Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.[N:8]1([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:38]=[C:26]4[CH:27]=[CH:28][CH:29]=[C:30]([C:31]5[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=5)[N:25]4[N:24]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:8]1([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]3[N:38]=[C:26]4[CH:27]=[CH:28][CH:29]=[C:30]([C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH2:1][CH:2]6[CH2:3][CH2:4][CH2:5][O:6]6)[CH:32]=5)[N:25]4[N:24]=3)=[CH:18][CH:17]=2)[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: BrCC1CCCO1
Reactant: Oc1cccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1cc(OCC2CCCO2)cc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)c1
Temperature: 80 °C

Procedure:
Tetrahydrofurfuryl bromide (20 mg, 0.18 mmol) was added to a stirred solution of 3-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-5-yl}-phenol (50 mg, 0.12 mmol) and potassium carbonate (25 mg, 0.18 mmol) in dimethylformamide (1.5 ml). The mixture was heated overnight at 80° C. then cooled and transferred to a vial for purification by preparatory HPLC. RT: 2.70 min, MI: 500.22, Method: 2.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH3:27][C:28]([CH3:32])([CH3:31])[C:29]#[CH:30]>>[CH3:27][C:28]([CH3:32])([CH3:31])[C:29]#[C:30][C:3]1[C:4]2[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:13])[F:14])[CH2:7][CH2:6][C:5]=2[CH:17]=[CH:18][C:2]=1[F:1]
Reactant: O=C(N1CCc2ccc(F)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: C#CC(C)(C)C
Product: CC(C)(C)C#Cc1c(F)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Yield: 85.4 %

Procedure:
Use a method similar to the General Procedure 3 to couple 7-fluoro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1 g, 2.4 mmol) with 3,3-dimethyl-1-butyne (0.599 mL, 4.9 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1) to give 6-(3,3-dimethyl-but-1-ynyl)-7-fluoro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (700 mg, 84%).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[NH2:10][C:11]1[N:16]=[N:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1>>[CH2:4]([C:3]1[N:10]=[C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:18][CH2:19][N:20]([C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])=[O:24])[CH2:21][CH2:22]3)=[N:15][N:16]2[CH:2]=1)[CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC(=O)CBr
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: CCCCCc1cn2nc(N3CCN(C(=O)c4ccccc4C(F)(F)F)CC3)ccc2n1
Yield: 62 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to 1-bromoheptan-2-one in place of 1-bromobutan-2-one to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)methanone, the title compound was obtained as a white solid in 62% yield. 1H NMR (300 MHz, CDCl3) δ 7.71-7.69 (m, 1H), 7.64-7.49 (m, 3H), 7.42 (s, 1H), 7.34-7.32 (m, 1H), 6.7 (d, J=9.9 Hz, 1H), 4.01-3.83 (m, 2H), 3.57-3.48 (m, 2H), 3.37-3.27 (m, 4H), 2.73-2.68 (m, 2H), 1.75-1.65 (m, 2H), 1.4-1.25 (m, 4H), 0.91 (t, J=6.9 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 167.5, 154.3, 146.8, 135.7, 134.4, 132.3, 129.4, 127.1, 126.8, 126.7, 126.6, 125.4, 125.3, 121.8, 113.6, 109.3, 46.5, 46.4, 46.2, 41.1, 31.5, 29.1, 29.07, 22.5, 14.0. MS (ES+) m/z 446.2 (M+1).
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1C=CC=CC=1.[NH2+]1CCCCC1.O.[CH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[O:9]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:2][C:1]1=[O:8]
Reactant: c1ccccc1
Reactant: O=C([O-])c1ccccc1
Agent: C1CC[NH2+]CC1
Solvent: O
Product: O=C1Cc2ccccc2O1

