Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:50])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([C:46]([F:49])([F:48])[F:47])[CH:41]=2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:50])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([C:46]([F:47])([F:48])[F:49])[CH:41]=2)[CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C(F)(F)F)c2)c1
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (262 mg, 0.70 mmol) and 3-oxo-3-[3-(2-trifluoromethyl-pyridin-4-yl)-phenyl]-propionic acid tert-butyl ester (Example K38) (256 mg, 0.70 mmol) according to the general procedure M. Obtained as a light brown foam (440 mg, 94%).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH:58]([CH3:60])[CH3:59])[C:10]([O:12][CH2:13][CH:14]1[N:19]2[C:20]3[CH:21]=[CH:22][CH:23]=[C:24]([F:27])[C:25]=3[CH:26]=[C:18]2[C:17]2[N:28]=[C:29]([C:32]3[C:33]([N:52]([CH3:57])[S:53]([CH3:56])(=[O:55])=[O:54])=[CH:34][C:35]4[O:39][C:38]([C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)=[C:37]([C:47](=[O:50])[NH:48][CH3:49])[C:36]=4[CH:51]=3)[CH:30]=[CH:31][C:16]=2[O:15]1)=[O:11])=O)(C)(C)C.C([O-])(O)=O.[Na+]>ClCCl.C(O)(C(F)(F)F)=O>[NH2:8][C@@H:9]([CH:58]([CH3:60])[CH3:59])[C:10]([O:12][CH2:13][C@H:14]1[N:19]2[C:20]3[CH:21]=[CH:22][CH:23]=[C:24]([F:27])[C:25]=3[CH:26]=[C:18]2[C:17]2[N:28]=[C:29]([C:32]3[C:33]([N:52]([CH3:57])[S:53]([CH3:56])(=[O:54])=[O:55])=[CH:34][C:35]4[O:39][C:38]([C:40]5[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=5)=[C:37]([C:47](=[O:50])[NH:48][CH3:49])[C:36]=4[CH:51]=3)[CH:30]=[CH:31][C:16]=2[O:15]1)=[O:11]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3C(COC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)O4)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3[C@H](COC(=O)[C@@H](N)C(C)C)O4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a solution of (2S)-(11-fluoro-2-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-(N-methylmethylsulfonamido)benzofuran-5-yl)-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-6-yl)methyl 2-((tert-butoxycarbonyl)amino)-3-methylbutanoate (30 mg, 0.04 mmol) in dichloromethane (2 mL), TFA (0.5 mL) was added. The mixture was stirred at room temperature overnight. The mixture was poured into sat NaHCO3 solution (20 mL) and extracted with dichloromethane. The combined organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified using prep-TLC (dichloromethane:MeOH=40:1) to provide the product Compound 102 (25 mg, yield: 94%). 1H-NMR (CDCl3, 400 MHz) δ 8.03 (s, 1H), 7.95˜7.99 (m, 2H), 7.66 (s, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.19˜7.25 (m, 5H), 6.84˜6.89 (m, 1H), 6.63˜6.66 (m, 1H), 5.95 (br s, 1H), 4.41˜4.47 (m, 1H), 4.32˜4.37 (m, 1H), 3.39 (s, 3H), 3.23 (d, J=5.2 Hz, 1H), 3.01 (d, J=4.8 Hz, 3H), 2.74 (s, 3H), 1.82˜1.91 (m, 1H), 0.91 (d, J=6.8 Hz, 3H), 0.81 (d, J=6.8 Hz, 3H). MS (M+H)+: 744.
Reaction SMILES: C([C:4](=[C:10]([NH2:18])[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)C.[OH-].[NH4+]>>[NH2:18][C:10]([C:11]([F:16])([F:17])[C:12]([F:13])([F:14])[F:15])=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(C(C)=O)=C(N)C(F)(F)C(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Product: CCOC(=O)C=C(N)C(F)(F)C(F)(F)F
Yield: 88.5 %

