Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1.[CH3:17][O:18][C:19](=[O:25])[CH:20]([CH3:24])[C:21](O)=[O:22]>ClCCl.CO>[CH3:17][O:18][C:19](=[O:25])[CH:20]([CH3:24])[C:21]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]2[CH:14]=[CH:15][CH:16]=[C:2]([F:1])[CH:3]=2)=[CH:8][CH:9]=1)=[O:22]
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Reactant: COC(=O)C(C)C(=O)O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(C)C(=O)Nc1ccc(OCc2cccc(F)c2)cc1

Procedure:
The title compound is prepared in analogy to example 2, starting from 4-(3-fluoro-benzyloxy)-phenylamine (as prepared in example 1b) and 2-methyl-malonic acid monomethyl ester (Nader et al., Chem. Ber. 1986, 119, 1196). Yield after flash-chromatography with dichloromethane/methanol 98:2: 40%. Colorless solid. Mp=119° C.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[F:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[OH:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([O:30][C:24]3[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=3[F:22])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Oc1ccc(F)cc1F
Reactant: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(Oc2ccc(F)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 150 °C
Yield: 68.5 %

Procedure:
A mixture of 4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (1.0 g, 3.19 mmol), 2,4-difluoro-phenol (585 mg, 4.5 mmol), and potassium carbonate (882 mg, 6.38 mmol) in DMF (11 mL) was heated under microwave irradiation for 80 min at 150° C. The crude mixture was concentrated in vacuo and purified by HPLC to provide Compound C117 as a beige solid (890 mg, 69%). 1H NMR (CDCl3, 400 MHz) δ 1.19 (d, 6H), 1.66-1.76 (m, 2H), 1.86-1.95 (m, 2H), 2.11 (s, 3H), 3.30-3.40 (m, 2H), 3.63-3.73 (m, 2H), 4.86 (m, 1H), 5.26 (m, 1H), 6.80-6.91 (m, 2H), 7.09 (q, 1H), 7.19 (s, 1H). Exact mass calculated for C20H23F2N3O4 407.41, found 408.3 (MH+).
Reaction SMILES: O=P(Cl)(Cl)Cl.[Br:6][C:7]1[CH:8]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[C:10]2[CH:11]=[CH:12][N:13]([CH:16]([CH3:18])[CH3:17])[C:14]=2[CH:15]=1.[OH-].[Na+].CN([CH:28]=[O:29])C>O>[Br:6][C:7]1[CH:8]=[C:9]([C:19]([O:21][CH3:22])=[O:20])[C:10]2[C:11]([CH:28]=[O:29])=[CH:12][N:13]([CH:16]([CH3:18])[CH3:17])[C:14]=2[CH:15]=1
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1cc(Br)cc2c1c(C=O)cn2C(C)C
Reaction time: 0.33 h
Yield: 91.3 %

Procedure:
To a stirred solution of DMF (1.04 lit) POCl3 (40.3 g, 263 mmol) was added at 0° C. and stirred for 20 min. Then methyl 6-bromo-1-isopropyl-1H-indole-4-carboxylate (65 g, 219.5 mmol) in DMF (260 mL) was added to the reaction mixture at 0° C. The reaction mixture was stirred at room temperature for 3 h. Diluted the reaction mixture with cold water and adjusted PH˜8 using with 2N NaOH solution, extracted with ethylacetate (4×1 lit). The organic layer washed with cold water, brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford desired product methyl 6-bromo-3-formyl-1-isopropyl-1H-indole-4-carboxylate (65 g, 91.3%). 1H NMR (CDCl3, 400 MHz): δ 1.588 (d, 6H, J=6.8 Hz), 3.994 (s, 3H), 4.634-4.701 (m, 1H), 7.760 (d, 1H, J=1.6 Hz), 7.958 (d, 1H, J=1.6 Hz), 8.122 (s, 1H), 10.446 (s, 1H). LC-MS (ES+) m/z=324.02 (M+H)
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(O)(=O)C.[Br:18]N1C(=O)CCC1=O>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:18])=[C:10]([OH:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)N1CCc2ccc(O)cc21
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2cc(Br)c(O)cc21
Temperature: 12.5 °C
Reaction time: 0.75 h
Yield: 73.6 %

