Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:20])=[C:4]([CH3:19])[C:5]2[O:9][CH:8]([CH2:10][CH2:11][CH2:12][O:13][CH2:14][O:15][CH3:16])[S:7][C:6]=2[C:17]=1[CH3:18].[C:21](OC(=O)C)(=[O:23])[CH3:22].C1C=CC=CC=1>N1C=CC=CC=1>[C:21]([O:1][C:2]1[C:3]([CH3:20])=[C:4]([CH3:19])[C:5]2[O:9][CH:8]([CH2:10][CH2:11][CH2:12][O:13][CH2:14][O:15][CH3:16])[S:7][C:6]=2[C:17]=1[CH3:18])(=[O:23])[CH3:22]
Reactant: COCOCCCC1Oc2c(C)c(C)c(O)c(C)c2S1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COCOCCCC1Oc2c(C)c(C)c(OC(C)=O)c(C)c2S1

Procedure:
100 mg of 5-hydroxy-2-(3-methoxymethoxypropyl)-4,6,7-trimethyl-1,3-benzoxathiole (prepared as described in Example 83) were dissolved in 1 ml of pyridine, and 50 mg of acetic anhydride were added. The reaction mixture was allowed to react for 20 hours at room temperature. Benzene was then added to the reaction mixture, and the benzene solution was washed with water and then dried over anhydrous sodium sulfate. The benzene was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography. The title compound was obtained from the fraction eluted with a 20:1 by volume mixture of benzene and ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[NH:25][N:24]=[N:23][N:22]=3)[C:9]=2[CH3:26])=[CH:4][CH:3]=1.[CH2:27](O)[C:28]1[O:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]3[N:25]([CH2:27][C:28]4[O:32][CH:31]=[CH:30][CH:29]=4)[N:24]=[N:23][N:22]=3)[C:9]=2[CH3:26])=[CH:4][CH:3]=1
Reactant: Cc1c(-c2nnn[nH]2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: OCc1ccco1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1c(-c2nnnn2Cc2ccco2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 16.2 %

Procedure:
A mixture of 5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-1H-tetrazole (113 mg, 0.28 mmol) obtained in Step 1 of Example 52, furfuryl alcohol (0.05 ml, 0.56 mmol) and triphenylphosphine (146 mg, 0.56 mmol) was dissolved in tetrahydronfuran (3 ml) and cooled down to 0° C. Then, diisopropyl azodicarboxylate (0.11 ml, 0.56 mmol) was slowly added thereto at 0° C. After stirring for 2 hours at room temperature, the resulting solution was quenched with saturated ammonium chloride solution (1 ml). The mixture was extracted with ethyl acetate, and then the solvent of the organic layer was removed under a reduced pressure. The residue contained two regioisomers were separated by silica gel column chromatography (hexane/ethyl acetate=1/5), and repurified by reverse phase preparative HPLC, to obtain two compound, one of which was the title compound (22 mg, 16%).
Reaction SMILES: [O:1]1[C:6]2=[C:7]3[C:12](=[CH:13][CH:14]=[C:5]2[O:4][CH2:3][CH2:2]1)[N:11]=[CH:10][CH:9]=[C:8]3O.P(Br)(Br)[Br:17].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Br:17][C:8]1[C:7]2[C:12](=[CH:13][CH:14]=[C:5]3[O:4][CH2:3][CH2:2][O:1][C:6]3=2)[N:11]=[CH:10][CH:9]=1
Reactant: BrP(Br)Br
Reactant: Oc1ccnc2ccc3c(c12)OCCO3
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccnc2ccc3c(c12)OCCO3
Temperature: 25 °C
Yield: 90 %

Procedure:
2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-10-ol (2.8 g) in dry DMF (8 mL) was cooled in ice and phosphorus tribromide (0.7 mL) added drop-wise, and the mixture was stirred, with ice-cooling for 30 minutes then allowed to warm to room temperature and stirred for a further 2 hours. It was cooled in ice and sodium carbonate solution was added and the solid was collected, washed well with water, and dried in vacuo, to afford a pale yellow solid (1.65 g, 90%). LC/MS (ES) m/z 267.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([NH:10][C:11](=O)[CH2:12][Cl:13])=[C:4]([F:15])[CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:17].P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([N:10]=[C:11]([Cl:17])[CH2:12][Cl:13])=[C:4]([F:15])[CH:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COc1cc(NC(=O)CCl)c(F)cc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(N=C(Cl)CCl)c(F)cc1Cl
Reaction time: 1 h
Yield: 78.3 %

