Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[N:3]1([C:9]2[CH:10]=[C:11]([OH:17])[C:12](=[CH:15][CH:16]=2)[CH:13]=[O:14])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.CC(C)=O.Cl>O>[OH:14][CH2:13][C:12]1[CH:15]=[CH:16][C:9]([N:3]2[CH2:4][CH2:5][O:6][CH2:7][CH2:8]2)=[CH:10][C:11]=1[OH:17]
Reactant: O=Cc1ccc(N2CCOCC2)cc1O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: OCc1ccc(N2CCOCC2)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.2 %

Procedure:
A solution of sodium borohydride (NaBH4) (0.66 g, 17 mmol) in water (25 mL) was treated with 4-morpholinylsalicylaldehyde (1.8 g, 9 mmol) in small portions over 30 min and stirred at room temperature for 3 h. The reaction was quenched with acetone (5.1 mL, 100 mmol), acidified to pH 7 with 7.8 mL of 5% hydrochloric acid (aqueous) and extracted with chloroform (CHCl3) (2×100 mL). The combined CHCl3 extracts were dried over sodium sulfate (Na2SO4) and concentrated in vacuo to yield 0.7 g of pale yellow solid which was purified by trituration with 60/40 CHCl3/ethyl acetate (EtOAc) to yield the product as a white solid (0.25 g).
Reaction SMILES: BrBr.[Br:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].P(Br)(Br)[Br:12]>>[Br:12][CH:7]([CH2:6][CH2:5][CH2:4][Br:3])[C:8]([OH:10])=[O:9]
Reactant: BrP(Br)Br
Reactant: O=C(O)CCCCBr
Agent: BrBr
Product: O=C(O)C(Br)CCCBr
Reaction time: 0.5 h

Procedure:
39 ml of bromine is added to a mixture of 106 g of 5-bromo pentanoic acid and 1 ml of phosphorus tribromide. The reaction mixture is taken to 70˜80° C. for 16 hours 30 minutes. The reaction medium is taken to 100° C. for 15 minutes, then allowed to return to ambient temperature. 147 g of sought product is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[CH:4][N:3]=1.[CH2:15]([OH:19])[C:16]#[C:17][CH3:18].[H-].[Na+].O>CN(C)C=O>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([O:19][CH2:15][C:16]#[C:17][CH3:18])[N:3]=[CH:4][N:5]=1
Reactant: Fc1ccccc1-c1cc(Cl)ncn1
Reactant: CC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1cc(-c2ccccc2F)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
In 5 ml of N,N-dimethylformamide were dissolved 207 mg of 4-chloro-6-(2-fluorophenyl)pyrimidine and 83 mg of 2-butyn-1-ol, to which 48 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 8 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 160 mg of 4-(2-fluorophenyl)-6-(2-butynyloxy)pyrimidine (the present compound (55)).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:31]=[CH:30][CH:29]=[CH:28][C:12]=1[C:13]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[O:26][CH3:27])=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:32]I>CN(C)C=O>[CH3:32][N:15]([C:13](=[O:14])[C:12]1[CH:28]=[CH:29][CH:30]=[CH:31][C:11]=1[O:10][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[O:26][CH3:27]
Reactant: CI
Reactant: COC(=O)c1ccc(NC(=O)c2ccccc2OCc2ccccc2)c(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(C)C(=O)c2ccccc2OCc2ccccc2)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (60% oil suspension, 88.3 mg) in N,N-dimethylformamide (6 ml) was added a solution of methyl 4-(2-benzyloxybenzoyl)amino-3-methoxybenzoate (600 mg) in N,N-dimethylformamide (4 ml) and the mixture was stirred at 0° C. for 1 hour. Methyl iodide (0.14 ml) was added dropwise to the above solution and the mixture was stirred at 0° C. for 30 minutes. The reaction temperature was raised to ambient temperature over 30 minutes and the reaction was quenched with 1 N hydrochloric acid, and then the resulting solution was extracted with ethyl acetate. Drying, filtering and removal of solvents afforded a crude product. The crude product was purified by column chromatography (eluent; hexane:ethyl acetate=3:1) to give methyl 4-(N-methyl-2-benzyloxybenzoylamino)-3-methoxybenzoate (650 mg).
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:17])[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:9](=[O:12])[C:10]=1[CH3:11])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[CH3:20][OH:21].Cl>C(Cl)Cl>[C:1]([C:5]1[C:10]([CH3:11])=[C:9]([O:12][CH:20]2[CH2:10][CH2:5][CH2:1][CH2:2][O:21]2)[CH:8]=[C:7]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CC1=C(C(C)(C)C)C(=O)C(C(C)(C)C)=CC1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(OC2CCCCO2)cc(C(C)(C)C)c(O)c1C(C)(C)C
Reaction time: 3 h
Yield: 81 %

