Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([Cl:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([O:21]CC)=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.C([O-])(=O)C.S(=O)(=O)(O)O>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([Cl:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC)c(Cl)c(F)cc2c1=O
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1c(Cl)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Yield: 88.1 %

Procedure:
29.4 g of ethyl 1-cyclopropyl-7-chloro-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylate (0.088 mol), 160 ml of acetate acid, 100 ml of water and 18 ml of concentrated sulfuric acid were stirred at 100-110° C. for 40 minutes. The resulting mixture was cooled and filtered. The precipitate was re-crystallized from chloroform-ethanol to give 23.8 g of 1-cyclopropyl-7-chloro-6-fluoro-8-methoxy-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.0775 mol) in 88.1% yield, mp 288-293° C.
Reaction SMILES: [C:1]([Si:5]([CH3:41])([CH3:40])[O:6][CH:7]([C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[O:31][C:30]([CH:32]=O)=[CH:29][CH:28]=3)=[C:23]([CH3:34])[CH:22]=2)([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:12][C:11]=1[CH3:35])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Cl-].[CH3:53][O:54][CH2:55][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:1]([Si:5]([O:6][CH:7]([CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH2:17][CH3:18])([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[O:31][C:30]([CH:32]=[CH:53][O:54][CH3:55])=[CH:29][CH:28]=3)=[C:23]([CH3:34])[CH:22]=2)[CH2:19][CH3:20])=[CH:12][C:11]=1[CH3:35])[C:36]([CH3:38])([CH3:39])[CH3:37])([CH3:40])[CH3:41])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C=O)o2)c(C)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C=COC)o2)c(C)c1
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
5-[4-(1-{4-[3-(t-Butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-furan-2-carbaldehyde (Example 3-(6); 47.4 mg, 0.082 mmol) was added to a solution of potassium bis(trimethylsilyl)amide (0.5 M in toluene, 0.36 mL, 0.18 mmol) and (methoxymethyl)triphenylphosphonium chloride (56.2 mg, 0.164 mmol) in toluene (0.5 mL) at room temperature, and the mixture was stirred for 30 minutes. A saturated aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column (hexane only to hexane/ethyl acetate=9/1) to give the title compound (42 mg, 85%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][S:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].C1(C)C=CC(S([CH2:28][N+:29]#[C-:30])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[O:12]1[C:11]([C:10]2[CH:9]=[C:8]([S:7][CH2:6][C:5]3[CH:4]=[C:3]([CH:18]=[CH:17][CH:16]=3)[CH2:2][OH:1])[CH:15]=[CH:14][CH:13]=2)=[CH:30][N:29]=[CH:28]1
Reactant: O=Cc1cccc(SCc2cccc(CO)c2)c1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCc1cccc(CSc2cccc(-c3cnco3)c2)c1
Yield: 84.3 %

Procedure:
When the same reaction as in Referential Example 33 was carried out except using 172 mg of the resulting aldehyde compound, 130 mg of p-toluenesulfonylmethyl isocyanide and 92 mg of potassium carbonate, 167 mg (yield 84%) of the captioned compound wss obtained.
Reaction SMILES: [O:1]=[C:2]([C@@:18]1([OH:59])[CH2:35][C@H:34]([O:36][C@@H:37]2[O:51][C@@H:50]([CH3:52])[C@H:40]3[O:41][C@H:42]4[N:47]([C@H:39]3[CH2:38]2)[CH2:46][CH2:45][O:44][C@@H:43]4[O:48][CH3:49])[C:33]2[C:20](=[C:21]([OH:58])[C:22]3[C:23](=[O:57])[C:24]4[C:29]([C:30](=[O:54])[C:31]=3[C:32]=2[OH:53])=[C:28]([O:55][CH3:56])[CH:27]=[CH:26][CH:25]=4)[CH2:19]1)[CH2:3][O:4][C:5]1([O:11][CH2:12][C:13]([O:15]CC)=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[OH-].[Na+]>O.C(O)(=O)C>[O:1]=[C:2]([C@@:18]1([OH:59])[CH2:35][C@H:34]([O:36][C@@H:37]2[O:51][C@@H:50]([CH3:52])[C@H:40]3[O:41][C@H:42]4[N:47]([C@H:39]3[CH2:38]2)[CH2:46][CH2:45][O:44][C@@H:43]4[O:48][CH3:49])[C:33]2[C:20](=[C:21]([OH:58])[C:22]3[C:23](=[O:57])[C:24]4[C:29]([C:30](=[O:54])[C:31]=3[C:32]=2[OH:53])=[C:28]([O:55][CH3:56])[CH:27]=[CH:26][CH:25]=4)[CH2:19]1)[CH2:3][O:4][C:5]1([O:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CCOC(=O)COC1(OCC(=O)[C@]2(O)Cc3c(O)c4c(c(O)c3[C@@H](O[C@H]3C[C@H]5[C@H](O[C@@H]6[C@@H](OC)OCCN65)[C@H](C)O3)C2)C(=O)c2c(OC)cccc2C4=O)CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)COC1(OCC(=O)O)CCCCC1)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
To 30 mg of 45, 5 mL of in 01N NaOH was added. The suspension was cooled at 5° C. and stirred under argon for 3 hours. The aqueous solution was brought to pH≅8 with 10% acetic acid water solution and extracted with dichloromethane (2×10 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, the solvent removed under vacuum and the residue purified by flash chromatography (DCM/MeOH 90:10) to give 5 mg (y=8% 2 steps) of the acid intermediate 46 as a red solid. MS (ESI): 798 [M+H]+. Retention time=3.94 min. Method 2
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19]Br)[CH3:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:15]([O:17][CH:18]([O:21][CH2:22][CH3:23])[CH2:19][O:14][C:11]1[CH:12]=[CH:13][C:8]([S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:9][CH:10]=1)[CH3:16]
Reactant: Oc1ccc(Sc2ccccc2)cc1
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(Sc2ccccc2)cc1)OCC
Temperature: 25 °C