Procedure:
First, 2.00 g of N-(4-chloro-2-fluoro-5-methoxyphenyl)-2-chloroacetamide was mixed with 1.66 g of phosphorus pentachloride, and the stirring was continued for 1.0 hr at 60° C. After letting the mixture stand to cool the same, the produced phosphorus oxychloride was distilled out under reduced pressure. Then, the residue was refined by vacuum distillation to obtain 1.68 g of N-(4-chloro-2-fluoro-5-methoxyphenyl)-2-chloroacetimidoylchloride. The boiling point was 121° C./0.5 mm Hg.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21]1[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=1>>[CH3:19][O:20][C:21]1[C:22]([NH:27][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[CH:11]=2)=[N:23][CH:24]=[CH:25][CH:26]=1
Reactant: COc1cccnc1N
Reactant: O=C(O)c1cccc(S(=O)(=O)c2ccccc2)c1
Product: COc1cccnc1NC(=O)c1cccc(S(=O)(=O)c2ccccc2)c1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(phenylsulfonyl)benzoic acid and 3-methoxypyridine-2-amine as the starting materials.
Reaction SMILES: C(O)C.Cl.Cl.[Cl:6][C:7]1[C:8]([F:33])=[C:9]([CH:30]=[CH:31][CH:32]=1)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:28][CH3:29])=[C:18]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH:19]=2)[N:14]=[CH:13][N:12]=1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>CN(C)C1C=CN=CC=1.C(#N)C>[Cl:6][C:7]1[C:8]([F:33])=[C:9]([CH:30]=[CH:31][CH:32]=1)[NH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:28][CH3:29])=[C:18]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:38](=[O:37])[CH2:39][OH:40])[CH2:24][CH2:23]3)[CH:19]=2)[N:14]=[CH:13][N:12]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: CC#N
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(C(=O)CO)CC1
Reaction time: 1 h
Yield: 83.9 %

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxy-6-(piperidin-4-yloxy)-quinazoline dihydrochloride ethanol solvate (91.8 g), 4-(dimethylamino)pyridine (73.3 g) and acetonitrile (330 ml) were stirred at 20° C. to 25° C., under nitrogen. Acetoxyacetyl chloride (28 ml) was added maintaining the temperature at less than 30° C., followed by an acetonitrile line wash (37 ml). The reaction mixture was stirred at ambient for 60 minutes before water (250 ml) and 47% w/w sodium hydroxide solution (77.2 ml) were added followed by a water line wash (25 ml), keeping the temperature at less than 30° C. The reaction mixture was stirred at ambient for 120 minutes before the lower aqueous layer was separated. Water (735 ml) was added to the organic layer and mixture stirred at ambient until a solid crystallised. The solid was filtered, washed with a 50% aqueous acetonitrile (2×90 ml), and then dried in a vacuum oven between 50° C. and 55° C. to give the title product (65.8 g; 83.9% yield); melting point 195.5–196.5° C.; NMR Spectrum: (DMSO d6) 1.64–1.83 (m, 2H); 1.98–2.14 (m 2H); 3.28–3.48 (m, 1H); (m, 2H); 3.57–3.67 (m, 1H); 3.81–3.92 (m, 1H); 4.00 (s 3H); 4.14 (s, 2H); 4.81 (m 1H); 7.27 (s 1H); 7.36 (t 1H); 7.54–7.64 (m 2H); 8.00 (s 1H); 8.66 (s 1H); Mass Spectrum: (M+H)30 460.9.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([Cl:25])=[CH:6][C:7]2[C:8]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13][C:9]=3[NH:10][C:11]=2[CH:12]=1.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C>[Cl:3][C:4]1[C:5]([Cl:25])=[CH:6][C:7]2[C:8]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13][C:9]=3[N:10]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:11]=2[CH:12]=1
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(Cl)c(Cl)cc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2c(c3cc(Cl)c(Cl)cc31)CCN(C(=O)OC(C)(C)C)CC2
Reaction time: 0.33 h
Yield: 84.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.34 g, 8.5 mmol) was added to a solution of tert-butyl 8,9-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (2.00 g, 5.63 mmol) in DMF (30 mL). After 20 min, ethyl bromoacetate (1.25 mL, 11.3 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 4 h and extracted with EtOAc (3×50 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography with heptane/EtOAc (3:1) to give 2.10 g (84%) of a pale yellow solid: mp 137.5-139.5° C.; IR (diffuse reflectance) 2985, 1742, 1687, 1473, 1411, 1377, 1367, 1341, 1318, 1249, 1218, 1193, 1167, 1118, 922 cm−1; MS (CI) m/z 441 (M+H+), 404, 402, 387, 385, 343, 341, 339, 307, 52, 5 1; Anal. Calcd for C21H26Cl2N2O4: C, 57.15; H, 5.94; N, 6.35; found: C, 57.13; H, 6.05; N, 6.24.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[CH:8]=[N:7]2.P(Cl)(Cl)([Cl:15])=O>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:15])[CH:8]=[N:7]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cnc2cccc(Br)c2[nH]1
Product: Clc1cnc2cccc(Br)c2n1
Temperature: 50 °C
Yield: 55 %

