Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Cl[CH2:12][C:13]1[O:17][C:16]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[N:15][C:14]=1[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:12][C:13]2[O:17][C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:27])[F:28])=[CH:22][CH:21]=3)=[N:15][C:14]=2[CH3:30])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1nc(CCc2ccc(C(F)(F)F)cc2)oc1CCl
Reactant: N#Cc1ccc(O)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nc(CCc2ccc(C(F)(F)F)cc2)oc1COc1ccc(C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
To a solution of 2.63 g 2-chloro-4-hydroxy-benzonitrile in 25 ml dimethylformamide were added 4.0 g 5-chloromethyl-4-methyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-oxazole and 8.58 g cesium carbonate. The mixture was stirred at room temperature overnight. Then 150 ml of ethyl acetate were added, the mixture washed with 40 ml water and brine and then dried over MgSO4. The solvent was removed in vacuo. The resulting crude material was purified by RP-HPLC to obtain 3.0 g 2-chloro-4-{4-methyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-oxazol-5-ylmethoxy}-benzonitrile.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9](Br)=[CH:10][C:11]3[C:12]4[C:20]([NH:21][C@H:22]([CH:27]5[CH2:29][CH2:28]5)[C:23]([F:26])([F:25])[F:24])=[N:19][CH:18]=[C:17]([C:30]([NH2:32])=[O:31])[C:13]=4[NH:14][C:15]=3[CH:16]=2)=[CH:4][N:3]=1.[CH3:34]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:34])=[CH:10][C:11]3[C:12]4[C:20]([NH:21][C@H:22]([CH:27]5[CH2:29][CH2:28]5)[C:23]([F:26])([F:25])[F:24])=[N:19][CH:18]=[C:17]([C:30]([NH2:32])=[O:31])[C:13]=4[NH:14][C:15]=3[CH:16]=2)=[CH:4][N:3]=1
Reactant: NC(=O)c1cnc(N[C@H](C2CC2)C(F)(F)F)c2c1[nH]c1cc(-c3cnc(N)nc3)c(Br)cc12
Reactant: CB1OB(C)OB(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc2c(cc1-c1cnc(N)nc1)[nH]c1c(C(N)=O)cnc(N[C@H](C3CC3)C(F)(F)F)c12
Temperature: 100 °C

Procedure:
A mixture of 7-(2-aminopyrimidin-5-yl)-8-bromo-1-{[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]amino}-5H-pyrido[4,3-b]indole-4-carboxamide (100 mg, 0.19 mmol), trimethylboroxin (48 mg, 0.38 mmol), Pd(PPh3)4 (11 mg, 0.0096 mmol), and sodium carbonate (61 mg, 0.58 mmol) in 1,4-dioxane (3 mL) was purged with nitrogen, heated to 100° C. overnight, and cooled to room temperature. The mixture was concentrated and purified by flash chromatography to afford the title compound. 1H NMR (500 MHz, CD3SOCD3) δ 11.55 (s, 1H); 8.47 (s, 1H), 8.36 (s, 1H); 8.27 (s, 2H); 7.95 (br s, 1H); 7.55 (s, 1H); 7.23 (br s, 1H); 6.91 (d, 1H); 6.73 (br s, 1H); 4.83 (m, 1H); 2.42 (s, 3H); 1.59 (m, 1H); 0.75 (m, 1H); 0.63 (m, 1H); 0.55 (m, 1H); 0.33 (m, 1H). LRMS (APCI) calc'd for (C22H20F3N7O) [M+H]+, 456.2. found 456.1.
