Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[C:11]([O:14][CH3:15])=[CH:10][N:9]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:18][C:17]=2[O:27][CH3:28])[N:8]=1)=O.Cl.[Cl:31][C:32]1[CH:33]=[C:34]([NH:38][NH2:39])[CH:35]=[CH:36][CH:37]=1.C(O)(C(F)(F)F)=O>C(O)C>[Cl:31][C:32]1[CH:33]=[C:34]([N:38]2[C:5]([C:7]3[C:12](=[O:13])[C:11]([O:14][CH3:15])=[CH:10][N:9]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH:26]=[CH:25][CH:24]=[N:23]5)=[CH:18][C:17]=4[O:27][CH3:28])[N:8]=3)=[CH:4][CH:3]=[N:39]2)[CH:35]=[CH:36][CH:37]=1
Reactant: NNc1cccc(Cl)c1
Reactant: COc1cc(-n2cccn2)ccc1-n1cc(OC)c(=O)c(C(=O)C=CN(C)C)n1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: COc1cc(-n2cccn2)ccc1-n1cc(OC)c(=O)c(-c2ccnn2-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.6 %

Procedure:
To a suspension of 3-[3-(dimethylamino)prop-2-enoyl]-5-methoxy-1-[2-methoxy-4-(1H-pyrazol-1-yl)phenyl]pyridazin-4(1H)-one (136 mg) in ethanol (1.5 mL) was added dropwise a solution of 3-chlorophenylhydrazine hydrochloride (67.7 mg) and TFA (0.15 mL) in ethanol (1.5 mL), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate), crystallized from ethyl acetate, and recrystallized from ethanol/water to give the title compound (68.0 mg).
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[N:5][CH:4]=1.[F:17][C:18]1[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[CH:21][C:19]=1[NH2:20]>CC(O)CCC>[F:17][C:18]1[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[CH:21][C:19]=1[NH:20][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[N:5][CH:4]=1
Reactant: COc1cc2nncc(Cl)c2cc1OC
Reactant: Cc1cc(F)c(N)cc1O
Agent: Cl
Solvent: CCCC(C)O
Product: COc1cc2nncc(Nc3cc(O)c(C)cc3F)c2cc1OC
Temperature: 120 °C

Procedure:
A solution of 4-chloro-6,7-dimethoxycinnoline hydrochloride (261 mg, 1 mmol), (prepared as described for the starting material in Example 1), and 2-fluoro-5-hydroxy-4-methylaniline (170 mg, 1.2 mmol), (prepared as described for the starting material in Example 11), in 2-pentanol (5 ml) was heated at 120° C. for 3 hours. After cooling, the solid was filtered off, washed with isopropanol and ether and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6,7-dimethoxycinnoline as an hydrochloride salt (301 mg, 82%).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:22]([O:26][C:27](=[O:32])[CH2:28][CH:29](Br)[CH3:30])([CH3:25])([CH3:24])[CH3:23].[I-].[Na+].C1CCN2C(=NCCC2)CC1>CC#N>[C:22]([O:26][C:27](=[O:32])[CH2:28][CH:29]([N:18]1[CH2:19][CH2:20][O:21][CH:16]([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:14]=2)[CH2:17]1)[CH3:30])([CH3:25])([CH3:24])[CH3:23]
Reactant: CCCCCCCCOc1ccc(C2CNCCO2)cc1
Reactant: CC(Br)CC(=O)OC(C)(C)C
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCCCCCOc1ccc(C2CN(C(C)CC(=O)OC(C)(C)C)CCO2)cc1
Temperature: 120 °C
Yield: 31.4 %

