Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][NH:9][CH:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:20])[CH:16]=2)[CH2:11]1.C1([O:27][C:28](=O)[NH:29][C:30]2[CH:35]=[C:34]([C:36]3[N:40]([CH3:41])[N:39]=[N:38][N:37]=3)[CH:33]=[C:32]([CH2:42][CH3:43])[CH:31]=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH2:42]([C:32]1[CH:31]=[C:30]([NH:29][C:28]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[CH2:8][NH:9][CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([F:20])[CH:16]=3)[CH2:11]2)=[O:27])[CH:35]=[C:34]([C:36]2[N:40]([CH3:41])[N:39]=[N:38][N:37]=2)[CH:33]=1)[CH3:43]
Reactant: N[C@@H]1CCCC[C@H]1CNC1CCc2cc(F)ccc2C1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)cc(-c2nnnn2C)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1cc(NC(=O)N[C@@H]2CCCC[C@H]2CNC2CCc3cc(F)ccc3C2)cc(-c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.6 %

Procedure:
A mixture of N-{[(1S,2R)-2-aminocyclohexyl]methyl}-(2RS)-6-fluoro-1,2,3,4-tetrahydronaphthalen-2-amine (60 mg, 217 μmol) and phenyl[3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)phenyl]carbamate (54 mg, 217 μmol) in acetonitrile (2 mL) was treated with triethylamine (75 μL, 540 μmol). After being stirred at room temperature for 18 hours, the mixture was concentrated under vacuum. The residue was purified by flash column chromatography, eluting with 5% methanol in dichloromethane containing 0.5% aqueous ammonia, to provide an amorphous solid (50 mg, 45%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:30]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:32]=[CH:33][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:37]4[CH:36]=[C:35]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:29][CH:30]=5)[CH:40]=[CH:39][CH:38]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cccc(-c2ccccc2)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccccc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 68, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-bromo-biphenyl.
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]([N:9]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:11][CH:10]1[C:20]([O:22]CC)=[O:21])=[O:8])(=O)C.[OH-].[K+].C>CO.O.ClCCl>[SH:4][CH2:5][CH2:6][C:7]([N:9]1[N:13]=[C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:11][CH:10]1[C:20]([OH:22])=[O:21])=[O:8]
Reactant: CCOC(=O)C1OC(c2ccccc2)=NN1C(=O)CCSC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: O=C(O)C1OC(c2ccccc2)=NN1C(=O)CCS
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.8 %

Procedure:
A solution of the product from step (c) (1.44 g) in methanol (40 ml) was cooled to 15° under nitrogen and treated dropwise with a solution of potassium hydroxide (0.69 g) in water (40 ml). The mixture was stirred at room temperature for 2 hours and then the solvents were evaporated. The residue was taken up in water and washed with ether. The aqueous phase was acidified with 2N HCl and extracted with ethyl acetate. The separated organic phase was washed with water, dried and evaporated. The residue was purified by flash chromatography to give a pale yellow solid. The solid was taken up in dichloromethane, treated with charcoal, filtered and the filtrate evaporated to give the title product (0.24 g) as an off-white solid. mp 106°-9°.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:29]#[N:30])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:21]=[CH:22][C:23]3[O:27][CH2:26][CH2:25][C:24]=3[CH:28]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:31][CH2:32][C:33]([OH:35])=[O:34]>>[C:29]([C:10]1[C:11]2[C:16](=[CH:15][C:14]([O:19][C:20]3[CH:21]=[CH:22][C:23]4[O:27][CH2:26][CH2:25][C:24]=4[CH:28]=3)=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:31][CH2:32][C:33]([OH:35])=[O:34])=[O:7])[N:9]=1)#[N:30]
Reactant: NCC(=O)O
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccc4c(c3)CCO4)cc2c1O
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2cc(Oc3ccc4c(c3)CCO4)ccc12

Procedure:
Prepared in analogy to example 31h from 1-cyano-6-(2,3-dihydro-benzofuran-5-yloxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and glycine. ESI MS (m/z): 404 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[OH-].[Na+].C(O)(=[O:18])C>O1CCCC1>[Cl:1][C:2]1[NH:11][C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc2nc(Cl)[nH]c(=O)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.6 %

