Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([O:8][C@@H:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])=[CH:4][CH:3]=1.[CH3:15][S-:16].[Na+].CN(C=O)C.O>CC(=O)OCC>[CH3:15][S:16][C:2]1[N:7]=[CH:6][C:5]([O:8][C@@H:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])=[CH:4][CH:3]=1
Reactant: O=C1NCC[C@H]1Oc1ccc(Br)nc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1ccc(O[C@@H]2CCNC2=O)cn1
Temperature: 100 °C

Procedure:
A mixture of (R)-3-(6-bromo-pyridin-3-yloxy)-pyrrolidin-2-one (0.8 g), sodium methanethiolate (327 mg) and DMF (15 mL) was heated to 100° C. for 15 minutes. After the mixture reached room temperature, it was distributed between water and EA. The organic phase was dried (Na2SO4) and concentrated. The residue was purified by preparative HPLC to provide the title compound. MS ESI+: m/z=225 [M+H]+.
Reaction SMILES: B.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[Br:23][CH2:24][C:25]([C:27]1[N:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[S:30][CH:31]=1)=[O:26]>O1CCCC1>[Br:23][CH2:24][C@H:25]([C:27]1[N:28]=[C:29]([C:32]([F:35])([F:34])[F:33])[S:30][CH:31]=1)[OH:26]
Reactant: O=C(CBr)c1csc(C(F)(F)F)n1
Agent: B
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: C1CCOC1
Product: O[C@H](CBr)c1csc(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 66.2 %

Procedure:
Borane (in THF, 1M, 10.35 mL, 10.5 mmol) was added dropwise into a mixture of (R)-2-methyl-CBS-oxazaborolidine monohydrate (0.38 g, 1.31) mmol and tetrahydrofuran (15 mL) under a nitrogen atmosphare at ambient temperature. The mixture was stirred for 10 minutes and then 2-bromo-1-[2-(trifluoromethyl)-1,3-thiazole-4-yl]ethanone (which was obtained in Example 102) (3.6 g, 13.13 mmol) in tetrahydrofuran (20 mL) was added dropwise over 10 minutes. The new mixture was stirred at room temperature for 4 hours. The reaction mixture was cooled to 0° C. and quenched with a hydrogen chloride/ethyl ether solution (1M, 1.0 mL). After stirring at 0° C. for 30 minutes, H2O (20 mL) was added dropwise and the mixture was extracted with ethyl ether. The organic layer was washed with aqueous ammonium chloride and dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/dichloromethane/ethanol 1/1/0.01) gave a clear oil (2.4 g, 66% yield); MS (ES) m/z: 334/336 (M+acetic acid−H)−; 1H NMR (400 MHz, CDCl3) δ 2.94 (m, 1H), 3.74 (m, 1H), 3.94 (m, 1H), 5.16 (m, 1H), 7.62 (s, 1H).
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[CH:5]([O:7][CH2:8][CH3:9])=[CH2:6].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>>[CH2:5]([O:7][CH:8]([O:4][CH2:1][CH:2]=[CH2:3])[CH3:9])[CH3:6]
Reactant: C=CCO
Reactant: C=COCC
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Product: C=CCOC(C)OCC
Reaction time: 3 h

Procedure:
Allyl alcohol (46.8 ml. 40 g., 0.69 mol) and ethyl vinyl ether (98.8 ml., 74.5 g., 1.033 mols) were stirred together at -12°. dl-Camphorsulfonic acid (150 mg.) was added acid and stirring continued for 3 hours at that temperature. The mixture was then washed 1×100 ml. saturated NaHCO3, 1×100 ml. brine, dried and stripped to yield title product as an oil (100 ml., essentially quantitative yield). 1H-nmr 1.14 (t, 3H), 1.29 (d, 3H), 3.56 (dp, 2H), 4.06 (m, 2H), 4.75 (q, 1H), 5.26 (m, 2H), 5.99 (m, 1H).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1>>[C:9]1([C:3]2[N:4]=[C:5]([NH2:8])[N:6]=[N:7][C:2]=2[O:24][C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([O:17][C:16]([F:15])([F:25])[F:26])[CH:19]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1nnc(Oc2cccc(OC(F)(F)F)c2)c(-c2ccccc2)n1
Yield: 3.2 %

