Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([F:11])[F:10])=[CH:6][C:5]([N+:12]([O-])=O)=[C:4]([F:15])[CH:3]=1.Cl.[OH-].[Na+].C(Cl)(Cl)Cl>C(O)C>[Cl:1][C:2]1[C:7]([O:8][CH:9]([F:10])[F:11])=[CH:6][C:5]([NH2:12])=[C:4]([F:15])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(OC(F)F)c(Cl)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Nc1cc(OC(F)F)c(Cl)cc1F
Reaction time: 20 h
Yield: 86.8 %

Procedure:
To 5 g of 4-chloro-5-difluoromethoxy-2-fluoronitrobenzene XII-1 were added 10.4 ml of ethanol and 20.7 ml of hydrochloric acid, and the resultant mixture was stirred at room temperature. A solution of 14 g of stannous chloride dihydrate in 20.7 ml of ethanol was dropwise added in 10 minutes to the mixture, which was stirred for 20 hours. The reaction mixture was basified with 10% aqueous sodium hydroxide and shaken with chloroform. The chloroform layer was dried and concentrated. The residue was chromatographed on a column of silica gel, eluting with n-hexane-ethyl acetate (100:15 v/v). The eluate was concentrated to give 3.8 g of the titled compound XIII-1.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([NH:26][C:27]([CH:29]5[CH2:33][CH2:32][CH2:31][N:30]5C([O-])=O)=[O:28])=[CH:22][CH:21]=4)[CH:17]=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.O1CCOC[CH2:39]1>C(OCC)(=O)C.CO>[CH3:39][C@@:29]1([C:27]([NH:26][C:23]2[CH:22]=[CH:21][C:20]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]([NH:13][C:10]4[CH:9]=[CH:8][C:7]([N:1]5[CH2:6][CH2:5][O:4][CH2:3][CH2:2]5)=[CH:12][CH:11]=4)[N:19]=3)=[CH:25][CH:24]=2)=[O:28])[CH2:33][CH2:32][CH2:31][NH:30]1
Reactant: O=C(Nc1ccc(-c2ccnc(Nc3ccc(N4CCOCC4)cc3)n2)cc1)C1CCCN1C(=O)[O-]
Reactant: C1COCCO1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@@]1(C(=O)Nc2ccc(-c3ccnc(Nc4ccc(N5CCOCC5)cc4)n3)cc2)CCCN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
1,1-Dimethylethyl (2R)-2-{([(4-{2-[(4-morpholin-4-ylphenyl)amino]pyrimidin-4-yl}-phenyl)amino]carbonyl}pyrrolidine-1-carboxylate (0.38 g, 0.698 mmoles), was dissolved in an ethyl acetate (10 ml) and methanol (2 ml) mixture. 4 M hydrogen chloride in 1,4-dioxane (1.75 ml, 6.98 mmoles, 10 equivalents, purchased from Sigma-Aldrich) was then added in a drop wise fashion over 5-10 minutes. Upon completion of addition, the reaction mixture was stirred at room temperature, and the progress of the reaction monitored by LC/MS. After 16 hours, additional 4M hydrogen chloride in 1,4-dioxane (0.87, 1.25 mmoles, 5 equivalents) was added. After a total of 48 hours the reaction was complete and the resulting slurry was filtered off. The reaction flask was rinsed with ethyl acetate to ensure complete transfer of product. The resulting solid was washed with ethyl acetate (3×10 ml), followed by diethyl ether (3×25 ml) and dried under reduced pressure to give of 0.264 mg 2-methyl-N-(4-{2-[(4-morpholin-4-ylphenyl)amino]-pyrimidin-4-yl}phenyl)prolinamide (68% yield).
Reaction SMILES: O1CCC[CH2:2]1.[Cl:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH:12]([CH3:31])[C:13](=[O:30])[N:14]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[N:9][CH:8]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>O.C(OCC)(=O)C>[Cl:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][C:12]([CH3:2])([CH3:31])[C:13](=[O:30])[N:14]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:19][CH2:18]2)=[N:9][CH:8]=1
Reactant: CC1Cc2ncc(Cl)cc2N(C2CCN(C(=O)OC(C)(C)C)CC2)C1=O
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)C(C)(C)Cc3ncc(Cl)cc32)CC1
Reaction time: 0.33 h

