Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][N:6]([C:8]([O:10][CH3:11])=[O:9])[C@H:5]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C@@H:4]([C:26]([O:28][CH3:29])=[O:27])[CH2:3]1.O1CCCC1.[F:35][C:36]1[CH:37]=[C:38](O)[CH:39]=[CH:40][CH:41]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[F:35][C:36]1[CH:41]=[C:40]([CH:39]=[CH:38][CH:37]=1)[O:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][CH3:11])=[O:9])[C@H:5]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[C@@H:4]([C:26]([O:28][CH3:29])=[O:27])[CH2:3]1
Reactant: Oc1cccc(F)c1
Reactant: COC(=O)[C@H]1C[C@@H](O)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](Oc2cccc(F)c2)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 70 °C

Procedure:
To a solution of dimethyl(2S,3S,5R)-5-hydroxy-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate (50.0 mg, 0.000123 mol) in tetrahydrofuran (0.50 mL, 0.00617 mol) was added 3-fluoro-phenol (0.0134 mL, 0.000148 mol), triphenylphosphine (38.8 mg, 0.000148 mol), followed by diethyl azodicarboxylate (0.0233 mL, 0.000148 mol). The mixture was heated at 70 Celsius overnight. After concentrated to dry, the mixture was purified on silica gel, eluting with 0 to 40% EtOAc in hexane, to generate the phenyl ether compound (27 mg, 44%). MS (ESI): (M+H)+=500.05.
Reaction SMILES: Cl[C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH:9]2[CH2:11][CH2:10]2)=[O:7])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[NH:17]1[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH2:19][CH2:18]1>C(#N)C>[CH:9]1([NH:8][C:6](=[O:7])[C:5]2[CH:12]=[CH:13][C:2]([N:17]3[CH2:18][CH2:19][CH:20]([CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[CH2:21][CH2:22]3)=[C:3]([N+:14]([O-:16])=[O:15])[CH:4]=2)[CH2:11][CH2:10]1
Reactant: O=C(NC1CC1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: C1CCN(CCC2CCNCC2)CC1
Solvent: CC#N
Product: O=C(NC1CC1)c1ccc(N2CCC(CCN3CCCCC3)CC2)c([N+](=O)[O-])c1
Temperature: 110 °C
Yield: 79.9 %

Procedure:
A mixture of 0.612 g (2.51 mmol) of 4-chloro-N-cyclopropyl-3-nitro-benzamide and 0.50 g (2.5 mmol) of 1-(2-piperidin-4-yl-ethyl)-piperidine in acetonitrile (0.5 mL) are heated at 110° C. for 30 minutes in a microwave reactor. The mixture is cooled to room temperature and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to provide 0.80 g (79%) of N-cyclopropyl-3-nitro-4-[4-(2-piperidin-1-yl-ethyl)-piperidin-1-yl]-benzamide.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[N:19]=3)=[C:14]([Cl:17])[CH:15]=2)[C:10]([CH3:25])([CH3:24])[CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11]([C:10]([CH3:24])([CH3:25])[CH2:9][NH:8]2)=[CH:12][C:13]=1[C:18]1[O:22][N:21]=[C:20]([CH3:23])[N:19]=1
Reactant: Cc1noc(-c2cc3c(cc2Cl)N(C(=O)OC(C)(C)C)CC3(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(-c2cc3c(cc2Cl)NCC3(C)C)n1
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
6-Chloro-3,3-dimethyl-5-(3-methyl-[1,2,4]oxadiazol-5-yl)-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (36 mg, 0.11 mmol) was dissolved in 50% TFA in DCM (0.534 mL) and the mixture was stirred for 30 minutes and concentrated. The residue was dissolved in methanol, loaded onto an SCX column and eluted with methanol then 2.0M ammonia in methanol to release the amine and fractions concentrated, to give the title compound (26 mg), MS: [M+H]+=264.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:29]([OH:31])=O)[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:28])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1.[N:36]1([CH:42]2[CH2:47][CH2:46][N:45]([CH2:48][CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH2:44][CH2:43]2)[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:21]=[C:22]([CH3:28])[C:23]([OH:27])=[C:24]([CH3:26])[CH:25]=3)[C:29]([N:39]3[CH2:40][CH2:41][N:36]([CH:42]4[CH2:47][CH2:46][N:45]([CH2:48][CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH2:44][CH2:43]4)[CH2:37][CH2:38]3)=[O:31])=[O:16])[CH2:13][CH2:14]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1
Reactant: CCOC(=O)CCCN1CCC(N2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Product: CCOC(=O)CCCN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
Prepared analogously to Example 8 from 500 mg (1.04 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1h) and 385 mg (1.20 mmol) ethyl 4-(4-piperazin-1-yl-piperidin-1-yl)-butanoate.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH:12]=[CH:13][C:14](=O)[CH3:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[CH:29]=[CH:28][C:26]([N:27]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[CH:12][CH:13]=[C:14]2[CH3:15])=[CH:25][CH:24]=1
Reactant: CC(=O)C=CC(=O)c1ccc(S(C)(=O)=O)cc1
Reactant: Nc1ccc(-c2ccco2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(-c2ccco2)cc1
Yield: 24.3 %

