Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][C@H:10]2[C:21]([O:23]C)=[O:22])[CH:5]=[CH:6][C:7]=1[Cl:8].[Li+].[OH-].Cl>CO>[C:17]([O:16][C:14]([N:12]1[CH2:13][C@@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C@H:10]([C:21]([OH:23])=[O:22])[CH2:11]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Boc anhydride (3.0 g, 13.7 mmol) was added to a solution of (3S,4R)-methyl 4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylate (3.10 g, 11.3 mmol) in THF (100 mL) and TEA (4 mL) was added. The mix was stirred at room temperature overnight. The solvent was removed and the residue was subject to column chromatography, eluted by hexane/ethyl acetate (8:1) to give (3S,4R)-1-tert-butyl 3-methyl 4-(3,4-dichlorophenyl)pyrrolidine-1,3-dicarboxylate (LCMS (APCI+) [M-Boc+H]+274.1; Rt: 4.17 min.). The (3S,4R)-1-tert-butyl 3-methyl 4-(3,4-dichlorophenyl)pyrrolidine-1,3-dicarboxylate was re-dissolved in MeOH (50 mL), and LiOH (3M, 10 mL) was added. The mixture was stirred at room temperature for 6 hours. 2N HCl (15 mL) was added to the mixture. The solvent was removed, and the residue was subject to column chromatography, eluted by DCM/MeOH (40:1-10:1) to give (3S,4R)-1-(tert-butoxycarbonyl)-4-(3,4-dichlorophenyl)pyrrolidine-3-carboxylic acid (1.95 g). LCMS (APCI+) [M-Boc+H]+260.1; Rt: 3.67 min.
Reaction SMILES: [H-].[Na+].[N:3]1[NH:4][N:5]=[N:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.Cl[CH2:20][C:21]1[N:22]=[C:23]([CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([C:36]([F:39])([F:38])[F:37])=[O:35])=[CH:30][CH:29]=2)[O:24][CH:25]=1.Cl>CN(C)C=O.O>[F:39][C:36]([F:37])([F:38])[S:34]([C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][C:7]4[N:6]=[N:5][NH:4][N:3]=4)=[CH:17][CH:16]=3)[N:22]=2)=[CH:29][CH:30]=1)=[O:35]
Reactant: O=S(c1ccc(C=Cc2nc(CCl)co2)cc1)C(F)(F)F
Reactant: Oc1ccc(CCCCc2nn[nH]n2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S(c1ccc(/C=C/c2nc(COc3ccc(CCCCc4nn[nH]n4)cc3)co2)cc1)C(F)(F)F
Reaction time: 0.25 h
Yield: 16.9 %

Procedure:
47.5 mg (1.88 mmol) 95% sodium hydride were given at 0° C. to a solution of 200 mg (0.916 mmol) 4-(4-2H-tetrazol-5-yl-butyl)-phenol in 5.0 ml N,N-dimethylformamide and stirred for 15 min. 308 mg (0.916 mmol) 4-chloromethyl-2-[2-(4-trifluoromethanesulfinyl-phenyl)-vinyl]-oxazole were added and stirring continued at 25° C. for 2 h. The reaction mixture was neutralized with HCl, poured into water and the resulting precipitate washed with little methanol and diethyl ether. The obtained material (180 mg) was purified by chromatography on silica gel (dichloromethane/methanol 100:4) to give 80 mg of the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][C@H:20]3[CH2:23][C:24]([O:26]C)=[O:25])=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:7]=1[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[F:36])[CH2:2][CH2:3][CH3:4].[OH-].[Li+]>C1COCC1.CO>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][C@@H:20]3[CH2:23][C:24]([OH:26])=[O:25])=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:7]=1[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[F:36])[CH2:2][CH2:3][CH3:4].[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][C@H:20]3[CH2:23][C:24]([OH:26])=[O:25])=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:7]=1[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:29]=1[F:36])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(COc2ccc3c(c2)[C@H](CC(=O)OC)CC3)ccc1-c1cc(OC)ccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOc1cc(COc2ccc3c(c2)[C@@H](CC(=O)O)CC3)ccc1-c1cc(OC)ccc1F