Procedure:
A mixture of 8-bromoquinoxalin-2(1H)-one (483 mg, 2.146 mmol) in phosphoryl trichloride (100 mL) was heated to 50° C. for 2 h. The crude material was concentrated to remove the POCl3, diluted with EtOAc (150 ml), added to a separatory funnel, and washed with water (2×100 ml) and saturated aq. NaHCO3 (100 ml) before the organic layer was separated, dried over Na2SO4, and concentrated. The mixture and was adsorbed onto silica and was purified via automated flash chromatography (silica gel) with 100% hexanes to 5% EtOAc/hexanes to give 8-bromo-2-chloroquinoxaline (210e, 55% yield) as an off-white solid. MS (ESI, pos. ion) m/z: 243.0/245 (M+1).
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3](OCC)=O.[O-]CC.[Na+].Cl.[CH2:17]([N:24]1[CH:28]=[CH:27][N:26]=[C:25]1C[Cl:30])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C(O)C>[ClH:30].[CH2:17]([N:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH2:3][CH2:2][C:1]([OH:9])=[O:8])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: ClCc1nccn1Cc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CCc1nccn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of diethyl malonate (57.8 g) in absolute ethanol (100 ml) was added to a stirred solution of sodium ethoxide in absolute ethanol (prepared from sodium (8.31 g) and absolute ethanol (150 ml)). The mixture was stirred at ambient temperature for 30 minutes. The mixture was cooled in ice water and a solution of 1-benzyl-2-chloromethylimidazole hydrochloride (25.0 g) in absolute ethanol (210 ml) was added over 30 minutes. The mixture was stirred at ambient temperature for 2 hours and then concentrated under reduced pressure. Ice cold 2 M hydrochloric acid (200 ml) was added to the residue and the solution washed with ethyl acetate. The aqueous layer was neutralised with sodium carbonate and extracted with ether to give a residue which was warmed at 95° C. for 18 hours with concentrated hydrochloric acid (100 ml). The mixture was evaporated to dryness to give 3-(1-benzylimidazol-2-yl)propionic acid hydrochloride as a glasslike product.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[CH:8]1([CH2:11][O:12][C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=2[O:22][CH:23]([F:25])[F:24])[C:16](Cl)=[O:17])[CH2:10][CH2:9]1>>[CH:8]1([CH2:11][O:12][C:13]2[CH:14]=[C:15]([C:16](=[O:17])[C:2]([CH3:7])([CH3:1])[C:3]([O:5][CH3:6])=[O:4])[CH:19]=[CH:20][C:21]=2[O:22][CH:23]([F:25])[F:24])[CH2:10][CH2:9]1
Reactant: O=C(Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: COC(=O)C(C)C
Product: COC(=O)C(C)(C)C(=O)c1ccc(OC(F)F)c(OCC2CC2)c1

