Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]([C:21]2[C:30]3[C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[S:33][C:29]=3[C:28]([O:38][CH2:39][C:40]([OH:42])=[O:41])=[C:27]3[C:22]=2[CH:23]=[CH:24][CH:25]=[CH:26]3)[CH:18]=[C:17]([Br:43])[C:3]=1[O:4][C@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8]C)=[O:7].[OH-]>O1CCCC1.CO>[Br:1][C:2]1[CH:20]=[C:19]([C:21]2[C:30]3[C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[S:33][C:29]=3[C:28]([O:38][CH2:39][C:40]([OH:42])=[O:41])=[C:27]3[C:22]=2[CH:23]=[CH:24][CH:25]=[CH:26]3)[CH:18]=[C:17]([Br:43])[C:3]=1[O:4][CH:5]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(OCC(=O)O)c3sc4ccccc4c23)cc1Br
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)COc1c2ccccc2c(-c2cc(Br)c(OC(Cc3ccccc3)C(=O)O)c(Br)c2)c2c1sc1ccccc12
Reaction time: 3.5 h
Yield: 87.2 %

Procedure:
To a solution of (R)-2-[2,6-dibromo-4-(6-carboxymethoxy-benzo [b]naphtho[2,3-d]thiophen-11-yl)-phenoxy]-3-phenyl-propionic acid, methyl ester (0.436 g, 0.594 mmol) in tetrahydrofuran (9 mL) and methanol (3 mL) was added an aqueous solution of potassuim hydroxide (1 N, 2.37 mL, 2.37 mmol, 4 eq) dropwise at room temperature. After stirring 3.5 hours the solvents were removed and the residue was combined with water. The suspension was acidified with 10% aqueous hydrochloric acid and diethyl ether was added. The biphasic mixture was shaken well before the layers were separated. The organic phase was washed with water and concentrated. The residue was triturated with petroleum ether and dried in vacuo to provide the title compound as a white solid (0.366 g, 87%): mp 110-120° C.; [a]25/D =+49.620 (10.076 mg/mL, methanol); NMR (DMSO-d6): δ13.21 (broad s, 2 H), 8.40 (d, J=8 Hz, 1H), 8.03 (d, J=8 Hz, 1H), 7.74 (dd, J=2, 8 Hz, 2 H), 7.68 (ddd, J=8, 7, 1 Hz, 1 H), 7.57 (ddd, J=8, 7, 1 Hz, 1H), 7.52 - 7.45 (m, 2 H), 7.43 - 7.38 (m, 2 H), 7.37 -7.11 (m, 2 H), 7.10-7.20 (m, 2 H), 6.69 (d, J=8Hz, 1H), 5.30 (t, J=7 Hz, 1 H), 4.90 (s, 2 H), 3.41 (d, J=7 Hz, 2 H); MS (+FAB): [M+], 2 bromine isotope pattern, 704 (9%), 706 (22%), 708 (22%); Anal. Calc. for C33212Br2O6S: C, 56.11, H, 3.14, N, 0.00. Found: C, 55.93, H, 3.28, N, 0.09.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[NH:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccnc2)CC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: c1cncc(OC2CCNCC2)c1
Reaction time: 0.5 h

Procedure:
A cold (0-5° C.), stirring solution of 3-(N-(tert-butoxycarbonyl)-4-piperidinyloxy)pyridine (500 mg, 1.796 mmol) in anisole (8 mL) was treated with trifluoroacetic acid (8 mL, 11.84 g, 103.8 mmol). The resulting solution was stirred for 30 min. The volatiles were removed on a rotary evaporator, and the residue was neutralized and basified to pH 9 with solid K2CO3 and water. The mixture was extracted with chloroform (4×20 mL). The combined chloroform extracts were dried (K2CO3), filtered and concentrated. The crude product was purified by column chromatography over silica gel, eluting with chloroform-acetone (9:1, v/v). Selected fractions were collected and concentrated to give 260 mg (81.2%) of an off-white, viscous liquid.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])[CH:7]=[CH:6][C:5]=1[NH:18][C:19](=[O:22])[CH2:20][CH3:21].CO[C:26](=O)[C:27]1C=C(SC2C=CC=CC=2N)C=C[C:28]=1NC(=O)CC>>[C:19]([NH:18][C:5]1[CH:6]=[CH:7][C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][CH2:26][CH2:27][CH3:28])=[CH:9][C:4]=1[C:3]([OH:2])=[O:23])(=[O:22])[CH2:20][CH3:21]
Reactant: CCC(=O)Nc1ccc(Oc2ccccc2N)cc1C(=O)OC
Reactant: CCC(=O)Nc1ccc(Sc2ccccc2N)cc1C(=O)OC
Product: CCCNc1ccccc1Oc1ccc(NC(=O)CC)c(C(=O)O)c1

