Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[N:11]=[CH:12]/[CH:13]2[C:18](=[O:19])OC(C)(C)OC2=O)[CH:6]=[N:7][C:8]=1[O:9][CH3:10].C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[CH3:10][O:9][C:8]1[N:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[NH:11][CH:12]=[CH:13][C:18]2=[O:19]
Reactant: COc1cc(/N=C/C2C(=O)OC(C)(C)OC2=O)cnc1OC
Solvent: CCCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cc2[nH]ccc(=O)c2nc1OC
Temperature: 200 °C

Procedure:
A round bottom flask was charged with (E)-5-((5,6-dimethoxypyridin-3-ylimino)methyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (450 mg, 1460 μmol) and 4.2 mL diphenyl ether. A reflux condenser was attached, and the solution was heated at 200° C. for 0.5 h. Upon cooling, hexane was added and the solids were filtered and washed with hexane. 6,7-dimethoxy-1,5-naphthyridin-4(1H)-one was isolated as a tan solid. MS [M+H]=207
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[O:37][C@H:11]2[CH2:12][C@@H:13]([O:30]C3CCCCO3)[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23]C3CCCCO3)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1>O1CCCC1.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:38])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[O:37][C@H:11]2[CH2:12][C@@H:13]([OH:30])[C@H:14](/[CH:15]=[CH:16]/[C@@H:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:10]2[CH2:9]1
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@H]2CC(CCCCC(=O)OC)O[C@H]2C[C@H]1OC1CCCCO1)OC1CCCCO1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2CC(CCCCC(=O)OC)O[C@H]2C[C@H]1O
Yield: 73.7 %

Procedure:
By proceeding as described in Example 2 but using 435 mg of (13E)-(6RS,9α,11α,15S)-6,9-epoxy-11,15-bis-(tetrahydropyran-2-yloxy)prost-13-enoic acid methyl ester (prepared as described in Example 5) dissolved in a mixture of 0.7 ml of tetrahydrofuran and 9 ml of 65% aqueous acetic acid, there were obtained 220 mg of the title compound having the following physical characteristics:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][N:9]2[CH2:12][CH2:13][C:14]#[N:15])=[CH:4][C:3]=1[F:22].[NH:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25][CH2:24]1>ClCCl>[C:32]([O:31][C:30]([NH:29][CH:26]1[CH2:25][CH2:24][N:23]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][N:9]3[CH2:12][CH2:13][C:14]#[N:15])=[CH:4][C:3]=2[F:22])[CH2:28][CH2:27]1)=[O:36])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(Cl)c(F)cc2c1=O
Solvent: ClCCl
Product: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC(NC(=O)OC(C)(C)C)CC3)c(F)cc2c1=O

Procedure:
A solution of EXAMPLE 7C (0.5 g) and 1,1-dimethylethyl piperidin-4-ylcarbamate in dichloromethane (100 mL) was stirred for 2 hours, diluted with dichloromethane (100 mL), washed with water, 10% citric acid, and brine, and dried (MgSO4), filtered, and concentrated.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.[F:16][C:17]([F:23])([F:22])[C:18](OC)=[O:19]>CO>[F:16][C:17]([F:23])([F:22])[C:18]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1)=[O:19]
Reactant: COC(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](NC(=O)C(F)(F)F)CC1
Temperature: 0 °C

Procedure:
A solution of tert-butyl cis-4-aminocyclohexanecarbamate (22.1 g, 103 mmol) and methyl trifluoroacetate (11 ml, 110 mmol) in 110 ml of methanol is stirred at RT for 4 h. After the reaction mixture has been cooled down to 0° C., the precipitate is filtered off, washed with diethyl ether and dried. Yield: 17.6 g.
Reaction SMILES: N[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[C:3]=1[CH3:12].N([O-])=O.[Na+].C1(C)C=CC=CC=1.[BrH:24]>O>[Br:24][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[C:3]=1[CH3:12]
Reactant: Cc1c(N)ccc(C(=O)O)c1F
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1c(Br)ccc(C(=O)O)c1F
Reaction time: 1 h

