Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([CH2:7][C:8]([OH:10])=O)=[CH:4][S:3]1.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[C:34]([O:37][CH2:38][C:39]1[CH2:40][S:41][C@@H:42]2[CH:49]([NH2:50])[C:48](=[O:51])[N:43]2[C:44]=1[C:45]([OH:47])=[O:46])(=[O:36])[NH2:35].C[Si](CC(N)=O)(C)C>O1CCCC1.C(OCC)(=O)C.O>[C:34]([O:37][CH2:38][C:39]1[CH2:40][S:41][C@@H:42]2[CH:49]([NH:50][C:8](=[O:10])[CH2:7][C:5]3[NH:6][C:2](=[O:1])[S:3][CH:4]=3)[C:48](=[O:51])[N:43]2[C:44]=1[C:45]([OH:47])=[O:46])(=[O:36])[NH2:35]
Reactant: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: O=C(O)Cc1csc(=O)[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C1CCC(=O)N1O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(=O)[nH]3)[C@H]2SC1
Temperature: 25 °C
Yield: 5.8 %

Procedure:
To a mixture of 2-oxo-2,3-dihydrothiazol-4-ylacetic acid (0.4 g.) and N-hydroxysuccinimide (0.3 g.) in tetrahydrofuran (15 ml.) was added N,N'-dicyclohexylcarbodiimide (0.52 g.) with stirring at room temperature, and the mixture was further stirred for 2 hours at the same temperature. Thus obtained solution was added to a solution of 3-carbamoyloxymethyl-7-amino-3-cephem-4-carboxylic acid (0.816 g.) and trimethylsilylacetamide (0.27 g.) in ethyl acetate (30 ml.) at room temperature, and the mixture was stirred for 16 hours at the same temperature. After the reaction, the reaction mixture was cooled to at -20° C., and then water (20 ml.) was added thereto. After stirring the mixture sufficiently, the mixture was filtered, and then the ethyl acetate layer was separated therefrom. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated carbon, and then the solvent was distilled off under reduced pressure. The residue was pulverized in diethyl ether, collected by filtration and then dried to give 3-carbamoyloxymethyl-7-(2-oxo-2,3-dihydrothiazol-4-yl)acetamido-3-cephem-4-carboxylic acid (60 mg.).
Reaction SMILES: C(OC(C)(C)CC)(=O)C=C.C[O:12][P:13]([CH:25]([NH:27]C(OCC1C=CC=CC=1)=O)[CH3:26])([CH2:15][CH:16]([C:21]([O:23]C)=[O:22])[CH2:17][CH:18]([CH3:20])[CH3:19])=[O:14]>>[NH2:27][CH:25]([P:13]([CH2:15][CH:16]([C:21]([OH:23])=[O:22])[CH2:17][CH:18]([CH3:19])[CH3:20])(=[O:12])[OH:14])[CH3:26]
Reactant: COC(=O)C(CC(C)C)CP(=O)(OC)C(C)NC(=O)OCc1ccccc1
Agent: C=CC(=O)OC(C)(C)CC
Product: CC(C)CC(CP(=O)(O)C(C)N)C(=O)O

Procedure:
By methods outlined in Example 2 and using methyl-2-isobutyl acrylate was made methyl-1-benzyloxycarbonylaminoethyl-[2-carbomethoxy-4-methyl-1-n-pentyl]phosphinate. NMR (D2O) 1.9 (overlapping d, 6H); 1.5-3.2 (m, 9H); 4.6 (d, 3H); 3.8-4.3 (m, 1H); 5.1 (s, 2H); 5.5 (d, 0.05H); 5.9 (d, 0.5H); 7.2 (s, 5H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[C:15]([N+:16]([O-])=O)=[CH:14][N:13]=[C:12]([Cl:19])[N:11]=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[C:15]([NH2:16])=[CH:14][N:13]=[C:12]([Cl:19])[N:11]=1
Reactant: [H][H]
Reactant: COC(=O)C[C@H]1CCCN1c1nc(Cl)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C[C@H]1CCCN1c1nc(Cl)ncc1N

