Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.C([Sn](CCCC)(CCCC)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=1)CCC>>[F:20][C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][C:23]=2[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=2)[CH:17]=1)[O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:34])=[C:8]([CH3:33])[CH:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(F)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2cc(F)cc(Oc3ccc(C(F)(F)F)cc3-c3ccccn3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepare by reacting the compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-fluoro-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with 2-tributylstannyl pyridine as in Example 39 to afford 0.085 g (36%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C28H21NO4F4 512.1485, found 512.1487.
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][C@H:6]([CH2:14][OH:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].O.[C:17]1(C)[CH:22]=CC(S(O)(=O)=O)=C[CH:18]=1.COC(C)=C>C(Cl)Cl>[Br:1][CH2:2][C:3]([N:5]1[C@@H:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][O:15][C:17]1([CH3:22])[CH3:18])=[O:4]
Reactant: O=C(CBr)N[C@H](CO)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=C(C)OC
Solvent: O
Solvent: ClCCl
Product: CC1(C)OC[C@H](Cc2ccccc2)N1C(=O)CBr
Reaction time: 0.25 h
Yield: 889.5 %

Procedure:
To a mixture of 2-bromo-N-(1(S)-hydroxymethyl-2-phenylethyl)acetamide (1.55 g, 5.45 mmol) and p-toluenesulfonic acid monohydrate (100 mg) in CH2Cl2 (50 mL) was added 2-methoxypropene (1.50 mL, 15.7 mmol) dropwise via syringe. After 15 minutes at ambient temperature, the resultant mixture was washed with 1M pH7 phosphate buffer (25 mL) and brine (25 mL), dried over Na2SO4, and concentrated to give a dark solid, which was triturated with MTBE/hex to provide 1.46 g (86%) of 3-(2-bromoacetyl)-2,2-dimethyl-4(S)-phenylmethyl-oxazolidine as a pale yellow solid. 1H NMR (DMSO-d6): δ 7.33-7.17 (m, 5H), 4.21-4.15 (m, 1H), 4.04, 3.86 (AB quartet, 2H, J=12.1 Hz), 3.79 (dd, 1H, J=4.8, 9.2 Hz), 3.71 (d, 1H, J=9.2 Hz), 2.99 (dd, 1H, J=5.0, 13.4 Hz), 2.70 (dd, 1H, J=9.2, 13.2 Hz), 1.55 (s, 3H), 1.38 (s, 3H). Anal. Calculated for C14H18NO2Br: C, 53.86; H, 5.81; N, 4.49; Br, 25.59. Found: C, 53.91; H, 5.82; N, 4.47; Br, 25.58.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:12][C:13]3[N:14]=[C:15]([N:22]4[CH2:27][CH2:26][CH:25]([CH2:28][C:29]([O:31]CCCC)=[O:30])[CH2:24][CH2:23]4)[C:16]4[CH:21]=[CH:20][NH:19][C:17]=4[N:18]=3)[CH:8]=2)[NH:3]1.[Li+].[OH-].CC(O)=O>C1COCC1>[O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:12][C:13]3[N:14]=[C:15]([N:22]4[CH2:23][CH2:24][CH:25]([CH2:28][C:29]([OH:31])=[O:30])[CH2:26][CH2:27]4)[C:16]4[CH:21]=[CH:20][NH:19][C:17]=4[N:18]=3)[CH:8]=2)[NH:3]1
Reactant: CCCCOC(=O)CC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)nc3[nH]ccc23)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(O)CC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)nc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.4 %