Procedure:
A mixture of 2-(4-octyloxy-phenyl)-morpholine (0.24 gram, 1.1 mmol), 3-bromobutyric acid tert-butyl ester (0.24 g; 1.1 mmol), sodium iodide (27.4 mg; 0.2 mmol), and DBU (0.4 mL; 2.7 mmol) in CH3CN (10 mL) was heated in a closed vessel at 120° C. After cooling to RT the reaction mixture was partitioned between 5% aqueous NaHCO3 solution and EtOAc. The layers were separated and the organic layer was dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (SiO2, Et2O) to afford 3-[2-(4-octyloxy-phenyl)-morpholin-4-yl]-butyric acid tert-butyl ester (0.15 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[S:5][CH2:4][CH2:3]1.[C:13](Cl)(=[O:15])[CH3:14].O.Cl>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CC1(C)CCSc2ccccc21
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCS2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 14.3 g (80.21 mmol) of 4,4-dimethylthiochroman (from Example 2) and 6.76 g (86.12 mmol) of acetyl chloride in 65 ml benzene was cooled in an ice bath and treated dropwise with 26.712 g (102.54 mmol) of stannic chloride. The mixture was stirred at room temperature for 12 hours, then treated with 65 ml water and 33 ml conc. hydrogen chloride and heated at reflux for 0.5 hours. After being cooled to room temperature, the organic layer was separated and the aqueous layer extracted with 5×50 ml benzene. The recovered organic fractions were combined and washed with 5% sodium carbonate, water, saturated NaCl and then dried (MgSO4). The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ethyl acetate in hexanes) followed by kugelrohr distillation (150° C., 0.7 mm) to give the title compound as a pale yellow oil. PMR (CDCl): δ 1.35 (6H, s), 1.92-1.98 (2H, m) 2.54 (3H, s), 3.02-3.08 (2H, m), 7.13 (1H, d, J~8.6 Hz), 7.58 (1H, dd, J~8.6 Hz, 2 Hz), 7.99 (1H, d, J~2 Hz).
Reaction SMILES: N#N.CS(O[CH2:8][CH:9]([OH:39])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]2[C:25]([F:26])=[CH:24][N:23]=[C:22]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:30][CH:29]=3)[N:21]=2)[CH:14]=1)=[O:11])(=O)=O.C1COCC1.[H-].[Na+]>C(OCC)(=O)C.O.CCCCCC.C(OCC)(=O)C>[F:26][C:25]1[C:20]([NH:19][C:15]2[CH:14]=[C:13]([NH:12][C:10]([CH:9]3[CH2:8][O:39]3)=[O:11])[CH:18]=[CH:17][CH:16]=2)=[N:21][C:22]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][O:37][CH3:38])=[CH:32][CH:33]=2)=[N:23][CH:24]=1
Reactant: COCCOc1ccc(Nc2ncc(F)c(Nc3cccc(NC(=O)C(O)COS(C)(=O)=O)c3)n2)cc1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCOc1ccc(Nc2ncc(F)c(Nc3cccc(NC(=O)C4CO4)c3)n2)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 44.7 %