Procedure:
A stirred suspension of finely powdered 1-acetyl-6-hydroxyindoline (D63, 2.4 g, 0.013 mole) in a mixture of DMF (25 ml) and glacial acetic acid (125 ml) at 15° C. was treated portionwise over 5 minutes with N-bromosuccinimide (2.65 g, 0.015 mole). The reaction mixture changed from yellow to grey-green in colour. The mixture was stirred at 1 5-20° C. for 45 minutes, then cooled to 5° C. and the solid filtered off, washed with acetic acid and dried to give the title compound as a grey solid (2.45 g, 71%).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([OH:12])[CH:6]=1)=O.[C:13](=[S:16])([S-:15])[NH2:14].[NH4+]>CO>[OH:12][C:7]1[CH:6]=[C:5]([C:3]2[N:14]=[C:13]([SH:16])[S:15][CH:2]=2)[CH:10]=[CH:9][C:8]=1[OH:11]
Reactant: O=C(CCl)c1ccc(O)c(O)c1
Reactant: NC(=S)[S-]
Agent: [NH4+]
Solvent: CO
Product: Oc1ccc(-c2csc(S)n2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
10.0 g (53.6 mmol) of 2-chloro-3'4'-dihydroxyacetophenone was dissolved in 100 ml of methanol, and then 5.90 g (53.6 mmol) of ammonium dithiocarbamate was added thereto. The mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure. To the residue, water was added to adjust the mixture to pH2.0, and then the mixture was extracted twice with ethyl acetate. The extract was dried over anhydrous sodium sulfate and-then concentrated. The crystal residue was washed with diethyl ether to obtain 8.80 g (yield: 72.9%) of the above-identified compound.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[F:7][C:8]([F:25])([F:24])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(I)CC>C1COCC1>[F:7][C:8]([F:24])([F:25])[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:18])[F:16])=[CH:11][C:10]=1[CH:19]([CH2:1][CH2:2][CH3:3])[C:20]([O:22][CH3:23])=[O:21]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)Cc1cc(C(F)(F)F)ccc1C(F)(F)F
Agent: [K+]
Solvent: CCCI
Solvent: C1CCOC1
Product: CCCC(C(=O)OC)c1cc(C(F)(F)F)ccc1C(F)(F)F
Reaction time: 1 h
Yield: 87 %

Procedure:
Potassium t-butoxide (7.7 ml, 1M in THF, 7.7 mmol) was added to a solution of methyl 2-[2,5-bis(trifluoromethyl)phenyl]acetate (2 g, 7 mmol) in THF at 0° C. The resulting yellow solution was stirred for 40 min. n-Propyl iodide (1.7 g, 10.5 mmol) was added and the mixture stirred for 1 h. The mixture was poured onto HCl (2M) and extracted into EtOAc. The combined organic phases were washed with Na2S2O3 solution, brine, then dried (MgSO4) and concentrated in vacuo to give the product as a yellow oil (2 g, 87%). 1H NMR (400 MHz, CDCl3): δ 0.92 (3H, t, J 7.3), 1.23-1.29 (1H, m), 1.35-1.43 (1H, m), 1.67-1.81 (1H, m), 2.05-2.17 (1H, m), 3.69 (3H, s), 4.10 (1H, t, J 7.5), 7.62 (1H, s, J 8.2), 7.78 (1H, d, J 8.2), 7.90 (1H, s).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([CH3:14])[CH:7]=1.BrCCC[Cl:19].CC1C=C(O)C=CC=1C=O.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:19][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[C:8]([CH3:14])[CH:7]=1
Reactant: ClCCCBr
Reactant: Cc1cc(OCCCI)ccc1C=O
Agent: Cc1cc(O)ccc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(OCCCCl)ccc1C=O
Temperature: 65 °C
Yield: 82 %