Procedure:
To a solution of 2,4-dichloro-6-methylquinazoline (2.13 g, 10 mmol) in tetrahydrofuran (20 mL) was added sodium hydroxide (2 N, 20 mL). After being stirred at room temperature for 4 hours, the reaction mixture was chilled and acidified to pH 5 with acetic acid. The formed solid was collected by filtration, washed with water, and dried in vacuo to afford 1.7 g of the desired product as a white solid (yield was 87.6%).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1Cl)=[O:13])[CH2:8]2.[CH3:26][CH:27]1[O:32][CH:31]([CH3:33])[CH2:30][NH:29][CH2:28]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:18]=1[N:29]1[CH2:28][CH:27]([CH3:26])[O:32][CH:31]([CH3:33])[CH2:30]1)=[O:13])[CH2:8]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1cnn(-c2ccccc2)c1Cl
Reactant: CC1CNCC(C)O1
Product: CC1CN(c2c(C(=O)NC3C4CC5CC(C4)CC3C5)cnn2-c2ccccc2)CC(C)O1

Procedure:
5-(2,6-Dimethyl-morpholin-4-y1)-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide was prepared using Procedure A from 5-chloro-1-phenyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Intermediate 3) and 2,6-dimethylmorpholine. Mass spectrum (ES) MH+=435.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH3:16])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[I:18]Cl>C(O)(=O)C.O>[CH3:17][C:2]([CH3:1])([C:8]1[CH:13]=[CH:12][C:11]([I:18])=[C:10]([O:14][CH2:15][CH3:16])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: ClI
Reactant: CCOC(=O)C(C)(C)c1cccc(OCC)c1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(C)c1ccc(I)c(OCC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.8 %

Procedure:
To a cooled solution (5° C.) of ethyl dimethyl-3-ethoxyphenylacetate (5.0 g, 21.1 mmol) in acetic acid (40 mL) was added dropwise a solution of iodine monochloride (5.0 g, 30.9 mmol) in acetic acid. The reaction was stirred at room temperature for 18 h and diluted with water and extracted with methylene chloride. The combined organic layers were washed with aqueous sodium thiosulfate, aqueous sodium bicarbonate and brine. The solution was dried over anhydrous magnesium sulfate, filtered and concentrated to give ethyl dimethyl-(3-ethoxy-4-iodophenyl)acetate (6.25 g, 82%) as a yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=2)[N:7]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[C:6]=1[CH2:26][CH2:27][CH3:28])=[O:4].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)[C:5]([C:3](=[O:4])[CH2:2][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[C:6]1[CH2:26][CH2:27][CH3:28]
Reactant: C1COCCN1
Reactant: CCCc1c(C(=O)CCl)c2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl
Product: CCCc1c(C(=O)CN2CCOCC2)c2ccc(C(=O)OC)cc2n1Cc1ccccc1Cl
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
A mixture of methyl 3-chloroacetyl-1-(2-chlorobenzyl)-2-propylindole-6-carboxylate (123 mg) and morpholine (1 ml) was stirred at 50° C. for 2.5 hours. After cooled to 20° C., the reaction mixture was extracted with ethyl acetate. The organic phase was washed with 1N hydrochloric acid and water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:2) to give methyl 1-(2-chlorobenzyl)-3-morpholinoacetyl-2-propylindole-6-carboxylate (94 mg) as colorless amorphous.
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:17])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH3:16].[C:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][C:21]=1[O:30][CH2:31][CH3:32])#[N:19]>C1COCC1.C1COCC1.CN(C=O)C>[C:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:4])=[O:17])=[C:8]2[CH3:16])(=[O:28])=[O:27])=[CH:22][C:21]=1[O:30][CH2:31][CH3:32])#[N:19]
Reactant: CCOc1cc(S(=O)(=O)Cl)ccc1C#N
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOc1cc(S(=O)(=O)n2c(C)c(CC(=O)O)c3cccnc32)ccc1C#N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred, ice-cooled (0° C.) suspension of sodium hydride (26.3 mg of a 60% dispersion in mineral oil, 0.686 mmol) in dry THF (10 ml) under an inert atmosphere of Argon is added dropwise (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((0.1 g, 0.49 mmol) in THF/DMF (4 ml of a 3:1 mixture). The reaction mixture is stirred at 0° C. for 1 hour and then treated with 4-cyano-3-ethoxy-benzenesulfonyl chloride (168 mg, 0.686 mmol) in dry THF (1 ml). Stirring continued at 0° C. for 10 minutes and at room temperature for 10 minutes and then the reaction mixture is poured onto water (50 ml). The mixture is extracted with ethyl acetate (2×50 ml) and the organic portions are combined, washed brine (50 ml), dried (MgSO4) and concentrated in vacuo. The resulting crude is purified by chromatography on silica eluting with iso-hexane/ethyl acetate (0%-20% ethyl acetate) to yield the titled product. (MH+ 414).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:12][CH2:13][OH:14])[CH:2]=1.[C:15]([O:22]C(OC(C)(C)C)=O)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:12][CH2:13][OH:14])[CH:2]=1.[C:18]([O:17][C:15](=[O:16])[O-:22])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: OCC=Cc1cnc2ccccc2c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[O-]