Procedure:
A mixture of 1-[4-(methylsulfonyl)phenyl]pentene-1,4-dione (0.305 g, 1.2 mmol prepared according to the method of J. Med. Chem., 1997, 40 , 1619), 4-(2-furyl)aniline (0.35 g, 2 mmol), and p-toluenesulfonic acid monohydrate (0.015 g) in toluene (40 mL) was heated at reflux temperature for 16 hours using Dean-Stark apparatus. After cooling, volatiles were removed by evaporation. The residue was purified by flash chromatography eluting with hexane/ethyl acetate (4/1). The resulting solid was recrystallized from CH2Cl2/hexane to give the title compound (0.11 g, 24.3% yield).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[S:9][CH:10]=1>C(O)(C(F)(F)F)=O.ClCCl>[Br:5][C:6]1[C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[S:9][C:10]=1[N+:1]([O-:4])=[O:2]
Reactant: Brc1csc2ccccc12
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=[N+]([O-])c1sc2ccccc2c1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Add dropwise fuming nitric acid(90%, 8.6 mL, 183 mmol) to a mixture of 3-bromo benzo[b]thiophene (39g, 183 mmol) in TFA(100 mL) and dichloromethane (400mL) at 0° C. The reaction turn greenish, then yellow precipitates. To this reaction mixture, add dichloromethane (200 mL) and the reaction stir at 0° C. for 30 min. Then pour the reaction into ice-water (2 L). Extract with dichloromethane (3×500mL) and the organic layer dry over MgSO4. Evaporation give a yellow solid. The resulting yellow solid triturate with diethyl ether to give a yellow solid. (Total: 34.8 g, 73%). Mass spectrum (m/e): 259 (M+1); 1HNMR(300 MHz, DMSO-d6) δ ppm: 7.70 (tt, 2H), 8.04 (d, 1H), 8.17 (d, 1H). 3CNMR(75 MHz, DMSO-d6) δ ppm: 112.5, 124.8, 126.9, 127.9, 131.3, 137.0, 137.2, 166.1.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=3)[S:12][C:11]=2[C:10]([CH:24]=O)=[CH:9][CH:8]=1)[CH3:2].[CH:28]([NH2:30])=[O:29].[OH-].[Na+]>>[CH2:1]([N:3]([CH2:26][CH3:27])[CH2:4][CH2:5][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:22][CH3:23])[CH:17]=3)[S:12][C:11]=2[C:10]([CH2:24][NH:30][CH:28]=[O:29])=[CH:9][CH:8]=1)[CH3:2]
Reactant: NC=O
Reactant: CCN(CC)CCNc1ccc(C=O)c2sc3ccc(OC)cc3c(=O)c12
Agent: [Na+]
Agent: [OH-]
Product: CCN(CC)CCNc1ccc(CNC=O)c2sc3ccc(OC)cc3c(=O)c12
Temperature: 170 °C

