Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([C@H:8]1[NH:13][C:12]([CH3:18])([C:14]([NH:16][NH2:17])=[O:15])[CH2:11][C:10](=[O:19])[N:9]1[CH3:20])=O)(C)(C)C.CC[N:23](CC)CC.[C:28]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](Cl)=O)#[N:29].S(Cl)(C1C=CC(C)=CC=1)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH:23]=[C:8]1[NH:13][C@@:12]([C:14]2[O:15][C:33]([C:32]3[CH:31]=[C:30]([CH:38]=[CH:37][CH:36]=3)[C:28]#[N:29])=[N:17][N:16]=2)([CH3:18])[CH2:11][C:10](=[O:19])[N:9]1[CH3:20]
Reactant: CN1C(=O)CC(C)(C(=O)NN)N[C@@H]1C(=O)OC(C)(C)C
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CN1C(=N)N[C@](C)(c2nnc(-c3cccc(C#N)c3)o2)CC1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 16.1 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonyl)-1,4-dimethyl-6-oxo-hexahydropyrimidine-4-carbohydrazide (CY1; R6=Me, 0.037 g, 0.12 mmol) in DCM (0.3 mL) at 0° C. was added Et3N (0.035 mL, 0.24 mmol, 2 eq) followed by 3-cyanobenzoyl chloride (0.027 g, 0.16 mmol, 1.3 eq). The mixture was stirred at RT for 6 h. The mixture was diluted with DCM (20 mL), washed with H2O (10 mL) and saturated brine (10 mL), and concentrated in vacuo. The residue was then treated with TsCl (0.035 g, 0.18 mmol, 1.5 eq), Et3N (0.046 mL, 0.31 mmol, 2.6 eq), and DMAP (0.002 g, 0.016 mmol, 0.13 eq) in DCM (0.25 mL) at RT for 16 h. The mixture was diluted with DCM (20 mL), washed with H2O (10 mL) and saturated brine (10 mL), and concentrated in vacuo. The residue was treated with 30% TFA/DCM (1 mL) at RT for 1 h. The mixture was concentrated in vacuo and the residue was purified on reverse phase HPLC (B) to give 0.006 g (12%) of 3-(5-((S)-2-imino-1,4-dimethyl-6-oxo-hexahydropyrimidin-4-yl)-1,3,4-oxadiazol-2-yl)benzonitrile as a white solid (CZ1; R6=Me). 1HNMR (CD3OD, 300 MHz): 8.49 (m, 2H), 8.12 (d, 1H), 7.92 (t, 1H), 3.75 (m, 2H), 3.36 (s, 3H), 1.82 (s, 3H). MS (ESI): MH+=311.2, HPLC (A) Rt=4.175 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:5]2[C:10](=[C:11]([N+:13]([O-])=O)[CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16].O.O(CCCC)CCCC>[Fe].CC(O)=O>[NH2:13][C:11]1[CH:12]=[C:3]([O:2][CH3:1])[C:4]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[C:6]2[CH3:16]
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCCCCCc1ccccc1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Solvent: CCCCOCCCC
Product: COc1cc(N)c2nccc(C)c2c1OCCCCCCCCCc1ccccc1
Temperature: 80 °C
Yield: 64 %

Procedure:
A stirred mixture of 6-methoxy-4-methyl-8-nitro-5-(9-phenylnonoxy) quinoline (11 g, 0.025 mol), degreased 40 mesh Fe filings (30 g), H2O (100 ml), HOAc (20 ml) and n-Bu2O (20 ml) was heated at 80° C. for 2 h, cooled and filtered. The solid residue and the filtrate were thoroughly extracted with warm Et2O and the combined extracts were dried (Na2SO4), treated with Darco, and concentrated. The resulting solid was dissolved in pet ether (Darco) and cooled in dry ice - Me2CO to give 6.5 g (64%) of 8-amino-6-methoxy-4-methyl-5-(9-phenylnonoxy) quinoline as pale yellow crystals, mp 32°-32.5° C.
Reaction SMILES: Cl[C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:7]=1.[CH3:18][NH2:19].CO>O1CCCC1.C(OCC)(=O)C>[CH3:18][NH:19][C:2]1[C:3]([C:14]([O:16][CH3:17])=[O:15])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(-c2ccccc2)cnc1Cl
Reactant: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CNc1ncc(-c2ccccc2)nc1C(=O)OC
Temperature: 92.5 °C
Yield: 24 %