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[CH:8]=[C:9]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[C:10](N(OC)C)=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH3:25][Mg]Cl>C1COCC1.CCOCC>[C:1]([Si:5]([CH3:24])([CH3:23])[O:6][C:7]1[CH:8]=[C:9]([C:10](=[O:11])[CH3:25])[CH:16]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:18]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)c1cc(O[Si](C)(C)C(C)(C)C)cc(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)c1cc(O[Si](C)(C)C(C)(C)C)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99950.2 %

Procedure:
To an ice-cold suspension of 3-(tert-butyl-dimethyl-silanyloxy)-N-methoxy-N-methyl-5-trifluoromethyl-benzamide (500 mg, 1.37 mmol) in THF (5 mL) was added dropwise 3.0M CH3MgCl (687 mL, 2.06 mmol) at 0° C. The mixture was stirred for 3 hours at room temperature, and then diluted with Et2O. The reaction mixture was washed with saturated ammonium chloride, water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to give 1-[3-(tert-butyl-dimethyl-silanyloxy)-5-trifluoromethyl-phenyl]-ethanone (436 g, 99%).
Reaction SMILES: [CH2:1]([O:5][P:6](Cl)(=[O:12])[O:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH3:4].[CH2:14]([Si:18]([CH2:23][CH2:24][CH2:25][CH3:26])([CH3:22])[CH2:19][CH2:20][OH:21])[CH2:15][CH2:16][CH3:17].N1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[P:6]([O:21][CH2:20][CH2:19][Si:18]([CH2:14][CH2:15][CH2:16][CH3:17])([CH2:23][CH2:24][CH2:25][CH3:26])[CH3:22])([O:5][CH2:1][CH2:2][CH2:3][CH3:4])([O:7][CH2:8][CH2:9][CH2:10][CH3:11])=[O:12]
Reactant: CCCC[Si](C)(CCO)CCCC
Reactant: CCCCOP(=O)(Cl)OCCCC
Solvent: c1ccncc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCOP(=O)(OCCCC)OCC[Si](C)(CCCC)CCCC
Reaction time: 8 h

Procedure:
Dibutylphosphorochloridate (3.74 g) was added to a solution of 2-(di-n-butyl methylsilyl)-ethanol (3 g) and pyridine (1.04 g) in carbon tetrachloride (10 ml). The mixture was left overnight, filtered, and the filtrate passed through an alumina column (20 g), eluting with a further 3 × 20 ml of carbon tetrachloride. Removal of the solvent under vacuum left the phosphate as a colourless oil (2.7 g).
Reaction SMILES: [CH3:1][C:2]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].Br[CH2:18][CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>>[CH2:21]([O:20][CH:19]([O:23][CH2:24][CH3:25])[CH2:18][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)([CH3:1])[CH3:3])=[CH:15][CH:14]=1)[CH3:22]
Reactant: CC(C)(c1ccccc1)c1ccc(O)cc1
Reactant: CCOC(CBr)OCC
Product: CCOC(COc1ccc(C(C)(C)c2ccccc2)cc1)OCC

Procedure:
Synthesized according to Scheme 1, Step 1 from (4-(2-phenylisopropyl)phenol) and 2-bromo-1,1-diethoxyethane to give 1-(2,2-diethoxyethoxy)-4-(2-phenylpropan-2-yl)benzene as a yellow-orange oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.19-7.29 (m, 4H), 7.14-7.19 (m, 1H), 7.13 (d, J=9.0 Hz, 2H), 6.82 (d, J=8.5 Hz, 2H), 4.82 (t, J=5.3 Hz, 1H), 3.98 (d, J=5.0 Hz, 2H), 3.70-3.81 (m, 2H), 3.57-3.68 (m, 2H), 1.65 (s, 6H), 1.24 (t, J=7.0 Hz, 6H).