Procedure:
In 14 ml of 4.7% hydrobromic acid was suspended 0.55 g of 4-amino-2-fluoro-3-methylbenzoic acid, and 3.7 g of cupric bromide was added thereto. To the resulting suspension was added dropwise a solution of 0.38 g of sodium nitrite in 4 ml of water under ice-cooling over a period of 15 minutes, and the resulting mixture was stirred at the same temperature for 1 hour and then at room temperature for 24 hours. To the reaction mixture was added 20 ml of toluene and the organic layer was separated. The organic layer obtained was washed with 20 ml of 20% hydrobromic acid, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. n-Hexane was added to the resulting residue and the crystals were collected by filtration to obtain 0.68 g of colorless 4-bromo-2-fluoro-3-methylbenzoic acid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:9]([N+:18]([O-])=O)=[C:8]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:7]=1)[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1[CH:7]=[C:8]([O:21][CH2:22][C:23]([F:25])([F:24])[F:26])[C:9]([NH2:18])=[C:10]([O:12][CH2:13][C:14]([F:16])([F:17])[F:15])[CH:11]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cc(OCC(F)(F)F)c([N+](=O)[O-])c(OCC(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1cc(OCC(F)(F)F)c(N)c(OCC(F)(F)F)c1
Yield: 89.5 %

Procedure:
[4-Nitro-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethyl ester (10.0 g, 24.7 mmol) was dissolved in EtOH (200 mL) and hydrogenated at 50 psi, 25° C. for 16 h in the presence of Pd—C catalyst (10%, 1 g). The catalyst was filtered off and the solvent evaporated to give a crude brown oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc to give [4-amino-3,5-bis-(2,2,2-trifluoro-ethoxy)-phenyl]-acetic acid ethyl ester as a yellow oil (8.3 g, 90%). 1H NMR (300 MHz, CDCl3/TMS): δ 6.52 (s, 2H), 4.37 (q, J=8.0 Hz, 4H), 4.14 (q, J=7.2 Hz, 2H), 3.90 (br s, 2H), 3.48 (s, 2H), 1.25 (t, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3/TMS): δ 171.4, 145.0, 126.3, 123.2, (q, 1JCF=277.6 Hz), 122.6, 110.0, 109.8 (two signals), 66.8 (q, 2JCF=35.5 Hz), 61.0, 41.0, 14.2.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[CH2:9]([O:11][P:12](C(C)(C)CN)(=[O:16])[O:13][CH2:14][CH3:15])[CH3:10].N1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24]C=1C.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl.C(OCC)(=O)C>[PH:12](=[O:16])([O:11][CH2:9][C:10]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[O:13][CH2:14][C:15]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cccc(C)n1
Reactant: CCOP(=O)(OCC)C(C)(C)CN
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=[PH](OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of triflate 9 (94 mg, 0.214 mmol) in CH2Cl2 (2 mL) was added a solution of aniline 6 (100 mg, 0.173 mmol) in CH2Cl2 (2 mL) at −40° C., followed by 2,6-lutidine (0.026 mL). The mixture was warmed up to room temperature and stirred for 1 h. Cesium carbonate (60 mg) was added and the reaction mixture was stirred for additional 1 h. The mixture was diluted with ethyl acetate, washed with HCl (0.2N), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by HPLC to afford dibenzyl phosphonate (40 mg). To a solution of this dibenzyl phosphonate in ethanol (3 mL) and ethyl acetate (1 mL) was added 10% Pd/C (40 mg). The mixture was stirred under hydrogen atmosphere (balloon) for 4 h. The reaction mixture was diluted with methanol, filtered and concentrated under reduced pressure. The residue was washed with ethyl acetate and dried to give desired product diacid 10 (20 mg). 1H NMR (CD3OD) δ 7.8 (d, 2H), 7.3 (d, 2H), 7.1 (2d, 4H), 5.6 (d, 1H), 4.9 (m, 2H), 3.4-4.0 (m, 6H), 3.9 (s, 3H), 2.53.2 (m, 9H), 2.0 (m, 2), 1.4-1.7 (m, 2H), 0.9 (2d, 6H); 31P NMR (CD3OD) δ 22.1; MS (ESI): 686 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[N:32]=[C:33]=[O:34]>C(Cl)Cl.O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([C:33](=[O:34])[NH:32][C:26]3[C:27]([F:31])=[CH:28][CH:29]=[CH:30][C:25]=3[F:24])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: O=C=Nc1c(F)cccc1F
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)Nc3c(F)cccc3F)CC2)c1C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
To a solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester (which may be prepared as described above; 75.5 mg, 0.239 mmol) in methylene chloride (8.0 mL) was added neat 2,6-difluorophenyl isocyanate (74.1 mg, 0.478 mmol) at room temperature under nitrogen. The resulting light brown solution was stirred overnight. The reaction mixture was diluted with water (˜20 mL) and the resulting mixture was extracted with methylene chloride (2×30 mL). The combined organic layers were washed with saturated aqueous NaHCO3, dried over anhydrous Na2SO4, filtered, then concentrated to a yellowish film. Silica gel chromatography (33% ethyl acetate in hexanes) provided {4-[1-(2,6-difluoro-phenylcarbamoyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (95.4 mg, 85%) as a colorless film. MS cald. for C26H26F3N2O3 [(M+H)+]: 471, obsd. 471.2.
Reaction SMILES: [Na].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-]CC.[Na+:16].Br[CH:18]([CH2:20][CH2:21][CH3:22])[CH3:19]>C(O)C>[O-:5][CH2:4][CH3:3].[Na+:16].[CH3:19][CH:18]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])[CH2:20][CH2:21][CH3:22]
Reactant: CCCC(C)Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCCC(C)C(C(=O)OCC)C(=O)OCC
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Sodium ethoxide was prepared from sodium metal (7.61 g) and absolute ethanol (200 ml). Diethyl malonate (50.3 ml) was added dropwise to the ethanol containing sodium ethoxide. After heating to 80° C., 2-bromopentane (50 g) was added and the mixture was reflued for 24 h. Diethyl (2-pentyl)malonate (62.7 g) was obtained after the usual work-up. Diethyl (2-pentyl)malonate was added to a 50% potassium hydroxide solution and the mixture was heated for 3 h while water/ethanol being distilled off. After cooling, the solution was acidified with concentrated hydrochloric acid. Then, the solution was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the resulting product was heated to 180° C. until bubbling ceased. After distillation, colorless 3R,S-methy-caproic acid was obtained. Yield: 27.7 g (35%), b.p. 200° C./760 mmHg.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[F:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:9]2[CH2:10][CH2:11][C:6]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:27][CH:28]=3)(=[O:22])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1
Reactant: CCCCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(F)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(F)cc3)CC2)cc1

