3CCOCC3)c(F)c2)c2ccccc2Cl)ccc1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1cc(/C(CC(c2ccc(C(=O)NC3CCOCC3)c(F)c2)c2ccccc2Cl)=N/O)ccc1=O

Procedure:
In analogy to example 151, step 3, 4-(1-(2-chlorophenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-2-fluoro-N-(tetrahydro-2H-pyran-4-yl)benzamide was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing 4% of the corresponding Z isomer as a colorless foam, MS (ESI+): m/z=512.3 [M+H]+.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[Br:6][C:7]1[CH:8]=[N:9][C:10](Cl)=[N:11][CH:12]=1.[H-].[Na+]>O1CCOCC1>[Br:6][C:7]1[CH:8]=[N:9][C:10]([O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[N:11][CH:12]=1
Reactant: Clc1ncc(Br)cn1
Reactant: OC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Brc1cnc(OC2CCC2)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.42 mL (31.0 mmol) cyclobutanol and 3.00 g (15.5 mmol) 5-bromo-2-chloropyrimidine are added to 40 mL 1,4-dioxane and cooled down to 0° C. Then the reaction mixture is charged with 1.86 g (46.5 mmol) NaH. After removing of the cooling bath the reaction mixture is stirred at r.t. for 1 h. The reaction is quenched by the addition of water and sat. aq. NaHCO3 solution. The 1,4-dioxane is removed in vacuo and the aq. residue is extracted with DCM. The org. phases are combined, washed with water and dried with MgSO4. The solvent is removed under reduced pressure. The crude product is used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=1.[H-].[Na+]>CN(C=O)C>[Cl:27][C:25]1[CH:26]=[C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][N:9]2[CH2:10][CH2:11][N:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[C:8]2=[O:12])[CH:22]=[N:23][CH:24]=1
Reactant: O=C1NCCN1c1ccncc1
Reactant: Clc1cncc(OCCCCCCBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(CCCCCCOc2cncc(Cl)c2)CCN1c1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4-pyridyl)-2-imidazolidinone (100 mg, 0.61 mmol) and 3-[(6-bromohexyl)oxy]-5-chloropyridine (269 mg, 0.92 mmol) in DMF (5 mL) was added sodium hydride (39 mg, 1.23 mmol, 75% in mineral oil) in an ice bath. The mixture was stirred at room temperature overnight. After removing the solvent under reduced pressure, the crude residue was purified by column chromatography eluted with 15% methanol in ethyl acetate to afford the product (i.e., Compound 11) as a light yellow solid (0.17 g, 75%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[C:19]([CH3:20])=[CH:18][C:17]([N+:21]([O-:23])=[O:22])=[C:16]3[C:12]=2[CH2:13][CH2:14][CH2:15]3)=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>CN(C)C=O>[CH2:30]([O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[C:19]([CH3:20])=[CH:18][C:17]([N+:21]([O-:23])=[O:22])=[C:16]3[C:12]=2[CH2:13][CH2:14][CH2:15]3)=[CH:6][C:3]=1[CH:4]=[O:5])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(O)c(C=O)c1)CCC2
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(OCc3ccccc3)c(C=O)c1)CCC2

Procedure:
A suspension of 2-hydroxy-5-(5-methyl-7-nitroindan-4-yloxy)benzaldehyde (3.20 g) and potassium carbonate (1.55 g) in N,N-dimethylformamide (25 mL) was stirred under ice-cooling. After adding dropwise benzyl bromide (1.34 mL), the mixture was stirred at room temperature for 24 hours. The reaction mixture was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate) to give the title compound (3.30 g).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: C1CCNC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Clc1cccc(CN2CCCC2)c1Cl
Reaction time: 8 h
Yield: 80045 %

