Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[O:21][CH3:22])[CH:6]=[C:5]2[NH:23][CH2:24][CH2:25][O:26][CH3:27].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][NH2:35])[CH:29]=1>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][NH:12][C:7]2[CH:6]=[C:5]([NH:23][CH2:24][CH2:25][O:26][CH3:27])[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:35][CH2:34][C:30]4[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=4)[CH:3]=3)[N:8]=2)=[C:15]([O:21][CH3:22])[CH:16]=1
Reactant: NCc1cccnc1
Reactant: COCCNc1cc(NCc2ccc(F)cc2OC)nc2ccc(Cl)cc12
Product: COCCNc1cc(NCc2ccc(F)cc2OC)nc2ccc(NCc3cccnc3)cc12

Procedure:
The title compound, MS: m/e=462.5 (M+H+), was prepared in accordance with the general method of example 30, step D from 6-chloro-N2-(4-fluoro-2-methoxy-benzyl)-N4-(2-methoxy-ethyl)-quinoline-2,4-diamine and 3-picolylamine.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1.Cl[C:19]([O:22]C(Cl)=O)(Cl)Cl>C1C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([N:15]=[C:19]=[O:22])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CN1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Solvent: c1ccccc1
Product: CN1CCN(S(=O)(=O)c2ccc(N=C=O)cc2)CC1
Temperature: 25 °C

Procedure:
4-(4-Methylpiperazin-1-sulfonyl)aniline (0.5 g, 1.96 mmol) dissolved in anhydrous benzene was added dropwise to a solution of trichloromethylchloroformate (0.3 mL, 2.35 mmol) in anhydrous benzene at −10° C. The mixture was warmed to room temperature for 10 minutes, then heated to 90° C. for 2 h The mixture was concentrated under reduced pressure to provide 4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl isocyanate as a solid, used as an intermediate in the production of Compound 105 IR: 1166, 1339, 2265 cm−1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:13][C:14]3[C:15]([C:20]4[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=4[Cl:27])=[N:16][N:17]([CH3:19])[CH:18]=3)=[O:12])=[C:4]2[N:3]=1.[NH3:28]>C(O)C>[Cl:27][C:21]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:20]=1[C:15]1[C:14]([NH:13][C:11]([C:10]2[CH:9]=[N:8][N:5]3[CH:6]=[CH:7][C:2]([NH2:28])=[N:3][C:4]=23)=[O:12])=[CH:18][N:17]([CH3:19])[N:16]=1
Reactant: N
Reactant: Cn1cc(NC(=O)c2cnn3ccc(Cl)nc23)c(-c2cc(Cl)ccc2Cl)n1
Solvent: CCO
Product: Cn1cc(NC(=O)c2cnn3ccc(N)nc23)c(-c2cc(Cl)ccc2Cl)n1
Yield: 77 %

