Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([Cl:23])[C:14]=1[NH:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C>>[CH3:29][C:27]([C:26]1[O:31][C:1](=[O:2])[N:24]([C:14]2[C:13]([Cl:12])=[CH:18][C:17]([C:19]([F:20])([F:22])[F:21])=[CH:16][C:15]=2[Cl:23])[N:25]=1)([CH3:28])[CH3:30]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)C(=O)NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(=O)o1
Temperature: 80 °C
Yield: 45.1 %

Procedure:
In 4.6 ml (8.9 mmols) of 20% phosgene-toluene solution, 0.33 g (1 mmol) of N'-(2,6-dichloro-4-trifluoromethylphenyl)-2,2-dimethylpropionhydrazide was heated to reflux for 16 hours (inner temperature of 80° C.). Then, an excess of phosgene and toluene was distilled off. After the residue was dissolved in 5 ml of methylene chloride, 0.65 g (6.4 mmols) of triethylamine was added to the solution and the mixture was heated to reflux for 30 minutes. Next, the mixture was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The thus obtained crude product was subjected to silica gel column chromatography to give 0.16 g of 5-(1,1-dimethylethyl)-3-(2,6-dichloro-4-trifluoromethylphenyl)-1,3,4-oxadiazolin-2-one.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=1[NH2:17].O.[N:19]#[C:20]Br>C(O)C>[NH2:19][C:20]1[NH:1][C:2]2[C:7]3[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=3[C:5]([C:13]([O:15][CH3:16])=[O:14])=[CH:4][C:3]=2[N:17]=1
Reactant: COC(=O)c1cc(N)c(N)c2c1OC(C)(C)C2
Reactant: N#CBr
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc2nc(N)[nH]c2c2c1OC(C)(C)C2
Yield: 45.2 %

Procedure:
To a solution of methyl 4,5-diamino-2,2-dimethyl-2,3-dihydro-1-benzofuran-7-carboxylate (Intermediate-1, 2.00 g, 8.47 mmol) in ethanol:water (50:4 mL) was added cyanogen bromide (1.07 g, 10.16 mmol). The reaction mass was refluxed for 4-5 h. The reaction mass was quenched in water, neutralised with sodium bicarbonate and extracted with solution of (10%) DCM: methanol. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 1.0 g of the desired product. 1HNMR (DMSO-d6): δ 1.42 (s, 6H), 3.03 (s, 2H), 3.71 (s, 3H), 6.67 (bs, 2H), 7.33 (s, 1H), 10-11 (bs, 1H). MS [M+H]+: 237.03.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:13])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[OH-].[K+]>C1COCC1.C(OCC)C>[CH2:15]([O:13][C@H:10]([CH2:11][O:12][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])[CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCBr
Reactant: OC[C@@H](O)COCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCCCCCCCCCCOC[C@H](COCc1ccccc1)OCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-(benzyloxy)propane-1,2-diol (1 eq) in THF (0.3 M) was added n-tetrabutylammonium bromide (0.2 eq), 1-bromododecane (4 eq) and potassium hydroxide (5 eq). The reaction mixture was stirred at room temperature overnight. The mixture was diluted with ethyl ether, washed with water, 1 N hydrochloric acid, water, and brine, dried over anhydrous Na2SO4, and concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-10% EtOAc/Hex to give the product.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[O:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)[O:11][C:12]=1[CH3:13].[CH2:22]([N:29]1[CH:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:31]([OH:39])=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:22]([N:29]1[CH:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:31]([O:39][CH2:2][C:3]2[CH:21]=[CH:20][CH:19]=[C:5]([O:6][CH2:7][C:8]3[N:9]=[C:10]([C:14]4[O:15][CH:16]=[CH:17][CH:18]=4)[O:11][C:12]=3[CH3:13])[CH:4]=2)=[N:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Reactant: Cc1oc(-c2ccco2)nc1COc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1cccc(OCc2nc(-c3ccco3)oc2C)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 78.6 %