Procedure:
A mixture of 4-(phenylthio)phenol (4.7 g, 23 mmol), bromoacetaldehyde diethyl acetal (4.3 mL, 28 mmol) and K2CO3 (3.82 g, 28 mmol) in DMF (40 mL) was stirred at reflux for 6 h. The reaction mixture was allowed to cool down to room temperature and poured over ice and diluted to 100 mL with water. The solution was extracted with Et2O (20 mL×3); the combined extracts were washed with 1N NaOH solution, water and brine, dried, and concentrated under reduced pressure to yield a yellow oil that was used without further purification: 1H NMR (400 MHz, CDCl3) δ 7.42 (d, 2H), 7.27-7.06 (m, 5H), 6.92 (d, 2H), 4.84 (t, 1H), 4.02 (d, 2H), 3.84-3.68 (m, 4H), 1.13 (m, 6H).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[Cl:17])=[C:6]([Cl:18])[N:5]=[CH:4][N:3]=1.[CH:19]([C:22]1[CH:23]=[CH:24][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[N:26][CH:27]=1)([CH3:21])[CH3:20].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:18][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:31][S:28]([C:25]2[CH:24]=[CH:23][C:22]([CH:19]([CH3:21])[CH3:20])=[CH:27][N:26]=2)(=[O:30])=[O:29])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[Cl:17]
Reactant: COc1ccc(Cl)c(Oc2c(Cl)ncnc2Cl)c1
Reactant: CC(C)c1ccc(S(N)(=O)=O)nc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CS(C)=O
Product: COc1ccc(Cl)c(Oc2c(Cl)ncnc2NS(=O)(=O)c2ccc(C(C)C)cn2)c1
Temperature: 25 °C
Yield: 53.2 %

Procedure:
306 mg of 4,6-dichloro-5-(2-chloro-5-methoxy-phenoxy)-pyrimidine, 320 mg of 5-isopropyl-2-pyridine-sulphonamide and 180 mg of K tert.butylate dissolved in 2 ml of DMSO were reacted at 90° C. for 3 hours. After cooling to room temperature the reaction medium was acidified with aqueous citric acid; the compound was extracted with ethyl acetate and, after distillation of the solvent, crystallized from ethanol. 250 mg of N-[6-chloro-5-(2-chloro-5-methoxy-phenoxy)-pyrimidin-4-yl]-5-isopropyl-pyridine-sulphonamide were obtained as white crystals with m.p. 174°-175° C.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([NH2:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].I[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)CO>[Cu]I.CCCCCC.C(OCC)(=O)C.CC(O)C>[C:17]1([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH2:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Ic1ccccc1
Reactant: CCCCCCN
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: NCCCCCCc1ccccc1
Yield: 85.7 %