Procedure:
A mixture of 3.3 g (0.011 mole) of [(R)-1-(2-chloro-5-nitro-pyrimidin-4-yl)-pyrrolidin-2-yl]-acetic acid methyl ester (IV-102) in 150 mL of ethyl acetate and 0.8 g of 10% palladium on carbon catalyst was stirred under an atmosphere of hydrogen until hydrogen uptake was complete. The mixture was filtered through a pad of Celite, washing the filter pad with dichloromethane. The filtrate was concentrated under reduced pressure to give [(R)-1-(5-amino-2-chloro-pyrimidin-4-yl)-pyrrolidin-2-yl]-acetic acid methyl ester (V-102), which also contained a small amount of (R)-9-chloro-2,3,3a,4-tetrahydro-1H,6H-6,8,10,10b-tetraaza-benzo[e]azulen-5-one. This material was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9]C)=[CH:4][C:3]=1[C:11]1[C:12](=[O:22])[N:13]([CH3:21])[C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:16]=1.Br.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[C:11]1[C:12](=[O:22])[N:13]([CH3:21])[C:14]([C:17]([F:18])([F:20])[F:19])=[CH:15][N:16]=1
Reactant: COc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(C(F)(F)F)cnc(-c2cc(O)c(Cl)cc2Cl)c1=O
Temperature: 140 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
A mixture of 1.00 g of 3-(2,4-dichloro-5-methoxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-358) and 16 ml of 48% hydrobromic acid was dissolved in 5.7 ml of acetic acid, and the solution was stirred at 140° C. for 1 hour. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium hydrogencarbonate, water, and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 0.74 g (yield, 77%) of 3-(2,4-dichloro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-357; m.p., 173.5° C.).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@H:13]([OH:21])[CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:7][C:5]=2[N:6]=1.Br[CH2:23][CH2:24][N:25]1[C:29](=[O:30])[C:28]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:27]2[C:26]1=[O:35].CCN(CC)CC>CCO>[OH:21][C@@H:13]([CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[CH:7]=1)[CH2:14][N:15]1[CH2:16][CH2:17][N:18]([CH2:23][CH2:24][N:25]2[C:29](=[O:30])[C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[C:26]2=[O:35])[CH2:19][CH2:20]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CCN4C(=O)c5ccccc5C4=O)CC3)ccc2s1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a solution of (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazin-1-ylpropan-2-ol (500 mg, 1.63 mmol) in EtOH (25 mL) was added N-(2-bromoethyl) phthalimide (435 mg, 1.71 mmol) and Et3N (0.79 mL, 5.7 mmol). The reacting solution was shaken at 90° C. for 16 hours. Upon cooling, the solution was concentrated to an oil and purified via flash column chromatography (4:1 EtOAc/MeOH) to afford 2-(2-{4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinyl}ethyl)benzo[c]azolidine-1,3-dione.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10](O)[CH3:11])=[CH:6][CH:5]=1.C(Br)(Br)(Br)[Br:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:16][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:14])([F:13])[F:1])=[CH:5][CH:6]=1)[CH3:11]
Reactant: CC(O)c1ccc(OC(F)(F)F)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(Br)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-(4-(trifluoromethoxy)phenyl)ethanol (150 mg; 0.72 mmol) in anh. DCM (5 ml) was treated at rt with CBr4 (241 mg; 0.72 mmol), and with PPh3 (190 mg; 0.72 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 16 h. Concentration to dryness under reduced pressure, and subsequent purification by FC (DCM) afforded 1-(1-bromoethyl)-4-(trifluoromethoxy)benzene as a colorless oil which was directly used for the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:20][C:21]([N:23]2[CH2:32][CH2:31][C:30]3[CH:29]=[N:28][C:27]([NH:33][CH:34]([CH3:36])[CH3:35])=[N:26][C:25]=3[CH2:24]2)=[O:22])[CH2:10][CH2:11][NH:12][C:13](=O)OC(C)(C)C)[CH:5]=[CH:6][C:7]=1[Cl:8]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([NH:20][C:21]([N:23]2[CH2:32][CH2:31][C:30]3[CH:29]=[N:28][C:27]([NH:33][CH:34]([CH3:36])[CH3:35])=[N:26][C:25]=3[CH2:24]2)=[O:22])[CH2:10][CH2:11][NH:12][CH3:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)Nc1ncc2c(n1)CN(C(=O)NC(CCNC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1)CC2
Solvent: C1CCOC1
Product: CNCCC(NC(=O)N1CCc2cnc(NC(C)C)nc2C1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of tert-butyl 3-(3,4-dichlorophenyl)-3-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carboxamido)propylcarbamate (89 mg, 0.17 mmol) in THF (5 mL) under N2 was added BH3.THF complex (0.36 mL, 0.36 mmol) and the reaction was heated at reflux under N2 for 19 h. The reaction was cooled to RT, quenched with MeOH (10 mL), and heated at reflux for 1 h. The reaction was concentrated, then partitioned between DCM (25 mL) and sat. aq. NaHCO3 (25 mL). The phases were separated, the aqueous phase extracted with DCM (25 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated. The crude product was purified on a preparative SiO2 TLC (1 mm) plate developed with MeOH/DCM/NH4OH (9/90/1) to afford 11 mg (15%) of I-111 as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.36 (m, 2H), 7.13 (dd, 1H), 4.91 (m, 1H), 4.80 (d, 1H), 4.37 (m, 2H), 4.10 (m, 1H), 3.69 (m, 1H), 3.61 (m, 1H), 2.64-2.75 (m, 4H), 2.48 (s, 3H), 2.02 (m, 1H), 1.73 (m, 1H), 1.22 (dd, 6H); LRMS (APCI pos) m/e=451.1 (M+H).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][NH:7]2.O[C@H:14]1[CH2:19][CH2:18][C@H:17]([N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[CH2:16][CH2:15]1.CS(C1C(OC2CCCN(C(OC(C)(C)C)=O)CC2)=CC=C2C=1C=NN2)(=O)=O.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH3:1][S:2][C:3]1[C:11]([O:12][C@@H:14]2[CH2:15][CH2:16][C@H:17]([N:20]3[C:21](=[O:30])[C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:28]3=[O:29])[CH2:18][CH2:19]2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][NH:7]2
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](O)CC1
Reactant: CSc1c(O)ccc2[nH]ncc12
Agent: CC(C)(C)OC(=O)N1CCCC(Oc2ccc3[nH]ncc3c2S(C)(=O)=O)CC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CSc1c(O[C@H]2CC[C@@H](N3C(=O)c4ccccc4C3=O)CC2)ccc2[nH]ncc12
Temperature: 100 °C
Reaction time: 7 h
Yield: 57.9 %