Reaction SMILES: [OH:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:20][N:19]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:16]3=[N:17][CH:18]=2)[CH:8]=1)([CH3:6])[C:3](O)=[O:4].[CH3:38][NH:39][CH3:40].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C1COCC1>[OH:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[N:20][N:19]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:35])[CH3:36])[C:16]3=[N:17][CH:18]=2)[CH:8]=1)([CH3:6])[C:3]([N:39]([CH3:40])[CH3:38])=[O:4]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(C)(O)C(=O)O)c3)cc12
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(C)(O)C(=O)N(C)C)c3)cc12
Temperature: 60 °C

Procedure:
To a solution of 2-hydroxy-2-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-propionic acid (100 mg, 0.19 mmol), dimethylamine (2 N in THF, 0.143 mL, 0.29 mmol), and diisopropylethylamine (37 mg, 0.29 mmol) in THF (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (110 mg, 0.29 mmol.). The resulting suspension was heated to 60° C. with stirring until all was dissolved. The solvent was evaporated and the residue was used in next step without purification. MS: m/z 547 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:3]=1[CH:13]=[O:14].[OH-].[K+].[Mn]([O-])(=O)(=O)=[O:18].[K+]>O.ClCCl>[Cl:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[C:4]([C:9]([F:10])([F:12])[F:11])[C:3]=1[C:13]([OH:18])=[O:14]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCn1nc(C(F)(F)F)c(C=O)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCn1nc(C(F)(F)F)c(C(=O)O)c1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
A mixture of 29.5 g (131 mmol) of 5-chloro-1-ethyl-3-(trifluoromethyl)-pyrazole-4-carboxaldehyde in 350 mL of distilled water was prepared and 0.733 g (131 mmol) of potassium hydroxide and 20.6 g (131 mmol) of potassium permanganate were added to it. The mixture was heated to 60° C. with stirring for 2 hours. The color turned from purple to dark brown. An aliquot was taken, filtered to remove the solids, acidified, and analyzed by gas chromatography to determine that the reaction was complete. The reaction mixture was then filtered to remove the solids and the filtrate was acidified to pH 2. The precipitate that formed was recovered by filtration and washed with water to obtain a white solid. This solid was partially dissolved in hot dichloromethane and the insoluble portion removed by gravity fIltration. The filtrate was concentrated by evaporation under reduced pressure to obtain 23.4 g of the title compound as a white solid melting at 164°-166° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][NH:5][C:6](=[O:21])[C@H:7]([CH2:16][O:17][CH2:18][CH:19]=[CH2:20])[NH:8]C(OC(C)(C)C)=O.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>C(Cl)Cl>[F:26][C:25]([F:28])([F:27])[C:23]([OH:29])=[O:24].[CH3:1][O:2][C:3](=[O:22])[CH2:4][NH:5][C:6](=[O:21])[C@H:7]([CH2:16][O:17][CH2:18][CH:19]=[CH2:20])[NH2:8]
Reactant: C=CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC[C@H](N)C(=O)NCC(=O)OC

Procedure:
N-tert-butoxycarbonyl O-allyl L-seryl glycine methyl ester 18 (5.86 g, 18.3 mmol) was dissolved in CH2Cl2 (30 mL) and TFA (30 mL) added at room temperature. The reaction mixture was stirred for 2 hours before the solvent and bulk of excess TFA were evaporated affording a brownish liquid (7.50 g). The residue was washed with Et2O (2×25 mL), redissolved in CH2Cl2 (25 mL), the solvents evaporated and the residue dried under reduced pressure affording a brownish, viscous liquid (6.01 g, 98%); δH (300 MHz; d6-DMSO) 9.02 (1H, t, J 6, NH), 8.33 (3H, br s, NH3+), 5.87 (1H, ddt, J 5, 10 and 17, CH═CH2), 5.29 (1H, ddt, J 1, 2 and 17, CH═CHH), 5.21-5.14 (1H, m, CH═CHH), 4.10 (1H, m, CαH(Ser(All))), 4.00 (2H, ddd, J 1, 1 and 5, CH2CH═CH2), 3.95 (2H, d, J 6, CαH2(Gly)), 3.78-3.67 (2H, m, CH2), 3.64 (3H, s, OCH3); δC (75 MHz; d6-DMSO) 169.7, 167.0, 158.4 (q, JCF 32), 134.4, 116.7 (q, JCF 296), 71.4, 68.0, 54.9, 52.3, 51.8, 40.7; m/z (ESI) 217.1194 (M+; C9H17N2O4 requires 217.1188)