Procedure:
5-Phenyl-6-[3-(trifluoromethoxy)phenoxy]-1,2,4-triazin-3-amine (22 mg, 3%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.50 g, 1.99 mmol) and 3-(trifluoromethoxy)phenol (0.42 g, 2.39 mmol) according to the general procedure of Example 3.
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[CH:16]=[C:9]2[N:10]=[CH:11][C:12]([Br:15])=[C:13]([CH3:14])[C:8]2=[N:7]1)[C:3]#[N:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[S:25])=[CH:22][CH:21]=1>>[Br:15][C:12]1[CH:11]=[N:10][C:9]2=[CH:16][N:6]([CH2:5][C:2]([NH:1][C:24](=[S:25])[C:23]3[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:28][CH:27]=3)([C:3]#[N:4])[CH3:17])[N:7]=[C:8]2[C:13]=1[CH3:14]
Reactant: Cc1c(Br)cnc2cn(CC(C)(N)C#N)nc12
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: Cc1c(Br)cnc2cn(CC(C)(C#N)NC(=S)c3ccc(C(F)(F)F)cc3)nc12

Procedure:
Using a procedure adapted from that described in Example 1, using 2-amino-3-(6-bromo-7-methyl-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (56.7 mg, described in Example 150) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (26 mg, 27%). MS (ES): M/Z [M+H]=498. 1H NMR: (400 MHz, CHLOROFORM-d): 1.97 (s, 3H), 2.67 (s, 3H), 4.82 (d, 1H), 4.97 (d, 1H), 7.77 (d, J=8.2 Hz, 2H), 7.92 (d, J=8.3 Hz, 2H), 8.38 (s, 1H), 8.54 (s, 1H) and 8.61 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.3 (s, 3F).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)[C:9]([CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([N:32]3[CH2:36][CH2:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]1)=[C:8]2[C:37](O)=[O:38])(=[O:4])=[O:3].[F:40][C:41]([F:51])([F:50])[C@H:42]([NH2:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)C(C)C)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCCP(=O)=O>C(OCC)(=O)C.ClCCl.O>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=1)[C:9]([CH2:25][N:26]1[CH2:31][CH2:30][CH:29]([N:32]3[CH2:33][CH2:34][CH2:35][CH2:36]3)[CH2:28][CH2:27]1)=[C:8]2[C:37]([NH:49][C@H:42]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:41]([F:50])([F:51])[F:40])=[O:38])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCCC4)CC3)c(C(=O)O)c2c1
Reactant: N[C@H](c1ccccc1)C(F)(F)F
Agent: CCCP(=O)=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc2nc(-c3cccc(C(F)(F)F)c3)c(CN3CCC(N4CCCC4)CC3)c(C(=O)N[C@H](c3ccccc3)C(F)(F)F)c2c1
Reaction time: 2 h
Yield: 29.9 %