Procedure:
3-(3-quinolyl)-2-propen-1-ol t-butyl carbonate was prepared as follows. To a 500-mL three-necked round-bottom flask equipped with an overhead mechanical stirrer was charged 3-(3-quinolyl)-2-propen-1-ol (13.03 g, 70.43 mmol) as a mixture of cis and trans isomers (81% cis, and 19% trans), di-t-butyl dicarbonate (16.91 g, 77.48 mmol, 1.11 equiv), tetra n-butyl ammonium hydrogensulfate (742 mg, 2.17 mmol) and methylene chloride (135 mL). The stirred mixture was cooled to 0 to 5° C. at which time aqueous 25% sodium hydroxide (33.3 mL) was added over 45 minutes such that the internal temperature did not rise above 20° C. Upon completion of the reaction (1 to 4 hours), the reaction mixture was diluted with methylene chloride (50 mL) and washed with water (2×125 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to provide the 3-(3-quinolyl)-2-propen-1-ol t-butyl carbonate: 18.35 g (91.4%) as an oil. This material can be further purified by chromatography on silica gel to provide purified carbonate as a colorless oil which retains the original ratio of cis and trans isomers: 17.50 g, 87.2%.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]2[C:21]([CH:22]=1)=[N:20][C:19]1[C:14](=[CH:15][CH:16]=[C:17]([NH2:23])[CH:18]=1)[CH:13]=2.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CS(C)=O>[CH2:25]([NH:23][C:17]1[CH:16]=[CH:15][C:14]2[C:19]([CH:18]=1)=[N:20][C:21]1[C:12](=[CH:11][CH:10]=[C:9]([NH:8][CH2:11][CH2:10][CH2:9][CH2:22][CH2:21][CH2:12][CH2:13][CH3:14])[CH:22]=1)[CH:13]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCBr
Reactant: Nc1ccc2cc3ccc(N)cc3nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCCCCNc1ccc2cc3ccc(NCCCCCCCC)cc3nc2c1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
6.33 g of anhydrous potassium carbonate are added to a solution of 2.5 g of 3,6-diaminoacridine hydrochloride and 3.55 ml of 1-bromooctane in 50 ml of dimethyl sulfoxide, and the mixture is stirred at 80° C. for 48 hours. The cooled reaction mixture is subsequently poured onto ice, and the brown suspension is extracted with methylene chloride. The organic phase is washed with saturated aqueous NaCl solution and dried over sodium sulfate. After evaporation, the red-brown oil is chromatographed on silica gel using methylene chloride/methanol (9:1). After evaporation of the solvent, the residue is taken up in diethyl ether/methanol (10:1) and chromatographed on aluminium oxide. The eluate is taken up in methanol, 2N HCl is added, the mixture is extracted with diethyl ether, and the ether phase is dried and evaporated. The residue is dissolved in methylene chloride, n-hexane is added, and the red crystalline precipitate formed is filtered off. Further product can be isolated from the mother liquor after evaporation. The melting point of the title compound is 245° C. Absorption spectrum (ethanol): λmax =472 nm; ε=51 400.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:9]=[C:8]([CH:10]=[O:11])[N:7]=[CH:6]2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:18][C:19]([Si](C)(C)C)([F:21])[F:20]>CN(C)C=O>[CH:1]1([CH2:4][N:5]2[CH:9]=[C:8]([CH:10]([OH:11])[C:19]([F:21])([F:20])[F:18])[N:7]=[CH:6]2)[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1cn(CC2CC2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(c1cn(CC2CC2)cn1)C(F)(F)F
Yield: 43.7 %