Procedure:
4-(3-Iodo-propoxy)-2-methyl-benzaldehyde. 1-Bromo-3-chloropropane (5.03 g, 32.0 mmol, 1.0 equiv) was added to a solution of 2-methyl-4-hydroxybenzaldehyde (4.35 g, 32.0 mmol, 1.0 equiv) and K2CO3 (8.8 g, 64.0 mmol, 2.0 equiv) in acetonitrile (75 mL). The mixture was heated at 65° C. for 16 h, then cooled to rt and filtered through diatomaceous earth. The filtrate was concentrated and the residue was purified by column chromatography (silica gel, 10% ethyl acetate in hexanes) to afford 5.58 g (82%) of 4-(3-chloro-propoxy)-2-methyl-benzaldehyde. To a refluxing solution of 4-(3-chloro-propoxy)-2-methyl-benzaldehyde in acetone (100 mL), KI (58 g) was added portion wise over 3 d. The mixture was cooled to rt and water was added. The aqueous mixture was extracted three times with ethyl acetate and the combined extracts were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, 5% ethyl acetate in hexanes) to afford 6.13 g (77%) of the title compound. 1H NMR (400 MHz, CD3OD): 10.1 (s, 1H), 7.75 (d, J=8.6 Hz, 1H), 6.84 (dd, J=8.6, 2.5 Hz, 1H), 6.74 (d, J=2.2 Hz, 1H), 4.11 (t, J=5.8 Hz, 2H), 3.36 (t, J=6.7 Hz, 2H), 2.65 (s, 3H), 2.29 (m, 2H).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=[O:8])=[N+:2]=[N-:3].[C:14]([C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:20][CH:21]=1)#[CH:15]>CCO>[CH3:13][C:12]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N:1]1[CH:15]=[C:14]([C:16]2[CH:21]=[N:20][C:19]([CH2:22][N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[CH:18][CH:17]=2)[N:3]=[N:2]1
Reactant: C#Cc1ccc(CN2CCOCC2)nc1
Reactant: Cc1ccc(C(=O)O)cc1N=[N+]=[N-]
Solvent: CCO
Product: Cc1ccc(C(=O)O)cc1-n1cc(-c2ccc(CN3CCOCC3)nc2)nn1
Temperature: 140 °C
Yield: 80 %

Procedure:
A suspension of 87.5 mg (0.494 mmol) of 3-azido-4-methyl-benzoic acid and 100 mg (0.494 mmol) of 4-(5-ethynyl-pyridin-2-ylmethyl)-morpholine were suspended in 200 μL of EtOH and heated to 140° C. for 1 h in a microwave reactor. After cooling, the mixture was concentrated to provide 150 mg of 4-methyl-3-[4-(6-morpholin-4-ylmethyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzoic acid, and its triazole isomer 4-methyl-3-[5-(6-morpholin-4-ylmethyl-pyridin-3-yl)-1,2,3-triazol-1-yl]-benzoic acid in a 2:1 ratio
Reaction SMILES: Cl[C:2](=[O:14])[CH2:3][C:4]1([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[Br:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:2](=[O:14])[CH2:3][C:4]2([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8][O:7][CH2:6][CH2:5]2)=[CH:18][CH:17]=1
Reactant: Brc1ccccc1
Reactant: COC(=O)C1(CC(=O)Cl)CCOCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C1(CC(=O)c2ccc(Br)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
To a solution of methyl 4-(2-chloro-2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate (1.06 g, 4.8 mmol) and bromobenzene (1.13 g, 7.21 mmol) in dichloromethane (20 mL) at 0° C. was added aluminum chloride (1.92 g, 14.4 mmol). The ice-water bath was removed and the reaction mixture was stirred at rt for 16 h. The mixture was then cooled at 0° C. and quenched by the addition of 1 N HCl solution and water. The mixture was extracted with dichloromethane, and the combined organic phases were dried over sodium sulfate. The crude material was then purified by flash chromatography (Biotage Flash 40 M, 2:1 hexane/ethyl acetate, to afford methyl 4-[2-(4-bromo-phenyl)-2-oxoethyl]tetrahydro-2H-pyran-4-carboxylate (900 mg, 55%). LC-MS ret. time 2.76 min; m/z 342.9 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.58–1.69 (m, 2H), 2.12–2.18 (m, 2H), 3.28 (s, 2H), 3.64 (s, 3H), 3.69–3.77 (m, 4H), 7.59 (d, 2H), 7.77 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[OH:13].[Cl:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[Cl:14][C:15]1[CH:23]=[N:22][CH:21]=[CH:20][C:16]=1[C:17]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:10])[F:11])=[CH:4][C:3]=1[OH:13])=[O:18]
Reactant: O=C(O)c1ccncc1Cl
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1O
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cc(Cl)c(C(F)(F)F)cc1O)c1ccncc1Cl
Temperature: 80 °C
Yield: 69.9 %