Procedure:
2,6-di-tert-butyl-3-methyl-1,4-benzoquinone (49 g) was dissolved in methylene chloride (300 ml) and sodium borohydride (15 g) was added to the solution under a nitrogen atmosphere. After adding methanol (30 ml) dropwise, the mixture was stirred for 3 h, poured into 5% HCl under ice cooling, and subjected to extraction with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was dissolved in methylene chloride (200 ml) and, after adding 3,4-2H-dihydropyran (26 ml) and a catalytic amount of paratoluenesulfonic acid, the mixture was stirred overnight at room temperature. The reaction mixture was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel chromatography (10% ethyl acetate in n-hexane) to afford 2,6-di-tert-butyl-3-methyl-4-tetrahydropyranyloxyphenol [54.4 g (yield, 81%)] as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH:5]([C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1)[CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[N:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:8]=1)[CH3:2].[CH3:36][Si]([N-][Si](C)(C)C)(C)C.[Na+].IC>C1COCC1>[CH2:1]([O:3][C:4](=[O:35])[C:5]([CH3:36])([C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1)[CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[N:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:8]=1)[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)C(Cc1cc(-c2ccc(Cl)c(Cl)c2)n(-c2ccc(OC)cc2)n1)c1cccc(C)c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)(Cc1cc(-c2ccc(Cl)c(Cl)c2)n(-c2ccc(OC)cc2)n1)c1cccc(C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a solution of 3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-m-tolyl-propionic acid ethyl ester (Method 2, product from alkylation step before hydrolysis) (50 mg, 0.10 mmol) in THF (1.0 mL) at 0° C. was added a 1.0 M solution of NaHMDS (0.15 mL, 0.15 mmol). The solution was stirred at 0° C. for 2 h, then iodomethane (41 mg, 0.29 mmol) was added neat. After stirring for 1 h the reaction was quenched with saturated ammonium chloride (50 mL), and the reaction mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (1×50 mL) and dried with Na2SO4, and the solvent was removed under reduced pressure. The crude material was purified by flash chromatography (EtOAc/hexanes) giving 31 mg (60%) of 3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-methyl-2-m-tolyl-propionic acid ethyl ester. HPLC: Rt=3.79 (Method B). MS (ES+): mass calculated for C29H28Cl2N2O3, 522.15; m/z found 523.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 7.58 (d, J=8.4 Hz, 1H), 7.42 (d, J=2.0 Hz, 1H), 7.25 (t, J=7.6 Hz, 1H), 77.17-7.14 (m, 4H), 7.08 (d, J=7.4 Hz, 1H), 7.05 (dd, J=2.0 Hz, 8.3 Hz, 1H), 6.97 (d, J=8.9 Hz, 2H), 6.22 (s, 1H), 4.10 (m, 2H), 3.77 (s, 3H), 3.40 (d, J=13.9 Hz, 1H), 3.17 (d, J=13.9 Hz, 1H), 2.13 (s, 3H), 1.49 (s, 3H), 1.12 (t, J=7.1 Hz, 3H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]([C:14]([NH:16][C:17]2[CH:22]=[N:21][CH:20]=[C:19]3[NH:23][CH:24]=[CH:25][C:18]=23)=[O:15])=[C:7]2[N:8]=[CH:9][C:10]([F:12])=[CH:11][N:6]2[N:5]=1.N[C@H:27](C(O)=O)CCSC>CN(C=O)C.O>[NH2:3][C:4]1[C:13]([C:14]([NH:16][C:17]2[CH:22]=[N:21][CH:20]=[C:19]3[N:23]([CH3:27])[CH:24]=[CH:25][C:18]=23)=[O:15])=[C:7]2[N:8]=[CH:9][C:10]([F:12])=[CH:11][N:6]2[N:5]=1
Reactant: CSCC[C@H](N)C(=O)O
Reactant: Nc1nn2cc(F)cnc2c1C(=O)Nc1cncc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc2c(NC(=O)c3c(N)nn4cc(F)cnc34)cncc21
Yield: 19 %