Procedure:
Into a 25 mL 3-neck RBF equipped with N2-bubbler and thermo pocket was charged 3-((3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)amino)-2-hydroxy-3-oxopropyl methanesulfonate (0.03 g) and THF (2.0 mL). The reaction mixture was cooled to 0° C. and NaH (2.2 mg) was added. The reaction mixture was warmed to room temperature and stirred for 45 min. Completion of reaction was monitored on TLC using hexane:ethyl acetate (2:8) as mobile phase. After completion of reaction, the mixture was diluted with ethyl acetate (20 mL) and water was added. The organic layer was dried over sodium sulfate and solvent was removed under reduced pressure. Crude product purified by tituration with diethyl ether to give 0.011 g of N-(3-((5-fluoro-2-((4-(2-methoxyethoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)oxirane-2-carboxamide. 1H NMR: DMSO-d6 (400 MHz): 2.881 (d, 1H, J=4.4), 2.98 (t, 1H), 3.30 (s, 3H), 3.63 (m, 3H), 4.01 (t, 2H, J=4.0), 6.77 (d, 2H, J=9.2), 7.27 (t, 1H, J=8), 7.35 (d, 1H, J=8.4), 7.52 (d, 3H, J=8.8), 7.93 (s, 1H), 8.07 (d, 1H, J=3.2), 8.99 (s, 1H), 9.37 (d, 1H, J=18), 10.19 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([O:8][CH2:9][C@@H:10]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][C:12]([F:16])([F:15])[CH2:13]O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[N-:49]=[N+:50]=[N-:51].[Na+]>C(Cl)Cl>[N:49]([CH2:13][C:12]([F:16])([F:15])[CH2:11][C@H:10]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:9][O:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N+:50]=[N-:51]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](COC(=O)OC(C)(C)C)CC(F)(F)CO
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CN(C(=O)OC(C)(C)C)[C@H](COC(=O)OC(C)(C)C)CC(F)(F)CN=[N+]=[N-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a mixture of (S)-tert-butyl 1-(tert-butoxycarbonyloxy)-4,4-difluoro-5-hydroxypentan-2-yl(methyl)carbamate (35.3 g, 0.0956 mol) and lutidine (22.2 mL, 0.191 mol) in DCM (300 mL) was added trifluoromethanesulfonic anhydride (19.3 mL, 0.115 mol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h. LC-MS showed the reaction was complete. The reaction mixture was concentrated down. The resulting residue was dissolved in DMF (100 mL) and sodium azide (62.1 g, 0.956 mol) was added. The reaction mixture was stirred at RT overnight. The reaction solution was partitioned between EtOAc and saturated sodium bicarbonate solution. After separating layers, the aqueous layer was extracted further with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated, and the resulting residue was purified by silica gel column (hexanes/EtOAc) to give (S)-tert-butyl 5-azido-1-(tert-butoxycarbonyloxy)-4,4-difluoropentan-2-yl(methyl)carbamate (0.0956 mol, 100%). LRMS (M+Na+) m/z 417.4.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CN(C=O)C>[C:21]1([C:18]2[O:17][C:16]([C:4]3[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=[C:2]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[N:3]=3)=[N:20][N:19]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)nc1-c1nnc(-c2ccccc2)o1
Reactant: C1CNCCN1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ncc(N2CCNCC2)nc1-c1nnc(-c2ccccc2)o1
Temperature: 100 °C
Yield: 88.3 %

Procedure:
Tert-butyl 5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-ylcarbamate (2.56 g, 6.121 mmol) was dissolved in DMF (20 mL) and piperazine (5.272 g, 61.21 mmol) was added. The mixture was heated to 100° C. for 30 minutes, allowed to cool to ambient temperature and the solvent removed in vacuo. The mixture was partitioned between DCM/Water and the organic layer washed with brine, dried over MgSO4, filtered and concentrated to give a yellow oil. The resultant residue was purified on silica gel by flash column chromatography (0-10% MeOH/DCM) to afford the title compound (2.29 g, 89% Yield).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][OH:6].C([O-])([O-])=O.[K+].[K+].[CH2:13]([NH:16][CH3:17])[CH:14]=[CH2:15]>CC(C)=O>[CH2:13]([N:16]([CH3:17])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][OH:6])[CH:14]=[CH2:15]
Reactant: OC/C=C/CBr
Reactant: C=CCNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN(C)C/C=C/CO
Temperature: 25 °C
Reaction time: 40 h

Procedure:
3.58 g of (E)-4-bromo-2-buten-1-ol are dissolved in 100 ml of acetone and treated with 9.84 g of K2CO3 and 3.4 ml of N-allyl-methyl-amine. The suspension is stirred at RT for 40 h., filtered and the crude product obtained after concentration is purified on silica gel with methylene chloride:methanol (gradient 9:1-3:1). 1.52 g of (E)-4-(allyl-methyl-amino)-but-2-en-1-ol are obtained as a colourless liquid, MS: m/e 141 (M).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:10]([N:11]2[CH2:15][CH2:14][C@H:13]([NH2:16])[C:12]2=[O:17])[CH2:9][CH2:8][C@@H:7]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:6]1)(=[O:3])[CH3:2].Cl[C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[CH:35]=2)[N:30]=[CH:29][N:28]=1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[C:1]([NH:4][C@H:5]1[C@@H:10]([N:11]2[CH2:15][CH2:14][C@H:13]([NH:16][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[C:34]([C:37]([F:39])([F:40])[F:38])[CH:35]=4)[N:30]=[CH:29][N:28]=3)[C:12]2=[O:17])[CH2:9][CH2:8][C@@H:7]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reactant: FC(F)(F)c1ccc2ncnc(Cl)c2c1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N1CC[C@H](Nc2ncnc3ccc(C(F)(F)F)cc23)C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 106.8 %

