Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5](O)=[O:6].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:24][NH:25][O:26][CH3:27].CCOCC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:5](=[O:6])[N:25]([CH3:24])[O:26][CH3:27])[CH:8]=[CH:9][N:10]=1
Reactant: CNOC
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccnc(Cl)c1
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
To a suspension of 2-chloroisonicotinic acid (18.0 g, 0.105 mol) in 250 mL of methylenechloride was added 1,1′-carbonyldiimidazole (17.0 g, 0.105 mol) portionwise. The mixture was stirred for 0.5 h and N,O-dimethylhydroxylamine hydrochloride (10.2 g, 0.105 mol) was added rapidly. The reaction mixture was stirred at room temperature overnight. Ether was added and the organic layer was washed with water, dried, dried over magnesium sulfate and filtered. The filtrate was concentrated to give 14.5 g (70%) of product as a yellow oil. This was used in next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:13][O:14][C:15](=[O:22])[C:16]([N:19]=[C:20]=[O:21])([CH3:18])[CH3:17]>>[CH3:13][O:14][C:15](=[O:22])[C:16]([CH3:18])([CH3:17])[NH:19][C:20](=[O:21])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: COC(=O)C(C)(C)N=C=O
Product: COC(=O)C(C)(C)NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
9.75 g. of 5-amino-2-chlorobenzotrifluoride and 7.15 g. of 2-isocyanato-2-methylpropionic acid methyl ester are melted at 80° and the melt is kept at this temperature for 30 minutes. The product which has crystallized out during this process is recrystallized from isopropanol/methylene chloride and dried under greatly reduced pressure at 50° for 20 hours. N-[(3-trifluoromethyl-4-chlorophenyl)-carbamoyl]-2-methylalanine methyl ester, which melts at 141°-142° is obtained.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:8][CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+].Cl>C(O)C.C1COCC1>[OH:3][CH:1]([C:4]1[N:5]=[CH:6][C:7]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)c1cnc(NC(=O)C(C)(C)C)cn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(O)c1cnc(NC(=O)C(C)(C)C)cn1
Reaction time: 0.5 h
Yield: 104.1 %

Procedure:
To a solution of N-(5-acetylpyrazin-2-yl)-2,2-dimethylpropanamide (500 mg) in ethanol (10 mL) and THF (10 mL) was added sodium borohydride (86 mg) under ice-cooling, followed by stirring for 30 minutes under ice-cooling. To the reaction mixture was added 1 M hydrochloric acid under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and then concentrated to obtain N-[5-(1-hydroxyethyl)pyrazin-2-yl]-2,2-dimethylpropanamide (525 mg) as a brown solid.
Reaction SMILES: C([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[N:9]1)C1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:10]1[C:11]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[CH:12][C:13](=[O:14])[NH:8][N:9]=1
Reactant: O=c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)nn1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=c1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n[nH]1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 84.3 %

Procedure:
To a solution of 2-benzyl-6-(2-chlorophenyl)-5-(4-chlorophenyl)pyridazin-3(2H)-one (6.4 g, 15.7 mmol) in toluene (100 mL) at 90° C. was added aluminum chloride (5.23 g, 39.3 mmol) in one portion. After addition, the reaction mixture was stirred at 90° C. for 20 min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to reduce the volume to about 50 mL, then water (150 mL) was added. The resulting mixture was sonicated for 5 min, then stirred at room temperature for 10 min. The resulting suspension was filtered, the colleted solid washed with water (20 mL×3), hexanes (20 mL×3) and dried in a 50° C. vacuum oven for 16 h to afford 4.2 g (76%) of the title compound as a white solid. LC/MS (method A): retention time=3.27 min, (M+H)+=317. 1H NMR (CDCl3, 400 MHz): δ 11.6 (S, 1H), 7.17-7.40 (m, 6H), 6.90-7,10 (m, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH:15]1[CH:16]=[CH:17][C:12]([NH:11][C:2]2[C:3]([N+:8]([O-:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:14]=1
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1ccccc1Cl
Product: O=[N+]([O-])c1ccccc1Nc1ccccc1