Procedure:
A mixture of 1-[[2-(diethylamino)ethyl]amino]-7-methoxy-9-oxothioxanthen-4-carboxaldehyde (3.6 g, 0.0094 mol), formamide (48 mL) nd formic acid (6 mL) was heated to 170° C. under N2 for 8 hours. The mixture was poured into ice-water, basified with 35% NaOH and extracted with chloroform. The organic layer was separated, washed with water (2X), then brine and was dried over Na2SO4 and concentrated in vacuo to afford 3.88 g of N-[[1-[[2-(diethylamino)ethyl]amino]-7-methoxy-9-oxothioxanthen-4-yl]methyl]formamide.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].C(N(CC)CC)C.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[S:24](Cl)(=[O:26])=[O:25].Cl>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[S:24]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8])(=[O:25])=[O:26]
Reactant: OCC1CCCCN1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(Cl)c1S(=O)(=O)N1CCCCC1CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
Piperidin-2-yl-methanol (17.39 mmol, 1 eq) was dissolved in methylene chloride (20 ml) and triethylamine (43.47 mmol, 2.5 eq) at 0° C. and a solution of 2-chloro-6-methyl-benzenesulfonyl chloride (17.39 mmol, 1 eq) in methylene chloride (65 ml) was added dropwise. The reaction solution was stirred at room temperature for 90 min. 0.5 M HCl (75 ml) was then added and the mixture was stirred for a further 15 min. The organic phase was washed with water (10 ml), dried over sodium sulfate and concentrated to dryness under reduced pressure. Yield: 90%
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]([C:5]1[S:6][C:7]([Br:10])=[CH:8][CH:9]=1)[OH:4].[Na].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Br:10][C:7]1[S:6][C:5]([C:3](=[O:4])[C:2]([F:1])([F:11])[F:12])=[CH:9][CH:8]=1
Reactant: OC(c1ccc(Br)s1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na]
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc(Br)s1)C(F)(F)F

Procedure:
2.93 g (0.011 mol) of 2,2,2-trifluoro-1-(5-bromo-2-thienyl)ethanol and 0.19 g (0.0006 mol) of tetrabutylammonium hydrogen sulfate are dissolved in 100 ml of methylene chloride at room temperature. 6.9 ml (0.014 mol) of an approximately 12% strength sodium hyochlorite solution are metered in within 5 minutes with vigorous stirring and the mixture is stirred for a further 4 hours at room temperature. The reaction mixture is added to 100 ml of water, the phases are separated, the aqueous phase is extracted several times with methylene chloride and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product in a kugelrohr (0.3 mbar, 40°-60° C. bath temperature), 0.48 g (39% of theory) of 5-bromo-2-trifluoroacetylthiophene. nD20 : 1.5309.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:30][CH2:29][CH2:28][C:27]3=[O:31])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=O)=[C:4]([CH3:32])[CH:3]=1.Cl.[NH2:34][OH:35].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:21]=[CH:22][C:23]([N:26]3[CH2:30][CH2:29][CH2:28][C:27]3=[O:31])=[CH:24][CH:25]=2)[CH2:9]/[C:10](/[C:12]2[CH:13]=[CH:14][C:15](=[O:19])[N:16]([CH3:18])[CH:17]=2)=[N:34]\[OH:35])=[C:4]([CH3:32])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(N2CCCC2=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(N2CCCC2=O)cc1

Procedure:
In analogy to example 151, step 3, 5-{3-(4-chloro-2-methyl-phenyl)-3-[4-(2-oxo-pyrrolidin-1-yl)-phenyl]-propionyl}-1-methyl-1H-pyridin-2-one was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing less than 10% of the corresponding Z isomer as a colourless solid, MS (ESI+): m/z=464.2 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:39])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:39][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([CH:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(C2CCN(C(=O)OC(C)(C)C)CC2)nc(N2CCOCC2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(C2CCNCC2)nc(N2CCOCC2)n1