Procedure:
To a solution of tert-butyl (1R,3R,4S)-3-acetamido-4-((S)-3-amino-2-oxopyrrolidin-1-yl)cyclohexylcarbamate (˜3.4 mmol) in isopropanol (10 mL) was added 4-chloro-6-(trifluoromethyl)quinazoline (0.97 g, 1.2 eq) and diisopropylethylamine (0.88 g, 2 eq). The mixture was stirred at room temperature for 2.5 h. The solvent was removed under reduced pressure. The residue was purified with silica gel column chromatography eluting with 1% and 5% MeOH in dichloromethane to provide tert-butyl (1R,3R,4S)-3-acetamido-4-((S)-2-oxo-3-(6-(trifluoromethyl)quinazolin-4-ylamino)pyrrolidin-1-yl)cyclohexylcarbamate (2.0 g, ˜100%). LC/MS found [M+H]+=551.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([F:19])[C:5]2[N:6]([CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:20][S:21]([C:24]1[C:32]2[C:27](=[CH:28][N:29]=[CH:30][CH:31]=2)[NH:26][N:25]=1)(=[O:23])=[O:22].CS(N1C2C(=CC=CC=2)C=N1)(=O)=O>>[Cl:1][C:2]1[CH:18]=[C:17]([F:19])[C:5]2[N:6]([CH2:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:7]([CH2:9][N:26]3[C:27]4=[CH:28][N:29]=[CH:30][CH:31]=[C:32]4[C:24]([S:21]([CH3:20])(=[O:22])=[O:23])=[N:25]3)=[N:8][C:4]=2[CH:3]=1
Reactant: Fc1cc(Cl)cc2nc(CCl)n(CCC(F)(F)F)c12
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Agent: CS(=O)(=O)n1ncc2ccccc21
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)cc(F)c3n2CCC(F)(F)F)c2cnccc12

Procedure:
Example 5-1 was prepared in analogy to Example 4-1 by using 5-chloro-2-(chloromethyl)-7-fluoro-1-(3,3,3-trifluoropropyl)-1H-benzo[d]imidazole and 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine instead of 5-chloro-2-chloromethyl-1-(4,4,4-trifluoro-butyl)-1H-benzoimidazole and methanesulfonyl-1H-indazole.
Reaction SMILES: [Li]CCCC.Br[C:7]1[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=1.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([C:27]3[C:28]([CH3:34])=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)=[O:26])[CH:23]=2)[N:18]=[C:17]([O:35][CH3:36])[C:16]=1[CH2:37][C:38]1[CH:39]=[N:40][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:43]=1>C1COCC1>[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([C:7]3[N:11]([CH3:12])[C:10]([CH3:13])=[N:9][CH:8]=3)([C:27]3[C:28]([CH3:34])=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)[OH:26])[CH:23]=2)[N:18]=[C:17]([O:35][CH3:36])[C:16]=1[CH2:37][C:38]1[CH:39]=[N:40][C:41]([C:44]([F:46])([F:45])[F:47])=[CH:42][CH:43]=1
Reactant: Cc1ncc(Br)n1C
Reactant: COc1nc2ccc(C(=O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C)nc3C)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 1.2 mL, 3.0 mmol) was added dropwise by syringe to a solution of 5-bromo-1,2-dimethyl-1H-imidazole (570.8 mg, 3.261 mmol) in dry THF (6 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of (4-chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinolin-6-yl)(2,6-dimethylpyridin-3-yl)methanone (0.790 g, 1.626 mmol, Intermediate 47: step b) in dry THF (2 mL) was added dropwise. The reaction was stirred for 5 minutes, then was moved into an ice bath and allowed to warm to ambient temperature. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was partitioned between water and dichloromethane. The separated aqueous phase was further extracted with dichloromethane. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-5% MeOH-DCM) followed by reverse-phase HPLC (acetonitrile/H2O+0.05% TFA). The product fractions were basified with saturated aqueous sodium bicarbonate and extracted with DCM, before being dried (Na2SO4), filtered, and concentrated to dryness to provide the title compound. 1H NMR (400 MHz, CDCl3) δ 8.76 (d, J=2.0 Hz, 1H), 8.13 (d, J=2.2 Hz, 1H), 7.79-7.73 (m, 2H), 7.57 (dd, J=8.1, 0.9 Hz, 1H), 7.41 (dd, J=8.7, 2.2 Hz, 1H), 7.11 (d, J=8.0 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 6.04 (s, 1H), 4.35 (s, 2H), 4.08 (s, 3H), 3.39 (s, 3H), 2.53 (s, 3H), 2.41 (s, 3H), 2.37 (s, 3H); MS m/e 582.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][C:13]=1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N.[CH2:30]([NH2:33])[CH2:31][CH3:32]>>[CH2:1]([O:8][C:9]1[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:33][CH2:30][CH2:31][CH3:32])(=[O:20])=[O:19])=[CH:14][C:13]=1[F:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1ccc(Oc2ccc(S(=O)(=O)Cl)cc2F)c(OCc2ccccc2)c1
Reactant: CCCN
Agent: N
Product: CCCNS(=O)(=O)c1ccc(Oc2ccc(CC)cc2OCc2ccccc2)c(F)c1
Yield: 41 %

