Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([OH:46])[C@@H:16]([NH:18][CH2:19][CH2:20][O:21][C:22]2[C:27]([CH3:28])=[CH:26][C:25]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([O:37]CC4C=CC=CC=4)=[O:36])=[CH:31][CH:30]=3)=[CH:24][C:23]=2[CH3:45])[CH3:17])=[CH:11][C:10]=1[NH:47][S:48]([CH3:51])(=[O:50])=[O:49])C1C=CC=CC=1>CN(C)C=O.[C].[Pd]>[OH:46][C@H:15]([C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:11]=1)[C@@H:16]([NH:18][CH2:19][CH2:20][O:21][C:22]1[C:27]([CH3:28])=[CH:26][C:25]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([OH:37])=[O:36])=[CH:31][CH:30]=2)=[CH:24][C:23]=1[CH3:45])[CH3:17]
Reactant: Cc1cc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc(C)c1OCCN[C@@H](C)[C@H](O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(C(=O)O)cc2)cc(C)c1OCCN[C@@H](C)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 65.2 %

Procedure:
To a solution of benzyl 4′-{2-[(1S,2R)-2-(4-benzyloxy-3-methanesulfonylaminophenyl)-2-hydroxy-1-methylethylamino]ethoxy}-3′,5′-dimethylbiphenyl-4-carboxylate (0.074 g) in N,N-dimethylformamide (4 mL) was added 10% palladium-carbon (0.05 g), and the mixture was stirred at room temperature for 1.5 hrs under an atmosphere of hydrogen. The catalyst was removed by filtration, and the solvent was evaporated under reduced pressure. Methylene chloride was added to the residue, and the resulting precipitated materials were collected by filtration. The crude product was purified by ODS column chromatography (eluent: acetonitrile/water=1/1) to afford the title compound (0.036 g).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:25][CH:26]([CH3:30])[C:27](Cl)=[O:28]>O>[Cl:25][CH:26]([CH3:30])[C:27]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:2]=1[CH3:1])=[O:28]
Reactant: CC(Cl)C(=O)Cl
Reactant: Cc1ccc(Cl)cc1NCC=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: Cc1ccc(Cl)cc1N(CC=O)C(=O)C(C)Cl
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2-methyl-5-chloroanilino)-acetaldehyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0°C and α-chloropropionyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochoric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-chloropropionyl-2-methyl-5-chloroanilino)-acetaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][N:20]4[CH:24]=[N:23][CH:22]=[N:21]4)[C:16](=[O:25])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.[C:26](OC(=O)C)(=[O:28])[CH3:27].C(O)C>N1C=CC=CC=1>[C:26]([O:15][C:10]1[CH:11]=[C:12]2[C:7]3=[C:8]([C:16](=[O:25])[C:17]([CH2:19][N:20]4[CH:24]=[N:23][CH:22]=[N:21]4)=[CH:18][N:6]3[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:14][C:13]2=3)[CH:9]=1)(=[O:28])[CH3:27]
Reactant: O=c1c(Cn2cncn2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=O)Oc1cc2c(=O)c(Cn3cncn3)cn3c4ccc(Br)cc4c(c1)c23
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
10-bromo-2-hydroxy-5-(1H-1,2,4-triazole-1-ylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (30 mg) obtained in Example 96 was suspended in pyridine (0.8 ml), and acetic anhydride (0.021 ml) was added, and the mixture was stirred at room temperature for 3 hours. After adding dropwise a small amount of ethanol to the reaction mixture, the solvent was evaporated under reduced pressure. The residue was washed with ethanol and ether in succession to obtain the title compound (24 mg, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11](Cl)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:15]([O:19][CH2:20][CH3:21])(=[O:18])[NH:16][NH2:17]>C(O)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:17][NH:16][C:15]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2ccc(Br)cc2)nn1
Reactant: CCOC(=O)NN
Solvent: CCCCO
Product: CCOC(=O)NNc1ccc(-c2ccc(Br)cc2)nn1
Temperature: 25 °C

