Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[O:12]=[C:13]1[C:18]2=[CH:19][NH:20][C:21]([CH:22]=O)=[C:17]2[CH2:16][CH2:15][O:14]1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[CH:22][C:21]3[NH:20][CH:19]=[C:18]4[C:13](=[O:12])[O:14][CH2:15][CH2:16][C:17]=34)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(F)cc2N1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Product: O=C1Nc2cc(F)ccc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
6-Fluoro-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7-tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: [CH2:1]1[O:21][C:20]2[C:3](=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:19]=2)[CH2:7][CH:8]([C:14]([O:16]CC)=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:2]1.[OH-].[K+]>C(O)C.O>[CH2:1]1[O:21][C:20]2[C:3](=[CH:4][C:5]([O:22][CH3:23])=[C:6]([CH:19]=2)[CH2:7][CH:8]([C:14]([OH:16])=[O:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:2]1
Reactant: CCOC(=O)C(Cc1cc2c(cc1OC)OCO2)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(Cc1cc2c(cc1OC)OCO2)C(=O)O
Yield: 88.5 %

Procedure:
To a solution of the diethyl 2-(4,5-methylenedioxy-2-methoxybenzyl)-malonate (20.00 g, 0.066 mol) of in ethanol (50 mL) was added a solution of potassium hydroxide (3.50 g, 0.066 mol) in water (25 mL). The solution stirred at reflux for 6 h. After cooling the aqueous layer was washed with ether and acidified with concentrated HCl to pH 1 and extracted with ethyl acetate. The organic extracts were dried (Na2SO4) and concentrated to afford the title compound as a yellow solid (17.30 g, 89%): 1H NMR (400 MHz, CDCl3) δ 10.20 (b, 1H), 6.68 (s, 1H), 6.50 (s, 1H), 5.90 (s, 2H), 4.15 (q, 2H), 3.72 (s, 3H), 3.10 (dd, 2H), 1.20 (t, 3H); MS(ESI) m/e 297.0 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>ClCCl>[Si:1]([O:8][CH2:9][CH:10]1[O:15][CH2:14][CH2:13][NH:12][CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCOC(CO[Si](C)(C)C(C)(C)C)C1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OCC1CNCCO1
Temperature: 0 °C
Yield: 79.7 %

Procedure:
To a round bottom flask charged with (+/−)-tert-butyl 2-(((tert-butyldimethylsilyl)oxy)methyl)morpholine-4-carboxylate (3.04 g, 9.17 mmol) in dichloromethane (45.8 ml) and cooled to 0° C. was added 2,6-lutidine (2.136 ml, 18.34 mmol). Trimethylsilyl trifluoromethanesulfonate (3.31 ml, 18.34 mmol) was added drop wise over 5 min. The reaction was slowly warmed to room temperature over 4 h. The reaction mixture was quenched by the addition of saturated aqueous sodium bicarbonate and dichloromethane. The mixture was transferred to a separatory funnel and the aqueous layer was extracted with dichloromethane (3×). The combined organics were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by column chromatography on the ISCO system (0-10% MeOH/CH2Cl2). (+/−)-2-(((tert-Butyldimethylsilyl)oxy)methyl)morpholine (1.692 g) was isolated as a clear oil.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1CCN2C(=NCCC2)CC1.[CH2:39]([O:46][C:47]1[CH:48]=[C:49]2[C:53](=[CH:54][CH:55]=1)[N:52]([CH3:56])[C:51]([CH:57]=O)=[CH:50]2)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C(#N)C>[CH2:39]([O:46][C:47]1[CH:48]=[C:49]2[C:53](=[CH:54][CH:55]=1)[N:52]([CH3:56])[C:51]([CH:57]=[CH:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[CH:50]2)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: Cn1c(C=O)cc2cc(OCc3ccccc3)ccc21
Agent: [Br-]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cn1c(C=Cc2ccccc2)cc2cc(OCc3ccccc3)ccc21
Reaction time: 0.17 h
Yield: 34.6 %

