Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([SH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[N:13][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: O=C(O)c1cc(F)ccc1S
Reactant: N#Cc1ccccn1
Solvent: c1ccncc1
Product: O=c1nc(-c2ccccn2)sc2ccc(F)cc12
Temperature: 135 °C
Yield: 4 %

Procedure:
A mixture of 5-fluoro-2-mercaptobenzoic acid (1.50 g, 8.7 mmol), 2-cyanopyridine (0.92 g, 8.8 mmol) and pyridine (30.0 ml) was refluxed at 135° C. for 48 hrs as described in Example 9. The reaction mixture was concentrated. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (2:1, v/v). The resultant product was recrystallized from ethanol to give the titled compound (0.09 g, 4%).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][O:5][C:4]2[CH:7]=[C:8]([CH3:18])[C:9]([C:11]3[N:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[CH:10][C:3]1=2.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:17][C:14]1[CH:13]=[N:12][C:11]([C:9]2[C:8]([CH3:18])=[CH:7][C:4]3[O:5][CH2:6][C:2]([CH3:19])([CH3:1])[C:3]=3[CH:10]=2)=[CH:16][N:15]=1)=[O:24]
Reactant: Cc1cc2c(cc1-c1cnc(N)cn1)C(C)(C)CO2
Reactant: O=C(Cl)c1ccccc1Cl
Product: Cc1cc2c(cc1-c1cnc(NC(=O)c3ccccc3Cl)cn1)C(C)(C)CO2
Yield: 50.1 %

Procedure:
Similarly, (2-chlorophenyl)-N-[5-(3,3,6-trimethyl(2,3-dihydrobenzo[b]furan-5-yl))-pyrazin-2-yl]carboxamide (180) (14.8 mg, yield: 50.1%, purity>95%) as white solid was prepared from 5-(3,3,6-trimethyl-2,3-dihydrobenzo[3,4-b]furan-5-yl)pyrazine-2-ylamine (177) (19 mg, 0.075 mmol) and 2-chlorobenzoyl chloride (19 μl).
Reaction SMILES: [F:1][C:2]1[C:6]([F:7])=[CH:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:26]=[CH:25][CH:24]=4)=[N:15]3)=[C:10]([OH:34])[CH:9]=2)[CH:3]=1.FC(F)(F)S(O[CH2:41][C:42]([F:45])([F:44])[F:43])(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[C:6]([F:7])=[CH:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17](=[O:22])[C:16]([C:23]4[N:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[N:26]=[CH:25][CH:24]=4)=[N:15]3)=[C:10]([O:34][CH2:41][C:42]([F:45])([F:44])[F:43])[CH:9]=2)[CH:3]=1
Reactant: COc1cn(-c2ccc(-n3cc(F)c(F)c3)cc2O)nc(-c2ccnn2-c2ccccc2)c1=O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cn(-c2ccc(-n3cc(F)c(F)c3)cc2OCC(F)(F)F)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
A suspension of 1-[4-(3,4-difluoro-1H-pyrrol-1-yl)-2-hydroxyphenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (138 mg), 2,2,2-trifluoroethyl trifluoromethanesulfonate (104 mg) and potassium carbonate (82 mg) in DMF (1.5 mL) was stirred at room temperature for 30 min. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, THF), and crystallized from methanol to give the title compound (131 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:4]=1[NH2:5].[Cl:13][CH2:14][CH:15]([CH3:19])[C:16](Cl)=[O:17]>C1C=CC=CC=1.O>[Cl:13][CH2:14][CH:15]([CH3:19])[C:16]([NH:5][C:4]1[CH:6]=[C:7]([C:10](=[O:12])[CH3:11])[CH:8]=[CH:9][C:3]=1[O:2][CH3:1])=[O:17]
Reactant: CC(CCl)C(=O)Cl
Reactant: COc1ccc(C(C)=O)cc1N
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(C(C)=O)cc1NC(=O)C(C)CCl
Reaction time: 2 h
Yield: 77 %

