Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]([CH:30]([CH3:32])[CH3:31])[C:5](=O)[CH2:6][CH:7]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[BH4-].[Na+].B(F)(F)F.CCOCC.Cl>O.O1CCCC1>[CH:30]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][CH:7]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:32])[CH3:31]
Reactant: Cc1ccc(OCc2ccccc2)c(C(CC(=O)N(C(C)C)C(C)C)c2ccccc2)c1
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(OCc2ccccc2)c(C(CCN(C(C)C)C(C)C)c2ccccc2)c1
Temperature: 2 °C
Reaction time: 11 h

Procedure:
N,N-diisopropyl-3-(2-benzyloxy-5-methyl-phenyl)-3-phenyl propane amide (1.0 Kg,), Tetrahydrofuran (5.0 lit) and Sodium borohydride (0.43 Kg) were taken into the round bottom flask. The contents were cooled to 2±3° C. followed by drop wise addition of Borontrifluoride etherate (1.93 Kg). The reaction mixture was stirred for 10-12 hrs at 33±2° C. After completion of the reaction a solution of Conc. Hydrochloric acid (2.83 L) into Process water (2.83 L) was added to the reaction mass at 40±10° C. and stirred for 2-3 hrs at 62±3° C. The product was extracted in dichloromethane (4.0 L). Dichloromethane distilled out completely under vacuum below 50° C. This was followed by addition of Isopropyl alcohol (1.0 L) and distilled it completely to give (±) N,N-diisopropyl-3-(2-benzyloxy-5-methylphenyl)-3-phenyl propane amine.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10](#[N:13])[CH:11]=[CH2:12].C([O-])(=O)C.[Na+]>CN(C=O)C.[Pd]>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([CH:12]=[CH:11][C:10]#[N:13])=[CH:3][CH:4]=1)=[O:7]
Reactant: C=CC#N
Reactant: O=Cc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC=Cc1ccc(C=O)cc1
Temperature: 130 °C
Reaction time: 10 h
Yield: 72.8 %

Procedure:
A stock solution consisting of 0.0260 g (3.125×10-5 mol) of diacetato-bis-(tris-o-tolylphosphine)-palladium(II) in 50 ml of DMF is prepared under argon. 1 ml of stock solution, 4.63 g (25 mmols) of 4-bromobenzaldehyde, 1.83 ml (27.5 mmols) of acrylonitrile and 2.26 g (27.5 mmols) of anhydrous sodium acetate are added to 9 ml of DMF under argon, and the reaction mixture is stirred at 130° C. for 10 hours. 2.86 g (18.2 mmols) of 4-formylcinnamonitrile are obtained, corresponding to a yield of 73% of theory (conversion figure 29200; Pd content 0.0025 mol %).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][C:14]3=[O:19])=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:20][N:21]2C(=O)C3C(=CC=CC=3)C2=O)[O:3]1.CN.[ClH:34]>CO>[ClH:34].[NH2:21][CH2:20][C@@H:4]1[O:3][C:2](=[O:1])[N:6]([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][C:14]3=[O:19])=[CH:9][CH:8]=2)[CH2:5]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Agent: CN
Agent: Cl
Solvent: CO
Product: NC[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 27.5 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
In a four neck round bottom flask, charged methanol (100 ml), 2-([(5S)-2-Oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-1H-isoindole-1,3(2H)-dione (10 g), and 40% aqueous methylamine (5 g) at 25 to 30° C. Reaction mass is stirred for 1 h at 25 to 30° C. Added second lot of 40% aqueous methylamine (5 g) to reaction mass at 25 to 30° C. After complete addition of methylamine solution, reaction mass is heated to 60 to 65° C., and maintained at same temperature for 4 h. Reaction mixture then cooled to 25 to 30° C. and added conc. hydrochloric acid (2 ml, pH should be 1 to 2). Finally reaction mass is cooled to 10° C. and stirred for 30 minutes. Obtained solid is filtered off and washed by chilled methanol (10 ml). Yield 80%
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]=2[S:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[N:3]1.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24]>O1CCCC1>[CH2:21]([NH:25][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[C:2](=[O:1])[N:3]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[S:5][C:6]=2[CH:11]=1)=[O:14])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN
Reactant: O=C(O)c1ccc2c(=O)nc(-c3ccccn3)sc2c1
Solvent: C1CCOC1
Product: CCCCNC(=O)c1ccc2c(=O)nc(-c3ccccn3)sc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 50.3 %