Procedure:
Under N2, to a suspension of benzyltriphenylphosphonium bromide (980 mg, 2.26 mmol) in acetonitrile (10 ml) was added DBU at room temperature. After stirring for 10 min., 5-(benzyloxy)-1-methyl-1H-indole-2-carbaldehyde (500 mg, 1.88 mmol) was added and the mixture was stirred overnight at room temperature. The resulting mixture was filtered and washed with acetonitrile. The filtrate was concentrated in vacuo and then the residue was purified by silica gel (70 g) chromatography eluted with chloroform to give 5-(benzyloxy)-1-methyl-2-(2-phenylethenyl)-1H-indole (221 mg, 34.5%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:47][C:48]1[CH:49]=[C:50]([CH:53]=[C:54]([CH3:56])[CH:55]=1)[CH2:51][NH2:52]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([NH:52][CH2:51][C:50]4[CH:53]=[C:54]([CH3:56])[CH:55]=[C:48]([F:47])[CH:49]=4)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(F)cc(CN)c1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)NCc2cc(C)cc(F)c2)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with 3-fluoro-5-methylbenzylamine (Jrd-Fluoro) to give the title product. LC-MS (ES+) 786 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Cl:11])=[C:4]([CH3:12])[N:3]=1>[Pd].CO>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:11])=[C:4]([CH3:12])[N:3]=1
Reactant: Cc1nc(N)c([N+](=O)[O-])cc1Cl
Agent: [Pd]
Solvent: CO
Product: Cc1nc(N)c(N)cc1Cl
Reaction time: 20 h
Yield: 88.1 %

Procedure:
A mixture of the nitropyridine 46 (1.48 g, 7.85 mmol), MeOH (50 mL), and 5% Pd-C (150 mg) was shaken under H2 (20-30 psi) for 20 h. The mixture was filtered and the filtrate was rota-evaporated to dryness to give 1.09 g (87%) of the diamine 47 as a brown powder, mp 128°-130° C. 1H NMR (CDCl3) δ 1.661 (s, 3H), 3.233 (bs, 2H), 4.183 (bs, 2H), 6.880 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH:18]=[C:17]([O:19][CH2:20][O:21][CH3:22])[CH:16]=[C:15]([O:23][CH2:24][O:25][CH3:26])[C:11]=1[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:27]N1C(=O)CCC1=O.O>CN(C)C=O>[CH2:1]([O:8][CH2:9][C:10]1[C:18]([Br:27])=[C:17]([O:19][CH2:20][O:21][CH3:22])[CH:16]=[C:15]([O:23][CH2:24][O:25][CH3:26])[C:11]=1[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCOc1cc(COCc2ccccc2)c(C(=O)O)c(OCOC)c1
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cc(OCOC)c(C(=O)O)c(COCc2ccccc2)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.3 %

Procedure:
2-(Benzyloxymethyl)-4,6-bis(methoxymethoxy)benzoic acid (60 mg, 0.17 mmol) obtained in Step 6 of Example 22 was dissolved in N,N-dimethylformamide (10 mL), and N-bromosuccinimide (62 mg, 0.35 mmol) was added thereto followed by stirring at a room temperature for 2 hours. The reaction mixture was added with water and extracted with chloroform 3 times. The organic layers were combined and sequentially washed with saturated aqueous sodium thiosulfate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by preparative thin-layer chromatography (chloroform/methanol=20/1) to obtain 2-(benzyloxymethyl)-3-bromo-4,6-bis(methoxymethoxy)benzoic acid (16 mg, 22%).
Reaction SMILES: [C:1]([C:3]1([CH3:27])[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH2:4]1)#[N:2].[OH-].[Na+].[O:30]1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[CH3:27][C:3]1([C:1]([NH2:2])=[O:30])[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH2:4]1
Reactant: CN(c1cccc2cc(C3=NCC(C)(C#N)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: C1CCOC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(c1cccc2cc(C3=NCC(C)(C(N)=O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A mixture of N-[2-(5-cyano-5-methyl-4,5-dihydro-1,3-thiazol-2-yl)-1H-indol-7-yl]-N-methylthiophene-2-sulfonamide (0.38 g), 2N aqueous sodium hydroxide solution (0.90 mL), tetrahydrofuran (4 mL) and ethanol (4 mL) was heated under reflux for 4 hr. 10% Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. A mixture of the obtained residue, 1H-1,2,3-benzotriazol-1-ol (0.15 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.21 g) and N,N-dimethylformamide (6 mL) was added at room temperature for 1 hr, and 28% aqueous ammonia (0.22 mL) was added. The mixture was stirred overnight at room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water, and dried. The obtained solid was suspended in ethanol, and the mixture was stirred for 15 min. The crystals were collected by filtration, washed with ethanol and ethyl acetate, and dried to give the title compound (0.29 g, yield 74%) as colorless crystals. melting point 248-249° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]=2)[CH:3]=1.O.[NH2:23][NH2:24].C(=O)([O-])[O-].[K+].[K+]>CC1OCCC1>[NH:23]([C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([C@@H:9]2[CH2:11][C@H:10]2[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]=2)[CH:3]=1)[NH2:24]
Reactant: Cc1nc(Cl)cc([C@@H]2C[C@H]2c2nc3ccccc3n2C)n1
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC1CCCO1
Solvent: O
Product: Cc1nc(NN)cc([C@@H]2C[C@H]2c2nc3ccccc3n2C)n1
Temperature: 25 °C

