Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1CCCC1.C(O)(=O)C.[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1[OH:19])[CH:14]=O.[O:23]=[C:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=1)=[O:30]>O1CCCC1>[OH:10][C:11]1[CH:12]=[C:13](/[CH:14]=[CH:42]/[C:24](=[O:23])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([NH:31][C:32]2[CH:33]=[CH:34][C:35]([C:38]([F:39])([F:40])[F:41])=[CH:36][CH:37]=2)=[O:30])[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]=1[OH:19]
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Reactant: CC(=O)CCCCC(=O)Nc1ccc(C(F)(F)F)cc1
Solvent: C1CCNC1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(/C=C/c1cc(O)c(O)c([N+](=O)[O-])c1)CCCCC(=O)Nc1ccc(C(F)(F)F)cc1
Reaction time: 56 h

Procedure:
0.875 ml of pyrrolidine in 35 ml of tetrahydrofuran is treated at 5° with 0.605 ml of acetic acid and subsequently with 1.73 g of 3,4-dihydroxy-5-nitrobenzaldehyde and 2.87 g of 6-oxo-4'-(trifluoromethyl)-heptananilide and stirred at 23° under argon for 56 hours. The residue obtained after evaporating the reaction mixture is partitioned between ethyl acetate and 1N sodium hydroxide solution. The combined sodium hydroxide extracts are made acid with conc, hydrochloric acid, extracted with ethyl acetate, the combined ethyl acetate extracts are washed with saturated sodium chloride solution, dried over sodium sulfate, evaporated and the residue is chromatographed on 120 g of silica gel with methylene chloride/methanol (91:9). After recrystallization from ethyl acetate/petroleum ether there is obtained (E)-8-(3,4-dihydroxy-5-nitrophenyl)-6-oxo-4'-(trifluoromethyl) -7-octenanilide of m.p. 194°-197°.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13]1([C:19]2([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>ClCCCl.[Fe](Cl)Cl>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([C:16]2[CH:15]=[CH:14][C:13]([C:19]3([C:25]4[CH:26]=[CH:27][C:28]([C:8](=[O:9])[C:7]5[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=5)=[CH:29][CH:30]=4)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]3)=[CH:18][CH:17]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: c1ccc(C2(c3ccccc3)CCCCC2)cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl[Fe]Cl
Agent: Cl
Solvent: ClCCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1)c1ccc(C2(c3ccc(C(=O)c4ccc([N+](=O)[O-])cc4)cc3)CCCCC2)cc1
Temperature: 80 °C
Yield: 54.3 %

Procedure:
In a 10-liters three-necked flask equipped with a stirring device, a thermometer and a nitrogen substituting device, 703 g (4.33 mole) of iron chloride and 1.7 liters of 1,2-dichloroethane were mixed, and 732 g (3.94 mole) of paranitrobenzoyl chloride was introduced with ice cooling to be dissolved. After warming the reaction solution to 80° C., a solution of 395 g (1.67 mole) of diphenylcyclohexane in 630 milliliters of 1,2-dichloroethane was added dropwise for 3 hours and 40 minutes. After the dropwise addition was ended, the solution was stirred gently at reflux for 6 hours. After the end of the reaction was confirmed by a liquid chromatography, the reaction solution was poured in 2 liters of ice, 1 liter of a 4N-HCl aqueous solution was added and then extracted with 1.5 liters of chloroform. The solution was washed with a 6N-HCl aqueous solution, an aqueous solution of sodium hydrogencarbonate, brine and water, and then dried with magnesium sulfate. After removing off chloroform by a rotary evaporator, 700 milliliters of ethyl acetate was added still hot and cooled to deposit crystals. Deposited crystals were filtered off and the filtrate was treated with a silica gel column and purified by recrystallization from chloroform/ethyl acetate, to obtain 485 g of 1,1-bis(4-(4-nitrobenzoyl)phenyl)cyclohexane as crystals.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]([OH:24])=O)=[CH:4][C:5]2[C:6]3[N:15]([CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:14]=[CH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:26]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(=O)([O-])O.[Na+].C(OCC)(=O)C.[ClH:80]>CO.CN(C=O)C>[ClH:80].[ClH:80].[CH3:1][C:2]1[C:3]([C:22]([N:35]2[CH2:36][CH2:37][N:32]([CH2:31][C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)[CH2:33][CH2:34]2)=[O:24])=[CH:4][C:5]2[C:6]3[N:15]([CH:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:14]=[CH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1
Reactant: c1cncc(CN2CCNCC2)c1
Reactant: Cc1cc2[nH]c(=O)c3cnn(C4CCOCC4)c3c2cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc2[nH]c(=O)c3cnn(C4CCOCC4)c3c2cc1C(=O)N1CCN(Cc2cccnc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 120 mg of 7-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline-8-carboxylic acid and 2.4 mL of DMF were added 130 mg of 1-(pyridin-3-ylmethyl)piperazine, 0.19 mL of DIPEA, and 177 mg of TBTU, followed by stirring at room temperature overnight. The reaction mixture was ice-cooled and poured into a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol=100/0-92/8) to obtain white powder. The powder was suspended in 1 mL of methanol, and 0.37 mL of a 4 M hydrogen chloride-ethyl acetate solution was added thereto, followed by stirring for 30 minutes. The obtained powder was collected by filtration, washed with methanol, and then dried under reduced pressure to obtain 82 mg of 7-methyl-8-{[4-(pyridin-3-ylmethyl)piperazin-1-yl]carbonyl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one dihydrochloride as a white solid.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[CH2:3][CH2:4][C@H:5]([NH:9][C@@H:10]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)[C:11]([F:14])([F:13])[F:12])[C:6](O)=[O:7].Cl.[NH2:34][CH2:35][C:36]#[N:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.O.C(OCC)(=O)C>[C:36]([CH2:35][NH:34][C:6](=[O:7])[C@@H:5]([NH:9][C@@H:10]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:17][CH:16]=1)[C:11]([F:12])([F:14])[F:13])[CH2:4][CH2:3][C:2]([F:1])([F:32])[F:31])#[N:37]
Reactant: N#CCN
Reactant: CS(=O)(=O)c1ccc(-c2ccc([C@H](N[C@@H](CCC(F)(F)F)C(=O)O)C(F)(F)F)cc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2ccc([C@H](N[C@@H](CCC(F)(F)F)C(=O)NCC#N)C(F)(F)F)cc2)cc1
Temperature: -20 °C
Reaction time: 3 h