Procedure:
24.8 g of 2-methoxy 5-acetyl aniline [obtained according to Oelschager Arzneimit. Forschung 8 532-539 (1958)] dissolved in 150 ml benzene are added with 10.6 g of 3-chloro isobutyric acid chloride in 40 ml benzene. The mixture is kept at room temperature for 2 hours under stirring then diluted with 250 ml water. The benzenic phase is separated. The aqueous phase is extracted twice with benzene. The benzenic solutions are united, washed with 2N hydrochloric acid and then with water, dried on sodium sulphate, filtered and evaporated to dryness. The residue is recrystallised from isopropyl ether from which 15.5 g or pure compound are recovered (yield = 77%) -1-(β-chloroα-methyl propionylamino) 2-methoxy 5-acetylbenzene melts at 92-97°.
Reaction SMILES: C(=O)(O)[O-].[Na+].[Cl:6][C:7]1[C:16]([CH:17]=[CH:18][C:19](=[N:21][OH:22])[CH3:20])=[C:15]([Cl:23])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10].[I-].[K+].II.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O.O1CCCC1>[Cl:6][C:7]1[C:16]([C:17]2[O:22][N:21]=[C:19]([CH3:20])[CH:18]=2)=[C:15]([Cl:23])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccc(Cl)c(C=CC(C)=NO)c1Cl
Agent: II
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)(=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(Cl)c(-c2cc(C)no2)c1Cl
Yield: 60.3 %

Procedure:
4.7 g (55.6 mmol) of sodium bicarbonate in 50 ml of water were added to 4.0 g (13.9 mmol) of methyl 2,4-dichloro-(2-hydroxyiminobut-3-en-4-yl)benzoate in 100 ml of tetrahydrofuran. Under the exclusion of light, 7.9 g (47.8 mmol) of potassium iodide and 3.7 g (14.6 mmol) of iodine in 50 ml of water were then added and the mixture was heated under reflux for 4 hours. The mixture was then cooled and 100 ml of a 24% strength sodium pyrosulfite solution were added a little at a time and the solution was extracted with diethyl ether and concentrated. The residue was subsequently chromatographed over silica gel (eluent: cyclohexane:ethyl acetate=9:1). 2.4 g (60% of theory) of methyl 2,4-dichloro-3-(3-methylisoxazol-5-yl)benzoate were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([OH:19])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:21]1([C:27]2([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:35]3[CH:31]([CH2:32][NH:33][CH2:34]3)[C:30](=[O:36])[CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([N:33]1[CH2:32][CH:31]2[CH:35]([C:27]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:28][CH2:29][C:30]2=[O:36])[CH2:34]1)=[O:19])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: CC(C)(C)OC(=O)NCc1ccccc1CC(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1ccccc1CC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.5 h
Yield: 8619 %

Procedure:
N,N'-Carbonyldiimidazole (0.37 g) is added to a solution of 2-(tert-butoxycarbonylaminomethyl)phenylacetic acid (0.6 g) in dry dichloromethane (20 cc), cooled to +5° C. The mixture is stirred for 30 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (0.75 g) and triethylamine (0.6 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 16 hours, then washed with water (2×100 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). (3aRS,7aRS)-2-[(2-(tert-butoxycarbonylaminomethyl)phenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (105 g) is obtained in the form of a white meringue.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:25])[N:4]([CH3:24])[CH:5]=[C:6]([C:8]([OH:23])([C:19]([F:22])([F:21])[F:20])[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[Cl:18])[CH3:10])[CH:7]=1.[CH3:26][O:27][C:28](=[O:40])[C:29]1[C:34]([C:35]([F:38])([F:37])[F:36])=[CH:33][C:32](Cl)=[N:31][CH:30]=1.N12CCN(CC1)CC2>C(N(CC)CC)C>[CH3:26][O:27][C:28](=[O:40])[C:29]1[C:34]([C:35]([F:36])([F:37])[F:38])=[CH:33][C:32]([O:17][C:14]2[CH:15]=[CH:16][C:11]([CH:9]([CH3:10])[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[C:3](=[O:25])[N:4]([CH3:24])[CH:5]=3)([OH:23])[C:19]([F:21])([F:22])[F:20])=[C:12]([Cl:18])[CH:13]=2)=[N:31][CH:30]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1cc(Cl)c(=O)n(C)c1)C(F)(F)F
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Agent: C1CN2CCN1CC2
Solvent: CCN(CC)CC
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3cc(Cl)c(=O)n(C)c3)C(F)(F)F)c(Cl)c2)cc1C(F)(F)F