Procedure:
A slurry of 6-4 (4 g, 13.39 mmol), hydrazine hydrate (1.261 ml, 40.2 mmol) and potassium carbonate (5.55 g, 40.2 mmol) in 2-MeTHF (100 ml) was heated at 80° C. for 16 h. After cooling to room temperature, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered and concentrated to afford Intermediate 6 as a tan solid. MS: m/z=295.4 (M+H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[Cl-].[Al+3].[Cl-].[Cl-].[Cl:13][C:14]([Cl:16])=[CH2:15].O>C(Cl)Cl>[Cl:13][C:14]([Cl:16])=[CH:15][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: O=C(Cl)CCCCCl
Reactant: C=C(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(C=C(Cl)Cl)CCCCCl
Reaction time: 1 h

Procedure:
100 g (0.62 mol) 5-Chlorovaleroyl chloride was added dropwise to 78.53 g (0.589 mmol) aluminium chloride in 150 ml methylene chloride at room temperature. After stirring for 1 hour, 45 ml (0.558 mol) 1,1-dichloroethylene in 25 ml methylene chloride was added dropwise. Under ice-cooling 100 ml water was added dropwise and solid material suction filtered on Celite. The filtrate was washed with water and the organic phase dried and concentrated. The residue was distilled in a rotary evaporator.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][S:8][C:4]=2[CH:3]=1.N1C=CN=C1.[CH3:16][C:17]([Si:20](Cl)([CH3:22])[CH3:21])([CH3:19])[CH3:18].O>ClCCl>[Si:20]([O:1][C:2]1[CH:10]=[CH:9][C:5]2[CH:6]=[CH:7][S:8][C:4]=2[CH:3]=1)([C:17]([CH3:19])([CH3:18])[CH3:16])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc2ccsc2c1
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2ccsc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
6-Hydroxybenzothiophene (22, 8.55 g, 56.9 mmol) and imidazole (4.65 g, 68.3 mmol) were dissolved in dichloromethane (120 mL) and TBDMS-Cl (9.73 g, 62.6 mmol) dissolved in dichloromethane (50 mL) was slowly added at 0° C. The reaction mixture was agitated at 0° C. for 1 hour. After adding water and transferring the resulting solution to a separatory funnel, the dichloromethane layer was separated. The remaining organic compound was extracted three times with dichloromethane. After removing water using sodium sulfate, the solvent was removed under reduced pressure. Column chromatography yielded 6-(t-butyldimethylsilyloxy)benzothiophene (23, 13.6 g, 90%) as a liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:33]=[CH:32][C:22]([CH2:23][NH:24][C:25](=[O:31])OC(C)(C)C)=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1.Cl.[C:35](OCC)(=O)[CH3:36]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2/[CH:14]=[CH:15]/[C:16]([NH:18][C:19]2[CH:33]=[CH:32][C:22]([CH2:23][NH:24][C:25](=[O:31])[CH2:35][CH3:36])=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1
Reactant: CCOC(C)=O
Reactant: Cn1ncc(/C=C/C(=O)Nc2ccc(CNC(=O)OC(C)(C)C)cc2)c1-c1ccc(F)cc1
Agent: Cl
Product: CCC(=O)NCc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1
Temperature: 70 °C
Reaction time: 15 h

Procedure:
A mixture of tert-butyl [4-({(2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]prop-2-enoyl}amino)benzyl]carbamate (2.0 g) and 4N hydrogenchloride in ethyl acetate (80 mL) was stirred at 70° C. for 15 hrs. The precipitated crystals were collected by filtration, and washed with ethyl acetate. Triethylamine (0.39 g) was added to a solution (10 mL) of the obtained crystals (1.00 g) in N,N-dimethylacetamide at room temperature. The reaction mixture was stirred at room temperature for 30 min. and propionyl chloride (0.27 g) was added. The reaction mixture was further stirred at room temperature for 2.5 days. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate-tetrahydrofuran. The organic layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]-N-{4-[(propionylamino)methyl]phenyl}acrylamide as colorless crystals (0.51 g). Recrystallization thereof from acetone-hexane gave colorless prism crystals. melting point: 271-272° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1)[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.O[C@H:32]1[CH2:37][CH2:36][O:35][C:33]1=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1(C)C=CC=CC=1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:23][C:24]1[CH:25]=[C:26]([O:30][C@@H:32]2[CH2:37][CH2:36][O:35][C:33]2=[O:34])[CH:27]=[CH:28][CH:29]=1)[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: O=C1OCC[C@@H]1O
Reactant: COc1ccc(OCCCN(Cc2cccc(O)c2)c2nc3ccccc3o2)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(OCCCN(Cc2cccc(O[C@@H]3CCOC3=O)c2)c2nc3ccccc3o2)cc1
Temperature: 40 °C
Reaction time: 24 h