Procedure:
Prepared analogously as described for the example D1 using methyl 2-methylproponate and 3-cyclopropylmethoxy-4-difluoromethoxybenzoyl chloride as starting compounds.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:19]([CH3:21])[CH3:20])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:22]=[CH:23][CH:24]=[CH:25][C:6]=2[N:5]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:4](=[O:32])[CH:3]1[CH2:33][C:34]1[N:38]=[C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:36][N:35]=1.[H-].[Na+].[CH3:47]I>CN(C=O)C>[CH:19]([N:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](=[O:11])[CH2:9][N:8]1[C:2](=[O:1])[C:3]([CH3:47])([CH2:33][C:34]2[N:38]=[C:37]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[O:36][N:35]=2)[C:4](=[O:32])[N:5]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:6]2[CH:25]=[CH:24][CH:23]=[CH:22][C:7]1=2)([CH3:20])[CH3:21]
Reactant: CC(C)N(C(=O)CN1C(=O)C(Cc2noc(-c3ccccc3)n2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(C(=O)CN1C(=O)C(C)(Cc2noc(-c3ccccc3)n2)C(=O)N(c2ccccc2)c2ccccc21)c1ccccc1
Reaction time: 0.08 h
Yield: 53.1 %

Procedure:
To a stirring solution of 65 mg (0.11 mmol) of 2-[2,4-Dioxo-5-phenyl-3-(5-phenyl-[1,2,4]oxadiazol-3-ylmethyl)-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-phenyl acetamide, prepared as in Intermediate 40, in 2 mL of DMF at 0° C. is added 8 mg (0.17 mmol, 1.5 equiv) of sodium hydride (60% dispersion in mineral oil). The resulting solution is stirred 5 min, then 10 mL (0.17 mmol, 1.5 equiv) of methyl iodide is added. The reaction mixture is stirred 30 min at 0° C. then 3 h at RT and quenched with 1 mL H2O. The reaction mixture is diluted with 40 mL Et2O and washed with 40 mL H2O. The organic layer is dried (MgSO4) and the solvents removed in vacuo. Purification of the resulting oil via reverse phase MPLC using a C-18 column and 70% acetonitrile/30% H2O with 0.1% TFA as eluent followed by lyophilization afforded 35 mg of the title compound as a white amorphous solid: 1H NMR (CDCl3, 300 MHz) δ8.11 (m, 2H), 7.63-6.86 (m, 17H), 5.08 (m, 1H), 4.43 (m, 0.66H), 4.03 (d, br, 0.66H, J=16.3), 3.83 (d, 0.33H, J=16.9), 3.55 (d, 0.33H, J=16.9), 2.87 (dd, 2H, J=15.4, 33.0), 1.62 (s, 2H), 1.35 (s, 1H), 1.11 (m, 6H); low resolution MS (FAB)m/e 600 (MH+), 465, 223.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9](=O)[NH:8][C:7]=2[CH:12]=1.[CH3:15][S:16]([C:19]1[CH:24]=[CH:23]C(F)=[C:21]([Cl:26])[CH:20]=1)(=[O:18])=[O:17]>>[Cl:26][C:21]1[CH:20]=[C:19]([S:16]([CH3:15])(=[O:18])=[O:17])[CH:24]=[CH:23][C:9]=1[NH:8][C:7]1[CH:12]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:4]=[CH:5][C:6]=1[OH:10]
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2o1
Product: CS(=O)(=O)c1ccc(Nc2cc(C(F)(F)F)ccc2O)c(Cl)c1

Procedure:
The subtitle compound was prepared by the method of example 60 step (ii) using 5-(trifluoromethyl)-1,3-benzoxazol-2(3H)-one and the product from example 7 step (ii).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH2:27][O:28][Si](C(C)(C)C)(C)C)[CH:22]=3)=[CH:16][C:15]=2[F:36])=[O:12])[N:7]([C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[N:43]=[CH:42][CH:41]=[CH:40]3)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][N:24]=[C:23]([CH2:27][OH:28])[CH:22]=3)=[CH:16][C:15]=2[F:36])=[O:12])[N:7]([C:37]2[CH:38]=[C:39]3[C:44](=[CH:45][CH:46]=2)[N:43]=[CH:42][CH:41]=[CH:40]3)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc(CO[Si](C)(C)C(C)(C)C)c3)cc2F)n(-c2ccc3ncccc3c2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccnc(CO)c3)cc2F)n(-c2ccc3ncccc3c2)n1
Yield: 90 %

