Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].CO.[O:5]=[C:6]([CH:21]([CH3:31])[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:7][C:8]([O:10][CH2:11]C1C=CC([N+]([O-])=O)=CC=1)=[O:9]>C(OCC)(=O)C>[O:5]=[C:6]([CH:21]([CH3:31])[CH2:22][O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: CC(COCc1ccccc1)C(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CC(=O)C(C)COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium borohydride (1.89 g; 50 mmole) was added to methanol (20 ml), and the solution was heated under reflux for 10 minutes and then allowed to cool to room temperature. p-Nitrobenzyl 3-oxo-5-benzyloxy-4-methylpentanoate (3.7 g; 10 mmole) was dropwise added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid and an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give methyl 3-oxo-5-benzyloxy-4-methylpentanoate.
Reaction SMILES: N#N.[I:3][C:4]1[CH:8]=[CH:7][NH:6][N:5]=1.[CH3:9][C:10](O)([CH3:12])[CH3:11].S(=O)(=O)(O)O>>[C:10]([N:6]1[CH:7]=[CH:8][C:4]([I:3])=[N:5]1)([CH3:12])([CH3:11])[CH3:9]
Reactant: CC(C)(C)O
Reactant: Ic1cc[nH]n1
Agent: N#N
Agent: O=S(=O)(O)O
Product: CC(C)(C)n1ccc(I)n1
Temperature: 100 °C

Procedure:
To a round-bottomed flask equipped with a stifling bar and a N2 tee, 3-iodo-1H-pyrazole (2.00 g, 10 mmol), 2-methylpropan-2-ol (7.64 g, 103 mmol), and concentrated sulfuric acid (1.08 g, 11 mmol) were added. The resulting mixture was heated at 100° C. for 3 hrs.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][C:5](=[CH:10][C:11]1[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=3)[CH:14]=[CH:15][CH:16]=1)[CH2:6]2.[ClH:25]>CO.[OH-].[OH-].[Pd+2]>[ClH:25].[ClH:25].[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][CH:5]([CH2:10][C:11]1[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][NH2:24])[CH:18]=3)[CH:14]=[CH:15][CH:16]=1)[CH2:6]2
Reactant: CN1C2CCC1CC(=Cc1cccc(-c3cccc(C#N)c3)c1)C2
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CN1C2CCC1CC(Cc1cccc(-c3cccc(CN)c3)c1)C2
Yield: 173 %

Procedure:
To a solution of 3′-[(8-methyl-8-azabicyclo[3.2.1]oct-3-ylidene)methyl]-3-biphenylcarbonitrile (1.21 g, 3.85 mmol) in MeOH (192 mL) was added HCl (3.85 mL, 1N, 3.85 mmol). This mixture was then applied to an H-cube hydrogenation apparatus using 20% Pd(OH)2 cartridge at a flow rate of 1 mL/min. and H2 (1 atm) at 20° C. until reaction complete by monitoring with LC-MS. The reaction mixture was concentrated to afford 1.31 g (87%) of the title compound. LC-MS m/z 321 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11](=[O:21])[C@@H:12]1[C:16]([CH3:18])([CH3:17])[CH2:15][C:14](=[O:19])[N:13]1[CH3:20].ClC1C([C:29]([F:32])([F:31])[F:30])=CC=CC=1C[N+]#[C-]>>[Cl:1][C:2]1[C:7]([C:29]([F:32])([F:31])[F:30])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11](=[O:21])[C@@H:12]1[C:16]([CH3:18])([CH3:17])[CH2:15][C:14](=[O:19])[N:13]1[CH3:20]
Reactant: CN1C(=O)CC(C)(C)[C@H]1C(=O)NCc1ccc(Cl)cc1Cl
Reactant: [C-]#[N+]Cc1cccc(C(F)(F)F)c1Cl
Product: CN1C(=O)CC(C)(C)[C@H]1C(=O)NCc1cccc(C(F)(F)F)c1Cl

