Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:9][CH:10]=[C:11]([CH:12]([OH:35])[C:13]3[C:14]([F:34])=[C:15]([NH:20][S:21]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])[C:4]=12)#[N:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:9][CH:10]=[C:11]([C:12]([C:13]3[C:14]([F:34])=[C:15]([NH:20][S:21]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:35])[C:4]=12)#[N:2]
Reactant: N#Cc1ccnc2[nH]cc(C(O)c3c(F)ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)c3F)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccnc2[nH]cc(C(=O)c3c(F)ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)c3F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
To N-{3-[(4-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-2,4-difluoro-phenyl}-4-trifluoromethyl-benzenesulfonamide (6, 15 mg, 0.030 mmol) dissolved in 0.2 mL of tetrahydrofuran, Dess-Martin periodinane (13.8 mg, 0.0324 mmol) was added. The reaction mixture was stirred at room temperature for one hour. The reaction mixture was poured into saturated sodium thiosulfate, the organic layer separated and washed with brine, then dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum and the resulting material was purified by silica gel column chromatography, eluting with ethyl acetate and hexane. The appropriate fractions were combined and the solvent removed under vacuum to provide the desired compound (P-0001, 4 mg). MS (ESI) [M−H+]−=505.5.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]1([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][C:25]#[CH:26])[CH2:21][CH:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(N(CC)CC)C.C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:26]#[C:25][CH2:24][CH2:23][N:20]2[CH2:19][CH:18]=[C:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:22][CH2:21]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Reactant: C#CCCN1CC=C(c2ccccc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 2-bromo-5-nitropyridine (4.23 g, 0.02 mol) and the alkyne prepared in Step (a) (4.0 g, 0,019 mol) in 7.9 mL of triethylamine and 100 mL of acetonitrile is degassed by bubbling in dry nitrogen for 15 minutes, and 0.27 g (0.0004 mol) of bis(triphenylphosphine)palladium chloride and 0.07 g (0.0004 mol) of cuprous iodide are added. The flask is flushed with nitrogen and the mixture is stirred at room temperature for 6 hours. The solvent is removed under reduced pressure and the residue is partitioned between 100 mL of dichloromethane and 100 mL of saturated aqueous sodium bicarbonate. The aqueous layer is extracted with 50 mL of dichloromethane and the combined organic layers are washed with 50 mL of water and dried (sodium sulfate), and the solvent is removed in vacuo. The residue is chromatographed (silica gel, 1% methanol/99% dichloromethane) to give the title compound, containing 0.3 mol of water; mp 133°-134° C.
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:30]=[CH:29][C:9]([O:10][C:11]2[C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:13][N:14]([CH3:22])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:7]=1.[ClH:31]>O>[Cl:31][C:6]1[CH:30]=[CH:29][C:9]([O:10][C:11]2[C:12]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:13][N:14]([CH3:22])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:8][CH:7]=1
Reactant: Cn1nc(-c2ccccc2)c(Oc2ccc(N)cc2)c1-c1ccccc1
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cn1nc(-c2ccccc2)c(Oc2ccc(Cl)cc2)c1-c1ccccc1

Procedure:
A solution of sodium nitrite (3.1 g, 0.0442 mole) in water (10 ml) is added slowly at 0° C. to 5° C. to a well stirred, chilled solution of 4-(p-aminophenoxy)-1-methyl-3,5-diphenylpyrazole (15.1 g, 0.0442 mole) in concentrated hydrochloric acid (50 ml).
Reaction SMILES: C([CH:5]1[CH2:10][C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)([C:11]#[N:12])[CH2:8][CH2:7][C:6]1=[O:20])(OC)=O.S(=O)(=O)(O)O>C(O)(=O)C>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:9]2([C:11]#[N:12])[CH2:8][CH2:7][C:6](=[O:20])[CH2:5][CH2:10]2)=[CH:18][CH:17]=1
Reactant: COC(=O)C1CC(C#N)(c2ccc(Cl)cc2)CCC1=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: N#CC1(c2ccc(Cl)cc2)CCC(=O)CC1
Yield: 82 %