Procedure:
To a solution of methyl 3-chloro-6-phenylpyrazine-2-carboxylate (0.13 g, 0.53 mmol) in tetrahydrofuran (3 mL) was added 0.65 mL of 2.0 N methylamine in THF (1.30 mmol). The reaction was heated in a sealed high-pressure test tube to 90-95° C. overnight. The reaction was cooled to room temperature and diluted with ethyl acetate (100 mL). The organic layer was washed 2.0 N aqueous hydrochloric acid (20 mL), saturated aqueous sodium bicarbonate (30 mL), and saturated aqueous sodium chloride (30 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford a yellowish product. Trituration with methanol (2 mL) gave a solid, which was filtered and washed with ether to afford afford methyl 3-(methylamino)-6-phenylpyrazine-2-carboxylate (31 mg, 24%) as yellow solid: MS (EI) for C13H13N3O2: 244 (MH+). This intermediate ester was directly used in the next step.
Reaction SMILES: [CH:1]1([Mg]Cl)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C@@H:11]([O:17][C:18](=[O:27])[C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:10]2.[Cl-].[NH4+]>CCOCC.C1COCC1>[N:9]12[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16]1)[C@@H:11]([O:17][C:18](=[O:27])[C:19]([CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)([OH:26])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:10]2
Reactant: Cl[Mg]C1CCCCC1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(=O)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Cyclohexylmagnesium cloride, 0.127 mol (63.6 ml of a solution 2M in ether), was added to a solution of 28.7 g (0.111 mol) of 2-oxo-2-phenylacetic acid (3R)-1-azabicyclo[2.2.2]oct-3-yl ester dissolved in 350 ml of THF, at −70° C. under a N2 atmosphere. The mixture was stirred at this temperature for 10 minutes, and then warmed to room temperature. After 1 h, the reaction mixture was treated with a saturated solution of ammonium chloride and extracted twice with ethyl acetate. The organic phases were combined, washed with water, and dried over MgSO4. After removal of the solvent, the oil obtained (27.0 g) was purified by chromatography on silica gel eluting with chloroform/methanol 10:1. The yield was 18.7 g (49.2%) of a pure product, mixture of diastereomers: I-16a and I-16b.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[CH:25]=[CH:24][O:23][CH:22]=1.[Cl:26]N1C(=O)CCC1=O.CCOCC.O>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:17])([F:15])[F:16])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1[CH:25]=[CH:24][O:23][C:22]=1[Cl:26]
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccoc1
Solvent: O
Solvent: CCOCC
Solvent: CC#N
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1-c1ccoc1Cl
Reaction time: 1.5 h

Procedure:
To a solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(furan-3-yl)pyrazole (0.095 g) in acetonitrile (6 ml) was added N-chlorosuccinimide (0.0345 g). The mixture was left at room temperature for 1.5 hours and then poured into ether (50 ml) and water (50 ml). The layers were separated and the aqueous phase extracted with a second portion of ether (50 ml). The combined organic layers were washed with water (25 ml), then dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (10 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a white solid, m.p. 153° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)=[S:12])=[O:9])[CH:5]=[C:4]([CH3:22])[N:3]=1.[H-].[Na+].[CH3:25]I>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11](=[N:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[S:12][CH3:25])=[O:9])[CH:5]=[C:4]([CH3:22])[N:3]=1
Reactant: CI
Reactant: Cc1cc(C(=O)NC(=S)Nc2ccc(F)c(F)c2)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSC(=Nc1ccc(F)c(F)c1)NC(=O)c1cc(C)nc(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of intermediate D1 (38 g; 111.4 mmol) in THF (400 ml) was cooled to 0° C. and NaH (60% pure) (6.7 g; 167 mmol) was carefully added. The reaction mixture was stirred for 15 minutes and then CH3I (14.2 g; 100 mmol) was added. The mixture was then warmed to room temperature and stirred for 2 hours. The reaction was quenched by the addition of water and then the mixture was extracted by CH2Cl2 (3×100 ml). The combined organic solvent was washed with brine, dried over MgSO4, filtered and the solvent was evaporated in vacuo. The residue was purified by silica column chromatography (gradient: Heptane/EtOAc from 80/20 to 50/50). Yield: 22.2 g of intermediate D2.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][C:7]=3[CH2:8][O:9]2)=[CH:4][CH:3]=1.[C:19](Cl)(=O)C(Cl)=O.C[Si](C=[N+]=[N-])(C)C.[BrH:32].CC(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CCOC(C)=O>[Br:32][CH2:19][C:16]([C:13]1[CH:14]=[CH:15][C:6]2[C:5]3[C:10](=[CH:11][C:2]([Br:1])=[CH:3][CH:4]=3)[O:9][CH2:8][C:7]=2[CH:12]=1)=[O:18]
Reactant: O=C(O)c1ccc2c(c1)COc1cc(Br)ccc1-2
Reactant: O=C(Cl)C(=O)Cl
Reactant: Br
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(CBr)c1ccc2c(c1)COc1cc(Br)ccc1-2
Temperature: 45 °C
Reaction time: 12 h

