Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7](N)=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.N([O-])=O.[Na+].[BrH:15]>O.[Cu]Br>[Br:15][C:7]1[C:2]([Cl:1])=[N:3][C:4]([CH3:10])=[CH:5][C:6]=1[CH3:9]
Reactant: Br
Reactant: Cc1cc(C)c(N)c(Cl)n1
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c(Br)c(Cl)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2-chloro-4,6-dimethylpyridin-3-amine (2.85 g) was dissolved in hydrobromic acid (15 mL, 48% aqueous solution), and the solution was cooled to 0° C. A solution of sodium nitrite (1.51 g) in water (2 mL) was slowly added dropwise to the solution, and the mixture was stirred at 0° C. for 15 minutes. A suspension of copper(I) bromide (4.18 g) in hydrobromic acid (5 mL, 48% aqueous solution) was added dropwise to the solution, and the mixture was stirred at 0° C. for 10 minutes and then at 60° C. for one hour. The reaction mixture was cooled to room temperature, followed by extraction with ethyl acetate. The organic layer was directly subjected to an NH-silica gel pad and eluted with ethyl acetate. The resulting solution was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate/n-heptane, 0% to 30%) to give the title compound (2.97 g).
Reaction SMILES: [C:1]([CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][C:18]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=3)=[CH:19][C:14]=2[C:13](=[O:29])[N:12]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:11][C:10]1=[O:37])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].IC.[C:42]([O-:45])(=[O:44])[CH3:43].[NH4+:46]>>[C:1]([CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][C:18]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:46])[NH2:28])=[CH:23][CH:22]=3)=[CH:19][C:14]=2[C:13](=[O:29])[N:12]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:11][C:10]1=[O:37])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2].[C:42]([O-:45])(=[O:44])[CH3:43]
Reactant: [NH4+]
Reactant: CCOC(=O)CCN1CC(=O)N(CC(=O)OC(C)(C)C)c2ccc(Cc3ccc(C#N)cc3)cc2C1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Product: CCOC(=O)CCN1CC(=O)N(CC(=O)OC(C)(C)C)c2ccc(Cc3ccc(C(=N)N)cc3)cc2C1=O

Procedure:
1-(Carbo-t-butoxymethyl)-4-(2-carboethoxyethyl)-7-[(4-cyanophenyl)methyl]-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (16.0 g, 31 mmol) was placed in a dry 3-necked flask equipped with an inlet tube for gas dispersion and an outlet tube connected to a trap containing 1:1 2M NaOH/Clorox bleach. The flask was flushed with argon gas and anhydrous pyridine (90 mL) was added followed by the addition of triethylamine (70 mL). The resulting solution was saturated with hydrogen sulfide gas. The inlet and outlet tubes were removed and the reaction mixture was heated at 55° C.-60° C. for 21 hours. The reaction mixture was purged with argon and the volatiles removed in vacuo on a rotary evaporator. The residue was taken up in 5:4 dichloromethane/toluene (450 mL) and this was also removed in vacuo on a rotary evaporator. The treatment with dichloromethane/toluene was repeated once more. The residue was taken up in acetone (300 mL) and iodomethane (5.2 mL, 84 mmol) was added via syringe. The reaction mixture was stirred and heated at 60° C.-65° C. for 5.5 hours. The reaction mixture was cooled and the volatiles removed in vacuo on a rotary evaporator. The residue was taken up in anhydrous methanol (200 mL) under and atmosphere of argon and ammonium acetate (9.25 g, 120 mmol) was added. The reaction mixture was stirred at room temperature under an atmosphere of argon for 21 hours. The volatiles removed in vacuo on a rotary evaporator and the residue was taken up in acetonitrile (200 mL) and filtered through a sintered glass funnel. The reaction vessel was rinsed with additional acetonitrile (100 mL) which was also filtered through the sintered glass funnel. The filtrate was concentrated in vacuo on a rotary evaporator and the residue pumped on under high vacuum to yield 1-(carbo-t-butoxymethyl)-4-(2-carboethoxyethyl)-7-[(4-amidinophenyl)methyl]-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione, acetate (18.2 g, 99% yield)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C@@H:10]1[CH2:12][C@H:11]1[CH2:13][NH2:14].CCN(CC)CC.[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C@@H:10]1[CH2:12][C@H:11]1[CH2:13][NH:14][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: COc1ccc(F)c([C@@H]2C[C@H]2CN)c1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(F)c([C@@H]2C[C@H]2CNC(=O)C(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.2 %