Procedure:
To a solution of butyl 2-(1-(2-(2-oxo-1,2,3,4-tetrahydroquinolin-6-ylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-yl)acetate (48 mg, 0.101 mmol) in THF (2 mL), aq. 1N LiOH (1.00 mL, 1.00 mmol) was added. The mixture was stirred at room temperature for 20 h. HOAc (1 mL) was added to neutralize LiOH. It was then purified by HPLC to give the titled compound (32 mg). MS 421.3 (M+H); UV 207.8, 279.8 nm
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C:12]3([CH3:25])[CH3:24])=[C:8]([C:26](=[O:28])[NH2:27])[CH:7]=[N:6][N:5]2[CH:29]=1.[CH3:30][O:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].CN(C=O)C>[C:26]([C:8]1[CH:7]=[N:6][N:5]2[CH:29]=[C:2]([C:35]3[CH:36]=[N:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=3)[CH:3]=[C:4]2[C:9]=1[NH:10][C@@H:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[CH2:13][C:12]1([CH3:25])[CH3:24])(=[O:28])[NH2:27]
Reactant: COc1ccc(B(O)O)cn1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)C(C)(C)C1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3c(N[C@@H]4CCN(C(=O)OC(C)(C)C)CC4(C)C)c(C(N)=O)cnn3c2)cn1
Temperature: 90 °C
Yield: 102.3 %

Procedure:
A stirred DMF (8.0 mL) solution of (R)-tert-butyl 4-(6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-ylamino)-3,3-dimethylpiperidine-1-carboxylate (1.20 g, 2.57 mmol), 6-methoxypyridin-3-ylboronic acid (0.787 g, 5.15 mmol), potassium phosphate (1.639 g, 7.72 mmol), palladium acetate (0.058 g, 0.257 mmol) and 1,1′-Bis(di-tert-butylphosphino)ferrocene (0.124 g, 0.257 mmol) was degassed by purging with argon for 5 min. The sealed tube was then heated at 90° C. for 1 h then cooled and partitioned between ethyl acetate and water. The layers were separated and the organic portion was washed with water, 10% LiCl (×2), brine and dried over anhyd. magnesium sulfate, filtered and concentrated under vacuum to afford the title compound as a tan solid (1.30 g, quantitative). HPLC (Method B) retention time=3.90 min. LCMS (m+1)=495.3. Material contained ˜10% of unreacted bromide starting material but was used without any further purification in next transformation.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C@H:16]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:17]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18].[CH:28]([C:30]1[CH:35]=[CH:34][N:33]=[C:32]2[N:36]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:37]=[C:38]([C:39]([O:41][CH3:42])=[O:40])[C:31]=12)=O>ClCCCl.C(O)(=O)C>[CH3:26][CH:25]([CH3:27])[CH2:24][C@@H:16]([NH:15][CH2:28][C:30]1[CH:35]=[CH:34][N:33]=[C:32]2[N:36]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH:37]=[C:38]([C:39]([O:41][CH3:42])=[O:40])[C:31]=12)[C:17](=[O:18])[N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(C=O)c12
Reactant: CC(C)C[C@@H](N)C(=O)N1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@H](CC(C)C)C(=O)N3CCCC3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102.9 %

Procedure:
A mixture of sodium triacetoxyborohydride (139 mg, 0.657 mmol) and (R)-2-amino-4-methyl-1-(pyrrolidin-1-yl)pentan-1-one (91 mg, 0.493 mmol) in DCE (2 mL) was stirred at room temperature for 30 min. The reaction mixture was cooled to 0° C. A solution of 1-tert-butyl 3-methyl 4-formyl-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate (100 mg, 0.329 mmol) in DCE (2 mL) was added, followed by acetic acid (1 drop). The reaction was stirred at 0° C. for 30 min and then at room temperature for 3 h. Purification by silica column chromatography (EtOAc/DCM, 0-10%) afforded the title compound as a yellow oil (160 mg, 93%). [M+H] calc'd for C25H36N4O5, 473; found, 473.7.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C1(C)C(S(O[CH2:37][C@@H:38]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH3:39])(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].O.C(O)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:39][C@@H:38]([NH:40][C:41](=[O:42])[O:43][C:44]([CH3:45])([CH3:47])[CH3:46])[CH3:37])=[C:20]([O:25][CH3:26])[CH:19]=4)[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1O
Reactant: Cc1ccccc1S(=O)(=O)OC[C@H](C)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: COc1cc(-n2cnc3cc(-c4ccc(Cl)cc4)sc3c2=O)ccc1OC[C@H](C)NC(=O)OC(C)(C)C
Temperature: 75 °C
Yield: 49 %