Procedure:
A mixture of 9.1 g (0.05 mole) of 4-methyl-3-(3-oxobutyl)-maleic acid anhydride and 11 g (0.053 mole) of piperidinium benzoate in 200 ml of benzene is heated under reflux for 48 hours using a water separator. The benzene is removed in vacuo and the residue that remains is partitioned between methylene chloride and saturated sodium bicarbonate solution. The crude product remaining after drying and after removal of the methylene chloride is chromatographed over silica gel with petroleum ether/ether. Subsequent recrystallisation from ether/petroleum ether yields 3-methyl-6-(piperidin)-1-yl)-benzofuran-2(3H)-one having a melting point of 78°-80° C.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([O:18][CH3:19])[CH:7]=[C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:9]=1[C:10]#[N:11])=[N+]=[N-].[Mg]>CO>[NH2:1][C:4]1[CH:5]=[C:6]([O:18][CH3:19])[CH:7]=[C:8]([O:12][CH2:13][C:14]([F:16])([F:17])[F:15])[C:9]=1[C:10]#[N:11]
Reactant: COc1cc(N=[N+]=[N-])c(C#N)c(OCC(F)(F)F)c1
Agent: [Mg]
Solvent: CO
Product: COc1cc(N)c(C#N)c(OCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 88.1 %

Procedure:
3-Azido-4-cyano-5-(2,2,2-trifluoroethoxy)anisole (5.66 g, 0.0208 mol) was added to a suspension of magnesium turnings (1.86 g, 0.0775 mol) in methanol (150 ml) and the reaction stirred at room temperature for 40 hours. The reaction was concentrated under reduced pressure to a minimum volume and ethyl acetate (200 ml) added. The mixture was washed with saturated aqueous ammonium chloride solution (75 ml) and brine (75 ml) and then dried (MgSO4), filtered and evaporated under reduced pressure. Trituration with diethyl ether:hexane gave the subtitle compound as a brown solid (4.51 g, 88%). Rf 0.46 (ethyl acetate:hexane, 1:1, v/v). MS m/z 247 (MH)+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[N+:16]([O-])=O>[C].[Pd].C1COCC1>[O:2]=[C:3]1[CH2:4][CH2:5][C:6]2[C:7](=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=2)[NH:16]1
Reactant: COC(=O)CCc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 96 h
Yield: 76 %

Procedure:
The mixture of methyl 4-(3-methoxy-3-oxopropyl)-3-nitrobenzoate (12 g), THF (180 ml), and palladium-carbon (1.2 g) was stirred at room temperature for 4 days under a hydrogen atmosphere. The insolubles of the reaction mixture were separated by filtration through Celite and the filtrate was concentrated under reduced pressure. To the residue were added methanol (100 ml) and p-toluenesulfonic acid monohydrate (0.10 g), followed by heating under reflux for 1 hour, and then allowing to be cooled at room temperature. The reaction mixture was concentrated under reduced pressure. To the residue was added chloroform, followed by washing with a saturated sodium bicarbonate solution and drying over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure. The residue was washed with methanol to obtain methyl 2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate (7.0 g).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([C:27]1[N:28]=[C:29](N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)[CH3:24].Cl.ClCC1C=NC=CC=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:29]=[N:28][CH:27]=[CH:23][CH:24]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: Cl
Agent: ClCc1cccnc1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3cccnc3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(chloromethyl)pyridine hydrochloride and isolated as light-yellow gum (2.5 mg, 16%). MS (m/e): 374.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][NH2:17])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[O:18]1[CH2:23][CH2:22][CH:21]([C:24](O)=[O:25])[CH2:20][CH2:19]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>O.CN(C)C=O>[Cl:1][C:2]1[C:3]([NH:16][NH:17][C:24]([CH:21]2[CH2:22][CH2:23][O:18][CH2:19][CH2:20]2)=[O:25])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: O=C(O)C1CCOCC1
Reactant: COC(=O)c1ccc2nc(NN)c(Cl)nc2c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2nc(NNC(=O)C3CCOCC3)c(Cl)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a mixture of 100 mg of methyl 3-chloro-2-hydrazinoquinoxaline-6-carboxylate, 57 mg of tetrahydro-2H-pyran-4-carboxylic acid, 0.16 mL of diisopropylethylamine, and 1.0 mL of N,N-dimethylformamide was added 203 mg of bromo(tripyrrolidin-1-yl)phosphonium hexafluorophosphate, followed by stirring at room temperature overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 144 mg of methyl 3-chloro-2-[2-(tetrahydro-2H-pyran-4-ylcarbonyl)hydrazino]quinoxaline-6-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]2)=[C:4]([F:22])[CH:3]=1.[C:23]1(=O)[CH2:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>>[F:22][C:4]1[CH:3]=[C:2]([NH:1][CH:23]2[CH2:26][CH2:25][CH2:24]2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(c2ccc(N)cc2F)C1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Product: CC(C)(C)OC(=O)NC[C@H]1CCN(c2ccc(NC3CCC3)cc2F)C1

