Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2]O.C([O:6][C:7](=O)[CH2:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)C>>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]2[O:18][N:2]=[C:7]([OH:6])[CH:8]=2)=[CH:11][CH:12]=1
Reactant: NO
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Agent: Cl
Product: COc1ccc(-c2cc(O)no2)cc1

Procedure:
The above-identified compound was synthesized according to the process of (Example 2) using hydroxylamine hydrochloride and 4-methoxybenzoylacetic acid ethylester.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[NH:11]1)C1C=CC=CC=1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([C:32]3[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=3[CH3:39])[CH2:28][CH2:27]2)=[O:25])=[C:20]([F:40])[CH:19]=1>>[CH3:39][C:33]1[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:32]=1[N:29]1[CH2:28][CH2:27][N:26]([C:24]([C:21]2[CH:22]=[CH:23][C:18]([N:11]3[C@H:10]([CH2:9][OH:8])[CH2:14][CH2:13][S:12]3(=[O:15])=[O:16])=[CH:19][C:20]=2[F:40])=[O:25])[CH2:31][CH2:30]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: O=S1(=O)CC[C@@H](COCc2ccccc2)N1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](CO)CCS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 60.5 %

Procedure:
Using (S)-3-benzyloxymethylisothiazolidine 1,1-dioxide (536 mg) described in Preparation Example 1 and (4-bromo-2-fluorophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (869 mg) described in Preparation Example 116 and by the reaction and treatment in the same manner as in Example 32, the title compound (620 mg) was obtained.
Reaction SMILES: [CH:1]1([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:10]=2[O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[CH2:4][CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:22]>ClCCl>[CH:1]1([C:5]2[CH:6]=[N+:7]([O-:22])[CH:8]=[CH:9][C:10]=2[O:11][CH2:12][C:13]([F:16])([F:14])[F:15])[CH2:2][CH2:3][CH2:4]1
Reactant: FC(F)(F)COc1ccncc1C1CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1ccc(OCC(F)(F)F)c(C2CCC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.3 %

Procedure:
To a solution of 3-cyclobutyl-4-(2,2,2-trifluoroethoxy)pyridine (Example 108c, 3.81 g, 16.5 mmol) in dichloromethane (100 ml) was added 3-chloroperoxybenzoic acid (5.54 g, 24.7 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was transferred into a separatory funnel and extracted with an 2.0M aqueous solution of sodium carbonate. The organic phase was collected and the aqueous phase was back-extracted with dichloromethane. The organic phases were combined, dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a dichloromethane/methanol gradient to yield the title compound (3.52 gr, 82%) as a white solid. MS (ESI, m/z): 248.5 (M+H+).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].FC(F)(F)C(O)=O.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:31][C:32]2[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=2)=[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:19]=1.C(=O)(O)[O-].[Na+]>>[NH2:13][C:14]1[C:15]([N+:1]([O-:4])=[O:2])=[CH:16][C:17]([O:31][C:32]2[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:39])=[O:40])=[CH:34][CH:33]=2)=[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][N:21]2[C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH:19]=1
Reactant: O=[N+]([O-])[O-]
Reactant: CS(=O)(=O)c1ccc(Oc2ccc(N)cc2C2CCCN2C(=O)C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2cc([N+](=O)[O-])c(N)cc2C2CCCN2C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
153 mg of potassium nitrate was added to a trifluoroacetic acid (2 ml) solution of 588 mg of 1-(2-(5-amino-2-(4-methanesulfonyl-phenoxy)-phenyl)-pyrrolidin-1-yl)-2,2,2-trifluoro-ethanone, and the reaction liquid was stirred overnight at room temperature. Aqueous saturated sodium bicarbonate was added to the reaction liquid to neutralize it, and this was then extracted with ethyl acetate. The organic layer was washed with saturated saline, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=1/1) to obtain the entitled compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]=[C:12]([C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([CH3:18])([CH3:17])[CH3:16])[NH:11][N:10]=1.C([O-])([O-])=O.[Cs+].[Cs+].[F:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]Br>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]=[C:12]([C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([CH3:18])([CH3:17])[CH3:16])[N:11]([CH2:37][C:36]2[CH:39]=[CH:40][CH:41]=[C:34]([F:33])[CH:35]=2)[N:10]=1
Reactant: Fc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1nc(-c2cc(F)ccc2F)n[nH]1)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](c1nc(-c2cc(F)ccc2F)nn1Cc1cccc(F)c1)C(C)(C)C