Procedure:
According to Reference Example 8-2, by use of 1-(cyclopropylmethyl)-1H-imidazole-4-carbaldehyde (133 mg, 0.886 mmol) obtained in Step 1 of Reference Example 8-49 and dissolved in N,N-dimethylformamide (2.7 mL), potassium carbonate (24 mg, 0.18 mmol) and (trifluoromethyl)trimethylsilane (0.196 mL, 1.33 mmol), the mixture was stirred and reacted at room temperature for 2 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=15/1) was performed to give 1-(1-(cyclopropylmethyl)-1H-imidazol-4-yl)-2,2,2-trifluoroethanol (Compound DX) (85.2 mg, yield: 44%).
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9].Cl[C:14]1[CH:15]=[C:16]2[N:23]([CH:24]([CH3:26])[CH3:25])[CH2:22][CH2:21][N:17]2[C:18](=[O:20])[N:19]=1>C1COCC1.CN(C=O)C>[CH:24]([N:23]1[C:16]2[N:17]([C:18](=[O:20])[N:19]=[C:14]([O:3][CH2:4][C:5]3[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=3)[C:8]#[N:9])[CH:15]=2)[CH2:21][CH2:22]1)([CH3:26])[CH3:25]
Reactant: N#Cc1cccc(CO)c1
Reactant: CC(C)N1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)N1CCn2c1cc(OCc1cccc(C#N)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using sodium hydride (17.97 mg, 0.449 mmol) in THF (4 mL), 3-(hydroxymethyl)benzonitrile (59.8 mg, 0.449 mmol) and 7-chloro-1-isopropyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (80 mg, 0.374 mmol) in DMF (2.00 mL).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH:9]=[C:8](Cl)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].C(COC)OC.C(O)C.O.[C:32]1(B(O)O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH:9]=[C:8]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)Oc1cc(-c2c[nH]c3ncccc23)cc(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1cc(-c2c[nH]c3ncccc23)cc(-c2ccccc2)n1
Temperature: 160 °C

Procedure:
To a solution of EXAMPLE 34C (0.13 g, 0.43 mmol) in 7:3:2 dimethoxyethane/ethanol/water (3 mL) was added phenyl boronic acid (0.053 g, 0.43 mmol), 1M aqueous sodium carbonate (0.6 mL) and dichlorobis(triphenylphosphine)-palladium (II) (0.015 g, 0.022 mmol). The solution was heated to 160° C. in a CEM microwave @100 W for 20 minutes. The crude material was diluted with ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated. Purification by flash chromatography (Analogix 280, gradient elution, 5-75% ethyl acetate/hexane) gave the title compound. MS (ESI) m/e 344.0 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([SH:14])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[CH3:15][O-].[Na+].IC>CO>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([S:14][CH3:15])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: C[O-]
Reactant: CC(=O)N1CCc2ccc(S)cc2C1
Agent: [Na+]
Solvent: CO
Solvent: CI
Product: CSc1ccc2c(c1)CN(C(C)=O)CC2
Temperature: 25 °C