Procedure:
tert-Butyl (R)-[1-(4-amino-2-fluorophenyl)pyrrolidin-3-yl]methylcarbamate was alkylated with cyclobutanone using triacetoxyborohydride as reducing agent by method N. This resulted in the product with the molecular weight of 363.48 (C20H30FN3O2); MS (ESI): 364 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[Si:11]([O:18][CH2:19][CH2:20][CH2:21]Br)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][CH2:21][CH2:20][CH2:19][O:18][Si:11]([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:12])[CH3:13])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1Br
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Product: Cc1cc(OCCCO[Si](C)(C)C(C)(C)C)cc(C)c1Br
Yield: 102.3 %

Procedure:
According to the method of (Example 17) <Step 1>, from 4-bromo-3,5-dimethylphenol (4.00 g) and 3-((tert-butyldimethylsilyl)oxy)propyl bromide (5.55 g), the subject compound (7.60 g) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][CH:15]2[CH:10]([NH:11][CH2:12][CH2:13][CH2:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=O.[OH-].[Na+]>C(O)=O>[CH2:1]([N:8]1[CH2:16][CH:15]2[CH:10]([N:11]([CH3:17])[CH2:12][CH2:13][CH2:14]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CC3CCCNC3C2)cc1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN1CCCC2CN(Cc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 4 h
Yield: 45 %

