Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:17]2[C:25](=[O:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:18]2)[CH2:13][CH2:14][NH:15][OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[O-:33][C:34]#[N:35].[K+]>O>[NH2:35][C:34]([N:15]([CH2:14][CH2:13][C@@H:12]([N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH2:18]1)[C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[OH:16])=[O:33]
Reactant: N#C[O-]
Reactant: CCOc1cc([C@@H](CCNO)N2Cc3cccc(NC(=O)C(C)C)c3C2=O)ccc1OC
Agent: [K+]
Solvent: O
Product: CCOc1cc([C@@H](CCN(O)C(N)=O)N2Cc3cccc(NC(=O)C(C)C)c3C2=O)ccc1OC
Reaction time: 1 h
Yield: 55.6 %

Procedure:
To a solution of (1R)-N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-hydroxyamino-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide (1.3 g, 2.6 mmol) in water (30 mL) was added a solution of potassium cyanate (442 mg, 5.5 g) in water (10 mL) at room temperature. After 1 h, the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with HCl (1N, 25 mL), brine (25 mL) and dried over MgSO4. The solvent was removed in vacuo and the residue was purified by prep HPLC to give (1R)-N-{2-[3-(N-aminocarbonyl-N-hydroxy-amino)-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide as a white solid (0.70 g, 55% yield): mp: 137-139° C. 1H NMR (DMSO-d6) δ 1.18 (d, J=7 Hz, 6H, 2CH3), 1.31 (t, J=7 Hz, 3H, CH3), 2.25-2.34 (m, 2H, CH2), 2.51-2.66 (m, 1H, CH), 3.22-3.40 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.95-4.06 (m, 2H, CH2), 4.10 (d, J=18 Hz, 1H, NCHH), 4.55 (d, J=18 Hz, 1H, NCHH), 5.26 (t, J=8 Hz, 1H, NCH), 6.34 (s, 2H, NH2), 6.92-6.98 (m, 3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.50 (t, J=8 Hz, 1H, Ar), 8.29 (d, J=8 Hz, 1H, Ar), 9.34 (s, 1H, CH), 10.48 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.70, 19.18, 28.73, 35.94, 46.25, 47.22, 52.04, 55.43, 63.76, 111.94, 112.40, 116.55, 117.52, 117.60, 119.58, 131.99, 132.73, 137.12, 142.20, 147.89, 148.43, 161.57, 168.34, 174.93; Anal Calcd for C25H32N4O6+0.9 H2O: C, 59.96; H, 6.80; N, 11.19; H2O, 3.24. Found: C, 60.16; H, 6.58; N, 10.81; H2O, 3.24.
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[S:24][C@@H:23]([N:25]2[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]2=[O:27])[C@H:22]([O:33][CH2:34][CH2:35][O:36][CH3:37])[C@@H:21]1[OH:38])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C>C1COCC1>[CH3:37][O:36][CH2:35][CH2:34][O:33][C@@H:22]1[C@H:21]([OH:38])[C@@H:20]([CH2:19][OH:18])[S:24][C@H:23]1[N:25]1[CH:32]=[CH:31][C:29](=[O:30])[NH:28][C:26]1=[O:27]
Reactant: COCCO[C@@H]1[C@H](O)[C@@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)S[C@H]1n1ccc(=O)[nH]c1=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COCCO[C@@H]1[C@H](O)[C@@H](CO)S[C@H]1n1ccc(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a solution of Compound 114 (0.49 g, 0.88 mmol) in anhydrous THF (37 mL) 1M tetrabutylammonium fluoride in THF (1.8 mL) was added. Acetic acid (0.12 mL, 2.03 mmol) was added to this mixture and the resulting reaction mixture stirred at room temperature for 30 min. The solvent was removed under reduced pressure and the residue obtained was purified by flash silica gel column chromatography and eluted with acetone to yield Compound 51 (0.23 g, 83%). 1H NMR (300 MHz, DMSO-d6): 11.2 (s, 1 H), 8.04 (d, 1H,), 5.94 (d, 1H), 5.69 (d, 1H), 5.20 (d, 1H), 4.15 (t, 1H), 4.04 (m, 1H), 3.67-3.53 (m, 6 H), 3.47-3.36 (m, 2H), 3.31 (s, 3H); MS (API-ES) m/z 341.0 [M+Na]+.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl.[NH:37]1[CH2:41][CH2:40][C@@H:39]([OH:42])[CH2:38]1>C(Cl)Cl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:37]3[CH2:41][CH2:40][C@@H:39]([OH:42])[CH2:38]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O[C@@H]1CCNC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCC(F)(F)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC[C@@H](O)C3)ccc2n1CC1CCC(F)(F)CC1