Procedure:
N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-1,3,3-trimethyl-5-oxoprolinamide was prepared in a manner analogous to that described above for the synthesis of N-[(2,4-dichlorophenyl)methyl]-1,3,3-trimethyl-5-oxoprolinamide (E127) but using [2-chloro-3-(trifluoromethyl)phenyl]methyl isocyanide (prepared as described in example 40) in the place of (2,4-dichlorophenyl)methyl isocyanide.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:20])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16](=[O:18])[CH3:17])[C:12]([F:19])=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].BrC1C(F)=CC=C2C=1N=C(NC1(C)CC1)C(C)=N2>>[F:19][C:12]1[C:13]([C:16](=[O:18])[CH3:17])=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:20])[C:6]([NH:5][C:1]1([CH3:4])[CH2:3][CH2:2]1)=[N:15]2
Reactant: CC(=O)c1c(F)ccc2nc(C)c(NC(C)(C)C)nc12
Agent: Cc1nc2ccc(F)c(Br)c2nc1NC1(C)CC1
Product: CC(=O)c1c(F)ccc2nc(C)c(NC3(C)CC3)nc12
Yield: 60 %

Procedure:
1-(6-Fluoro-2-methyl-3-((1-methylcyclopropyl)amino)quinoxalin-5-yl)ethanone (610b) (740 mg, 60% yield) as a light yellow solid was prepared according to the procedure described for Intermediate 605b, using 8-bromo-7-fluoro-3-methyl-N-(1-methylcyclopropyl)quinoxalin-2-amine (610a) (1.39 g, 4.49 mmol) as the starting material. m/z (ESI, +ve ion) 274.2 (M+H)+.
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)[C:10]#[N:11])[CH:5]=[CH:4]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>C1COCC1>[CH3:27][S:28]([O:1][N:2]=[C:3]1[CH:8]=[CH:7][C:6](=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)[C:10]#[N:11])[CH:5]=[CH:4]1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(C(C#N)=C2C=CC(=NO)C=C2)cc1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C(C#N)=C2C=CC(=NOS(C)(=O)=O)C=C2)cc1C
Temperature: 0 °C
Yield: 70.8 %

Procedure:
10 g (40 mmol) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-(3,4-dimethylphenyl)-acetonitrile are dissolved in 160 ml of THF and cooled in an ice bath. After adding 8.4 ml (60 mmol) of triethylamine to the solution, 3.4 ml (44 mmol) of methanesulfonyl chloride are added dropwise, keeping the temperature below 5° C. The reaction mixture is stirred in the ice bath for 30 min. The reaction mixture is poured into 150 ml of water, and extracted with ethyl acetate. The organic phase is washed with hydrochloric acid solution, water, and sodium chloride solution. The organic phase is dried over MgSO4, the solvent is distilled off, and the residue is purified by recrystallization from toluene. 9.3 g (71%) of (4-methylsulfonyloxyiminocyclohexa-2,5-dienylidene)-(3,4-dimethylphenyl)-acetonitrile are obtained in the form of yellow crystals having a melting point of 131-133° C. (dec.).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[O:16][C:15](=O)[NH:14][C:13]=2[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:28])=O>N1C=CC=CC=1>[Cl:28][C:15]1[O:16][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([F:1])=[CH:3][CH:4]=2)=[C:13]([CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:14]=1
Reactant: CCOC(=O)CCCc1[nH]c(=O)oc1-c1ccc(F)c2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CCOC(=O)CCCc1nc(Cl)oc1-c1ccc(F)c2ccccc12
Temperature: 125 °C
Reaction time: 0.75 h