Procedure:
To a stirred mixture of 65 g (0.4995 mole) of ethyl acetoacetate, 200 ml. of methanol and 100 ml. of saturated sodium acetate at 50° C. was introduced 100 g (0.769 mole) of pentafluoropropionitrile in 3 hours. The reaction mixture was poured into 1200 ml. of water. An oil separated from the reaction mixture. The aqueous solution was extracted with ether. The ether solution was combined with the oil, dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 40 g (37%) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate. A mixture of 21.8 g (0.0790 mole) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 75 ml. of 58% ammonium hydroxide was stirred for 66 hours. The reaction mixture was extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 16.3 g (88%) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate, nD25 =1.4011. A well stirred mixture of 54 g (0.23 mole) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 31 g (0.237 mole) of chlorocarbonylsulfenyl chloride was held at 100° C. for 1 hour. The reaction mixture was cooled and triturated with hexane. The solid precipitate was washed with water and recrystallized from hexane-ether to give 31 g (46%) of ethyl 2,3-dihydro-2-oxo-4-pentafluoroethyl-5-thiazolecarboxylate, m.p. 95°-97° C. A mixture of 10 g (0.0344 mole) of ethyl 2,3-dihydro-2-oxo-4-pentafluoroethyl-5-thiazolecarboxylate, 4 g (0.0506 mole) of pyridine and 150 ml. of phosphorus oxychloride was held at reflux for 18 hours. Excess phosphorus oxychloride was removed under reduced pressure. The residue was treated with water and extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 7.5 g (71%) of ethyl 2-chloro-4-pentafluoroethyl-5-thiazolecarboxylate, nD25 =1.4460.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:4].[Cl:17][S:18](O)(=[O:20])=[O:19]>C(Cl)(Cl)Cl>[F:16][C:2]([F:1])([F:15])[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([S:18]([Cl:17])(=[O:20])=[O:19])=[CH:10][CH:11]=2)[CH2:6]1)=[O:4]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(N1CCc2ccccc2C1)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Reaction time: 8 h

Procedure:
To a solution of 2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinoline 45.84 g. (0.2 mole) in 300 ml. of chloroform was added slowly 82.4 ml. (1.24 mole) of chlorosulfonic acid. The solution was stirred and the temperature allowed to come down to 25° C. The solution was quenched in ice water and extracted with chloroform. The extract was washed with water and dried over magnesium sulfate and concentrated. The residue was treated with ether and allowed to stand overnight. The resultant solid was filtered off, added to chloroform, cooled, treated with ether and allowed to stand in the cold for several hours. The resultant solid was again taken up in chloroform and treated with ether to give 2-trifluoroacetyl-7-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline, m.p. 108°-109° C.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]=[O:7])[N:3]=[CH:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:26][C:27]([Si](C)(C)C)([F:29])[F:28]>C1COCC1>[F:26][C:27]([F:29])([F:28])[CH:6]([C:4]1[N:3]=[CH:2][S:1][CH:5]=1)[OH:7]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1cscn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1cscn1)C(F)(F)F
Yield: 33.4 %

Procedure:
The method described in Example 4 (step 4.5.) is followed. Starting from 1 g (8.84 mmol) of thiazole-4-carboxaldehyde, 0.10 ml (0.10 mmol) of a 1M solution of tetrabutylammonium fluoride in THF and 1.38 g (9.72 mmol) of trifluoromethyltrimethylsilane (TMS-CF3), and after chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, gives 0.54 g of pure product in the form of a colourless oil.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]2[NH:27][C:28]([CH:31]([C:39]3[CH:44]=[CH:43][C:42]([S:45]([CH3:48])(=[O:47])=[O:46])=[CH:41][CH:40]=3)[CH2:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:29][CH:30]=2)[CH:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[CH3:48][S:45]([C:42]1[CH:43]=[CH:44][C:39]([CH:31]([C:28]2[NH:27][C:26]([C:22]3[CH:21]=[C:20]([CH2:19][OH:18])[CH:25]=[CH:24][N:23]=3)=[CH:30][CH:29]=2)[CH2:32][CH:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)=[CH:40][CH:41]=1)(=[O:47])=[O:46]
Reactant: CC(C)(C)[Si](OCc1ccnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(C)(=O)=O)cc3)[nH]2)c1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2ccc(-c3cc(CO)ccn3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a solution of 4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-(5-{1-[4-(methylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine (870 mg) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (1M tetrahydrofuran solution, 1.54 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (533 mg, yield 95%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate. MS: 441 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][NH2:10])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[CH2:9][NH:10][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][N:13]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: NCc1ccc(Cl)c(Cl)c1
Solvent: CCO
Product: COC(=O)c1ccc(NCc2ccc(Cl)c(Cl)c2)nc1
Temperature: 120 °C
Yield: 30.3 %