Product: CCCCOc1cc(COc2ccc3c(c2)[C@H](CC(=O)O)CC3)ccc1-c1cc(OC)ccc1F
Temperature: 23 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a solution of 17.1 (0.024 g, 0.0485 mmol) in THF/MeOH (2/1) (1.5 mL) was added lithium hydroxide (0.50 mL, 0.50 mmol). The resulting mixture was stirred overnight at 23° C., quenched with excess 1N HCl, and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel chromatography (0 to 40% EtOAc/hexanes) to afford ((1R)-6-(((2-(butyloxy)-2′-fluoro-5′-(methyloxy)-1,1′-biphenyl-4-yl)methyl)oxy)-2,3-dihydro-1H-inden-1-yl)acetic acid or ((1S)-6-(((2-(butyloxy)-2′-fluoro-5′-(methyloxy)-1,1′-biphenyl-4-yl)methyl)oxy)-2,3-dihydro-1H-inden-1-yl)acetic acid 17 (0.0098 g, 42% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.26-7.31 (1H, m), 7.15 (1H, d, J=7.8 Hz), 7.00-7.09 (3H, m), 6.81-6.90 (4H, m), 5.07 (2H, s), 4.00 (2H, t, J=6.5 Hz), 3.80 (3H, s), 3.59 (1H, m), 2.78-2.94 (3H, m), 2.55-2.40 (2H, m), 1.86-1.76 (1H, m), 1.64-1.71 (2H, m), 1.33-1.43 (2H, m), 0.89 (3H, t, J=7.4 Hz).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]2[CH2:23][C:22](=O)[O:21][C:19](=[O:20])[CH2:18]2)[CH:14]=[CH:15][CH:16]=1>>[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]([CH2:23][C:22]2[NH:9][C:4]3[CH:3]=[C:2]([I:1])[CH:7]=[CH:6][C:5]=3[N:8]=2)[CH2:18][C:19]([OH:21])=[O:20])[CH:14]=[CH:15][CH:16]=1.[ClH:10]
Reactant: Nc1ccc(I)cc1N
Reactant: O=C1CC(c2cccc(Cl)c2)CC(=O)O1
Product: Cl
Product: O=C(O)CC(Cc1nc2ccc(I)cc2[nH]1)c1cccc(Cl)c1

Procedure:
By a procedure similar to that of example 1.4, starting from 4-iodo-1,2-phenylenediamine and 3-(3-chlorophenyl)glutaric anhydride, 3-(3-chlorophenyl)-4-(5-iodo-2-benzimidazolyl)butanoic acid•HCl was obtained as light beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH2:23][CH3:24])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34](Cl)=[O:35]>ClCCl>[CH:18]1([C:17]2[N:10]3[C:11]([C:12](=[O:14])[NH:13][C:8]([C:4]4[CH:3]=[C:2]([NH:1][C:34](=[O:35])[C:33]([CH3:38])([CH3:37])[CH3:32])[CH:7]=[CH:6][CH:5]=4)=[N:9]3)=[C:15]([CH2:23][CH3:24])[N:16]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCc1nc(C2CCCC2)n2nc(-c3cccc(N)c3)[nH]c(=O)c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1nc(C2CCCC2)n2nc(-c3cccc(NC(=O)C(C)(C)C)c3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
50 mg (0.16 mmol) 2-(3-aminophenyl)-7-cyclopentyl-5-ethylimidazo[5,1-f][1,2,4]-triazin-4(3H)-one (Example 29) and 78 mg (0.77 mmol) triethylamine are dissolved in 4 ml dichloromethane. 37 mg (0.31 mmol) 2,2-dimethylpropanoyl chloride are added dropwise. The mixture is stirred for 2 hours at room temperature and then washed with 1 N potassium hydrogensulfate solution and with saturated sodium hydrogencarbonate solution. The organic layers are dried and evaporated to dryness in vacuo. The product is purified by chromatography (flash or column chromatography).