Procedure:
A mixture of ethyl 4-[5-(4-fluoro-1-naphthyl)-2-oxo-4-oxazolin-4-yl]butanoate (3.09 g), phosphorus oxychloride (6.00 g) and pyridine (0.80 g) was heated to 120-130° C. and stirred for 45 minutes. There action mixture was poured into 100 ml of ice water and extracted with ethyl acetate (100 ml×2). The organic layer was washed in sequence with a 10% aqueous solution of sodium hydrogen carbonate (50 ml) and a saturated aqueous solution of sodium chloride (50 ml), and dried over anhydrous magnesium sulfate. The organic layer was concentrated, the residue was subjected to silica gel column chromatography, and ethyl 2-chloro-5-(4-fluoro-1-naphthyl)-4-oxazolebutanoate was obtained as a yellow oil (903 mg, 28%) from an ethyl acetate-hexane (1:4, v/v)-eluted fraction.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[CH:23][C:21]=3[N:22]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:30](O)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].N1(C2C=CN=CC=2)CCCC1>ClCCl>[CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:28])=[CH:23][C:21]=3[N:22]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc(-c2nc3cc(C(=O)O)ccc3o2)cc1
Reactant: CCCCCCCCO
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCCCCCCCCOc1ccc(-c2nc3cc(C(=O)OCCCCCCCC)ccc3o2)cc1
Temperature: 25 °C
Yield: 49.3 %

Procedure:
In a 30 ml round-bottom flask, 0.30 g (0.76 m mole) of 2-(4-decyloxyphenyl)-5-carboxybenzooxazole, 0.11 g (0,84 m mole) of octanol and 8 ml of dichloromethane were placed. To the mixture solution 0.16 g (0.78 m mole) of N,N'-dicyclohexycarbodiimide and 0.04 g of 4-pyrrolidinopyridine were added in order under stirring at room temperature, followed by stirring for 8 hours at room temperature to precipitate N,N'-dicyclohexylurea. The resultant N,N'-dicyclohexylurea was filtered off and the filtrate was dried under reduced pressure. The resultant was purified by silica gel column chromatography (eluent: toluene) and recrystallized twice from acetone to obtain 0.19 g of 2-(4-decyloxyphenyl)-5-octyloxycarbonyl benzooxazole (Yield: 49.3%). ##STR89##
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[CH:4]([OH:12])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:29]([N:42]1[CH2:45][CH:44](O)[CH2:43]1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[CH:29]([N:42]1[CH2:45][CH:44]([O:12][CH:4]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)[C:3]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:2]=2[Cl:1])[CH2:43]1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc2Cl)cc1
Yield: 49.7 %

Procedure:
A solution of 2,4,4′-trichlorobenzhydrol (2) (174 mmol), p-toluenesulfonic acid (174 mmol) and 1-benzhydryl-3-azetidinol (1) (87 mmol) in toluene (700 mL) was heated at reflux under Dean-Stark conditions for 30 minutes. The solution was cooled, washed with sodium hydrogen carbonate (saturated aqueous solution, 700 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography [SiO2; (10% ethyl acetate:isohexane)] to furnish the product as a yellow oil (22.0 g, 50%).
Reaction SMILES: [CH2:1]([C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][C:5]21[O:9][CH2:8][CH2:7][O:6]2)[CH:2]=C.I([O-])(=O)(=O)=[O:21].[Na+].CCOC(C)=O>C1COCC1.O.CC(O)(C)C.O=[Os](=O)(=O)=O>[C:14]1([C:4]2([CH2:1][CH:2]=[O:21])[CH2:13][CH2:12][CH2:11][CH2:10][C:5]32[O:6][CH2:7][CH2:8][O:9]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=CCC1(c2ccccc2)CCCCC12OCCO2
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=CCC1(c2ccccc2)CCCCC12OCCO2
Reaction time: 3 h

Procedure:
To a solution of 6-allyl-6-phenyl-1,4-dioxaspiro[4.5]decane (444 mg, 1.719 mmol) in THF (5 mL) was added a solution of sodium periodate (441 mg, 2.062 mmol) in water (5.00 mL), and 0.175 ml of 2.5% OsO4 in t-BuOH, and the mixture was stirred for 3 hrs. Next, the stirring was stopped and the mixture was added to EtOAc and washed with water, aq. Na2S2O3, and brine. The resulting material was dried over Na2SO4 and evaporated to give an oily residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=1[CH2:12]Br.C(N(CC)CC)C>ClCCl>[F:9][C:10]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=1[CH2:12][S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: Fc1ccc(F)c(CBr)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Fc1ccc(F)c(CSc2ccc(Cl)cc2)c1
Reaction time: 2 h
Yield: 75.6 %