Procedure:
To a tetrahydrofuran solution (161 ml) of tert-butyl 4-(7-chloro-3-methyl-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (10.7 g) was added dropwise at −78° C. lithium hexamethyldisilazide (1.0 M tetrahydrofuran solution, 31.0 ml). After stirring at the same temperature for 15 minutes and under ice cooling for 20 minutes, a tetrahydrofuran solution (54 ml) of methyl iodide (2.10 ml) was added dropwise. After stirring at the same temperature for 10 minutes and at room temperature for 30 minutes, ethyl acetate and water were added to the reaction solution, and the solution was separated. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford tert-butyl 4-(7-chloro-3,3-dimethyl-2-oxo-3,4-dihydro-1,5-naphthyridin-1(2H)-yl)piperidine-1-carboxylate (9.31 g).
Reaction SMILES: [O:1]=[S:2]1(=[O:51])[CH2:7][CH2:6][N:5]([CH2:8][C:9]([NH:11][C@:12]23[CH2:47][CH2:46][C@@H:45]([CH:48]([CH3:50])[CH3:49])[C@@H:13]2[C@@H:14]2[C@@:27]([CH3:30])([CH2:28][CH2:29]3)[C@@:26]3([CH3:31])[C@@H:17]([C@:18]4([CH3:44])[C@@H:23]([CH2:24][CH2:25]3)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]3[CH:43]=[CH:42][C:37]([C:38]([O:40]C)=[O:39])=[CH:36][CH:35]=3)=[CH:20][CH2:19]4)[CH2:16][CH2:15]2)=[O:10])[CH2:4][CH2:3]1.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53].O.[OH-].[Li+]>C1COCC1.O>[O:51]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][C:9]([NH:11][C@:12]23[CH2:47][CH2:46][C@@H:45]([CH:48]([CH3:49])[CH3:50])[C@@H:13]2[C@@H:14]2[C@@:27]([CH3:30])([CH2:28][CH2:29]3)[C@@:26]3([CH3:31])[C@@H:17]([C@:18]4([CH3:44])[C@@H:23]([CH2:24][CH2:25]3)[C:22]([CH3:33])([CH3:32])[C:21]([C:34]3[CH:43]=[CH:42][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=3)=[CH:20][CH2:19]4)[CH2:16][CH2:15]2)=[O:10])[CH2:4][CH2:3]1.[C:52]([OH:58])([C:54]([F:57])([F:56])[F:55])=[O:53]
Reactant: COC(=O)c1ccc(C2=CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(NC(=O)CN6CCS(=O)(=O)CC6)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@@H]1CC[C@]2(NC(=O)CN3CCS(=O)(=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Reaction time: 5.5 h

Procedure:
To a solution of methyl 4-[(1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-[[2-(1,1-dioxo-1,4-thiazinan-4-yl)acetyl]amino]-1-isopropyl-5a,5b,8,8,11a-pentamethyl-1,2,3,4,5,6,7,7a,11,11b,12,13,13a,13b-tetradecahydrocyclopenta[a]chrysen-9-yl]benzoate, TFA (33 mg, 0.040 mmol) in THF (Volume: 3 mL) was added a 0.753 molar solution of lithium hydroxide monohydrate (0.316 mL, 0.158 mmol) in H2O. The reaction mixture was heated to 75° C. After 5.5 h, the reaction was concentrated to dryness. The crude residue was dissolved in THF (1.2 mL), MeOH (0.3 mL) and 1N HCl (0.2 mL). The solution was filtered and injected into reverse phase HPLC for purification using HPLC method 3 to give 4-((1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(((1,1-dioxido-4-thiomorpholinyl)acetyl)amino)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, TFA (17.9 mg, 0.021 mmol, 54.1% yield) as a white solid. LCMS: m/z 707.6 (M+H+), retention time 2.030 min (method 6). 1H NMR (500 MHz, METHANOL-d4) δ=7.93 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H), 7.13 (s, 1H), 5.31 (dd, J=1.5, 6.1 Hz, 1H), 3.26-3.22 (m, 5H), 3.21-3.15 (m, 4H), 2.66-2.59 (m, 1H), 2.37 (dd, J=6.7, 12.5 Hz, 1H), 2.17 (dd, J=6.4, 17.1 Hz, 1H), 1.99-1.91 (m, 1H), 1.80-1.70 (m, 4H), 1.67-1.57 (m, 2H), 1.57-1.45 (m, 9H), 1.44-1.39 (m, 1H), 1.39-1.26 (m, 3H), 1.18-1.11 (m, 2H), 1.09 (s, 3H), 1.04 (s, 6H), 0.96 (s, 3H), 0.95 (s, 3H), 0.91 (d, J=7.0 Hz, 3H), 0.82 (d, J=6.7 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH:12]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Cc1ccc(OC2CCC(=O)CC2)nc1
Product: Cc1ccc(OC2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)nc1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(5-methyl-pyridin-2-yloxy)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4](=[S:7])[N:3]1[NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:32][C:31]([CH:33]=O)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].C(O)(=O)C.C(O)(=O)C.C(N)CN.S([O-])(O)=O.[Na+]>CO>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:32][C:31](/[CH:33]=[C:6]3\[C:2](=[O:1])[N:3]([NH:8][C:9]4[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=4[C:11]([OH:13])=[O:12])[C:4](=[S:7])[S:5]\3)=[CH:30][CH:29]=2)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(O)c1ccccc1NN1C(=O)CSC1=S
Reactant: CC(C)(C)c1ccc(-c2ccc(C=O)o2)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CO
Solvent: NCCN
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(-c2ccc(/C=C3/SC(=S)N(Nc4ccccc4C(=O)O)C3=O)o2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 86 %