Procedure:
N,N′-carbonyldiimidazole (570 mg, 3.5 mmol) was added to a mixture of 4-oxo-2-(2-pyridyl)-4H-1,3-benzothiazine-7-carboxylic acid (800 mg, 2.8 mmol) and tetrahydrofuran (20 ml), and the mixture was stirred at 60° C. for 2 hrs. Successively, butylamine (410 mg, 5.6 mmol) was added to the reaction mixture, and the mixture was stirred at 60° C. for 30 minutes. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (1:3, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (478 mg, 50%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([NH:26][CH2:27][CH2:28][OH:29])=[O:25])[CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:30][N:31](C)[C:32](=O)OC(C)(C)C)[CH:9]=1.Cl.C(=O)(O)[O-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=2)[O:22][CH2:23][C:24]([NH:26][CH2:27][CH2:28][OH:29])=[O:25])(=[O:14])=[O:15])[CH:11]=[C:10]([CH2:30][NH:31][CH3:32])[CH:9]=1
Reactant: CN(Cc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC(=O)NCCO)c2)c1)C(=O)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CNCc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(OCC(=O)NCCO)c2)c1
Reaction time: 2 h

Procedure:
tert-Butyl ((5-(2-fluorophenyl)-1-((3-(2-((2-hydroxyethyl)amino)-2-oxoethoxy) phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 10a (83 mg, 0.15 mmol) was added to a solution of hydrogen chloride in 1,4-dioxane (4 N, 20 mL), and then the reaction solution was stirred for 2 h. The pH of the reaction solution was adjusted to 7 to 8 with a saturated sodium bicarbonate solution, and it was extracted with dichloromethane (50 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography with elution system A to obtain the title product 2-(3-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)-N-(2-hydroxyethyl)acetamide 10 (34 mg, a yellow oil) in 50% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]2[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=2[O:32][CH3:33])=[CH:11][C:10]=1[C:34](O)=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:49]1[CH:54]=[CH:53][C:52]([CH2:55][CH2:56][NH2:57])=[CH:51][CH:50]=1>CN(C=O)C.O>[CH2:56]([NH:57][C:34]([C:10]1[CH:11]=[C:12]([C:23]2[CH:28]=[C:27]([CH:29]([CH3:30])[CH3:31])[CH:26]=[CH:25][C:24]=2[O:32][CH3:33])[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:35])[CH2:55][C:52]1[CH:53]=[CH:54][CH:49]=[CH:50][CH:51]=1
Reactant: NCCc1ccccc1
Reactant: COc1ccc(C(C)C)cc1-c1cc(C(=O)O)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)C)cc1-c1cc(C(=O)NCCc2ccccc2)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 2 h
Yield: 94 %

Procedure:
4,6-Bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-carboxylic acid (965 mg, 2 mmol) was dissolved in DMF (anhydrous, 10 ml), and CDI (324 mg, 2 mmol) was added and the resulting solution was stirred at r.t for 2 h. 2-Phenethylamine (267 mg, 2.2 mmol) solution in DMF (5 ml) was added and the resulting solution was stirred at r.t. until the reaction was complete. The reaction was diluted with water (50 ml), extracted with dichloromethane (50 ml×3), and the combined organics were washed thoroughly with water to remove DMF and dried over sodium sulfate. After filtration and concentration, the residue was purified by flash chromatography on silica gel to give 4,6-bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-carboxylic acid phenethyl-amide (1101 mg, 94%). M.p.: 138-140° C.; 400 MHz 1H NMR (CDCl3) δ: 8.17 (s, 1H), 7.87 (t, J=5.6 Hz, 1H), 7.40-7.36 (m, 3H), 7.32-7.11 (m, 14H), 6.87 (d, J=8.0 Hz, 1H), 6.54 (s, 1H), 5.03 (s, 2H), 5.00 (s, 2H), 3.72 (s, 3H), 3.64 (q, J=6.4 Hz, 2H), 2.92-2.81 (m, 1H), 2.75 (t, J=7.2 Hz, 2H), 1.23 (d, J=7.2 Hz, 6H); LCMS: 586 [M+H].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[CH2:9][CH:10](OCC)OCC>Cl>[N:7]1[C:2]2[NH:1][CH:10]=[CH:9][C:3]=2[C:4](=[O:8])[NH:5][CH:6]=1
Reactant: CCOC(Cc1c(N)nc[nH]c1=O)OCC
Agent: Cl
Product: O=c1[nH]cnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
6-Amino-5-(2,2-diethoxy-ethyl)-3H-pyrimidin-4-one (150 mg, 0.7 mmol) was dissolved in 5.0 mL of 1N HCl solution. The mixture was stirred at room temperature for 1 hour and the precipitate was filtered, washed with minimal amount of water and dried in a vacuum oven overnight to give 60 mg (64%) of 3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one as a white solid. 1H NMR (360 MHz, DMSO-d6) δ 11.83 (s, 1H, NH), 1.75 (s, 1H, NH), 7.80 (s, 1H), 7.01 (dd, J=2.65, 3.21 Hz, 1H), and 6.42 (dd, J=2.09, 3.21 Hz, 1H). MS m/e 134 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=2)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[C:26]([F:33])[CH:25]=1>>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:3]=[C:4]([NH:14][C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=3)[CH:5]=[N:6][C:7]=2[O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[C:26]([F:33])[CH:25]=1
Reactant: O=C(Nc1cnc(OCC(F)(F)F)c(Br)c1)c1cccnc1
Reactant: OB(O)c1ccc(Cl)cc1F
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2F)c1)c1cccnc1