Procedure:
A suspension of 6-(methylsulfonyl)-3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.125 g, 0.223 mmol), [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.061 g, 0.289 mmol), N,N-diisopropylethylamine (0.117 mL, 0.668 mmol), and T3P (propylphosphonic anhydride, 0.170 mL of a 50% w/v solution in ethyl acetate, 0.289 mmol) in dichloromethane (3.42 mL) was stirred at room temperature for 20 h. Additional portions of [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.031 g, 0.145 mmol) and T3P (propylphosphonic anhydride, 0.085 mL of a 50% w/v solution in ethyl acetate, 0.145 mmol) were added, and the mixture stirred for 2 h. Water (2 mL) was added, and the mixture was poured through a hydrophobic frit. The isolated organic phase was absorbed onto florisil and purified via column chromatography (ISCO, 4 g silica, 1-6% methanol/methylene chloride) to afford 6-(methylsulfonyl)-3-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.048 g, 28% yield). MS (m/z) 719.2 (M+H+).
Reaction SMILES: [F:1][C:2]1([F:13])[CH2:7][CH2:6][CH:5]([C:8]([O:10]CC)=[O:9])[CH2:4][CH2:3]1.O.O.[OH-].[Li+].Cl>C1COCC1.CCOC(C)=O>[F:1][C:2]1([F:13])[CH2:3][CH2:4][CH:5]([C:8]([OH:10])=[O:9])[CH2:6][CH2:7]1
Reactant: CCOC(=O)C1CCC(F)(F)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)C1CCC(F)(F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A solution of ethyl 4,4-difluorocyclohexanecarboxylate (0.385 g, 2.003 mmol) in THF (12 mL) was treated with H2O (6 mL) followed by lithium hydroxide monohydrate (0.420 g, 10.02 mmol) and the mixture stirred vigorously at RT overnight. The mixture was treated with EtOAc, acidified with 1M HCl until pH 4, the layers separated and the aqueous layer extracted with additional EtOAc (1×). The combined organics were washed with brine, dried over MgSO4 and concentrated to dryness to afford 4,4-difluorocyclohexanecarboxylic acid (318 mg, 97%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.28 (s, 1H), 2.40 (m, 1H), 2.02-1.75 (m, 6H), 1.59 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26]([OH:28])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl.[N:34]1[CH:39]=[CH:38][C:37]([C:40]2([NH2:43])[CH2:42][CH2:41]2)=[CH:36][N:35]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:28])[NH:43][C:40]5([C:37]6[CH:38]=[CH:39][N:34]=[N:35][CH:36]=6)[CH2:42][CH2:41]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: NC1(c2ccnnc2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccnnc5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.080 g, 0.184 mmol, 1.0 eq), 1-(pyridazin-4-yl)cyclopropanamine HCl (0.025 g, 0.185 mmol, 1.0 eq) in DMF at 0° C. was added TEA (0.093 g, 0.920 mmol, 5.0 eq) and BOP reagent (0.120 g, 0.271 mmol, 1.5 eq). The reaction mixture was to stirred at RT overnight. The reaction mixture was diluted with water, extracted with EtOAc. The organic layer was washed with brine and dried over Na2SO4, filtered and concentrated. The crude product was purified by silica gel (60-120) column chromatography using 4% MeOH/CHCl3 as eluent and further purified by prep HPLC. Yield: 0.053 g (52.42%). 1H NMR (400 MHz, CD3OD): δ 9.21-9.16 (m, 2H), 8.01-7.94 (m, 2H), 7.81 (br. s., 1H), 7.77 (s, 1H), 7.66 (s, 1H), 7.60 (s, 1H), 7.34 (dd, J=1.8, 8.5 Hz, 1H), 7.32-7.25 (m, 2H), 7.17 (s, 1H), 4.10 (s, 3H), 2.96 (s, 3H), 2.38 (s, 3H), 1.75 (s, 4H). 19F NMR (376.51 MHz, CD3OD): δ−77.43 (TFA), −112.62. LCMS: (ES+) m/z=551.2 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[C:13]([Cl:20])[C:14]4[N:15]([CH:17]=[CH:18][N:19]=4)[CH:16]=[C:11]3[NH:10]C2=O)=[C:4]([Cl:22])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:33]1([S:36](N)(=[O:38])=[O:37])[CH2:35][CH2:34]1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:12]2[C:11]([NH:10][S:36]([CH:33]3[CH2:35][CH2:34]3)(=[O:38])=[O:37])=[CH:16][N:15]3[CH:17]=[CH:18][N:19]=[C:14]3[C:13]=2[Cl:20])=[C:4]([Cl:22])[CH:3]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: O=c1[nH]c2cn3ccnc3c(Cl)c2n1-c1ccc(Br)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1Cl)C1CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of the crude product (Step J) in 3 ml anhydrous THF was added LHMDS (0.4 ml, 0.4 mmol, 1M/THF) at 0° C. and the mixture was stirred for 5 min. The cyclopropyl sulfonamide (83 mg, 0.59 mol) was added neat and the mixture was warmed to room temperature and stirred for 15 h. The mixture was quenched with brine, diluted with H2O and extracted using a mixture of EtOAc/THF (3:1). The organic phase was washed with brine and dried with Na2SO4. Subsequent column chromatography (100% EtOAc) gave the title product as a brown oil (36 mg, 20% over the 2 last steps). Rf (100% EtOAc)=0.35. 1H-NMR (500 MHz, MeOH-D3): δ=8.80 (s, 1H), 7.89 (s, 1H), 7.86-7.85 (d, 1H), 7.68-7.66 (dd, 1H), 7.60-7.58 (d, 1H), 7.46 (s, 1H), 1.51-1.37 (m, 2H), 1.23-1.15 (m, 2H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH:21](OCC)=[O:22]>CCOCC>[CH:21]([NH:2][CH2:3][CH:4]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:22]
Reactant: CCOC=O
Reactant: CCOC(=O)CCCC(CN)c1cccc(OC)c1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)CCCC(CNC=O)c1cccc(OC)c1