Procedure:
The 4-(methylthio)-1H-indazol-5-ol (0.166 g, 0.92 mmol) obtained in Example 607 and the trans-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (0.151 g, 0.61 mmol) obtained in Example 323, (a) were added to a solution of cyanomethylenetri-n-butylphosphorane (0.247 g, 0.92 mmol) in toluene (6 ml), and the resulting mixture was heated at 100° C. and stirred for 7 hours. The reaction solution was concentrated and then diluted with chloroform, and a 1N-aqueous sodium hydroxide solution was added thereto, followed by extraction with chloroform (three times). The extract solution was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by a silica gel chromatography (hexane/ethyl acetate=2/1˜1/1) to obtain 2-(cis-4-{[4-(methylthio)-1H-indazol-5-yl]oxy}cyclohexyl)-1H-isoindole-1,3(2H)-dione (0.144 g: 58%).
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[CH2:7][S:8][CH2:9]2)=[CH:4][CH:3]=1.[CH3:13][N:14](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[O:12]=[C:6]1[C:5]2[C:10](=[CH:11][C:2]([C:13]#[N:14])=[CH:3][CH:4]=2)[CH2:9][S:8][CH2:7]1
Reactant: CN(C)C=O
Reactant: O=C1CSCc2cc(I)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(c1)CSCC2=O
Temperature: 95 °C

Procedure:
To a solution of 7-iodo-isothiochroman-4-one (290 mg, 1.0 mmol) in DMF (5 mL) is added Zn(CN)2 (117 mg, 1.0 mmol) and Pd(PPh3)4 (124 mg, 0.1 mmol). The reaction is then heated to 95° C. for 3 hours, at which time it is cooled to room temperature and concentrated to dryness. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 1:10 to 3:10) to furnish 4-oxo-isothiochroman-7-carbonitrile; MS: (ESI) m/z 188.2 (M−H)−.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:24][C:23]=3[F:36])[N:19]=[C:18]3[N:37]([CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)[N:38]=[C:39]([CH3:40])[C:17]=23)=O)[C:10]([CH3:48])([CH3:47])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:24][C:23]=3[F:36])[N:19]=[C:18]3[N:37]([CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)[N:38]=[C:39]([CH3:40])[C:17]=23)[C:10]([CH3:48])([CH3:47])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(C(=O)N3CCN(Cc4ccccc4)CC3(C)C)c12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(OCc4ccccc4)cc3F)cc(CN3CCN(Cc4ccccc4)CC3(C)C)c12
Temperature: 0 °C
Yield: 49.9 %