Procedure:
The general procedure under argon or air was followed using copper(I) iodide (10 mg, 0.05 mmol or 2.0 mg, 0.01 mmol), K3PO4 (425 mg, 2.00 mmol), hexylamine (159 μL, 1.20 mmol), iodobenzene (112 μL, 1.00 mmol), ethylene glycol (111 μL, 2.00 mmol) and 2-propanol (1.0 mL). Column chromatography using a solvent mixture (hexane/ethyl acetate=20/1, Rf=0.5) afforded N-(phenyl)hexylamine (152 mg, 86% isolated yield) as colorless liquid. The spectral data (1H NMR) matched with the literature references and GC analysis indicated >95% purity. See Bomann, M. D.; Guch, I. C.; DiMare, M. J. Org. Chem. 1995, 60, 5995-5996.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4](O)=[O:5].[NH2:10][C:11]([NH2:13])=[O:12].C(OC(=O)C)(=O)C>CN(C)C=O>[F:1][C:2]([F:9])([F:8])[CH:3]1[CH2:7][NH:13][C:11](=[O:12])[NH:10][C:4]1=[O:5]
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: NC(N)=O
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: O=C1NCC(C(F)(F)F)C(=O)N1
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 63.7 %

Procedure:
A mixture of α-trifluoromethylacrylic acid (350 mg; 2.5 mmoles), urea (170 mg: 2.8 mmoles) and acetic anhydride (1 ml) in dimethyl-formamide (2 ml) was stirred at 100° C. for 40 minutes. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol to give 290 mg (yield: 64%) of 5-trifluoromethyldihydrouracil.
Reaction SMILES: F[CH:2]1[CH:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=O)[CH:6]=[CH:5][CH:4]=[C:3]1[C:16]([F:19])([F:18])[F:17].O.[NH2:21][NH2:22]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.[Cl-].[Na+].O.CCOC(C)=O>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]1[NH:21][N:22]=[C:2]2[C:7]=1[CH:6]=[CH:5][CH:4]=[C:3]2[C:16]([F:19])([F:18])[F:17]
Reactant: O=C(c1ccccn1)C1C=CC=C(C(F)(F)F)C1F
Reactant: NN
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: FC(F)(F)c1cccc2c(-c3ccccn3)[nH]nc12
Yield: 76 %

Procedure:
Next, a solution of (6-fluoro-5-trifluoromethyl-cyclohexa-2,4-dienyl)-pyridin-2-yl-methanone (1.5 g, 5.6 mmol), 4-dimethylaminopyridine (0.5 g) and hydrazine hydrate (5 mL) in pyridine (20 mL) was heated at 100° C. overnight. The reaction mixture was cooled and diluted with brine and EtOAc. The organics were washed with water (3×25 mL), then brine (25 mL) and dried over MgSO4. The reaction mixture was concentrated in vacuo and purified by flash chromatography (silica gel 60, EtOAc/CH2Cl2, 19:1) to afford 3-pyridin-2-yl-7-(trifluoromethyl)-2H-indazole as a pale yellow solid (1.1 g, 76%).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:51][N:52]([CH:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[C:59]([F:62])([F:61])[F:60]>CN(C=O)C.O>[CH3:51][N:52]([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[C:59]([F:62])([F:60])[F:61])[CH:63]1[CH2:68][CH2:67][N:66]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:11][N:10]=2)=[O:13])[CH2:65][CH2:64]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)on1
Reactant: CN(c1ccccc1C(F)(F)F)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(c1ccccc1C(F)(F)F)C1CCN(C(=O)CNC(=O)c2cc(-c3ccccc3)on2)CC1
Reaction time: 8 h
Yield: 14.7 %