Procedure:
NaH (3.958 mg, 0.09894 mmol) was added to a suspension of 2-amino-6-fluoro-N-(1H-pyrrolo[2,3-c]pyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (28 mg, 0.08995 mmol) (synthesized according to a procedure similar to Example 1 or Example 3a) and Met (11.49 mg, 5.039 μL, 0.08096 mmol) in DMF (3 mL) under N2. The suspension was stirred at RT for 5 h before water (2 drops) was added. The crude mixture was purified by fractionlynx HPLC. Clean fractions were liophilized to yield 2-amino-6-fluoro-N-(1-methyl-1H-pyrrolo[2,3-c]pyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (5 mg, 16%). MS (ES+) 326.1.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7](O)[CH:6]=[C:5]([C:14]([F:17])([F:16])[F:15])[N:4]=1.N1C(C)=CC=CC=1C.O=P(Cl)(Cl)[Cl:30]>>[F:1][C:2]([F:19])([F:18])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([Cl:30])[CH:6]=[C:5]([C:14]([F:17])([F:16])[F:15])[N:4]=1
Reactant: COC(=O)c1c(O)cc(C(F)(F)F)nc1C(F)(F)F
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: COC(=O)c1c(Cl)cc(C(F)(F)F)nc1C(F)(F)F
Yield: 19.7 %

Procedure:
A mixture of 6.7 g (0.0232 mol) of product of Example 4, 2.8 g (0.026 mol) of 2,6-lutidine, and 50 ml of POCl3 was held at reflux for 18 hours and concentrated. The residue was treated with water and extracted with ether. The ether extract was washed with 10% NaOH and then with saturated NaCl, dried, and concentrated. The residue was kugelrohr distilled at 133 Pa (pot temperature 90° C.). The distillate was recrystallized from hexane at low temperature to give 1.4 g (19.7%) of product; mp 48°-49° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:30]([O-])([N+]([O-])=O)=[O:31]>O1CCCC1.C(Cl)Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:30]=[O:31])[C:5]([N:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CCCCCN(C(=O)NCCCl)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCN(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 71.3 %

Procedure:
3.5 g of 1-(2-chloroethyl)-3-n-pentyl-3-D-galactopyranosylurea are dissolved in a mixture of 80 ml of tetrahydrofuran and 80 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling. The mixture is treated in the same manner as described in Example 2. 2.7 g of 1-(2-chloroethyl)-1-nitroso-3-n-pentyl-3-D-galactopyranosylurea are thereby obtained as yellow caramel.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:22]2[C:26]([CH2:27][CH3:28])=[N:25][N:24]([C:29]3[CH:34]=[C:33]([N+:35]([O-])=O)[CH:32]=[CH:31][C:30]=3[C:38]([F:41])([F:40])[F:39])[C:23]2=[O:42])=[C:17]([F:43])[CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCO.[H][H]>O=[Pt]=O.CCOC(C)=O>[NH2:35][C:33]1[CH:32]=[CH:31][C:30]([C:38]([F:39])([F:41])[F:40])=[C:29]([N:24]2[C:23](=[O:42])[N:22]([CH2:21][C:18]3[CH:19]=[CH:20][C:15]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[S:6](=[O:7])(=[O:8])[NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:16][C:17]=3[F:43])[C:26]([CH2:27][CH3:28])=[N:25]2)[CH:34]=1
Reactant: CCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1nn(-c2cc(N)ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F