Procedure:
A mixture of 2.69 g. of 6-(p-bromophenyl)-3-chloropyridazine and 3.12 g. of ethyl carbazate in 50 ml. of n-butyl alcohol is prepared. This solution is stirred and heated at reflux temperature for 4 hours. The reaction mixture is cooled to room temperature and the solvent removed on a rotation evaporator. The residue is triturated with water and the resulting solid collected by filtration. The product is recrystallized from ethanol to give crystalline material, m.p. 190°-192° C.
Reaction SMILES: [CH3:1][N:2](C)C=O.Cl[C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[C:10]([Cl:17])=[CH:9][N:8]=1>[C-]#N.[Zn+2].[C-]#N.O>[Cl:17][C:10]1[C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]([C:1]#[N:2])=[N:8][CH:9]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cc(Cl)ncc1Cl
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1cc(C(F)(F)F)c(Cl)cn1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To 14 ml of N,N-dimethylformamide were added 1 g of 2,5-dichloro-4-trifluoromethylpyridine, 1.71 g of zinc cyanide and 0.34 g of tetrakistriphenylphosphine palladium, and the mixture was stirred at 90° C. for 10 hours. After allowing to cool, the reaction solution was poured into water, and the resultant solution was extracted with diethyl ether three times, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.7 g of 5-chloro-4-trifluoromethylpyridine-2-carbonitrile.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O)[C:6]#[N:7].[H][H]>[Pd].CO>[NH2:11][C:10]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N:2]([CH3:14])[CH3:1]
Reactant: [H][H]
Reactant: CN(C)c1cc(C#N)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CN(C)c1cc(C#N)ccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 16 g (84 mmol) of 3-(dimethylamino)-4-nitrobenzonitrile was added 1 g of palladium on carbon (10%, w/w) and 100 mL of methanol. The mixture was saturated with hydrogen and stirred at room temperature overnight. The palladium on carbon was then filtered off. Concentration of the filtration gave 12.8 of a dark-red solid as the desired product. MS ESI (m/z) 162 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[F:14])=[N:4][C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:30])[C:22]=1[CH:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)=[O:16].[BH4-].[Na+]>CO>[NH2:1][C:2]1[S:6][C:5]([C:7]2[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=2[F:14])=[N:4][C:3]=1[C:15]([NH:17][C:18]1[CH:19]=[N:20][N:21]([CH3:30])[C:22]=1[CH:23]1[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]1)=[O:16]
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1C1CCC(O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(4-oxocyclohexyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide (57 mg, 0.13 mmol), prepared according to the procedures provided in Example 347, was dissolved in methanol (2 mL). Sodium borohydride (15.1 mg, 0.40 mmol) was added. The mixture was stirred at RT for 1 h, quenched with sat. NaHCO3 and extracted with ethyl acetate three times. Combined organic layers were concentrated and purified via reverse phase HPLC to give 361. 1H NMR (400 MHz, DMSO) δ 8.69 (s, 1H), 7.61-7.48 (m, 2H), 7.46 (s, 2H), 7.26 (dd, J=14.5, 5.8 Hz, 2H), 4.57 (d, J=4.4 Hz, 1H), 3.76 (s, 3H), 3.50-3.34 (m, 1H), 3.02 (td, J=6.6, 4.0 Hz, 1H), 2.84-2.60 (m, 1H), 1.91 (d, J=9.9 Hz, 2H), 1.84-1.59 (m, 5H), 1.37-1.17 (m, 2H). MS (ESI) m/z: 434.2 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)[N:3]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](O)=[O:25].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>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][N:14]([C:24]([C:23]4[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=4[C:18]4[S:17][CH:21]=[CH:20][CH:19]=4)=[O:25])[CH2:15]3)[CH2:10]2)[N:5]=1
Reactant: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Reactant: O=C(O)c1ccccc1-c1cccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(N2C[C@@H]3CCN(C(=O)c4ccccc4-c4cccs4)C[C@@H]32)n1
Yield: 58.9 %