Procedure:
To 3-Bromo-6H-benzo[c]chromene-8-carboxylic acid (0.5 mmol) was added a solution of oxalyl chloride in DCM (2.0 N, 5 ml, 10 mmol). The mixture was heated at 45° C. for 2 hours and cooled to 25° C. Excess reagents and solvent were removed under reduced pressure and co-evaporated with toluene. To the solution of above residue in DCM (5 ml) at 0° C. trimethylsilyldiazomethane (2.0 N, 0.75 ml, 1.5 mmol) was added dropwise. The mixture was stirred at 25° C. for 12 hours and was concentrated. The residue was dissolved in EtOAc and was cooled to 0° C. To above solution HBr/HOAc (0.28 ml, 1.5 mmol) was added dropwise. The mixture was stirred at 25° C. for 1 hour. Solid sodium bicarbonate was added and the mixture was stirred for 30 minutes. The mixture was diluted with EtOAc, and was washed with water and brine and was dried with Na2SO4. Concentration gave 2-Bromo-1-(3-bromo-6H-benzo[c]chromen-8-yl)-ethanone, which was used for next step without purification.
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8]2([CH2:15][C:14]([CH3:17])([CH3:16])[N:13]([CH2:18][CH:19]3[O:21][CH2:20]3)[C:12]([CH3:23])([CH3:22])[CH2:11]2)[NH:7][C:6]1=[O:24])[CH2:2][CH2:3][CH3:4].[OH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)=[CH:28][CH:27]=1.[H-].[Na+]>C(O)CC(C)C>[CH2:1]([N:5]1[C:9](=[O:10])[C:8]2([CH2:11][C:12]([CH3:22])([CH3:23])[N:13]([CH2:18][CH:19]([OH:21])[CH2:20][O:25][C:26]3[CH:27]=[CH:28][C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([O:39][CH2:20][CH:19]([OH:21])[CH2:18][N:13]5[C:14]([CH3:17])([CH3:16])[CH2:15][C:8]6([NH:7][C:6](=[O:24])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:9]6=[O:10])[CH2:11][C:12]5([CH3:22])[CH3:23])=[CH:35][CH:34]=4)=[CH:30][CH:31]=3)[C:14]([CH3:17])([CH3:16])[CH2:15]2)[NH:7][C:6]1=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)NC2(CC(C)(C)N(CC3CO3)C(C)(C)C2)C1=O
Reactant: Oc1ccc(Cc2ccc(O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)CCO
Product: CCCCN1C(=O)NC2(CC(C)(C)N(CC(O)COc3ccc(Cc4ccc(OCC(O)CN5C(C)(C)CC6(CC5(C)C)NC(=O)N(CCCC)C6=O)cc4)cc3)C(C)(C)C2)C1=O

Procedure:
A mixture of 4.0 g of 3-butyl-8-(2,3-epoxypropyl)-7,7,9,9-tetramethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione and 1.0 g of bis(p-hydroxyphenyl)methane in 5 ml of isopentyl alcohol with a catalytic amount of sodium hydride was refluxed for 10 hours. After completion of the reaction, the residue obtained by evaporating the solvent under reduced pressure from the reaction mixture was purified by column chromatography through silica gel eluted with a 1:1 by volume mixture of benzene and ethyl acetate, giving the desired Compound No. 351 in the form of white crystals melting at 202°-204° C.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([Cl:15])[CH:8]=1.[Br:16][C:17]1[CH:18]=[C:19](/[C:23](/[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[C:38]#[N:39])=[N:24]\S(C(C)(C)C)=O)[CH:20]=[CH:21][CH:22]=1.Cl.CO>O1CCCC1>[Br:16][C:17]1[CH:18]=[C:19]([C:23]2([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([Cl:15])[CH:8]=3)[C:31]3[C:32](=[C:33]([F:37])[CH:34]=[CH:35][CH:36]=3)[C:38]([NH2:39])=[N:24]2)[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)S(=O)/N=C(\c1cccc(Br)c1)c1cccc(F)c1C#N
Reactant: COc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C2(c3cccc(Br)c3)N=C(N)c3c(F)cccc32)cc1Cl
Reaction time: 0.08 h
Yield: 41.9 %