Procedure:
Reaction of tert-butyl 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperidine-carboxylate (0.23 g, 0.37 mmol) with TFA (0.45 mL) in CH2Cl2 (8 mL) gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-morpholinyl)-6-(4-piperidinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole, which was treated subsequently with methanesulfonyl chloride and Et3N in CH2Cl2. The reaction mixture was purified by chromatography on silica eluting first with hexanes/EtOAc (1:1) and then hexanes/EtOAc (3:5) to give 0.13 g (67% yield) of 2-(difluoromethyl)-4-methoxy-1-[4-[1-(methylsulfonyl)-4-piperidinyl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole: mp 256-258° C.; 1H NMR (CDCl3) δ 7.99 (dd, J=8.4, 0.7 Hz, 1H), 7.55 (t, JHF=53.6 Hz, 1H), 7.39 (t, J=8.3 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H), 4.06 (s, 3H), 4.02-3.89 (m, 6H), 3.87-3.76 (m, 4H), 2.92-2.75 (m, 6H), 2.24-2.16 (m, 2H), 2.10-1.97 (m, 2H); Anal. Calcd. for C22H27F2N7O4S: C, 50.5; H, 5.2; N, 18.7. Found: C, 50.6; H, 5.3; N, 18.6%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](Cl)=O)[CH3:13]>O1CCOCC1.C(OCC)(=O)C>[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17]1[NH:1][C:2]2[C:3](=[N:4][CH:5]=[CH:6][CH:7]=2)[S:8](=[O:10])(=[O:9])[N:11]=1)[CH3:13]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: Nc1cccnc1S(N)(=O)=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)CC1=NS(=O)(=O)c2ncccc2N1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 10.7 %