Procedure:
To a stirred suspension of (R)-tert-butyl 1-(3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropylcarbamate (5.89 g, 16.1 mmol) and Cs2CO3 (10.5 g, 32.2 mmol) in DMF (46 mL, 0.35 M) was added 3-fluorobenzyl bromide (2.17 mL, 17.7 mmol). Once the reaction was complete, the mixture was partitioned between EtOAc and H2O. The organic layer was separated and washed with H2O, brine, then dried over Na2SO4, filtered, and evaporated in vacuo to give (R)-tert-butyl 1-(3-(2,5-difluorophenyl)-1-(3-fluorobenzyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropylcarbamate. The desired less polar regioisomer was obtained by silica gel column (0% to 100% EtOAc in Hexanes, 5.05 g, 66.2%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:5][CH2:4][CH2:3][CH2:2][N:10]1[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]1
Reactant: CN1CCNCC1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1CCN(CCCO)CC1
Temperature: 25 °C

Procedure:
A mixture of 3-bromopropanol (20 ml), N-methylpiperazine (29 ml), potassium carbonate (83 g) and ethanol (200 ml)was stirred and heated to reflux for 20 hours. The mixture was cooled to ambient temperature and filtered. The filtrate was evaporated and the residue was triturated under diethyl ether. The resultant mixture was filtered and the filtrate was evaporated. The residue was purified by distillation at about 60–70° C. under about 0.2 mm Hg to give 1-(3-hydroxypropyl)-4-methylpiperazine (17 g); NMR Spectrum: (CDCl3) 1.72 (m, 2H), 2.3 (s, 3H), 2.2–2.8 (m, 8H), 2.6 (t, 2H), 3.8 (t, 2H), 5.3 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[OH:10].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15]Br>>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][O:10][C:4]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: BrCCCCBr
Reactant: COc1cccc(C)c1O
Product: COc1cccc(C)c1OCCCCBr

Procedure:
Analogously to Example 50b, 2.50 g of 2-methoxy-6-methylphenol and 2.67 ml of 1,4-dibromobutane are used to prepare the title compound. Rf=0.58 (1:1 EtOAc-heptane); Rt=5.28.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=2)[N:3]=1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Reactant: NCc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Product: Clc1ccc(CNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1

Procedure:
2-Chloro-6-[(4-chlorobenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-chlorobenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [F:1][C:2]1[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:23]>ClCCl>[CH3:27][C:26]([CH3:29])([CH3:28])[CH2:25][O:24][C:22]([N:6]1[CH:7]=[C:2]([F:1])[C:3]([N:9]=[CH:10][N:11]([CH3:13])[CH3:12])=[N:4][C:5]1=[O:8])=[O:23]
Reactant: CC(C)(C)COC(=O)Cl
Reactant: CN(C)C=Nc1nc(O)ncc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C=Nc1nc(=O)n(C(=O)OCC(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 20.5 %

Procedure:
To an 8 mL screw-cap vial was added dichloromethane (CH2Cl2; 3 milliliters (mL)), N′-(5-fluoro-2-hydroxy-pyrimidin-4-yl)-N,N-dimethylformamidine (100 milligrams (mg), 0.54 millimole (mmol)), triethylamine (Et3N; 120 mg, 1.18 mmol), and 2,2-dimethylpropyl chloroformate (90 mg, 0.60 mmol). After shaking for 1.5 hours (h) at room temperature, the mixture was partitioned between ethyl acetate (EtOAc) and water (H2O). The organic phase was dried over magnesium sulfate (MgSO4), filtered, and evaporated. The crude material was purified by reverse phase chromatography to yield 4-(dimethylamino-methyleneamino)-5-fluoro-2-oxo-2H-pyrimidine-1-carboxylic acid 2,2-dimethyl-propyl ester as a white solid (33 mg, 20%): mp 162-164° C.; 1H NMR (300 MHz, CDCl3) δ 8.77 (s, 1H), 7.93 (d, J=6.6 Hz, 1H), 4.08 (s, 2H), 3.27 (s, 3H), 3.20 (s, 3H), 1.05 (s, 9H); ESIMS m/z 299 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][C:9]([CH:21]3[CH2:26][CH2:25][N:24]([CH:27]([CH3:31])[CH2:28][CH2:29][NH2:30])[CH2:23][CH2:22]3)([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:32][C:33]1[C:38]([C:39](O)=[O:40])=[C:37]([CH3:42])[N:36]=[CH:35][N:34]=1>>[F:1][C:2]1[C:7]2[CH2:8][C:9]([CH:21]3[CH2:26][CH2:25][N:24]([CH:27]([CH3:31])[CH2:28][CH2:29][NH:30][C:39]([C:38]4[C:33]([CH3:32])=[N:34][CH:35]=[N:36][C:37]=4[CH3:42])=[O:40])[CH2:23][CH2:22]3)([C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=3)[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ncnc(C)c1C(=O)O
Reactant: CC(CCN)N1CCC(C2(c3ccc(C(F)(F)F)cc3)Cc3c(F)cccc3O2)CC1
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(C2(c3ccc(C(F)(F)F)cc3)Cc3c(F)cccc3O2)CC1
Yield: 40.1 %