Procedure:
A mixture of 4-(3-chloromethylphenoxy)methyl-2-(2-furyl)-5-methyl-1,3-oxazole (2.04 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (1.50 g), potassium carbonate (0.84 g) and N,N-dimethylformamide (50 mL) was stirred at 80° C. for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v) to give ethyl 1-benzyl-3-[(3-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1H-pyrazole-4-carboxylate as colorless crystals (2.46 g, yield 79%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 92-93° C.
Reaction SMILES: [CH:1]1([CH:4]2[N:8]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7](=O)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.S(C)C>C1COCC1>[CH:1]1([CH:4]2[CH2:5][CH2:6][CH2:7][N:8]2[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCC(C2CC2)N1Cc1ccccc1
Solvent: CSC
Solvent: C1CCOC1
Product: c1ccc(CN2CCCC2C2CC2)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 44.4 %

Procedure:
To 5-cyclopropyl-1-(phenylmethyl)-2-pyrrolidinone (240 mg, 1.12 mmol) in THF (5 mL) was added BH3.SMe2 2M in THF (5.6 mL, 11.2 mmol), and the reaction mixture was stirred over the weekend at room temperature. The reaction was quenched with the dropwise addition of CH3OH (˜2 mL, caution: vigorous H2 evolution occurs). The solution was poured onto water (˜50 mL) and EtOAc (˜50 mL), and the mixture was stirred at 60° C. for 3 hours. A saturated aqueous solution of NaHCO3 (˜25 mL) and EtOAc (˜50 mL) were added, and the organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. Flash chromatography on SiO2 (gradient: 100% hexanes to 75% EtOAc/hexanes) afforded the title compound (100 mg, 45%) as a yellow oil. LC-MS (ES) m/z=202 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:44])[CH:7]([CH2:28][N:29](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:21][CH2:20][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd].C(OCC)C>[C:1]([O:5][C:6](=[O:44])[CH:7]([CH2:28][NH2:29])[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:17][CH2:18][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:21]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(CN(Cc3ccccc3)Cc3ccccc3)C(=O)OC(C)(C)C)CCCC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(CN)C(=O)OC(C)(C)C)CCCC2)CC1

Procedure:
The product from step (c) above (4.6 g, 7.62 mmole) in ethanol (75 ml) was hydrogenated in an atmosphere of hydrogen (50 p.s.i., 3.46 bar) over palladium on charcoal (200 mg), at room temperature overnight. The reaction mixture was filtered through a Solkaflok pad, and the filtrate evaporated to dryness to yield the crude product as an oil. This was dissolved in diethyl ether, and extracted into dilute hydrochloric acid (pH 2) (2x). The combined aqueous layers were washed with diethyl ether, then neutralised with saturated aqueous sodium bicarbonate and extracted with dichloromethane (3x). The combined organic phases were dried (Na2SO4) and evaporated to yield the title amine as an oil (2.91 g, 90%). Found: C,64.80; H,9.28; N,6.76. C23H40N2O5 requires C,65.06; H,9.50; N,6.60%.
Reaction SMILES: [C:1]([CH:5]([C:9]([F:11])=[O:10])[C:6]([F:8])=[O:7])([F:4])([F:3])[F:2].[CH2:12](N(CC)CC)C.S(OC)(OC)(=O)=O>CCOCC>[CH3:12][C:5]([C:1]([F:4])([F:3])[F:2])([C:6]([F:8])=[O:7])[C:9]([F:11])=[O:10]
Reactant: O=C(F)C(C(=O)F)C(F)(F)F
Reactant: CCN(CC)CC
Solvent: COS(=O)(=O)OC
Solvent: CCOCC
Product: CC(C(=O)F)(C(=O)F)C(F)(F)F
Reaction time: 3 h
Yield: 48.9 %