Procedure:
4-Chlorothiophenol (3.6 g, 0.025 mol) in dichloromethane (100 mL) was treated with 2,5-difluorobenzyl bromide (5.17 g, 0.025 mol) and triethylamine (3.9 ml, 0.028 mol). The reaction was stirred for 2 hours then diluted with dichloromethane (250 mL) and washed with water (100 mL) and brine (100 mL). The separated organic layer was dried (MgSO4), evaporated to dryness, and the product purified by passing down a plug of silica eluting with hexane-ethyl acetate mixtures to give 4-chlorophenyl 2,5-difluorobenzyl sulfide (5.12 g). 1H NMR CDCl3 7.23 (4H, s), 6.69–6.86 (3H, m) and 4.04 (2H, s).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:10][CH:11]1[NH:15][C:14](=[O:16])[CH:13]=[CH:12]1)[CH:7]([CH3:9])[CH3:8].[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[C:17]1([S:23]([N:15]2[CH:11]([O:10][CH2:6][CH:7]([CH3:9])[CH3:8])[CH:12]=[CH:13][C:14]2=[O:16])(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)COC1C=CC(=O)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)COC1C=CC(=O)N1S(=O)(=O)c1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 27.2 %

Procedure:
13.2 cm3 of a 1.6M solution of n-butyllithium in hexane is added to a solution cooled to -45° C. of 3.3 g of 1,5-dihydro-5-isobutyloxy-2H-pyrrol-2-one obtained at stage A, in 80 cm3 of tetrahydrofuran. The mixture is agitated for 30 minutes at -45° C./-40° C., then a solution of 3.74 g of benzenesulphonyl chloride in 12 cm3 of tetrahydrofuran is added. The temperature is allowed to return to the ambient over 2 hours. After evaporating to dryness, the residue is chromatographed on silica (eluent: ethyl acetate-n-hexane, 1--1), and 1.7 g of the expected product is obtained. m.p. 82°-83° C., crystallized from isopropanol.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.[C:13](Cl)(=[O:17])[CH:14]([CH3:16])[CH3:15].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[CH3:1][N:2]([CH3:12])[C:3]1[C:11]([C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1
Reactant: CN(C)c1cc2ccccn2n1
Reactant: CC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(C)C(=O)c1c(N(C)C)nn2ccccc12
Yield: 26.1 %

Procedure:
A mixture of 560 mg (3.45 mmol) of N,N-dimethylpyrazolo[1,5-a]pyridin-2-amine, 355 μl (3.45 mmol) of isobutyryl chloride and 100 mg of AlCl3 was stirred in 3 ml of DCE at RT overnight. The mixture was quenched with saturated NH4Cl and extracted with EtOAc, and the crude product was purified on an Al2O3 column to provide 208 mg of 1-(2-(dimethylamino)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one. Compound 1072.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Cl)[CH3:9])=[CH:4][CH:3]=1.[Na].[SH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=1[O-:19]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=2[O-:19])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(Cl)c1ccc(Br)cc1
Reactant: [O-][n+]1ccccc1S
Agent: [Na]
Product: CC(Sc1cccc[n+]1[O-])c1ccc(Br)cc1
Yield: 85 %

Procedure:
The compound 2-(1-[4-bromophenyl]ethylthio)-pyridine N-oxide is prepared from 1-(4-bromophenyl)-ethylchloride and 2-mercaptopyridine N-oxide sodium salt by the procedure described in Example 1. The melting point is 113° - 115°C. Structure is confirmed by IR and NMR.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.[F:17][C:18]1[CH:23]=[C:22]([C:24]2([CH3:27])[CH2:26][CH2:25]2)[CH:21]=[CH:20][C:19]=1[C@@H:28]([NH2:30])[CH3:29].CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>CS(C)=O>[F:17][C:18]1[CH:23]=[C:22]([C:24]2([CH3:27])[CH2:25][CH2:26]2)[CH:21]=[CH:20][C:19]=1[C@@H:28]([NH:30][C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1)[CH3:29]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Reactant: C[C@H](N)c1ccc(C2(C)CC2)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(C3(C)CC3)cc2F)n1
Temperature: 110 °C
Yield: 5.3 %