Procedure:
A reaction mixture consisting of 29.8 gm. (0.102 mole) of 2-carbomethoxy-4-(p-chlorophenyl)-4-cyanocyclohexanone (prepared in Part b, above), 550 ml. glacial acetic acid, and 330 ml. 10 percent sulfuric acid is heated on a steam bath at about 100° C. for 24 hours. The mixture is stirred continuously. After cooling, the mixture is diluted with 1000 ml. water, and extracted with benzene. The benzene phase is recovered and washed successively with water, with aqueous sodium bicarbonate, and with brine. The benzene is then removed by evaporation under reduced pressure to give a solid residue. The solid residue is recrystallized from diethyl ether to give 12.13 gm. (82% yield) of 4-(p-chlorophenyl)-4-cyanocyclohexanone having a melting point at 94.5° to 97° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=3[N:10]=[C:9]2[CH3:19])[CH2:4][CH2:3]1.[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][CH:25]([CH:30]=O)[CH2:24]2>>[Cl:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[CH2:26][CH:25]([CH2:30][NH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=4[N:10]=[C:9]3[CH3:19])[CH2:6][CH2:7]1)[CH2:24]2
Reactant: Cc1nc2cc(C#N)ccc2n1[C@H]1CC[C@@H](N)CC1
Reactant: O=CC1Cc2ccc(Cl)cc2C1
Product: Cc1nc2cc(C#N)ccc2n1[C@H]1CC[C@@H](NCC2Cc3ccc(Cl)cc3C2)CC1

Procedure:
This compound was prepared from the hydrochloride salt of cis-1-(4-amino-cyclohexyl)-2-methyl-1H-benzoimidazole-5-carbonitrile and 5-chloro-indan-2-carbaldehyde. 1H-NMR is consistent with the assigned structure, LC-MS showed a single peak, C25H27ClN4 (m/e) calcd 418.1924, obsd 419.2 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([NH2:18])=[O:17].C[N:20]([CH:22]=O)C>C(O)(=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][C:3]([C:16]([NH2:18])=[O:17])=[C:2]2[NH:20][C:22]1[CH:4]=[CH:3][CH:2]=[CH:11][C:10]=1[CH2:9][CH2:8][CH3:7]
Reactant: COc1cc2ncc(C(N)=O)c(Cl)c2cc1OC
Reactant: CN(C)C=O
Solvent: CC(=O)O
Product: CCCc1ccccc1Nc1c(C(N)=O)cnc2cc(OC)c(OC)cc12
Yield: 41 %

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-3-quinolinecarboxamide (0.062 g, 0.23 mmol) 2-propylanilin (0.038 g, 0.28 mmol), 2-butanole (2 ml), DMF (2 ml) and acetic acid (8.2 μl) was heated over night at 100 C. After cooling, the solution was reduced by evaporation. The residue was dissolved in water (3 ml) and treated with aqueous ammonia. The solid product was filtered off washed with water air dried for 0.5 h, washed again with heptane and dried in a vacuum oven at 50 C. to give a yellow-brown solid, 35 mg (41%) of the title compound. APCI-LC/MS m/z 366.1 (MH+): 1H NMR (DMSO-d6) δ 10.95 (1H, s); 8.88 (1H, s); 8.28 (1H, br s); 7.62 (1H, br s); 7.29 (1H, m); 7.24 (1H, s); 7.05 (2H, m); 6.68 (1H, m); 6.63 (1H, s); 3.88 (3H, s); 3.21 (3H, s); 2.67 (2H, t); 1.65 (2H, m); 0.93 (3H, t).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:24])[C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=1[Cl:23])[N:11]=[CH:10][N:9]=[C:8]2[CH3:25])=[O:4].[Li+].[OH-].Cl>C1COCC1.O.O>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14]2[C:13]([F:24])=[C:12]3[C:7]([C:8]([CH3:25])=[N:9][CH:10]=[N:11]3)=[CH:6][C:5]=2[C:3]([OH:4])=[O:2])=[C:17]([Cl:23])[CH:18]=1
Reactant: COC(=O)c1cc2c(C)ncnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ncnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(=O)O)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To a solution of 7-(4-bromo-2-chlorophenylamino)-8-fluoro-4-methylquinazoline-6-carboxylic acid methyl ester (137 mg, 0.323 mmol) in THF-water (3 mL/l mL) was added 1 M aqueous LiOH (0.67 mL, 0.67 mmol) at room temperature. The resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was acidified to pH 6 with 1 N aqueous HCl, diluted with water, and extracted with EtOAc. The organic layer was washed with water, dried over MgSO4, filtered, and concentrated in vacuo to give the desired product (96 mg, 73%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([O:11][C:12](=[O:14])[CH3:13])[CH:3]=1.S(Cl)([Cl:17])=O>>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:17])=[O:7])=[C:4]([O:11][C:12](=[O:14])[CH3:13])[CH:3]=1
Reactant: CC(=O)Oc1cc(C)ccc1C(=O)O
Reactant: O=S(Cl)Cl
Product: CC(=O)Oc1cc(C)ccc1C(=O)Cl
Reaction time: 8 h

