Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:30]([C:32]1[CH:37]=[CH:36][C:35]([C@H]2CC[C@H](C=O)CC2)=[CH:34][CH:33]=1)#[N:31].[C:46]1([CH3:52])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(OC)(C)(C)C.O>[CH3:2][O:3][CH:4]=[CH:52][C@H:46]1[CH2:51][CH2:50][C@H:49]([C:37]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[C:30]#[N:31])[CH2:48][CH2:47]1
Reactant: N#Cc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: O
Product: COC=C[C@H]1CC[C@H](c2ccccc2C#N)CC1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
Commercially available methoxymethyltriphenylphosphonium chloride (127.5 g, 0.372 mol) was added to methyl t-butyl ether (1 l), followed by adding potassium t-butoxide (43.1 g, 0.384 mol) in argon atmosphere with stirring at -10° C. over 10 minutes, agitating the reaction solution at 0° C. for one hour, dropwise adding a solution of trans-4-(4-cyanophenyl)cyclohexylcarboaldehyde (V) obtained in Example 1, (i) (44.1 g, 0.207 mol) in methyl t-butyl ether (200 ml) at =10° C. over 15 minutes, agitating the resulting reaction solution at 0° C. for one hour, adding toluene (0.3 l) and water (0.3 l), subjecting the resulting toluene solution to four times washing with water (0.3 l) and separating, drying with anhydrous sodium sulfate, separating the drying agent, distilling off toluene, dissolving the resulting residue in ethyl acetate (100 ml) on heating, allowing the solution to stand still for one day, filtering off deposited crystals, concentrating the mother liquor, dissolving the concentrate in heptane, purifying according to silica gel column chromatography to obtain trans-1-(2-methoxy-1-ethenyl)-4-(cyanophenyl)cyclohexane (39.8 g, 0.165 mol), adding to the total quantity, tetrahydrofuran (500 ml) and 2N-hydrochloric acid (120 ml), heating the mixture under reflux with stirring for one hour, cooling the resulting reaction solution, adding toluene (300 ml) and water (1 l), washing subjecting the resulting toluene solution to three times washing with water (1 l) and separating, drying with anhydrous sodium sulfate, separating the drying agent and distilling off toluene to obtain trans-4-(4-cyanophenyl)cyclohexylacetaldehyde (VII) (35.4 g, 0.156 mol).
Reaction SMILES: [NH3:1].[B:2]([O-:5])([O-:4])[O-:3].[Na+:6].[Na+].[Na+]>>[Na+:6].[NH4+:1].[B:2]([O-:5])([O-:4])[O-:3].[Na+:6].[Na+:6].[Na+:6]
Reactant: N
Agent: [Na+]
Agent: [O-]B([O-])[O-]
Product: [NH4+]

Procedure:
About 100 parts by weight of powdered borax (Na2B4O7 ·4H2O) are added to 100 parts by weight of concentrated aqueous ammonia containing 25% ammonia while agitating. The mixture is reacted for about 4 hours at ambient temperature and pressure thereby hydrolyzing the sodium borate and splitting the molecules into smaller molecules. The ammonia reacts with the sodium borate to produce an ammonium sodium salt of polyboron oxyacid and polyammonium sodium borate which is dried and pulverized into a powder with the general formula
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:2].[BH4-].[Na+].FC(F)(F)C(O)=O.O>C1COCC1>[NH2:2][CH2:1][CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cccc(CC#N)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc(CCN)c1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
To a solution of 1.31 g (7.48 mmol) of methyl 3-(cyanomethyl)benzoate in 31 mL of THF stirred at −10° C. was slowly added 710 mg (18.7 mmol) of sodium borohydride followed by 1.44 mL (18.7 mmol) of trifluoroacetic acid. The mixture was warmed to 22° C. and stirred for about 16 h. About 100 mL of water was carefully added to the mixture (gas evolution). The mixture was extracted with ethyl acetate (5×50 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give methyl 3-(2-aminoethyl)benzoate which was used in the next step without purification.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[NH:3][C:4]([N:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[OH:7])=[O:5].[OH-].[Na+].Cl[C:20](OCC)=[O:21]>O1CCOCC1>[F:14][C:11]1[CH:12]=[CH:13][C:8]([N:6]2[C:4](=[O:5])[N:3]([C:2]([F:15])([F:1])[F:16])[C:20](=[O:21])[O:7]2)=[CH:9][CH:10]=1
Reactant: O=C(NC(F)(F)F)N(O)c1ccc(F)cc1
Reactant: CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=c1on(-c2ccc(F)cc2)c(=O)n1C(F)(F)F