Procedure:
A solution of 5-chloro-N-(3-(2,5-dichlorophenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (110 mg, 0.26 mmol) in ethanol saturated with ammonia (4 mL) was heated at 95° C. for 30 minutes with microwave irradiation. The mixture was concentrated. Purification by flash column chromatography afforded 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [3-(2,5-dichloro-phenyl)-1-methyl-1H-pyrazol-4-yl]-amide as a solid (80 mg, 77% yield). 1H NMR (400 MHz, DMSO-d6): 9.37 (s, 1H), 8.63 (d, J=7.6 Hz, 1H), 8.14-8.16 (m, 2H), 7.70 (m, 1H), 7.52-7.55 (m, 2H), 6.39 (d, J=8.0 Hz, 1H), 3.91 (s, 3H).
Reaction SMILES: [C:1]([N:4]1[CH2:21][CH2:20][C:7]2([NH:11][C:10](=[O:12])[C@H:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:8]2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>C1COCC1>[C:1]([N:4]1[CH2:5][CH2:6][C:7]2([N:11]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:10](=[O:12])[C@H:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:8]2)[CH2:20][CH2:21]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC2(CC1)NC(=O)[C@H](Cc1ccccc1)N2
Reactant: ClCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N1CCC2(CC1)N[C@@H](Cc1ccccc1)C(=O)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 8-acetyl-3-(S)-benzyl-1,4,8-triazaspiro[4,5]decan-2-one (2.8 g, 9.7 mmol) in 20 mL of dry THF there was added sodium hydride (350 mg, 14.6 mmol) at 0° C. and under a blanket of nitrogen. Following stirring over a period of 1 h at 0° C., benzyl chloride (1.36 g, 10.7 mmol) was slowly added dropwise, and the mixture was allowed to warm up to RT and then heated under reflux over a period of 24 h. Following the addition of an aqueous saturated HCl solution (25 mL), the reaction mixture was isolated by filtration and the filtrate was extracted with EE (3×20 mL), and the combined organic phases were dried over Na2SO4. Following removal, by distillation, of the solvent, there was obtained the crude product as a yellow oil. Further purification was carried out by column chromatography. The product 8-acetyl-1,3-(S)-dibenzyl-1,4,8-triazaspiro[4,5]decan-2-one was obtained in a yield of 1.25 g (34%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([N:20]2[CH2:21][CH2:22][CH:17]([O:16][C:13]3[CH:14]=[CH:15][C:8]4[CH2:7][CH2:6][N:5]([CH:1]5[CH2:2][CH2:3][CH2:4]5)[CH2:11][CH2:10][C:9]=4[CH:12]=3)[CH2:18][CH2:19]2)=[O:32])=[CH:26][CH:25]=1
Reactant: c1cc2c(cc1OC1CCNCC1)CCN(C1CCC1)CC2
Reactant: O=C=Nc1ccc(F)cc1
Product: O=C(Nc1ccc(F)cc1)N1CCC(Oc2ccc3c(c2)CCN(C2CCC2)CC3)CC1

Procedure:
Example 67 was prepared from 3-cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) and 4-fluorophenyl-isocyanate using the method described for Example 66 (E66); MS (ES+) m/e 438 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][O:9]CC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].S(=O)(=O)(O)[OH:19]>C(Cl)(Cl)Cl.CO>[CH:7]1[C:2]([C:1]([O:8][OH:9])=[O:19])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(O)O
Reactant: c1ccc(COOCc2ccccc2)cc1
Agent: [Na]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(OO)c1ccccc1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
19 g (78 mmol) of dibenzyl peroxide is dissolved in 125 ml of chloroform at −5° C. 2.2 g (94 mmol) of sodium dissolved in 50 ml of methanol under a nitrogen stream, is added dropwise. After stirring for 30 minutes at −5° C., ice water is added and the medium is acidified with an aqueous solution of 2N sulphuric acid. It is extracted with dichloromethane, then the organic phase is dried over magnesium sulphate, filtered and concentrated. 9 g of perbenzoic acid is obtained in the form of white solid at a yield of 83%.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:10]([C:33]([F:36])([F:35])[F:34])=[C:11]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[C:32]4[CH2:31][CH2:30][NH:29][CH2:28][C:27]=4[NH:26][N:25]=3)=[O:23])[CH2:18][CH2:17]2)[CH:12]=[CH:13][C:14]=1[F:15].Br[CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>>[F:8][C:9]1[C:10]([C:33]([F:34])([F:35])[F:36])=[C:11]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([C:24]3[C:32]4[CH2:31][CH2:30][N:29]([CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:28][C:27]=4[NH:26][N:25]=3)=[O:23])[CH2:20][CH2:21]2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2ccc(F)c(F)c2C(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)CN1CCc2c(C(=O)N3CCC(c4ccc(F)c(F)c4C(F)(F)F)CC3)n[nH]c2C1