Procedure:
The following compounds were obtained by reacting the intermediate 2-propionylamino-5-(2-amino-phenoxy)-benzoic methyl ester or 5-(2-amino-phenylsulfanyl)-2-propionylamino-benzoic acid methyl ester (EXAMPLE 17) with boronic acids according to EXAMPLE 6 or with aldehydes as described above.
Reaction SMILES: [CH2:1]([NH:7][C:8](=[O:33])[NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH:34][C@@H:35]([CH2:48][NH2:49])[CH2:36][O:37][C:38]1[C:46]2[NH:45][C:44](=[O:47])[NH:43][C:42]=2[CH:41]=[CH:40][CH:39]=1>>[CH2:1]([NH:7][C:8]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:27][CH2:28][CH:29]([NH:49][CH2:48][C@H:35]([OH:34])[CH2:36][O:37][C:38]4[C:46]5[NH:45][C:44](=[O:47])[NH:43][C:42]=5[CH:41]=[CH:40][CH:39]=4)[CH2:30][CH2:31]3)=[CH:22][CH:21]=2)(=[O:17])=[O:18])=[CH:12][CH:11]=1)=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)cc2)cc1

Procedure:
The title compound was prepared from 4-(3-hexyl-ureido)-N-[4-(4-oxo-piperidine-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 225) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) according to the procedure of Example 255 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.86 (t, J=6.8 Hz, 3H), 1.20-1.60 (m, 10H), 1.90-2.05 (m, 2H), 2.50-3.50 (m, 9H), 3.50-3.65 (m, 1H), 3.95-4.05 (m, 2H), 6.43 (t, J=5.6 Hz, 1H), 6.58 (d, J=7.8 Hz, 1H), 6.61 (d, J=8.2 Hz, 1H), 6.70-6.89 (m, 5H), 7.46 (d, J=9.0 Hz, 2H), 7.51 (d, J=9.0 Hz, 2H), 9.06 (s, 1H), 9.60 (brs, 1H), 10.60 (s, 1H), 10.75 (s, 1H); MS (ES) m/z: 680.3 (MH+); HRMS Calcd. for C34H46N7O6S(MH+): 680.3230. Found: 680.3221.
Reaction SMILES: [CH:1]1([C@@H:4]([NH:9][C:10]2[C:22]3[C:21]4[CH:20]=[CH:19][C:18]([C:23]#[C:24][Si](C)(C)C)=[CH:17][C:16]=4[NH:15][C:14]=3[C:13]([C:29]([NH2:31])=[O:30])=[CH:12][N:11]=2)[C:5]([F:8])([F:7])[F:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO.CCOC(C)=O>[CH:1]1([C@@H:4]([NH:9][C:10]2[C:22]3[C:21]4[CH:20]=[CH:19][C:18]([C:23]#[CH:24])=[CH:17][C:16]=4[NH:15][C:14]=3[C:13]([C:29]([NH2:31])=[O:30])=[CH:12][N:11]=2)[C:5]([F:8])([F:6])[F:7])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C#Cc1ccc2c(c1)[nH]c1c(C(N)=O)cnc(N[C@H](C3CC3)C(F)(F)F)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1ccc2c(c1)[nH]c1c(C(N)=O)cnc(N[C@H](C3CC3)C(F)(F)F)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1-{[(1R)-1-Cyclopropyl-2,2,2-trifluoroethyl]amino}-7-[(trimethylsilyl)ethynyl]-5H-pyrido[4,3-b]indole-4-carboxamide (0.15 g, 0.33 mmol) in MeOH (3.3 mL) was added potassium carbonate (0.055 g, 0.40 mmol). The reaction mixture was left to stir at room temperature for 16 h, diluted with EtOAc, washed with water and brine, dried (sodium sulfate), and concentrated to give the title compound. LRMS (APCI) calc'd for (C19H15F3N4O) [M+H]+, 373.1. found 373.1.
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[O:22][CH3:23])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>ClCCl>[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([C:2]2([NH:1][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:10](=[O:11])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:12])=[C:14]([O:22][CH3:23])[CH:15]=1)([CH3:21])[CH3:20]
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc(C(C)C)ccc1C1(N)C(=O)c2ccccc2C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(C)C)ccc1C1(NC(=O)c2ccccc2)C(=O)c2ccccc2C1=O
Yield: 100.8 %