Procedure:
In an argon atmosphere, N-(benzoxazole-2-yl)-N-(3-(4-methoxyphenoxy)propyl)-3-hydroxybenzylamine (2.0 g), (S)-2-hydroxybutyrolactone (1.0 g), and triphenylphosphine (2.6 g) were dissolved in toluene (30 mL), and a solution of di-tert-butyl azodicarboxylate (2.3 g) in toluene (10 mL) was dropwise to the solution at 0° C., followed by stirring for 24 hours at 40° C. Subsequently, triphenylphosphine (1.3 g) and di-tert-butyl azodicarboxylate (1.1 g) were added to the mixture at 40° C., followed by stirring for 24 hours at the same temperature. The reaction mixture was returned to room temperature. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine. The washed mixture was dried over sodium sulfate anhydrate. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography (n-hexane/ethyl acetate=1/1), to thereby yield a colorless oil (2.2 g, 92%, 98% ee).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]([NH:8][CH2:9][C:10]2[CH:20]=[CH:19][C:13]3[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=3[CH:11]=2)=[CH:6][CH:7]=1.Br[C:23]1C=C(N)C(NCC2C=CC3N=C(SC)SC=3C=2)=CC=1OC>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=4[CH:11]=3)[CH:23]=[N:21][C:4]=2[CH:3]=1
Reactant: CSc1nc2ccc(CNc3ccc(Br)cc3N)cc2s1
Reactant: COc1cc(NCc2ccc3nc(SC)sc3c2)c(N)cc1Br
Product: CSc1nc2ccc(Cn3cnc4cc(Br)ccc43)cc2s1

Procedure:
6-((5-Bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole was synthesized as a white solid (630 mg, 62% over two steps) using a procedure analogous to that described in Step 3 of Example 41, substituting 4-bromo-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine from the previous step for 4-bromo-5-methoxy-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine used in Example 41. 1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.00 (s, 1H), 7.87 (d, J=1.7 Hz, 1H), 7.81 (d, J=8.5 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.33-7.45 (m, 2H), 5.62 (s, 2H), 2.77 (s, 3H); LCMS (ESI) m/z 390, 392 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[OH:22].Cl[CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=[O:26]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[N:13][C:14]([C:18]([F:19])([F:20])[F:21])=[CH:15][CH:16]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][C:3]=1[O:22][CH2:24][C:25]([N:27]([CH3:29])[CH3:28])=[O:26]
Reactant: CN(C)C(=O)CCl
Reactant: Oc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Product: CN(C)C(=O)COc1cc(-c2ccnc3nc(C(F)(F)F)ccc23)ccc1F
Yield: 58.5 %

Procedure:
2-Fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenol (50.0 mg, 0.16 mmol) was alkylated with 2-chloro-N,N-dimethylacetamide (20.1 μL, 23.7 mg, 0.20 mmol) as described in Example 47, affording 2-[2-fluoro-5-(7-trifluoromethyl[1,8]naphthyridin-4-yl)phenoxy]-N,N-dimethylacetamide (36.8 mg, 58%). δH (360 MHz, CDCl3) 2.99 (3H, s), 3.10 (3H, s), 4.85 (2H, s), 7.05-7.09 (1H, m), 7.18 (1H, dd, J 2.1 and 8.1), 7.31 (1H, dd, J 8.1 and 10.9), 7.54 (1H, d, J 4.2), 7.82 (1H, d, J 8.4), 8.53 (1H, d, J 8.4), 9.25 (1H, d, J 4.6). m/z (ES+) 394 [MH]+.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:13][CH:14]=2)O1.[C:22]([N:25]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH:30]=[CH:29][C:28]2[N:37]=[C:38](C3C=NC(OC)=CC=3)[C:39](F)=[CH:40][C:27]=2[CH2:26]1)(=[O:24])[CH3:23]>>[C:22]([N:25]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH:30]=[CH:29][C:28]2[N:37]=[C:38]([C:9]3[CH:14]=[N:13][C:12]([N:15]4[CH2:16][CH2:17][O:18][CH2:19][CH2:20]4)=[CH:11][CH:10]=3)[CH:39]=[CH:40][C:27]=2[CH2:26]1)(=[O:24])[CH3:23]
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Reactant: COc1ccc(-c2nc3c(cc2F)CN(C(C)=O)c2ccccc2C=C3)cn1
Product: CC(=O)N1Cc2ccc(-c3ccc(N4CCOCC4)nc3)nc2C=Cc2ccccc21
Yield: 91 %

