Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[N+:22]([O-:24])=[O:23].C(N(CC)CC)C.[N+](C1C=NC2C(C=1O)=CC=CC=2)([O-])=O>ClCCl.Cl.NCC1(O)CCCCC1>[N+:22]([C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:12]=1[NH:2][CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)=[CH:20][CH:19]=[CH:18][CH:17]=2)([O-:24])=[O:23]
Reactant: NCC1(O)CCCCC1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: Cl
Agent: O=[N+]([O-])c1cnc2ccccc2c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCC1(O)CCCCC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 105.3 %

Procedure:
A suspension of 1-aminomethyl-1-cyclohexanol hydrochloride (20.0 g, 121 mmol) and 4-chloro-3-nitroquinoline (24.0 g, 115 mmol) in dichloromethane (550 mL) was cooled to 0° C., and triethylamine (40 mL, 290 mmol) was added dropwise over a period of 30 minutes. The reaction was allowed to warm to room temperature over two hours. An analysis by HPLC indicated that the 4-chloro-3-nitroquinoline starting material actually contained some 3-nitroquinolin-4-ol, and additional pure 4-chloro-3-nitroquinoline (12.0 g, 57.5 mmol) was added. The reaction was stirred for four hours, and additional 1-aminomethyl-1-cyclohexanol hydrochloride (2.0 g, 12 mmol) was added, and the resulting suspension was stirred for three days. The solvent was removed under reduced pressure, and the residue was triturated in water for one hour and isolated by filtration. The resulting solid was triturated with hot dichloromethane and isolated by filtration from the hot mixture to provide 36.5 g of 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclohexanol as a bright yellow powder.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1B1OC(C)(C)C(C)(C)O1)(=[O:3])[CH3:2].Br[C:37]1[N:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:57][CH2:56][N:55]([CH:58]4[CH2:61][O:60][CH2:59]4)[CH2:54][CH2:53]3)=[CH:48][CH:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1>>[C:1]([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:37]1[N:38]=[C:39]([NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH2:57][CH2:56][N:55]([CH:58]4[CH2:61][O:60][CH2:59]4)[CH2:54][CH2:53]3)=[CH:48][CH:47]=2)[C:40](=[O:44])[N:41]([CH3:43])[CH:42]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)nc(Nc2ccc(N3CCN(C4COC4)CC3)cc2)c1=O
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc(N4CCN(C5COC5)CC4)cc3)n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 50.8 %

Procedure:
Following Example 148h, 300 mg of 4-fluoro-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 210d and 287 mg of 327e were reacted to give 327f as a yellow solid (220 mg, 51%). LCMS: [M+H]+ 696
Reaction SMILES: C1C(=O)N(Cl)C(=O)C1.[CH:9](=[N:16][OH:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:18][C:19]1[N:20]=[C:21]([C:40]#[CH:41])[C:22]([N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[N:23][CH:24]=1.CCN(CC)CC>CN(C=O)C>[Br:18][C:19]1[N:20]=[C:21]([C:40]2[O:17][N:16]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:41]=2)[C:22]([N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[N:23][CH:24]=1
Reactant: ON=Cc1ccccc1
Reactant: C#Cc1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc(-c2ccccc2)no1
Temperature: 55 °C
Reaction time: 0.75 h
Yield: 44.3 %

Procedure:
NCS (12.19 g, 91.26 mmol) was added to a solution of benzaldehyde oxime (10.05 g, 82.96 mmol) in DMF (40.20 mL) and the mixture heated at 55° C. for 15 minutes. The reaction mixture was cooled to ambient temperature and tert-butyl N-(5-bromo-3-ethynyl-pyrazin-2-yl)-N-tert-butoxycarbonyl-carbamate (36.34 g, 91.26 mmol) and DMF (30.15 mL) were added followed by the dropwise addition of Et3N (10.07 g, 13.87 mL, 99.55 mmol). The reaction mixture was stirred at ambient temperature for 45 minutes and then heated to 65° C. for 1 hour. The reaction mixture was cooled to ambient temperature and the solvent removed under high vacuum. The residue was taken up in ethyl acetate (50 ml). Remaining solid was filtered off and the filtrate concentrated in vacuo and then purified by column chromatography on silica using the ISCO column companion system, eluting with ethyl acetate/petroleum ether (0-40% EtOAc). Product fractions were combined and concentrated in vacuo to give tert-butyl (5-bromo-3-(3-phenylisoxazol-5-yl)pyrazin-2-yl)-N-tert-butoxycarbonyl-carbamate as a pale yellow solid (19 g, 46%). LC/MS m/z 419 [M−100+1]+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[C:11]([CH:20]=O)=[CH:12][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:14][CH:15]=2)[CH:9]=1)([CH3:3])[CH3:2].Cl.NO.[N:27]1C=CC=CC=1.C(OCC)(=O)C>C(O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:22][CH3:23])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH2:27])[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1C=O
Reactant: c1ccncc1
Agent: Cl
Agent: NO
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN
Temperature: 80 °C
Reaction time: 1 h