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[OH-].[Li+].Cl.[NH2:13]O.Cl>C(O)C.O>[NH2:9][C:8]1[CH:7]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[O:6][N:13]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(N)no1
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
In a 100 ml. round bottom 3-neck flask there was placed 2 g. of pivalyl acetonitrile, 25 ml. of ethanol, and 10 ml. of water. While this mixture was refluxed, a solution of 0.89 g. of lithium hydroxide and 1.5 g. of hydroxylamine hydrochloride in 25 ml. of water was added. At the end of the addition, the pH of the reaction mixture was about 7.2. The pH was adjusted to about 6.8 using concentrated aqueous hydrochloric acid. After 30 minutes the pH was about 6.0 and was readjusted to about 6.5 using an aqueous solution of lithium hydroxide. After 1 hour the pH was about 6.2 and was adjusted to about 6.8 using an aqueous solution of lithium hydroxide. At 1.5 hours the pH was about 6.6. At 2 hours the pH was about 6.7. At 21/2 hours the pH was about 6.8. At 3 hours the pH was about 7.0 and was adjusted to about 6.5 using concentrated aqueous hydrochloric acid. After 20 hours the pH was about 7.0. The reaction mixture was cooled and the ethanol stripped on the rotovapor. The solid which precipitated was filtered off and dried. It weighed 1.4 g., had a melting point of about 105°-106° C., and was determined by vpc to contain 98.5% of 3-amino-5-(t-butyl)isoxazole and 1% of 5-amino-3-(t-butyl)isoxazole. Yield: 62.5% of desired isomer.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][NH:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[C:8]([O:13][CH3:14])[N:7]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CN(C=O)C>[CH3:16][O:15][CH:3]([O:2][CH3:1])[CH2:4][NH:5][C:6]1[C:11]([NH:12][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:10][CH:9]=[C:8]([O:13][CH3:14])[N:7]=1
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(N)c(NCC(OC)OC)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccc(OC)nc1NCC(OC)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N2-[2,2-bis(methyloxy)ethyl]-6-(methyloxy)-2,3-pyridinediamine (2.2 g, 10 mmol), ethyl bromoacetate (1.1 mL, 1.65 g, 10 mmol) and potassium carbonate (2.1 g, 20 mmol) in acetonitrile (50 mL) and DMF (5 mL) was stirred at room temperature overnight. The mixture was filtered and evaporated. The residue was dissolved in ethyl acetate and washed with water and brine. The organic extract was concentrated and added to a silica column which was then eluted with 0-100% ethyl acetate in hexane affording product (2.5 g, 82%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([F:11])[CH:5]=1)[CH3:2].CN(C)CCN(C)CCN(C)C.[Li]CCCC.[CH2:29]([O:31][C:32](=[O:35])[CH:33]=[O:34])[CH3:30]>C1COCC1.C1(C)C=CC=CC=1>[CH2:29]([O:31][C:32](=[O:35])[CH:33]([C:7]1[C:6]([F:11])=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][C:8]=1[F:10])[OH:34])[CH3:30]
Reactant: CCOC(=O)C=O
Reactant: CCOc1cc(F)cc(F)c1
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1c(F)cc(OCC)cc1F
Reaction time: 2 h
Yield: 66.4 %

Procedure:
To a solution of 1-ethoxy-3,5-difluoro-benzene (7.50 g, 47.42 mmol, 1.0 equiv) and N-(2-dimethylamino-ethyl)-N,N′,N′-trimethyl-ethane-1,2-diamine (8.63 g, 10.40 mL, 49.80 mmol, 1.05 equiv) in anhydrous THF (125 mL) was added n-BuLi (31.13 mL, 49.80 mmol, 1.05 equiv; 1.6 M solution in hexane) within 1 h at −100° C. A solution of glyoxylic acid ethyl ester (9.68 g, 94.85 mmol, 2.0 equiv) in toluene (19 mL) was slowly added over a time period of 45 min and stirring continued for 2 h at −100° C. The cooling bath was removed and at −30° C. a solution of 2 M HCl (105 mL) was added. The solution was concentrated by evaporation under reduced pressure and the reaction mixture extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4 and concentrated by evaporation under reduced pressure. The crude material was purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate to give 8.2 g (66%) of the title compound. 1H NMR (300 MHz, CDCl3): 1.24 (t, J=7.5 Hz, 3H), 1.41 (t, J=7.5 Hz, 3H), 3.47 (d, J=6.0 Hz, 1H), 4.00 (q, J=7.5 Hz, 2H), 4.28 (q, J=7.5 Hz, 2H), 5.38 (d, J=6.0 Hz, 1H), 6.41-6.47 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7]([O:9][C:10](=[O:11])[C:2]=12)=[O:8].[Cl-:12].[Al+3].[Cl-].[Cl-].[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[ClH:12].[C:7]([C:3]1[C:2]([C:10]([OH:9])=[O:11])=[N:1][CH:6]=[CH:5][CH:4]=1)(=[O:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: c1ccccc1