Procedure:
Following general procedure GP-G2, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone TFA salt (34) and tert-butyl 2-bromoacetate were converted to provide tert-butyl 2-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)acetate as a clear, glassy solid (55 mg, 69%): 1H NMR (500 MHz, DMSO-d6) δ 12.94 (br s, 0.25H), 12.71 (br s, 0.75H), 7.37-7.33 (m, 1H), 7.50-7.49 (m, 1H), 4.86-4.84 (m, 1H), 4.68-4.66 (m, 1H), 3.67-3.63 (m, 2H), 3.34-3.30 (m, 2H, partially merged with H2O peak), 3.14-3.13 (m, 2H), 2.59-2.58 (m, 3H), 2.59-2.50 (m, 2H, partially merged with DMSO peak), 1.76-1.70 (m, 4H), 1.43 (s, 9H); ESI MS m/z 529 [M+H]+.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:18]=[C:17]([Cl:19])[C:16]([O:20][CH3:21])=[C:15]([Cl:22])[C:10]=1[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:18]=[C:17]([Cl:19])[C:16]([O:20][CH3:21])=[C:15]([Cl:22])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1c(NC(=O)OC(C)(C)C)cc(Cl)c(OC)c1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(N)cc(Cl)c(OC)c1Cl
Yield: 87 %

Procedure:
A solution o#methyl 2-(tert-butoxycarbonylamino)-4,6-dichloro-5-methoxybenzoate (2.3 g, 6.6 mM) and trifluoroacetic acid (6.0 g, 53 mM) in methylene chloride (23 mL) was stirred at room temperature for 1.5 hr. The reaction mixture was then washed with saturated aqueous sodium bicarbonate, drie (MgSO4), filtered and concentrated to obtain (87%) the title compound as a yellow oil; MS(CI): 250 (M+H).
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[NH:8]/[C:7]/1=[N:16]\[NH2:17])[CH2:2][CH2:3][CH2:4][CH3:5].[C:18](=S)=[S:19]>N1C=CC=CC=1>[CH2:1]([N:6]1[C:14]2[N:13]=[CH:12][NH:11][C:10]=2[C:9](=[O:15])[N:8]2[C:18](=[S:19])[NH:17][N:16]=[C:7]12)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]cnc21
Reactant: S=C=S
Solvent: c1ccncc1
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(=S)[nH]nc12
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A solution of (2e)-3-pentyl-3,7-dihydro-1h-purine-2,6-dione 2-hydrazone (1.90 g, 8.04 mmol) and carbon disulfide (0.58 ml, 9.64 mmol) in pyridine (30 ml) was stirred at 60° C. for 3 hours. After cooling to room temperature, the solid formed was filtered and dried to yield the desired product (1.90 g, 84.9%). LCMS calculated for: C11H14N6OS (M+H) 280.1. found: 280.1.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])=[CH:7][CH:6]=2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])=[CH:7][CH:6]=3)=[CH:21][CH:20]=1
Reactant: CON(C)C(=O)c1ccc2ncc(Cl)nc2c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CON(C)C(=O)c1ccc2ncc(-c3ccc(Cl)cc3)nc2c1
Temperature: 80 °C
Yield: 61 %

Procedure:
A mixture of 3-chloro-N-methoxy-N-methylquinoxaline-6-carboxamide (5 g, 0.02 mol, 1.0 eq.), (4-chlorophenyl)boronic acid (3.43 g, 0.022 mol, 1.1 eq.) Pd(dppf)2C12 (816 mg, 0.001 mol, 0.05 eq.) and Na2CO3 (4.24 g, 0.04 mol, 2.0 eq.) in dioxane and water (90 mL/10 mL) was heated at 80° C. for 4 hs under N2 protection, then cooled and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=4/1, v/v) to afford 3-(4-chlorophenyl)-N-methoxy-N-methylquinoxaline-6-carboxamide (4 g, 61.0%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH:15]=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl-].[CH2:18]([CH:22]([CH2:25]O)[CH2:23][OH:24])[CH2:19][CH2:20][CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:10][CH2:11][C@H:12]([CH:15]3[O:24][CH2:23][CH:22]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:25][O:16]3)[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCCCC(CO)CO
Reactant: O=C[C@H]1CC[C@H](c2ccc(F)c(F)c2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC1COC([C@H]2CC[C@H](c3ccc(F)c(F)c3)CC2)OC1