Procedure:
To a magnetically stirred solution of (trans)-2-(2-fluoro-5-methoxyphenyl)cyclopropanemethanamine (600 mg, 3.1 mmol), Et3N (909 mg, 9.0 mmol), in dry dichloromethane (15 mL) at 0° C. was added isobutyryl chloride (352 mg, 3.3 mmol) dropwise. The resulting suspension was then allowed to warm to room temperature and stirred for 18 h. The solvents were removed and the residue was taken into EtOAc (100 mL) and washed sequentially with H2O, 5% citric acid, 5% K2CO3, brine, and dried over K2CO3. Concentration by rotary evaporation yielded a crude oil which was then purified by Kugelrohr distillation. Recrystallization of the resultant solid from Et2O/hexane (1:1) gave 380 mg (47% yield) of the title compound: mp 93°-94° C.; 1H NMR (300 MHz, CDCl3) δ0.82-0.88 (m, 1H), 0.97-1.03 (m, 1H), 1.13 (d, J=8.1 Hz, 6H), 1.14-1.24 (m, 1H), 1.85-1.91 (m, 1H), 2.25-2.30 (m, 1H), 2.93-3.02 (m, 1H), 3.52 (dt, I=7.8, 13.8 Hz, 1H), 3.72 (s, 3H), 5.74 (br s, 1H), 6.41-6.44 (m, 1H), 6.59-6.64 (m, 1H), 6.91 (t, J=6.5 Hz, 1H); IR (NaCl Film) 3298, 2962, 1642, 1546, 1502, 1428 cm-1 ; MS (isobutane--DCI) m/e 253; Analysis calc'd for C15H20NO2F: C, 67.90; H, 7.60; N, 5.28; found: C, 68.18; H, 7.77; N, 5.24.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[OH:10]S(O)(=O)=O.[C:15]1([CH3:21])[CH:20]=CC=C[CH:16]=1.N>C(O)(C)(C)C.O>[CH3:16][C:15]([NH:2][C:1]([C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][N:4]=1)=[O:10])([CH3:21])[CH3:20]
Reactant: Cc1cccnc1C#N
Reactant: O=S(=O)(O)O
Reactant: Cc1ccccc1
Agent: N
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1cccnc1C(=O)NC(C)(C)C
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
Suspend 2-cyano-3-methyl pyridine (400 g) in t-butanol (800 mL) and heat to 70° C. Add concentrated H2SO4 (400 mL) dropwise over 45 minutes. Maintain the temperature at 75° C., until the reaction is complete, and for an additional 30 minutes. Dilute the mixture with water (400 mL), charge with toluene (600 mL) and bring to pH 10 with concentrated aqueous ammonia. Maintain the temperature at 50°-55° C. during the work up. Separate the toluene phase, and reextract the aqueous layer. Combine toluene phases and wash with water. Remove the toluene to yield the title compound N-(1,1-dimethylethyl)-3-methyl-2-pyridine carboxamide, as an oil, from which solid product is crystallized. (Yield 97%, as determined by an internal standard assay with gas chromatography).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:28])[C:15]([C:25](=O)[CH3:26])=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:29]1([CH:35]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:36][CH2:37][O:38][C:39](=[O:44])/[CH:40]=[C:41](\[NH2:43])/[CH3:42])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CC(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:15]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[CH3:24])[C:40]([C:39]([O:38][CH2:37][CH2:36][CH:35]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[O:44])=[C:41]([CH3:42])[NH:43][C:25]=2[CH3:26])=[O:28])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C/C(N)=C/C(=O)OCCC(c1ccccc1)c1ccccc1
Reactant: CC(=O)C(=Cc1ccc(C)cc1C)C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CC(C)O
Product: CC1=C(C(=O)OCCC(c2ccccc2)c2ccccc2)C(c2ccc(C)cc2C)C(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)=C(C)N1

Procedure:
648 mg (1.67 mmol) of 4-[2-acetyl-3-(2,4-dimethylphenyl)-2-propenoyl]-1-piperazinecarboxylic acid t-butyl ester and 493 mg (1.67 mmol) of 3-aminocrotonate (3,3-diphenylpropyl) ester were heated and stirred in 5 ml of 2-propanol at 80° C. for two nights. After evaporating 2-propanol under reduced pressure, the residue was purified by the silica gel chromatography (hexane/ethyl acetate=5/1 to 1/9) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1Cl.[CH3:10][O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][NH2:23])=[CH:14][CH:13]=1>C(O)C>[Cl:1][C:2]1[C:3](=[O:9])[NH:4][N:5]=[CH:6][C:7]=1[NH:23][CH2:22][C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([O:11][CH3:10])=[CH:13][CH:14]=1
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: COc1ccc(CN)c2ccccc12
Solvent: CCO
Product: COc1ccc(CNc2cn[nH]c(=O)c2Cl)c2ccccc12
Reaction time: 8 h