Reactant: [Cl-]
Reactant: O=C1OC(=O)c2ncccc21
Agent: [Al+3]
Product: Cl
Product: O=C(c1ccccc1)c1cccnc1C(=O)O
Reaction time: 4 h

Procedure:
To a mixture of 2,3-pyridine dicarboxylic anhydride (21.0 g) and benzene (210 ml) was added anhydrous aluminum chloride (30.0 g), which was stirred for 4 hours under reflux. The reaction mixture was cooled and poured into ice water-hydrochloric acid. Resulting crystalline precipitate was collected by filtration, which was washed with a small volume of water, then with ethyl ether to give 3-benzoyl-2-pyridine carboxylic acid hydrochloride as pale yellow crystals (23.7 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH2:13]([I:15])[CH3:14]>>[I-:15].[CH2:13]([N+:8]1([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]2[CH3:1])[CH2:12][CH2:11][CH2:10][CH2:9]1)[CH3:14]
Reactant: CCI
Reactant: CC1CCCCC1N1CCCC1
Product: CC[N+]1(C2CCCCC2C)CCCC1
Product: [I-]

Procedure:
Using the same procedure described in examples 4 and 9 above, N-(2-methylcyclohexyl)pyrrolidine was quaternized with ethyl iodide to give N-ethyl-N-(2-methylcyclohexyl)pyrrolidinium iodide which ion-exchanged with hydroxide ion using the aforementioned exchange procedures to give the hydroxide solution of the N-ethyl-N-(2-methylcyclohexyl)pyrrolidinium in a combined yield 86% for both the quaternization and the exchange.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:10][CH2:11][CH2:12][CH3:13])[C:5](=[O:9])[O:6][CH2:7][CH3:8].S(Cl)([Cl:16])=O>C(Cl)Cl>[Cl:16][CH2:2][CH2:3][N:4]([CH2:10][CH2:11][CH2:12][CH3:13])[C:5](=[O:9])[O:6][CH2:7][CH3:8]
Reactant: CCCCN(CCO)C(=O)OCC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCN(CCCl)C(=O)OCC

Procedure:
52 g of ethyl (2-hydroxyethyl)-n-butylcarbamate are placed in 125 ml of methylene chloride and treated dropwise with 41.6 g of thionyl chloride during 45 minutes at 20°-25° C. Then the mixture is allowed to react for an additional 1 hour at room temperature. After removing the solvent, the residue is distilled to yield pure ethyl (2-chloroethyl)-n-butylcarbamate; b.p. 91° C./0.07 Torr.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:19]2[C:14]([CH:15]=[N:16][C:17]([S:20][CH3:21])=[N:18]2)=[CH:13][CH:12]=1.ClC1C=C(C=CC=1)C(OO)=[O:27]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[N:19]2[C:14]([CH:15]=[N:16][C:17]([S:20]([CH3:21])=[O:27])=[N:18]2)=[CH:13][CH:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2ccc3cnc(SC)nn23)c(OC)c1
Solvent: ClCCl
Product: COc1ccc(-c2ccc3cnc(S(C)=O)nn23)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-(2,4-Dimethoxy-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (592 mg, 1.00 equiv) and m-chloroperoxybenzoic acid (77%, 462 mg, 1.05 equiv) were dissolved in methylene chloride and stirred for 2 hours at room temperature. Partitioned between methylene chloride and saturated aqueous sodium bicarbonate. Dried over magnesium sulfate. Triturated with ether to afford 7-(2,4-dimethoxy-phenyl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid, 605 mg. LCMS (E/I+) 318 (M+H). NMR 1H (CDCl3) 9.02 (s, 1H), 7.22-7.34 (m, 2H), 7.03 (s, 1H), 6.67-6.77 (m, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 3.02 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C1(C)C=CC=CC=1.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)/C=C/c1c(C)cccc1Br
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCOC(=O)CCc1c(C)cccc1Br
Temperature: 25 °C

Procedure:
To a solution of commercially available ethyl (2E)-3-(2-bromo-6-methylphenyl)acrylate (1 eq.) in toluene (0.1M) at reflux was added benzenesulfonyl hydrazide (3 eq). The reaction mixture was refluxed for 3 h, cooled to room temperature, and diluted with Et2O. The organic phase was washed with aqueous 1N NaOH, brine, dried over MgSO4 filtered and concentrated. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 20%, in 30 min) afforded the desired compound.