Procedure:
A solution of 17.6 g (0.10 mol) of CF3CH(COF)2 in 25 ml of ether was cooled at 0°C and stirred while 9.2 g (0.10 mol) of triethylamine was added dropwise in 15 minutes. Then 25.2 g (0.20 mol) of dimethyl sulfate was added all at once, and the mixture was allowed to stand at 25°C for 3 hours. Distillation gave 9.3 g (49%) of methyltrifluoromethylmalonyl fluoride, bp 62°-65°C. Redistillation gave an analytical sample, bp 64°-65.5°C; ir and nmr spectra were taken on a similarly prepared sample; ir (CCl4): 5.37 (COF) and 7.5-8.5 μ (CF); nmr (CCl4): 1H at 1.92 ppm (broadened singlet, CH3); 19F at 37.8 (quartet, JFF = 10 Hz into quartets, JHF = 1 Hz, 2, (COF) and -71.1 ppm (triplet, JFF = 10 Hz, into quartets, JHF = 0.8 Hz, 3, CF3).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[C:4](=[N:6][OH:7])Cl.[CH3:13][O:14][C:15](=[O:19])[C:16]#[C:17][CH3:18].C(N(CC)CC)C>C(OCC)C>[CH3:13][O:14][C:15]([C:16]1[C:4]([C:3]2[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:8]=2[F:12])=[N:6][O:7][C:17]=1[CH3:18])=[O:19]
Reactant: CC#CC(=O)OC
Reactant: ON=C(Cl)c1c(F)cccc1F
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)c1c(-c2c(F)cccc2F)noc1C
Yield: 60.9 %

Procedure:
In a fashion similar to that for preparation 15, 2,6-difluorobenzoylchloride oxime (1.00 g, 5.19 mmol), methyl-2-butynoate (1.01 g, 10.4 mmol), triethyl amine (0.94 ml, 6.8 mmol) in diethyl ether (3 ml), and diethyl ether (25 ml) afforded 4-methoxycarbonyl-5-methyl-3-(2,6-difluorophenyl)isoxazole (0.80 g, 61%) after purification by column chromatography (silica gel, hexanes/diethyl ether gradient).
Reaction SMILES: Cl.O1CCOCC1.[CH2:8]([O:10][C:11]([C@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[C@H:14]1[C:28]1[CH:33]=[CH:32][C:31]([NH:34]C(OC(C)(C)C)=O)=[CH:30][CH:29]=1)=[O:12])[CH3:9].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:8]([O:10][C:11]([C@H:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[C@H:14]1[C:28]1[CH:29]=[CH:30][C:31]([NH2:34])=[CH:32][CH:33]=1)=[O:12])[CH3:9]
Reactant: CCOC(=O)[C@H]1CCCN(C(=O)c2ccccc2C)[C@H]1c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CCCN(C(=O)c2ccccc2C)[C@H]1c1ccc(N)cc1
Reaction time: 1 h
Yield: 97.1 %

Procedure:
4N HCl in 1,4-dioxane (5 mL, 20 mmol) was slowly added to a 0° C. solution of the above crude product (2R,3S)-2-(4-tert-Butoxycarbonylaminophenyl)-1-(2-methylbenzoyl)piperidine-3-carboxylic acid ethyl ester (840 mg, 1.72 mmol) in dry CH2Cl2 (4 mL). After the addition of the HCl, the reaction mixture was allowed to attain r.t and stirred for 1 h. It was diluted with CH2Cl2 (30 mL), cooled to 0° C. and neutralized with saturated aqueous NaHCO3 to get the (2R,3S)-2-(4-aminophenyl)-1-(2-methylbenzoyl)piperidine-3-carboxylic acid ethyl ester (612 mg) in 97% yield over two steps.
Reaction SMILES: [CH:1]1([CH2:4][C@@H:5]2[O:10][CH2:9][C@@:8]([NH:19][C:20]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[S:21])([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])[C@H:7]([CH2:31]O)[CH2:6]2)[CH2:3][CH2:2]1.C(OC[C@@H]1OC[C@]2(C3C=CC(F)=CC=3F)N=C(NC(=O)C3C=CC=CC=3)SC[C@@H]2C1)C1C=CC=CC=1>>[CH:1]1([CH2:4][C@@H:5]2[O:10][CH2:9][C@:8]3([C:11]4[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=4[F:18])[N:19]=[C:20]([NH:22][C:23](=[O:30])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[S:21][CH2:31][C@@H:7]3[CH2:6]2)[CH2:3][CH2:2]1
Reactant: O=C(NC(=S)N[C@@]1(c2ccc(F)cc2F)CO[C@@H](CC2CC2)C[C@H]1CO)c1ccccc1
Agent: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](COCc3ccccc3)C[C@H]2CS1)c1ccccc1
Product: O=C(NC1=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CC3CC3)C[C@H]2CS1)c1ccccc1