Procedure:
To tetrahydrofuran (20 mL) at −100° C. was added tert-butyllithium (1.7M in pentane, 4.30 mL, 7.31 mmol) dropwise over 5 min. 4-Bromo-2-chloro-1-methoxybenzene (0.81 g, 3.66 mmol) dissolved in tetrahydrofuran (5 mL) was added over 10 min. The mixture was stirred for 5 min then was (E)-N-((3-bromophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (1.241 g, 3.05 mmol) in tetrahydrofuran (10 mL) added over 10 min. The reaction mixture was held at −100° C. for 20 min and then slowly allowed to reach r.t. over night. Hydrogen chloride-methanol solution (14.63 mL, 18.29 mmol) was added and the resulting mixture was stirred at r.t. for 1 h. The mixture was concentrated and purified on a silica gel column eluted with 0-10% 0.1M NH3 in MeOH in DCM to give the title compound (570 mg, 42%). MS (ES+) m/z 445, 447 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.S(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([Cl:15])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C=Cc1ccc(Br)cc1
Product: O=C(Cl)C=Cc1ccc(Br)cc1

Procedure:
A solution of compound 2 (113.8 g, 0.5 mol) in thionyl chloride was refluxed for 1.5 h. Then the mixture was concentrated in vacuo and the crude product 3 was obtained (126.9 g, 93%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH:20]=[CH:19]3)=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:27]>[C].[Pd].C(O)C.O>[ClH:27].[N:11]1([C:14]([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH:20]=[CH:19]3)=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: O=C(c1ccc2[nH]c(=O)ccc2c1)N1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(c1ccc2[nH]c(=O)ccc2c1)N1CCNCC1

Procedure:
26.4 Grams of 6-[(4-benzyl-1-piperazinyl)carbonyl]carbostyril was suspended in 800 ml of a mixed solvent of ethanol-water and the pH of the suspension was adjusted to about pH 1 by adding concentrated hydrochloric acid. To this mixture was added 2.6 g of 5% palladium-carbon and catalytic reduction was conducted under a normal pressure at 45°-65° C. After the reaction was completed, the catalyst was removed by filtration and the solvent was removed by distillation under a reduced pressure. The residue obtained was crystallized by adding acetone and the crude crystals thus obtained were recrystallized from ethanol-water to obtain 19.9 g of 6-(1-piperazinylcarbonyl)carbostyril monohydrochloride. Colorless granular crystals. Melting point: over 300° C.
Reaction SMILES: [CH3:1][O:2][C@@H:3]1[C@H:7]2[CH2:8][C@@H:9]3[C@@H:14]([C:15](=[CH2:16])[C@H:6]2[C@H:5]([CH3:17])[O:4]1)[CH2:13][CH2:12][CH2:11][CH2:10]3.[OH2:18].OO.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[OH:18][CH2:16][C@H:15]1[C@@H:6]2[C@@H:7]([C@@H:3]([O:2][CH3:1])[O:4][C@H:5]2[CH3:17])[CH2:8][C@@H:9]2[C@@H:14]1[CH2:13][CH2:12][CH2:11][CH2:10]2.[OH:18][CH2:16][C@@H:15]1[C@@H:6]2[C@@H:7]([C@@H:3]([O:2][CH3:1])[O:4][C@H:5]2[CH3:17])[CH2:8][C@@H:9]2[C@@H:14]1[CH2:13][CH2:12][CH2:11][CH2:10]2
Reactant: C=C1[C@@H]2[C@H](C[C@H]3CCCC[C@H]13)[C@@H](OC)O[C@H]2C
Reactant: O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CO[C@H]1O[C@@H](C)[C@H]2[C@@H]1C[C@H]1CCCC[C@@H]1[C@@H]2CO
Product: CO[C@H]1O[C@@H](C)[C@H]2[C@@H]1C[C@H]1CCCC[C@@H]1[C@H]2CO
Reaction time: 4.5 h
Yield: 81 %
Yield: 11 %