Procedure:
Using general procedure E, 3-{4-[4-fluoro-2-(4-trifluoromethyl-phenyl)-2,3-dihydro-benzofuran-2-yl]-piperidin-1-yl}-butylamine (see EXAMPLE 251) (60 mg, 0.14 mmol) and 4,6-dimethyl-pyrimidine-5-carboxylic acid (42 mg, 0.28 mmol) afforded COMPOUND 257 as a white solid (32 mg, 41%). 1H NMR (CDCl3) δ 0.62-0.92 (m, 2H), 0.92-0.97 (m, 3H), 1.09-1.23 (m, 1H), 1.50-1.55 (m, 1H), 1.69-1.78 (m, 2H), 1.84-2.02 (m, 2H), 2.24-2.45 (m, 1H), 2.50 (s, 6H), 2.61-2.86 (m, 3H), 3.17-3.47 (m, 3H), 3.70-4.00 (m, 1H), 6.51-6.57 (m, 1H), 6.84, 6.89 (d, 1H, J=8.1 Hz), 7.10-7.17 (m, 1H), 7.36-7.43 (m, 2H), 7.58-7.62 (m, 2H), 8.44, 8.59 (m, 1H), 9.04, 9.09 (s, 1H). 13C NMR (CDCl3) δ 14.55, 14.95, 23.47, 27.69, 28.14, 28.30, 29.01, 31.91, 32.79, 38.48, 38.90, 41.46, 41.67, 45.53, 45.79, 48.46, 48.52, 53.92, 54.00, 61.60, 62.16, 94.67, 94.84, 107.08, 109.15, 109.42, 113.35, 113.62, 123.78, 126.91, 127.05, 127.16, 127.39, 131.29, 131.40, 131.48, 132.30, 150.24, 150.40, 158.92, 159.20, 162.19, 162.56, 164.50, 167.87, 168.26. ES-MS m/z 571 (M+H). Anal. Calcd. for C31H34N4O2F4.0.5H2O: C, 64.24; H, 6.09; N, 9.67. Found: C, 64.25; H, 6.00; N, 9.68.
Reaction SMILES: [NH4+:1].C([O-])(=O)C.[Cl:6][C:7]1[CH:12]=[C:11]([N:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])[CH:15]=[N:14]2)[CH:10]=[CH:9][C:8]=1[C:21]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)([CH3:25])[C:22](Cl)=[O:23]>CC(=O)C>[Cl:6][C:7]1[CH:12]=[C:11]([N:13]2[C:18](=[O:19])[NH:17][C:16](=[O:20])[CH:15]=[N:14]2)[CH:10]=[CH:9][C:8]=1[C:21]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)([CH3:25])[C:22]([NH2:1])=[O:23]
Reactant: [NH4+]
Reactant: CC(C(=O)Cl)(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Agent: CC(=O)[O-]
Solvent: CC(C)=O
Product: CC(C(N)=O)(c1ccc(Cl)cc1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.4 %

Procedure:
Acetic acid, ammonium salt (3 g) was added at RT to a solution of (±)-2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α-methylbenzeneacetyl chloride (0.007 mol) in 2-propanone (30 ml). The mixture was stirred at RT for 5 hours. Acetic acid, ammonium salt was filtered off and the solvent was evaporated. The residue was taken up in CH2Cl2, washed with water, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The pure fractions were collected and the solvent was evaporated, yielding 1.6 g (57%) of (±)-2-chloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)-α-methylbenzeneacetamide (comp. 1.18).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11]([C:14]1[C:15]([C:20]([F:23])([F:22])[F:21])=[N:16][CH:17]=[CH:18][CH:19]=1)=[CH:10][C:9]2=[O:24])([O-])=O.[NH4+].[Cl-].CO>[Fe].CCOC(C)=O>[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[O:12][C:11]([C:14]1[C:15]([C:20]([F:23])([F:22])[F:21])=[N:16][CH:17]=[CH:18][CH:19]=1)=[CH:10][C:9]2=[O:24]
Reactant: O=c1cc(-c2cccnc2C(F)(F)F)oc2c([N+](=O)[O-])cccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cccc2c(=O)cc(-c3cccnc3C(F)(F)F)oc12
Temperature: 90 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
A mixture of 8-nitro-2-(2-(trifluoromethyl)pyridin-3-yl)-4H-chromen-4-one 27 (118 mg, 0.38 mmol), Fe (96 mg, 1.7 mmol), sat. aq NH4Cl (7 mL) and MeOH (14 mL) was stirred at 90° C. for 2 h. After cooling to room temperature the reaction mixture was poured into EtOAc and the layers separated. The organic layer was dried (MgSO4) and concentrate to give 28 as a yellow solid (90 mg, 77% yield over two steps).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[C:18]([C:20]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:21]=1[NH2:22])#[N:19]>>[C:18]([C:20]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1)#[N:19]
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1cc(N)c(C#N)cc1OC
Product: COc1cc(C#N)c(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)cc1OC