Procedure:
According to the procedure of example 65(b) except substituting 4-(4-ethyl-2-methoxyphenoxy)-3-fluorobenzene sulfonyl chloride for 4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluorobenzene sulfonyl chloride and NH3 for propylamine (1.7 mmol; 0.14 mL), the title compound (140 mg; 0.32 mmol; 41%) was obtained as a brown oil after purification on preparative TLC (dichloromethane).
Reaction SMILES: C1(C[O:5][C:6](=[O:33])[CH:7]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)[C:15]([C:23]3[CH:24]=[CH:25][C:26]4[C:27]([CH:31]=3)=[N:28][S:29][N:30]=4)=[C:14]([Cl:32])[CH:13]=2)[CH2:8][CH:9]([CH3:11])[CH3:10])CC1.[OH-].[K+]>CCO.O>[N:30]1[S:29][N:28]=[C:27]2[CH:31]=[C:23]([C:15]3[C:16]([O:18][CH2:19][CH:20]4[CH2:22][CH2:21]4)=[CH:17][C:12]([CH:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:6]([OH:33])=[O:5])=[CH:13][C:14]=3[Cl:32])[CH:24]=[CH:25][C:26]=12
Reactant: CC(C)CC(C(=O)OCC1CC1)c1cc(Cl)c(-c2ccc3nsnc3c2)c(OCC2CC2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)CC(C(=O)O)c1cc(Cl)c(-c2ccc3nsnc3c2)c(OCC2CC2)c1
Yield: 46.4 %

Procedure:
2-(4-Benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester (0.08 g, 0.19 mmol) was dissolved in a mixture of EtOH and H2O (9 mL /1 mL) and KOH (0.1 g, 1.76 mmol) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5, and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4 and evaporated under reduced pressure to give 2-(4-benzo[1,2,5]thiadiazol-5-yl-3-chloro-5-cyclopropylmethoxy-phenyl)-4-methyl-pentanoic acid as a yellow oil (0.038 g, 55%). 1H NMR (300 MHz, CDCl3/TMS): δ 8.02 (d, J=9.0 Hz, 1H), 7.96 (s, 1H), 7.53 (d, J=9.0 Hz, 1H), 7.13 (s, 1H), 6.89 (s, 1H), 3.81 (d, J=6.4 Hz, 2H), 3.68 (t, J=7.6 Hz, 1H), 2.04-1.96 (m, 1H), 1.78-1.69 (m, 1H), 1.63-1.55 (m, 1H), 1.10-1.00 (m, 1H), 0.97 (d, J=6.4 Hz, 6H), 0.50-0.39 (m, 2H), 0.22-0.12 (m, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 179.1, 157.2, 154.6, 154.0, 140.5, 136.7, 134.0, 132.9, 127.8, 122.9, 121.6, 120.1, 111.0, 73.4, 49.4, 42.0, 25.9, 22.6, 22.3, 10.0, 3.1.
Reaction SMILES: [C:1]1([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[SiH](OCC)OCC)C>C1C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:1]1([CH:7]=[CH:8][N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)N1CCOCC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CCO[SiH](OCC)OCC
Solvent: c1ccccc1
Product: C(=CN1CCOCC1)c1ccccc1
Temperature: 60 °C
Yield: 63.4 %