Procedure:
A solution of 6-benzyloctahydro-1H-pyrrolo[3,4-b]pyridine (2.00 g) and 37% HCHO (6.0 mL) in HCO2H was heated to 90° C. and stirred for 4 h. The reaction mixture was cooled to rt and poured into ice-water. The mixture was adjusted to pH 10 with 2M NaOH aqueous solution and extracted with CH2Cl2 (70 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) DCM/MeOH) to give the title compound as pale yellow oil (0.95 g, 45.00%), HPLC: 85.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 231.2 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29]O)=[CH:22][CH:21]=1.C(Br)(Br)(Br)[Br:38]>C(Cl)Cl>[Br:38][CH2:29][CH2:28][CH2:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:21][CH:22]=1
Reactant: OCCCOc1ccc(-c2ccccc2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCOc1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
Triphenylphosphine (1.61 g, 6.14 mmol) was added to a solution of 3-(biphenyl-4-yloxy)-propan-1-ol (Example 291, Step 6) (1.00 g, 4.38 mmol) and carbon tetrabromide (1.81 g, 5.47 mmol) in CH2Cl2 (20 mL) at 0° C. The mixture was warmed to room temperature and stirred for about an hour and then extracted with ethyl acetate (50 mL). The organic layer was washed with H2O (3×50 mL) and brine (3×25 mL), and then dried (MgSO4), filtered and concentrated. The crude product was purified by silica gel column chromatography (silica gel, hexanes/ethyl acetate, 9:1) to produce 4-(3-bromo-propoxy)-biphenyl. 1H-NMR (200.15 MHz, CDCl3): d 7.57–7.29 (m, 7H), 6.98 (dd, 2H, J=6.72, 1.88), 4.45 (t, 2H, J=5.92), 3.62 (t, 2H, J=6.44), 2.34 (qn, 2H, J=5.92).
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.N1C=CC=CC=1.Cl[C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21]>O1CCCC1>[N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH:10][C:20](=[O:21])[O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc(-n2ccnc2)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-n2ccnc2)cc1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a solution of 4-(1H-imidazol-1-yl)aniline (1.00 g, 6.28 mmol) and pyridine (1.52 ml, 18.8 mmol) in tetrahydrofuran (20 ml) was added 2,2,2-trichloroethyl chloroformate (1.30 ml, 9.42 mmol) with ice-cooling, the mixture was stirred for 1 hour with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the desired product (1.83 g, 87.1%) as a solid.
Reaction SMILES: [SH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=O.Br.[NH2:12][CH2:13][CH2:14]Br.C[O-].[Na+]>C1(C)C=CC=CC=1.CO>[S:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7](=[O:9])[NH:12][CH2:13][CH2:14]1
Reactant: COC(=O)c1sccc1S
Reactant: NCCBr
Agent: Br
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C1NCCSc2ccsc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
aca) Method A: 17.4 g of methyl 3-mercapto-thiophene-2-carboxylate were dissolved in 350 ml of toluene under an inert gas atmosphere, whereupon the solution was treated with 20.5 g of 2-aminoethyl bromide hydrobromide and then with 100 ml of 3N sodium methylate solution in methanol. The mixture was stirred at room temperature for 30 minutes and thereafter heated under reflux until the reaction finished. The mixture was evaporated in vacuo, the residue was taken up in 300 ml of water, acidified with 2N hydrochloric acid and the crystals were removed by filtration. By recrystallization from chloroform there was obtained 3,4-dihydro-thieno[2,3-f][1,4]thiazepin-5-(2H)-one as white crystals of m.p. 186°-188°.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([C:14]3[CH:15]=[C:16]([CH:29]=[CH:30][CH:31]=3)[CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH:13]=1)[N:10]=[CH:9][CH:8]=[CH:7]2)([CH3:3])[CH3:2].[H-].[Na+].[CH:34]1([CH2:37]Br)[CH2:36][CH2:35]1>CN(C=O)C>[CH:34]1([CH2:37][N:18]([CH2:17][C:16]2[CH:29]=[CH:30][CH:31]=[C:14]([C:12]3[CH:13]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[C:6]4[C:11]=3[N:10]=[CH:9][CH:8]=[CH:7]4)[CH:15]=2)[C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:36][CH2:35]1
Reactant: BrCC1CC1
Reactant: CC(C)c1cc(-c2cccc(CNc3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1cc(-c2cccc(CN(CC3CC3)c3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1
Reaction time: 0.25 h