Procedure:
A mixture of (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane (Intermediate 4, 28 mg, 0.13 mmol), 2-thiophen-2-yl-benzoic acid (29 mg, 0.14 mmol), HATU (73.2 mg, 0.19 mmol), diisopropylethylamine (50 mg, 0.38 mmol) was stirred in DMF (4 mL) at room temperature for 2 h. Then the reaction mixture was partitioned between water and ethyl acetate mixture. The organic phase was separated and washed with 1N aq. NaOH (10 mL) and then with water (2×15 mL). The organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified on HPLC (basic system) to yield the title compound (31.0 mg, 59.8%). MS (ESI) mass calcd. for C23H24N4OS, 404.53; m/z found, 405.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.60-6.75 (m, 7H), 6.43-6.10 (m, 1H), 4.10-1.78 (m, 16H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:28][C:27]([C:29](O)=[O:30])=[C:26]([CH3:32])[CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.S(Cl)([Cl:35])=O>ClCCl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][CH2:14][C:15]3[N:19]4[N:20]=[C:21]([C:24]5[S:28][C:27]([C:29]([Cl:35])=[O:30])=[C:26]([CH3:32])[CH:25]=5)[CH:22]=[CH:23][C:18]4=[N:17][N:16]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5cc(C)c(C(=O)O)s5)nn34)ccnc2c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2c(OCc3nnc4ccc(-c5cc(C)c(C(=O)Cl)s5)nn34)ccnc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 5-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-3-methylthiophene-2-carboxylic acid (prepared by General Method A) (0.150 g, 0.335 mmol) in dichloromethane (2 mL) was added thionyl chloride (0.734 ml, 10.1 mmol and DMF (1 drop). The solution was stirred at room temp for three hours then concentrated and taken forward without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[C:8](=[O:11])[C:7]1[C:12]([OH:20])=[C:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=[CH:15][C:6]=1[O:5]2.[Cl-].Cl[CH:23]=[N+:24]([CH3:26])[CH3:25].C([BH3-])#N.[Na+]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[N:9]([C:10]=1[CH2:23][N:24]([CH3:26])[CH3:25])[C:8](=[O:11])[C:7]1[C:12]([OH:20])=[C:13]([CH2:17][CH2:18][CH3:19])[C:14]([OH:16])=[CH:15][C:6]=1[O:5]2
Reactant: C[N+](C)=CCl
Reactant: CCCc1c(O)cc2oc3cc(Cl)cn3c(=O)c2c1O
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCc1c(O)cc2oc3cc(Cl)c(CN(C)C)n3c(=O)c2c1O
Reaction time: 1 h
Yield: 71.3 %

Procedure:
To 60 mg (0.20 mmol) of 2-chloro-6,8-dihydroxy-7-propyl-9H-pyrrolo [2,1-b][1,3]benzoxazin-9-one in 20 mL of CH2Cl2 was added 157 mg (1.22 mmol) of chloromethylene dimethylammonium chloride and the reaction stirred for 1 hr. The mixture was concentrated, diluted with 50 mL of dry MeOH and 1.0 g (15.9 mmol) of sodium cyanoborohydride was added. After 24 hr the mixture was quenched with saturated NaHCO3 and the mixture extracted with ethylacetate which was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (Silica Gel EtOAc 100% to acetone 100%) to give 50 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]=[CH:6][C:5]2=O.[CH3:13][NH:14][NH2:15].B(F)(F)F.CCOCC>C(O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([OH:8])=[C:4]([C:5]2[N:14]([CH3:13])[N:15]=[CH:7][CH:6]=2)[CH:3]=1
Reactant: CNN
Reactant: O=c1ccoc2ccc(Br)cc12
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCO
Product: Cn1nccc1-c1cc(Br)ccc1O
Yield: 44.6 %

Procedure:
To a suspension of 6-bromochromone (1.58 g, 0.0070 mol) in ethanol (30 mL) was added methylhydrazine (0.41 mL, 0.0077 mol) and boron trifluoride etherate (1.15 mL, 0.0091 mol). The reaction was heated to reflux for 22 hours. After cooling, the reaction was concentrated in vacuo and the residue purified by automated flash column chromatography using a 0-100% ethyl acetate/hexanes gradient. This provided the title compound (0.79 g, 44%) as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl>CO>[O:18]1[CH2:17][CH:16]1[CH2:14][N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: ClCC1CO1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CC2CO2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of 1-(tert-butoxycarbonyl)piperazine (18.6 g, 100 mmol) and epichlorohydrine (10.2 ml, 12.0 g, 130 mmol) in methanol (50 ml) was stirred at room temperature for 24 hours and the solvent was evaporated. The residue was dissolved in 200 ml of ether and the solution was stirred with 10N aqueous NaOH (100 ml) at room temperature for 2 hours. Then the organic layer was separated, washed with brine until neutral, dried over MgSO4 and concentrated to afford the title compound (21.8 g) as a pale yellowish viscous oil, yield: 90.1%.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8])=[O:4].[Br:11][CH2:12][C:13]([OH:15])=[O:14].[K].CCOCC>CN(C)C=O>[Br:11][CH2:12][C:13]([O:15][CH2:2][C:3]([O:5][CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8])=[O:4])=[O:14]
Reactant: CCC(CC)OC(=O)CBr
Reactant: O=C(O)CBr
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCC(CC)OC(=O)COC(=O)CBr
Temperature: 0 °C