Procedure:
1-Trifluoromethyl-3-(4'-fluorophenyl)-3-hydroxyurea (11.9 grams; 0.05 mol) is dissolved in dioxane (80 ml) and mixed with 2N aqueous sodium hydroxide (30 ml). Ethyl chloroformate (5.7 ml; 0.06 mol) is then added dropwise to the mixture at 10° to 15°C, with stirring, resulting in the formation of a precipitate. The precipitate is recovered by filtration, washed with water and dried to yield 2-(4'-fluorophenyl)-4-trifluoromethyl-1,2,4-oxadiazolidine-3,5-dione.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:10])[CH2:7][C:8]#[N:9])[CH3:4].Br[CH2:12][CH2:13][CH:14]=[CH2:15]>CN(C=O)C>[CH2:3]([O:5][C:6](=[O:10])[CH:7]([C:8]#[N:9])[CH2:15][CH2:14][CH:13]=[CH2:12])[CH3:4]
Reactant: CCOC(=O)CC#N
Reactant: C=CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCC(C#N)C(=O)OCC
Reaction time: 0.5 h

Procedure:
To a flame dried flask charged with NaH (1.4 g, 35.46 mmol, 60% dispersion in mineral oil) and DMF (90 mL) equipped with a Firestone valve and under a stream of dry nitrogen was added, dropwise ethylcyanoacetate (3.14 mL, 29.56 mmol) over 20 min. The reaction mixture was then allowed to stir for 30 min, followed by addition of 4-bromobutene (3.0 mL, 29.56 mmol). The reaction mixture was allowed to stir overnight after which the solvent was removed by reduced pressure. The resulting crude mixture was dissolved in ethyl acetate, washed 3 times with 1N HCl solution and once with a saturated solution of brine. The organic and aqueous layers were separated and the organic layer was dried with sodium sulfate, filtered and the solvent was removed under reduced pressure to yield a residue. The residue was purified by flash chromatography using a mixture of 9:1 heptanes to ethyl acetate to yield a clear colorless oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][C:21]2=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:26][O:27][CH2:28]Cl>C1COCC1>[CH:13]1([CH2:19][C:20]2([CH2:26][O:27][CH3:28])[CH2:25][CH2:24][O:23][C:21]2=[O:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=C1OCCC1CC1CCCCC1
Reactant: COCCl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCC1(CC2CCCCC2)CCOC1=O
Temperature: -78 °C
Reaction time: 4.5 h
Yield: 25 %

Procedure:
A solution of diisopropylamine (19.0 mL) in THF was treated dropwise with butyl lithium (82.5 mL of 1.6M solution in hexanes) at −10° C. Next the reaction mixture was cooled to −78° C. and treated dropwise with 2-(cyclohexyl-methyl)-γ-butyrolactone (18.0 mL) keeping the speed of the addition at such a rate that the temperature of the mixture remained below −60° C. After completion of the addition, the mixture was stirred for 4.5 h at −78° C., then warmed-up to −40° C. and treated dropwise at this temperature with chloromethyl methyl ether (10.8 mL). After that, the mixture was allowed to slowly warm-up to room temperature and stirred at this temperature for 60 h. The solvents were removed in vacuum and the residue was redissolved in dichloromethane, then washed with a saturated aqueous solution of ammonium chloride, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and finally distilled in vacuum to give 5.90 g (25%) of the title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C@H:11]1[N:21]2[C@@H:15]([S:16][CH2:17][CH2:18][C@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]2=[O:22])[CH2:14][CH2:13][CH2:12]1)(=O)[NH2:9].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[C:8]([C@H:11]1[N:21]2[C@@H:15]([S:16][CH2:17][CH2:18][C@H:19]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[C:20]2=[O:22])[CH2:14][CH2:13][CH2:12]1)#[N:9]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(N)=O)N2C1=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C#N)N2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
Triethylamine (58.8 mg, 0.581 mmol) was added to a 0° C. solution of tert-butyl (4S,7S,10aS)-7-carbamoyl-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (57 mg, 0.17 mmol) in DCM (1.2 mL). TFAA (52.3 mg, 0.249 mmol) was then slowly added to the reaction. The ice bath was removed and the reaction mixture was left to stir at rt for 1 hr. The reaction was diluted with DCM (2 mL) and quenched by the addition of aqueous 10% Na2CO3 (2 mL). The aqueous phase was isolated and extracted with DCM (2 mL). All organic phases were combined, dried over MgSO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give tert-butyl (4S,7S,10aS)-7-cyano-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (36 mg, 0.11 mmol, 67% yield) as a light yellow solid. Anal. Calcd. for C15H23N3O3S m/z 325.4. found: 326.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:13]([C:14]2[NH:15][C:16](=[O:27])[C:17]3[C:18](=[C:20]([CH2:24][CH2:25][CH3:26])[N:21]([CH3:23])[N:22]=3)[N:19]=2)=[CH:12][C:9]([C:10]#[N:11])=[CH:8][N:7]=1)[CH:2]([CH3:4])[CH3:3].P(S)(OCC)(OCC)=[S:29]>O.ClCCl>[CH2:1]([O:5][C:6]1[N:7]=[CH:8][C:9]([C:10](=[S:29])[NH2:11])=[CH:12][C:13]=1[C:14]1[NH:15][C:16](=[O:27])[C:17]2[C:18](=[C:20]([CH2:24][CH2:25][CH3:26])[N:21]([CH3:23])[N:22]=2)[N:19]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCCc1c2nc(-c3cc(C#N)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Reactant: CCOP(=S)(S)OCC
Solvent: ClCCl
Solvent: O
Product: CCCc1c2nc(-c3cc(C(N)=S)cnc3OCC(C)C)[nH]c(=O)c2nn1C
Temperature: 25 °C