Procedure:
To solution of the previous amine from step 2 (1.1 eq) in DMF (0.12M) was added NaH (60% dispersion in oil; 3.0 eq). The mixture was stirred for 15 min, then cyclopropylmethyl bromide was added (1.2 eq). The final mixture was stirred for 12 h, quenched with AcOH, poured in water and extracted with Et2O. The combined organic extracts were washed with water (2×), brine, dried over Na2 SO4, filtered and concentrated. Flash chromatography (Tol:Ace; 9:1) afforded the title compound as a foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:6][CH:7]([CH2:13][CH2:14][CH2:15][CH3:16])[C:8](OCC)=[O:9].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:6][CH:7]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:8][OH:9]
Reactant: CCCCC(Cc1ccc(OC)c(OC)c1)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCC(CO)Cc1ccc(OC)c(OC)c1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
Part D. A solution of the ester prepared in Part C above (4.00 g, 13.6 mmol) in tetrahydrofuran (20 mL) was added dropwise to an ice-cooled solution of lithium aluminum hydride (30 mmol) in tetrahydrofuran (30 mL).The ice bath was removed, and the mixture was warmed to ambient temperaturefor 14 hours. The solution was then recooled to 0° C., and quenched by the slow addition of 1 mL water, 3 mL 15% sodium hydroxide, and 3 mL water. The resulting mixture was filtered through a plug of celite, and the filtrate was dried over anhydrous potassium carbonate, filtered and evaporated. The residue was separated by flash chromatography (1:4 ethyl acetate-hexane) to afford the product, 2-(3,4-dimethoxybenzyl)-1-hexanol, as an oil (3.39 g, 13.4 mmol, 99%). 1H NMR (CDCl3): δ 6.81-6.70 (3H, m); 3.87 (3H, s); 3.86 (3H, s); 3.54 (2 H, t, J=5.1 Hz); 2.59 (2H, d, J=7.0 Hz); 1.80-1.71 (1H, m); 1.39-1.17 (7H, m); 0.89 (3H, t,J=7.0 Hz). Mass spectrum (NH3 -CI/DDIP): m/z 254 (5%); 253 (33%); 235 (100%); 151 (43%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:12][CH3:13])=[C:4]([OH:11])[C:5]([S:9][CH3:10])=[C:6]([CH3:8])[CH:7]=1.[CH3:14][S:15]C1C=C(SC)C=CC=1O>>[CH3:1][C:2]1[C:3]([S:12][CH3:13])=[C:4]([OH:11])[C:5]([S:9][CH3:10])=[C:6]([CH3:8])[C:7]=1[S:15][CH3:14]
Reactant: CSc1c(C)cc(C)c(SC)c1O
Reactant: CSc1ccc(O)c(SC)c1
Product: CSc1c(C)c(SC)c(O)c(SC)c1C

Procedure:
NMR shows fraction 2 to be a mixture of about 90:10 of 3,5-dimethyl-2,6-bis(methylthio)phenol and 2,4-bis(methylthio)phenol.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C@H:4]([CH2:5][CH2:6][C:7]3[C@@H:21]2[CH2:20][C@H:19]([OH:26])[C@@:18]2([CH3:27])[C:8]=3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15][OH:16])[CH2:3]1.C(N(CC)CC)C.[C:35]1([CH3:45])[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>C(Cl)Cl.C(#N)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.CO>[C:35]1([CH3:45])[CH:40]=[CH:39][C:38]([S:41]([O:16][CH2:15][CH2:14][CH2:13][C@H:12]([C@@H:11]2[C@:18]3([CH3:27])[C:8](=[C:7]4[C@H:21]([CH2:20][C@@H:19]3[OH:26])[C@:22]3([CH3:25])[C@@H:4]([CH2:3][C@H:2]([OH:1])[CH2:24][CH2:23]3)[CH2:5][CH2:6]4)[CH2:9][CH2:10]2)[CH3:17])(=[O:43])=[O:42])=[CH:37][CH:36]=1
Reactant: C[C@H](CCCO)[C@H]1CCC2=C3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@@]21C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCC[C@@H](C)[C@H]2CCC3=C4CC[C@@H]5C[C@H](O)CC[C@]5(C)[C@H]4C[C@H](O)[C@@]32C)cc1
Reaction time: 18 h

Procedure:
A solution of 3α, 12α-dihydroxy-5β-chol-8(14)-en-24-ol (12.8 g) in methylene chloride/acetonitrile (1:1) (180 ml) is cooled to -5° C. Triethylamine (6 ml), 4-dimethylaminopyridine (0.435 g), and p-toluenesulfonyl chloride (6.65 g) are added and the solution stirred at 0° to 4° C. for about 18 hours. The solution is diluted with ethyl acetate/methanol (9:1), washed with brine and the organic solution dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product is purified by flash chromatography in ether, followed by 10% methanol in ethyl acetate to give the desired product.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[F:13])[NH:9][CH:8]=[CH:7]2.[CH3:14][C@@H:15]1[CH2:17][O:16]1.O>O1CCCC1.CCOCC>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[F:13])[N:9]([CH2:14][C@H:15]([OH:16])[CH3:17])[CH:8]=[CH:7]2
Reactant: C[C@@H]1CO1
Reactant: Fc1cc2[nH]ccc2cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)Cn1ccc2cc(Cl)c(F)cc21
Reaction time: 1 h
Yield: 77 %