Procedure:
NaHB(OAc)3 (15.1 g, 0.0714 mmol) was added under vigorous stirring in portions to a solution of 2,3-dichlorobenzaldehyde (10 g, 0.057 mmol) and pyrrolidine (5.97 mL, 0.0714 mmol) in CH2Cl2 (200 mL). The reaction mixture was vigorously stirred overnight. Then 5N NaOH (50 mL) was added, and the layers were separated. The product was extracted from the aqueous layer with CH2Cl2 (2×50 mL). The combined extracts were washed with 5N NaOH (50 mL), water, brine, dried with anhydrous Na2SO4, and evaporated. The residue was distilled in vacuum to give title compound (10.5 g, 90%) as a colorless liquid (bp 80-84° C./0.5 mmHg). LC/MS data: 229.9, 230.9, 231.9 (M+H) (calculated for C11H13Cl2N 230.14). 1H NMR data (DMSO-d6): δ 7.52 (dd, 1H, J1=1.5 Hz, J2=7.8 Hz), 7.46 (dd, 1H, J1=1.5 Hz, J2=7.8 Hz), 7.33 (t, 1H, J=7.8 Hz), 3.70 (s, 2H), 2.46-2.52 (m, 4H), 1.66-1.75 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:8])[S:5][CH:6]=1.[Cl:18][S:19](O)(=[O:21])=[O:20]>>[Br:1][C:2]1[CH:3]=[C:4]([C:7](=[O:8])[NH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[S:5][C:6]=1[S:19]([Cl:18])(=[O:21])=[O:20]
Reactant: O=C(NCCN1CCOCC1)c1cc(Br)cs1
Reactant: O=S(=O)(O)Cl
Product: O=C(NCCN1CCOCC1)c1cc(Br)c(S(=O)(=O)Cl)s1
Temperature: 95 °C

Procedure:
To a flask containing 4-bromo-N-[2-(morpholin-4-yl)ethyl]thiophene-2-carboxamide (1.6 g, 5.1 mmol) was added chlorosulfonic acid (10 ml, 30 equiv). The reaction was heated to 95° C. for 90 minutes before careful addition to ice. The resulting solid was filtered and dried in vacuo. The crude material was trituated with heptane:ethyl acetate to afford the title compound without need for further purification (0.62 g, 29%). δH (500 MHz, DMSO-d6) 9.01 (1H, t, 5.5 Hz), 7.76 (1H, s), 3.97 (2H, d, 10.4 Hz), 3.78 (2H, t, 11.5 Hz), 3.63 (2H, q, 6.0 Hz), 3.51 (2H, d, 12.3 Hz), 3.29 (2H, q, 5.7 Hz), 3.03-3.17 (2H, m), TR=1.22 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH:9]=2)[CH:4]=1.C1C(=O)N([Cl:28])C(=O)C1>C(#N)C>[Cl:28][C:4]1[C:5]2[C:10](=[CH:9][C:8]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2)cc1
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(Cl)c(OC)ccc3c2)cc1
Temperature: 25 °C
Yield: 71.1 %

Procedure:
A suspension of 2-methoxy-6-(4-methoxyphenyl)naphthalene (0.51 g, 1.93 mmol) and NCS (0.28 g, 2.13 mmol) in acetonitrile (20 mL) was heated to reflux for 3 hr. The resulting solution was cooled to room temperature and the resulting solid was collected by filtration and rinsed with acetonitrile to yield 0.41 g (72%) of the title compound as a white solid: mp 158–164° C.; 1H NMR (CDCl3): δ 3.87 (3H, s), 4.05 (3H, s), 7.03 (2H, d, J=8.62 Hz), 7.32 (1H, d, J=9.02 Hz); 7.65 (2H, d, J=8.55 Hz), 7.82 (2H, d, J=9.01 Hz), 7.95 (1H, d, J=1.36 Hz), 8.27 (1H, d, J=8.81 Hz); MS (El) m/z 298 (M)+.
Reaction SMILES: [CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH3:16][C:17]1[CH:25]=[CH:24][C:20]([CH:21]2[O:23][CH2:22]2)=[CH:19][CH:18]=1.[H-].[Na+].C(O)(C(F)(F)F)=O>CN(C=O)C>[CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[N:7]([CH2:22][CH:21]([C:20]3[CH:24]=[CH:25][C:17]([CH3:16])=[CH:18][CH:19]=3)[OH:23])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: CCN1CCc2[nH]c3ccccc3c2C1
Reactant: Cc1ccc(C2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCc2c(c3ccccc3n2CC(O)c2ccc(C)cc2)C1
Yield: 17.9 %