Reaction SMILES: Cl[C:2](=[N:13][OH:14])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1.[C:15]1(N2CCOCC2)[CH2:19][CH2:18][CH2:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[O:14]1[C:16]2[CH2:17][CH2:18][CH2:19][C:15]=2[C:2]([C@H:3]2[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]2)=[N:13]1
Reactant: COC(=O)[C@H]1CC[C@H](C(Cl)=NO)CC1
Reactant: C1=C(N2CCOCC2)CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)[C@H]1CC[C@H](c2noc3c2CCC3)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of trans-methyl 4-(chloro(hydroxyimino)methyl)cyclohexanecarboxylate (0.900 g, 4.10 mmol) and 4-cyclopentenylmorpholine (1.23 ml, 8.19 mmol) in dichloromethane (21 ml) was added triethylamine (0.714 ml, 5.12 mmol) at 0-5° C. The reaction mixture was allowed to warm to room temperature and stirred for 20 h. The solvent was evaporated. The residue was redissolved in 6 M aqueous hydrogen chloride solution (20.5 ml) and stirred at reflux for 4 h. After cooling to room temperature the reaction mixture was poured on ice, basified with 2 M aqueous sodium hydroxide solution (80 ml) and washed with two 50-ml portions of ethyl acetate. The combined organic layers were extracted with two 50-ml portions of 1 M aqueous sodium hydroxide solution. The combined aqueous layers were acidified to pH 2-3 by addition of concentrated hydrochloric acid and extracted with three 100-ml portions of ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated in tert-butyl methyl ether (50 ml). The precipitate was removed by filtration. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography with n-heptane/ethyl acetate as eluent to give the title compound (0.060 g, 6%) as off-white solid. MS m/e: 234 ([M−H]−)
Reaction SMILES: [Na].[C:2]1([S:8]([NH2:11])(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][N:13]1[C:21]2[C:16](=[N:17][C:18]([Cl:23])=[N:19][C:20]=2[Cl:22])[N:15]=[C:14]1Cl.Cl>CN(C=O)C>[Cl:23][C:18]1[N:17]=[C:16]2[C:21]([N:13]([CH3:12])[C:14]([NH:11][S:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)(=[O:10])=[O:9])=[N:15]2)=[C:20]([Cl:22])[N:19]=1
Reactant: Cn1c(Cl)nc2nc(Cl)nc(Cl)c21
Reactant: NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: Cn1c(NS(=O)(=O)c2ccccc2)nc2nc(Cl)nc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10.8 g (50.0 mmol) of the sodium salt of benzenesulfonamide was suspended in 100 ml of DMF; at 60° C., 11.9 g (50.0 mmol) of 7-methyl-2,6,8-trichloropurine was added. After 8 hours at 80° C. and cooling to room temperature, H2O/ice was added, the mixture was acidified with 10% strength hydrochloric acid and the precipitate was suction filtered and dried.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH3:19][O:20][CH2:21][C@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1>>[CH3:19][O:20][CH2:21][C@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:14]([C:10]1[CH:11]=[N:12][O:13][C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:18])[F:17])=[CH:8][CH:7]=1)=[O:16]
Reactant: COC[C@H]1CCCN1
Reactant: O=C(O)c1cnoc1-c1ccc(C(F)(F)F)cc1
Product: COC[C@H]1CCCN1C(=O)c1cnoc1-c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared from 5-(4-trifluoromethylphenyl)isoxazole-4-carboxylic acid (12.9 mg, 0.050 mmol) and (R)-2-methoxymethyl-pyrrolidine (6.9 mg, 0.060 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (10.1 mg). Calcd for C17H17F3N2O3: 354.1191, found 354.1190.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([CH3:12])[N:3]=1.[Br:13]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:4]1[CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=[C:2]([Cl:1])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C(F)(F)F)cc(Cl)n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: FC(F)(F)c1cc(Cl)nc(CBr)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(2-chloro-6-methyl-4-(trifluoromethyl)pyridine (10.0 g, 51 mmol), N-bromosuccinimide (10.9 g, 61 mmol), and 2,2′-azobis(2-methylpropionitrile) (164 mg, 1 mmol) were combined in carbon tetrachloride (200 mL) and heated to reflux. After 16 h, the reaction mixture was cooled to 0° C. and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (100% hexanes) to produce 9.1 g (70%) as a light yellow oil. 1H-NMR (CDCl3, 400 MHz) δ 7.59 (s, 1H), 7.47 (s, 1H), 4.52 (s, 2H).