Procedure:
A solution of 2-amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (200 mg, 0.60 mmol) in dichloromethane (10 ml) was stirred overnight together with benzoyl chloride (0.09 mL, 0.77 mmol) and triethylamine (0.27 mL, 1.9 mmol) at room temperature. The reaction mixture was extracted with dichloromethane, and purified by silica gel column chromatography (30% ethylacetate in hexane) to afford the title compound (250 mg, 97%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[N:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:31][CH2:30]4)=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1>>[CH:29]1([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH:19]3[CH2:18][CH2:17][N:16]([C:14]([C:11]4[CH:10]=[CH:9][C:8]([N:1]5[CH2:5][CH2:4][CH2:3][C:2]5=[O:6])=[N:13][CH:12]=4)=[O:15])[CH2:21][CH2:20]3)=[CH:24][CH:25]=2)[CH2:30][CH2:31]1
Reactant: O=C(c1ccc(Br)nc1)N1CCC(Oc2ccc(C3CC3)cc2)CC1
Reactant: O=C1CCCN1
Product: O=C(c1ccc(N2CCCC2=O)nc1)N1CCC(Oc2ccc(C3CC3)cc2)CC1
Yield: 58.7 %

Procedure:
Using pyrrolidin-2-one (94 mg) and (6-bromopyridin-3-yl)[4-(4-cyclopropylphenoxy)piperidin-1-yl]methanone (401 mg) described in Preparation Example 192 and by the reaction and treatment in the same manner as in Example 1, the title compound (238 mg) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([CH3:18])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:17])[NH:15][CH3:16])[CH:9]=1)[CH3:6])[CH3:2].[CH3:20][C:21]1[C:26]([CH2:27]OS(C)(=O)=O)=[CH:25][CH:24]=[C:23]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)[N:22]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:19])[C:5]([CH3:18])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:17])[N:15]([CH3:16])[CH2:27][C:26]2[C:21]([CH3:20])=[N:22][C:23]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=3)=[CH:24][CH:25]=2)[CH:9]=1)[CH3:6])[CH3:2]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1COS(C)(=O)=O
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1cccc(C(=O)N(C)Cc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c1
Temperature: 0 °C
Yield: 46.1 %

Procedure:
0.28 g (1.05 mmol) of 2-methyl-2-(3-methylcarbamoyl-phenoxy)-propionic acid ethyl ester and 0.36 g (1.05 mmol) of methanesulfonic acid 2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl ester (example 59E]) were dissolved in 15 ml of DMF. The reaction mixture was cooled down to 0° C. and 0.05 g (1.20 mmol) of sodium hydride (55% in mineral oil) was added. After stirring for sixteen hours at ambient temperature, the reaction mixture was poured into crashed ice and extracted twice with Et2O. The combined organic phases were washed with water and brine and dried over anhydrous magnesium sulfate. After evaporation of the solvent, the crude product was purified by flash chromatography (SiO2, heptane/EtOAc) to give 0.249 g of the title compound as yellow oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:10][N:5]2[CH2:6][CH2:7][NH:8][CH2:9][C@@H:4]2[CH2:3]1.Cl[C:12]1[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:1][C@H:2]1[CH2:10][N:5]2[CH2:6][CH2:7][N:8]([C:12]3[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=3)[CH2:9][C@@H:4]2[CH2:3]1
Reactant: O[C@@H]1C[C@H]2CNCCN2C1
Reactant: Fc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O[C@@H]1C[C@H]2CN(c3ncc(F)cn3)CCN2C1
Yield: 85 %