Procedure:
410 mg of (4-benzyl-2,2-dimethyl-piperazin-1-yl)-[6-(4-benzyloxy-2-fluoro-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-methanone were dissolved in 8 ml of THF. Under Argon-atmosphere, 0.53 ml of lithium aluminium hydride (2.4M in THF) was added and the reaction was heated to reflux for 2 h. The reaction was then cooled to 0° C., and quenched by the addition of 3 ml EtOAc and 3 ml water. The mixture was filtered over celite by suction and washed with EtOAc. The solvents were removed in vacuo and 200 mg (50%) of the title compound were obtained and used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C@@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([NH2:23])[CH3:22])[CH:16]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][C:36]=1[F:37])[CH:29]=[CH:30][C:31](O)=[O:32].C(Cl)CCl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C@@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([NH:23][C:31](=[O:32])[CH:30]=[CH:29][C:28]3[CH:34]=[CH:35][C:36]([F:37])=[C:26]([F:25])[CH:27]=3)[CH3:22])[CH:16]=2)[CH2:10]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(N)c1cccc(N2CCO[C@@H](CNC(=O)OC(C)(C)C)C2)c1
Reactant: O=C(O)C=Cc1ccc(F)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(NC(=O)C=Cc1ccc(F)c(F)c1)c1cccc(N2CCO[C@@H](CNC(=O)OC(C)(C)C)C2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Mixture of (S)-{4-[3-(1-amino-ethyl)-phenyl]-morpholin-2-ylmethyl}-carbamic acid tert-butyl ester, Preparation 28 (20 mg, 0.06 mmol), 3,4-difluorocinnamic acid (12.1 mg, 0.07 mmol), EDC (23 mg, 0.12 mmol), DMAP (7.3 mg, 0.06 mmol), triethylamine (0.03 ml, 0.24 mmol) in dichloromethane (0.6 ml) was stirred at room temperature overnight. The reaction mixture was purified by filtering through 2 g silica-gel syringe with 80% ethyl acetate/hexanes. The filtrate was concentrated under vacuum to provide the title compound as a white solid.
Reaction SMILES: C([O-])(=[O:3])C.[Na+].[Br:6][C:7]1[CH:8]=[C:9]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:10]=[C:11]([Br:24])[C:12]=1[O:13][C:14]1[N:15]=[N:16][C:17](Cl)=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=1>C(O)(=O)C>[Br:6][C:7]1[CH:8]=[C:9]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:10]=[C:11]([Br:24])[C:12]=1[O:13][C:14]1[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[C:17](=[O:3])[NH:16][N:15]=1
Reactant: CC(=O)[O-]
Reactant: CC(C)c1cc(Oc2c(Br)cc(CCC(=O)O)cc2Br)nnc1Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)c1cc(Oc2c(Br)cc(CCC(=O)O)cc2Br)n[nH]c1=O
Temperature: 120 °C
Yield: 72 %

Procedure:
A mixture of glacial acetic acid (16.7 mL), sodium acetate (480 mg, 5.85 mmol) and [3,5-dibromo-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-proprionic acid (22) (800 mg, 1.67 mmol) was heated to 120° C. for 24 h. The reaction mixture was cooled to room temperature and concentrated. The resulting residue was diluted with water (200 mL) and was made basic to pH=9 by the addition of a 1N aqueous sodium hydroxide solution. This solution was extracted with ethyl acetate (1×100 mL) and the ethyl acetate was discarded. The water layer was acidified to pH=3 by the addition of a 1N aqueous hydrochloric acid solution. The water layer was extracted with ethyl acetate (3×100 mL). The organic layers were combined, dried with sodium sulfate, filtered and concentrated under vacuum. The resulting solid was slurried in ethyl acetate (20 mL). Heptane (20 mL) was added to this mixture. The solvents were then concentrated under vacuum to a volume of approximately 20 mL. The solids were filtered and washed with a 1:1 ethyl acetate:heptane solution (2×10 mL). The solid was dried under high vacuum to afford [3,5-dibromo-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-proprionic acid (23) (553 mg, 72%) as an off-white solid; LRMS for C16H16Br2N2O4 (M+H) m/z=461. Molecular Weight=460.1249; Exact Mass=457.9477
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=O.[F:19][C:20]([F:28])([F:27])[C:21](=[O:26])[CH2:22][C:23](=O)[CH3:24]>C(O)(=O)C.S(=O)(=O)(O)O>[F:19][C:20]([F:28])([F:27])[C:21]([C:22]1[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:3]2[C:4]3[CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:23]=1[CH3:24])=[O:26]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Nc1sc2c(c1C(=O)c1ccc(F)cc1)CCC2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F)CCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 13.9 %