Reaction SMILES: CN(C)C=O.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[NH:30][C:31](=[O:41])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40].[CH2:42](I)[CH3:43]>O>[Cl:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH3:29])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH:12]=[CH:11][C:10]=1[N:30]([CH2:42][CH3:43])[C:31](=[O:41])[O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH3:40]
Reactant: CCI
Reactant: COc1cc2ncnc(Oc3ccc(NC(=O)OCc4ccccc4C)c(Cl)c3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(C(=O)OCc1ccccc1C)c1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
Dimethylformamide (5 ml) was added to sodium hydride (11 mg), and 2-methylbenzyl N-{2-chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]phenyl}carbamate (62 mg) was added to the mixture. Subsequently, a dimethylformamide solution (2 ml) of ethyl iodide (84 mg) was added thereto, and the mixture was stirred at room temperature for 10 min. Water was added to stop the reaction, and the reaction solution was then extracted with ethyl acetate, followed by washing with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (53 mg, yield 79%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:45][C@@H:46]1[NH:51][CH2:50][CH2:49][N:48]([S:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]([F:64])([F:63])[F:62])=[CH:57][CH:56]=2)(=[O:54])=[O:53])[CH2:47]1>CN(C=O)C>[CH3:1][C:2]1[C:7]([C:8]([N:51]2[CH2:50][CH2:49][N:48]([S:52]([C:55]3[CH:56]=[CH:57][C:58]([C:61]([F:64])([F:62])[F:63])=[CH:59][CH:60]=3)(=[O:53])=[O:54])[CH2:47][C@@H:46]2[CH3:45])=[O:10])=[CH:6][CH:5]=[C:4]([CH3:11])[N:3]=1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1
Reactant: Cc1ccc(C(=O)O)c(C)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]2C)c(C)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 65.1 %

Procedure:
2,6-Dimethyl-3-pyridinecarboxylic acid (GSK1770624A, Atlantic) (98 mg, 0.65 mmol) and HATU (247 mg, 0.65 mmol) were suspended in DMF (2 ml) and DIPEA (0.170 ml, 0.97 mmol) was added. This mixture was stirred for 40 min at ambient temperature. (3S)-3-Methyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Description 2) (100 mg, 0.32 mmol) was added and stirring continued for 3 h. The reaction mixture was partitioned between DCM and sat aq. NaHCO3 solution (10 ml each). The layers were separated and the aqueous was washed with further DCM (2×5 ml). The combined organic layers were concentrated to leave a brown oil. This was purified by MDAP to give the title compound (92 mg) as an orange solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:9]2[C:14]([OH:15])=[CH:13][CH:12]=[C:11]([CH3:16])[N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(Cl)(Cl)Cl>N1C=CC=CC=1>[C:17]([O:15][C:14]1[C:9]([C:3]2[C:2]([O:1][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=2)=[N:10][C:11]([CH3:16])=[CH:12][CH:13]=1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(O)c(-c2nc(C)ccc2O)n1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(OC(=O)c2ccccc2)c(-c2nc(C)ccc2OC(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3,3'-Dihydroxy-6,6'-dimethyl-2,2'-bipyridine (5) (0.22 g, 1.02 mmoles) was dissolved in 12 ml pyridine and benzoylchloride (0.30 g, 2.13 mmoles) was added. After stirring for 1.5 hours at room temperature, 100 ml chloroform was added and the solution was extracted with 100 ml saturated sodium hydrogen carbonate solution. The chloroform phase was dried and evaporated to dryness. The product was crystallized as a grey powder from cyclohexane.