Procedure:
The amine obtained in Step B, in the form of a base (6.4 g; 27 mmol), is dissolved in 60 ml of ethyl formate. The reaction mixture is heated at reflux for 6 hours with stirring and then evaporated under reduced pressure. The residue obtained is taken up in ether. The organic phase is then washed in succession with acidic water (1N HCl), water, and a 10% hydrogen carbonate solution, subsequently dried over magnesium sulphate, filtered and evaporated under reduced pressure to yield the title product in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([OH:31])[CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]5[CH:26]=[CH:27][CH:28]=[C:19]([C:20]=45)[S:18]3(=[O:30])=[O:29])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:34]I>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([O:31][CH3:34])[CH2:16][N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[C:25]5[CH:26]=[CH:27][CH:28]=[C:19]([C:20]=45)[S:18]3(=[O:29])=[O:30])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CC(O)CN1CCN(c2ccc(F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CN1CCN(c2ccc(F)cc2)CC1)CN1c2cccc3cccc(c23)S1(=O)=O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A solution of 2-{3-[4-(4-fluorophenyl)-1-piperaziny]-2-hydroxypropyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (4.41 g) in dimethylformamide (50 cc) is poured over 30 minutes into a mixture of sodium hydride (0.53 g) in a 50% dispersion in vaseline oil, and dimethylformamide (10 cc), under a current of argon, maintaining the temperature between 20° and 30° C. The reaction medium is stirred for 1 hour at temperature of about 20° C. and then methyl iodide (0.7 cc) is added over 10 minutes. Stirring is maintained for 15 hours at a temperature of about 20° C. The mixture is redissolved in distilled water (200 cc) and the organic phase is extracted with dichloromethane (4×100 cc), dried over anhydrous magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue is purified by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallized from boiling acetonitrile (10 cc). 2-{3-[4-(4-Fluorophenyl)-1-piperazinyl]-2-methoxypropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.1 g) is obtained, m.p. 128° C.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([C@H:23]5[C@H:27]([F:28])[CH2:26][NH:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.[CH:36](=O)[CH3:37]>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([C@H:23]5[C@H:27]([F:28])[CH2:26][N:25]([CH2:36][CH3:37])[CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:34])([F:35])[F:33])[CH:3]=1
Reactant: CC=O
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1[C@@H]1CNC[C@H]1F
Product: CCN1C[C@@H](F)[C@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)C1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(trans)-1-ethyl-4-fluoropyrrolidin-3-yl]-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(trans)-4-fluoropyrrolidin-3-yl]-1,3-thiazolidine-2,4-dione (Example 317) and acetaldehyde (in place of formaldehyde) following General Procedure R2.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:35][CH2:36][CH3:37])=[C:29]([O:32][CH2:33][CH3:34])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(O)(C)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:35][CH2:36][CH3:37])=[C:29]([O:32][CH2:33][CH3:34])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Reactant: CCOc1cc2ncnc(Cl)c2cc1OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Product: CCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCC
Temperature: 90 °C

Procedure:
A mixture of 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A (0.137 g, 0.5 mmol), 4-chloro-6,7-diethoxyquinazoline from the previous step (0.126 g, 0.5 mmol), and Cs2CO3 (0.326 g, 1 mmol) in isopropanol (6 mL) was heated at 90° C. for 4 hours. The reaction was quenched with water and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography with EtOAc/hexane as eluant to afford 1-(5-tert-butylisoxazol-3-yl)-3-[3-(6,7-diethoxyquinazolin-4-yloxy)phenyl]urea as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.03 (s, 1H), 8.56 (s, 1H), 7.57 (m, 1H), 7.55 (s, 1H), 7.40 (t, 1H), 7.37 (s, 1H), 7.25 (d, 1H), 6.96 (dd, 1H), 6.47 (s, 1H), 4.26 (m 4H), 1.43 (m, 6H), 1.27 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][N:9]2[C@@H:17]3[C@@H:12]([C:13]4[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:14]=4[CH2:15][CH2:16]3)[CH2:11][CH2:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:30]([N:34]=[C:35]=[O:36])[CH2:31][CH2:32][CH3:33].C(=O)([O-])O.[Na+].[ClH:42]>C(#N)C.CO>[ClH:42].[CH2:30]([NH:34][C:35](=[O:36])[O:22][C:18]1[C:14]2[CH2:15][CH2:16][C@H:17]3[C@H:12]([CH2:11][CH2:10][N:9]3[CH2:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:13]=2[CH:21]=[CH:20][CH:19]=1)[CH2:31][CH2:32][CH3:33]
Reactant: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCC1CCCCC1
Reactant: CCCCN=C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCNC(=O)Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCC1CCCCC1
Yield: 38 %