Procedure:
5′-Isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-carbaldehyde (8.0 g), hydroxylamine hydrochloride (3.45 g) and pyridine (28 ml) are dissolved in ethanol (140 ml), and the mixture is stirred at 80° C. for 1 hour. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated sodium carbonate, water and a saturated brine, and the mixture is dried over magnesium sulfate and concentrated under reduced pressure. Thereto are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a 1N-hydrochloric acid, a saturated sodium carbonate, water and a saturated brine, and the mixture is dried over magnesium sulfate and concentrated under reduced pressure. The residue is dissolved in methanol (100 ml), and thereto is added Raney nickel, and the mixture is stirred under hydrogen atmosphere at room temperature for 30 minutes and at 50° C. overnight. The reaction solution is cooled to room temperature, and Raney nickel is removed by filtration, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (chloroform:methanol=1:0→23:2) to give C-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-yl)-methylamine (5.50 g). MS (m/z): 324 [M+H]+
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][NH:5][S:6]([C:9]1[C:10]2[CH:11]=[CH:12][N:13]=[CH:14][C:15]=2[CH:16]=[CH:17][CH:18]=1)(=[O:8])=[O:7].S(O)(O)(=O)=O.CS[C:32](=[NH:34])[NH2:33].C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH:1]([CH2:2][CH:3]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:4][NH:5][S:6]([C:9]1[C:10]2[CH:11]=[CH:12][N:13]=[CH:14][C:15]=2[CH:16]=[CH:17][CH:18]=1)(=[O:8])=[O:7])[C:32]([NH2:34])=[NH:33]
Reactant: CSC(=N)N
Reactant: NCC(CNS(=O)(=O)c1cccc2cnccc12)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: N=C(N)NCC(CNS(=O)(=O)c1cccc2cnccc12)c1ccccc1
Yield: 85.9 %

Procedure:
In 30 ml of a 60% methanol/water solution (volume ratio) was dissolved 2 g of N-(3-amino-2-phenylpropyl)-5-isoquinolinesulfonamide obtained Referential example 2, 2.05 g of S-methylisothiourea sulfate and 1.67 g of potassium carbonate, and the mixed solution was heated at reflux for two hours. After the reflux, the methanol was distilled therefrom under reduced pressure and the white crystalline residue the obtained was separated by filtration under reduced pressure. The residue was recrystallized from methanol to give 1.93 g of N-(3-guanidino-2-phenylpropyl)-5-isoquinolinesulfonamide, i.e., Compound (31) in a yield of 86%.
Reaction SMILES: ON=[CH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])=[O:5].S(=O)(=O)(O)[OH:17]>>[N+:13]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[NH:6][C:4](=[O:5])[C:3]2=[O:17])([O-:15])=[O:14]
Reactant: O=C(C=NO)Nc1ccccc1[N+](=O)[O-]
Reactant: O=S(=O)(O)O
Product: O=C1Nc2c(cccc2[N+](=O)[O-])C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Hydroxyimino-N-(2-nitro-phenyl)-acetamide (15 g, 72 mmol) was carefully added in small portions to a stirred solution of preheated (90° C.) conc. sulphuric acid (45 mL) over a period of 30 min and the resulting mixture was stirred for another 2 h at the same temperature. It was then cooled to room temperature, poured into crushed ice, the precipitated products was collected by filtrations. The collected precipitated products were washed with water and dried in a vacuum oven to get a brick red colour powder.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[O:12])[C:7]([OH:9])=O.[C:20](OC(=O)CC)(=O)[CH2:21]C.O>N1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]([NH:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[O:12])[C:7](=[O:9])[CH2:20][CH3:21]
Reactant: Cc1ccc(C(=O)NC(CCCCCl)C(=O)O)cc1
Reactant: CCC(=O)OC(=O)CC
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)C(CCCCCl)NC(=O)c1ccc(C)cc1
Temperature: 90 °C
Reaction time: 2.5 h