Procedure:
A solution of 1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(4-(2-((tert-butyldimethylsilyloxy)methyl)pyridin-4-yloxy)-2-fluorophenyl)urea (0.12 g, 0.19 mmol) in THF (2 ml) was treated with TBAF (1.0 ml, 1.0 M solution in THF) at RT for 1 hour. Water (10 ml) was added and the separated solid was filtered, washed with water and dried to give desilylated product 1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(hydroxymethyl)pyridin-4-yloxy)phenyl)urea as a white solid (0.090 g, 91% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.01 (brs, 1H), 8.97 (dd, J=4.2, 1.6 Hz, 2H), 8.50 (brd, J=8.3 Hz, 1H), 8.36 (d, J=5.5 Hz, 2H), 8.18 (m, 2H), 7.97 (dd, J=9, 2 Hz, 1H), 7.63 (dd, J=9, 4.4 Hz, 1H), 7.22 (dd, J=12, 2.5 Hz, 1H), 6.99 (m, 1H), 6.93 (d, J=2.5 Hz, 1H), 6.82 (dd, J=5.7, 2.5 Hz, 1H), 6.48 (s, 1H), 5.40 (t, J=6 Hz, 1H), 4.50 (d, J=8 Hz, 2H), 1.32 (s, 9H); MS (ESI) m/z: 527.2 (M+H+). The free base was converted to hydrochloride salt. 1H NMR (400 MHz, DMSO-d6) δ 9.31 (brs, 1H), 9.23 (m, 1H), 9.07 (dd, J=4.2, 1.6 Hz, 1H), 8.70 (brd, J=8.3 Hz, 1H), 8.65 (d, J=6.8 Hz, 2H), 8.32 (d, J=2 Hz, 1H), 8.27 (d, J=9 Hz, 1H), 8.22 (d, J=9 Hz, 1H), 8.09 (dd, J=9, 2.3 Hz, 1H), 7.75 (dd, J=8, 4.5 Hz, 1H), 7.43-7.37 (m, 2H), 7.34 (d, 2.8 Hz, 1H), 7.12 (m, 1H), 6.48 (s, 1H), 4.77 (s, 2H), 1.32 (s, 9H); MS (ESI) m/z: 527.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][OH:11].[H-].[Na+].Cl[CH2:15][C:16]([OH:18])=[O:17]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][O:11][CH2:15][C:16]([OH:18])=[O:17]
Reactant: O=C(O)CCl
Reactant: COc1ccccc1CCO
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccccc1CCOCC(=O)O
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
The solution of 10.0 g of 2-(2-methoxyphenyl)ethanol in 130 ml of dimethyl sulphoxide is admixed with stirring with sodium hydride dispersion (60%) and stirred at 60° C. over 10 min. The suspension is admixed slowly with 6.20 g of chloroacetic acid and subsequently stirred at 80° C. over 2 hours. The reaction mixture is cooled, poured onto ice-water (0.5 l) and washed with ethyl acetate (1×250 ml). The aqueous phase is acidified with 2M HCl and extracted with ethyl acetate (2×250 ml). The organic phases are washed successively with water (250 ml) and brine (1×250 ml), dried over sodium sulphate, filtered and concentrated. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.04 (200:20:1 dichloromethane-methanol-conc. ammonia); Rt=3.44.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].[C-]#N.[CH3:18][N:19](C=O)C>C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1COCC1>[CH3:14][N:13]([CH3:15])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([C:18]#[N:19])[CH:3]=2)[NH:7][CH:6]=1
Reactant: CN(C)C=O
Reactant: CN(C)CCc1c[nH]c2ccc(Br)cc12
Agent: [Fe+2]
Agent: [C-]#N
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCc1c[nH]c2ccc(C#N)cc12
Temperature: 110 °C
Reaction time: 21 h
Yield: 84 %

Procedure:
Under an inert atmosphere a flask is charged with [2-(5-bromo-1H-indol-3-yl)ethyl]-dimethyl-amine (Example 3) (1.0 g, 3.74 mmol), zink cyanide (0.235 g, 2 mmol), Pd2(dba)3xCHCl3 (0.194 mg, 5 mol %), dppf (bis-diphenylphosphino ferrocene) (0.207 g, 0.374 mmol, 10 mol %), and DMF (12 mL). The orange slurry is heated to 110° C. and stirred for 21 hours. To the black suspension which has formed, THF (100 mL) is added, and this is extracted with 1 N NaOH (100 mL). The organic layer is washed with water twice (50 mL each), dried and removal of the solvent gives the title product (0.67 g, 84%) as brown solid. 1H-NMR (CDCl3, 300 MHz) δ 2.35 (s, 6H, 2 CH3); 2.67 (m, 2H, CH2NMe2); 2.91 (m, 2H, CH2); 7.01 (s, 1H, H-2); 7.13 (d, 1H, 3J=8.3 Hz, H-7); 7.26 (dd, 1H, 4J=1.6 Hz, H-6); 7.87 (d, 1H, H-4); 9.80 (br s, 1H, NH). 13C-NMR (CDCl3, 75 MHz) δ 23.48 (CH2); 45.42 (CH3); 60.06 (CH2N); 101.75 (C-5); 112.24 (C-7); 114.74 (C-3); 121.41 (CN); 124.49 (C-4); 124.62 (C-6); 124.75 (C-2); 127.31 (C-9); 138.47 (C-8).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].[S-:11][C:12]#[N:13].[K+].C(O)C>O>[S:11]([CH2:9][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)=[O:10])[C:12]#[N:13]
Reactant: N#C[S-]
Reactant: CC(=O)c1ccccc1Br
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CSCC(=O)c1ccccc1
Reaction time: 8 h