Procedure:
To a stirred solution of [(5-phenyl-isoxazole-3-carbonyl)-amino]-acetic acid (0.0576 g, 0.00021 mol) in DMF (1 mL), was added DIPEA (0.1317 g, 0.0010 mol), HOBt (0.035 g, 0.00025 mol) and EDCI.HCl (0.049 g, 0.00025 mol) at ambient temperature. After 2 minutes methyl-piperidin-4-yl-(2-trifluoromethyl-phenyl)-amine hydrochloride (0.06 g, 0.00021 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product extracted with ethyl acetate. The ethyl acetate layer was collected and washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC [(column-Zorbax SB C18-21.2×150 mm, mobile phase-0.1% TFA in water (A)/acetonitrile (B), gradient: (Time): (% B)-0:30; 2:50; 8:80)]) to afford 0.015 g (15%) of 5-phenyl-isoxazole-3-carboxylic acid (2-{4-[methyl-(2-trifluoromethyl-phenyl)-amino]-piperidin-1-yl}-2-oxo-ethyl)-amide. LCMS: 487.19 (M+1)+, 98.16%, 1H NMR (DMSO-d6): δ 8.58 (t, 1H), 7.94 (m, 2H), 7.7 (m, 2H), 7.56 (m, 3H), 7.34 (m, 2H), 4.3 (m, 1H), 4.15 (d, 2H), 3.8 (d, 1H), 3.0 (m, 2H), 2.6 (s, 3H), 1.7 (m, 2H), 1.4 (m, 1H), 1.3 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11]C)=[O:10])([CH3:5])[C:3]#[CH:4].O1CCCC1.[OH-].[Na+].Cl>CO>[CH3:5][C:2]([C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([OH:11])=[O:10])([CH3:1])[C:3]#[CH:4]
Reactant: C#CC(C)(C)c1cccc(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C#CC(C)(C)c1cccc(C(=O)O)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of methyl 3-(1,1-dimethylprop-2-yn-1-yl)benzoate (2.26 g, 11.2 mmol) in methanol (15 mL)/tetrahydrofuran (10 mL) was added 2N aqueous sodium hydroxide solution (11.2 mL, 22.4 mmol), and the mixture was stirred at 60° C. for 3 hr. The reaction mixture was neutralized with 6N hydrochloric acid (5 mL), 1N hydrochloric acid (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL, 20 mL). The combined organic layer was washed with saturated brine (10 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (1.94 g, 92%) as colorless crystals.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[CH2:12][CH2:13][OH:14])[CH3:2].N1C2C(=CC=CC=2)C(CCO)=C1.[CH2:27]([O:29][C:30]([CH:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([CH:32]1[CH2:37][CH2:36][C:35]2([C:9]3[NH:10][C:11]4[C:7]([C:8]=3[CH2:12][CH2:13][O:14]2)=[CH:6][CH:5]=[CH:4][C:3]=4[CH2:1][CH3:2])[CH2:34][CH2:33]1)=[O:31])[CH3:28]
Reactant: CCc1cccc2c(CCO)c[nH]c12
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: OCCc1c[nH]c2ccccc12
Product: CCOC(=O)C1CCC2(CC1)OCCc1c2[nH]c2c(CC)cccc12

Procedure:
Following the procedure of example 24.A. except using 2-(7-ethyl-1H-indol-3-yl)-ethanol as the 3-indolethanol component and 4-oxo-cyclohexane carboxylic acid ethyl ester as ketone component afforded the title compound as an oil. ESI (+) MS m/e=342 (MH+), ESI (−) MS m/e=340 (MH−).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14]1>CN(C)C=O>[O:19]=[C:13]([N:10]1[CH2:11][CH2:12][N:7]([C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:8][CH2:9]1)[CH2:14][CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C1CCC(=O)O1
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: CN(C)C=O
Product: O=C(O)CCC(=O)N1CCN(c2ncccn2)CC1
Yield: 70.7 %

Procedure:
A solution of 1-(2-pyrimidinyl)piperazine (3.28 g) and succinic anhydride (2.2 g) in dimethylformamide (15 ml) was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure and the concentrate was recrystallized from ethanol/ethyl ether to give the titled compound (3.73 g) as a colorless crystal.
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[CH:25]=[C:26]([S:28]([CH2:31][CH3:32])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])C.[OH-].[Na+]>>[C:42]([CH2:41][CH2:40][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[CH:25]=[C:26]([S:28]([CH2:31][CH3:32])(=[O:29])=[O:30])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:47])=[O:3])([OH:44])=[O:43]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccc(F)cc3)cc(S(=O)(=O)CC)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)cc2)c1
Yield: 48.8 %

Procedure:
A similar procedure as described in Example 40, step 8 was used, starting from 4-[3-[6-(5-ethanesulfonyl-4′-fluoro-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (115 mg, 0.17 mmol) and 1.0 N aqueous sodium hydroxide (1.7 mL) to afford 4-[2-(2-carboxy-ethyl)-3-[6-(5-ethanesulfonyl-4′-fluoro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid (51 mg, 48%) as an amorphous white solid: ES(+)-HRMS m/e calcd for C33H39FO8S (M+Na)+ 637.2242, found 637.2242.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1>C(Cl)Cl.O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][O:14]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: OCc1ccc(Br)c2cccnc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: Brc1ccc(COC2CCCCO2)c2ncccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 128.4 %