Procedure:
A mixture of 0.60 g of 2-amino-4-chloro-5-trifluoromethylphenol, 0.43 g of 3-chloroisonicotinic acid, 0.67 g of WSC and 5 ml of pyridine was stirred while heating at 80° C. for three hours. The reaction mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate three times. The combined organic layers were washed with water and a saturated sodium chloride solution, dried anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.67 g of 3-chloro-N-[5-chloro-2-hydroxy-4-trifluoromethylphenyl]isonicotinamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[N:21]=[C:20]([N:22]3[CH2:27][C@@H:26]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][C@@H:24]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:23]3)[N:19]=[C:18]([N:44]3[CH2:49][C@@H:48]([NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:47][C@@H:46]([NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:45]3)[N:17]=2)[CH:12]=[CH:11][C:10]=1[NH2:66])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:67][C:68]1[CH:79]=[CH:78][C:71]2[C:72](=O)[O:73]C(=O)[O:75][C:70]=2[CH:69]=1>CN1C(=O)CCC1.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[N:21]=[C:20]([N:22]3[CH2:27][C@@H:26]([NH:28][C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH2:25][C@@H:24]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:23]3)[N:19]=[C:18]([N:44]3[CH2:45][C@@H:46]([NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:47][C@@H:48]([NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:49]3)[N:17]=2)[CH:12]=[CH:11][C:10]=1[NH:66][C:72](=[O:73])[C:71]1[CH:78]=[CH:79][C:68]([Cl:67])=[CH:69][C:70]=1[OH:75])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc(Nc3ccc(N)c(OCc4ccccc4)c3)nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)n2)C1
Reactant: O=c1oc(=O)c2ccc(Cl)cc2o1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CN(c2nc(Nc3ccc(NC(=O)c4ccc(Cl)cc4O)c(OCc4ccccc4)c3)nc(N3C[C@H](NC(=O)OC(C)(C)C)C[C@H](NC(=O)OC(C)(C)C)C3)n2)C1
Temperature: 80 °C
Yield: 60 %

Procedure:
2-Benzyloxy-N4-(4,6-bis-((3R,5S)-3,5-bis-(tert-butoxycarbonylamino)-piperidin-1-yl)-[1,3,5]triazin-2-yl)-benzene-1,4-diamine (83) (0.16 g, 0.174 mmol) and 7-chloro-benzo[1,3]dioxine-2,4-dione (91) (0.2 g, 1.0 mmol) were combined and dissolved in NMP (8 mL). The mixture was heated to 80° C. for 16 h. LC-MS indicated complete reaction at this point. The mixture was diluted with EtOAc (30 mL), washed with water (2×15 mL), saturated aqueous NaHCO3 (2×15 mL) and brine (2×15 mL) via extraction, dried over MgSO4 and concentrated to give a brown oil. Purification by flash chromatography on silica gel using a gradient of hexane and EtOAc (15–100% EtOAc in hexane) gave the desired product (92) as a yellow powder upon concentration (0.111 g, 0.103 mmol, 60% yield). LC-MS (ESI): (exact mass: 1073.51) m/e=1074.6 [M+1]+ (100%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cc(I)ccc1Br
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(I)ccc1Br
Temperature: 60 °C
Reaction time: 60 h