Procedure:
As is known, a nitro group activates halogen substituents in both the ortho- and the para-positions. For example, if 2-chloronitrobenzene is reacted with aniline at from 175 to 205° C., 2-nitrodiphenylamine is obtained in quantitative yield. By contrast, 4-chloronitrobenzene does not react at all with aniline at from 175 to 205° C.(Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], IVth Edition, Volume XI/1, pages 63 and 64). This behavior shows that the nitro group activates the chlorine in the ortho- position to a very great extent, while its activating effect on the chlorine in the para-position is insufficient to permit the substitution reaction.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](Cl)=[O:15].Cl.[Cl:21][C:22]1[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][N:23]=1>C(Cl)Cl>[Cl:21][C:22]1[CH2:26][C:25]([CH3:28])([CH3:27])[N:24]([C:14]([C:13]2[CH:17]=[CH:18][CH:19]=[C:11]([F:10])[CH:12]=2)=[O:15])[N:23]=1
Reactant: CC1(C)CC(Cl)=NN1
Reactant: O=C(Cl)c1cccc(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC(Cl)=NN1C(=O)c1cccc(F)c1
Temperature: 0 °C
Yield: 37 %

Procedure:
A 250 mL round bottom flask equipped with a stir bar and nitrogen inlet was charged with dry CH2Cl2 (100 mL), Hunigs base (7.8 mL, 45 mmol) DMAP (5 mg) and 3-fluorobenzoyl chloride (1.8 mL. 15 mmol). The mixture was cooled to 0° C. To this mixture was added portionwise, 3-chloro-5,5-dimethyl-4,5-dihydro-1H-pyrazole.Hydrochloride (1.68 g, 10 mmol) and the reaction was allowed to warm to RT overnight. LC-MS showed consumption of SM. The reaction was added to water (100 mL), the phases were separated and the organic phase was washed with NaHCO3 (100 mL), dried (Na2SO4) and the solvent was evaporated under reduced pressure. The material was purified by chromatography using a 40 g silica cartridge eluting with heptane-EtOAc, gradient 0 to 20% EtOAc. Amount obtained: 0.9 g, 3.7 mmol, 37% yield. LC-MS (ESI) m/e 255 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.76 (s, 6H) 3.03 (s, 2 H) 7.14 (td, J=8.36, 1.98 Hz, 1H) 7.36 (td, J=7.96, 5.71 Hz, 1H) 7.43 (dd, J=9.57, 2.25 Hz, 1H) 7.51 (d, J=7.76 Hz, 1H).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[CH2:15][NH:14][C:13]1=[O:18])C1C=CC=CC=1>CO>[OH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[CH2:15][NH:14][C:13]1=[O:18]
Reactant: O=C1CNC(=O)N1CCCOCc1ccccc1
Solvent: CO
Product: O=C1CNC(=O)N1CCCO
Reaction time: 72 h
Yield: 72.8 %

Procedure:
3-(3-Benzyloxypropyl)imidazolidine-2,4-dione (1.3 g, 5.26 mmol) was dissolved in methanol (15 ml) and the system purged with nitrogen. 10% Palladium on carbon (130 mg, 10% by mass) and a few drops of glacial acetic acid were added and the mixture stirred under a hydrogen atmosphere (1 atmosphere) for 3 days. The mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with methylene chloride/methanol (98/2 to 95/5) to give 3-(3-hydroxypropyl)imidazolidine-2,4-dione (606 mg, 73%) as a viscous oil which crystallised on standing.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.CC1(C)[O:18][C:17](=O)[CH2:16][C:15](=[O:20])[O:14]1>CN(C)C=O>[OH:11][C:9]1[CH:8]=[C:3]2[N:2]([C:17](=[O:18])[C:16]=1[C:15]([OH:20])=[O:14])[CH:7]=[CH:6][CH:5]=[CH:4]2
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)Cc1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(O)c1c(O)cc2ccccn2c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
To a solution of pyridin-2-ylacetic acid hydrochloride (1 g) in N,N-dimethylformamide (10 ml) was added N,N'-carbonyldiimidazole (934 mg) at room temperature and the mixture was heated at 60° C. for 20 minutes. To the mixture was added 2,2-dimethyl-1,3-dioxane-4,6-dione (830 mg) at 60° C. and the mixture was stirred for 1 hour at the same temperature. The solvent was distilled off and the residue was diluted with chloroform and washed with water. The chloroform layer was extracted with aqueous sodium hydrogen carbonate and the aqueous layer was washed with chloroform and acidified to pH 2 with 6N hydrochloric acid at 0° C. and extracted with chloroform. The chloroform layer was washed with brine, dried over magnesium sulfate, and evaporated to give 2-hydroxy-4H-quinolizin-4-one-3carboxylic acid (220 mg).
Reaction SMILES: B(F)(F)F.P(=O)(O)(O)O.S(=O)(=O)(O)O.[CH3:15][C:16]1[C:21]([CH2:22]Cl)=[CH:20][CH:19]=[CH:18][CH:17]=1>C1C=CC=CC=1>[CH2:22]([C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:15])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccccc1CCl
Agent: FB(F)F
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: Cc1ccccc1Cc1ccccc1
Yield: 91.8 %