Procedure:
4-Methyl-2-acetoxy-benzoic acid (18 g.) was dissolved in thionyl chloride (200 ml.), and the solution was left to stand overnight at room temperature. Removal of excess thionyl chloride by suction gave a paste of crude 4-methyl-2-acetoxy-benzoyl chloride which was dissolved in acetone (200 ml.).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH:7]=[CH:8][CH:9]=1)=[O:4].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(N(CC)CC)C>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:6]1[CH:7]=[CH:8][CH:9]=[C:5]1[C:3](=[O:4])[CH2:2][N:22]1[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]1
Reactant: CN1CCNCC1
Reactant: O=C(CCl)c1cccn1Cc1ccccc1F
Solvent: CCN(CC)CC
Product: CN1CCN(CC(=O)c2cccn2Cc2ccccc2F)CC1

Procedure:
A mixture of 2-chloroacetyl-1-(2-fluorobenzyl)pyrrole Example 1a, N-methylpiperazine and triethylamine in methaol is treated by the procedure described in Example 1b to produce 1-(2-fluorobenzyl)-2-[α-(4-methylpiperazino)-acetyl]pyrrole.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH:12]([C:15]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]([CH3:24])[CH3:23])[C:16]=1[NH2:17])([CH3:14])[CH3:13]>>[CH:22]([C:18]1[CH:19]=[CH:20][CH:21]=[C:15]([CH:12]([CH3:14])[CH3:13])[C:16]=1[N:17]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])([CH3:24])[CH3:23]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)c1cccc(C(C)C)c1N
Product: CC(C)c1cccc(C(C)C)c1N1C(=O)c2ccccc2C1=O

Procedure:
7.41 g of phthalic anhydride and 8.86 g of 2,6-diisopropylaniline were mixed, and reacted at a temperature of 180° C. for 2 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:10]2[CH2:11][CH2:12]2)=[O:9])=[CH:6][C:7]=1[N+:13]([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: O=C(c1ccc(Cl)cc1)C1CC1
Product: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)C1CC1
Temperature: 5 °C
Reaction time: 6 h

Procedure:
Under argon and at −10° C., 20 g (110.7 mmol) of (4-chlorophenyl)(cyclopropyl)methanone were added slowly to 60 ml of concentrated nitric acid. The reaction mixture was then slowly warmed to 5° C. and stirred at this temperature for 6 h. Carefully, the reaction solution was then added with stirring to about 100 ml of ice-water. This resulted in the precipitation of a white solid which was filtered off with suction and washed repeatedly with water. The solid obtained in this manner was then dried under high vacuum. This gave 24.3 g (97% of theory) of the desired product.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Br[CH2:11][CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:11]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9])[CH2:12][CH3:13]
Reactant: CCCBr
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOc1ccccc1C=O
Temperature: 25 °C
Reaction time: 21.5 h
Yield: 94.3 %