Procedure:
To a solution of (5-bromoquinolin-8-yl)methanol (8.0 g, 33.6 mmol) in methylene chloride (120 mL) were added pyridinium p-toluenesulfonate (844 mg, 3.3 mmol) and 3,4-dihydro-2H-pyran (6.1 mL, 67.2 mmol) and stirred at RT for 16 h. The reaction mixture was diluted with water, extracted with methylene chloride, dried with magnesium sulfate and concentrated. Purification by MPLC (20% ethyl acetate in hexanes) afforded 13.9 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[Cl:44][C:45]1[CH:51]=[CH:50][CH:49]=[CH:48][C:46]=1[NH2:47]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([NH:47][C:46]4[CH:48]=[CH:49][CH:50]=[CH:51][C:45]=4[Cl:44])[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: Nc1ccccc1Cl
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(Nc4ccccc4Cl)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 61 %

Procedure:
In a manner analogous to that described in Example 3 a), the amination of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-4-(5-bromo-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.1) with 2-chloroaniline yielded the title compound (61% yield) as an off-white foam. MS (ISP): m/z=700.4 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1)([O-:3])=[O:2].[I-].[K+].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CCl)n1-2
Reactant: C1COCCN1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1)=NCc1nnc(CN3CCOCC3)n1-2

Procedure:
In the manner given in Preparation 48, 8-nitro-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, potassium iodide, and morpholine in tetrahydrofuran are reacted to give 8-nitro-1-(morpholinomethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:5][CH:4]=1)#[N:2].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:9]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)[C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[CH:18][CH:17]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: N#Cc1ccc(Nn2cncn2)cc1
Product: N#Cc1ccc(N(Cc2ccc(Cl)cc2)n2cncn2)cc1

Procedure:
Starting Compounds: 1-[N-(4-cyanophenyl)amino]-1H-1,2,4-triazole and 4-chlorobenzyl chloride
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].OS(O)(=O)=O.O=S(=O)=O>C(Cl)Cl>[C:1]([C:5]1[CH:13]=[CH:12][C:8]2[C:9](=[O:10])[C:20]3[C:15](=[CH:16][C:17]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:18][CH:19]=3)[C:14](=[O:21])[C:7]=2[CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ccc(C(=O)O)c(C(=O)c2ccccc2)c1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: ClCCl
Product: CC(C)(C)c1ccc2c(c1)C(=O)c1cc(C(C)(C)C)ccc1C2=O
Temperature: 120 °C
Reaction time: 3 h
Yield: 138 %

Procedure:
4-t-Butyl-2-benzoylbenzoic acid 4 (32.0 g, 95 mmol) was placed into a round-bottom flask and oleum (30%, 290 mL) was then added. The reaction mixture turned black and the reaction temperature was increased to 120° C. and stirred for 3 h. The mixture was then poured into ice. The aqueous mixture was extracted using CH2Cl2 (5×), dried over Na2SO4 and concentrated to give a dark solid. This solid was passed through a silica gel column using CH2Cl2 as eluent. After concentrating, the yellow-brown solid was recrystallized from hexane to give product as yellow crystals 21.0 g (69% yield). 1H NMR (CDCl3) δ(ppm): 1.42 (s, 18H), 7.80 (d, J=8.2 Hz, 1H), 7.81 (d, J=8.2 Hz), 8.20 (d, J=8.2 Hz, 1H),), 8.22 (d, J=8.2 Hz, 1H), 8.31 (s, 2H); 13C NMR (CDCl3): 31.01, 35.58, 123.83, 123.90, 127.17, 127.28, 131.08, 131.15, 131.34, 131.42, 133.40, 133.49, 157.94, 158.05, 182.76, 183.28,183.78
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][CH2:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[CH:22]=1)([NH:13]C(OC(C)(C)C)=O)[C:9]([F:12])([F:11])[F:10])[CH3:2].Cl.O1CCOCC1>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][CH2:7][C:8]([NH2:13])([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Br:27])[CH:22]=1)[C:9]([F:10])([F:12])[F:11])[CH3:2]
Reactant: CCOC(=O)COCC(NC(=O)OC(C)(C)C)(c1cccc(Br)c1)C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)COCC(N)(c1cccc(Br)c1)C(F)(F)F
Reaction time: 8 h

Procedure:
A solution of 1.4 g (2.47 mmol) [2-(3-bromo-phenyl)-2-tert-butoxycarbonylamino-3,3,3-trifluoro-propoxy]-acetic acid ethyl ester in 5 ml DCM was treated with 3.74 ml 4N HCl/dioxane. After standing overnight the mixture was evaporated, taken up in EtOAc and washed with 10% aqueous NaHCO3. The organic phase was washed with brine, dried with Na2SO4 and purified via chromatography on silica gel (c-hexane/10-15% EtOAc) to give the desired product as a colorless resin.