Procedure:
Following the same procedure in Example 1, using 2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole-5-sulfonyl chloride (50 mg, 0.12 mmol), N,N-diisopropylethylamine (0.1 mL, 0.48 mmol) and (R)-(−)-3-pyrrolidinol hydrochloride (23 mg, 0.19 mmol) in (1 mL) methylene chloride. The crude product was purified by LCMS using high pH column 40-70% acetonitrile gradient to give 42 mg (61% yield) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.43-1.52 (m, 2 H), 1.56 (s, 9 H), 1.60-1.69 (m, 3 H), 1.90-2.01 (m, 3 H), 2.09-2.21 (m, 1 H), 3.05-3.11 (m, 1 H), 3.20-3.25 (m, 2 H), 3.26-3.34 (m, 3 H), 4.13-4.18 (m, 1 H), 4.44 (d, J=7.62 Hz, 2 H), 7.81 (dd, J=8.79, 1.76 Hz, 1 H), 7.89-7.93 (m, 1 H), 8.04 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=455.2; Anal. Calc. for C22H31F2N3O3S+1.3 TFA+0.50H2O+0.2 CH3CN: C, 48.75; H, 5.46; N, 7.16. Found: C, 48.78; H, 5.48; N, 7.11.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[O:21][C:22]3[CH:28]=[CH:27][C:25]([NH2:26])=[C:24]([F:29])[C:23]=3[F:30])[CH:13]=2)=[N:10][CH:11]=1.[N:31]1[CH:36]=C[CH:34]=[CH:33][CH:32]=1.ClC(OC1C=CC=CC=1)=[O:39].C1(N)CC1>CN(C=O)C.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:20][C:19]3[C:14](=[N:15][CH:16]=[CH:17][C:18]=3[O:21][C:22]3[CH:28]=[CH:27][C:25]([NH:26][C:36]([NH:31][CH:32]4[CH2:34][CH2:33]4)=[O:39])=[C:24]([F:29])[C:23]=3[F:30])[CH:13]=2)=[N:10][CH:11]=1
Reactant: c1ccncc1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCO5)cn4)sc23)c(F)c1F
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCO5)cn4)sc23)c(F)c1F)NC1CC1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 86.1 %