Procedure:
rel-N-{[(3S,4R,6S)-6-(Cyclopropylmethyl)-3-(2,4-difluorophenyl)-4-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]carbamothioyl}benzamide (C72) was converted to the product using the method described for synthesis of N-[(4aR,6R,8aS)-6-[(benzyloxy)methyl]-8a-(2,4-difluorophenyl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C8) in Preparation P1. The product was obtained as a white solid. Yield: 430 mg, 0.97 mmol, 39%. LCMS m/z 443 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.22 (br d, J=7.2 Hz, 2H), 7.50 (t, J=7.2 Hz, 1H), 7.37-7.45 (m, 3H), 6.85-6.94 (m, 2H), 4.13 (q, J=8.5 Hz, 1H), 3.77 (d, J=12.0 Hz, 1H), 3.67-3.73 (m, 1H), 3.10-3.17 (m, 1H), 3.00 (dd, J=12.8, 3.0, 1H), 2.64 (dd, J=12.8, 2.8 Hz, 1H), 1.93 (q, J=12.4 Hz, 1H), 1.67-1.77 (m, 2H), 0.84-0.90 (m, 1H), 0.72-0.82 (m, 1H), 0.41-0.48 (m, 2H), 0.04-0.12 (m, 2H).
Reaction SMILES: [ClH:1].O1CCOCC1.[N:8]1([C:14]([C:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH:22]3[CH2:34][O:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[S:19][CH:20]=2)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1>CO>[ClH:1].[ClH:1].[O:11]1[CH2:12][CH2:13][N:8]([C:14]([C:16]2[N:17]=[C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH:22]3[CH2:34][O:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[S:19][CH:20]=2)=[O:15])[CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(C(=O)N3CCOCC3)cs2)C(COc2cccnc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(c1csc(N2CCNCC2COc2cccnc2)n1)N1CCOCC1
Reaction time: 8 h
Yield: 99 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(4-(morpholine-4-carbonyl)thiazol-2-yl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (35.4 mg, 0.0723 mmol) in MeOH (1 mL). After stirring overnight, the reaction mixture was concentrated under reduced pressure, yielding 33.2 mg (99%) of the title compound. LC-MS: RT=2.33 min, (M+H)+=390.6.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][N:13]=[CH:14]2)=[CH:9][C:8]=1[OH:17].Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][CH:20]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:17][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH:14]=[N:13][CH:12]=[CH:11]2
Reactant: Oc1cc2ccncc2cc1-c1ccccn1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4ccncc4cc3-c3ccccn3)c2cc1OC
Temperature: 140 °C
Reaction time: 24 h
Yield: 21.7 %

Procedure:
7-Pyridin-2-yl-isoquinolin-6-ol (20 mg), 4-chloro-6,7-dimethoxyquinoline (50 mg), and 4-dimethylaminopyridine (33 mg) were suspended in o-dichlorobenzene (3 ml), and the mixture was stirred at 140° C. for 24 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (8 mg, yield 22%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.Br[CH2:13][C@H:14]([CH3:24])[CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Si:17]([O:16][CH2:15][C@@H:14]([CH3:24])[CH2:13][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11])([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:18])[CH3:19]
Reactant: C[C@@H](CBr)CO[Si](C)(C)C(C)(C)C
Reactant: O=C1COc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)CN1C(=O)COc2ccccc21
Reaction time: 20 h
Yield: 77.9 %