Procedure:
2-Ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (400 mg, 2.0 mmol), 4-methylstyrene oxide (2.01 g, 15 mmol) and NaH (240 mg, 6 mmol) were heated in DMF (6 mL) at 120° C. for 16 h to obtain 120 mg of racemic-2-(2-ethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-1-p-tolylethanol as a TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL). 1H NMR (CDCl3, TFA salt) δ (ppm): 13.40-13.10 (bs, 1H), 7.40-7.30 (t, 2H), 7.29-7.10 (m, 6H), 5.07-4.95 (m, 1H), 4.75-4.60 (t, 1H), 4.25-4.02 (m, 3H), 3.75-3.65 (m, 1H), 3.40-3.0 (m, 5H), 2.35 (S, 3H), 1.47-1.40 (t, 3H).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C@H:10]([C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[S:20]([CH3:23])(=[O:22])=[O:21])[C:9]2[C:8](=[O:24])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.[H-].[Na+].O1CCCC1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>O>[CH3:23][S:20]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:12]=1[C@@H:10]1[C:9]2[C:8](=[O:24])[CH2:7][CH2:6][CH2:5][C:4]=2[N:3]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=2)[C:2](=[O:1])[N:11]1[S:43]([CH3:42])(=[O:45])=[O:44])[C:16]#[N:17])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1cc(C#N)ccc1[C@H]1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1cc(C#N)ccc1[C@@H]1C2=C(CCCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
(S)-4-(2,5-Dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-3-(methylsulfonyl)benzonitrile (example 18A, 50 mg, 0.10 mmol) is added to a suspension of sodium hydride (60% in mineral oil, 11 mg, 0.29 mmol) and tetrahydrofuran (3 mL), and the mixture is stirred at room temperature for 10 min. Methanesulfonyl chloride (16 μL, 0.22 mol) is added, and the mixture is heated at 50° C. for 2 h. The mixture is cooled at room temperature, diluted with water (0.5 mL) and purified by preparative HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 37 mg; ESI mass spectrum [M+H]+=568; Retention time HPLC: 0.81 min (005_CA01).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.C(NC(C)C)(C)C.[Li].C1(C)C=CC(S([Cl:31])(=O)=O)=CC=1>C1COCC1>[Cl:31][CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]1=[O:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc2c(c1)C(=O)C(Cl)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 7-Methoxy-3,4-dihydro-2H-naphthalen-1-one (25.6 g, 145.28 mmol) in THF (300 ml) is slowly added under an atmosphere of argon at −78° C. to a solution of lithium diisopropyl amine in THF (300 ml; prepared from 22.6 ml of diisopropylamine (160 mmol) and 100 ml of 1.6 M n-BuLi in hexane (160 mmol)). After 30 minutes at −78° C., a solution of para-tolylsulfonyl chloride (30.5 g, 159.8 mmol) in THF (300 ml) is added during 20 minutes. The dry ice cooling bath is removed, and the reaction mixture is allowed to reach RT. After 1 h, TLC analysis indicates complete consumption of starting material. A sat. aqueous solution of NH4Cl (100 ml) is added, and the mixture is stirred at RT for 15 minutes. The organic layer is separated, washed with brine, dried over Na2SO4 and concentrated. Purification by FCC (hexane/EtOAc 3:1) yields the title compound. 1H NMR (CDCl3, 400 MHz): δ 2.32-2.52 (m, 2H), 2.82-2.90 (m, 2H), 3.10-3.18 (m, 2H), 3.78 (s, 1H), 4.52-4.58 (m, 1H), 7.01-7.05 (m, 1H), 7.11 (d, J=8.8 Hz, 1H), 7.47-7.48 (m, 1H). ES+-MS: 211.3, 213.3 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH3:31][O:32][C:33]1[CH:46]=[CH:45][C:36]([CH:37]([NH2:44])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:35][CH:34]=1>>[CH3:31][O:32][C:33]1[CH:46]=[CH:45][C:36]([CH:37]([NH:44][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:30])[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc(C(N)c2ccccc2)cc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Product: COc1ccc(C(NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C#N)CC[C@]5(C)[C@H]4CC[C@]23C)c2ccccc2)cc1
Yield: 82 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 4-methoxybenzhydrylamine (prepared as described in Preparation 15) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 82%.
Reaction SMILES: CCN(CC)CC.Cl.[CH3:9][C:10]1[S:11][C:12]([NH2:15])=[CH:13][N:14]=1.[CH3:16][C:17](OC(C)=O)=[O:18]>C(Cl)Cl>[CH3:9][C:10]1[S:11][C:12]([NH:15][C:17](=[O:18])[CH3:16])=[CH:13][N:14]=1
Reactant: Cc1ncc(N)s1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cnc(C)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
To a solution of Et3N (1.4 ml, 10 mmol) and 2-methylthiazol-5-amine hydrochloride (1 g, 6.6 mmol) in DCM (30 mL) was added Ac2O (0.94 mL, 10 mmol). The mixture was stirred at room temperature for 3 h. The reaction solution was concentrated, deposited onto silica gel and loaded onto a silica gel column and eluted with EA to give the title compound (0.8 g, yield: 77%).
Reaction SMILES: [CH2:1]1[CH2:29][O:28][C:3]([CH2:16][O:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)(/[CH:4]=[CH:5]/[C@H:6]2[C@H:13]([OH:14])[CH2:12][C@H:11]3[C@@H:7]2[CH2:8][C:9](=[O:15])[O:10]3)[O:2]1.[O:30]1[CH:35]=[CH:34][CH2:33][CH2:32][CH2:31]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>O.C(Cl)Cl>[CH2:1]1[CH2:29][O:28][C:3]([CH2:16][O:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=2)(/[CH:4]=[CH:5]/[C@H:6]2[C@H:13]([O:14][CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35][O:30]3)[CH2:12][C@H:11]3[C@@H:7]2[CH2:8][C:9](=[O:15])[O:10]3)[O:2]1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/C3(COc4ccc5ccccc5c4)OCCO3)[C@H](O)C[C@@H]2O1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C1C[C@@H]2[C@@H](/C=C/C3(COc4ccc5ccccc5c4)OCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1