Procedure:
To a solution of 302 (1.7 g, 3.98 mmol) in DMF (7 mL) was added pyridine (0.55 mL, 6.77 mmol) at RT and the resultant reaction mixture was stirred for 10 min under Ar atmosphere. Phenyl chloroformate (0.75 mL, 5.97 mmol) was added at 0° C. and the mixture was stirred at RT for an additional 40 min. Cyclopropylamine (1.1 mL, 15.9 mmol) was added to the mixture, and the reaction mixture was warmed to 50° C. and stirred for 2 hours. The mixture was then cooled, poured into water (150 mL) and stirred for 30 min. The precipitate was collected by filtration, washed with water and dried overnight. The crude product was triturated with EtOAc for 1 h and collected by filtration to afford title compound 303 (1.75 g, 86% yield) as a pale violet solid. 1H NMR (300 MHz, DMSO-d6) δ (ppm): 8.71 (d, J=2.1 Hz, 1H), 8.55 (d, J=5.4 Hz, 1H), 8.46 (s, 1H), 8.42 (s, 1H), 8.33 (d, J=8.1 Hz, 1H), 8.10-7.95 (m, 1H), 7.99 (dd, J=8.1, 2.1 Hz, 1H), 7.40-7.22 (m, 1H), 6.87 (br, 1H), 6.78 (d, J=5.1 Hz, 1H), 5.90 (s, 1H), 4.16-3.96 (m, 4H), 2.64-2.50 (m, 1H), 0.75-0.60 (m, 2H), 0.50-0.35 (m, 2H)
Reaction SMILES: C1(S[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])C=CC=CC=1.[O-:23][S:24]([O-:27])(=O)=O.[Na+].[Na+].Cl[C:31]1[CH:32]=[C:33]([CH:38]=[CH:39][CH:40]=1)C(OO)=O>C(Cl)(Cl)Cl>[C:31]1([S:24]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=3)[NH:10][C:9]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:27])=[O:23])[CH:32]=[CH:33][CH:38]=[CH:39][CH:40]=1
Reactant: O=S(=O)([O-])[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1Sc1ccccc1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Reaction time: 5 h

Procedure:
Ethyl 3-phenylthio-5-chloroindole-2-carboxylate (642 mg, 1.94 mmol) was dissolved in chloroform (35 mL) and a dried (Na2SO4) solution of m-chloroperoxybenzoic acid (55% pure, 1.30 g, 4.1 mmol) in chloroform (20 mL) was added dropwise. The progress of the oxidation was monitored by tlc until complete. After 5 hours, the reaction was diluted with chloroform and some methanol and the solution washed with aq. NaHCO3 and aq. Na2CO3. The dried (Na2SO4) organic layer was filtered through a pad of charcoal and the solvents removed under reduced pressure. The residue was triturated with diethyl ether to yield the product. Crystallization from methylene chloride and diethyl ether gave analytically pure material, mp 201°-202° C.
Reaction SMILES: OO.[OH2:3].[C:4]1([S:10][C:11]2[C:12]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:21][C:13]=3[S:14][C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)(=[O:35])C>>[C:4]1([S:10]([C:11]2[C:12]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:21][C:13]=3[S:14][C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:35])=[O:3])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)O
Reactant: CCOC(=O)c1sc2cc(OCc3cccnc3)ccc2c1Sc1ccccc1
Reactant: O
Agent: OO
Product: CCOC(=O)c1sc2cc(OCc3cccnc3)ccc2c1S(=O)(=O)c1ccccc1
Temperature: 100 °C

Procedure:
Hydrogen peroxide in water (0.42 ml of 30% w/v, 3.75 mmol) was added to a solution of ethyl 3-(phenylsulfanyl)-6-(3-pyridylmethoxy)benzo[b]thiophene-2-carboxylate (Example 1, 633 mg, 1.5 mmol) in acetic acid (4.5 ml). The mixture was heated to 100° C. for 90 minutes. The solvents were removed by evaporation under reduced pressure, and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was separated, dried (magnesium sulfate) and concentrated under vacuo, and the residue flash chromatographed on silica gel using 1% methanol in dichloromethane as eluant. The less polar product was isolated and crystallised from dichloromethane and diethyl ether to give the title compound as a colourless solid (230 mg).
Reaction SMILES: [C:1]([CH2:3][C:4]([C:6]([CH2:10][CH3:11])([CH3:9])[CH2:7][CH3:8])=O)#[N:2].Cl.[NH2:13][OH:14].[OH-].[Na+]>O>[NH2:2][C:1]1[O:14][N:13]=[C:4]([C:6]([CH2:10][CH3:11])([CH3:9])[CH2:7][CH3:8])[CH:3]=1
Reactant: NO
Reactant: CCC(C)(CC)C(=O)CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(C)(CC)c1cc(N)on1