Procedure:
A mixture of 388 mg (0.625 mmol) of 4-[[2'-(N-t -butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-2,4-dihydro-5-ethyl-2-[5-nitro-2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Step A), 6 mL of EtOH, 8 mL of EtOAc, and 30 mg of 5% PtO2 was shaken with hydrogen for 3.5 hours on a Parr hydrogenation apparatus. Removal of the catalyst followed by evaporation of volatiles gave 383 mg (quantitative) of a cream-colored solid [top >105° C. (gradual)] of sufficient purity to be used in the next step without further purification; mass spectrum (FAB) m/e 599 (M+Li)+.
Reaction SMILES: CCCC([C:6]1[C:7](=[O:17])[O:8][CH:9]=[C:10](CC(C)C)[C:11]=1[OH:12])=O.O[C:19]1[CH:24]=C(CC(C)C)O[C:21](=O)[CH:20]=1.[K+].[Br-]>>[OH:12][C:11]1[CH:10]=[C:9]([CH2:24][CH2:19][CH2:20][CH3:21])[O:8][C:7](=[O:17])[CH:6]=1
Reactant: CCCC(=O)c1c(O)c(CC(C)C)coc1=O
Reactant: CC(C)Cc1cc(O)cc(=O)o1
Agent: [Br-]
Agent: [K+]
Product: CCCCc1cc(O)cc(=O)o1

Procedure:
Proceeding in a similar manner as described in Section D of this example, 3-(3-methylpropionyl)-4-hydroxy-5-isobutyl-2-pyrone was converted to 4-hydroxy-6-isobutyl-2-pyrone. M.p. 110°-111° C., IR (KBr): 3300-2700, 1705, 1680-1660, 1585 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([S:19][CH3:20])[N:14]=2)=[CH:4][CH:3]=1.[OH-:30].[NH4+]>O.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH2:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([S:19]([CH3:20])=[O:30])[N:14]=2)=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: CSc1nccc(-c2c(-c3ccc(F)cc3)ncn2CCCN2CCOCC2)n1
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)c1nccc(-c2c(-c3ccc(F)cc3)ncn2CCCN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73 %

Procedure:
A solution of K2S2O8 (0.20 g, 0.73 mmol) in water (5 mL) was added to 4-(4-fluorophenyl)-5-[2-(methylthio)-4pyrimidinyl]-1-[3-(4-morpholinyl)propyl]imidazole (0.20 g, 0.48 mmol) in glacial acetic acid (10 mL). After stirring at ambient temperature for 72 h, the reaction mixture was poured into water, neutralized with concentrated aqueous ammonium hydroxide and extracted four times with dichloromethane. The organic phases were combined and evaporated. The residue was purified by flash chromatography eluting successively with 1%, 2%, 4% and 10% methanol in dichloromethane to afford the title compound as a clear oil (0.15 g, 73%). 1H NMR (CDCl3) δ8.57(d, J=7 Hz, 1H), 7.77(s,1H), 7.47 (dd, 2H), 7.18(d, J=5 Hz, 1H)7.09(t, J=9 Hz, 2H), 4.56(m, 2H), 3.72(t, J=5 Hz, 4H), 3.00(s, 3H), 2.40(brd. s, 4H), 2.33(t, J=8 Hz, 2H), 1.94(m, 2H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([CH:13]2[CH2:22][C:21]([CH3:24])([CH3:23])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:25]#[N:26])[CH:19]=3)[NH:14]2)[CH:10]=[CH:11][CH:12]=1.N1C=CC=CC=1>ClCCl>[C:25]([C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]([C:9]1[CH:8]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:12]=[CH:11][CH:10]=1)[CH2:22][C:21]2([CH3:24])[CH3:23])#[N:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(C#N)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc(NS(C)(=O)=O)c2)Nc2ccc(C#N)cc21
Reaction time: 8 h
Yield: 52.1 %