Procedure:
A mixture of 2.2 g of trans-4-(3,4-difluorophenyl)-cyclohexanecarbaldehyde (obtainable by converting the corresponding acid into the chloride and Rosenmund reduction), 1.32 g of 2-butylpropane-1,3-diol, 0.01 g of p-toluenesulfonic acid and 15 ml of toluene is boiled on a water separator for 3 hours, cooled, washed with water and evaporated, to give 2-[trans-4-(3,4-difluorophenyl)cyclohexyl]-5-butyl-1,3-dioxane.
Reaction SMILES: [C:1]1([S:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[O-:22][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24].[C:30]1([I+]C2C=CC=CC=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CCOCC>O>[O-:25][S:23]([C:26]([F:29])([F:28])[F:27])(=[O:24])=[O:22].[C:1]1([S+:11]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(Sc3cccc4ccccc34)cccc2c1
Reactant: c1ccc([I+]c2ccccc2)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOCC
Solvent: O
Product: c1ccc([S+](c2cccc3ccccc23)c2cccc3ccccc23)cc1
Reaction time: 24 h
Yield: 90 %

Procedure:
Di(1-naphthyl)sulfide (3 g, 0.0104 mole), diphenyliodonium triflate (5.8 g, 0.0135 mole) and copperbenzoate (0.08 g, 0.003 mole) are heated without solvent for 3 hours at 120-145° C. under a nitrogen atmosphere. After cooling down, 75 ml ether was added and the mixture vigorously stirred overnight to achive solidification. Filtration and washing with ether yielded a brown solid, which was dissolved in hot water, the solution filtered and the water removed in vacuo. The resulting white solid was stirred in 50 ml ethyl ether for 24 hours, the mixture filtered and the residue washed with ethyl ether, yielding 4.8 g (90%) of the title compound, di-(1-naphtyl)phenylsulfonium triflate. The structure was confirmed by 1H/13C NMR spectroscopy.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](Br)=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2].[NH2:14][C:15]1[CH:16]=[N:17][CH:18]=[N:19][CH:20]=1>[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:11]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[N:19][CH:20]=2)=[CH:10][CH:9]=[C:8]([CH3:13])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C)ccc1Br
Reactant: Nc1cncnc1
Agent: [Pd]
Product: CCOC(=O)c1nc(C)ccc1Nc1cncnc1

Procedure:
The Pd catalyzed coupling of 3-Bromo-6-methyl-pyridine-2-carboxylic acid ethyl ester and 5-Amino-pyrimidine (CAS:[591-55-9] (J. Org. Chem., 20, 829 (1955)) was performed in accordance with the general method of Example 78, step 3 to yield the tide compound as a light brown solid, MS (ISP): m/e=259.3 (M+H+).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:21])=[C:16]([NH2:20])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CCCCCC.[C:28](OCC)(=[O:30])C>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[C:15]([CH3:21])=[C:16]([NH:20][CH:28]=[O:30])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: Cc1cc2c(c(C)c1N)C(c1ccc(C(C)C)cc1)CO2
Solvent: CCCCCC
Product: Cc1cc2c(c(C)c1NC=O)C(c1ccc(C(C)C)cc1)CO2
Yield: 81 %

Procedure:
Using 3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 32, the title compound was synthesized in the same manner as in Reference Example 73. Yield: 81%. Melting point: 193-196° C. (hexane-ethyl acetate).
Reaction SMILES: BrC1C=CC(C[O:7][C:8]2[N:12]([C:13]3[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][N:14]=3)[N:11]=[CH:10][CH:9]=2)=CC=1.B(Br)(Br)Br.CO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:7][C:8]1[N:12]([C:13]2[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][N:14]=2)[N:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccnc(-n2nccc2OCc2ccc(Br)cc2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccnc(-n2nccc2O)c1
Temperature: -78 °C
Yield: 60.2 %