Procedure:
A mixture of the crude (7R,8aS)-7-hydroxy-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]-pyrazine, 9.96 g (52.5 mmol) of 2-chloro-5-fluoropyrimidine (Dunaiskis, A. et al., Org. Prep. Proc. Int., 1995, 27, 600-602), 13.4 g (126 mmol) of sodium carbonate and 450 mL of water was heated at 95° C. for 72 hours. The mixture was cooled, extracted with chloroform (2×), and the combined organic phase was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 95:5 ethyl acetate:methanol gave 8.54 g (85%) of the title compound. 13C NMR (base, CDCl3): δ 39.1, 43.7, 48.7, 51.0, 60.2, 62.9, 69.4, 144.95, 145.24, 149.9, 153.2,158.9. m/z (MH+) 239.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:5]=[CH:4][CH:3]=1.[CH3:16][C:17](O)(C#C)C.Cl>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[F:8][C:7]1[C:6]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:5][CH:4]=[CH:3][C:2]=1[C:16]#[CH:17]
Reactant: CCCCCCOc1cccc(Br)c1F
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Product: C#Cc1cccc(OCCCCCC)c1F
Temperature: 0 °C
Yield: 63.1 %

Procedure:
117 g of potassium carbonate and 55.6 g of bromohexane are added to a solution of 53.6 g of 3-bromo-2-fluorophenol in 650 ml of acetone, and the mixture is refluxed for 8 hours. The mixture is filtered, evaporated to ⅓ of the original volume and poured into 600 ml of water. The pH is adjusted to 1 using hydrochloric acid, and the mixture is extracted three times with 150 ml of tert-butyl methyl ether each time. The combined organic phases are concentrated under reduced pressure, and the residue is subjected to vacuum distillation (103° C.; 1 mbar), giving 67 g of 6-bromo-2-hexyloxyfluorobenzene as a colorless oil. 1H-NMR (CDCl3): 6.9-7.1 (m; 3H); 4.0 (t; 2H), 0.9-1.8 (m, 11H), 19F-NMR (CDCl3): −128 ppm. A solution of 67.3 g of 6-bromo-2-hexyloxyfluorobenzene, 24.7 g of 2-methyl-3-butyn-2-ol [115-19-5], 0.7 g of bis(triphenylphosphine)palladium(II) chloride and 0.7 g of copper iodide in 340 ml of triethylamine is refluxed for 5 hours. The mixture is then poured into 1.5 of ice-water, the pH is adjusted to 1 using hydrochloric acid, and the mixture is extracted three-times with 200 ml of tert-butyl methyl ether each time. The combined organic phases are dried under reduced pressure. The crude 4-(2-fluoro-3-hexyloxyphenyl)2methyl-3-butyn-1-ol is refluxed for 3 hours in 1000 ml of toluene together with three mole-equivalents of sodium hydroxide. The mixture is filtered and washed with dilute hydrochloric acid, the solvent is removed by distillation, and the residue is distilled (90° C.; 0.5 mbar), giving 34 g of 1-(2-fluoro-3-hexyloxyphenyl)ethyne.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=O.[C:11]([O:15][C:16]([NH:18][CH:19](P(OC)(OC)=O)[C:20]([O:22][CH3:23])=[O:21])=[O:17])([CH3:14])([CH3:13])[CH3:12].O.C(OCC)(=O)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6](/[CH:7]=[C:19](\[NH:18][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])/[C:20]([O:22][CH3:23])=[O:21])[CH:9]=1
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Reactant: O=Cc1cc(Br)ccc1F
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)/C(=C/c1cc(Br)ccc1F)NC(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 4 h