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1)[CH2:21][CH:22]1[S:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]>>[F:17][C:18]1[CH:19]=[C:20]([CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][CH:35]([NH:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]2[C:14]3[NH:13][C:12](=[O:15])[NH:11][C:10]=3[CH:9]=[CH:8][CH:7]=2)[CH2:34][CH2:33]1)[CH2:21][CH:22]1[S:26][C:25](=[O:27])[NH:24][C:23]1=[O:28]
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2F)CC1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c(=O)[nH]c45)CC3)c(F)c2)S1

Procedure:
The title compound was prepared from 4-((2S)-3-amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one (U.S. Pat. No. 5,786,356/1998) and 5-[3-fluoro-4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 61) according to the procedure of Example 63 as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 1.56–1.62 (m, 2H), 2.04 (m, 2H), 2.63–2.75 (m, 5H), 2.86–2.95 (m, 4H), 3.01–3.10 (m, 4H), 4.50–4.55 (m, 1H), 5.33 (brs, 1H), 6.57–6.65 (m, 2H), 6.84–7.09 (m, 3H), 8.22 (s, 1H), 7.22–7.29 (m, 1H), 10.55 (s, 1H), 10.65 (s, 1H); MS (ES) m/z: 530.0 (MH+); HRMS Calcd. for C25H29FN5O5S (MH+): 530.1873. Found: 530.1876.
Reaction SMILES: [F:1][C:2]([S:5]([O:8]S(C(F)(F)F)(=O)=O)(=[O:7])=[O:6])([F:4])[F:3].O[C:17]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:21][C:18]=1[CH:19]=[O:20].CC1C=CC=C(C)N=1>ClCCl>[F:1][C:2]([F:4])([F:3])[S:5]([O:8][C:17]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:21][C:18]=1[CH:19]=[O:20])(=[O:7])=[O:6]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COCCOc1ccc(O)c(C=O)c1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COCCOc1ccc(OS(=O)(=O)C(F)(F)F)c(C=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Trifluoromethyl sulphonic anhydride (3.88 ml) was added dropwise over a period of 10 minutes to a stirred solution of 2-hydroxy-5-(2-methoxyethoxy)benzaldehyde (4.11 g) and 2,6-dimethylpyridine (2.67 ml) in dichloromethane (20 ml) at 0° C. under an atmosphere of argon. After stirring at room temperature for 16 hours, the mixture was added to ice (100 g). The organic phase was separated, washed with 5% aqueous sodium carbonate solution (2×10 ml), dried (MgSO4) and evaporated to give an oil which was purified by flash column chromatography on silica gel using dichloromethane as eluent to give 2-trifluoromethylsulphonyloxy-5-(2-methoxyethoxy)benzaldehyde (2.2 g) as an oil; NMR(CDCl3): 3.45(3H,s), 3.78(2H,m), 4.19(2H,m), 7.3(2H,m), 7.48(1H,d) and 10.23(1H,d); m/z 329(M+H).
Reaction SMILES: [CH:1]1[C:11]2[CH:10](O)[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[Cl:19][CH:10]1[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[CH2:7][S:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]1=2
Reactant: OC1c2ccccc2CSc2ccccc21
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: ClC1c2ccccc2CSc2ccccc21

Procedure:
19.5 G. of 6,11-dihydro-dibenzo[b,e]thiepin-11-ol, 25 ml. of thionyl chloride and 180 ml. of absolute benzene are heated under reflux conditions for 2 hours. The mixture is evaporated, treated several times with absolute benzene and then evaporated. The crude 11-chloro-6,11-dihydro-dibenzo[b,e]thiepin obtained as the residue is used without further purification.