Procedure:
Water (2 drops) was added to a stirred suspension of 6-isobutoxy-5-(2-methyl-7-oxo-3-propyl-6,7-dihydro-2H-pyrazolo[4,3-d]pyrimidin-5-yl)-nicotinonitrile (Example 36) (150 mg, 0.41 mmol) in (EtO)2P(S)SH (0.5 mL). The mixture was stirred at room temperature. After 5 h more (EtO)2P(S)SH (0.5 mL) was added and dichloromethane (5 mL) added to aid stirring. After 14 h the reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. After filtration and separation of the phases the organics were washed again with saturated sodium bicarbonate solution and brine, dried (MgSO4) and concentrated. The product was purified by flash column chromatography (gradient elution from 100% dichloromethane to 96% dichloromethane:methanol) to give 80 mg product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH2:24]([O:26][C:27](=[O:35])[CH2:28][C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1)[CH3:25].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O>[CH2:24]([O:26][C:27](=[O:35])[CH2:28][C:29]1[N:30]=[C:31]([NH:34][C:9](=[O:11])[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[S:32][CH:33]=1)[CH3:25]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2ccc(Cl)cc2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 43.5 %

Procedure:
A solution of 2-(4-chloro-phenyl)-3-cyclopentyl-propionic acid (252 mg, 1.0 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with a 2.0 M solution of oxalyl chloride in methylene chloride (0.55 mL, 1.1 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 15 min and then at 25° C. for 1.5 h. The reaction mixture was then treated with (2-amino-thiazol-4-yl)-acetic acid ethyl ester (409 mg, 2.2 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.4 mmol). This solution was stirred at 25° C. for 24 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 85/15 hexanes/ethyl acetate) afforded {2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester (183.3 mg, 43.5%) as a pale yellow oil: EI-HRMS m/e calcd for C21H25ClN2O3S (M+) 420.1274, found 420.1272.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[CH2:20][OH:21])[CH3:2].[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[N:30]=[C:31]=[O:32]>>[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[NH:30][C:31]([O:21][CH2:20][C:5]1[CH:6]=[C:7]([CH:18]=[CH:19][C:4]=1[O:3][CH2:1][CH3:2])[CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[O:32]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1CO
Product: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1COC(=O)Nc1ccc(F)cc1F