Procedure:
A 16.5 Kg portion of methyl 2-ethylbutyrate was reacted with 60 Kg of n-butyl lithium, diisopropylamine, and 19.1 Kg of methyl iodide to provide 17.4 Kg of methyl 2-ethyl-2-methylbutyrate. A 7.5 Kg portion of the ester thus formed was reacted with 3.25 Kg of acetonitrile and 5.03 g of sodium hydride in 33 liters of tetrahydrofuran to provide 1-ethyl-1-methylpropyl cyanomethyl ketone. The ketone thus formed was reacted with 4.35 Kg of hydroxylamine hydrochloride and 2.54 Kg of sodium hydroxide in 44 liters of water to provide 5.65 Kg of 5-amino-3-(1-ethyl-1-methylpropyl)isoxazole.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:28](O)=[O:29])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][C:37]=1[N:38]1[CH2:43][C@H:42]([C:44]([F:47])([F:46])[F:45])[CH2:41][C@H:40]([NH:48][C:49](=[O:55])[O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[CH2:39]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:51]([O:50][C:49]([NH:48][C@H:40]1[CH2:41][C@@H:42]([C:44]([F:47])([F:46])[F:45])[CH2:43][N:38]([C:37]2[CH:36]=[CH:35][N:34]=[CH:33][C:32]=2[NH:31][C:28]([C:13]2[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:21][C:20]3[C:15](=[CH:16][C:17]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[CH:18][CH:19]=3)[N:14]=2)=[O:29])[CH2:39]1)=[O:55])([CH3:54])([CH3:52])[CH3:53]
Reactant: O=C(Nc1cc2ccc(N3CCOCC3)cc2nc1C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](C(F)(F)F)CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-morpholin-4-ylquinoline-2-carboxylic acid (0.014 g, 0.034 mmol), tert-butyl [(3S,5R)-1-(3-aminopyridin-4-yl)-5-(trifluoromethyl)piperidin-3-yl]carbamate (0.015 g, 0.041 mmol) and HATU (0.033 g, 0.086 mmol) in DMF (0.14 mL), DIPEA (0.018 mL, 0.10 mmol) was added. The mixture was stirred at room temperature for 2 h, then quenched with 5 mL of EtOAc and 3 mL of 1 M NaOH. The layers were separated and aqueous phase was extracted with EtOAc. The organic phases were combined and concentrated under vacuum. The residue was purified by flash chromatography on 20 g silica gel column, eluting with 0-30% MeOH in EtOAc, to yield an amide intermediate, benzyl {2-[({4-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-(trifluoromethyl)piperidin-1-yl]pyridin-3-yl}amino)carbonyl]-7-morpholin-4-ylquinolin-3-yl}carbamate.
Reaction SMILES: CN(C(/N=N/C(N(C)C)=O)=O)C.C(OC([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:27]([O:32]CCO)=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.[C:36]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:37]=1.[F:55][C:56]1[CH:61]=[C:60]([F:62])[CH:59]=[CH:58][C:57]=1[OH:63]>C1COCC1>[F:55][C:56]1[CH:61]=[C:60]([F:62])[CH:59]=[CH:58][C:57]=1[O:63][CH2:36][CH2:37][N:28]1[CH:29]=[CH:30][N:31]=[C:26]([N:23]2[CH2:22][CH2:21][NH:20][CH2:25][CH2:24]2)[C:27]1=[O:32]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Oc1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Agent: CN(C)C(=O)/N=N/C(=O)N(C)C
Solvent: C1CCOC1
Product: O=c1c(N2CCNCC2)nccn1CCOc1ccc(F)cc1F
Reaction time: 2 h
Yield: 14.4 %