Procedure:
A mixture of (3,4-dichlorophenyl)methanamine (1.010 mL, 7.58 mmol), TEA (1.218 mL, 8.74 mmol), and methyl 6-chloronicotinate (1 g, 5.83 mmol) in ethanol (29 mL) was heated at 120° C. for 5 min in a microwave oven. The reaction mixture was further heated at 100° C. for 54 h, then concentrated. The residue was purified by flash chromatography on silica gel using 5-35% ethyl acetate in hexanes. The desired fractions were concentrated to give methyl 6-(3,4-dichlorobenzylamino)nicotinate as a pale yellow solid (0.55 g, 33%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.77 (1H, s), 8.01 (1H, dd, J=8.78, 2.01 Hz), 7.33-7.52 (2H, m), 7.19 (1H, d, J=8.03 Hz), 6.37 (1H, d, J=8.78 Hz), 5.37 (1H, br. s.), 4.58 (2H, d, J=6.02 Hz), 3.88 (3H, s). LCMS: R.T.=2.81; [M+H]+=311.18.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(N(CC)CC)C>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCN(S(=O)(=O)c2ccc(Cl)cc2)CC1
Yield: 77 %

Procedure:
In the manner given in Example 15, 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine is reacted with 4-chlorophenylsulfonyl chloride in the presence of triethylamine under nitrogen to give 1-[(4-chlorophenyl)sulfonyl]-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine of melting point 234°-236° C. in 77% yield.
Reaction SMILES: [CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[S:6][C:5]=1[CH:17]=O)([CH3:3])[CH3:2].[C:19]([C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[CH:29][C:30]([O:32][CH3:33])=[O:31])=[C:24]([CH3:34])[CH:23]=1)(=[O:21])[CH3:20]>>[CH:1]([C:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[S:6][C:5]=1[CH:17]=[CH:20][C:19]([C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[CH:29][C:30]([O:32][CH3:33])=[O:31])=[C:24]([CH3:34])[CH:23]=1)=[O:21])([CH3:2])[CH3:3]
Reactant: CC(C)c1c(C=O)sc2cc(C(F)(F)F)ccc12
Reactant: COC(=O)C=Cc1ccc(C(C)=O)cc1C
Product: COC(=O)C=Cc1ccc(C(=O)C=Cc2sc3cc(C(F)(F)F)ccc3c2C(C)C)cc1C

Procedure:
The titled compound was prepared from the above-mentioned 3-isopropyl-6-(trifluoromethyl)benzothiophen-2-carboxaldehyde (215 mg, 0.790 mmol) and methyl 3-(4-acetyl-2-methylphenyl)-acrylate (172 mg, 0.788 mmol) in a procedure similar to that of Example 7 (1) as a yellow crystal (259 mg, yield 69%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:7]([S:9]([NH:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])(=[O:11])=[O:10])[CH:8]=1)#[N:2].Br[CH2:28][CH2:29][N:30]1[C:34](=[O:35])[CH2:33][CH2:32][C:31]1=[O:36].[H-].[Na+]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:18][C:19]2[CH:20]=[C:21]([Cl:26])[CH:22]=[C:23]([Cl:25])[CH:24]=2)=[C:7]([S:9]([N:12]([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[CH2:28][CH2:29][N:30]2[C:34](=[O:35])[CH2:33][CH2:32][C:31]2=[O:36])(=[O:10])=[O:11])[CH:8]=1)#[N:2]
Reactant: O=C1CCC(=O)N1CCBr
Reactant: CN(C)CCNS(=O)(=O)c1cc(C#N)ccc1Oc1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCN(CCN1C(=O)CCC1=O)S(=O)(=O)c1cc(C#N)ccc1Oc1cc(Cl)cc(Cl)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a solution of 5-cyano-2-(3,5-dichloro-phenoxy)-N-(2-dimethylamino-ethyl)-benzene-sulfonamide (41.4 mg, 0.1 mmol) in dry DMF (2 ml) was added 1-(2-bromo-ethyl)-pyrrolidine-2,5-dione (30.9 mg, 0.15 mmol) and NaH (60%, 6.00 mg, 0.15 mmol). The mixture was stirred for 8 hours at 90° C. After cooled to room temperature, the solvent was evaporated. The mixture was diluted with EtOAc (60 ml), washed with brine, and dried over MgSO4. The solvent was evaporated and the residue was purified by preparative TLC (CH2Cl2/CH3OH=20/1) to give 5-cyano-2-(3,5-dichloro-phenoxy)-N-(2-dimethylamino-ethyl)-N-[2-(2,5-dioxo-pyrrolidin-1-yl)-ethyl]-benzenesulfonamide (44 mg, 81.6%) and the free base was converted into HCl salt by 4N HCl in dioxane.
Reaction SMILES: [CH2:1]([O:4][NH:5][C@@H:6]1[C:11]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])=[CH:10][C@@H:9]([CH2:17][O:18][CH3:19])[NH:8][CH2:7]1)[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C>[CH2:1]([O:4][N:5]1[C:30](=[O:32])[N:8]2[CH2:7][C@H:6]1[C:11]([C:12]([N:14]([CH3:16])[CH3:15])=[O:13])=[CH:10][C@H:9]2[CH2:17][O:18][CH3:19])[CH:2]=[CH2:3]
Reactant: C=CCON[C@H]1CN[C@H](COC)C=C1C(=O)N(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCON1C(=O)N2C[C@H]1C(C(=O)N(C)C)=C[C@H]2COC
Temperature: 25 °C
Reaction time: 8 h
Yield: 206.3 %