Procedure:
Methanesulfonyl chloride (93 mg, 0.81 mmol) was added dropwise to a mixture of 2-(3-amino-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonitrile (150 mg, 0.54 mmol) and pyridine (77 mg, 0.97 mmol) in dichloromethane (5 mL). The resultant mixture was allowed to stir overnight. The reaction mixture was washed by water, dried over magnesium sulfate. It was filtered and concentrated to provide the crude product. It was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=5:1) to afford N-[3-(6-cyano-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-methanesulfonamide as off-white solid (100 mg, Yield: 52.1%). MS (ESI+APCI) M+1=356.2.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(N)C1C=CC=CC=1.[CH3:18][C:19]([CH3:23])([CH3:22])[CH:20]=[CH2:21].Cl>C1COCC1>[CH3:18][C:19]([CH3:23])([CH3:22])[CH2:20][CH2:21][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: C=CC(C)(C)C
Reactant: CC(=O)c1ccccc1
Agent: Cl
Solvent: NCc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1ccccc1CCC(C)(C)C
Temperature: 150 °C
Yield: 95.5 %

Procedure:
In a 500 ml pressure reactor, acetophenone 26 mg (0.22 mmol), benzylamine 12 mg (0.11 mmol), tristriphenylphosphine rhodium (I) chloride 10.0 mg (0.011 mmol) and 3,3-dimethyl-1-butene 91 mg (1.1 mmol) were placed. While the reactor was stopped with a stopper, the reactants were heated at 150° C. for 6 hours with stirring. After completion of the on, a reactant mixture was dissolved in THF 3 ml and added with 1 N HCl soln. 10 ml, followed by hydrolysis with stirring for 12 hours at room temperature. After the mixture was two or three times extracted with Et2O and CH2Cl2, the organic layer was dried over MgSO4 and then filtered, and the solvent was evaporated under reduced pressure. The reactant mixture of the organic layer was purified by column chromatography on silica gel (5:2 hexane:ethyl acetate) to obtain 2-(3,3-dimethylbutyl)phenyl-1-ethanone 42 mg (0.21 mmol). Yield: 95%. Under the same conditions, various olefins were employed, and the results are given in Table 7, below.
Reaction SMILES: [NH2:1][C:2]1([CH3:16])[C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:3]1.[C:17](OC([O-])=O)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:9]([N:4]1[CH2:3][C:2]([NH:1][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:16])[C:6]2([CH2:8][CH2:7]2)[CH2:5]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: CC1(N)CN(Cc2ccccc2)CC12CC2
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1(C)CN(Cc2ccccc2)CC12CC2
Temperature: 25 °C
Reaction time: 15 h