Procedure:
To a solution of 6-(4-chlorophenyl)-3-(4-hydroxy-3-methoxyphenyl)thieno[3,2-d]pyrimidin4(3H)-one (0.29 g, 0.75 mmol, the preparation of which can be found in the section detailing the preparation of Example K1) in DMF was added (2S)-2-[(tert-butoxycarbonyl)amino]propyl toluenesulfonate (0.5 g, 1.50 mmol) and cesium carbonate (0.72 g, 2.25 mmol) and the mixture was stirred with heating at 75° C. for 12 h. The reaction was allowed to cool and 25 mL of a solution of 20% water/ethanol was added. The resulting precipitate was filtered and dried in a vacuum oven to give the product (200 mg, 49%). 1H NMR (DMSO-D6) δ 1.15 (3H, d, J=6.1 Hz), 1.40 (9H, s), 3.79 (6H, m), 7.22-7.20 (3H, m), 7.59 (2H, d, J=8.4 Hz), 7.95-7.99 (3H, m) 8.40 (1H, s). LCMS m/z=542 (m+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:13][S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][CH:10]1[CH2:12][CH2:11]1.[CH3:19][N:20]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:39].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:10]1([CH2:9][O:8][C:7]2[N:6]=[CH:5][C:4]([NH:13][S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])=[CH:3][C:2]=2[C:28]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21](=[O:39])[N:20]([CH3:19])[CH:29]=2)[CH2:12][CH2:11]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccccc2c1=O
Reactant: CCS(=O)(=O)Nc1cnc(OCC2CC2)c(Br)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)Nc1cnc(OCC2CC2)c(-c2cn(C)c(=O)c3ccccc23)c1
Temperature: 70 °C
Yield: 51.8 %

Procedure:
A mixture of N-[5-bromo-6-(cyclopropylmethoxy)pyridin-3-yl]ethanesulfonamide (60 mg, 0.21 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinolin-1-one (77 mg, 0.23 mmol), Pd2(dba)3 (7 mg), XPhos (7 mg), and K3PO4 (111 mg, 0.51 mmol) in dioxane (1.2 mL) and water (140 uL) was purged with nitrogen, capped, and heated to 70° C. for 2 h. After the mixture was filtered through a short bed of celite, the filtrate was concentrated in vacuo and purified by prep-HPLC to afford the title compound (45 mg, 52%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.09-0.15 (m, 2H) 0.29-0.40 (m, 2H) 0.97-1.08 (m, 1H) 1.20-1.28 (m, 3H) 3.07-3.16 (m, 2H) 3.56 (s, 3H) 4.02-4.18 (m, 2H) 7.17-7.22 (m, 1H) 7.52 (s, 3H) 7.62-7.69 (m, 1H) 8.06-8.11 (m, 1H) 8.27-8.33 (m, 1H) 9.47-10.31 (m, 1H). LCMS (M+H)+=414.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:26][C:11]3[CH:12]=[N:13][C:14]([NH:16][C:17]([CH:19]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[O:18])=[CH:15][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH:27]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.O.C([O-])(O)=O.[Na+]>N1C=CC=CC=1>[CH:27]1([C:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:26][C:11]4[CH:12]=[N:13][C:14]([NH:16][C:17]([CH:19]5[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]5)=[O:18])=[CH:15][C:10]=4[N:9]=3)=[CH:4][CH:3]=2)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Nc1ccc(-c2nc3cc(NC(=O)C4CCCCCC4)ncc3[nH]2)cc1
Reactant: O=C(Cl)C1CCCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1cc2nc(-c3ccc(C(=O)C4CCCCCC4)cc3)[nH]c2cn1)C1CCCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
The amine 19 (0.094 g, 0.27 mmol) was taken in dry Pyridine (5 ml) and cycloheptane carbonyl chloride (0.100 ml, 0.622 mmol) was added and the solution stirred at room temperature overnight. Water was added followed by sat. NaHCO3 solution. The mixture was stirred at room temperature for 1 h. The solid was filtered, dried and passed through a SiO2 gel column, eluting with ethyl acetate afforded a white solid 20 (0.050 g, 39%). M.p. 194° C.; 1H NMR (DMSO-d6, 500 MHz): δ13.40 (1H, brs, NH), 10.09 (2H, s, NH), 8.81 (1H, brs), 8.145 (2H, d, J=9.0 MHz), 7.82 (2H, d, J=9.0 Hz), 2.74 (1H, m), 2.49 (1H, m), 1.91-1.25 (24H, m); EIMS m/z: 474.4 (M+1) and 472.6 (M−1); Anal (C28H35N5O2) C, H, N.
Reaction SMILES: C(O)(=O)C.C(NC(=O)C(C)=CC1C=C(OC)C(OC)=CC=1N)CC1C=CC=CC=1.[CH3:30][C:31](=[CH:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[N+:44]([O-])=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33]>[Fe].O>[NH2:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[CH:37]=[C:31]([CH3:30])[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCOC(=O)C(C)=Cc1ccccc1[N+](=O)[O-]
Agent: [Fe]
Agent: COc1cc(N)c(C=C(C)C(=O)NCCc2ccccc2)cc1OC
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(C)=Cc1ccccc1N
Reaction time: 1 h