Procedure:
(2S)-5,5,5-trifluoro-2-({(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}amino)pentanoic acid (0.55 g, 0.114 mmol), aminoacetonitrile hydrochloride (21 mg, 0.228 mmol) and HATU (43 mg, 0.114 mmol) were dissolved in DMF (2 mL) and the reaction mixture was cooled to −20° C. Diisopropylethylamine (0.10 mL, 0.57 mmol) was added and the reaction mixture was stirred at −20° C. for three hours and then at ambient temperature for 16 hours. Ethyl acetate (ca. 30 mL) and water (ca. 30 mL) were added and the mixture was shaken vigorously. The organic layer was washed with water, dried with magnesium sulfate, and filtered. The filtrate was concentrated by rotary evaporation and the residue was purified by silica gel chromatography using 30% ethyl acetate in hexanes as eluant to yield (2S)-5,5,5-trifluoro-2-({(1S)-2,2,2-trifluoro-1-[4′-(methylsulfonyl)-1,1′-biphenyl-4-yl]ethyl}amino)pentanoic acid cyanomethyl amide as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:16]2[C:4](=[C:5]3[C:14]([N:15]=2)=[C:13](C(O)=O)[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]3)[C:3]=1[Cl:22]>C1(OC2C=CC=CC=2)C=CC=CC=1>[Br:1][C:2]1[CH:18]=[CH:17][C:16]2[C:4](=[C:5]3[C:14]([N:15]=2)=[CH:13][C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6]3)[C:3]=1[Cl:22]
Reactant: O=C(O)c1c2nc3ccc(Br)c(Cl)c3c-2[nH]c2ccccc12
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Clc1c(Br)ccc2nc3cc4ccccc4[nH]c-3c12
Yield: 95.8 %