Procedure:
21.32 ml (169.9 mmol) of N,N,N,N-tetramethylguanidine are added to a solution, cooled to −70° C., of 30 g (147.8 mmol) of 5-bromo-2-fluorobenzaldehyde and 50.51 g (169.9 mmol) of methyl [(tert-butoxycarbonyl)amino](dimethoxyphosphoryl)acetate in 450 ml anhydrous tetrahydrofuran. After stirring at −70° C. for 4 h, the reaction mixture is stirred at RT for 15 h. 1000 ml of water and 1000 ml of ethyl acetate are added to the mixture. The organic phase is washed with water, dried over sodium sulfate and concentrated. The crude product is purified by column chromatography on silica gel (mobile phase: cyclohexane:ethyl acetate 4:1).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[Cl:17][C:18]1[CH:19]=[C:20]([C:24]2[S:28][CH:27]=[N:26][C:25]=2[C:29](O)=[O:30])[CH:21]=[CH:22][CH:23]=1>>[F:4][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[C:14]([NH:16][C:29]([C:25]3[N:26]=[CH:27][S:28][C:24]=3[C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=3)=[O:30])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)([F:1])[CH3:3]
Reactant: O=C(O)c1ncsc1-c1cccc(Cl)c1
Reactant: CC(F)(F)c1ccc(Cn2cc(N)cn2)o1
Product: CC(F)(F)c1ccc(Cn2cc(NC(=O)c3ncsc3-c3cccc(Cl)c3)cn2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(3-chloro-phenyl)-thiazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.15 min; [M+H]+=449.00.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[N:15]=[CH:14][C:13]([C:20]#[N:21])=[C:12]2[Cl:22])C1C=CC=CC=1.C1(SC)C=CC=CC=1>FC(F)(F)C(O)=O.CO.C(OCC)(=O)C>[Cl:22][C:12]1[C:11]2[C:16](=[CH:17][C:18]([F:19])=[C:9]([OH:8])[CH:10]=2)[N:15]=[CH:14][C:13]=1[C:20]#[N:21]
Reactant: N#Cc1cnc2cc(F)c(OCc3ccccc3)cc2c1Cl
Solvent: CO
Solvent: CSc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1cnc2cc(F)c(O)cc2c1Cl
Yield: 49.9 %

Procedure:
A mixture of 6-benzyloxy-4-chloro-7-fluoro-3-quinolinecarbonitrile (733 mg, 2.34 mmol) and 1 mL of thioanisole in 12 mL of trifluoroacetic acid is heated at reflux for 9 hours then concentrated in vacuo. The residue is treated with ice water and then basified to pH 9-10 by the addition of aqueous ammonium hydroxide. The resultant solid is collected by filtration and washed with diethyl ether. The filtrate is extracted with 10% methanol in ethyl acetate. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo. The residue is combined with the solid obtained initially, and this material is dissolved in 5% methanol in ethyl acetate and absorbed onto silica gel. Purification by flash column chromatography eluting with a gradient of hexane to increasing amounts of ethyl acetate in hexane to 5% methanol in ethyl acetate provides 260 mg of 4-chloro-7-fluoro-6-hydroxy-3-quinolinecarbonitrile, mp>250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:26])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:25])[C:9]([OH:24])([C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([F:13])([F:12])[F:11].[CH3:27][O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([CH2:40]Br)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30]>>[CH3:27][O:28][C:29]([C:31]1([C:34]2[CH:35]=[CH:36][C:37]([CH2:40][O:26][C:4]3[CH:5]=[CH:6][C:7]([CH:8]([CH3:25])[C:9]([OH:24])([C:14]4[CH:15]=[N:16][C:17]5[C:22]([CH:23]=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)[C:10]([F:11])([F:13])[F:12])=[C:2]([Cl:1])[CH:3]=3)=[CH:38][CH:39]=2)[CH2:33][CH2:32]1)=[O:30]
Reactant: COC(=O)C1(c2ccc(CBr)cc2)CC1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1cnc2ccccc2c1)C(F)(F)F
Product: COC(=O)C1(c2ccc(COc3ccc(C(C)C(O)(c4cnc5ccccc5c4)C(F)(F)F)c(Cl)c3)cc2)CC1