Procedure:
7-Amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane (7.3 g) was dissolved in toluene (30 mL). t-Butyl dicarbonate (9.3 mL) and 1N aqueous sodium hydroxide (10 mL) were added to the solution, followed by stirring for 15 hours at room temperature and then for 4 hours at 50° C. After completion of reaction, the toluene layer was separated and washed with water, followed by drying with sodium sulfate. The desiccant was removed through filtration, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel chromatography (hexane:ethyl acetate), to thereby yield the title product (8.745 g, yield: 820). Notably, when optically active 7-amino-5-benzyl-7-methyl-5-azaspiro[2.4]heptane is treated in accordance with the above-described procedure, the corresponding optically active target product can be yielded without decreasing optical purity.
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].[Cl:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[CH:19]=[C:18]([C:25]([O:27]CC)=O)[C:17](/[N:30]=[CH:31]/N(C)C)=[CH:16]2.ClCCOC1C=C2C(C=C(/N=C/N(C)C)C(C(OCC)=O)=C2)=CC=1OC>O1CCCC1>[Cl:9][CH2:10][CH2:11][O:12][C:13]1[C:22]([O:23][CH3:24])=[CH:21][C:20]2[CH:19]=[C:18]3[C:17](=[CH:16][C:15]=2[CH:14]=1)[NH:30][CH:31]=[C:7]([C:6]#[N:8])[C:25]3=[O:27]
Reactant: CC#N
Reactant: CCOC(=O)c1cc2cc(OC)c(OCCCl)cc2cc1/N=C/N(C)C
Agent: CCOC(=O)c1cc2cc(OCCCl)c(OC)cc2cc1/N=C/N(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc2cc3c(=O)c(C#N)c[nH]c3cc2cc1OCCCl
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To 2.5 mL of dry tetrahydrofuran at −78° C. is added 1.8 mL of 2.5 M n-butyllithium (4.4 mmol). Then 0.24 mL of dry acetonitrile in 4.5 mL of dry tetrahydrofuran is added dropwise over 10 minutes. This is stirred and additional 15 minutes at −78° C., then the ethyl 6-(2-chloroethoxy)-3-{[(E)-(dimethylamino)methylidene]-amino}-7-methoxy-2-naphthoate and ethyl 7-(2-chloroethoxy)-3-{[(E)-(dimethylamino)methylidene]amino}-6-methoxy-2-naphthoate (1:1 mixture) is dissolved in 3 mL of tetrahydrofuran and added dropwise over 15 minutes. The reaction mixture is stirred for 30 minutes at −78° C., then quenched with 0.57 mL of glacial acetic acid, and warmed to room temperature. To the yellow mixture is added 10 mL of water. The solids are filtered, washed with water and dried to give 0.502 g of 8-(2-chloroethoxy)-7-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile and 7-(2-chloroethoxy)-8-methoxy-4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile (1:1 mixture) as a yellow green solid (76%), m.p. 260-73° C. dec.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]=[O:5].[CH:8]([Mg]Br)=[CH2:9].[Cl-].[NH4+]>O1CCCC1.O>[CH3:1][C:2]([CH3:7])([CH3:6])[CH2:3][CH:4]([OH:5])[CH:8]=[CH2:9]
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)CC=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC(O)CC(C)(C)C
Temperature: -20 °C
Yield: 15.3 %

Procedure:
A solution of 3,3-dimethylbutyraldehyde (5.0 mL, 39.8 mmol) in tetrahydrofuran (30 mL) was added dropwise to a solution of vinylmagnesium bromide (47.8 mL, 1M in tetrahydrofuran, 47.8 mmol) stirring at −20° C. The solution was stirred for 30 minutes at −20° C. at which time saturated ammonium chloride solution (75 mL) was added and the reaction was allowed to warm to 25° C. The solution was diluted with water and extracted three times with ethyl acetate. The ethyl acetate layers were combined and washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, followed by 5% and 10% ethyl acetate in hexane to give the title compound (0.780 g, 15%). 1H NMR (300 MHz, CDCl3): δ ppm 0.98 (m, 9 H) 1.45 (m, 2 H) 4.26 (m, 1 H) 5.06 (m, 1 H) 5.21 (m, 1 H) 5.90 (m, 1 H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]([CH2:11][C:12]([OH:14])=[O:13])[N:9]=[N:8][N:7]=2)=[CH:2]1.[CH2:15](O)[CH2:16][CH2:17][CH2:18][OH:19].C1(N=C=NC2CCCCC2)CCCCC1.C(O)(=O)C>CN(C)C=O>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][O:13][C:12](=[O:14])[CH2:11][N:10]1[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[N:7][N:8]=[N:9]1
Reactant: O=C(O)Cn1nnnc1-c1ccsc1
Reactant: OCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(Cn1nnnc1-c1ccsc1)OCCCCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
To a solution of 1 g (4.76 mM) of [5-(3-thienyl)tetrazol-1-yl] acetic acid and 514 mg (5.71 mM) of 1,4-butanediol in 10 ml of N,N-dimethylformamide was added 1.08 g (5.23 mM) of dicyclohexylcarbodiimide at room temperature. After the mixture was stirred at room temperature for 30 min, a small amount of acetic acid was added to the mixture and then was stirred for 30 min. The mixture was poured into ice-water. The precipitated crystal was filtered off and washed with water. The filtrate was extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/ethyl alcohol=30/1) for separation and purification, to give 810 mg (yield 60.3%) of [5-(3-thienyl)tetrazol-1-yl] acetic acid 4-hydroxybutyl ester.