Reaction SMILES: [S-2:1].[Na+].[Na+].Cl[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:6][C:7]#[N:8].Cl[CH2:14][C:15]#[N:16].C[O-].[Na+]>CN(C=O)C.CO.O>[C:9]([C:5]1[S:1][C:14]([C:15]#[N:16])=[C:7]([NH2:8])[CH:6]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)C(Cl)=CC#N
Reactant: N#CCCl
Reactant: [S-2]
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)c1cc(N)c(C#N)s1
Temperature: 75 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a suspension of sodium sulfide (3.26 g, 41.8 mmol) in DMF (42 mL) was added a solution of 3-chloro-4,4-dimethylpent-2-enenitrile (6.0 g, 41.8 mmol, Ohta, H.; Ishizaka, T.; Tatsuzuki, M.; Yoshinaga, M.; Iida, I.; Yamaguchi, T.; Tomishima, Y.; Futaki, N.; Toda, Y.; Saito, S. Bioorg. Med. Chem., 2008, 16, 1111-1124) in DMF (21 mL) at rt for 5 min and stirred the mixture at 70-80° C. for 2 h. Then chloroacetonitrile (5.3 mL, 83.6 mmol) was added dropwise to the reaction mixture and again stirred at 70-80° C. for 2 h. Then, a solution of sodium methoxide (2.26 g, 41.8 mmol) in dry methanol (42 mL) was added dropwise and stirring was continued for 2 h at the same temperature. The mixture was allowed to rt and poured into cold water and stirred for 30 min. The solution was extracted with chloroform (3×100 mL) and the combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-EtOAc (90:10) as eluent to give the product as a pale brown color solid (4.9 g, 65%), mp 118-122° C. 1H NMR (400 MHz, CDCl3): δ 6.32 (1H, s), 4.37 (2H, br s), 1.33 (9H, s); LC-MS (negative ion mode): m/z 179 (M−H)−.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:15][C:16]3[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=3[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:11]([CH3:14])[CH:12]=2)[C:7]([CH3:28])([CH3:27])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH2:29]1[CH:31]([CH:32](O)C#N)[CH2:30]1.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.C(#N)C>[CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([N:15]([C:16]3[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=3[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:32][CH:31]3[CH2:29][CH2:30]3)=[C:11]([CH3:14])[CH:12]=2)[C:7]([CH3:28])([CH3:27])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: N#CC(O)C1CC1
Reactant: CCOC(=O)c1ccccc1Nc1cc2c(cc1C)N(C(C)C)CCC2(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)c1ccccc1N(CC1CC1)c1cc2c(cc1C)N(C(C)C)CCC2(C)C
Yield: 49 %

Procedure:
Ethyl [(1-isopropyl-4,4,7-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl)amino)benzoate (Compound 20, 0.18 g, 0.47 mmol) was dissolved in a 10% acetic acid in acetonitrile solution (6.0 mL). The solution was treated with cyclopropylcarboxaldehyde (0.10 mL, 1.3 mmol) and then sodium cyanoborohydride (35 mg, 0.55 mmol) and the reaction was stirred at room temperature for 7 hours. 1M aqueous NaOH was added until pH=6 was reached and the solution was extracted with ether (2×), washed with brine, and dried (Na2SO4). The filtered solution was concentrated under reduced pressure and the residue purified using flash column chromatography (10% ethyl acetate in hexanes) to give the title compounds (0.1 g) as an oil.