Procedure:
1-(4-Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid was prepared starting from 1-(4-Fluoro-benzyl)-4-(4-butoxy-benzenesulfonyl)-piperidine-4-carboxylic acid ethyl ester (4.77 g, 10 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 3.5 g (79%); off white solid; mp 114° C.; MS: 450 (M+H)+.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[CH3:11][NH2:12].CCO>CC(C)=O>[CH3:11][NH:12][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: CN
Reactant: Clc1nc2ccccc2[nH]1
Solvent: CC(C)=O
Solvent: CCO
Product: CNc1nc2ccccc2[nH]1
Temperature: 160 °C
Yield: 51.4 %

Procedure:
2-Chloro-1H-benzo[d]imidazole (20 g, 131.08 mmol) was charged to high pressure autoclave PV10832 (Hastelloy 450 ml) with methylamine (260 mL, 131.08 mmol) and sealed on its trolley and the resulting solution heated to 160° C. in high pressure blast cell 60 for 16 hours. The pressure in the autoclave reached 11 bar. The solvent was removed under reduced pressure to afford a brown oil. EtOH was added and the solvent again removed to afford a brown foam. The foam was dissolved in a minimum of hot acetone. This was then allowed to cool. The resultant solid was filtered affording N-methyl-1H-benzo[d]imidazol-2-amine (9.91 g, 51%); 1H NMR (400 MHz, DMSO-d6) 2.83 (3H, s), 6.87-7.00 (2H, m), 7.05-7.25 (2H, m), 7.49 (1H, s).
Reaction SMILES: [O:1]=[S:2]1(=[O:18])[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1.[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[CH:23]=[C:24]([CH3:34])[C:25]([N:28]3[CH2:29][CH2:30][N:31]([C:13]([C:12]4[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:18])=[CH:17][CH:16]=4)=[O:15])[CH2:32][CH2:33]3)=[N:26][CH:27]=2)[CH2:21][CH2:20]1
Reactant: O=C(O)c1ccc(CCN2CCCS2(=O)=O)cc1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(CCN3CCCS3(=O)=O)cc2)CC1
Yield: 70.6 %