Procedure:
A reaction flask was charged with 4H-Benzo[1,4]oxazin-3-one (2.47 g, 16.5 mmol), (R)-(3-bromo-2-methylpropoxy)-tert-butyldimethylsilane (4.01 g, 15.0 mmol), and Cs2CO3 (12.2 g, 37.6 mmol) in DMF (20 mL) and stirred at 55° for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiO2; n-heptane/EtOAc 10:1) to give the title compound (3.92 g, 78%). 1H NMR (CDCl3) δ 7.15-7.11 (m, 1H), 6.99-6.91 (m, 3H), 4.60-4.50 (m, 2H), 3.98 (dd, J=8.3 Hz, J=12.4 Hz, 1H), 3.81 (dd, J=5.5 Hz, J=12.4 Hz, 1H), 3.51 (dd, J=4.1 Hz, J=9.7 Hz, 1H), 3.40 (dd, J=6.9 Hz, J=9.7 Hz, 1H), 2.12-2.02 (m, 1H), 0.90-0.82 (m, 12H), 0.02 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[CH:8]=[N:7]2.P(Cl)(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:15])[CH:8]=[N:7]2
Reactant: O=c1cnc2cccc(Br)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cnc2cccc(Br)c2n1
Temperature: 50 °C
Yield: 55 %

Procedure:
A mixture of 8-bromoquinoxalin-2(1H)-one (483 mg, 2.146 mmol) in phosphoryl trichloride (100 mL) was heated to 50° C. for 2 h. The crude material was concentrated to remove the POCl3, diluted with EtOAc (150 ml), added to a separatory funnel, and washed with water (2×100 ml) and saturated aq. NaHCO3 (100 ml) before the organic layer was separated, dried over Na2SO4, and concentrated. The mixture and was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% hexanes to 5% EtOAc/hexanes to give 8-bromo-2-chloroquinoxaline (210e, 55% yield) as an off-white solid. MS (ESI, pos. ion) m/z: 243.0/245 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][NH:8][CH:9]=1)=[O:4].I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=1)=[O:4]
Reactant: Ic1ccccc1
Reactant: COC(=O)c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CS(C)=O
Product: COC(=O)c1cn(-c2ccccc2)cn1
Yield: 54.9 %