Procedure:
Into 160 ml of acetic acid, 10 g (42.5 mmol) of (E) ethyl 2-methyl-3-(2-nitrophenyl)-2-propenate were dissolved. While the solution was stirred, 10.9 g (195.2 mmol) of iron powder (Koso Chem. Co.) and 12 ml of distilled water were added thereto at room temperature; and temperature was raised, so that reflux was carried out for 1 hour at 100° C. After the end point of the reaction was verified by TLC, the reaction liquid was cooled, and acetic acid was evaporated under a reduced pressure. Ethyl acetate was added to the residue, and insoluble matters were filtered out. Thus obtained filtrate was successively washed with water and a saturated aqueous sodium hydrogencarbonate solution. The washed solution was dried for one night with sodium sulfate being added thereto. After sodium sulfate anhydride was filtered out, the filtrate was concentrated under a reduced pressure. The resulting oily product was refined by a silica gel column chromatography (silica gel; developing solvent: ethyl acetate/hexane=1/3), whereby 6.4 g of the aimed compound were obtained as an oily product (yield: 71.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.C[O:13][C:14]([C:16]#[C:17][C:18](OC)=[O:19])=[O:15]>>[F:11][C:8]([F:9])([F:10])[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]2[C:3]=1[C:18](=[O:19])[CH:17]=[C:16]([C:14]([OH:15])=[O:13])[NH:1]2
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COC(=O)C#CC(=O)OC
Product: O=C(O)c1cc(=O)c2c(C(F)(F)F)cccc2[nH]1
Yield: 0.1 %

Procedure:
Using the method described in Example 15 with 3-aminobenzotrifluoride (40 g) and dimethylacetylene dicarboxylate (35 g) gave 5-trifluoromethyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (0.04 g) m.p. 265°-267° C. (dec), δ (360 MHz, DMSO-d6) 6.65 and (1H, s, 3-H), 7.78 (2H, m, 7-H, 8-H), 8.26 (1H, d, 6-H) and 12.08 (1H, N-H).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH3:29])=[O:8])[CH2:5][CH2:4]1)#[N:2]>CCCCCCC.C(O)(C)C>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=3[C:24]([F:27])([F:25])[F:26])(=[O:16])=[O:15])[CH2:11][C@H:10]2[O:28][CH3:29])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Solvent: CCCCCCC
Solvent: CC(C)O
Product: CO[C@@H]1C[C@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
Racemic (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 58) was subjected to chiral preparative HPLC on Chiralpak AD using heptane/isopropanol 75:25 as eluant. The title compound was eluated as the second peak. MS (EI): 495.1 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:12][C:11]=1[N+:21]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC1C=CC(C(O)=O)=C([N+]([O-])=O)C=1.C(I)CCC.C(=O)([O-])[O-].[K+].[K+].[OH-].[Na+].C(N)C1C=CC=CC=1>C(O)C.O.CN(C)C=O>[CH2:1]([N:8]1[C:9](=[O:24])[C:10]2[C:11](=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:14][CH:15]=2)[NH:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCOc1ccc(C(=O)NCc2ccccc2)c([N+](=O)[O-])c1
Agent: O=C(O)c1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCI
Solvent: CCO
Solvent: NCc1ccccc1
Product: CCCCOc1ccc2c(=O)n(Cc3ccccc3)[nH]c2c1
Yield: 27 %