Procedure:
470 parts of benzene are emulsified in a mixture of 200 parts of boron fluoride-phosphoric acid (containing 90 parts of boron fluoride in 110 parts of phosphoric acid) and 200 parts of sulfuric acid (85% strength by weight) by stirring thoroughly. A solution of 140 parts of o-xylyl chloride in 470 parts of benzene is added at from 75° to 80° C in the course of 2 hours. The reaction mixture is stirred for a further 5 hours at from 75° to 80° C and the organic phase is then separated off. 167 parts (91.8% of theory) of o-benzyltoluene (nD25 : 1.5739) are isolated by fractional distillation at from 98° to 100° C at 0.2 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[CH:7][CH:6]=1)=[O:4].C(O)(C)C.[Cl-].[NH4+]>[Fe].C(Cl)(Cl)Cl>[NH2:22][C:19]1[CH:20]=[CH:21][C:12]([S:11][C:8]2[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1ccc(Sc2ccc([N+](=O)[O-])cc2C(=O)OC)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(Sc2ccc(N)cc2C(=O)OC)cc1
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a mixture of 1.09 g of methyl 2-(4-methoxycarbonylphenylthio)-5-nitrobenzoate obtained in the same procedures as described in Reaction Scheme (24) of Example 1 and 1.75 g of iron powder, were added 3 ml of isopropyl alcohol and an aqueous solution of ammonium chloride (0.05 g of ammonium chloride and 0.95 ml of water). The mixture was stirred for 10 minutes at 85° C. Chloroform was added to the reaction mixture. The mixture was filtered with celite, and was subsequently washed with chloroform. A mixture of the filtrate and the washing was washed with saturated brine, and was subsequently dried over anhydrous magnesium sulfate. After the solvent was removed under reduced pressure, 0.996 g of methyl 5-amino-2-(4-methoxycarbonylphenylthio)benzoate (yellow viscous substance) was obtained (Reaction Scheme (31) described below).
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].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
According to the new process, the 4-nitrobenzoic acid chloride is condensed with aniline and the 4-nitro-benzanilide formed is extracted and nitrated.
Reaction SMILES: [CH:1]1([C:4]2([C:14]3[C:22]4[C:17](=[C:18]([CH2:24][S:25][CH3:26])[CH:19]=[C:20]([F:23])[CH:21]=4)[NH:16][CH:15]=3)[C:12]3[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.ClCCl.ClC1C=CC=C(C(OO)=[O:38])C=1>CO>[CH:1]1([C:4]2([C:14]3[C:22]4[C:17](=[C:18]([CH2:24][S:25]([CH3:26])=[O:38])[CH:19]=[C:20]([F:23])[CH:21]=4)[NH:16][CH:15]=3)[C:12]3[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cc(F)cc2c(C3(C4CC4)CCc4cc(F)ccc43)c[nH]c12
Solvent: CO
Solvent: ClCCl
Product: CS(=O)Cc1cc(F)cc2c(C3(C4CC4)CCc4cc(F)ccc43)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80.0 mg (0.22 mmol) of the compound from Example 94 were introduced into 6 ml of dichloromethane at 0° C., 56.1 mg (0.23 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. Methanol was added, and the residue after concentration was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 43.6 mg (52% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: CS(C)=O.[CH:5]1([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:21])=[C:15](F)[C:16]=3[O:18][CH3:19])[C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9]2)[CH2:7][CH2:6]1.C(OC([NH:33][C@H:34]1[C@@H:38]([CH2:39][F:40])[CH2:37][NH:36][CH2:35]1)=O)(C)(C)C>C(N(CC)CC)C>[NH2:33][C@H:34]1[C@@H:38]([CH2:39][F:40])[CH2:37][N:36]([C:15]2[C:16]([O:18][CH3:19])=[C:17]3[C:12]([C:11](=[O:22])[C:10]([C:23]([OH:25])=[O:24])=[CH:9][N:8]3[CH:5]3[CH2:6][CH2:7]3)=[CH:13][C:14]=2[F:21])[CH2:35]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNC[C@@H]1CF
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1c(N2C[C@H](CF)[C@H](N)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
To a dimethyl sulfoxide (2 ml) solution of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3carboxylic acid EF2 complex (345 mg, 1.00 mmol) were added 3-(S)-tert-butoxycarbonylamino-4-(S)-fluoromethylpyrrolidine (327 mg, 1.00 mmol) and triethylamine (400 μl), subsequently carrying out 1 day of stirring at room temperature. Triethylamine was evaporated, the resulting residue was mixed with 10% citric acid aqueous solution and then the thus precipitated material was collected by filtration and washed with water. This was dissolved in 80% water-containing ethanol (50 ml), mixed with triethylamine (5 ml) and then heated overnight under reflux. The solvent was evaporated, and the thus obtained residue was mixed with concentrated hydrochloric acid and stirred at room temperature for 15 minutes. The reaction solution was washed with chloroform and then, while cooling in an ice bath, alkalified with 50% sodium hydroxide aqueous solution. This was adjusted to pH 7.4 with concentrated hydrochloric acid, and the aqueous layer was extracted with chloroform (300 ml×3). The organic layer was dried over sodium sulfate, the solvent was evaporated, and the resulting residue was isolated and purified by a preparative TLC through its development with a lower layer of chloroform:methanol:water=7:3:1 and then recrystallized from 28% aqueous ammonia-ethanol to give 185 mg (47%) of the title compound in the form of light yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](O)=[C:6]([O:14][CH2:15][CH3:16])[CH:5]=1.C(Cl)(=O)C([Cl:21])=O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([Cl:21])=[C:6]([O:14][CH2:15][CH3:16])[CH:5]=1
Reactant: CCOc1cc(C(=O)OC)cc([N+](=O)[O-])c1O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)OC)cc([N+](=O)[O-])c1Cl
Temperature: 80 °C
Yield: 91.5 %