Procedure:
A solution of methyl 2-{5-[(4-bromobenzyl)oxy]-1H-pyrazol-1-yl}pyridine-4-carboxylate (765 mg, 1.97 mmol, EXAMPLE 68) in DCM (8 mL) was purged with nitrogen and cooled to −78° C. BBr3 (6 mL, 5.93 mmol, 1M in DCM) was added at this temperature. Thereto, the mixture was stirred at the same temperature for an hour, methanol was added until no gas released, and then the above mixture was basified with NaHCO3 aq (pH=3). Extracted with ethylacetate three times, and the organic phase was washed with brine and dried with Na2SO4, concentrated and the residue was washed with ethylacetate to give 260 mg of the title compound (60%). 1H NMR (400 MHz, CD3OD): δ 4.02 (3H, s), 7.91-7.97 (2H, m), 8.69-8.70 (2H, m). [M+H] Calc'd for C10H9N3O3, 220. Found, 220.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[NH:9][C@H:10]([C:15]([O:17]C)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(c1ccc(Br)cc1)c1ccc(S(C)(=O)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C[C@H](NC(c1ccc(Br)cc1)c1ccc(S(C)(=O)=O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl N-{(4-bromophenyl)[4-(methylsulfonyl)phenyl]methyl}-L-leucinate from step 2 (81 mg, 0.17 mmol) in THF (1 mL) and MeOH (0.5 mL) was added 1N LiOH (0.3 mL, 0.3 mmol). The resulting mixture was stirred at room temperature for 18 hours and then partitioned between EtOAc and water+1N HCl (0.5 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a colorless gum.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH2:12]([C@H:19]1[CH2:23][O:22][C:21](=[O:24])[NH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:25](Cl)(=[O:30])[CH2:26][CH2:27][CH:28]=[CH2:29]>C1COCC1>[CH2:12]([C@H:19]1[CH2:23][O:22][C:21](=[O:24])[N:20]1[C:25](=[O:30])[CH2:26][CH2:27][CH:28]=[CH2:29])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C=CCCC(=O)Cl
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
In a 250 mL round-bottomed flask was (S)-4-benzyloxazolidin-2-one (5 g, 28.2 mmol) and THF (30 mL) to give a colorless solution. Cooled in −78° C. bath. 2.5M BuLi in hexane (11.29 mL, 28.2 mmol) was added slowly to the oxazolidinone. Initially a thick white precipitate formed, added another 10 mL THF. At the end of the addition the reaction mixture became light orange and contained white solid material. The reaction mixture was stirred at −78° C. for 1 h, and then pent-4-enoyl chloride (3.11 mL, 28.2 mmol) was added dropwise to the oxazolidinone anion at −78° C. The orange color immediately discharged and the reaction became a pale yellow color. Still several large white chunks in the reaction. After 30 min. The reaction mixture was removed from −78° C. bath and let warm to room temperature. All the white chunks have dissolved. The reaction mixture was then stirred at room temperature for 4 h. The reaction was quenched with saturated NH4Cl. The reaction mixture was diluted with 10% aqueous LiCl and Et2O. The organic layer was separated and washed with saturated aqueous NaHCO3 and then washed with brine. The organic layer was dried over MgSO4, filtered and concentrated to give a crude material. This crude material was purified on silica gel column (120 g ISCO) eluting with a gradient from 100% hexane/EtOAc to 50% hexane/EtOAc. The product came off ˜20% EtOAc/hexane. The product was collected in tubes and concentrated to afford (S)-4-benzyl-3-(pent-4-enoyl)oxazolidin-2-one, Intermediate S8A (4.35 g, 16.78 mmol, 59.5% yield) as thick colorless oil. 1H NMR (400 MHz, chloroform-d) δ 7.43-7.22 (m, 5H), 6.01-5.81 (m, 1H), 5.20-5.02 (m, 2H), 4.78-4.62 (m, 1H), 4.29-4.16 (m, 2H), 3.34 (dd, J=13.4, 3.3 Hz, 1H), 3.19-3.02 (m, 2H), 2.80 (dd, J=13.3, 9.6 Hz, 1H), 2.50 (d, J=7.3 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](O)[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.O=P(Cl)(Cl)[Cl:15].CN(C)C1C=CC=CC=1>>[Cl:15][C:6]1[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Nc1nc(O)cc(C(F)(F)F)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Nc1nc(Cl)cc(C(F)(F)F)n1
Temperature: 70 °C