Procedure:
In accordance with the known process (Beilstein, 8, 94), 10.0 g (50 mmol) of o-bromoacetophenone and 4.9 g (50 mmol) of potassium thiocyanate were added to 80 ml of ethyl alcohol, and the resultant mixture was heated at 80° C. for 3 hours and then allowed to stand overnight. Added to the reaction mixture were 50 ml of water. Precipitated crystals were collected by filtration, washed with 50% aqueous ethyl alcohol and then dried, whereby the title compound was obtained as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]([CH3:15])=[CH:5]2.II.[F:18][C:19]([F:28])([F:27])[C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]([CH3:15])=[C:5]2[S:26][C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:27])[F:28])=[CH:25][CH:24]=1
Reactant: FC(F)(F)c1ccc(S)cc1
Reactant: Cc1cc2cc(F)ccc2n1CC(=O)O
Agent: II
Product: Cc1c(Sc2ccc(C(F)(F)F)cc2)c2cc(F)ccc2n1CC(=O)O

Procedure:
Prepared by the method of example 26 step c) using the product of example 26 step b) (0.55 g), iodine (0.98 g) and 4-trifluoromethylbenzenethiol (0.67 g) to give the subtitle compound as a solid (0.25 g).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]([CH3:29])([CH3:28])[CH2:5][CH2:6][NH:7][C:8]([C:10]1[N:11]=[CH:12][C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[C:15]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:14]=2)=[O:9].[OH-].[Na+].CO.Cl>O>[OH:20][C:19]1[C:18]2[C:13](=[CH:14][C:15]([O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:16][CH:17]=2)[CH:12]=[N:11][C:10]=1[C:8]([NH:7][CH2:6][CH2:5][C:4]([CH3:29])([CH3:28])[C:3]([OH:30])=[O:2])=[O:9]
Reactant: COC(=O)C(C)(C)CCNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(CCNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 25 %

Procedure:
A mixture of 4-[(4-Hydroxy-7-phenoxy-isoquinoline-3-carbonyl)-amino]-2,2-dimethyl-butyric acid methyl ester (25 mg, 0.064 mmol) and (1/1) 1 N NaOH aqueous solution/MeOH (2 mL) was stirred at room temperature for 2 days. It was diluted with water (50 mL), acidified by 1 N HCl to pH=3-4. Precipitate was collected and dried in vacuo to provide the title product 6.5 mg (0.016 mmol) in 26% yield. LC-MS ESI−: 393.10 (M−1)−.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([CH2:8][O:9][C:10]1[C:15]([CH3:16])=[CH:14][C:13]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[O:27])[N:19]([CH3:28])[N:18]=2)=[CH:12][C:11]=1[CH3:29])=[O:7]>O1CCCC1>[C:6]([CH2:8][O:9][C:10]1[C:11]([CH3:29])=[CH:12][C:13]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[O:27])[N:19]([CH3:28])[N:18]=2)=[CH:14][C:15]=1[CH3:16])([OH:7])=[O:5]
Reactant: COC(=O)COc1c(C)cc(-c2nn(C)c(=O)c3ccccc23)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(-c2nn(C)c(=O)c3ccccc23)cc(C)c1OCC(=O)O
Reaction time: 18 h

Procedure:
Lithium hydroxide monohydrate (0.22 g) was added to a solution of example 107 (1.52 g) in aqueous tetrahydrofuran (1:150 ml) and the reaction stirred 18 h. the mixture was the concentrated in vacuo and the residual slurry acidified with 10% hydrochloric acid.