Procedure:
A suspension of N-acetyl-7-mercapto-1,2,3,4-tetrahydroisoquinoline (1.0 gm., 0.0048 m.) in 20 ml. of methanol was stirred in a nitrogen atmosphere. Sodium methoxide (0.3 gm., 0.0055 m.) and 5 ml. of iodomethane were added to the suspension. The mixture was stirred at 25° C. for thirty minutes, evaporated and partitioned between chloroform and water. The chloroform layer was washed, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel, eluted with ethyl acetate to give pure N-acetyl-7-methylthio-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [C:1]([O:4][CH:5](SC)[C:6](=[O:26])[C@@H:7]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2].[BH4-].[Na+].Cl>CCO.O>[C:1]([O:4][CH2:5][CH:6]([OH:26])[C@@H:7]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CSC(OC(C)=O)C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)OCC(O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To a suitable reactor was added crude 3b in EtOH (100 mL) solution at 20-30° C. under N2. The mixture was cooled to −25 to −15° C., and NaBH4 (0.77 g) in H2O (7.7 mL) was added at below −8° C. The reaction mixture was warmed to −10 to −5° C. and stirred for 2 hr. The reaction was deemed completed as determined by TLC. 1N HCl aqueous solution (20 mL) was added at below 10° C. The mixture was extracted with EtOAc (100 mL×2). The separated organic portions were combined and concentrated under at 40-50° C. reduced pressure to afford crude 4b. The diastereomeric ratio of crude 4b was determined to be 97/3 by HPLC analysis.
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][N:4]=1.Br>C(O)(=O)C>[F:12][C:9]([F:10])([F:11])[C:8]1[C:3]([OH:2])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ncccc1C(F)(F)F
Agent: Br
Solvent: CC(=O)O
Product: Oc1ncccc1C(F)(F)F

Procedure:
Heat a mixture of 2-methoxy-3-trifluoromethyl-pyridine (1.0 g, 5.6 mmol) and 30% HBr in acetic acid (5 mL) at reflux for 1 hour. Cool the mixture and remove the volatiles by rotary evaporation. Add ether and collect the precipitate by filtration. Air-dry to give the title compound as the hydrogen bromide salt.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1(=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[C:16]1(=[N:12][CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NCc1cccc(Oc2ccccc2)c1
Reactant: O=C1CCCCC1
Product: c1ccc(Oc2cccc(CN=C3CCCCC3)c2)cc1
Yield: 58.8 %

Procedure:
The procedure is carried out as described in Example 1(b) but with the use of 50 g (0.25 mol) of 3-phenoxybenzylamine and 25 g (0.255 mol) of cyclohexanone. Distillation leaves 41 g (0.147 mol) of N-cyclohexylidene(3-phenoxybenzylamine), corresponding to a yield of 58.7% of theory; b.p. 135°-136° C./4 Pa.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]([CH2:13][CH3:14])[CH2:10][CH2:9][C:8]2=[O:15].N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>CN(C)C=O>[O:15]=[C:8]1[C:7]2[C:12](=[C:3]([CH2:2][O:1][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH:4]=[CH:5][CH:6]=2)[N:11]([CH2:13][CH3:14])[CH2:10][CH2:9]1
Reactant: CCN1CCC(=O)c2cccc(CO)c21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCC(=O)c2cccc(CO[Si](C)(C)C(C)(C)C)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
8-Hydroxymethyl-1-ethyl-4-oxo-1,2,3,4-tetrahydroquinoline (1.44 g) was dissolved in dimethyl formamide (2 ml). Imidazole (1.57 g) and t-butyl dimethylsilyl chloride (1.16 g) were added to the solution and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate-toluene. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off. The resulting residue was purified by silica gel column chromatography [eluent: n-hexane-ethyl acetate (3: 1) ] to give 4-oxo-8-t-butyldimethylsilyloxymethyl- 1-ethyl-1,2,3,4-tetrahydroquinoline (2.18 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].[Br:17]Br>C(O)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>[Br:17][C:6]1[C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=[C:8]([CH:10]=[O:11])[CH:7]=1
Reactant: O=Cc1ccc2c(c1)CCO2
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: O=Cc1cc(Br)c2c(c1)CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
To a solution of 2,3-dihydro-1-benzofuran-5-carbaldehyde (1.0 g, 6.75 mmol) in glacial acetic acid (8 ml) was added sodium acetate (664 mg, 8.1 mmol) and bromine (0.7 ml, 13.5 mmol) at 10° C. slowly. The reaction was stirred for 2 h at room temperature. The reaction was diluted with a saturated aqueous solution of sodium thiosulfate (10 ml), washed with a saturated aqueous solution of sodium bicarbonate, and then extracted with ethyl acetate. Organics were combined, dried over sodium sulfate and dried in vacuo to give the desired compound (1.4 g, 91%).