Procedure:
In analogy to Example 163, 3-chloro-5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 221, step 5) was reacted with methyl-6-chloro-4-(trifluoromethyl)-nicotinate in the presence of triethylamine and 1,4-diazabicyclo[2.2.2]octane to give the title compound as an off-white solid. MS (m/e)=599.1 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([CH2:23][OH:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CO)no1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.7 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl)1,2,4-oxadiazole-3-carboxylate (Preparation 3) (15.2 g, 38.50 mmol) in ethanol (120 ml) was treated with portions of sodium borohydride (1.46 g, 38.50 mmol) and the resulting mixture was was stirred at room temperature under a nitrogen atmosphere for 5 hours. Aqueous citric acid (5% w/v solution) was added slowly and the mixture was stirred at room temperature for a further 30 minutes. The organic solvent was removed under reduced pressure. The aqueous layer was diluted with water and extracted with ethyl acetate giving an emulsion. Anhydrous sodium chloride was added to break up the emulsion. The combined organic layers were washed with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as a colourless oil (13.4 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[S:17][C:16]([S:18][CH3:19])=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1.[C:21]1([CH2:27][C:28]([N:30]=[C:31]=[S:32])=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([NH:20][C:31]([NH:30][C:28](=[O:29])[CH2:27][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[S:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[S:17][C:16]([S:18][CH3:19])=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CSc1cc2ncnc(Oc3ccc(N)cc3F)c2s1
Solvent: C1CCOC1
Product: CSc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)cc3F)c2s1
Reaction time: 2 h
Yield: 51.6 %

Procedure:
A mixture of 282 (248 mg, 0.80 mmol) and 2-phenylacetyl isothiocyanate (214 mg, 1.20 mmol) in THF (8 mL) was stirred for 2 hours, and concentrated. The residue was purified by flash column chromatography, eluent EtOAc/hexane (3:7), to afford title compound 283 (200 mg, 52% yield) as an off-white solid. 1HNMR (DMSO-d6) δ (ppm): 12.42(s, 1H), 11.80(s, 1H), 8.63(s, 1H), 7.85(d, 1H), 7.54-7.44 (m, 3H), 7.35 (m, 4H), 7.30(m, 1H), 3.81(s, 2H), MS (m/z): 485.1(M+H) (found).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[C:11]([CH2:22][C:23]([OH:25])=O)=[N:12][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14](=[O:15])[C:3]1=2.[C:26](N1C=CN=C1)([N:28]1C=CN=[CH:29]1)=O.CNC>O1CCCC1>[CH3:26][N:28]([CH3:29])[C:23](=[O:25])[CH2:22][C:11]1[C:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[N:2]([CH3:1])[C:3]=2[C:14](=[O:15])[N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=1
Reactant: Cn1c2ccccc2c2c(CC(=O)O)nn(-c3ccccc3)c(=O)c21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cc1nn(-c2ccccc2)c(=O)c2c1c1ccccc1n2C
Temperature: 25 °C
Reaction time: 72 h
Yield: 66.7 %

Procedure:
A suspension of 1 g (3 mmol) of 5-methyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetic acid and of 0.7 g (4.3 mmol) of 1,1′-carbonylbis-1H-imidazole in 200 ml of tetrahydrofuran is stirred for 2 h at 60° C. The reaction mixture is cooled to 25° C., an excess of liquefied dimethylamine in solution in tetrahydrofuran is added and the reaction mixture is stirred for 72 h at room temperature. It is concentrated under reduced pressure, 300 ml of water are added and the precipitate is collected by filtration, washed with water and with ether and recrystallized from propan-2-ol. 0.75 g (2 mmol) of solid is isolated.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[CH:9]=[CH:10][N:11]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12](=[O:16])[C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>>[CH2:17]([N:11]1[CH:10]=[CH:9][C:8]2[C:7]([C:24]#[N:25])=[N:6][C:5]([C:3]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])=[C:14]([OH:15])[C:13]=2[C:12]1=[O:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2ccn(Cc3ccccc3)c(=O)c2c1O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(=O)n(Cc3ccccc3)ccc12
Temperature: 25 °C
Yield: 107.7 %