Procedure:
The title compound was synthesized in analogy to Example 39, using N45-bromo-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-nicotinamide (example G) and B-(4-chloro-2-fluorophenyl)-boronic acid (CAN 160591-91-3) as starting materials; LC-MS (UV peak area/ESI) 97.2%, 424.0483 (M−H)−.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C=O.[C:18](O)(=O)C.O([BH-](OC(C)=O)OC(C)=O)C(C)=O.[Na+]>ClCCl.CO>[CH3:18][N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: NC(=O)c1ccc(C2CCNCC2)cc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(c2ccc(C(N)=O)cc2)CC1
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of 4-piperidin-4-ylbenzamide (200 mg, 1.00 mmol), 37% aqueous formaldehyde (162 μL, 2.00 mmol), and acetic acid (86 uL, 1.5 mmol) in a mixture of dichloromethane and methanol (2:1, 6 mL) was added sodium triacetoxylborohydride (318 mg, 1.5 mmol) in portions over fifteen minutes and stirring was continued for 2 hr at room temperature. The reaction was then quenched with water and adjusted to pH 9 with 2N aqueous sodium hydroxide then extracted with dichloromethane (2×50 ml). The organic extracts were combined and dried over sodium sulfate, filtered and concentrated to give 4-(1-methylpiperidin-4-yl)benzamide (190 mg, 87%). MS (EI) for C13H18N2O: 218 (MH+).
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[C:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31]>C(#N)C>[CH3:31][C:30]([CH3:32])=[CH:29][CH2:28][N:15]1[CH:10]2[CH2:11][CH2:12][CH:13]1[CH2:14][C:8](=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:16]1[CH:20]=[CH:19][S:18][CH:17]=1)[CH2:9]2
Reactant: CC(C)=CCBr
Reactant: c1ccc(C(=C2CC3CCC(C2)N3)c2ccsc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)=CCN1C2CCC1CC(=C(c1ccccc1)c1ccsc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 100 mg (355 μmol) of 3-(phenyl-thiophen-3-yl-methylene)-8-aza-bicyclo[3.2.1]octane in 1 mL of acetonitrile was added 98 mg (710 μmol) of K2CO3 and 41 μL (355 μmol) of 4-bromo-2-methyl-2-butene at room temperature. The reaction mixture was allowed to stir overnight at room temperature. Next day, the crude was filtered and washed with acetonitrile. The combined filtrates were concentrated. The concentrated sample was purified by reverse phase chromatography (20×100 mm J'sphere H-80 YMC column using a gradient of 0.1% TFA/water to 5% water/0.1% TFA/acetonitrile). The eluent was evaporated to yield the title compound as a white solid; MS m/z (MH+) 350; 1H NMR 300 MHz (MeOD-d4) δ 6.87-7.39 (m, 8H), 5.35 (t, 1H), 3.94-4.00 (m, 2H), 3.29-3.31 (m, 2H), 2.58-2.89 (m, 4H), 1.62-2.25 (m, 10H).
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:21][OH:22])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:23]1([C:29]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)Cl)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O1CCCC1.C(#N)C>C(N(CC)CC)C>[CH2:1]([O:17][CH2:18][C@H:19]([CH2:21][O:22][C:29]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCOCC(O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCOC[C@@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
40 grams of 1-hexadecyl-glycerol and 43 grams triphenylchloromethane were added to a mixture of 500 ml dry tetrahydrofuran and 130 ml dry acetonitrile. 35 ml of dry triethylamine was added, and the reaction mixture was refluxed for 17 hours. The reaction mixture was then cooled to room temperature, poured on ice (1 kilogram) and extracted thrice with 250 ml diethyl ether. The organic phase was washed consecutively with 100 ml water, 100 ml dilute (1.5%) sulfuric acid, 100 ml water, 100 ml concentrated aqueous sodium bicarbonate and again with 100 ml water. The obtained organic phase was dried over anhydrous sodium sulfate and the solvent was thereafter removed under reduced pressure. The residue was dissolved in 200 ml ethyl acetate and the resulting solution was cooled at −20° C. overnight. The mixture was then centrifuged at −5° C. and the mother liquid solution was poured off. The solid was dissolved in hexane and refrigerated overnight at 5° C. Filtration of the precipitate yielded pure 1-hexadecyl-3-trityl-sn-glycerol.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[Br:1][C:2]1[C:3]([S:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: Sc1ccccc1
Product: Clc1ncc(Br)c(Sc2ccccc2)n1