Procedure:
6-Chloro-2-(p-toluoylamino)hexanoic acid (10.0 g) was dissolved in 15 ml of dry pyridine, and 15 ml of propionic anhydride was added and stirred for 2.5 hours at 90° C. To the mixture was added 15 ml of water slowly so that the maximum temperature did not exceed 85° C., and stirred for 20 minutes at 80° C. The reaction solution was cooled, poured into ice-cold water and extracted with diethyl ether. The extract was washed with 10% hydrochloric acid, an aqueous solution of saturated sodium hydrogen carbonate and brine sequentially, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane: ethyl acetate=8:1-4:1) to provide 6.0 g of the objective compound as colorless crystals. M.p. 85-86° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[O:6][C:5](=[O:7])[CH2:4][CH2:3]1.C[Al](C)C.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([OH:44])([C:40]([F:43])([F:42])[F:41])[C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)=[O:21])=[CH:16][CH:15]=1.CN(C)C=O>C1(C)C=CC=CC=1>[F:42][C:40]([F:41])([F:43])[C:35]([C:32]1[CH:31]=[CH:30][C:29]([CH2:28][N:25]2[CH2:24][CH2:23][N:22]([C:20]([C:17]3[CH:18]=[CH:19][C:14]([NH:13][C:5](=[O:7])[CH2:4][CH2:3][C:2]([OH:6])([CH3:8])[CH3:1])=[CH:15][CH:16]=3)=[O:21])[CH2:27][CH2:26]2)=[CH:34][CH:33]=1)([OH:44])[C:36]([F:39])([F:38])[F:37]
Reactant: CC1(C)CCC(=O)O1
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Agent: C[Al](C)C
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(O)CCC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 0.4 %

Procedure:
5,5-Dimethyldihydrofuran-2(3H)-one (0.433 mmol, 0.049 g) was stirred in toluene (5 mL). Trimethylaluminium (0.867 mmol, 0.867 mL, 1 M in heptane) was added and the reaction stirred for 10 minutes at room temperature. (4-Aminophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (0.433 mmol, 0.2 g) was added and the reaction heated to reflux for 1 hour then a drop of N,N-dimethylformamide was added. The reaction mixture was heated to reflux for 1 hour. The reaction mixture was quenched with water. Ethyl acetate was added and the layers separated. The organic phase was concentrated under vacuum and the resulting residue purified by acidic preparative HPLC to afford the desired compound (1 mg).
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([OH:8])[C@H:6]([OH:9])[C:5](=[O:10])[CH:4]=[CH:3]1.[H][H]>>[OH:8][C@H:7]1[C@H:6]([OH:9])[C@@H:5]([OH:10])[CH2:4][CH2:3][C:2]1=[O:1]
Reactant: O=C1C=C[C@H](O)[C@@H](O)[C@@H]1O
Reactant: [H][H]
Product: O=C1CC[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The method for producing catechol as described above, by reducing (4S,5R,6S)-4,5,6-trihydroxy-2-cyclohexene-1-one with hydrogen to produce (2S,3R,4S)-2,3,4-trihydroxycyclohexane-1-one represented by the following formula (3), and dehydrating the (2S,3R,4S)-2,3,4-trihydroxycyclohexane-1-one.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH:11]([CH3:13])[CH3:12])[C:3]=1[S:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH:22]#[C:23][CH3:24]>C(N(CC)CC)C.C(OCC)C.[Cu]I>[CH:11]([O:10][C:4]1[C:3]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:2]([C:22]#[C:23][CH3:24])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])([CH3:13])[CH3:12]
Reactant: C#CC
Reactant: COc1ccc(I)c(SCc2ccccc2)c1OC(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC#Cc1ccc(OC)c(OC(C)C)c1SCc1ccccc1
Temperature: -40 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
A mixture of the product of Step A (0.123 g; 0.296 mmol), Cl2Pd(PPh3)2 (0.040 g; 0.057 mmol), CuI (0.014 g; 0.073 mmol) in anhydrous triethylamine (3 ml) was cooled to −40° C., degassed under reduced pressure and saturated with dry N2. The propyne gas (0.45 g; 11.2 mmol) was added to it at −40° C. The reaction flask was sealed with septum and allowed to warm up to room temperature and stirred for 3 h at room temperature and diluted to 20 ml with diethyl ether and solid precipitated, filtered off. The filtrate was evaporated to dryness under reduced pressure and the residue, purified by flash column chromatography (SiO2, hexane, hexane/ethyl acetate, 9:1) to give the title compound (0.065 g; 67% yield) as colourless syrup. 1H-NMR (CDCl3) 1.26 (d, 6H, J=6.17 Hz); 2.09 (s, 3H); 3.79 (s, 3H); 4.2 (s, 2H); 4.44 (m, 1H, J=6.17 Hz); 6.73 (d, 1H, J=8.53 Hz); 7.12 (d, 1H, J=8.53 Hz); 7.15-7.4 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])/[C:12](=[CH:15]\[C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)/[N:11]([CH3:24])[C:10]2=[O:25])[CH:5]=[C:6]([Cl:8])[CH:7]=1.NCC(O)=O.[CH2:31]1N2CN3CN(C2)[CH2:33][N:32]1C3.Cl>CN1CCCC1=O.C1(C)C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]3([C@H:15]([C:16]4[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=4)[CH2:33][NH:32][CH2:31]3)[N:11]([CH3:24])[C:10]2=[O:25])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)/C1=C\c1ccc(C#N)cc1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: Cl
Agent: NCC(=O)O
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]12CNC[C@H]2c1ccc(C#N)cc1
Temperature: 140 °C
Reaction time: 0.21 h
Yield: 179.4 %