Procedure:
To a solution of 2-bromo-5-iodobenzoic acid (2-1), 5.0 g, 15.3 mmol, 1.0 equiv) in methanol (45 mL) was added sulfuric acid (1.06 mL, 19.9 mmol, 1.3 equiv). The reaction mixture was stirred for 60 hours at 60° C., then heated to reflux and stirred 24 hours more. The reaction mixture was cooled, partitioned between EtOAc and saturated sodium bicarbonate solution. The layers were separated and the aqueous layer extracted with ethyl acetate. The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated to afford the product (2-2) as a white solid. ESI+ MS [M]+ C8H6BrIO2: 340.7 found, 340.9 required.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([OH:14])=[O:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.N1C2C(=CC=CC=2)C(C(O[CH2:27][C:28]23[CH2:35][CH2:34][N:31]([CH2:32][CH2:33]2)[CH2:30][CH2:29]3)=O)=C1>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([O:14][CH2:27][C:28]34[CH2:35][CH2:34][N:31]([CH2:32][CH2:33]3)[CH2:30][CH2:29]4)=[O:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: O=C(OCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Reactant: COc1ccc2c(C(=O)O)c[nH]c2c1
Product: COc1ccc2c(C(=O)OCC34CCN(CC3)CC4)c[nH]c2c1

Procedure:
Quinuclidin-4-ylmethyl 6-methoxy-1H-indole-3-carboxylate was prepared starting from 6-methoxyindole-3-carboxylic acid (synthesized as described in J. Med. Chem. 51, 1849 (2008)) following the procedure of (Quinuclidin-4-yl)methyl 1H-indole-3-carboxylate. MS (m/e): 314.
Reaction SMILES: C([O:3][C:4](=[O:41])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4[N:27]=[C:28]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[O:29][C:30]=4[C:31]([F:34])([F:33])[F:32])=[O:25])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C.[Li+].[OH-]>C1COCC1.CO>[C:35]1([C:28]2[O:29][C:30]([C:31]([F:32])([F:34])[F:33])=[C:26]([C:24]([NH:23][C:20]3[CH:21]=[CH:22][C:17]([N:14]4[CH2:13][CH2:12][N:11]([C:8]5[CH:9]=[CH:10][C:5]([C:4]([OH:41])=[O:3])=[CH:6][CH:7]=5)[CH2:16][CH2:15]4)=[N:18][CH:19]=3)=[O:25])[N:27]=2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CCOC(=O)c1ccc(N2CCN(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cn3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(N2CCN(c3ccc(NC(=O)c4nc(-c5ccccc5)oc4C(F)(F)F)cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 4-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazin-1-yl)-benzoic acid ethyl ester (130 mg, 0.23 mmol) dissolved in a 1:1 mixture of THF/methanol (2 mL) was added 1N LiOH (2.60 mL, 2.60 mmol). The mixture was stirred at rt overnight. The crude mixture was acidified to pH=1 and purified by HPLC to give 4-(4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyridin-2-yl}-piperazin-1-yl)-benzoic acid. The NMR spectrum obtained on the sample is compatible with its structure. LCMS calcd for C27H22F3N5O4 (m/e) 537, obsd 538 (M+H).
Reaction SMILES: C(O)C.[CH:4]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)([CH3:6])[CH3:5].Cl[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(N(CC)CC)C>[CH2:18]([O:17][C:15]([CH2:14][N:10]1[CH2:11][CH2:12][N:7]([CH:4]([CH3:6])[CH3:5])[CH2:8][CH2:9]1)=[O:16])[CH3:19]
Reactant: CC(C)N1CCNCC1
Reactant: CCOC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CN1CCN(C(C)C)CC1
Yield: 68.3 %