Procedure:
A solution of (3R,6S)-3-(allyloxyamino)-6-(methoxymethyl)-N,N-dimethyl-1,2,3,6-tetrahydropyridine-4-carboxamide (Intermediate 142, 725 mg, 2.69 mmol) and Hunig's Base (1.880 mL, 10.77 mmol) in acetonitrile (350 mL) was cooled to below 0° C. in an ice-salt bath and then a solution of triphosgene (320 mg, 1.08 mmol) in ACN (22 mL) was added at a rate of 0.1 mL/min. The reaction was stirred overnight at rt. Upon completion of the reaction, the solvents were removed and the crude mixture was redissolved in EtOAc, washed with sat. NaHCO3 and brine, dried over MgSO4, filtered and concentrated to obtain the desired product (658 mg, 83%) as a pale yellow oil.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:4]=[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][NH:21][C:20](=[O:24])[CH:19]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.Cl[CH2:28][C:29]1[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=1>>[CH3:34][N:32]1[CH:33]=[C:29]([CH2:28][N:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:16][C:13]3[CH:14]=[CH:15][C:10]([O:9][C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:25])[F:26])[CH:4]=4)=[CH:11][CH:12]=3)=[CH:19][C:20]2=[O:24])[CH:30]=[N:31]1
Reactant: O=c1cc(OCc2ccc(Oc3cccc(C(F)(F)F)c3)cc2)cc[nH]1
Reactant: Cn1cc(CCl)cn1
Product: Cn1cc(Cn2ccc(OCc3ccc(Oc4cccc(C(F)(F)F)c4)cc3)cc2=O)cn1

Procedure:
The title compound was prepared by a procedure similar to that described for E21 starting from 4-{[(4-{[3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]oxy}-2(1H)-pyridinone and 4-(chloromethyl)-1-methyl-1H-pyrazole. LC-MS (ESI): m/z 456 [M+H]+; 3.40 min (ret time).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH3:13])=[CH:5][C:4]=1F)[CH3:2].Cl.Cl.[CH3:17][S:18]([N:21]1[CH2:26][CH2:25][N:24]([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:23][CH2:22]1)(=[O:20])=[O:19].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH3:13])=[CH:5][C:4]=1[N:30]1[CH2:29][CH2:28][CH:27]([N:24]2[CH2:25][CH2:26][N:21]([S:18]([CH3:17])(=[O:20])=[O:19])[CH2:22][CH2:23]2)[CH2:32][CH2:31]1)[CH3:2]
Reactant: CCc1cc([N+](=O)[O-])c(OC)cc1F
Reactant: CS(=O)(=O)N1CCN(C2CCNCC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCc1cc([N+](=O)[O-])c(OC)cc1N1CCC(N2CCN(S(C)(=O)=O)CC2)CC1
Temperature: 90 °C
Yield: 56.2 %

Procedure:
A mixture of 1-ethyl-2-fluoro-4-(methyloxy)-5-nitrobenzene (Example 187, step C) (0.93 g, 4.67 mmol), 1-(methylsulfonyl)-4-(4-piperidinyl)piperazine (Example 204, step C) (1.16 g, 4.67 mmol) and K2CO3 (0.774 g, 5.60 mmol) in DMSO (20 mL) was heated at 90° C. for 48 h. The reaction had not progressed sufficiently so the reaction was then heated at 120° C. for an additional 4 h. The reaction was cooled to rt, poured into H2O and extracted with DCM. Some saturated brine solution was added and the resultant was exhaustively extracted with DCM. The combined organics were washed with H2O then dried over MgSO4. The resultant solution was concentrated onto silica and purified by flash chromatography to afford 1-{1-[2-ethyl-5-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(methylsulfonyl)piperazine (1.12 g, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.73-7.80 (m, 1H), 6.75 (s, 1H), 3.91 (s, 3H), 3.23-3.30 (m, 1H), 3.05-3.19 (m, 3H), 2.87 (s, 2H), 2.70-2.84 (m, 2H), 2.53-2.67 (m, 5H), 1.77-1.94 (m, 2H), 1.48-1.67 (m, 2H), 1.19 (t, J=7.42 Hz, 3H).
Reaction SMILES: [Na].[OH:2][C:3]1([CH3:12])[CH2:7][CH2:6][C:5](=[N:8]O)[C:4]1([CH3:11])[CH3:10]>C(O)CC.[Cl-].[Na+].O>[NH2:8][CH:5]1[CH2:6][CH2:7][C:3]([CH3:12])([OH:2])[C:4]1([CH3:11])[CH3:10]
Reactant: CC1(O)CCC(=NO)C1(C)C
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CCCO
Product: CC1(O)CCC(N)C1(C)C
Temperature: 25 °C
Yield: 110.4 %