Procedure:
2-Amino-6-(trifluoromethyl)pyrimidin-4-ol (200 mg, 1.1 mmol) is dissolved in POCl3 (3 eq., 0.3 mL, 3.3 mmol) and dimethylaniline (0.28 mL, 2 eq.) is added. The reaction mixture is heated at 70° C. for 4 h. The resulting mixture is poured into a mixture of ice-water, and the resulting precipitate is collected to yield the desired compound 24 in 59%. ESI-MS m/z 198 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[C:4]([CH3:38])[CH:3]=1.Cl.[NH2:40][OH:41].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:20]=[CH:21][C:22]([CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)[CH2:9]/[C:10](=[N:40]\[OH:41])/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[C:4]([CH3:38])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)c2ccc(Cl)cc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)c2ccc(Cl)cc2C)=N/O)ccn1

Procedure:
In analogy to example 1, step 2, from (R)-tert-butyl 4-(4-(1-(4-chloro-2-methylphenyl)-3-(2-methylpyridin-4-yl)-3-oxopropyl)phenyl)piperidine-1-carboxylate and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=548.0 ([M+H]+).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:34]([C@@H:41]([CH2:45]O)[C:42]([OH:44])=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:47]([OH:50])(=[S:49])[CH3:48]>O1CCCC1>[C:47]([S:49][CH2:45][C@H:41]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:42]([OH:44])=[O:43])(=[O:50])[CH3:48]
Reactant: CC(O)=S
Reactant: O=C(O)[C@H](CO)Cc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SC[C@H](Cc1ccccc1)C(=O)O
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
2.44 g (12.05 mmol) of diisopropyl azodicarboxylate are added dropwise, at 0° C., to a solution of 3.16 g (12.05 mmol) of triphenylphosphine in 30 ml of tetrahydrofuran. Once the addition is complete, the mixture is stirred for 30 minutes at this temperature. The reaction medium is cooled to -10° C. and a solution of 1.45 g (8.05 mmol) of (S)-2-benzyl-3-hydroxypropionic acid (X S) and 0.92 g (12.05 mmol) of thioacetic acid in 10 ml of tetrahydrofuran is added dropwise. Once the addition is complete, the mixture is stirred for one hour at -10° C. and for a further two hours at room temperature.
Reaction SMILES: F[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[C:13]([CH3:19])=[N:14][N:15]([CH3:18])[C:16]=1[CH3:17]>C(O)C.O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:11][C:12]1[C:13]([CH3:19])=[N:14][N:15]([CH3:18])[C:16]=1[CH3:17])([O-:10])=[O:9]
Reactant: Cc1nn(C)c(C)c1N
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: O
Solvent: CCO
Product: Cc1nn(C)c(C)c1Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 49.3 %

Procedure:
To a solution of 1-fluoro-2-nitrobenzene (7.47 mL, 70.9 mmol) in ethanol (35 mL) and H2O (105 mL) was added 4-amino-1,3,5-trimethylpyrazole (8.8 g, 70.9 mmol). The solution was refluxed for 15 h, then cooled to room temperature. The precipate was separated by filteration and washed with 25% aqueous ethanol to yield the title compound (8.6 g): 1HNMR (CDCl3, 300 MHz) δ 8.81 (s, 1H), 8.18 (dd, 2H, J=1.6, 8.7), 6.69(m, 1H) 6.61 (dd, 1H, J=1.2, 8.7), 3.77 (s, 3H), 2.10 (s, 3H), 2.06 (s, 3H); low resolution MS(FAB) m/z 247(MH+).