Procedure:
Using dimethyl 2-[4-ethoxy-3-(hydroxymethyl)benzyl]-malonate and 2,4-difluorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b)
Reaction SMILES: FC(F)(F)[C:3]([O:5][C:6](=O)[C:7](F)(F)F)=O.[NH:14]1[CH2:23]C2C(=CC=CC=2)[CH2:16][C@H:15]1[C:24](O)=[O:25]>ClCCl>[CH3:3][O:5][C:6]1[CH:7]=[CH:16][C:15]([CH2:24][OH:25])=[N:14][CH:23]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C(O)[C@@H]1Cc2ccccc2CN1
Solvent: ClCCl
Product: COc1ccc(CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Trifluoroacetic anhydride (28.2 mL, 203 mmol) was added dropwise to an ice cooled solution of the product from preparation 20 (˜135 mmol) in dichloromethane (500 mL), the mixture was allowed to warm to room temperature and stirred overnight. Tic analysis indicated still largely starting material so a further portion of trifluoroacetic anhydride (15 mL, 108 mmol) was added dropwise and the mixture was allowed to stir for a further 27 hours. The reaction was quenched by the cautious addition of methanol (250 mL) and left to stir for 30 minutes before being concentrated in vacuo. 2.5 M sodium hydroxide (100 mL) was then added cautiously and the mixture was extracted with dichloromethane (4×100 mL). The combined organic extracts were dried (MgSO4) and evaporated to give the desired product (12 g, 64%) contaminated with recovered starting material (˜15 mol %). 1H NMR (CDCl3, 400 MHz) δ 3.80 (3H, s), 4.40 (1H, br), 4.66 (2H, s), 7.16 (1H, dd), 7.20 (1H, d), 8.17 (1H, d).
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1)#[N:28]>>[C:27]([C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH:26][C@H:23]2[CH2:22][CH2:21][C@H:20]([CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][CH:12]([C:11]4[C:6]5[CH2:5][CH2:4][O:3][C:7]=5[CH:8]=[CH:9][CH:10]=4)[CH2:13][CH2:14]3)[CH2:25][CH2:24]2)=[O:34])=[CH:31][CH:30]=1)#[N:28]
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: Cl
Product: N#Cc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4CCO5)CC3)CC2)cc1

Procedure:
The title compound, off-white solid (90 mg, 79%), MS (ISP) m/z=458.3 [(M+H)+], mp 230° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 4-cyano-benzoic acid.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:6]([CH2:18][CH3:19])[CH:5]=1.O1CCOCC1.[OH-].[Na+].Cl>CO>[CH2:18]([N:6]1[C:7]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[CH:8][C:9](=[O:10])[C:4]([C:3]([OH:20])=[O:2])=[CH:5]1)[CH3:19]
Reactant: CCN1C=C(C(=O)OC)C(=O)CC1c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CCn1cc(C(=O)O)c(=O)cc1-c1ccc(Cl)cc1

Procedure:
The starting material was obtained by dissolving 1.85 g. of 1-ethyl-6-(4-chlorophenyl)-4-oxo-1,4,5,6-tetrahydronicotinic acid methyl ester (prepared as described in Example 1) in 10 ml. of dioxane and 10 ml. of methanol and heating the solution under reflux for 3 hours in the presence of 20 ml. of 1-N sodium hydroxide. The mixture was cooled down, acidified with 0.5-N hydrochloric acid, the separated crystals were filtered off under suction and recrystallized from methanol/ether. Yield 1.3 g.; melting point 142°-144° C.
Reaction SMILES: Br[CH2:2][C:3](Br)=[O:4].[CH2:6]([NH:13][CH2:14][CH3:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:29][C:30]2[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[CH2:6]([N:13]([CH2:14][CH3:15])[C:3](=[O:4])[CH2:2][N:29]([S:26]([C:23]1[CH:24]=[CH:25][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:21][CH:22]=1)(=[O:28])=[O:27])[C:30]1[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Br)CBr
Reactant: CCNCc1ccccc1
Reactant: COc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1
Product: CCN(Cc1ccccc1)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of 2-bromoacetyl bromide with N-benzyl-N-ethylamine and 4-tert-butyl-N-(6-methoxy-pyridin-3-yl)-benzenesulfonamide
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:20])[CH2:6][C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[CH:10][CH:9]=1.[CH2:21](I)[CH3:22].[CH3:24]I>CN(C)C=O>[CH3:3][O:4][C:5](=[O:20])[C:6]([CH2:21][CH3:22])([CH3:24])[C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)=[CH:10][CH:9]=1
Reactant: CCI
Reactant: COC(=O)CC(=O)c1ccc(-n2ccnc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)(C(=O)OC)C(=O)c1ccc(-n2ccnc2)cc1
Reaction time: 48 h