Procedure:
Sodium (4.63 g, 201 mmol) was added in small portions over 1 h to a solution of the crude 3-hydroxy-2,2,3-trimethylcyclopentanone oxime (9.05 g, from Step 2) in n-propanol (80 mL) at 80° C. The resultant mixture stirred at 80° C. for 2 h, cooled to room temperature, poured into brine (100 mL) and extracted with dichloromethane (3×200 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated to give crude 3-amino-1,2,2-trimethylcyclopentanol (9.1 g), which was taken to the next reaction without purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[CH:6]2.CC([O-])(C)C.[K+].[C:19]([O:23][C:24]([N:26]1[C@@H:30]([CH3:31])[CH2:29]OS1(=O)=O)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[C:19]([O:23][C:24](=[O:25])[NH:26][C@@H:30]([CH3:29])[CH2:31][N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH:6]=[C:7]1[CH3:12])([CH3:22])([CH3:21])[CH3:20]
Reactant: C[C@H]1COS(=O)(=O)N1C(=O)OC(C)(C)C
Reactant: COc1ccc2[nH]c(C)cc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)cc(C)n2C[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
5-Methoxy-2 methylindole (806 mg) was dissolved in DMF (25 mL) and cooled to 0° C. with an ice bath. Potassium tert-butylate (1M in THF, 6 mL) was added over 15 minutes and the resulting mixture was allowed to stir for further 30 minutes. (S)-4-Methyl-2,2-dioxo-oxathiazolidine-3-carboxylic acid tert-butyl ester IV (1.42 g) was added in one portion and stirring was continued at RT until TLC analysis showed complete consumption of the starting material. The reaction mixture was partitioned between ether and saturated NH4Cl solution and the organic layer was separated, washed with sat. NH4Cl and brine, dried over Na2SO4, filtered and evaporated in vacuo. The residue was purified by flash chromatography (CH2Cl2). The appropriate fractions were combined and evaporated to give the product as an off-white solid (1.42 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)[CH2:6][C:7]1[C:8](Cl)=[N:9][C:10](Cl)=[N:11][CH:12]=1)[CH3:2].[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:1]([O:3][C:4](=[O:25])[CH:5]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1)[CH2:6][C:7]1[C:8]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:9][C:10]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1cnc(Cl)nc1Cl)c1ccc(OC)c(OC)c1
Reactant: Nc1ccccc1
Product: CCOC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1ccc(OC)c(OC)c1
Temperature: 110 °C

Procedure:
A mixture of 3-(2,4-dichloro-pyrimidin-5-yl)-2-(3,4-dimethoxy-phenyl)-propionic acid ethyl ester (440 mg, 1.1 mmol) (from Example 11a supra) and aniline (2.0 mL) (Aldrich) was heated at 110° C. for 2 hours. The reaction mixture was washed with hexanes (50 mL×3) and the supernatant was decanted off after each time. The residue was then dissolved in ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (30 mL), water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was then purified by flash column chromatography to give the crude 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-(3,4-dimethoxy-phenyl)-propionic acid ethyl ester as an off-white solid. (Yield 470 mg, 86%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10](=O)[CH2:11][CH2:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:14]O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][CH:13]([NH2:14])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(C(=O)CCC(=NO)c2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)N1CCN(CCCC(N)c2ccccc2)CC1
Temperature: 70 °C
Yield: 97.3 %

Procedure:
To a solution of 1-(4-isopropylpiperazin-1-yl)-4-phenylbutane-1,4-dione 4-oxime (625 mg, 2.0 mmol) in 10 mL of THF was slowly added lithium aluminum hydride (250 mg, 6.6 mmol). The reaction flask was heated at 70° C. for 4 h after which time the flask was cooled to 0 C and the reaction was quenched by slow addition of water and 1 N sodium hydroxide. The biphasic mixture was filtered through a pad of diatomaceous earth, and the filtered solution was concentrated to dryness to afford 536 mg (98%) of the title compound as a crude residue that was used without further purification.