Procedure:
7-Bromo-6-chloroquindoline-11-carboxylic acid from Example 77 (1.75 g, 4.66 mmol) was refluxed at 252° C. in diphenyl ether (30 mL) for 4 hours in an oversize flask. The mixture was cooled, diluted with petroleum ether (30 mL), and filtered. The filter cake was washed with petroleum ether (100 mL) and dried to yield 1.48 g (96%) of the title compound as a brown solid; H NMR (DMSO-d6) δ 11.92 (s, 1H), 8.39 (s, 1H), 8.21 (d, J=8.4, 1H), 8.13 (d, J=7.6, 1H) 7.90 (d, J=8.4, 1H), 7.69 (t, J=7.6, 1H), 7.60 (td, J=7.6, J=1.6, 1H), 7.52 (d, J=8.8, 1H); 13C NMR (DMSO-d6) δ 143.88, 143.64, 143.59, 133.31, 132.56, 129.23, 127.82, 127.53, 126.62, 125.62, 119.09, 118.6, 113.96, 112.14, 111.89.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7].C(N(CC)CC)C.ClC(OCC(C)C)=O.[NH2:33][C@@H:34]1[CH2:39][CH2:38][C@H:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH2:36][CH2:35]1>C1COCC1.C(Cl)Cl>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[C:6]([NH:8][CH2:9][C:10]([NH:33][C@@H:34]1[CH2:39][CH2:38][C@H:37]([NH:40][C:41](=[O:47])[O:42][C:43]([CH3:45])([CH3:44])[CH3:46])[CH2:36][CH2:35]1)=[O:12])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
2-(3-(trifluoromethyl)-benzamido)acetic acid (277 mg, 1.12 mmol, 1.2 eq) and triethylamine (0.15 mL, 1.12 mmol, 1.2 eq) were dissolved in THF (15 mL) at room temperature under nitrogen. Cooled to 0° C. Added isobutyl chloroformate (0.16 μL, 1.12 mmol, 1.2 eq) dropwise. Stirred for 10 mintues followed by the dropwise addition of tert-butyl cis-4-amino-cyclo-hexylcarbamate (200 mg, 0.93 mmol, 1 eq) in THF ((5 mL). Warmed to room temperature. Worked up after 3 hours by adding methylene chloride (25 mL) and rinsing 3 times with saturated sodium bicarbonate (25 mL). The organic layer was dried (sodium sulfate) and stripped to give an oil. Purified over silica gel in 1:1 hexanes/ethyl acetate to give tert-butyl cis-4-(2-(3-(trifluoromethyl)-benzamido)acetamido)cyclohexylcarbamate (350 mg) as an oil. MS found: (M+Na)+=466.20.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](Cl)=[O:9].C(N(CC)CC)C.[CH2:25]([NH:27][C:28]([CH:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH3:31])=[O:29])[CH3:26]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([N:35]1[CH2:34][CH2:33][N:32]([CH:30]([C:28]([NH:27][CH2:25][CH3:26])=[O:29])[CH3:31])[CH2:37][CH2:36]1)=[O:9]
Reactant: CCNC(=O)C(C)N1CCNCC1
Reactant: COc1cc(C=CC(=O)Cl)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCNC(=O)C(C)N1CCN(C(=O)C=Cc2cc(OC)c(OC)c(OC)c2)CC1
Reaction time: 1 h

Procedure:
17.19 g of 3,4,5-trimethoxycinnamoyl chloride and 6.78 g of triethylamine are added with ice cooling to a solution of 9.54 g of 1-[1-(ethylaminocarbonyl)ethyl]piperazine in 200 ml of chloroform, and the resulting solution is kept standing at room temperature for 1 hour.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[O:17][CH3:18])[C:9]1=[O:19])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[O:17][CH3:18])[C:9]1=[O:19]
Reactant: O=[O+][O-]
Reactant: CC=CCC1Cc2c(OC)cccc2C1=O
Solvent: ClCCl
Solvent: CO
Product: COc1cccc2c1CC(CC=O)C2=O
Reaction time: 0.58 h
Yield: 84 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted while stirring for 35 minutes through a solution, cooled to -70°, of 6.42 g of (RS)-2-(2-buten-1-yl)-4-methoxy-1-indanone in 180 ml of anhydrous dichloromethane and 60 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 3.3 ml of dimethyl sulfide, the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated in a vacuum, the residue was treated with 200 ml of dichloromethane and, after the addition of 20 ml of water and 20 ml of trifluoroacetic acid, stirred at room temperature for 2 hours. The mixture was subsequently poured into 100 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 100 ml of water were added, the phases were separated and the aqueous phase was extracted twice with 150 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate, concentrated in a vacuum and the crude product obtained was crystallized from ethyl acetate/hexane. 5.1 g (84%) of (RS)-2-(2-oxoethyl)-4-methoxy-1-indanone were obtained as a white solid with m.p. 71°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:23])[NH:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][C:9]=2[CH3:22])=[O:4].[Cu][C:25]#[N:26].O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:23])[NH:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:25]#[N:26])=[CH:10][C:9]=2[CH3:22])=[O:4]
Reactant: N#C[Cu]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)cc(C)c2[nH]c1=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)c2cc(C#N)cc(C)c2[nH]c1=O
Temperature: 130 °C
Yield: 100.3 %