Procedure:
Using an analogous method to that described in Method 1, but starting from 5-bromo-2,4-dichloropyrimidine and thiophenol, the product was obtained. NMR: 7.6 (m, 5H), 8.8 (s, 1H).
Reaction SMILES: Cl.[Br:2][C:3]1[N:7]([CH2:8]Cl)[N:6]=[C:5]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:4]=1.[F:14][C:15]([F:24])([F:23])[CH2:16][CH2:17][CH:18]([C:21]#[N:22])[C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:2][C:3]1[N:7]([CH2:8][C:18]([CH2:17][CH2:16][C:15]([F:14])([F:23])[F:24])([C:19]#[N:20])[C:21]#[N:22])[N:6]=[C:5]([C:10]([CH3:13])([CH3:12])[CH3:11])[N:4]=1
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: CC(C)(C)c1nc(Br)n(CCl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1nc(Br)n(CC(C#N)(C#N)CCC(F)(F)F)n1
Yield: 28.6 %

Procedure:
2.03 g of 5-bromo-3-t-butyl-l-(chloromethyl)-1H-1,2,4-triazole hydrochloride and 1.30 g of (3,3,3-trifluoropropyl)malononitrile were dissolved in 24 ml of N,N-dimethylformamide. 2.21 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.76 g of [(5-bromo-3-t-butyl-1H-1,2,4-triazole 1-yl)methyl](3,3, 3-trifluoropropyl)malononitrile (referred as the compound of the present invention (32), hereinafter) shown by below formula.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[C:5]([C:9]2[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2noc3ccsc23)c1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1cccc(-c2noc3ccsc23)c1
Yield: 39.9 %

Procedure:
Eight grams of 3-(3-methoxyphenyl)thieno[2,3-d]isoxazole was stirred with 80 g of pyridine hydrochloride for nine hours under nitrogen at 140° C. The reaction mixture was then allowed to cool and quenched with water. The organics were extracted into ether/ethyl acetate (1:1), which was then washed once with 3N hydrochloric acid and three times with water an dried over anhydrous magnesium sulfate. Evaporation of the solvents left 4 g of an oil, which was passed through a silica gel column packed in hexane. Elution of the column with 5% ethyl acetate/dichloromethane and recrystallization of the resultant solid from ether/hexane gave 3 g of a solid, m.p. 114°-116° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH3:30])=[CH:20][CH:19]=3)=[CH:17][C:12]=2[CH:11]=[C:10]([C:31]([O:33]C)=[O:32])[CH2:9][CH2:8]1)[CH3:2].[OH-].[Na+]>C1COCC1.CO>[CH2:1]([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][CH3:30])=[CH:22][CH:23]=3)=[CH:17][C:12]=2[CH:11]=[C:10]([C:31]([OH:33])=[O:32])[CH2:9][CH2:8]1)[CH3:2]
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CCCOCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCCOCC)cc1
Temperature: 50 °C
Reaction time: 62 h
Yield: 84.6 %

Procedure:
To a solution of methyl 1-(3-ethoxypropyl)-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (475 mg) in a mixture of THF-methanol (5-10 ml) was added 1N sodium hydroxide solution (3.0 ml) at room temperature, and the mixture was stirred at 50° C. for 62 hours. After concentration under reduced pressure, to the mixture was added 1N hydrochloric acid (3.0 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. After concentration under reduced pressure, the resulting crystals were collected by filtration. The crystals were washed with diisopropyl ether and hexane to give 1-(3-ethoxypropyl)-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (390 mg) as yellow crystals.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][NH2:13])=[CH:10][C:5]=2[S:4](=[O:14])[CH2:3]1.Br[CH2:16][CH2:17][CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][NH:13][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])=[CH:10][C:5]=2[S:4](=[O:14])[CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: CN1CS(=O)c2cc(CCN)ccc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CS(=O)c2cc(CCNCCCCN3C(=O)c4ccccc4C3=O)ccc21
Temperature: 60 °C
Reaction time: 6 h