Procedure:
A mixture comprising 330 mg of 4,5-dichloro-3(2H)pyridazinone, 1.12 g of 4-methoxy-1-naphthylmethylamine and 30 ml of ethanol, was refluxed under stirring overnight. The solvent was evaporated under reduced pressure, and a mixture of ethyl acetate and ethyl ether was poured to the residue, whereupon precipitated crystals were collected by filtration. The product was recrystallized from a mixture of methanol/water to obtain 410 mg of the above identified command as slightly yellow crystals having a melting point of from 265° to 266° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][C:21]([O:23][CH3:24])=[O:22].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[OH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([O:1][CH:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:14]=2)[C:21]([O:23][CH3:24])=[O:22])=[C:3]([CH2:10][CH2:11][CH3:12])[CH:4]=1
Reactant: COC(=O)Cc1ccccc1Br
Reactant: CCCc1cc(CO)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1cc(CO)ccc1OC(C(=O)OC)c1ccccc1
Yield: 82.6 %

Procedure:
To a solution of 0.484 g (2.91 mmol) of the product of Step F dissolved in 12 mL of acetone were added 0.667 g (2.91 mmol) of methyl 2-bromophenylacetate, 0.804 g (5.82 mmol) of anhydrous K2CO3 and the mixture was stirred and heated at reflux for 5 hours. The mixture was then cooled, filtered and evaporated in vacuo. The residual oil was purified on a silica gel flash chromatography column eluted with 30% ethyl acetate/hexane to afford 0.756 g (83%) of the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH:8](=O)[CH2:9][CH2:10][CH3:11].[F:13][C:14]([F:24])([F:23])[C:15]([N:17]1[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18]1)=[O:16].[H][H]>C(O)C.[Pd]>[CH2:8]([NH:22][C@H:19]1[CH2:20][CH2:21][N:17]([C:15](=[O:16])[C:14]([F:13])([F:23])[F:24])[CH2:18]1)[CH2:9][CH2:10][CH3:11]
Reactant: N[C@H]1CCN(C(=O)C(F)(F)F)C1
Reactant: [H][H]
Reactant: CCCC=O
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCN[C@H]1CCN(C(=O)C(F)(F)F)C1

Procedure:
Triethylamine (1.9 mL, 13.72 mmol) and butanal (1.3 mL, 14.41 mmol) were added to a solution of (S)-1-(trifluoroacetyl)pyrrolidin-3-yl amine (3.0 g, 13.72 mmol) (J. Med. Chem., 1996, 39(14), pg. 2771, No. 6) in ethanol (60 mL). The reaction mixture was treated with 10% Pd/C (300 mg) and placed under about 415 kPa (about 60 psi) of hydrogen at room temperature for 18 hours. The reaction mixture was filtered through Arbocel®, washing through with ethyl acetate. The filtrate was washed with saturated sodium hydrogencarbonate solution, dried over magnesium sulphate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with ethyl acetate:pentane:triethylamine 25:75:0 to 100:0:0 to 99:0:1 to yield the title product.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=1B(O)O>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=1[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][N:7]=1
Reactant: N#Cc1ccc(Cl)c(B(O)O)c1
Reactant: Brc1ccc(CNCCC2CCCCC2)cn1
Product: N#Cc1ccc(Cl)c(-c2ccc(CNCCC3CCCCC3)cn2)c1

Procedure:
Using the procedure outlined in Preparation 13, (6-bromopyridin-3-ylmethyl)-(2-cyclohexylethyl)amine and 2-chloro-5-cyanophenyl boronic acid were converted to the title compound: RT=2.79 min; m/z (ES+)=354.1 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:11]1[CH:17]=[C:16]([CH:18]([CH3:20])[CH3:19])[CH:15]=[C:14]([CH:21]([CH3:23])[CH3:22])[C:12]=1[NH2:13])([CH3:10])[CH3:9].[Br:24][CH2:25][C:26](Br)=[O:27]>C(Cl)(Cl)Cl>[Br:24][CH2:25][C:26]([NH:13][C:12]1[C:11]([CH:8]([CH3:10])[CH3:9])=[CH:17][C:16]([CH:18]([CH3:20])[CH3:19])=[CH:15][C:14]=1[CH:21]([CH3:23])[CH3:22])=[O:27]
Reactant: CC(C)c1cc(C(C)C)c(N)c(C(C)C)c1
Reactant: O=C(Br)CBr
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)c1cc(C(C)C)c(NC(=O)CBr)c(C(C)C)c1
Reaction time: 1 h
Yield: 80.8 %