Procedure:
A stirred solution of 1H-imidazole-4-carboxylic acid (0.5 g, 0.00446 mmol), concentrated sulfuric acid (0.5 mL) and MeOH (20 mL) was heated to reflux overnight. The reaction mixture was concentrated under reduced pressure. The residue was diluted with cold water, extracted with ethyl acetate and washed the organic layer with sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to afford 325 mg (58% Yield) of 1H-imidazole-4-carboxylic acid methyl ester. A mixture of 1H-imidazole-4-carboxylic acid methyl ester (225 mg, 1.8 mmol), cuprous oxide (225 mg, 1.8 mmol), iodobenzene (736 mg, 3.6 mmol), 1,10-phenanthroline (320 mg, 1.8 mmol) and cesium carbonate (1.74 g, 5.3 mmol) in DMSO (2 mL) in a seal tube was subjected to reaction in a microwave reactor (time: 5 min, temp: 90° C., power: zero) The reaction mixture was filtered through celite and the filtrate collected was concentrated under reduced pressure. The residue was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure to afford the residue. Purification by column chromatography (using 60-120 silica gel and 50% ethyl acetate in hexane as eluent) to afford 200 mg (55% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid methyl ester. LiOH.H2O (143 mg, 3.4 mmol) was added to a stirred solution of 1-phenyl-1H-imidazole-4-carboxylic acid methyl ester (231 mg, 1.1 mmol) in a mixture of THF (3 mL), MeOH (1 mL), H2O (1 mL) and stirring was continued at ambient temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure. Cold water was then added and acidified it with 10% aqueous HCl, the solid was collected to afford 180 mg (83.7% Yield) of 1-phenyl-1H-imidazole-4-carboxylic acid.
Reaction SMILES: C(O)(=[O:3])C.S(=O)(=O)(O)O.O.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:29])[C:19]([NH:21][C:22]([C:27]#N)([CH3:26])[CH:23]([CH3:25])[CH3:24])=[O:20])=[CH:14][CH:13]=1>C(OCC)(=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:19]2[O:20][C:26](=[O:3])[C:22]([CH:23]([CH3:25])[CH3:24])([CH3:27])[N:21]=2)[CH3:29])=[CH:14][CH:13]=1
Reactant: CC(C(=O)NC(C)(C#N)C(C)C)c1ccc(Cl)cc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C1=NC(C)(C(C)C)C(=O)O1)c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
40 ml of glacial acetic acid, 1.96 g (0.019 mole) of concentrated sulfuric acid and 0.36 g (0.02 mole) of water were added to 5.56 g (0.02 mole) of 2-(4-chlorophenyl)-N-(1-cyano-1,2-dimethylpropyl)propanamide. The mixture was stirred at 60° C. for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was cooled. Thereto were added 400 ml of water and 400 ml of ethyl acetate for layer separation. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and concentrated to obtain 5.58 g of 2-[1-(4-chlorophenyl)ethyl]-4-isopropyl-4-methyl-1,3-oxazol-5-one (yield=100%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([NH:8][NH2:9])=[O:7])#[N:2].C1COCC1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>CN(C=O)C>[Cl:18][CH2:19][C:20]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][CH:12]=[C:3]([C:1]#[N:2])[CH:4]=1)=[O:21]
Reactant: O=C(Cl)CCl
Reactant: N#Cc1cccc(C(=O)NN)c1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1cccc(C(=O)NNC(=O)CCl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
3-cyanobenzohydrazide (1.6 g, 10.0 mmol) was added to THF (40 ml) and DMF (10 ml). TEA (1.4 ml, 10.0 mmol) was added at 0° C. followed by chloroacetyl chloride (1.0 ml, 12.6 mmol) and the reaction mixture was stirred at 0° C. for 1 h and at rt for 2 h. The THF was evaporated, water was added to the remaining mixture, followed by filtratation over celite and purification with prep. HPLC to give the title compound (1.6 g, 69%). 1H NMR (DMSO-d6): 10.62 (br s, 2 H), 8.28 (m, 1 H), 8.18 (m, 1 H), 8.08 (m, 1 H), 7.75 (t, 1 H), 4.22 (s, 2 H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH:26]1[CH2:30][CH2:29][C@@H:28]([O:31][NH2:32])[CH2:27]1>>[NH:26]1[CH2:30][CH2:29][C@@H:28]([O:31]/[N:32]=[C:21](/[C:18]2[N:17]=[C:16]3[N:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[N:13]=[N:14][C:15]3=[N:20][CH:19]=2)\[CH3:22])[CH2:27]1
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: NO[C@@H]1CCNC1
Agent: Cl
Product: C/C(=N\O[C@@H]1CCNC1)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 60 %

Procedure:
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (22.4) (25 mg, 0.082 mmol) and (R)—O-(pyrrolidin-3-yl)hydroxylamine dihydrochloride in 60% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400 MHz, CDCl3) δ ppm 9.41 (s, 1H), 8.92 (d, 1H), 8.13 (d, 1H), 8.09 (d, 1H), 7.91 (s, 1H), 7.82 (d, 1H), 7.41 (dd, 1H), 6.10 (s, 2H), 5.30 (s, 1H), 5.09 (s, 1H), 3.31 (m, 3H), 2.38 (s, 3H), 2.25 (m, 2H). LCMS (method B): [MH]+=389, tR=1.17 min.