Procedure:
Using 4-[2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)ethyl]benzoic acid (162 mg) described in Preparation Example 41 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine (130 mg) described in Preparation Example 83 and by the reaction and treatment in the same manner as in Example 87, the title compound (198 mg) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][C:6]=1[CH:7]=[O:8].[H-].[Na+].Cl[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17].C([O-])(O)=O.[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1[nH]ncc1Br
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc(Br)c1C=O
Reaction time: 0.17 h
Yield: 68.5 %

Procedure:
To a stirred suspension of 4-bromo-1H-pyrazole-5-carbaldehyde (1.93 g, 11 mmol) in THF (50 mL) was added sodium hydride (0.484 g, 12.1 mmol) at 0° C. After 10 min, [2-(chloromethoxy)ethyl](trimethyl)silane (2.34 mL, 13.2 mmol) was added. After 2 h, the mixture was poured into saturated aqueous NaHCO3 and extracted with EtOAc (100 mL), and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, hexane to 80:20 hexane/EtOAc) to afford the title compound (2.30 g, 69%) as a colorless oil:
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27](O)=[O:28]>>[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1/[CH:25]=[CH:26]/[C:27]([NH:16][C:13]1[CH:14]=[CH:15][N:11]([CH2:10][C:8]2[O:9][C:5]([C:2]([F:1])([F:4])[CH3:3])=[CH:6][CH:7]=2)[N:12]=1)=[O:28]
Reactant: O=C(O)/C=C/c1cccc(Cl)c1Cl
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Product: CC(F)(F)c1ccc(Cn2ccc(NC(=O)/C=C/c3cccc(Cl)c3Cl)n2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(2,3-dichloro-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.17 min; [M+H]+=425.94.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([NH2:30])[C:23]([NH2:29])=[CH:24][CH:25]=4)[O:20][C:19]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][C:39](C)(C)C([O-])([O-])[O-].II>CC#N>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[CH:25]=[CH:24][C:23]5[N:29]=[C:38]([CH3:39])[NH:30][C:22]=5[C:21]=4[O:20][C:19]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C([O-])([O-])[O-]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(N)c(N)ccc4c3=O)cc2)CCC1
Agent: II
Solvent: CC#N
Product: Cc1nc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c2[nH]1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 41.9 %

Procedure:
To a solution of {1-[4-(7,8-diamino-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (80 mg, 0.16 mmol) in CH3CN (8 mL) was added trimethylorthoacetate (25 μL, 0.20 mmol) and iodine (4 mg, 0.016 mmol) and the reaction mixture was stirred at RT for 2.5 hours. Further trimethylorthoacetate (50 μL, 0.40 mmol) and iodine (24 mg, 0.096 mmol) were added and the reaction stirred for 1 hour. The reaction was quenched with aqueous Na2S2O3, diluted with ethyl acetate and the phases separated. The organic extracts were washed with brine, dried (NaSO4), filtered and the solvents were removed in vacuo. The resulting residue was subjected to flash chromatography (SiO2, ethyl acetate) to give the title compound as a brown solid (35 mg, 42%). LCMS (Method G): RT=3.18 min, [M+H]+=522.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>CCCCCCC.CCOC(C)=O>[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[CH:30][CH:29]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I
Reactant: COc1ccc(B(O)O)cn1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COc1ccc(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1