Procedure:
Triethylamine (111 mg, 1.1 mmol) was added to a solution of 2,4,6-triisopropylaniline (219 mg, 1.0 mmol) in chloroform (3 ml), then bromoacetyl bromide (222 mg, 1.1 mmol) was gradually dropped thereinto with ice-cooling and the mixture was stirred for 1 hour. The reaction mixture was concentrated and the residue was extracted with ethyl acetate. The organic layer was washed with diluted hydrochloric acid, an aqueous solution of sodium bicarbonate and a saturated sodium chloride solution successively and dried over magnesium sulfate and the solvent was evaporated therefrom. The residue was purified by a silica gel column chromatography (15 g of silica gel; developing solvent, hexane:acetone=5:1) followed by recrystallizing from hexane-ether to provide 275 mg (yield 81%) of 2-Bromo-N-(2,4,6-triisopropylphenyl)acetamide as colorless needles.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.CC[O-].[Na+].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][N:5]1[CH:6]=[C:2]([CH3:1])[N:3]=[CH:4]1)[CH3:17]
Reactant: CCOC(=O)CBr
Reactant: Cc1c[nH]cn1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cn1cnc(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4.4 g (53.6 mmol) 4-methyl-1H-imidazole are initially introduced into 20.0 ml (17.4 g, 53.6 mmol) 21% strength sodium ethylate solution in ethanol and 6.5 ml (9.8 g, 58.9 mmol) ethyl bromoacetate are added. The reaction mixture is stirred at RT for 16 h. For working up, the solid which has precipitated out is filtered off, the residue on the filter is washed with ethanol and the filtrate is concentrated in vacuo. The residue is purified by column chromatography over silica gel (mobile phase: acetonitrile/water 9:1). The product is obtained as a 3:2 mixture of the two regioisomers and is further reacted as such.
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[CH2:11][C:10](=[O:14])[N:9]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:8]2=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[N:31]([CH2:34][C:35]([O:37]CC)=[O:36])=[C:32]=[S:33]>C(Cl)(Cl)Cl>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:32]([NH:31][CH2:34][C:35]([OH:37])=[O:36])=[S:33])[C:10](=[O:14])[N:9]([CH:15]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]3)[C:8]2=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CC(=O)N(C2CCCCC2)C(=O)N1C1CCCCC1
Reactant: CCOC(=O)CN=C=S
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CNC(=S)c1c(O)n(C2CCCCC2)c(=O)n(C2CCCCC2)c1=O
Reaction time: 8 h
Yield: 14.7 %

Procedure:
A mixture of 1,3-dicyclohexyl-2,4,6(1H,3H,5H)-pyrimidinetrione (660 mg, 2.25 mmoles), diisopropylethylamine (780 uL, 4.5 mmoles) and ethyl isothiocyanatoacetate (340 uL, 2.75 mmoles) in chloroform (20 mL) was stirred overnight. The mixture was washed with 1 molar hydrochloric acid (×2), dried and evaporated. The solid residue was purified by flash chromatography (dichloromethane) and the fractions evaporated, dissolved in ethanol (5 mL, some heating) and treated with 1 molar sodium hydroxide (3 mL). The mixture was stirred for 30 minutes and acidified to give a solid which recrystallized from ethanol-water to give the title compound (135 mg, 15%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.16 (s, 1 H), 12.54 (t, J=4.80 Hz, 1 H), 4.69 (t, J=12.00 Hz, 2 H), 4.35 (d, J=5.05 Hz, 2 H), 2.25 (q, 4 H), 1.79 (d, J=12.38 Hz, 4 H), 1.63 (d, J=12.38 Hz, 6 H), 1.29 (q, 4 H), 1.13 (q, 2 H).
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][N:21](COCC[Si](C)(C)C)[C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][CH3:34])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.C1(OC2C=C(C3NC4C=NN(COCC[Si](C)(C)C)C(=O)C=4C=3C)C=CC=2OC(F)F)CC1>>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[CH2:33][CH3:34])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:2][CH2:3]1
Reactant: CCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Agent: Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Product: CCc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cn[nH]c(=O)c12
Yield: 102.6 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 4-(c) except for using 5.84 g (11.9 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-ethyl-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 5-(b) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-methyl-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one, whereby 4.41 g of the title compound was obtained as a white solid substantially quantitatively.
Reaction SMILES: Cl[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1.[C:8]([O:12][C:13]([N:15]1[CH2:21][CH2:20][C:19]2[C:22]([C:27]#[CH:28])=[C:23]([Cl:26])[CH:24]=[CH:25][C:18]=2[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13]([N:15]1[CH2:21][CH2:20][C:19]2[C:22]([C:27]#[C:28][N:2]3[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]3)=[C:23]([Cl:26])[CH:24]=[CH:25][C:18]=2[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: C#Cc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: ClN1C=CC=CN1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(C#CN3C=CC=CN3)c2CC1
Yield: 19.8 %