Procedure:
To salicylaldehyde (12.2 g) dissolved in DMF (100 ml) were added 1-bromopropane (14.7 g) and potassium carbonate (20.7 g), and the resulting mixture was stirred at room temperature for 21.5 hours. The reaction mixture was diluted with ethyl acetate and washed with water and an aqueous saturated solution of sodium chloride, and the organic layer was dried with anhydrous magnesium sulfate. The resulting organic layer was evaporated under reduced pressure to remove the solvent to obtain 2-propoxybenzaldehyde (15.47 g) as an oil.
Reaction SMILES: C1(O[C:8](=[O:26])[NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=3)[CH:13]=[CH:12][N:11]=2)C=CC=CC=1.[N:27]1([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[N+:23]([C:20]1[CH:19]=[CH:18][C:17]([O:16][C:14]2[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C:8]([N:35]3[CH2:36][CH2:37][CH:32]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:33][CH2:34]3)=[O:26])[CH:15]=2)=[CH:22][CH:21]=1)([O-:25])=[O:24]
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)Oc1ccccc1
Reactant: C1CCN(C2CCNCC2)C1
Solvent: C1CCOC1
Product: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCC(N2CCCC2)CC1
Reaction time: 0.83 h

Procedure:
[4-(4-Nitrophenoxy)pyridin-2-yl]carbamic acid phenyl ester (100 mg) was dissolved in tetrahydrofuran (2 ml) under a nitrogen atmosphere, and then 4-(pyrrolidin-1-yl)piperidine (148 mg) was added thereto, followed by stirring for 50 min. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of ammonium chloride. The organic layer was washed with a saturated aqueous solution of ammonium chloride, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; hexane:ethyl acetate=1:2 to 1:8). The solvent was evaporated under a reduced pressure to give a residue, which was then dried in vacuum to provide 4-(pyrrolidin-1-yl)piperidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridin-2-yl]amide as a crude product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([C:7]([C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([CH2:19][CH:20]=[CH2:21])=[C:15]([OH:22])[C:12]=3[C:13]=2[CH3:14])=O)=[CH:5][CH:4]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:9]2[O:10][C:11]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[C:15]([OH:22])[C:12]=3[C:13]=2[CH3:14])=[CH:23][CH:24]=1
Reactant: C=CCc1ccc2oc(C(=O)c3ccc(OC)cc3)c(C)c2c1O
Agent: [Pd]
Solvent: CCO
Product: CCCc1ccc2oc(Cc3ccc(OC)cc3)c(C)c2c1O

Procedure:
A solution of 2-(p-methoxybenzoyl)-3-methyl-4-hydroxy-5-allylbenzofuran (40 mg) in ethanol (50 mL) was hydrogenated in a Parr hydrogenator in the presence of 10% palladium on charcoal at 40 psi. The catalyst was filtered and the filtrate was concentrated to dryness to yield 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propylbenzofuran, identical to the product prepared by the route described in Example 1.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:22](=[O:23])[CH2:21][CH2:20][CH2:19][N:18]2C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>FC(F)(F)C(O)=O.ClCCl>[NH:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:22](=[O:23])[CH2:21][CH2:20][CH2:19][NH:18]2)[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)N1C1CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCCNN1C1CCNCC1
Reaction time: 15 h
Yield: 108.5 %