Reaction SMILES: COC([CH2:5][N:6]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:8]2([CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[C:7]1=[O:20])=O.[C:21]([CH:25]1[CH2:30][CH2:29][CH:28]([CH:31]=O)[CH2:27][CH2:26]1)([CH3:24])([CH3:23])[CH3:22].[C:33]([OH:36])(=[O:35])[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:34][C:33]([O:36][CH2:5][N:6]1[C:19]2[C:14](=[CH:15][C:16]([CH2:31][CH:28]3[CH2:27][CH2:26][CH:25]([C:21]([CH3:22])([CH3:23])[CH3:24])[CH2:30][CH2:29]3)=[CH:17][CH:18]=2)[C:8]2([CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[C:7]1=[O:20])=[O:35]
Reactant: CC(=O)O
Reactant: CC(C)(C)C1CCC(C=O)CC1
Reactant: COC(=O)CN1C(=O)C2(CCNCC2)c2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(=O)OCN1C(=O)C2(CCNCC2)c2cc(CC3CCC(C(C)(C)C)CC3)ccc21

Procedure:
1-(Methoxycarbonyl-methyl)-spiro[indoline-3,4′-piperidin]-2-one (0.0137 g, 0.049 mmol) and 4-tert-butyl-cyclohexanecarbaldehyde (0.01 g, 0.06 mmol) were dissolved in dry 1,2-dichloroethane (1.5 mL). To the reaction mixture was then added glacial acetic acid (0.003 g, 0.049 mmol) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture was then added, at room temperature, sodium triacetoxyborohydride (0.018 g, 0.084 mmol) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then partitioned with aqueous NaHCO3 and dichloromethane. The organic layer was washed with brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (4.5% ammonia 2.0 M in methanol/dichloromethane) to yield the title compound as an oil.
Reaction SMILES: [C:1]1([C:7]2([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[C:18]#N)[N:14]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[OH:24]>[Zn]>[C:1]1([C:7]2([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:16]=[C:17]([CH2:18][OH:24])[CH:20]=[CH:21][CH:22]=4)[N:14]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1cccc(-c2csc(C3(c4ccccc4)CC3)n2)c1
Reactant: CO
Agent: [Zn]
Product: OCc1cccc(-c2csc(C3(c4ccccc4)CC3)n2)c1

Procedure:
3-[2-(1-phenylcyclopropyl)-1,3-thiazol-4-yl]benzonitrile (1-10, 0.10 g, 0.33 mmol) in MeOH (20 mL) was treated with NiCl2-6H2O (0.24 g, 1.0 mmol) and Zn metal (0.17 g, 2.6 mmol) and the resulting mixture was stirred vigorously at reflux for 72 h. The reaction was filtered through celite, concentrated, and partitioned between EtOAc (100 mL) and H2O (100 mL). The organic layer was concentrated and the crude residue was purified by reverse phase HPLC (C-8, 5-95% MeOH—H2O w/0.1% TFA) to provide pure {3-[2-(1-phenylcyclopropyl)-1,3-thiazol-4-yl]phenyl}methanol (5-1): 1H NMR (300 MHz, CDCl3) δ 7.82 (s, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.52 (dt, J=6.8, 1.3 Hz, 2H), 7.40-7.30 (m, 5H), 7.32 (s, 1H), 4.76 (s, 2H), 1.87 (dd, J=6.8, 3.9 Hz, 2H), 1.44 (dd, J=6.8, 3.9 Hz, 2H); MS 307.9 found 309.4 (M+H+) required.