Procedure:
Using a similar procedure to that described in Example 34, but starting from N-benzyl-4-butoxy-2-nitrobenzamide [obtained as an oil of satisfactory purity by heating a mixture containing 4-hydroxy-2-nitrobenzoic acid (J.Chem.Soc., 1949, 1502), butyl iodide, potassium carbonate and N,N-dimethylformamide; hydrolysing a solution of the ester in ethanol with aqueous sodium hydroxide and coupling the resultant acid with benzylamine using the conditions described for the preparation of starting materials in Example 1], using a mixture of ethanol and water (3/1 v/v) as solvent and heating the reaction for 8 hours there was obtained 1,2-dihydro-2-benzyl-6-butoxy-3H-indazol-3-one as a solid, m.p. 148-149° C., in 27% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:14]CCCCC.IC.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:13])[CH:9]([CH:10]2[CH2:11][CH2:12]2)[CH3:14])=[CH:6][CH:7]=1
Reactant: CCCCCC
Reactant: O=C(CC1CC1)c1ccc(Cl)cc1
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: CC(C(=O)c1ccc(Cl)cc1)C1CC1
Temperature: -30 °C

Procedure:
Crude 1-(4-chlorophenyl)-2-cyclopropylethanone (from the previous reaction) in dry dimethylformamide (150 ml) was added dropwise to a stirred suspension of hexane-washed sodium hydride (4.57 g of a 60% dispersion in oil, 114 mmol) in dry dimethylformamide (35 ml) under nitrogen. After 1 hour the mixture was cooled to -30° C. and iodomethane (16.2 g, 114 mmol) in dry dimethylformamide (35 ml) added very slowly. The mixture was then poured into water and the resultant mixture extracted with ether. The extracts were washed with brine, dried and evaporated in vacuo. Chromatography [(SiO2, hexane-ethyl acetate (95:5)] gave 1-(4-chlorophenyl)-2-cyclopropylpropan-1-one (7.66 g, approximately 70% pure, approximately 28% based on 1-(4-chlorophenyl)-2-cyclopropylethanol).
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])=O.Cl.C([O-])([O-])=O.[K+].[K+]>COCCOC>[NH2:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=1[C:14](=[O:19])[C:15]([F:18])([F:17])[F:16]
Reactant: CC(C)(C)C(=O)Nc1c(F)cc(Cl)cc1C(=O)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Nc1c(F)cc(Cl)cc1C(=O)C(F)(F)F
Temperature: 25 °C
Yield: 92.9 %

Procedure:
A stirred solution of 0.35 g (1.07 mmol) of 2′-(trimethylacetamido)-5′-chloro-3′-fluoro-2,2,2-trifluoroacetophenone in 3 mL of 1,2-dimethoxyethane and treated with 24 mL of 6N aq. HCl. The mixture was stirred at reflux for 2 h, cooled to RT, and brought to pH 9 with K2CO3. The mixture was extracted twice with ether and the combined organic extracts were washed with brine, dried (MgSO4), and concentrated under reduced pressure to give 240 mg (92%) of 2′-amino-5′-chloro-3′-fluoro-2,2,2-trifluoroacetophenone as an oily orange solid. 1H NMR (300 MHz, CDCl3) δ7.54(m, 1H); 7.25(dd, 1H, J=10.6, 2.2 Hz); 6.40-6.60(br. s, 2H). High resolution mass spec: calculated for C8H4NOClF4(M+): 240.9918, found: 240.9914. 19F NMR (282 MHz, CDCl3) δ−132.7(s, 1F), −70.6(s, 3F).
Reaction SMILES: CS(O[CH:6]([CH3:15])[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=O)=O.[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:9]1([CH2:8][CH2:7][CH:6]([N:20]2[C:16](=[O:26])[C:17]3[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:19]2=[O:21])[CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(CCC1CCCCC1)OS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(CCC1CCCCC1)N1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Yield: 58.1 %