Procedure:
TMAD (0.129 g, 0.750 mmol) was added to a solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-pyrazinyloxy]ethanol (0.200 g, 0.620 mmol), triphenylphosphine (0.196 g, 1.23 mmol) and 2,4-difluorophenol (0.160 g, 1.23 mmol) in THF (1 mL) at room temperature. After being stirred for 2 h, the mixture was concentrated and put through a silica column using toluene/EtOAc (7:3) as eluent. Solvents were removed in vacuo and the resulting N-t-BOC derivative was treated with dichloromethane/TFA/H2O (50:45:5; 5 mL) for 15 min with stirring. The mixture was concentrated and the residue purified by chromatography on silica gel using EtOAc/HOAc/MeOH/H2O (20:3:3:2) as eluent. The product-containing fractions were concentrated, washed between dichloromethane/5% aqueous NaOH, and put through a silica column using dichloromethane/MeOH (8:2) as eluent to give 30 mg (14%) of the title compound. HRMS m/z calcd for C16H18F2N4O2 (M)+ 336.1398, found 336.1392.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[N:24]=[C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:26][C:27]=3[C:28]([F:31])([F:30])[F:29])=[O:22])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.CO.CCOCC>[N:11]1([C:14]2[N:15]=[CH:16][C:17]([NH:20][C:21]([C:23]3[N:24]=[C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:26][C:27]=3[C:28]([F:30])([F:31])[F:29])=[O:22])=[CH:18][CH:19]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: O=C(Nc1ccc(N2CCNCC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 113.2 %

Procedure:
4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester (300 mg, 0.58 mmol) from above was suspended in methylene chloride (5 mL) and methanol (5 mL). To this mixture was added hydrogen chloride in ether (4N, 3 mL). The mixture was stirred at room temperature overnight. The solvents were evaporated and the residue was dried in vacuum. The resulting solid was triturated with dry ether and then filtered to give a hydrochloride salt of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide (274 mg). LC-MS calcd C20H18F3N5O2 (m/e) 417.39, obsd 418.0 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:4]=1.[CH3:23]O.O.O[O:27][S:28]([O-:30])=O.[K+]>C(OCC)(=O)C>[CH3:23][S:28]([C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)[N:4]=1)(=[O:30])=[O:27]
Reactant: O=S([O-])OO
Reactant: CSc1nc(CCCO)cc(-c2cccc(C(F)(F)F)c2)n1
Reactant: CO
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1nc(CCCO)cc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To the solution of 2-methylsulfanyl-4-(3-hydroxypropyl)-6-(3-trifluoromethyl-phenyl)pyrimidine (7.8 g) in a mixed solvent of methanol and water (200 ml, 10:1) was added OXONE (34 g). The mixture was stirred at room temperature for 3 hours, then, diluted with ethyl acetate (500 ml). The mixture was washed with water (3×500 ml). Organic layer dried over sodium sulphate, solvent removed under reduced pressure to give 2-methanesulphonyl-4-(3-hydroxypropyl)-6-(3-trifluoromethylphenyl)-pyrimidine (8.9 g) as crude product which was used for next step without further purification. 1H NMR (CDCl3): δ 8.3-8.4 (m, 2H), 7.8-7.87 (m, 2H), 7.68 (dd, 1H), 3.77 (t, 2H), 3.43 (s, 3H), 3.10 (t, 2H), 2.10 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[OH:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[NH2:15].[CH:21]([O-])([O-])OC>>[OH:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[NH:15][CH:21]=[C:6]1[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]1=[O:5]
Reactant: COc1ccc(N)cc1O
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COC([O-])[O-]
Product: COc1ccc(NC=C2C(=O)OC(C)(C)OC2=O)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A solution of Meldrum's acid (32 g, 22.2 mmol)in methyl orthoformate (200 ml) was stirred at 100° C. 3-Hydroxy-4-methoxyaniline (28 g, 20 mmol) was added and the solution was heated at reflux for 15 minutes. After cooling, the mixture was stirred overnight at ambient temperature. The precipitate was collected by filtration, washed with methyl orthoformate followed by ether and dried under vacuum to give 5-((3-hydroxy-4-methoxyanilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (47.5 g, 82%).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:26][S:27][C:28]1[S:29][C:30]2[CH:36]=[C:35]([CH:37]=O)[CH:34]=[CH:33][C:31]=2[N:32]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:37][C:35]2[CH:34]=[CH:33][C:31]3[N:32]=[C:28]([S:27][CH3:26])[S:29][C:30]=3[CH:36]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: CSc1nc2ccc(C=O)cc2s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSc1nc2ccc(CNc3ccc(Br)cc3[N+](=O)[O-])cc2s1
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
To a stirred mixture of 4-bromo-2-nitroaniline (694 mg, 3.2 mmol) in TFA (5 mL) at −15° C. under argon was added NaBH(OAc)3 (1.1 g, 5.3 mmol) portionwise. The mixture was stirred for 10 min. To the stirred mixture was added dropwise 2-(methylthio)benzo[d]thiazole-6-carbaldehyde (735 mg, 3.5 mmol) from Step 1 of this Example in CH2Cl2 (3 mL). The mixture was stirred for 1 h and then concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 100% hexanes to 100% EtOAc to afford 4-bromo-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline (1.0 g, 77%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 8.84 (t, J=6.0 Hz, 1H), 8.19 (d, J=2.4 Hz, 1H), 7.98 (s, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.56 (dd, J=2.4, 9.3 Hz, 1H), 7.46 (d, J=8.3 Hz, 1H), 6.88 (d, J=9.2 Hz, 1H), 4.75 (d, J=6.0 Hz, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 410 and 412 (M+H)+.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([CH3:24])[NH:19][C:18]2=[O:25])=[CH:12][C:5]=1[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7]>C(O)(=O)C>[Cl:3][C:4]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[C:21]([Br:1])=[C:20]([CH3:24])[NH:19][C:18]2=[O:25])=[CH:12][C:5]=1[C:6]([O:8][CH:9]([CH3:11])[CH3:10])=[O:7]
Reactant: BrBr
Reactant: Cc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)[nH]1
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)c1Br