Procedure:
In analogy to Example 140, step 6, 3-chloro-4-(3,3,3-trifluoro-2-hydroxy-1-methyl-2-quinolin-3-yl-propyl)-phenol (Example 140, step 5) was reacted with 1-(4-bromomethyl-phenyl)-cyclopropanecarboxylic acid methyl ester (CAS 873372-30-6) to give the title compound as an off-white solid. MS (m/e)=570.4 [M+H+].
Reaction SMILES: C[O:2][C:3]1[CH:27]=[CH:26][C:6]([C:7]([C:9]2[S:10][C:11]3[CH:23]=[C:22]([O:24]C)[CH:21]=[CH:20][C:12]=3[C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[S:10][C:11]3[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:12]=3[C:13]=2[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:8])=[CH:26][CH:27]=1
Reactant: COc1ccc(C(=O)c2sc3cc(OC)ccc3c2-c2ccccc2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1ccc(O)cc1)c1sc2cc(O)ccc2c1-c1ccccc1
Temperature: 220 °C
Yield: 65 %

Procedure:
A mixture of 8.75 g. (0.023 mole) of the product from Example 7 and 25 g. of pyridine hydrochloride was prepared. The mixture was refluxed in a 220° C. oil bath for 30 minutes. The hot reaction mixture then was poured over ice, and the resulting mixture was added to a blender. The resulting yellow crystals were collected on a filter, washed with water, and vacuum dried at 100° C. This treatment caused some resinification of the sample. The residue was recrystallized from a mixture of ethyl acetate and benzene to obtain 5.3 g. (65 percent) of the title compound as bright yellow crystals, m.p. 198°-200° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].OS(O)(=O)=O.[CH2:21](O)[CH3:22]>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH3:15])[C:12]([O:14][CH2:21][CH3:22])=[O:13])=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)c1ccc(CC(C)C)cc1

Procedure:
Separately, 72.02g ethyl 2-(4-isobutylphenyl)-propionate, obtained by the esterification of 2-(4-isobutylphenyl)-propionic acid with ethanol and concentrated H2SO4, are solved with 100ml methanol, this solution is introduced drop by drop into the reaction flask, and stirred and cooled for 5 hours on an ice bath. Thereafter it is suction filtered, the residue is washed with alltogether 50ml methanol, the wash is added to the filtrate, thereafter the whole is evaporated in a water bath with a rotating evaporator at a reduced pressure, until 100-200 ml of a concentrated solution are obtained. This solution is poured into a 200 ml beaker into which are stirred approximately 1000 ml 1,25N acetic acid. This mixture is left standing for 24 hours, thereafter suction filtered. The resulting filtrate is taken up with 100ml. petroleum ether at 40°-60° C, in order to solve any possible residue of unreacted starting ester, and refiltered. Approximately 50g of 2-(4-isobutylphenyl)-propriohydroxamic acid are obtained, having a melting point of 119°-121° C on Kofler's hot stage.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9]2=[O:24])(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>CN(C=O)C>[O:38]1[CH2:39][CH2:40][N:35]([CH2:34][CH2:33][N:5]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[C:11](=[O:15])[N:10]([CH2:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C:9]3=[O:24])[S:2]([CH3:1])(=[O:3])=[O:4])[CH2:36][CH2:37]1
Reactant: ClCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(NS(C)(=O)=O)cc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccc(N(CCN3CCOCC3)S(C)(=O)=O)cc2C1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
To a solution of tert-butyl 2-(5-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (501 mg, 1.414 mmol) in dry DMF (15 ml) maintained under nitrogen atmosphere, K2CO3 (391 mg, 2.83 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (526 mg, 2.83 mmol) were added, and the mixture was stirred at 60° C. for 3 hours. The solid was filtered off, the solvent was evaporated and the resulting crude was purified by filtration on a silica gel cartridge (DCM/MeOH 9/1), obtaining tert-butyl 2-(5-(N-(2-morpholinoethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (570 mg, 1.22 mmol, 86% yield, MS/ESI+ 468.2 [MH]+).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1>>[Cl:31][C:28]1[CH:27]=[N:26][C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[C:14]([CH3:23])[N:13]=2)=[O:11])=[N:30][CH:29]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1
Reactant: Clc1cnc(Cl)nc1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncc(Cl)cn2)n1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 427 [M+1]+.