Procedure:
A mixture of 2-(4-oxo-2-thioxo-thiazolidin-3-ylamino)-benzoic acid (0.090 g, 0.34 mmol), 5-(4-tert-butyl-phenyl)-furan-2-carbaldehyde (0.082 g, 0.36 mmol) and ethylenediamine diacetate (0.065 g, 0.036 mmol) in methanol (8 mL) was stirred at room temperature for 17 h. The reaction mixture was poured into stirred 0.6 N aq sodium hydrogensulfite (50 mL). The mixture was vigorously stirred for 15 min. The solid product was filtered off and washed on funnel successively with 0.6 N aq sodium hydrogensulfite (2 mL), water (2×2 mL), ether (2 mL) and hexanes (2 mL). The material was dried in a vacuum oven at 65° C. for 19 h to afford 2-{5-[1-[5-(4-tert-Butyl-phenyl)-furan-2-yl]-meth-(E)-ylidene]-4-oxo-2-thioxo-thiazolidin-3-ylamino}-benzoic acid (140 mg, 87%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 1.32 (9H, s), 6.45 (1H, m), 6.82 (1H, m), 7.23 (1H, m), 7.30 (1H, d, J=3.6), 7.40 (1H, d, J=3.6), 7.61 (2H, m), 7.74 (1H, s), 7.82 (2H, m), 7.91 (1H, m), 11.20 (1H, bs). LC/MS APCI 477.9, HPLC 91.0%
Reaction SMILES: N1C2OCC(N)C=2C=CN=1.CO[N:13]=[C:14]1[C:22]2[C:17](=[C:18]([CH:23]3[CH2:25][CH2:24]3)[N:19]=[CH:20][CH:21]=2)[O:16][CH2:15]1>>[CH:23]1([C:18]2[N:19]=[CH:20][CH:21]=[C:22]3[CH:14]([NH2:13])[CH2:15][O:16][C:17]=23)[CH2:25][CH2:24]1
Reactant: CON=C1COc2c1ccnc2C1CC1
Agent: NC1COc2nnccc21
Product: NC1COc2c1ccnc2C1CC1

Procedure:
This compound was prepared using a method analogous to that of 5,6-dihydrofuro[2,3-c]pyridazin-5-amine (A.2.3.4), 7-cyclopropylfuro[2,3-c]pyridin-3(2H)-one O-methyl oxime replacing furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime;
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][CH2:8][CH2:9][CH2:10][S:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](OC)=[O:17])=[CH:14][CH:13]=1.O>O1CCCC1>[Cl:7][CH2:8][CH2:9][CH2:10][S:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][OH:17])=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(SCCCCl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(SCCCCl)cc1
Reaction time: 0.75 h
Yield: 85.3 %

Procedure:
5 g of lithium aluminum hydride are suspended in 200 ml of tetrahydrofuran, and a solution of 31.9 g of methyl 4-(3-chloropropylthio)benzoate in 200 ml of tetrahydrofuran is added thereto at 5° to 15° C. The mixture is stirred at the same temperature for 45 minutes. Water is added to the mixture at a temperature of below 20° C., and insoluble materials are filtered off. The filtrate is concentrated under reduced pressure to remove solvent, and the residue is distilled under reduced pressure. 24.1 g of 4-(3-chloropropylthio)benzylalcohol are obtained as an oil. Yield: 85%.
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([CH3:4])[CH3:3].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>ClCCl>[CH3:13][S:14]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])(=[O:16])=[O:15]
Reactant: CC(C)CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.3 %