Procedure:
To a slurry of 2.49 g of sodium hydride (60% dispersion in Nujol) in 50 ml of dimethylformamide is added a solution of 24.4 g of 4-(1H-imidazol-1yl)-β-oxobenzenepropanoic acid methyl ester in 75 ml of dimethylformamide at 15°-20° C. After the addition is completed 15.6 g of ethyl iodide is added and stirring is continued for 48 hours. The reaction mixture is filtered, poured into water, and the mixture is extracted with ether. Removal of the solvent and trituration with isopropyl ether gives an oil. A solution of 2.72 g of the oil in 10 ml of dimethylformamide is added to a slurry of 0.24 g of sodium hydride (60% dispersion in Nujol) at 15°-20°. A solution of 1.42 g of methyl iodide in 5 ml of dimethylformamide is added and stirring is continued for 20 hours at room temperature. The reaction mixture is filtered, poured into water, and is extracted with ether.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([NH:13][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[C:15]([F:18])([F:17])[F:16])=[O:12])=[CH:5][C:4]=1[C:29]([F:32])([F:31])[F:30])#[N:2].[Cl-].[OH:34][NH3+:35].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[OH:34][N:35]=[C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([NH:13][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[C:15]([F:16])([F:17])[F:18])=[O:12])=[CH:5][C:4]=1[C:29]([F:30])([F:32])[F:31])[NH2:2]
Reactant: N#Cc1ccc(/C=C/C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1C(F)(F)F
Reactant: [NH3+]O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=NO)c1ccc(/C=C/C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1C(F)(F)F

Procedure:
1.17 g (2.51 mmol) of (2E)-3-[4-cyano-3-(trifluoromethyl)phenyl]-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}acrylamide from Example Ia-46 were initially charged in a mixture of 11.7 ml of ethanol and 2.9 ml of water and admixed with 209.6 mg (3.01 mmol) of hydroxylammonium chloride and 399.5 mg (3.77 mmol) of sodium carbonate. The reaction mixture was heated under reflux for 18 hours and then admixed with water. After extracting repeatedly with ethyl acetate, the combined organic phases were dried over magnesium sulphate, the solvent was distilled off under reduced pressure and the residue was chromatographed using silica gel with cyclohexane/ethyl acetate as the eluent (gradient from 0% ethyl acetate to 100% ethyl acetate).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[C@H:9]([CH3:16])[CH2:8][N:7]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[C:6]=2[CH:25]=1.CC1(C)C(C)(C)OB([C:34]2[CH:35]=[N:36][NH:37][CH:38]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][C:12]1[N:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:34]4[CH:35]=[N:36][NH:37][CH:38]=4)=[CH:25][C:6]=3[N:7]([C:17]3[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=3)[CH2:8][C@@H:9]([CH3:16])[C:10]2=[N:14][N:13]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(C#N)cc1)C[C@H]2C
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Cc1nnc2n1-c1ccc(-c3cn[nH]c3)cc1N(c1ccc(C#N)cc1)C[C@H]2C
Temperature: 130 °C
Reaction time: 0.33 h
Yield: 15.1 %

Procedure:
To a solution of (R)-4-(8-bromo-1,4-dimethyl-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzonitrile (100 mg, 0.26 mmol) in DME/H2O (3:1, 2 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (70 mg, 0.36 mmol), cesium carbonate (164 mg, 0.50 mmol) and Tetrakis(triphenylphosphine)palladium(0)(22 mg, 0.02 mmol). The mixture was stirred in the microwave at 130° C. for 20 min. The reaction mixture was concentrated and purified by prep-TLC (elute: DCM:MeOH=15:1) to give (R)-4-(1,4-dimethyl-8-(1H-pyrazol-4-yl)-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-6(5H)-yl)benzonitrile (15 mg, 15%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH:6](=O)[CH3:7].[CH:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=1)([CH3:11])[CH3:10]>C(O)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH:18][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([CH:9]([CH3:11])[CH3:10])=[CH:13][CH:14]=1)[CH3:7]
Reactant: CC=O
Reactant: CC(C)c1ccc(C(N)=O)cc1
Reactant: c1ccsc1
Solvent: CC(=O)O
Product: CC(C)c1ccc(C(=O)NC(C)c2cccs2)cc1

Procedure:
Thiophene, acetaldehyde and 4-isopropylbenzamide were stirred in a mixture of acetic acid/concentrated hydrochloric acid in the following ratio under the following reaction condition to obtain N-[1-(2-thienyl)ethyl]-4-isopropylbenzamide. In Runs 1 and 2, a large part of the product was a tar-like material.