Procedure:
To a microwave vial with stir bar was added (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (30 mg, 0.12 mmol) and DMSO (1 mL). To this reaction mixture was added (S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethanamine (51 mg, 0.22 mmol) and DIEA (0.09 ml, 0.50 mmol). The vial was capped and the reaction mixture was heated in a preheated oil bath at 110° C. for 18 hr. Solution was purified by reverse phase HPLC. Product fractions combined, frozen and lyophilized to afford (S)-3-(2-((S)-1-(2-fluoro-4-(1-methylcyclopropyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one (3.3 mg, 6.3 μmol, 5% yield) as a TFA salt. 1H NMR (400 MHz, CD3OD) δ 0.58 (br. s., 3H) 0.77 (td, J=5.23, 1.76 Hz, 5H) 0.80-0.86 (m, 2H) 1.38 (s, 3H) 1.57 (d, J=6.94 Hz, 3H) 4.34-4.41 (m, 2H) 4.67 (br. s., 1H) 5.33 (d, J=7.97 Hz, 1H) 6.95-7.05 (m, 2H) 7.22 (t, J=7.97 Hz, 1H) 7.67 (d, J=6.85 Hz, 1H) 8.14 (d, J=6.65 Hz, 1H). LCMS m/z 399.4 (M+H)+, Rt 0.93 min. HRMS(A) m/z 399.2202 (M+H)+, Rt 2.23 min.
Reaction SMILES: [CH2:1]([C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]([O:22]CC)=[O:21])[N:19]=[C:15]3[CH:14]=[C:13]([CH3:25])[C:12]=2[C@H:26]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:27]([O:29][CH3:30])=[O:28])[CH2:7][CH2:6]1)[CH2:2][CH:3]=[CH2:4].[OH-].[Na+:38]>CO>[Na+:38].[CH2:1]([C:5]1([CH3:36])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]([O-:22])=[O:21])[N:19]=[C:15]3[CH:14]=[C:13]([CH3:25])[C:12]=2[C@H:26]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:27]([O:29][CH3:30])=[O:28])[CH2:7][CH2:6]1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(C(=O)OCC)cn23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCCC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(C(=O)[O-])cn23)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 103.8 %

Procedure:
To a solution of (S)-ethyl 5-(4-(but-3-en-1-yl)-4-methylpiperidin-1-yl)-6-(1-(tert-butoxy)-2-methoxy-2-oxoethyl)-7-methylimidazo[1,2-a]pyridine-2-carboxylate (0.164 g, 0.328 mmol, 1 equiv) in MeOH (3.3 mL) was added 1 N NaOH (0.36 mL, 0.36 mmol, 1.1 equiv). After stirring 18 h, the reaction was heated to 60° C. for 2 h. Upon cooling to ambient temperature, the reaction was concentrated in vacuo. The residue was then concentrated in vacuo with toluene (×3) to remove residual MeOH to provide the product as a yellow solid (0.168 g, 100%). LCMS (ESI, M+1): 472.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH2:38]([O:40][C:41]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)=[O:42])[CH3:39]>>[CH2:38]([O:40][C:41]([N:43]1[CH2:44][CH2:45][N:46]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:47][CH2:48]1)=[O:42])[CH3:39]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Reactant: CCOC(=O)N1CCNCC1
Product: CCOC(=O)N1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and piperazine-1-carboxylic acid ethyl ester according to conditions described in general procedure C. 1HNMR (400 MHz, CDCl3) δ 1.27 (t, J=7.6 Hz, 3 H), 3.27 (s, 4 H), 3.44 (m, 4 H), 3.64 (s, 4 H), 3.89 (m, 4 H), 4.12-4.17 (m, 2 H), 6.07-6.09 (m, 1H), 6.78-6.81 (m, 1 H), 7.10 (d, J=8.0 Hz, 1 H), 7.31-7.35 (m, 2 H), 7.51-7.61 (m, 2 H), 7.92-8.01 (m, 2 H), 8.19-8.24 (m, 2 H).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][S:6][C:7]1[C:16]([CH3:17])=[N:15][C:14]2[C:9](=[CH:10][C:11]([CH3:19])=[C:12]([CH3:18])[CH:13]=2)[N:8]=1.ClC1C=CC=C(C(OO)=[O:33])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[CH3:24][N:2]([CH3:1])[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[CH2:5][S:6]([C:7]1[C:16]([CH3:17])=[N:15][C:14]2[C:9](=[CH:10][C:11]([CH3:19])=[C:12]([CH3:18])[CH:13]=2)[N:8]=1)=[O:33]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc2nc(C)c(SCc3ccccc3N(C)C)nc2cc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1cc2nc(C)c(S(=O)Cc3ccccc3N(C)C)nc2cc1C
Yield: 28.8 %