Procedure:
To an ice cooled solution of 37 g (46.1 ml, 0.5 mol) of isobutyl alcohol and 75.75 g (104.3 ml, 0.75 mol) of triethylamine in 1800 ml of dichloromethane is added dropwise 63 g (42.57 ml, 0.55 mol) of methanesulfonyl chloride. The temperature of the reaction mixture during the addition is ca. 10°. The reaction mixture is then stirred for 1.5 hours at 10°. The reaction mixture is then diluted with dichloromethane, washed with ice water, cold 10% HCl, saturated KHCO3, saturated NaCl and dried (MgSO4). Solvent is removed in vacuo to yield 68 g (90%) of the isobutyl methanesulfonate as an oil.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][NH2:20])[CH:13]=1>C(Cl)Cl>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][NH:20][C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])[CH:13]=1
Reactant: NCCc1cccnc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C(O)c1ccccc1C(=O)NCCc1cccnc1

Procedure:
A mixture of 4.44 g of phthalic anhydride and 75 ml of methylene chloride was stirred and 3.66 g of 2-(3-pyridinyl)ethylamine was added. Solution occured followed by separation of a white precipitate. The desired product was separated by filtration and melted at 183°-185° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:33][C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])=[C:6]([CH:32]=1)[C:7]([N:9]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:31][CH2:30]2)=[CH:25][CH:24]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[O:8].[CH3:40]N1C(=O)N(C)CCC1.[H-].[Na+].CI>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:33]([CH3:40])[C:34](=[O:39])[C:35]([F:36])([F:37])[F:38])=[C:6]([CH:32]=1)[C:7]([N:9]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:30][CH2:31]2)=[CH:25][CH:24]=1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[O:8]
Reactant: O=C(c1cc(Cl)ccc1NC(=O)C(F)(F)F)N(CCc1cccc(C(F)(F)F)c1)Cc1ccc(C2CC2)cc1
Reactant: CN1CCCN(C)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C(=O)C(F)(F)F)c1ccc(Cl)cc1C(=O)N(CCc1cccc(C(F)(F)F)c1)Cc1ccc(C2CC2)cc1
Temperature: 25 °C
Yield: 70 %

Procedure:
50 mg of 5-chloro-N-(4-cyclopropyl-benzyl)-2-(2,2,2-trifluoro-acetylamino)-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide (0.09 mmol) were dissolved in 1 ml DMF and 0.1 ml DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2-pyridinon) under argon and cooled down to 0° C. 6 mg of sodium hydride (55% dispersion in oil, 0.135 mmol) were then added and after 15 min stirring at RT the reaction mixture was again cooled down to 0° C. 0.008 ml of methyl iodide (0.135 mmol) were added and after 4 h stirring at RT a second portion of the same amount was added. After 20 hours stirring at RT the reaction mixture was diluted with ethyl acetate and washed with water and brine. The aqueous phases were reextracted with ethyl acetate, and the combined organic phases were dried over magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (silica gel; heptane/EtOAc 9:1) to give 36 mg (70%) 5-chloro-N-(4-cyclopropyl-benzyl)-2-[methyl-(2,2,2-trifluoro-acetyl)-amino]-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide as a colorless viscous oil. MS (ISP) 583.2 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].F[C:8]1[CH:23]=[C:22]([C:24]([F:30])([F:29])[C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=1)=[O:11].[F:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([O:39][CH3:40])[CH:33]=1.O.C(OCC)(=O)C>CN1C(=O)CCC1>[F:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][C:8]2[CH:23]=[C:22]([C:24]([F:30])([F:29])[C:25]([F:26])([F:27])[F:28])[CH:21]=[CH:20][C:9]=2[C:10]([NH:12][C:13]2[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=2)=[O:11])=[C:34]([O:39][CH3:40])[CH:33]=1
Reactant: COc1cc(F)ccc1O
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1Oc1cc(C(F)(F)C(F)(F)F)ccc1C(=O)Nc1cc[nH]c(=O)c1
Temperature: 100 °C
Reaction time: 0.75 h