Procedure:
A solution of 1.7 g of bromine in 20 ml of acetic acid is added dropwise with stirring to a solution of 3.4 g of isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate in 20 ml of acetic acid at 25° C. during 25 minutes. The reaction mixture is stirred for a further hour and evaporated to dryness under reduced pressure. The residue is dissolved in diethyl ether and washed with aqueous sodium bicarbonate solution, thereafter with water. The organic phase is dried over anhydrous sodium sulphate and evaporated to dryness. The residue is recrystallized from diethyl ether/n-hexane. There is obtained isopropyl 2-chloro-4-fluoro-5-[5-bromo-3,6-dihydro-4-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 187°-189° C.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>C(OCC)(=O)C.C(O)C.[Pd]>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1ccc(-n2ccnc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(-n2ccnc2)cc1
Yield: 80 %

Procedure:
A solution of 4-(1H-imidazol-1-yl)-nitrobenzene (20 g; ~0.11 mol) in a mixture of 500 ml ethyl acetate and 500 ml ethanol was hydrogenated in a Parr hydrogenation apparatus at 28.12 kPa (40 psi) and 25° C. by using 0.5 g 5% Pd-C as a catalyst. The reaction mixture was filtered and evaporated in vacuo to give the title compound (14 g) as crystals. M.p. 142°-144° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([O:13][C:14](=[O:21])[NH:15][C@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([CH3:12])([CH3:11])[CH3:10].C(N(C(C)C)C(C)C)C.ClCCl>C(#N)C>[C:9]([O:13][C:14](=[O:21])[NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:17]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: Clc1ncc(Br)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ncc(Br)cn2)C1
Yield: 56.1 %

Procedure:
Stir a solution of 5-bromo-2-chloropyrimidine (3.67 g, 19 mmol), (S)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (3.54 g, 19 mmol), and ethyldiisopropylamine (6.6 mL, 38 mmol) in acetonitrile (50 mL) at room temperature for 4 h. Pour into dichloromethane (200 mL) and wash with water (3×). Dry (sodium sulfate) and concentrate to give (S)-[1-(5-bromopyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester as a tan solid (3.66 g, 71%).