Procedure:
In a mixture of 35 ml of chloroform and 3 ml of methanol was dissolved 3.71 g of 2-(2-dimethylaminobenzylthio)-3,6,7-trimethylquinoxaline. To the chilled solution kept at a temperature of lower than 0° C. (temperature of solution) was slowly added 2.45 g of m-chloroperbenzoic acid (purity: 80%). After the reaction was complete, chloroform and saturated aqueous NaHCO3 solution were added to the reaction mixture. The organic layer was separated and dried over sodium sulfate. The sodium sulfate was then removed by filtration, and the solvent was evaporated under reduced pressure from the filtrate. The residue was purified by silica gel column chromatography (acetone/hexane). The eluate was concentrated and the resulting residue was crystallized from ether/hexane to give 1.12 g of 2-(2-dimethylaminobenzylsulfinyl)-3,6,7-trimethylquinoxaline as a yellow crystalline powder, m.p. 83°-88° C. (decompn.).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:18][C:19](OCC)=[O:20])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:24][CH2:25][CH2:26][CH2:27][OH:28].C(O)C>C(N(CC)CC)C.O>[OH:28][CH2:27][CH2:26][CH2:25][NH:24][C:19](=[O:20])[CH2:18][N:10]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[N:9]1
Reactant: NCCCO
Reactant: CCOC(=O)Cn1ncc(-c2ccccc2)c1-c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Cn1ncc(-c2ccccc2)c1-c1ccccc1)NCCCO
Temperature: 100 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A mixture of 1.47 g (0.0048 mol) of ethyl 4,5-diphenyl-1H-pyrazole-1-acetate of Example 1, 0.72 g (0.0096 mol) of 3-amino-1-propanol and 0.024 g (0.00024 mol) of triethylamine was stirred at 100° C. for two hours. Five mL of ethanol was added and the solution was poured into 20 mL of water and allowed tostand 18 hours at 5° C. to crystallize. The product was filtered off, air-dried and recrystallized from 25 mL of ethyl acetate to yield 1.47 g of N-(3-hydroxypropyl)-4,5-diphenyl-1H-pyrazole-1-acetamide, mp 138°-139° C.
Reaction SMILES: FC(F)(F)C([O-])=O.C(OC([N:15]1[CH2:20][CH:19]=[C:18]([C:21]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]3[C:22]=2[CH:23]=[C:24]([C:38](=[O:40])[NH2:39])[N:25]3[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH2:31]([N:25]1[C:26]2[C:22](=[C:21]([CH:18]3[CH2:17][CH2:16][NH:15][CH2:20][CH2:19]3)[CH:29]=[C:28]([F:30])[CH:27]=2)[CH:23]=[C:24]1[C:38]([NH2:39])=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(F)cc3c2cc(C(N)=O)n3Cc2ccccc2)CC1
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cc2c(C3CCNCC3)cc(F)cc2n1Cc1ccccc1

Procedure:
1-Benzyl-6-fluoro-4-piperidin-4-yl-1H-indole-2-carboxylic acid amide was prepared as trifluoroacetate salt by hydrogenation of 4-(1-Benzyl-2-carbamoyl-6-fluoro-1H-indol-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester, followed by deprotection with trifluoroacetic acid, using the procedure of steps 3 and 4 of Example 2. MS: (M+H)+ 352.