Procedure:
A suspension of 128 mg of sodium hydride dispersion in 8 ml of tetrahydrofuran was treated with 0.5 7 g of 5-chloro-6-fluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 0.48 ml of (R)-methyloxirane the reaction mixture was stirred at room temperature for 48 hours and subsequently treated with water. The mixture was diluted with ether, washed with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removing the solvent the residue was chromatographed over 25 g of silica gel with toluene-ethyl acetate (19:1). There was obtained 0.59 g (77%) of (R)-1-(5-chloro-6-fluoro-indol-1-yl)-propan-2-ol as beige crystals with m.p. 108°-110°.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3][CH:2]=1.[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]2[N:22]=[C:21]([NH2:23])[NH:20][N:19]=2)[CH:13]=[C:14]([Cl:16])[CH:15]=1.ClC1C=C(N=C=S)C=C(Cl)C=1C#N>O>[Cl:9][C:10]1[CH:11]=[C:12]([NH:17][C:18]2[N:22]=[C:21]([NH:23][CH2:7][C:5]3[CH:6]=[N:1][CH:2]=[N:3][CH:4]=3)[NH:20][N:19]=2)[CH:13]=[C:14]([Cl:16])[CH:15]=1
Reactant: O=Cc1cncnc1
Reactant: Nc1nc(Nc2cc(Cl)cc(Cl)c2)n[nH]1
Agent: N#Cc1c(Cl)cc(N=C=S)cc1Cl
Solvent: O
Product: Clc1cc(Cl)cc(Nc2n[nH]c(NCc3cncnc3)n2)c1
Yield: 76.2 %

Procedure:
A solution of pyrimidine-5-carbaldehyde (54 mg, 0.5 mmol) and N3-(3,5-dichlorophenyl)-1H-1,2,4-triazole-3,5-diamine Intermediate 2 (122 mg, 0.50 mmol) and picolineborane (54 mg, 0.5 mmol) was stirred at rt for 4 hours. The mixture was poured into water (20 mL) and extracted with EtOAc (3×10 mL). The extract was dried with sodium sulfate and the solvent was reduced to 2 mL. The remaining residue was loaded on a 25 g silica gel column and eluted with 5% MeOH in ethyl acetate to give 128 mg (76.2%) of desired product as a white solid. MS +m/z: 335.90 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH:9][CH:10]([CH3:15])[C:11]([O:13]C)=[O:12])=[C:4]([O:16][CH3:17])[CH:3]=1.O1CCCC1.O[Li].O>O>[Cl:1][C:2]1[C:7]([I:8])=[CH:6][C:5]([NH:9][CH:10]([CH3:15])[C:11]([OH:13])=[O:12])=[C:4]([O:16][CH3:17])[CH:3]=1
Reactant: COC(=O)C(C)Nc1cc(I)c(Cl)cc1OC
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)c(I)cc1NC(C)C(=O)O
Reaction time: 1 h
Yield: 70.3 %

Procedure:
To a solution of methyl 2-(4-chloro-5-iodo-2-methoxyphenylamino)propanoate (1.12 g, 3.04 mmol) in mixture of tetrahydrofuran (20 mL) and water (10 mL) at RT, LiOH.H2O (0.51 g, 12.16 mmol) was added and the resulting mixture was stirred for 1 h. The aqueous phase was washed with TBME and then acidified with aqueous HCl (1N) to adjust the pH to 5. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the crude product (760 mg) which was used directly in the next step without further purification. ESI-MS m/z: 356.1[M+H]+.