Procedure:
190 mg. of (1S,5R,6R,7R)-6-[(E)-3,3-ethylenedioxy-4-(2-naphthyloxy)-1-butenyl]-7-hydroxy-2-oxabicyclo[3,3,0]octan-3-one (prepared according to Example 5[a]), 0.2 ml. of freshly distilled dihydropyran, and 1.4 mg. of p-toluenesulfonic acid in 5 ml. of absolute methylene chloride were stirred for 30 minutes at ice bath temperature under argon. After dilution with methylene chloride, the mixture was shaken successively with sodium bicarbonate solution and water, dried over magnesium sulfate, and evaporated under vacuum. The residue was recrystallized from diisopropyl ether/methylene chloride, thus obtaining 204 mg. of the title compound as colorless crystals, m.p. 113°. IR: 1770, 1630, 1600, 975 cm-1.
Reaction SMILES: Cl.[CH2:2]=[C:3]([CH2:7][CH2:8][CH2:9][NH2:10])[C:4]([OH:6])=[O:5].[O-2].[Mg+2].[CH3:13][O:14][C:15]1[CH:27]=[CH:26][C:18]([CH2:19][O:20][C:21](N=[N+]=[N-])=[O:22])=[CH:17][CH:16]=1>O.O1CCOCC1>[CH2:2]=[C:3]([CH2:7][CH2:8][CH2:9][NH:10][C:21]([O:20][CH2:19][C:18]1[CH:26]=[CH:27][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)=[O:22])[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(COC(=O)N=[N+]=[N-])cc1
Reactant: C=C(CCCN)C(=O)O
Agent: Cl
Agent: [Mg+2]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: O
Product: C=C(CCCNC(=O)OCc1ccc(OC)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 116.8 %