Procedure:
One hundred milliliters of an ethanol solution containing 7 g of 1-isopropylpiperazine, 6.2 g of ethyl chloroacetate and 9.2 m of triethylamine was heated and refluxed for 4 hours. After being concentrated under reduced pressure, the resulting mixture was added with ethyl acetate. Insoluble matter was removed by filtration. Thereafter, the residue was purified by silica gel chromatography (eluent: a 20:1 mixture of chloroform and methanol) to obtain 7.4 g of 1-ethoxycarbonylmethyl-4-isopropylpiperazine as a light brownish oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[C:16](Cl)=[O:17].S1C=CC=C1C(Cl)=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:16](=[O:17])[C:15]2[CH:19]=[C:20]([C:22]([F:23])([F:24])[F:25])[CH:21]=[C:13]([F:12])[CH:14]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=C(Cl)c1cc(F)cc(C(F)(F)F)c1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C(Cl)c1cccs1
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cc(F)cc(C(F)(F)F)c1

Procedure:
4-Fluoro-3-nitro-phenylamine was reacted with 3-fluoro-5-trifluoromethyl-benzoyl chloride according to the procedure of Example 256a substituting 3-fluoro-5-trifluoromethyl-benzoyl chloride for thiophene-2-carbonyl chloride to provide N-(4-Fluoro-3-nitro-phenyl)-3-fluoro-5-trifluoromethyl-benzamide which was then reacted according to the procedures of Examples 256b and 256c to provide the title product.
Reaction SMILES: ClC1C=CC=C(Cl)C=1C(Cl)=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=1[C:42]([N:44]=[C:45]=[S:46])=[O:43]>C1(C)C=CC=CC=1.C(O)C>[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=1[C:42]([N:44]=[C:45]=[S:46])=[O:43].[Cl:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([Cl:41])[C:36]=1[C:42]([NH:44][C:45]([NH:31][C:30]1[CH:32]=[CH:33][C:27]([O:26][C:17]2[C:16]3[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=3)[N:20]=[CH:19][N:18]=2)=[CH:28][CH:29]=1)=[S:46])=[O:43]
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1c(Cl)cccc1Cl
Agent: O=C(N=C=S)c1c(Cl)cccc1Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4c(Cl)cccc4Cl)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
2,6-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,6-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,6-dichloro-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (56 mg, yield 63%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:7][C:6]=2[CH:14]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:22]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](=[O:12])(=[O:11])[NH2:13])=[N:7][C:6]=2[CH:14]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NS(=O)(=O)c1nc2cc(O)ccc2s1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1nc2cc(OC(=O)c3ccccc3)ccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 5-hydroxy-2-benzothiazolesulfonamide (7.0 g., 0.03 mole), triethylamine (4.2 ml., 0.03 mole) and 4-dimethylaminopyridine (200 mg., catalyst) in dimethylformamide (25 ml.) is added benzoyl chloride (1.4 g., 0.01 mole). The reaction mixture is stirred at 25° C. for 11/2 hours and then poured into ice water (150 ml.) containing excess hydrochloric acid to give 2-sulfamoyl-5-benzothiazolyl benzoate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]([CH3:16])=[C:9]2[C:17]([OH:19])=O)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[F:30])[NH:26][N:25]=[CH:24]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]([CH3:16])=[C:9]2[C:17]([NH:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][C:29]=2[F:30])[NH:26][N:25]=[CH:24]3)=[O:19])=[CH:6][CH:7]=1
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2)CC(=O)N1C
Reactant: Nc1cc2cn[nH]c2cc1F
Product: CC1=C(C(=O)Nc2cc3cn[nH]c3cc2F)C(c2ccc(Cl)cc2)CC(=O)N1C

Procedure:
The title compound was prepared from the product of Example 56, Step 2 and 5-amino-6-fluoroindazole using the method described in Example 56, Step 3. MS (ES+) m/e 413 [M+H]+