Procedure:
In a round-bottomed flask, 2.2 mmol of 3-methyl-6-(2-aminoethyl)benzothiazolinone, obtained in the previous example, are dissolved in 20 ml of dimethyl-formamide in the presence of 2.4 mmol of N-(4-bromo-butyl)phthalimide, 6.6 mmol of potassium carbonate and a catalytic amount of potassium iodide. The mixture is left stirring at 60° C. for 6 hours. After cooling, the solvent is evaporated off and/or extracted with chloroform after adding water.
Reaction SMILES: [ClH:1].[CH2:2]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH2:16][CH3:17])[C:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([O:29][CH:30]([CH3:32])[CH3:31])[CH:20]=1)=[N:10][CH2:9][CH2:8]2)[CH3:3].[Na]>CO.C(OCC)C.C(OC(C)C)(C)C>[ClH:1].[CH2:2]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH2:16][CH3:17])[CH:11]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([O:29][CH:30]([CH3:32])[CH3:31])[CH:20]=1)[NH:10][CH2:9][CH2:8]2)[CH3:3]
Reactant: CCOc1cc2c(cc1OCC)C(Cc1ccc(OC(C)C)c(OC(C)C)c1)=NCC2
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: CC(C)OC(C)C
Solvent: CCOCC
Product: CCOc1cc2c(cc1OCC)C(Cc1ccc(OC(C)C)c(OC(C)C)c1)NCC2
Yield: 92.4 %

Procedure:
21 g (0.0455 mole) of 6,7-diethoxy-1-(3',4'-diisopropoxybenzyl)-3,4-dihydroisoquinoline hydrochloride was dissolved in 300 ml of methanol in a 1 liter 3-necked flask. The solution was cooled in an ice/water bath and 2.1 g (0.0555 moles) of sodium borhydride was added in two portions with agitation. Stirring was continued for half an hour, the solvent removed under reduced pressure and the residue obtained taken up in 500 ml of diethyl ether. The ethereal solution was washed 3 times with 200 ml of water, dried over sodium sulphate and the solvent removed under reduced pressure. The oil obtained was dissolved in 20 ml of isopropyl ether, and allowed to crystallize. The product was filtered and re-dissolved in 200 ml of diethyl ether, then a solution of hydrochloric acid in diethyl ether added to pH 2. The solvent was removed under reduced pressure and the residue obtained triturated, firstly in isopropyl ether and then in diethyl ether. After drying, 19.5 g of the title hydrochloride was obtained. Yield=92.5%, m.p. 168° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.NN>[Pd].C(O)C>[N:13]1([S:10]([C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)(=[O:12])=[O:11])[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)N2CCOCC2)c1
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Temperature: 0 °C

Procedure:
4-(3-Nitro-benzenesulfonyl)-morpholine (5.9 g, 21.7 mmol) was combined with 10% palladium on carbon (1 g), ethanol (60 mL), and hydrazine (5 mL) and heated at reflux for 18 h. The solution was filtered through celite, concentrated, and cooled to 0° C. Product precipitated out an colorless crystal (4.7 g, 89%). MS (ESI) m/z=243 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:15])[N:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]([CH3:8])[C:6]=1[CH3:7].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23].N>O.CC(O)C.[Fe-3](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+]>[Cl:16][C:17]1[C:18](=[O:23])[CH:19]=[CH:20]/[C:21](=[N:1]/[C:2]2[C:3](=[O:15])[N:4]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:5]([CH3:8])[C:6]=2[CH3:7])/[CH:22]=1
Reactant: Cc1c(N)c(=O)n(-c2ccccc2)n1C
Reactant: Oc1ccccc1Cl
Agent: N#C[Fe-3](C#N)(C#N)(C#N)(C#N)C#N
Agent: N
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: Cc1c(/N=C2/C=CC(=O)C(Cl)=C2)c(=O)n(-c2ccccc2)n1C

Procedure:
10 mmol of 4-amino-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one was dissolved in 30 ml of water. This solution was admixed with 10 mmol of 2-chlorophenol in solution in 30 ml of 2-propanol, 3 ml of 20% aqueous ammonia and 22 mmol of potassium ferricyanide at a temperature ranging from 5 to 10° C.