Procedure:
3-Amino-pyridine-2-sulfonic acid amide (1.8 g, 10.4 mmol) was dissolved in 1,4-dioxane (45 mL). Chlorocarbonyl-acetic acid ethyl ester (1.57 mL, 12.48 mmol) was added. The mixture was stirred at 90° C. for 1.5 h. Upon cooling, the mixture was diluted with ethyl acetate (300 mL) and washed with half-saturated aqueous sodium bicarbonate solution (100 mL) followed by saturated aqueous brine solution (100 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oily residue was treated with toluene (36 mL) and triethylamine (9 mL). The mixture was stirred at 110° C. in a sealed tube for 1.5 h. The residue never completely dissolved. Upon cooling, the mixture was concentrated in vacuo to afford a thick oil. Trituration with a minimal amount of ethyl acetate (˜5 mL) solidified the product. The solids were collected by vacuum filtration and dried in vacuo for 16 h to afford the desired product, (1,1-dioxo-1,4-dihydro-1λ6-thia-2,4,8-triaza-naphthalen-3-yl)-acetic acid ethyl ester (0.3 g, 1.11 mmol, 11%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.21 (3H, t, J=7.0 Hz), 3.71 (2H, s), 4.16 (2H, quartet, J=7.1 Hz), 7.70-7.76 (2H, m), 8.62 (1H, dd, J1−4.0 Hz, J2=1.5 Hz), 12.29 (1H, bs). LC-MS (ESI) calcd for C10H11N3O4S 269.05, found 270.1 [M+H+].
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)=[CH:7][N:6]=1)(=O)=O.[OH:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[N:29]1[CH:30]=[CH:31][CH:32]=[C:27]([O:26][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[Cl:18])[C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)=[CH:7][N:6]=2)[CH:28]=1
Reactant: Oc1cccnc1
Reactant: CS(=O)(=O)c1ncc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Product: Clc1ccc(-c2cnc(Oc3cccnc3)nc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylsulfonyl-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine from Reference Example 3 was reacted with 3-hydroxypyridine according to the procedure described in Example 74 to afford 2-(3-pyridyloxy)-4-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyrimidine: HPLC/MS: m/e=428 (M++1); Rt=3.49 min; 1H-NMR 400 MHz (CDCl3): δ 7.05 (d, J=9 Hz, 2H), 7.19-7.30 (m, 4H), 7.38-7.42 (m, 2H), 7.65 (m, 1H), 8.55 (d, J=6 Hz, 1H), 8.60 (s, 1H), 8.65 (d, J=2 Hz, 1H).
Reaction SMILES: CS(O[CH2:6][C:7]([CH3:17])([N:9]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[N:10]1)[CH3:8])(=O)=O.[I-:18].[Na+].O>CN(C)C=O>[I:18][CH2:6][C:7]([N:9]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[N:10]1)([CH3:17])[CH3:8]
Reactant: CC(C)(COS(C)(=O)=O)n1cc([N+](=O)[O-])cn1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(CI)n1cc([N+](=O)[O-])cn1
Temperature: 130 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
To a solution of the crude 2-methyl-2-(4-nitro-1H-pyrazol-1-yl)propyl methanesulfonate (18 g) obtained in Step A of Example 115 in N,N-dimethylformamide (150 mL) was added sodium iodide (20 g), and the mixture was stirred overnight at 130° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (14 g).
Reaction SMILES: C(OC([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[C:12]([O:79]C(OC(C)(C)C)=O)[CH:13]=[CH:14][C:15]=2[C@@H:19]([O:71][Si](C(C)(C)C)(C)C)[CH2:20][N:21]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([NH:46][C:47]([NH:49][CH2:50][C:51]3[C:52]([NH:64][CH:65]4[CH2:70][CH2:69][O:68][CH2:67][CH2:66]4)=[C:53]4[CH:61]=[N:60][N:59]([CH2:62][CH3:63])[C:54]4=[N:55][C:56]=3[CH2:57][CH3:58])=[O:48])=[CH:42][CH:41]=2)C(=O)OC(C)(C)C)[N:10]=1)=O)(C)(C)C.Cl>CO>[CH2:62]([N:59]1[C:54]2=[N:55][C:56]([CH2:57][CH3:58])=[C:51]([CH2:50][NH:49][C:47]([NH:46][C:43]3[CH:44]=[CH:45][C:40]([CH2:39][CH2:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][NH:21][CH2:20][C@H:19]([OH:71])[C:15]4[CH:14]=[CH:13][C:12]([OH:79])=[C:11]5[C:16]=4[CH:17]=[CH:18][C:9](=[O:8])[NH:10]5)=[CH:41][CH:42]=3)=[O:48])[C:52]([NH:64][CH:65]3[CH2:70][CH2:69][O:68][CH2:67][CH2:66]3)=[C:53]2[CH:61]=[N:60]1)[CH3:63]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)Nc1ccc(CCCCOCCCCCCN(C[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(OC(=O)OC(C)(C)C)c3nc(OC(=O)OC(C)(C)C)ccc23)C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CO
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)Nc1ccc(CCCCOCCCCCCNC[C@H](O)c2ccc(O)c3[nH]c(=O)ccc23)cc1

Procedure:
The crude concentrated reaction mixture containing Intermediate 57 was taken up in methanol (approximately 0.50 mL) and treated with a solution of hydrogen chloride in dioxanes (4 N, 2 mL). The mixture was subsequently concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography (RP-HPLC, acetonitrile/water/0.1% TFA) to provide, after concentration, the trifluoroacetic acid salt of the title compound as a powder (107 mg, 58% over two steps).
Reaction SMILES: [CH2:1]([C:5]1[N:13]2[C:8]([C:9](=[N:31]O)[CH2:10][CH2:11][CH:12]2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:30][N:29]=[N:28][N:27]=3)=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[H][H]>[Pd].CO>[CH2:1]([C:5]1[N:13]2[C:8]([CH:9]([NH2:31])[CH2:10][CH2:11][CH:12]2[C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]3[NH:27][N:28]=[N:29][N:30]=3)=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCc1ccc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2=NO
Agent: [Pd]
Solvent: CO
Product: CCCCc1ccc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2N