Procedure:
A suspension of 6-bromo-8-methyl-2-oxo-4-phenyl-1,2-dihydro-quinoline-3-carboxylic acid methyl ester (prepared as described in example 54 step C) (140 mg, 376 μmol, Eq: 1.00) and copper(I) cyanide (121 mg, 41.5 μl, 1.35 mmol, Eq: 3.6) in DMF (2.8 ml) was heated to 130° C. for 2 d. Then water was added and the mixture was extracted with DCM (3×). The combined extracts were washed with water and brine, dried with Na2SO4 and evaporated to give the title compound as off-white solid (120 mg). MS (ESI): 317.2 (M−H)−
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:9]=1[CH2:10][N:11]1[CH:15]=[C:14]([C:16](O)=[O:17])[N:13]=[N:12]1.C[N:25](C=O)C>C1COCC1>[F:7][C:8]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:9]=1[CH2:10][N:11]1[CH:15]=[C:14]([C:16]([NH2:25])=[O:17])[N:13]=[N:12]1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cn(Cc2c(F)cccc2F)nn1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: NC(=O)c1cn(Cc2c(F)cccc2F)nn1
Temperature: 25 °C
Yield: 65.3 %

Procedure:
75.4 ml of Oxalyl chloride (919.8 mmol) were added at 25° C. to a stirred suspension of (2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxylic acid (200.0 g, 836.2 mmol) in THF (500 ml) and DMF (0.5 ml). The stirring was maintained for 4 hr at 25° C. until the solid dissolved. Afterwards, 1000 ml of THF were added and reduced pressure (200-250 mbar) was applied leading to the distillation of 300 ml of THF and to the maintenance of the internal temperature at about 25-35° C. After that, the mixture was slightly cool to 25° C. and 160 g of ammonium chloride were added in portions followed by slow addition of 400 ml of an 8% NaHCO3 solution and 176 g of solid NaHCO3 (vigorous stirring was also needed to prevent frothing). The heterogeneous mixture was stirred for 2 hr, filtered and the solid re-suspended in 1 L water. The solid was filtered and dried (at 200 mbar/50° C.) yielding 130 g (65.3%) of 1-(2,6-difluorobenzyl)-1H-1,2,3-triazole-4-carboxamide, as a white solid in form R5.
Reaction SMILES: Cl.[C:2]1([CH3:17])[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[C:11]([CH3:16])=[N:12][NH:13][C:14]=1[NH2:15].[C:18]([C:20](=[C:26](OCC)[CH3:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])#[N:19]>CO>[NH2:19][C:18]1[N:13]2[N:12]=[C:11]([CH3:16])[C:10]([C:3]3[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:17])=[C:14]2[N:15]=[C:26]([CH3:27])[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: Cc1cc(C)c(-c2c(C)n[nH]c2N)c(C)c1
Reactant: CCOC(=O)C(C#N)=C(C)OCC
Agent: Cl
Solvent: CO
Product: CCOC(=O)c1c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn2c1N
Yield: 20.4 %

Procedure:
Concentrated hydrochloric acid (0.1 mL) was added to a solution of 4-mesityl-3-methyl-1H-5-pyrazoleamine (2.5 g, 11.61 mmol) and ethyl 2-cyano-3-ethoxy-2-butenoate (2.13 g, 11.61 mmol) in methanol (30 mL), followed by heating under reflux for 18 hours. The reaction mixture was evaporated as it was. Then, water was added and a 5N aqueous solution of sodium hydroxide was added under ice-cooling, to neutralize. Further, the mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (15% ethyl acetate/hexane), to give the title compound (835 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[C:20]2[F:23])=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:23][C:20]1[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=1)=[N:15][N:14]([CH2:10][CH2:11][C:12]#[C:13][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1)[CH:22]=2
Reactant: C#CCCn1cc2c(F)cccc2n1
Reactant: FCc1cccc(Br)n1
Product: FCc1cccc(C#CCCn2cc3c(F)cccc3n2)n1
Yield: 36.4 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (0.12 g, 0.61 mmol) and 2-but-3-ynyl-4-fluoro-2H-indazole (104 mg, 0.55 mmol). Reaction time: 3 hours. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 3:2) to yield 60 mg (0.20 mmol, 36%) of 4-fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-2H-indazole as a brown solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)=[N:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.O.[NH2:31][NH2:32]>C1COCC1.CO>[N:1]1[CH:6]=[CH:5][C:4]([O:7][C@H:8]2[CH2:13][CH2:12][C@H:11]([C:14]([NH:31][NH2:32])=[O:16])[CH2:10][CH2:9]2)=[N:3][CH:2]=1
Reactant: O=C(O)[C@H]1CC[C@H](Oc2ccncn2)CC1
Reactant: NN
Agent: CCOC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: NNC(=O)[C@H]1CC[C@H](Oc2ccncn2)CC1
Reaction time: 1 h