Procedure:
A mixture of 6-benzyl-1-cyano-4-hydroxy-5-oxo-5,6-dihydro-[2,6]naphthyridine-3-carboxylic acid methyl ester (27 mg, 0.081 mmol), glycine (805 mg, 10.7 mmol), and NaOMe solution (16 mL, 8.06 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 1. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was dried over MgSO4 and concentrated. The crude residue was dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH about 1 with 4 M HCl and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to give 33 mg of the title compound. MS: (+) m/z 379.00 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:16])[C@H:13]([CH3:15])[NH2:14])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:16])[C@H:13]([CH3:15])[NH:14][S:27]([CH2:25][CH3:26])(=[O:29])=[O:28])([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: -20 °C
Yield: 31.1 %

Procedure:
L-alanyl-L-proline t-butylester (2.42 g, 10 mmole) was dissolved in methylene chloride (50 ml), and triethylamine (1.01 g, 10 mmole) was added thereto with cooling to -20° C and stirring. Methylene chloride (5 ml) solution of ethanesulfonylchloride (1.29 g, 10 mmole) was added dropwise to the solution while keeping the temperature thereof to -20° C. and then stirred overnight at room temperature. The solution was washed with 10% aqueous citric acid, water, 5% aqueous sodium bicarbonate and water in the order given, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give oily residue of N-ethanesulfonyl-L-alanyl-L-proline t-butylester(yield: 1.04 g, 31.1%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[C:7]2[CH2:20][CH2:21][C:22]([OH:24])=[O:23].I[CH3:26].O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:26])[C:8]([C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)=[C:7]2[CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: CI
Reactant: O=C(O)CCc1c(-c2ccc(Cl)cc2)[nH]c2ccc(Cl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(-c2ccc(Cl)cc2)c(CCC(=O)O)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 5.98 g) was added in portions to a stirred, cooled (0° C.) solution of 5-chloro-2-(4-chlorophenyl)-1H-indole-3-propanoic acid (Description 30, 10 g, 30 mmol) in dimethylformamide (100 mL) and the mixture was stirred at 0° C. for 30 min. Iodomethane (9 mL) was added in one portion and the mixture was stirred at room temperature for 30 min. Water (1.5 L) was added and the mixture was extracted with ether (3×400 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (240 mL) and aqueous sodium hydroxide (4M, 60 mL) was added. The mixture was heated under reflux for 1 h., cooled and the pH was adjusted to 1.0 with hydrochloric acid (2M). The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was triturated with hexane and the solid was collected and dried in vacuo to give the title compound (7.5 g, 72%). 1H NMR (360 MHz, CDCl3) δ 7.58 (1H, d, J 1.8 Hz), 7.44-7.48 (2H, m), 7.18-7.30 (4H, m), 3.53 (3H, s), 2.96-3.00 (2H, m), and 2.54-2.59 (2H, m).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:13][CH2:14]OC)[CH2:11][CH2:10][NH:9][C:8](=[O:12])[CH2:7]1)=[O:5])C.[F:17][C:18]([F:28])([F:27])[CH2:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>[Cl-].C[Al+]C>[F:17][C:18]([F:27])([F:28])[CH2:19][C:20]1[CH:26]=[CH:25][C:23]([N:24]2[CH2:14][CH2:13][C:6]3([CH2:11][CH2:10][NH:9][C:8](=[O:12])[CH2:7]3)[C:4]2=[O:5])=[CH:22][CH:21]=1
Reactant: Nc1ccc(CC(F)(F)F)cc1
Reactant: CCOC(=O)C1(CCOC)CCNC(=O)C1
Agent: C[Al+]C
Agent: [Cl-]
Product: O=C1CC2(CCN1)CCN(c1ccc(CC(F)(F)F)cc1)C2=O