Procedure:
Alternatively, the title compound of Example 1955 can be prepared from the corresponding oxime. A suspension of the biphenyl imidazolyl oxime (0.059 mmol, the title compound of Example 1953) and 20 mg (0.0188 mmol) of 10% palladium on charcoal in 1.5 mL of methanol is stirred at room temperature under 50 psi of hydrogen gas until the reaction is complete. The mixture is filtered through a pad of celite, concentrated in vacuo and purified to give the title compound of Example 1955.
Reaction SMILES: [Cl:1][C:2]1[C:11](/[CH:12]=C/C2C=CC=CC=2)=[N:10][C:9]2[NH:8][C:7](=[O:20])[CH2:6][O:5][C:4]=2[CH:3]=1.CSC.CN(C=[O:28])C>CO>[Cl:1][C:2]1[C:11]([CH:12]=[O:28])=[N:10][C:9]2[NH:8][C:7](=[O:20])[CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C1COc2cc(Cl)c(/C=C/c3ccccc3)nc2N1
Solvent: CSC
Solvent: CO
Product: O=Cc1nc2c(cc1Cl)OCC(=O)N2
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 68 %

Procedure:
7-Chloro-6-((E)-styryl)-4H-pyrido[3,2-b][1,4]oxazin-3-one (8.0 g, 27.9 mmole) was dissolved in a mixture of DMF (400 mL) and methanol (40 mL), and the solution was cooled to −78° C. Ozone was bubbled through the solution with stirring for 45 minutes, then the excess ozone was removed by bubbling oxygen through the solution for 30 min. Dimethylsulfide (21 mL, 279 mmole) was added to the solution, and the reaction was stirred at −78° C. for 3 hr, then at room temperature overnight. The solvent was removed in vacuo, and the residue was triturated with Et2O (150 mL). The collected solid was washed with additional Et2O and dried to afford a white solid (4 g, 68%).
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](I)[C:8]=1[CH3:14].[F:15][CH:16]([F:23])[C:17]1[CH:22]2[CH:20]([CH2:21]2)[O:19][N:18]=1.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1.C(OCC)C>[F:15][CH:16]([F:23])[C:17]1([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[C:8]=2[CH3:14])[CH:22]2[CH:20]([CH2:21]2)[O:19][NH:18]1
Reactant: FC(F)C1=NOC2CC12
Reactant: Cc1c(F)cccc1I
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1c(F)cccc1C1(C(F)F)NOC2CC21
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 44.3 %

Procedure:
To a flame dried RBF was added a solution of n-butyllithium (2.5M in hexanes; 3.01 ml, 7.51 mmol) and diethyl ether (15 ml). The solution was cooled to −78° C., and 2-fluoro-6-iodotoluene (0.981 ml, 7.51 mmol) was added dropwise and the reaction was stirred at −78° C. for 10 minutes. A −78° C. premixed solution of 4-(difluoromethyl)-2-oxa-3-azabicyclo[3.1.0]hex-3-ene (1.00 g, 7.51 mmol) and boron trifluoride diethyl etherate (0.927 ml, 7.51 mmol) in toluene (10 ml) was added to the reaction via syringe. The reaction was stirred at −78° C. for 10 minutes, quenched with saturated ammonium chloride and warmed to RT. The reaction was diluted with water and EtOAc. The organic layer was separated and concentrated under reduced pressure. The crude residue was purified via silica gel flash chromatography eluting with 0-20% ethyl acetate in hexanes to afford 4-(difluoromethyl)-4-(3-fluoro-2-methylphenyl)-2-oxa-3-azabicyclo[3.1.0]hexane (0.81 g, 3.33 mmol, 44.3% yield).