Procedure:
To a solution of 3-ethoxy-4-hydroxy-5-nitro-benzoic acid methyl ester (2.0 g, 8.29 mmol, 1.0 equiv) in anhydrous DMF (100 mL) at −25° C. under Ar was added slowly oxalyl chloride (1.40 mL, 2.11 g, 16.58 mmol, 2.0 equiv) over a period of 30 min. After the addition was completed the reaction mixture was heated to 80° C. for 3 h. The reaction mixture was poured on ice, the yellow precipitate washed with cold dichloromethane (3×20 mL), filtered and dried providing 1.97 g (86%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.53 (t, J=7.0 Hz, 3H), 3.96 (s, 3H), 4.24 (q, J=7.0 Hz, 2H), 7.74 (d, J=1.8 Hz, 1H), 8.00 (d, J=1.8 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ 14.47, 52.91, 66.17, 115.93, 117.25, 120.95, 129.82, 149.61, 156.03, 164.56. MS (ISP): 276.9 [M+NH4]+.
Reaction SMILES: [CH2:1]([C:8]1([OH:15])[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1[N:25]=[CH:24][N:23]=[C:22]2[C:18]=1[NH:19][C:20](=[O:26])[NH:21]2>>[CH2:1]([C:8]1([OH:15])[CH2:13][CH2:12][N:11]([C:14]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[NH:19][C:20](=[O:26])[NH:21]3)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCC(O)(Cc2ccccc2)CC1
Reactant: O=c1[nH]c2ncnc(Cl)c2[nH]1
Product: O=c1[nH]c2ncnc(N3CCC(O)(Cc4ccccc4)CC3)c2[nH]1