Procedure:
Use a method similar to the General Procedure 8 to couple 2-chloro-pyridazine (98 mg, 0.86 mmol) with 3-tert-butoxycarbonyl-7-chloro-6-ethynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (104 mg, 0.34 mmol). Purify by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 4:1 gradient over 30 min) to give 3-tert-butoxycarbonyl-7-chloro-6-pyridazin-2-ylethynyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (26 mg, 10%). MS (ES+) m/z: 384 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH:7]=[C:8]([CH:13]=O)[C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[OH-].[Na+].Cl.[CH3:25][O:26][NH2:27]>C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH:7]=[C:8]([CH:13]=[N:27][O:26][CH3:25])[C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CON
Reactant: CCOc1cc(NC(=O)OC(C)C)cc(C=O)c1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cc(NC(=O)OC(C)C)cc(C=NOC)c1OCC
Reaction time: 12 h
Yield: 93 %

Procedure:
Isopropyl N-(3,4-diethoxy-5-formylphenyl)carbamate (0.6 g) was dissolved in ethanol (20 ml). To the solution was added an aqueous solution (10 ml) containing sodium hydroxide (0.32 g) and methoxyamine hydrochloride (0.66 g). After being allowed to stand for 12 hours, the reaction mixture was concentrated in vacuo, and the residue was dissolved in ethyl acetate. The resultant solution was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane to give isopropyl N-(3,4-diethoxy-5-methoxyiminomethylphenyl)carbamate (Compound No. 191) (0.61 g) in a yield of 93%. M.P., 110°-111.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13]CC)=O)=[N:9][N:10]=2)[CH:7]=1.Cl.Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[C:21]([C:31]([F:34])([F:33])[F:32])[CH:20]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([N:28]3[CH2:29][CH2:30][CH:25]([C:22]4[CH:23]=[CH:24][C:19]([F:18])=[CH:20][C:21]=4[C:31]([F:34])([F:32])[F:33])[CH2:26][CH2:27]3)=[O:13])=[N:9][N:10]=2)[CH:7]=1
Reactant: Fc1ccc(C2CCNCC2)c(C(F)(F)F)c1
Reactant: CCOC(=O)c1nnc2ccc(Br)cn12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2ccc(F)cc2C(F)(F)F)CC1
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (81 mg, 0.30 mmol) in THF (2.5 mL) was added a solution of LiOH monohydrate (14 mg, 0.30 mmol) in H2O (1.7 mL). The mixture stirred for 20 min and was neutralized with 2 N HCl. The mixture was concentrated under reduced pressure. The obtained residue was diluted in DMF (3.2 mL) under an atmosphere of N2. To this mixture was added 4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidine hydrochloride (85 mg, 0.30 mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (267 mg, 0.60 mmol), and diisopropylethylamine (0.15 mL, 0.91 mmol). The mixture was stirred at ambient temperature for 18 h. The resulting mixture was diluted with H2O (20 mL) and the resulting precipitate was collected by filtration. The obtained solids were chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0 to 50% EtOAc in hexanes) to provide (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as an orange film (92 mg, 64%): 1H NMR (300 MHz, DMSO-d6) δ 9.13 (dd, J=1.7, 0.9 Hz 1H), 7.98 (dd, J=10, 0.9 Hz, 1H), 7.77-7.69 (m, 2H), 7.60-7.47 (m, 2H), 5.30-5.18 (m, 1H), 4.77-4.68 (m, 1H), 3.43-3.34 (m, 1H), 3.28-3.12 (m, 1H), 3.11-2.90 (m, 1H), 1.97-1.69 (m, 4H); ESI MS m/z 472 [M+H]+.