Procedure:
Bromoacetic acid, 3-pentyl ester (330 g, 1.6 mole) was dissolved in 300 ml of dimethylformamide. Bromoacetic acid, potassium salt (142 g) was added portionwise with stirring and the mixture was stirred overnight. It was then poured into 1 liter of ice-cold water and 500 ml of ether was added. After washing with water, NaHCO3 solution and drying with MgSO4, the ether was evaporated. On distillation 156 g of the starting ester was recovered and 103.5 g of the title compound (boiling point 160°-162° C. at 12 mm of Hg) was obtained.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[C:6]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:5]=1.[OH-].[K+].O.Cl>C(O)C>[CH2:19]([O:18][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:3]([OH:26])=[O:2])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCOc1ccc(C(=O)OC)cc1OCCCCCCC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCOc1ccc(C(=O)O)cc1OCCCCCCC
Temperature: 25 °C
Yield: 93.9 %

Procedure:
A mixture of 25 g of product from Example 109, 11.54 g of potassium hydroxide, 30 ml of water and 500 ml ethyl alcohol is heated at reflux temperature for 24 hours. The reaction mixture is cooled and maintained at room temperature for 48 hours. The mixture is acidified to pH 2 with concentrated hydrochloric acid, concentrated in vacuo, diluted with water and extracted with chloroform. The combined chloroform extracts are washed with saturated sodium chloride, dried and concentrated in vacuo to give 22.58 g of the desired product as colorless crystals.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[CH:15]=O)(=[O:3])[CH3:2].Cl.[NH2:18][OH:19]>C(OCC)(=O)C>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[CH:15]=[N:18][OH:19])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(NC(C)=O)c(C=O)c1
Reactant: NO
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(C)=O)c(C=NO)c1
Yield: 52.9 %

Procedure:
A mixture of methyl 4-acetylamino-3-formylbenzoate (Gassman, P. G.; Drews, H. R. J. Am. Chem. Soc. 1978, 100, 7600-7610) (0.442 g, 0.002 mol) and hydroxylamine hydrochloride (0.174 g, 0.0025 mol) in ethyl acetate (10 mL) was heated at reflux for 16 h. White precipitate formed which was removed by filtration and the filtrate was concentrated to dryness. The residue was recrystallized from ethyl acetate-hexane to give 0.25 g (53%) of methyl 4-acetylamino-3-[(N-hydroxylimino)methyl]benzoate as a pale yellow powder, mp 200°-203° C.
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)=[N:27][C:22]([NH:1][C:2]2[C:18]([O:19][CH3:20])=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Reactant: Clc1ncc(Cl)c(Nc2ccccc2-n2cccn2)n1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3-n3cccn3)n1)CCN(CC(=O)N(C)C)CC2
Yield: 60.7 %

Procedure:
Following a procedure analogous to Example 113, 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide (47 mgs) and (2,5-Dichloro-pyrimidin-4-yl)-(2-pyrazol-1-yl-phenyl)-amine (47 mgs) were converted to the title compound (51 mgs) as a white foam. 1H-NMR (CDCl3): δ 10.16 (s, 1H), 8.53 (d, J=7.4 Hz, 1H), 8.06 (s, 2H), 7.85 (d, J=14.4 Hz, 2H), 7.48 (s, 1H), 7.40-7.34 (m, 2H), 7.20 (t, J=7.6 Hz, 1H), 6.65 (s, 1H), 6.52 (s, 1H), 3.88 (s, 3H), 3.30 (s, 2H), 3.17 (s, 3H), 3.00 (s, 3H), 2.90-2.70 (complex m 7H). LC/MS, found 547.18 (M+H)+; MP: 66-67° C.;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.[CH2:36](I)[CH3:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[N:23]([CH2:36][CH3:37])[C:22]2=[O:35])[CH2:17][CH2:16]1
Reactant: CCI
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Product: CCn1c(=O)n(C2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)c(=O)c2cc([N+](=O)[O-])ccc21
Yield: 67 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.63 mmol) of Compound 24 was used and ethyl iodide was used in place of methyl iodide. As a result, 213.1 mg (yield: 67%) of Compound 2 was obtained as pale yellow crystals.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH:10]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:11]2=O)=[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:6]=1[O:26][CH3:27])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C1COCC1.Cl>O>[C:1]([C:5]1[CH:13]=[C:12]2[C:8](=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:6]=1[O:26][CH3:27])[CH2:9][C:10]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:11]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)CC(CC(C)(C)C)C2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C(C)(C)C)cc2c(c1-c1ccccc1)CC(CC(C)(C)C)=C2
Temperature: 5 °C
Yield: 91.8 %