Procedure:
The title compound was prepared in analogy to example 72, from N-(4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 98, intermediate a) and 6-methoxypyridin-3-ylboronic acid (CAS RN 163105-89-3) and using a gradient of n-heptane:EtOAc (100:0 to 60:40) for the chromatographic separation. Colorless solid (74%). MS (ESI): m/z=456.113 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[OH:16])=[O:8].[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[C:3]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=2)[C:7]([NH:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[OH:16])=[O:8])=[CH:31][CH:30]=1
Reactant: O=C(N[C@H]1CCCC[C@H]1O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=C(N[C@H]1CCCC[C@H]1O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nc1C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1d, using 5-bromo-N-((1S,2R)-2-hydroxy-cyclohexyl)-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinamide and 4-chlorophenylboronic acid as starting materials, MS (ISP) 497.1 (M+H)+; [α]D20=−20.0°.
Reaction SMILES: [N:1]1[C:2](=[O:10])[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[Cl-].[Li+].[CH2:13]1[O:15][CH:14]1[CH2:16][OH:17]>CN(C)C(=O)C>[OH:15][CH:14]([CH2:16][OH:17])[CH2:13][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]([CH2:13][CH:14]([OH:15])[CH2:16][OH:17])[C:2]1=[O:10]
Reactant: OCC1CO1
Reactant: O=C1N=c2ccccc2=N1
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)N(C)C
Product: O=c1n(CC(O)CO)c2ccccc2n1CC(O)CO
Temperature: 135 °C
Reaction time: 5 h

Procedure:
1.5 mols of benzimidazolone (201.2 g) are dissolved in 1.5 liters of N,N-dimethylacetamide at 120°C and 2.5 g of lithium chloride are added. 244.2 g (3.3 mols) of glycerol glycide (glycidol) are added dropwise over the course of 2 hours to this solution. The solution is then stirred for a further 5 hours at 135°C. After bringing the solution to room temperature, it is filtered and completely concentrated. The residue is dried for a further 5 hours at 95°C under 0.8 mm Hg. This gives 448 g of a brownish, very viscous liquid (theoretical yield: 423.5 g) which is the crude product still contaminated with a little dimethylacetamide.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:9]([C:19]([F:22])([F:21])[F:20])[CH:8]=1.C1C(=O)N([Br:35])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:35][CH2:27][C:25]1[CH:24]=[CH:23][C:4]2[S:5][C:6]([C:7]3[CH:12]=[CH:11][C:10]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)=[C:9]([C:19]([F:22])([F:21])[F:20])[CH:8]=3)=[C:2]([Cl:1])[C:3]=2[CH:26]=1
Reactant: Cc1ccc2sc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)c(Cl)c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(-c2sc3ccc(CBr)cc3c2Cl)ccc1-c1ccccc1
Yield: 38 %

Procedure:
To a solution of 3-chloro-5-methyl-2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophene (110 mg, 0.273 mmol) in CCl4 (3 ml) is added NBS (49 mg, 1 eq.). The mixture is heated at reflux for 15 minutes before AIBN (4.5 mg, 0.1 eq.) is added. The reaction is further heated at reflux overnight. The mixture is filtered through Celite and washed with CCl4. The filtrate is concentrated and purified by column chromatography (EtOAc/Hexane, gradient) to give 50 mg of 5-bromomethyl-3-chloro-2-(2-trifluoromethyl-biphenyl-4-yl)-benzo[b]thiophene in 38% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]([OH:11])[C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15].CCN(CC)CC>C1COCC1>[C:14]([O:11][CH:7]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:13][CH:12]=1)[C:8]([OH:10])=[O:9])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C(O)C(=O)O)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(OC(C)=O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
4-Methoxymandelic acid (5.00 g, 27.44 mmol) was dissolved in 100 mL of THF. To this solution was added acetic anhydride (2.85 mL, 30.18 mmol), followed by Et3N (10 mL). The resulting mixture was stirred at room temperature overnight, concentrated, re-suspended in water, and extracted with EtOAc. The combined organic phase was dried over Na2SO4, and concentrated to give 5.95 g yellow syrup as the intermediate 79a. 1H NMR (300 MHz, CDCl3) δ 7.38 (d, 2H, J=8.67 Hz), 6.90 (d, 2H, J=8.67 Hz), 5.87 (s, 1H), 3.80 (s, 3H), 2.16 (s, 3H). LCMS (ESI−) [M−H]/z Calc'd 223, found 223.