Procedure:
tert-Butyl 2-{1-[(benzyloxy)carbonyl]piperidin-4-yl}-3-oxotetrahydropyridazin-1(2H)-carboxylate (0.84 g) obtained in Example 29a} was dissolved in trifluoroacetic acid (1 mL) and dichloromethane (1.5 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was made alkaline with an aqueous sodium bicarbonate solution and then extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethanol (10 mL), and 10% palladium on carbon (0.1 g) was added, followed by stirring under a hydrogen atmosphere for 15 hours. After the catalyst was removed, the solvent was distilled off under reduced pressure to obtain the title compound (0.40 g, quantitative) as a yellow oil.
Reaction SMILES: [N+:1]([CH:4]([CH3:6])[CH3:5])([O-:3])=O.[CH:7]1[CH:15]=[CH:14][C:13]2[C:9](=[N:10][O:11][N+]=2[O-])[CH:8]=1.C(NCC)C>O1CCCC1>[CH3:5][C:4]1([CH3:6])[N+:1]([O-:3])=[C:13]2[CH:14]=[CH:15][CH:7]=[CH:8][C:9]2=[N+:10]1[O-:11]
Reactant: [O-][n+]1onc2ccccc21
Reactant: CC(C)[N+](=O)[O-]
Solvent: CCNCC
Solvent: C1CCOC1
Product: CC1(C)[N+]([O-])=c2ccccc2=[N+]1[O-]
Reaction time: 8 h

Procedure:
To a mixture containing 2-nitropropane (10.7 g., 0.12 moles), benzofuroxan (13.6 g., 0.10 moles) and tetrahydrofuran (50 ml.) is added dropwise diethylamine (8.7 g., 0.12 mole). The reaction temperature rises during addition. Upon completion of addition, the reaction mixture is allowed to sit overnight at room temperature.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[CH3:5][C:6]1[O:7][C:8]([CH3:14])=[CH:9][C:10]=1[C:11](Cl)=[O:12]>C(Cl)Cl>[CH:1]([O:4][C:11]([C:10]1[CH:9]=[C:8]([CH3:14])[O:7][C:6]=1[CH3:5])=[O:12])([CH3:3])[CH3:2]
Reactant: CC(C)O
Reactant: Cc1cc(C(=O)Cl)c(C)o1
Solvent: ClCCl
Product: Cc1cc(C(=O)OC(C)C)c(C)o1
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Isopropanol (5 ml) was added to a solution of 2,5-dimethylfuran-3-carbonylchloride (1.64 g; 10.3 mmol) in 15 ml of methylene chloride at rt. After allowing the reaction mixture to stand at rt for 30 mins, the volatiles were removed in vacuo and the residue was co-evaporated from isopropanol to afford compound 865A (1.8 g, 96%) as a light amber liquid. 1HNMR (CDCl3): δ 1.30 (d, j=6.5 Hz, 6H), 2.23 (s, 3H), 2.52 (s, 3H), 5.14 (m, 1H), 6.21 (s, 1H).
Reaction SMILES: [CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:5]([C:7]2[CH:8]=[N:9][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[CH3:18])=[N:11][CH:12]=2)=[O:6])[CH2:3][CH2:2]1.F[C:26]1[C:31]([F:32])=[CH:30][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:28][N:27]=1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH:1]1([N:4]([CH:19]2[CH2:24][CH2:23][N:22]([C:26]3[C:31]([F:32])=[CH:30][C:29]([C:33]([F:36])([F:34])[F:35])=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[C:5]([C:7]2[CH:12]=[N:11][C:10]([N:13]3[CH:17]=[CH:16][N:15]=[C:14]3[CH3:18])=[N:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1nccn1-c1ncc(C(=O)N(C2CCNCC2)C2CC2)cn1
Reactant: Fc1cc(C(F)(F)F)cnc1F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nccn1-c1ncc(C(=O)N(C2CC2)C2CCN(c3ncc(C(F)(F)F)cc3F)CC2)cn1
Temperature: 200 °C