Procedure:
To a mixture of 19.7 g of 6-tert-butyl-2-(2,2-dimethylpropyl)-5-methoxy-4-phenyl-1-indanone of 93% purity (50.3 mmol), 15.0 g of NaBH4, and 200 ml of THF 100 ml of water was slowly (for ca. 10 h) added by vigorous stirring at 5° C. The resulting mixture was stirred overnight at room temperature. Further on, 500 ml of cold water was added, the resulting mixture was acidified by 12 N HCl to pH 1, and then the crude product was extracted with 3×150 ml of dichloromethane. To a solution of the residue in 300 ml of toluene 0.5 g of TsOH was added, the resulting mixture was refluxed for 15 min with Dean-Stark head, then quickly cooled to room temperature, and treated with 50 ml of 10% aqueous K2CO3 to remove acidic impurities. The organic layer was separated, the aqueous layer was extracted with 2×75 ml of dichloromethane. The combined organic extract was dried over K2CO3 and then evaporated to dryness. The product was isolated by flash-chromatography on silica gel 60 (40-64 um, 450 m3 of silica gel, eluent: hexanes-dichloromethane=4:1, vol.). Yield 17.3 g (99%) of the title product as yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][CH:15]=2)[C:4](=[O:26])[CH:3]=1.[C:27](Cl)(=[O:30])[CH:28]=[CH2:29].O>CN(C)C(=O)C>[F:24][C:22]([F:25])([F:23])[CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([N:5]2[C:4](=[O:26])[C:3]3[CH2:29][CH2:28][C:27](=[O:30])[NH:1][C:2]=3[N:7]=[C:6]2[CH2:8][CH2:9][C:10]([F:13])([F:11])[F:12])=[CH:19][CH:18]=1
Reactant: C=CC(=O)Cl
Reactant: Nc1cc(=O)n(-c2ccc(OCC(F)(F)F)cc2)c(CCC(F)(F)F)n1
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C1CCc2c(nc(CCC(F)(F)F)n(-c3ccc(OCC(F)(F)F)cc3)c2=O)N1
Reaction time: 0.17 h

Procedure:
A solution of 6-amino-3-(4-(2,2,2-trifluoroethoxy)phenyl)-2-(3,3,3-trifluoropropyl)pyrimidin-4(3H)-one (1.0 g) in N,N-dimethylacetamide (30 mL) was heated to 60° C., acryloyl chloride (0.85 mL) was added thereto, and the mixture was stirred for 10 min. To the reaction mixture was added water under ice-cooling, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), diolpropylsilane-bonded silica gel column chromatography (ethyl acetate/hexane) and then silica gel column chromatography (ethyl acetate/hexane). The obtained solid was recrystallized from ethyl acetate-hexane to give the title compound (0.72 g) as a solid. The solid (487 mg) was recrystallized from ethyl acetate to give the title compound (300 mg) as a solid.
Reaction SMILES: [C:1]([NH:8][C:9]1[S:10][C:11](Br)=[C:12]([C:14]([O:16][CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:27]([Sn](CCCC)(CCCC)C=C)[CH2:28]CC.[F-].[Na+]>CN(C=O)C.O.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>[C:1]([NH:8][C:9]1[S:10][C:11]([CH:27]=[CH2:28])=[C:12]([C:14]([O:16][CH2:17][P:18]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])=[O:19])=[O:15])[N:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCOP(=O)(COC(=O)c1nc(NC(=O)OC(C)(C)C)sc1Br)OCC
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=Cc1sc(NC(=O)OC(C)(C)C)nc1C(=O)OCP(=O)(OCC)OCC
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of 2-[N-Boc(amino)]-5-bromo-4-diethylphosphonomethoxycarbonylthiazole (1 mmole) and dichlorobis(triphenylphosphine)palladium(II) (0.1 mmole) in DMF (5 mL) was treated with tributyl(vinyl)tin (2.5 mmole) and the reaction was stirred at 60° C. for 2 h. The solvent was removed and the residue taken up in EtOAc and stirred with 2 mmol NaF in 5 ml water for 1 h. Extraction and chromatography gave 2-[N-Boc(amino)]-5-vinyl-4-diethylphosphonomethoxycarbonylthiazole as a yellow solid.