Procedure:
A solution of 7.00 g 3-cyclohexyl-1-methylpropyl methanesulfonate in 20 mL DMF was added to a solution of 5.14 g phthalimide and 7.43 g of potassium carbonate in 50 mL DMF at room temperature. The reaction mixture was stirred at 80° C. over night. Aqueous work-up followed by silica gel filtration yielded 4.95 g (58%) of a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.O.C(OCC)(=O)C.[CH:16]([NH2:18])=[O:17]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:18][CH:16]=[O:17])[N:3]=1
Reactant: NC=O
Reactant: Fc1cccc(F)n1
Solvent: CCOC(C)=O
Solvent: O
Product: O=CNc1cccc(F)n1
Temperature: 25 °C

Procedure:
A solution of 0.63 g of 2,6-difluoropyridine in 0.2 mL of formamide was stirred for 3 hours at 150° C. The reaction mixture was cooled to room temperature, to which were added water (100 mL) and ethyl acetate (100 mL×3) for extraction. The extract solution was dried over anhydrous magnesium sulfate, followed by concentration to give powdery precipitate of 2-fluoro-6-(formylamino)pyridine. The powdery product was collected by filtration and dried for 2 hours at 40° C. under reduced pressure (0.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([C:9]2[C:10](=[O:20])[CH:11]=[C:12]([C:15]([O:17]CC)=[O:16])[O:13][CH:14]=2)=[O:8])=[CH:5][CH:4]=1.B(Br)(Br)Br>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[C:10](=[O:20])[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[O:13][CH:14]=2)=[O:8])=[CH:21][CH:22]=1
Reactant: CCOC(=O)c1cc(=O)c(C(=O)c2ccc(OC)cc2)co1
Agent: BrB(Br)Br
Product: COc1ccc(C(=O)c2coc(C(=O)O)cc2=O)cc1

Procedure:
Treatment of ethyl 5-(4-methoxybenzoyl)-4-oxo-4H-pyran-2-carboxylate with boron tribromide under the conditions described in Example 45 caused preferential cleavage of the ester group to give the title product (mp 185°-190° C. with decomposition).
Reaction SMILES: C([O:3][C:4](=[O:42])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[C:18]([CH2:38][CH:39]4[CH2:41][CH2:40]4)=[N:19][C:20]([C:27]4[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=4)=[CH:21][C:22]=3[C:23]([F:26])([F:25])[F:24])[CH:13]=2)[CH:8]=[CH:7]1)C.[Li+].[OH-]>>[CH:39]1([CH2:38][C:18]2[C:17]([CH2:16][O:15][C:12]3[CH:13]=[C:14]4[C:9]([CH:8]=[CH:7][N:6]4[CH2:5][C:4]([OH:42])=[O:3])=[CH:10][CH:11]=3)=[C:22]([C:23]([F:24])([F:25])[F:26])[CH:21]=[C:20]([C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:31][CH:32]=3)[N:19]=2)[CH2:41][CH2:40]1
Reactant: CCOC(=O)Cn1ccc2ccc(OCc3c(C(F)(F)F)cc(-c4ccc(OC(F)(F)F)cc4)nc3CC3CC3)cc21
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cn1ccc2ccc(OCc3c(C(F)(F)F)cc(-c4ccc(OC(F)(F)F)cc4)nc3CC3CC3)cc21

Procedure:
In analogy to the procedure described in example 5 g], {6-[2-cyclopropylmethyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester was treated with LiOH to obtain the title compound as brown solid.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]2[CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClCCl.Cl.O1CCOCC1>CO>[O:16]1[CH2:15][CH2:14][CH:13]([C:11]2[N:10]=[C:9]([CH:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)[N:8]([CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:12]=2)[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)cn2CCN2CCCC2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: c1c(C2CCOCC2)nc(C2CCNCC2)n1CCN1CCCC1
Reaction time: 1 h
Yield: 124.6 %

Procedure:
Combine tert-butyl 4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate (1.74 g, 4.03 mmol), dichloromethane (53 mL) and methanol (21 mL). Add 4 M hydrogen chloride in 1,4-dioxane (10.4 mL, 10.3 eq). After one hour, concentrate in vacuo. Dry the resulting residue under vacuum to give the title compound as a white solid (1.67 g, 94%). MS (ES) m/z=333 [M]+.