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 2-cyano-4,5-dimethoxyaniline (48 mg, 0.288 mmol) similar to Example 185 and isolated as a solid (8 mg, 10%). 1H NMR (CDCl3): 9.62 (d, J=1.4 Hz, 1H), 8.69 (m, 2H), 7.43 (dd, J=5.4, 1.5 Hz, 1H), 7.07 (s, 1H), 6.93 (s, 1H), 6.70 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:15])[CH:12](Cl)[F:13])=[CH:8][S:7][CH:6]=1)=[O:4].[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>>[F:13][CH:12]([O:29][C:26]1[CH:25]=[CH:24][C:23]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)=[CH:28][CH:27]=1)[C:11]([NH:10][C:9]1[C:5]([C:3]([OH:2])=[O:4])=[CH:6][S:7][CH:8]=1)=[O:15]
Reactant: COC(=O)c1cscc1NC(=O)C(F)Cl
Reactant: Oc1ccc(-c2ccc(F)cc2)cc1
Product: O=C(O)c1cscc1NC(=O)C(F)Oc1ccc(-c2ccc(F)cc2)cc1

Procedure:
In analogy to Example 2, the title compound was prepared using 4-(2-chloro-2-fluoro-acetylamino)-thiophene-3-carboxylic acid methyl ester and 4-fluoro-4′-hydroxybiphenyl. MS (m/e): 388.2 (M−H).
Reaction SMILES: CCN(S(F)(F)[F:7])CC.O[C:11]([C:14]1[CH:32]=[C:17]2[C:18]([C:24]3[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=3)=[CH:19][CH:20]=[C:21]([O:22][CH3:23])[N:16]2[N:15]=1)([CH3:13])[CH3:12]>C(Cl)(Cl)Cl>[F:7][C:11]([C:14]1[CH:32]=[C:17]2[C:18]([C:24]3[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=3)=[CH:19][CH:20]=[C:21]([O:22][CH3:23])[N:16]2[N:15]=1)([CH3:13])[CH3:12]
Reactant: CCN(CC)S(F)(F)F
Reactant: COc1ccc(C2=NNC(=O)CC2C)c2cc(C(C)(C)O)nn12
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2=NNC(=O)CC2C)c2cc(C(C)(C)F)nn12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
DAST (27.9 mg) was added dropwise to a solution of the compound of Example 242 (21.9 mg) in chloroform (5.0 mL) and the mixture was stirred at 0° C. for 30 min. Subsequently, the reaction was quenched by adding a saturated aqueous sodium bicarbonate solution and the mixture was extracted with chloroform (30 mL). The extract was washed with water and saturated brine and dried over anhydrous sodium sulfate. The dried extract was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=1:3→ :4) to afford the title compound as a colorless powder (16.0 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([OH:19])=O)=[CH:12][C:11]=3[CH:20]=2)=[CH:3][CH:2]=1.[CH3:21][N:22]([CH2:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[CH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>CN(C)C=O>[N:1]1[CH:2]=[CH:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][C:13]([C:17]([NH:34][C:33]4[CH:35]=[CH:36][C:30]([CH2:29][N:22]([CH:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)[CH3:21])=[CH:31][CH:32]=4)=[O:19])=[CH:12][C:11]=3[CH:20]=2)=[CH:5][CH:6]=1
Reactant: O=C(O)C1=Cc2cc(-c3ccncc3)ccc2OCC1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccncc4)ccc3OCC2)cc1)C1CCOCC1
Temperature: 25 °C
Yield: 27.4 %