Procedure:
4-(2-phenylacetyl) morpholine (0.410 g, 2.0 mmol) was dissolved in C6H6 (5 mL) under a nitrogen atmosphere and then triethoxysilane (0.92 mL, 5.0 mmol) and titanium (IV) isopropoxide (0.03 mL, 0.1 mmol) were added. The reaction mixture was heated to 60° C. for 15 hours. The C6H6 was removed in vacuo and the resulting cream colored solid was dissolved in warm (60° C.) hexane (3 mL). The hexane solution was cooled to room temperature, and cream colored crystals appeared in the flask. The recrystallization flask was put in an acetone-filled dewar, which was cooled to -78° C. overnight. The hexane solution was decanted from the cream colored crystals which were dried in vacuo, and 0.38 g of product was collected, although 1H NMR showed the presence of a silicon byproduct. The material was dissolved in 3 mL of warm hexane (60 ° C.) and slowly cooled to room temperature. The hexane was decanted and the product was dried in vacuo to produce 0.24 g (63% yield) of 4-(2-phenylethenyl) morpholine as a cream colored solid.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.CO.O.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]=[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=4)=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)cc2)cc1
Temperature: 50 °C

Procedure:
Methyl 4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]biphenyl-4-carboxylate (94 mg, 0.25 mmol) was suspended in THF (3 mL), MeOH (3 mL), and water (1.5 mL), and NaOH (0.10 g, 2.5 mmol) was added. The reaction mixture was heated at 50° C. for 3 h. Upon cooling to rt, the reaction mixture was concentrated in vacuo, acidified with 2N HCl, and the resulting solid was collected by filtration. This yielded 90 mg (99%) of the title compound. LC/MS m/z 365.2 (MH+), retention time 3.46 min. 1H NMR (400 MHz, DMSO-d6) δ 7.08 (t, 1H), 7.49-7.80 (m, 6H), 7.82-8.01 (m, 4H), 10.75 (br, 1H).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=1)[CH:10]=[CH:9]2)=[C:2]=[O:3].[NH2:25][C:26]1[S:27][CH:28]=[CH:29][N:30]=1>C1(C)C=CC=CC=1>[S:27]1[CH:28]=[CH:29][N:30]=[C:26]1[NH:25][C:2]([NH:1][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:22])[F:23])[CH:15]=1)[CH:10]=[CH:9]2)=[O:3]
Reactant: Nc1nccs1
Reactant: O=C=Nc1cccc2ccc(-c3cccc(OC(F)(F)F)c3)nc12
Solvent: Cc1ccccc1
Product: O=C(Nc1nccs1)Nc1cccc2ccc(-c3cccc(OC(F)(F)F)c3)nc12
Temperature: 140 °C

Procedure:
To a mixture of 8-isocyanato-2-(3-(trifluoromethoxy)phenyl)quinoline (0.277 mmol) in toluene (5 mL) was added 2-aminothiazole (0.553 mmol, 55 mg). The mixture was concentrated to dryness, redissolved in pyridine and microwave heated (140° C.×10 min). The reaction mixture was diluted with CH2Cl2, washed with saturate aqueous NaHCO3, water, brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography (0% to 100% ethyl acetate in pentane) afforded the desired product. MS (ESI) calcd for C20H13F3N4O2S (m/z): 430.07. found: 431 [M+1].
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14](=[O:16])[CH3:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][C:21]=1[CH3:28]>>[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH:15][C:14]([C:12]2[S:13][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:17])([F:1])[F:18])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[O:16])=[CH:22][C:21]=1[CH3:28]
Reactant: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)s1
Reactant: Cc1cc(C=O)ccc1O
Product: Cc1cc(C=CC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)ccc1O

Procedure:
3-(4-Hydroxy-3-methylphenyl)-1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)prop-2-en-1-one is prepared from 1-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)ethanone and 4-hydroxy-3-methylbenzaldehyde according to general procedure B. The evaporation residue is washed with dichloromethane.