Procedure:
To 99.8 mg(0.42 mmol) of (1S,3S,3aS,4aS,8aR,9aS)-1-methoxy-3-methyl-4-methylene-dodecahydronaphtho[2,3-c]furan in 10 ml of dehydrated tetrahydrofuran solution were added dropwise 633.4 μl (1.5 equivalents) of borane-tetrahydrofuran complex(1M) under cooling with ice and under an atmosphere of argon, and the mixture was stirred for 4.5 hours while raising temperature naturally. The reaction mixture was cooled with ice and 1 ml of water was added to stop the reaction. Then, 0.50 ml of 30% aqueous hydrogen peroxide and 0.50 ml of 10% aqueous solution of sodium hydroxide were added, which was stirred for 30 minutes. Solvent was distilled off and 20 ml of water were poured to the residue, which was extracted with methylene chloride(10 ml×3). The organic layer was dried over anhydrous magnesium sulfate, filtered and solvent was distilled off under reduced pressure. The residue was purified by means of silica gel column chromatography(hexane:ethyl acetate=4:1, then 1:1) to obtain 86.7 mg of (1S,3S,3aR,4R,4aS,8aR,9aS)-4-hydroxymethyl-1-methoxy-3-methyl-dodecahydronaphtho[2,3-c]furan (yield 81%) and 11.7 mg of (1S,3S,3aR,4S,4aS,8aR,9aS)-4-hydroxymethyl-1-methoxy-3-methyl-dodecahydronaphtho[2,3-c]furan (yield 11%). (1S,3S,3aR,4R,4aS,8aR,9aS)-4-hydroxymethyl-1-methoxy-3-methyl-dodecahydronaphtho[2,3-c]furan.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[CH2:8][CH2:7]2.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1.CC(C)=O.C(OCC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[S:28])[CH2:8][CH2:7]2
Reactant: O=C1CCc2cc(-c3cccnc3)cc(Cl)c2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CC(C)=O
Product: S=C1CCc2cc(-c3cccnc3)cc(Cl)c2N1

Procedure:
A mixture of 8-chloro-6-pyridin-3-yl-3,4-dihydro-1H-quinolin-2-one (900 mg, 3.48 mmol) and Lawessons reagent (985 mg, 2.44 mmol) was refluxed in 50 ml toluene for 2 h. After evaporation of the solvent under reduced pressure, the residue was purified by flash chromatography on silica gel (ethyl acetate, Rf=0.26) and crystallization from acetone/diethylether. 8-Chloro-6-pyridin-3-yl-3,4-dihydro-1H-quinoline-2-thione was obtained as yellow needles (212 mg, 0.77 mmol, 22%), mp (acetone/diethylether) 175° C. 1H-NMR (500 MHz, DMSO-d6): δ=2.91 (m, 2H), 3.00 (m, 2H), 7.46 (ddd, 3J=7.9 Hz, 3J=4.9 Hz, 5J=0.9 Hz, 1H), 7.66 (d, 4J=2.1 Hz, 1H), 7.76 (d, 4J=2.0 Hz, 1H), 8.09 (ddd, 3J=7.9 Hz, 4J=2.4 Hz, 4J=1.5 Hz, 1H), 8.56 (dd, 3J=4.9 Hz, 4J=1.5 Hz, 1H), 8.91 (dd, 4J=2.4 Hz, 5J=0.9 Hz, 1H), 11.31 (bs, 1H). 13C-NMR (125 MHz, DMSO-d5): δ=25.6, 39.4, 120.5, 123.8, 125.2, 126.0, 129.7, 133.4, 133.6, 133.8, 133.9, 147.5, 148.8, 201.5. MS m/z=273.95 (M35Cl+), 275.95 (M37Cl+).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.Cl[C:15]1[CH:20]=[CH:19][N:18]([C@@H:21]2[O:43][C@H:42]([CH2:44][O:45][C:46](=[O:53])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@@H:32]([O:33][C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:22]2[O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17](=[O:54])[N:16]=1>C1COCC1.[Cu]I>[C:1]([C:15]1[CH:20]=[CH:19][N:18]([C@@H:21]2[O:43][C@H:42]([CH2:44][O:45][C:46](=[O:53])[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@@H:32]([O:33][C:34](=[O:41])[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:22]2[O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17](=[O:54])[N:16]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C(OC[C@H]1O[C@@H](n2ccc(Cl)nc2=O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: C#CCCCC
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCC#Cc1ccn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)c(=O)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of bis-triphenylphosphine palladium (II) dichloride (0.35 g, 0.5 mmol) and copper (I) iodide (95 mg, 0.5 mmol) in THF (45 mL, distilled from Na-benzophenone ketyl) is sparged with dry argon gas for 10 min. To this suspension is added 1-hexyne (2.46 g, 30 mmol) followed by triethylamine (5 mL). The suspension is stirred at room temperature under argon for 15 min. A similarly sparged solution of the 2-chloro-1-(2,3,5-tri-O-benzoyl-b-D-ribofuranosyl)pyrimidin-4-one (13, 5.75 g, 10 mmol) in THF (15 mL) is added to the suspension of catalyst and the mixture stirred for 1 hr. The dark mixture is filtered through Celite and the filtrate evaporated in vacuo to afford a dark syrup. This syrup was triturated with cold diethylether, filtered and then dissolved in dichloromethane.
Reaction SMILES: CS(C)=O.F[C:6]1[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:8]([CH3:21])[C:9]([C:19]#[N:20])=[C:10]2[C:14]=1[O:13][C:12]([C:15]([F:18])([CH3:17])[CH3:16])=[N:11]2.C(N(CC)CC)C.[CH3:35][N:36]([CH3:42])[C@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1>[Cl-].[Na+].O>[CH3:35][N:36]([CH3:42])[C@H:37]1[CH2:41][CH2:40][N:39]([C:6]2[C:7]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[C:8]([CH3:21])[C:9]([C:19]#[N:20])=[C:10]3[C:14]=2[O:13][C:12]([C:15]([F:18])([CH3:17])[CH3:16])=[N:11]3)[CH2:38]1
Reactant: CN(C)[C@H]1CCNC1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(C)(C)F)nc2c1C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(C(C)(C)F)nc2c1C#N