Procedure:
The title compound (26.2 mg, 91%) was prepared from 13C (20.0 mg, 0.07 mmol) and 5A (30.5 mg, 0.105 mmol) by a route analogous to that used for the preparation of 2B. HPLC Rt=2.159 min; LCMS Found: (M+H)+=413.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:26])[C:10]([C:16]1[CH:23]=[C:22]([CH3:24])[C:19]([C:20]#[N:21])=[C:18]([CH3:25])[CH:17]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[C:34]([Cl:36])[C:33](Cl)=[N:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[C:34]([Cl:36])[C:33]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:26])[C:10]([C:16]3[CH:17]=[C:18]([CH3:25])[C:19]([C:20]#[N:21])=[C:22]([CH3:24])[CH:23]=3)([OH:15])[C:11]([F:14])([F:12])[F:13])=[C:2]([Cl:1])[CH:7]=2)=[N:32][CH:31]=1
Reactant: Cc1cc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cc(C)c1C#N
Reactant: COC(=O)c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3cc(C)c(C#N)c(C)c3)C(F)(F)F)c(Cl)c2)c(Cl)c1

Procedure:
In analogy to Example 147, 4-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-2,6-dimethyl-benzonitrile (Example 141, step 5) was reacted with methyl-5,6-dichloro-nicotinate in the presence of cesium carbonate to give the title compound as a colorless solid. MS (m/e)=553.3 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:4]([NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17](Cl)(=[O:19])=[O:18])=[CH:9][CH:8]=1)=[O:5].[N:29]([CH:32]([CH3:34])C)=[C:30]=[O:31]>C(N(CC)CC)C>[C:30]([N:29]1[CH2:32][CH2:34][CH:4]([NH:6][S:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:21]([C:25]([F:28])([F:27])[F:26])=[CH:22][CH:23]=[CH:24][C:2]=3[F:1])=[CH:8][CH:9]=2)(=[O:19])=[O:18])[CH2:3][CH2:2]1)(=[O:31])[CH2:8][CH2:7][CH3:16]
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)c2ccccc12)c1c(F)cccc1C(F)(F)F
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3c(F)cccc3C(F)(F)F)c3ccccc23)CC1

Procedure:
The title compound was prepared following the general procedure in Scheme 5, beginning with 4-(2-fluoro-6-trifluoromethyl-benzoylamino)-naphthalene-1-sulfonyl chloride and substituting butyric chloride and triethylamine for 2-isocyanato-propane. 1H NMR (300 MHz, DMSO) δ 11.12 (s, 1H), 8.71 (m, 1H), 8.26 (m, 2H), 8.13 (m, 1H), 7.98 (d, 1H), 7.79 (m, 6H), 4.01 (d, 1H), 3.60 (d, 1H), 2.93 (t, 1H), 2.59 (m, 2H), 2.15 (t, 2H), 1.45 (m, 2H), 1.43 (q, 2H), 1.17 (m, 2H), 0.81 (t, 3H). LC/MS m/z 514 (M−H)−, 516 (M+H)+
Reaction SMILES: [Na:1].CC1(C)COC(C[O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18]([C:20]3[NH:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[N:21]=3)=[O:19])[C:12]=2[CH3:29])OC1.[CH2:31]1[O:35][CH2:34][O:33][CH:32]1[CH2:36]O>>[Na:1].[O:35]1[CH2:31][CH:32]([CH2:36][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18]([C:20]3[NH:21][C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]=3)=[O:19])[C:12]=2[CH3:29])[O:33][CH2:34]1
Reactant: Cc1c(OCC2OCC(C)(C)CO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reactant: OCC1COCO1
Agent: [Na]
Product: Cc1c(OCC2COCO2)ccnc1CS(=O)c1nc2ccccc2[nH]1

Procedure:
The same procedure as in the steps (1c) to (1g) of Example 1 was repeated using glycerol formal (1.76 ml, 20.3 mmol) to obtain the title compound (87 mg, 0.22 mmol) as a beige solid.