Procedure:
Cs2CO3 (69.8 mg, 0.21 mmol) was added to a solution of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(perfluoroethyl)benzamide (25 mg, 0.07 mmol) and 4-fluoro-2-methoxyphenol (24.4 μL, 0.2 mmol) in NMP (0.3 mL) and the reaction was stirred at 100° C. for 45 minutes. The reaction mixture was poured into water: ethyl acetate (9:1). The mixture was shaken, and the solid was filtered off, washed with ether, then triturated with ethyl acetate and dried to give the desired product. The mother liquors were filtered and washed with ethyl acetate to give a second crop of material. Both solids were combined and dried under vacuum to give 2-(4-fluoro-2-methoxy-phenoxy)-N-(2-oxo-1H-pyridin-4-yl)-4-(1,1,2,2,2-pentafluoroethyl)benzamide (111) (15.4 mg, 45%) as a white solid. ESI-MS m/z calc. 472.08. found 473.3 (M+1)+; Retention time: 1.62 minutes. 1H NMR (400 MHz, DMSO) δ 11.32 (s, 1H), 10.62 (s, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.39-7.27 (m, 2H), 7.17 (dd, J=10.7, 2.8 Hz, 1H), 6.88 (dd, J=11.3, 5.7 Hz, 1H), 6.81 (s, 1H), 6.75 (s, 1H), 6.43 (d, J=7.1 Hz, 1H), 3.73 (s, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[F:23].C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:43][C:44]1[O:48][N:47]=[C:46]([CH3:49])[CH:45]=1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:32]([NH:43][C:44]2[O:48][N:47]=[C:46]([CH3:49])[CH:45]=2)=[O:34])=[CH:18][C:17]=1[F:23]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: Cc1cc(N)on1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cc(C)no4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 119.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (800 mg) was dissolved in chloroform (20 ml) and triethylamine (1.0 ml) to prepare a solution. A solution of triphosgene (378 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 5-amino-3-methylisoxazole (294 mg) was added thereto, and the mixture was further stirred at room temperature overnight. Iced water was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine and was then dried over anhydrous sodium sulfate. The dried organic layer was filtered and was then concentrated. Ether was added to the residue for crystallization, and the crystal was collected by filtration. The collected crystal was purified by chromatography (chloroform:acetone=2:1). A 10% solution of hydrogen chloride in methanol was added to the purification product, followed by concentration. The resultant crystal was washed with ether to give 669 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Br:13][CH2:14][CH2:15][CH2:16]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1.CCCCCC>[Br:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: OCCCBr
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COC(=O)Cc1cccc(OCCCBr)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
A solution of methyl 3-hydroxyphenylacetate (11.3 g, 0.068 mole) in 300 mL of anhydrous toluene was treated with 3-bromopropanol (12.2 g, 0.088 mole). Polymer bound triphenylphosphine (36.0 g, 0.108 mole, 3 mmol/g, Fluka Chemie) was then added, and the mixture reacted for 15 minutes. The reaction mixture was then cooled to 0° C. and diisopropylazodicarboxylate (16.9 g, 0.084 mol) was added in a dropwise fashion. After stirring at RT overnight, the crude reaction mixture was filtered and the solid washed with 100 mL toluene. After concentration of the filtrate in vacuo, the crude product was purified by column chromatography over silica gel (silica gel 60, EM Science) using 15% ethyl acetate:hexane as eluent to afford 15.8 g (81% yield) of the title compound as an oil: 1H NMR (CDCl3, 400 MHz) δ 7.23-7.19 (m, 1 H), 6.85-6.7 (m, 3), 4.09-4.06 (t, 2 H, J=5.8), 3.67 (s, 3 H), 3.67-3.56 (m, 4 H), 2.32-2.26 (p, 2 H, J=6.0); MS (ESI) 288 (MH+); TLC (hexanes:ethyl acetate/3:1) Rf=0.68. Anal. (C12H15O3Br) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:14])[S:12][CH:13]=2)=[CH:5][CH:4]=1.[CH2:15]([C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)[CH2:16][CH3:17]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([NH:14][S:24]([C:21]3[CH:22]=[CH:23][C:18]([CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=3)(=[O:26])=[O:25])[S:12][CH:13]=2)=[CH:7][CH:8]=1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(-c2csc(N)n2)cc1
Product: CCCc1ccc(S(=O)(=O)Nc2nc(-c3ccc(OC)cc3)cs2)cc1

Procedure:
The title compound was prepared from 4(4-methoxy-phenyl)-thiazol-2-ylamine and 4-n-propylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (32.2 mg) with purity >90%. MS (pos) m/z 389.2.
Reaction SMILES: C([SiH](CC)CC)C.FC(F)(F)C(O)=O.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](O)([CH3:24])[CH3:23])=[C:18]([Cl:26])[CH:17]=1.O>ClCCl>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:23])[CH3:24])=[C:18]([Cl:26])[CH:17]=1
Reactant: CC(C)(O)c1ccc(Br)cc1Cl
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.9 %

Procedure:
Triethylsilane (1.8 mL) and trifluoroacetic acid (5.8 mL) were added to a solution of 2-(4-bromo-2-chlorophenyl)propan-2-ol (1.9 g) in dichloromethane (76 mL), and the mixture was stirred at room temperature for one day. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane only) to give the title compound as a colorless oil (1.74 g, 98%).