Procedure:
This material was prepared as a white solid (0.72 g) in analogy to example 1 step D) from 4-(2-methoxy-ethyl)-2-oxo-piperidine-4-carboxylic acid ethyl ester (1.03 g), dimethylaluminium chloride (0.9 M in hexane, 20 ml) and 4-(2,2,2-trifluorethyl)aniline (1.2 g). MS (ESI): 327.13 (MH−).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])(=[S:3])[NH2:2].[F:14][C:15]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:16]=1[C:17](=O)[CH2:18]Br>>[F:14][C:15]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:16]=1[C:17]1[N:2]=[C:1]([C:4]2[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=2)[C:7]([O:9][CH3:10])=[O:8])[S:3][CH:18]=1
Reactant: O=C(CBr)c1ccc(F)cc1F
Reactant: COC(=O)c1cccc(C(N)=S)c1
Product: COC(=O)c1cccc(-c2nc(-c3ccc(F)cc3F)cs2)c1
Yield: 69 %

Procedure:
In the same manner as in Example 28, methyl 3-thiocarbamoylbenzoate was reacted with 2,4-difluorophenacyl bromide to obtain methyl 3-[4-(2,4-difluorophenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 69%. Pale yellow prisms. Melting point: 121 to 122° C.
Reaction SMILES: [CH3:1][N:2]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[CH:7]2[CH2:15][CH:3]1[N:4]([CH3:16])[CH2:5][CH2:6]2.[C:17](OC(=O)C)(=[O:19])[CH3:18].C(=O)(O)[O-].[Na+]>ClCCl>[C:17]([O:14][C:12]1[CH:11]=[CH:10][C:9]2[N:2]([CH3:1])[CH:3]3[CH2:15][CH:7]([CH2:6][CH2:5][N:4]3[CH3:16])[C:8]=2[CH:13]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CN1CCC2CC1N(C)c1ccc(O)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(c1)C1CCN(C)C(C1)N2C
Reaction time: 0.25 h
Yield: 31.8 %

Procedure:
A catalytic amount, (0.019 g) of N,N-dimethylaminopyridine was added to a deoxygenated solution of 5.8 g of 1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol and 5.4 g of acetic anhydride in 270 ml of dichloromethane. After stirring for 15 minutes, the reaction mixture was treated with a saturated sodium bicarbonate solution. The aqueous layer was separated and extracted with dichloromethane. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil (7.1 g). Column chloromatography of a 3.5 g aliquot of the oil (silica gel; elution with triethylamine-methanol-ethyl acetate) afforded 2.2 g of 1,2,3,4,5,6-hexahydro-1,3-dimethyl-2,6-methano-1,3-benzodiazocin-8-ol acetate as a solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH2:22][CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)=[C:19]([O:36][CH3:37])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][CH2:22][CH:23]4[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]4)=[C:19]([O:36][CH3:37])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[N:2]1
Reactant: COc1ccc2c(c1CCC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc2c(c1CCC1CCNCC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.6 %

Procedure:
A solution of tert-butyl (Z)-4-(2-{2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}ethyl)piperidine-1-carboxylate (0.0506 g, 0.100 mmol) in methylene chloride (2 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol) to obtain (Z)-2-[(1H-indazol-3-yl)methylene]-6-methoxy-7-[2-(piperidin-4-yl)ethyl]benzofuran-3(2H)-one (0.0172 g, 43%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)=[CH:11][C:10]=1C=O)[CH3:2].[O-][CH2:28]C.[Na+].Cl>C(=O)(OCC)OCC.C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=3)=[CH:11][C:10]=2[CH:28]=1)=[O:26])[CH3:2]
Reactant: CCOC(=O)CCCOc1ccc(-c2ccc(OCC)cc2)cc1C=O
Reactant: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(=O)OCC
Solvent: CCO
Product: CCOC(=O)C1=Cc2cc(-c3ccc(OCC)cc3)ccc2OCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of 4-[(4′-ethoxy-3-formyl-1,1′-biphenyl-4-yl)oxy]butyric acid ethylester (0.50 g) in diethyl carbonate (5 ml) was added a solution of 20% sodium ethoxide in ethanol (0.57 g) at room temperature, and the mixture was then heated to 50° C. and stirred for 1 hour. The solution was neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed, and concentrated. The concentrate was purified by silica gel chromatography (n-hexane/ethyl acetate=10/1) and subsequent concentration of the appropriate eluate gave white crystal of the title compound (0.39 g, yield 82%).