Procedure:
4-Benzyl-1-methyl-piperidin-4-ol was reacted with 6-chloro-7,9-dihydro-purin-8-one under conditions analogous to those set out in Example 3A to give the title compound LC/MS: (LCT) Rt 5.68 [M+H]+ 326.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[C:8]([CH3:17])=[N:7]1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[S:42][CH2:43][C:44](=[O:46])[N:45]=2)[CH2:37][C@@H:36]1[CH2:47][OH:48])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[S:42][C:43](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:18]=[CH:19][C:20]([C:22]([F:25])([F:23])[F:24])=[CH:21][C:3]=3[C:2]([F:26])([F:1])[F:27])[N:7]=[C:8]4[CH3:17])[C:44](=[O:46])[N:45]=2)[CH2:37][C@@H:36]1[CH2:47][OH:48])=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1nn(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2ccc(C=O)cc12
Reactant: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)CS2)C[C@@H]1CO
Product: Cc1nn(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c2ccc(C=C3SC(N4CCN(C(=O)OC(C)(C)C)[C@@H](CO)C4)=NC3=O)cc12

Procedure:
4-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-3-methyl-1H-indazole-5-carbaldehyde and 2-(R)-Hydroxymethyl-4-(4-oxo-4,5-dihydro-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester following general procedure D.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15](=O)[NH2:16])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH3:14])([C:15](=[S:27])[NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(N)=O)CC1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C)(C(N)=S)CC1
Temperature: 50 °C

Procedure:
To a solution of 4-carbamoyl-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (2.1 g, 8.7 mmol) in THF (30 mL) was added Lawesson's reagent (3.5 g, 8.7 mmol) at room temperature. The mixture was heated at 50° C. for 3 hours. After cooling to room temperature, the solvent was removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was washed with saturated NaHCO3, and brine. After drying (Na2SO4), the solvent was removed in vacuo, and the residue was purified by silica column chromatography with EtOAc/hexanes to afford the desired product.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[CH3:30][OH:31]>O1CCOCC1.CN(C=O)C>[CH3:30][O:31][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6]
Reactant: CO
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Cl)c3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: COc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and methanol in dioxane and DMF. ES-MS m/e (%): 423 (M+Na+, 31), 401 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].O1CCCC1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)ccc1Oc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(Cl)ccc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.6 %

Procedure:
A mixture of methyl 5-chloro-2-(4-fluorophenoxy)benzoate (step 1, 2.60 g, 9.26 mmol), tetrahydrofuran (20 mL), methanol (20 mL), and 2 N sodium hydroxide (20 mL) was stirred at room temperature for 3 h. The mixture was poured into 2 N hydrochloric acid (50 mL) and the aqueous mixture was extracted with ethyl acetate (200 mL). The organic layer was dried over magnesium sulfate and evaporated to give 2.41 g (98%) of the title compound as white solids: 1H-NMR (CDCl3) δ 8.11 (1H, d, J=2.8 Hz), 7.43 (1H, dd, J=9.0, 2.8 Hz), 7.14–7.02 (4H, m), 6.80 (1H, d, J=8.8 Hz); MS (ESI) m/z 265 (M−H)−.
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:20])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:14]=2)[C:9]1=[O:20]
Reactant: CC=CCC1Cc2ccc(C(C)C)cc2C1=O
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: CC(C)c1ccc2c(c1)C(=O)C(CC=O)C2
Reaction time: 0.83 h
Yield: 95 %

Procedure:
An ozone stream (2 g ozone/hour) was conducted for 50 minutes while stirring through a solution, cooled to -70°, of 5.6 g of (RS)-2-(2-buten-1-yl)-6-isopropyl-1-indanone in 125 ml of anhydrous dichloromethane and 25 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 2.7 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 60 ml of dichoromethane and, after the addition of 10 ml of water and 10 ml of trifluoroacetic acid, stirred at room temperature for 3 hours. The mixture was subsequently poured into 50 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added, the phases were separated and the aqueous phase was extracted twice with 200 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 5.08 g (95%) of (RS)-2-(2-oxoethyl)-6-isopropyl-1-indanone were obtained as a yellow oil.