Procedure:
To a solution of 7-(4-pyridyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.15 g), 4-(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl)aniline (0.12 g) and triethylamine (0.16 ml) in dimethylformamide (50 ml) was added diethyl cyano-phosphate (O.1 ml) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature over night. The solvent was evaporated, and the residue was purified with silica gel column (methanol/ethyl acetate/triethylamine) to give crude crystals, which were recrystallized from ethanol-hexane to give 7-(4-pyridyl)-N-(4-((N-tetrahydropyran-4-yl-N-methylamino)methyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 147) (0.07 g) as pale brown crystals.
Reaction SMILES: BrC[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7].C(N(CC)CC)C.Cl>O1CCCC1>[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])[C:5]1[CH:14]=[CH:15][CH:16]=[CH:3][CH:4]=1
Reactant: O=C(c1ccccc1)c1cccc(CBr)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 1374.3 %

Procedure:
The free base of 2-isopropoxyphenyl piperazine was prepared by treatment of the fumarate salt with aqueous bicarbonate followed by extraction into chloroform, to provide a brown oil (7.28 g, 33.0 mmol) which was dissolved in 75 mL of tetrahydrofuran. To this solution was added a solution of 3-(bromomethyl)benzophenone (10.0 g, 3.63 mmol) in 75 mL of tetrahydrofuran followed by triethylamine (5.53 mL, 39.6 mmol). The reaction mixture was refluxed for 19 h. After cooling to ambient temperature the reaction mixture was poured into 1N HCl solution. After washing with ether, the aqueous solution was basified with solid K2CO3 and extracted with chloroform. The chloroform extracts were combined, dried (Na2SO4), and concentrated to provide a dark brown oil which was purified on a Waters 500A Prep LC apparatus (1% hexanes-chloroform) to afford 9.09 g of pure benzophenone intermediate as a brown oil. The oil was dissolved in acetone and treated with concentrated HBr (2.5 mL). When diethyl ether was added, a fine white precipitate fell out of solution. This solid was recrystallized from acetone/ether to provide 4.59 g of a white solid. A second crop of crystals was also collected. These were combined to provide 7.94 g (46%) of aryl piperazine benzophenone intermediate, mp 193°-197° C. The 1H NMR in CD3OD supported the assigned structure.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8]1.[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([C@H:9]3[CH2:10][CH2:11][CH:7]([N:3]4[CH2:4][CH2:5][CH2:6][C@@H:2]4[CH3:1])[CH2:8]3)=[CH:13][CH:14]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: C[C@H]1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: C[C@H]1CCCN1C1CC[C@H](c2ccc(NC(=O)c3ccc(Cl)cc3)cc2)C1

Procedure:
The title compound was synthesized essentially in the same manner as Example 28 by employing 4-[(S)-3-((S)-2-methyl-pyrrolidin-1-yl)-cyclopentyl]-phenylamine (Intermediate 14) and 4-chlorobenzoyl chloride.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:8][CH:7]=[CH:6][CH2:5][CH2:4]1.[OH-].[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1>O1CCOCC1.O>[F:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:2][N:3]2[CH2:4][CH:5]=[CH:6][CH2:7][CH2:8]2)=[O:20])=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: NN1CC=CCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1ccc(F)cc1)NN1CC=CCC1
Temperature: 5 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
N-Amino-1,2,3,6-tetrahydropyridine hydrochloride (3.42 g) was dissolved in a mixture of dioxane (30 ml) and water (20 ml). The solution was adjusted to pH 7.5 with 1N-aqueous sodium hydroxide and to the resultant mixture was added a solution of 4-fluorophenylisocyanate (0.548 g) in dioxane (5 ml). Then, the mixture was kept to pH 7.5 and stirred for 2 hours at 5° C. After evaporation of organic solvent, the crystalline product was collected by filtration and recrystallized from diisopropyl ether to give white needles of N-[[(4-fluorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine (0.73 g). mp: 156°-157° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](=O)(OCC)OCC.C([O-])([O-])=O.[K+].[K+]>C1OCCOCCOCCOCCOCCOC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH3:9])[CH:3]=1
Reactant: Fc1cccc(S)c1
Reactant: CCOC(=O)OCC
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CSc1cccc(F)c1
Temperature: 100 °C
Yield: 96.9 %

Procedure:
To a solution of 3-fluorothiophenol (4.73 g, 37.0 mmol) in diethyl carbonate (11 mL, 129 mmol) was added K2CO3 (7.67 g, 55.5 mmol) and 18-crown-6 ether (100 mg, 0.37 mmol). The reaction mixture was refluxed at 100° C. for 12 h. The reaction mixture was cooled to 20° C. then quenched by addition of H2O and extracted with Et2O. The combine organic solution was washed with H2O and brine, dried over MgSO4.to give 1-fluoro-3-(methylsulfanyl)benzene (5.10 g, 97%) as a colorless oil.