Procedure:
To a solution of cis/trans-4-(pyrimidin-4-yloxy)-cyclohexanecarboxylic acid (1:1) (0.750 g, 3.37 mmol) and triethylamine (0.470 ml, 3.37 mmol) in THF (16 ml) was added ethyl chloroformate (0.322 ml, 3.37 mmol) at 0° C. The reaction mixture was stirred for 1 h. The ammonium salts were removed by filtration. The filtrate was added to a cold solution of hydrazine hydrate (0.338 g, 6.75 mmol) in methanol (20 ml). The reaction mixture was stirred for 2 h at room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (100 ml) and a 1:1 mixture of 1 M aqueous sodium hydroxide solution and brine (30 ml). The organic layer was separated. The aqueous layer was extracted with three 100-ml portions of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound (0.588 g, 74%) as off-white solid, which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:12]=[C:11]([Cl:21])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=O.Cl.[Cl:23][C:24]([Cl:29])=[CH:25][CH2:26][O:27][NH2:28].Cl>N1C=CC=CC=1>[Cl:23][C:24]([Cl:29])=[CH:25][CH2:26][O:27][N:28]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]1[C:2]([Cl:1])=[CH:14][C:13]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])=[CH:12][C:11]=1[Cl:21]
Reactant: NOCC=C(Cl)Cl
Reactant: O=CCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: ClC(Cl)=CCON=CCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.6 %

Procedure:
To a mixture of 0.37 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentanal and 10 ml of pyridine was added 0.20 g of O-(3,3-dichloro-2-propenyl)hydroxylamine hydrochloride. After stirring at room temperature for 24 hours, the reaction mixture was poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.23 g (yield, 48%) of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentanal O-(3,3-dichloro-2-propenyl)oxime, nD25.2 1.5559.
Reaction SMILES: Cl[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:7]=2[S:6](=[O:18])(=[O:17])[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[N:3]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C(#N)C>[O:26]1[CH2:27][CH2:28][N:23]([C:2]2[C:8]3[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:7]=3[S:6](=[O:18])(=[O:17])[C:5]3[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=3[N:3]=2)[CH2:24][CH2:25]1
Reactant: C1COCCN1
Reactant: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccccc1N=C2Cl
Solvent: CC#N
Product: COC(=O)c1ccc2c(c1)S(=O)(=O)c1ccccc1N=C2N1CCOCC1

Procedure:
Reflux a mixture of 5.025 mg (15 mmole) of the 11-chloro ester of Example 14. 3.119 gm of morpholine and 75 ml of acetonitrile for 2 hours. Distill off the acetonitrile under a vacuum and dissolve the residue in 45 ml of methanol at room temperature. Filter, cool and separate the precipitate by filtration. Chromatograph over silica gel eluting with 1:4 ethylacetate in toluene. Recrystallize from ethanol to obtain the title product (m.p. 164°-166° C.).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[NH:17][C:18](=[O:21])[O:19][CH3:20])=[O:8])[N:4]([C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][N:23]=2)[N:3]=1.OS(O)(=O)=O.[N+:34]([O-])([OH:36])=[O:35]>>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([N+:34]([O-:36])=[O:35])=[CH:12][C:11]=2[NH:17][C:18](=[O:21])[O:19][CH3:20])=[O:8])[N:4]([C:22]2[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][N:23]=2)[N:3]=1
Reactant: COC(=O)Nc1cccc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)Nc1cc([N+](=O)[O-])cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 0 °C

Procedure:
Methyl (2-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamido)-3-methylphenyl)carbamate prepared in Example 54 (100 mg, 0.22 mmol) was introduced in a V-shaped vial, and the vial was placed in an ice bath. H2SO4 (0.5 mL) was added to the vial at 0° C. and subjected to a reaction until the solid disappeared. After the solid completely disappeared, HNO3 (77 μL, 1.29 mmol, 6.0 eq) was added to the solution dropwise. The vial was removed from the ice bath 10 minutes after the initiation of the reaction, and the reaction mixture was allowed to react at room temperature for 1 hour. Upon completion of the reaction, 15 mL of ice was placed in a 50 mL flask, and the reaction mixture was added thereto. The reaction mixture was washed with water several times and filtered. The residue was extracted with ether and H2O, dried over MgSO4 and concentrated under reduced pressure. Subsequently, the residue was purified by silica gel column chromatography (EA:Hex=1:1) to obtain the title compound in a white solid (95 mg, yield: 85%).