Procedure:
A suspension of 2.00 g (0.0067 mol) of rac-cis-3-(2-cyclohexylethyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-ol in 100 ml of acetonitrile was treated with 1.9 ml (0.013 mol) of triethylamine and 3.0 ml (0.027 mol) of butyl isocyanate. The mixture was boiled under reflux for 20 hours and then poured into aqueous sodium hydrogen carbonate solution, whereupon the mixture was extracted with methylene chloride. After drying the organic phase with sodium sulphate and distillation of the solvent the residue was chromatographed over silica gel with methylene chloride/methanol 20:1. The oil obtained was dissolved in methanol and treated with an equimolar amount of ethanolic HCl. After drying with sodium sulphate, concentration to a volume of about 30 ml and filtration there were obtained 1.11 g (38%) of rac-cis-3-(2-cyclohexylethyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-yl butylcarbamate hydrochloride with m.p. 192°-194°.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][CH:17]=[C:18]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[N:19]=2)=[CH:11][C:10]=1[F:27])C1C=CC=CC=1>C(O)C>[F:27][C:10]1[CH:11]=[C:12]([C:15]2[O:16][CH:17]=[C:18]([CH2:20][N:21]3[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]3)[N:19]=2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: Fc1cc(-c2nc(CN3CCCCC3)co2)ccc1OCc1ccccc1
Solvent: CCO
Product: Oc1ccc(-c2nc(CN3CCCCC3)co2)cc1F

Procedure:
2-fluoro-4-(4-piperidin-1-ylmethyl-oxazol-2-yl)-phenol i68 is synthesized according to the following method: a solution of 1-({2-[4-(benzyloxy)-3-fluorophenyl]-1,3-oxazol-4-yl}methyl)piperidine i63 (0.34 g, 0.94 mmol, 1 eq) in ethanol is placed under hydrogen atmosphere (20 psi) at 30° C. for 6 hours. The mixture is filtered over cellite and concentrated under vacuo to give 0.22 g of 2-fluoro-4-(4-piperidin-1-ylmethyl-oxazol-2-yl)-phenol i68 as a brown solid. This crude product is used in the next step without any purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=[O:6].[CH3:19]COCC.C[Mg]Br>O>[CH3:14][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]([C:4]1[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=1[O:2][CH3:1])([OH:6])[CH3:19]
Reactant: CCOCC
Reactant: COc1ccccc1C(=O)c1ccccc1OC
Agent: C[Mg]Br
Solvent: O
Product: COc1ccccc1C(C)(O)c1ccccc1OC
Temperature: 25 °C

Procedure:
2,2'-Dimethoxybenzophenone (24.2 g, 0.14 mole) and 400 ml of ether were placed in a 1 l flask and stirred at ambient temperature and methyl magnesium bromide (40 ml of 3.0M solution in ether) was added dropwise. The resulting mixture was stirred overnight and then a few ml of water were added to quench the Grignard reagent. About 300 ml of ethyl acetate and 250 ml of 10 percent hydrochloric acid were then added and the mixture was shaken. The organic layer was next recovered, extracted with 100 ml of water and 100 ml of saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 25.6 g (98 percent of theory) of the title compound as a white solid melting at 122°-123° C. The proton NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH3:11].[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[F:12])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH3:11]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CCOc1cccc(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOc1ccc(C(=O)c2ccccc2F)c(Cl)c1Cl
Temperature: 25 °C
Yield: 58.5 %

Procedure:
A mixture of 2,3-dichlorophenetole (57.3 g., 0.3 mole), 2-fluorobenzoyl chloride (47.8 g., 0.3 mole) and methylene chloride (300 ml.) at 5° C. was stirred vigorously and treated with finely powdered aluminum chloride (42.6 g., 0.32 ml.). The reaction mixture was slowly warmed to room temperature and then stirred overnight. The reaction mixture was decomposed with ice/concentrated hydrochloric acid (50 ml.) and the aqueous solution was extracted twice with methylene chloride. The combined organic extracts were washed with aqueous sodium bicarbonate solution and finally with aqueous sodium chloride solution. The methylene chloride solution was dried over MgSO4 and filtered. The solvent was removed in vacuo and the residue on triturating with methanol gave the product 55 g., m.p. 94°-95° C. This material was used in the next step without additional purification.