Procedure:
A mixture of (E)-4-((1-(3,5-dichlorophenyl)-3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl)benzonitrile (1.00 kg, 2.69 mol), glycine (0.50 kg, 6.72 mol) and hexamethylenetetramine (0.28 kg, 2.02 mol) in 1-methyl-2-pyrrolidinone (5.00 L) and toluene (2.50 L) was heated at 140° C. for 7-8 hours. The completeness of the reaction was followed by HPLC. Upon reaction completion, the mixture was cooled to 40-50° C. and filtered. The filtered solid was washed with toluene (0.67 L). To the filtrate was added HCl (1M, 13.33 L, 13.33 mol). The resulting biphasic mixture was heated to 50-60° C. and was stirred for 10-15 minutes. The aqueous phase was separated and the organic phase was washed with HCl (1M, 1.67 L, 1.67 mol) at 60-80° C. The aqueous phases were combined and were stirred at 80° C. for 2 hours. The solution was cooled slowly in 3-4 hours to 20-25° C. with gentle stirring and seeding. Crystallization occurred and the resulting suspension was put aside at 20-25° C. for at least 16 hours with occasional stirring, cooled to 0-5° C. in 2 hours, stirred gently at 0-5° C. for 2 hours and then filtered. The filter cake was washed with ice water (2×2.50 L) and dried at maximum 40° C. to a constant weight. 4-[(5S*,9R*)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile hydrochloride salt (1.09 kg, 90%) was obtained as beige crystalline solid. mp=183-185° C. 1H NMR (DMSO-d6): 7.87(2H, d, J=8.1 Hz), 7.61 (1H, m), 7.40 (2H, d, J=8.1 Hz), 6.68 (2H, m), 4.17 (1H, m), 3.85 (2H, m), 3.76 (2H, m), 3.43 (3H, s), 3.24(2H, s). 13C NMR (DMSO-d6): 14 Carbons (170.84, 152.92, 137.35, 133.94, 132.87, 132.35, 128.01, 124.50, 118.12, 111.30, 71.42, 46.57, 45.11, 25.51). Anal. Calcd for C20H17Cl3N4O2+1.3 H2O: C, 50.51; H, 3.91; N, 11.79; Cl, 22.39. Found: C, 50.56; H, 3.86; N, 11.58; Cl, 21.98; KF, 5.12.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](Cl)[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]([F:18])([F:17])[CH2:15][OH:16].[OH-].[Na+].Cl>O>[Cl:1][C:2]1[N:10]=[C:9]([O:16][CH2:15][C:14]([F:18])([F:17])[F:13])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Reactant: OCC(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cc(F)c(OCC(F)(F)F)nc1Cl
Temperature: 80 °C
Reaction time: 40 h
Yield: 80 %