Procedure:
To a solution of 8.8 g of 2-methylene-5-aminopentanoic acid hydrochloride in 100 ml of water is added with stirring 6.36 g of magnesium oxide, followed by a solution of 12.2 g of p-methoxybenzyloxycarbonyl azide in 100 ml of dioxane, and the resulting mixture is stirred at room temperature for two days. The reaction mixture is filtered, and the filtrate diluted with 200 ml of ethyl acetate, two equivalents of Dowex 50 ion exchange resin is added, and the mixture is stirred at room temperature for two hours. The resin is then filtered off and washed with water. The layers in the filtrate are separated and the aqueous layer is extracted twice with ethyl acetate. The combined organic layers are dried and concentrated in vacuo to give 18.2 g of 2-methylene-5-(p-methoxybenzyloxycarbonyl)aminopentanoic acid as an amber oil which crystallizes on standing. This is used without further purification.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][C@@H:5]([C:11]([CH3:13])=[CH2:12])[C@@H:4]1[CH2:14][OH:15].[H-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C@H:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH2:6][C@@H:5]([C:11]([CH3:13])=[CH2:12])[C@H:4]1[CH2:14][O:15][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=C(C)[C@@H]1CCC(C)(C)[C@H](OC)[C@H]1CO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C(C)[C@@H]1CCC(C)(C)[C@H](OC)[C@@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 83 %

Procedure:
A mixture of the above alcohol (621 g) and sodium hydride (141 mg, 60% dispersion in oil) and benzyl bromide (0.41 ml) in dry N,N-dimethylformamide (2.5 ml) was stirred for 10 hrs at room temperature. After the mixture was cooled to 0° C., the reaction was quenched by addition of water. The pH of the mixture was adjusted to pH 7 with 0.1N hydrochloric acid. The mixture was extracted with diethyl ether, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification of the residue by flash column chromatography (using n-hexane:ethyl acetate=20:1 as an eluent) gave benzyl [(1S,2R,6R)-2-methoxy-3,3-dimethyl-6-(1-methylvinyl)cyclohexyl]methyl ether (726 mg, 83% yield).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.O>CN(C)C=O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc(CCl)cc1
Reactant: CC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCC(OCc2ccc(F)cc2)CC1
Reaction time: 3 h
Yield: 57.4 %

Procedure:
1-Acetylpiperidin-4-ol (Preparation 193, 10 g, 70 mmol) in N,N-dimethylformamide (50 ml) was added dropwise to a stirred suspension of sodium hydride (50% wt dispersion in oil, 3.8 g, 80 mmol) in N,N-dimethylformamide (50 ml) at room temperature under nitrogen. After stirring the reaction mixture for 3 hours, 4-fluorobenzyl chloride (10.1 g, 70 mmol) in N,N-dimethylformamide (50 ml) was added dropwise and the reaction mixture was stirred for a further 4 h. The reaction mixture was filtered and the filtrate was evaporated to give an orange oil. Water was added and the mixture was extracted with petroleum ether (3×100 ml) and then with diethyl ether (3×100 ml). The combined organic extracts were washed with sodium hydroxide solution (1 M, 3×100 ml), before drying (Na2SO4) and concentrating to give the title compound as an oil (10.1 g, 99%).
Reaction SMILES: [CH2:1]1[O:8][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:9]([NH2:18])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17]>CO>[CH2:9]([NH:18][CH2:1][CH:2]([OH:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:1][CH:2]([OH:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCC1CO1
Reactant: NCCCCCCCCN
Solvent: CO
Product: CCCCCC(O)CNCCCCCCCCNCC(O)CCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-heptene oxide (52 g.) and 1,8-octanediamine (32.8 g.) and two recrystallizations of the resulting product from methanol gave N,N'-(1,8-octylene)-bis[2-hydroxyheptylamine] (I: R = CH3 (CH2)4, R' = H, X = (CH2)8, Z = H) (17.2 g., m.p. 128.0°-132.8° C.).