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (4 ml) solution of 7-fluoro-2-(1-fluoro-1-methylethyl)-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-312) (128 mg, 410 μmol), triethylamine (74 μl, 533 μmol) and (3S)-3-(dimethylamino)pyrrolidine (62 μl, 492 μmol) was stirred at 90° C. for 2.5 hours. After cooling, saturated-brine was added to the reaction liquid, and the mixture liquid was extracted with ethyl acetate. Next, the combined organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by middle-pressure liquid chromatography (eluent, dichloromethane:methanol=10:1, v/v) to obtain a rough product of the entitled compound, followed by suspension washing with diethyl ether to obtain the entitled compound as a pale yellow solid. The filtrate was concentrated, and the obtained solid was washed by suspension with isopropyl ether to obtain the entitled compound as a pale yellow solid (total 54 mg, 38%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH:19]1([C:24]([OH:26])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1.[C:27]([O:31][C:32](=[O:45])[C:33]([CH2:35][CH2:36][O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[CH2:34])([CH3:30])([CH3:29])[CH3:28]>O1CCCC1>[CH2:38]([O:37][CH2:36][CH2:35][CH:33]([C:32]([O:31][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:45])[CH2:34][C:19]1([C:24]([OH:26])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: C=C(CCOCc1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C(O)C1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)C(CCOCc1ccccc1)CC1(C(=O)O)CCCC1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (2.9 mL, 20.8 mmol) in dry tetrahydrofuran (50 mL) at -50° C. was added a 2.5M solution of n-butyllithium in hexane (8.4 mL, 21 mmol). The mixture was stirred at a temperature from -30° C. to 0° C. over 30 minutes and then cooled again to -40° C. A solution of cyclopentanecarboxylic acid (1.1 mL, 10.1 mmol) in tetrahydrofuran (20 mL) was added and the resulting mixture was allowed to warm to room temperature with stirring over 2 hours. The reaction was cooled to -79° C. and a solution of 2-(2-benzyloxyethyl) acrylic acid tert-butyl ester (2.6 g, 9.9 mmol) in dry tetrahydrofuran (10 mL) was added dropwise; stirring was continued at -40° C. for 2 hours. The mixture was quenched by the addition of 0.5M HCl solution and was extracted with ether. The extract was washed with brine, dried over MgSO4 and evaporated under vacuum to leave an oil from which 1-(4-benzyloxy-2-tert-butoxycarbonylbutyl)cyclopentane carboxylic acid, 2.9 g (78%), was isolated by chromatography on silica gel eluting with methylene chloride and then 1% methanol in methylene chloride.