Procedure:
A mixture of 2-(2-methyl-imidazol-1-yl)-pyrimidine-5-carboxylic acid cyclopropyl-piperidin-4-yl-amide (44 mg), 2,3-difluoro-5-(trifluoromethyl)pyridine (22 mg), and ethyldiisopropylamine (35 μL) in N-methyl-2-pyrrolidinone (1 mL) is heated to 200° C. for 0.5 h in a microwave oven. The reaction mixture is concentrated and the crude product is purified by preparative HPLC (MeOH/H2O/ammonia). LC (method 16): tR=1.29 min; Mass spectrum (ESI+): m/z=490 [M+H]+.
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([NH:9][NH2:10])[CH3:8].[CH3:11][CH2:12][O:13][C:14]([C:16]([CH2:18][C:19]([CH3:21])=O)=O)=[O:15]>C(O)C>[CH2:7]([N:9]1[C:19]([CH3:21])=[CH:18][C:16]([C:14]([O:13][CH2:12][CH3:11])=[O:15])=[N:10]1)[CH3:8]
Reactant: CCNN
Reactant: CCOC(=O)C(=O)CC(C)=O
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(CC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
Ethylhydrazine oxalate (23.7 g, 158 mmol) was added slowly to an 11° C. solution of ethyl acetopyruvate (50.0 g, 316 mmol) in ethanol so that the internal temperature did not exceed 14° C. The reaction was allowed to warm to ambient temperature and was stirred overnight. The reaction was concentrated under reduced pressure and 2 M sodium carbonate was added to adjust the mixture to pH 9. The mixture was transferred to a separatory funnel. The aqueous phase was extracted with methyl tert-butyl ether (3×600 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield 28.94 g of ethyl 1-ethyl-5-methyl-1H-pyrazole-3-carboxylate as an orange oil that was used without purification in the next reaction.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:20])[CH:15]2[CH2:19][CH2:18][O:17][CH2:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:20][N:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[CH:15]1[CH2:19][CH2:18][O:17][CH2:16]1
Reactant: CN(C1CCN(C(=O)OC(C)(C)C)CC1)C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C1CCNCC1)C1CCOC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-[methyl(tetrahydrofuran-3-yl)amino]piperidine-1-carboxylic acid tert-butyl ester (132 mg, 0.46 mmol) and TFA (2 mL) in DCM (5 mL) was stirred at room temperature for 2 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording Methyl(piperidin-4-yl)(tetrahydro-furan-3-yl)amine as a white solid (84 mg, quant.). 1H NMR (CDCl3, 300 MHz): δ 3.98-3.91 (m, 1H); 3.88-3.83 (m, 1H); 3.80-3.73 (m, 1H); 3.61-3.53 (m, 1H); 3.42-3.35 (m, 1H); 3.26-3.14 (m, 2H); 2.71-2.53 (m, 2H); 2.57-2.46 (m, 1H); 2.23 (s, 3H); 2.05-1.97 (m, 1H); 1.93-1.77 (m, 1H); 1.78-1.72 (m, 2H); 1.64-1.49 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:4]=1[CH2:5][NH:6][C:7]1[S:11][N:10]=[CH:9][N:8]=1.[Cl:18][C:19]1[CH:20]=[C:21]([S:26](Cl)(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1[F:25]>>[Cl:18][C:19]1[CH:20]=[C:21]([S:26]([N:6]([CH2:5][C:4]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=2[O:2][CH3:1])[C:7]2[S:11][N:10]=[CH:9][N:8]=2)(=[O:27])=[O:28])[CH:22]=[CH:23][C:24]=1[F:25]
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc(F)c(Cl)c2)c(OC)c1

Procedure:
Prepared according to Preparation 207 using (2,4-dimethoxybenzyl)-[1,2,4]thiadiazol-5-yl-amine (Preparation 14) and 3-chloro-4-fluorobenzenesulfonyl chloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=S)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH2:36][NH2:37].O>C1COCC1>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=[N:36][NH2:37])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=NN)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (20 mg, 0.04 mmol) in THF (2 mL) was added hydrazine.H2O (10 μL, 0.20 mmol) under nitrogen. The resulting mixture was stirred at room temperature for 1.5 h. After cooled down to room temperature, the mixture was concentrated to dryness under reduced pressure to give the title compound which was used directly in the next step without any purification.