Procedure:
A mixture of 2,6-dichloro-5-fluoronicotinic acid (1.0 g, 4.8 mmol), 2,2,2-trifluoroethanol (0.69 mL, 9.5 mmol) and sodium hydroxide (0.57 g, 14.3 mmol) in water (24 mL) is stirred at 80° C. for 40 hours. After cooling to 0° C., the mixture is acidified with conc. hydrochloric acid (pH 2). The resulting white precipitate is collected by filtration and dried to give 1.05 g (80% yield) of the title compound as white solid.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[O:25]1[CH2:31][CH2:30][CH2:29][O:28][C:27]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:26]1=2.O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[O:25]1[CH2:31][CH2:30][CH2:29][O:28][C:27]2[CH:32]=[C:33]([C:2]3[N:7]4[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]4[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]4[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=4)[CH:3]=3)[CH:34]=[CH:35][C:26]1=2
Reactant: OB(O)c1ccc2c(c1)OCCCO2
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc4c(c3)OCCCO4)n2n1
Temperature: 110 °C
Yield: 26.1 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 60 mg, 0.174 mmol), 3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylboronic acid (49 mg, 0.226 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7 mg, 9.5 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.58 mL of 1,4-dioxane and 0.29 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (50-55% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (20.8 mg, 26%). ESI-MS: m/z 459.2 (M+H)+.
Reaction SMILES: [C:1](=[C:4]([C:10]#[N:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:3])[CH3:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>C(O)C>[C:10]([C:4](=[C:1]([CH3:2])[CH:3]=[CH:14][N:15]([CH3:17])[CH3:16])[C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:11]
Reactant: CCOC(=O)C(C#N)=C(C)C
Reactant: COC(OC)N(C)C
Solvent: CCO
Product: CCOC(=O)C(C#N)=C(C)C=CN(C)C
Yield: 71 %

Procedure:
A mixture of 127.7 g (0.839 mole) of ethyl isopropylidenecyanoacetate (4) and 100 g (0.839 mole) of N.N-dimethylformamide dimethyl acetal in 500 mL of ethanol was refluxed for 24 hours. The ethanol was removed under reduced pressure to give 124 g (100%) of a dark oil.
Reaction SMILES: O[N:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[CH2:13]([OH:15])[CH3:14]>[Rh]>[CH3:3][C:11]1[CH:6]=[CH:7][C:8]([CH2:14][C:13]([NH:2][CH:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:12])=[O:15])=[CH:9][CH:10]=1
Reactant: O=C1Nc2ccccc2C1=NO
Reactant: CCO
Agent: [Rh]
Product: Cc1ccc(CC(=O)NC2C(=O)Nc3ccccc32)cc1
Reaction time: 12 h
Yield: 18 %

Procedure:
A solution of 4.86 g of 3-(hydroxyimino)indolin-2-one and 100 mg of 5% Rh/C in 300 ml of ethanol was stirred at room temperature under a hydrogen atmosphere for 1 day. The reaction mixture was filtered through Cerite, and the filtrate was concentrated. The concentrate was dissolved in 50 ml of N,N-dimethylformamide, and 5.15 g of dicyclohexyl-carbodiimide, 3.83 g of 1-hydroxybenzotriazole, and 3.75 g of p-tolylacetic acid were added thereto successively. The mixture was stirred at the same temperature for 12 hours, whereupon a precipitate formed. The precipitate was filtered off, and the filtrate was concentrated. The concentrate was diluted with ethyl acetate and washed successively with dilute hydrochloric acid and saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol=40/1) to afford 1.01 g (18%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=O.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH:29]C(OC(C)(C)C)=O)=[CH:24][C:23]=1[CH3:37].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:28]([C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[C:23]([CH3:37])[CH:24]=2)[N:29]=1
Reactant: Cc1cc(NNC(=O)OC(C)(C)C)ccc1Cl
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-n2nc(-c3cc(CNC(=O)C(F)(F)F)ccc3Cl)[nH]c2=O)ccc1Cl
Yield: 44921.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 1.0 g, 0.003 mmol), tert-butyl 2-(4-chloro-3-methylphenyl)hydrazinecarboxylate (Intermediate-105, 1.500 g), DCM (20 mL), and trifluoro acetic acid (5.0 mL) to afford 0.600 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 2.38 (s, 3H), 4.45 (d, J=5.4 Hz, 2H), 7.53 (d, J=9.3 Hz, 2H), 7.67 (s, 2H), 7.82 (d, J=8.1 Hz, 1H), 7.92 (s, 1H), 10.08 (t, 1H), 12.61 (s, 1H); MS (m/z): 445.31 (M+H)+.