Procedure:
To a stirred solution of 50 mg (0.19 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-(4-fluoro-phenyl)-methanone in 2 ml acetic acid was added 0.024 ml (0.19 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 9:1) afforded 10 mg (14%) 2,2,2-trifluoro-1-[4-(4-fluoro-phenyl)-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl)-ethanone as a light brown solid. ES-MS m/e (%): 380 (M+H+, 100).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[NH:16][CH:17]2[CH2:22][CH2:21][N:20](C(OCC)=O)[CH2:19][CH2:18]2)=[CH:2]1.[OH-].[K+].O>C(O)(C)C.O>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[NH:16][CH:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)=[CH:2]1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccoc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: c1ccc2c(c1)nc(NC1CCNCC1)n2Cc1ccoc1
Reaction time: 18 h

Procedure:
Combine (1-(fur-3-ylmethyl)-1H-benzimidazol-2-yl)(1-(ethoxycarbonyl)piperidin-4-yl)amine (0.98 g, 2.67 mmol), potassium hydroxide (1.8 g, 32 mmol) in isopropanol (18 mL) containing 1 drop of water. Heat to reflux. After 18 hours, cool, add water, and extract four times with dichloromethane (200 mL). Combine the organic layers, dry over MgSO4, filter, and concentrate in vacuo to give the title compound: Rf=0.40 (silica gel, ethyl acetate).
Reaction SMILES: C(S([C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:9]2[CH:18]=[C:19]([C:22]3[C:23]([C:46]4[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=4)=[N:24][N:25]([C:27]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:26]=3)[CH:20]=[CH:21][C:8]=2[N:7]=1)(=O)=O)C.[H-].[Na+].[CH3:55][C:56]1[C:61]([OH:62])=[CH:60][CH:59]=[CH:58][N:57]=1.O>CN(C)C=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]2[C:9]3[CH:18]=[C:19]([C:22]4[C:23]([C:46]5[CH:47]=[CH:48][C:49]([F:52])=[CH:50][CH:51]=5)=[N:24][N:25]([C:27]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)[C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH:26]=4)[CH:20]=[CH:21][C:8]=3[N:7]=[C:6]2[O:62][C:61]2[C:56]([CH3:55])=[N:57][CH:58]=[CH:59][CH:60]=2)=[CH:12][CH:13]=1
Reactant: Cc1ncccc1O
Reactant: CCS(=O)(=O)c1nc2ccc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3-c3ccc(F)cc3)cc2n1-c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncccc1Oc1nc2ccc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)nc3-c3ccc(F)cc3)cc2n1-c1ccc(F)cc1
Reaction time: 0.33 h

Procedure:
40 mg 2-(ethylsulfonyl)-1-(4-fluorophenyl)-6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-1H-benzo[d]imidazole obtained in Example 138 was dissolved in 2 mL N,N-dimethylformamide, then 6.8 mg sodium hydride was added thereto and stirred for 20 minutes, and 3 mL 2-methyl-3-pyridinol was added thereto and stirred at 80° C. for 3 hours. Water was added thereto, and the reaction solution was extracted with ethyl acetate, and the organic layer was washed with water and brine and dried over sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give 1-(4-fluorophenyl)-6-[3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolyl]-2-[(2-methyl-3-pyridyl)oxy]-1H-benzo[d] imidazole. This product was subjected to deprotection of the trityl group by the same method as in Example 84 and then purified by NAM silica gel chromatography (ethyl acetate/methanol), to give 6 mg of the title compound as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:10][CH:9]1[CH2:28][OH:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30]I.[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH2:10][CH:9]1[CH2:28][O:29][CH3:30])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CI
Reactant: COc1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)C(CO)C2)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1CN(C(=O)c2cc(OC)c(OC)c(OC)c2)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 100.7 %

Procedure:
To a mixture of 1-tert-butoxycarbonyl-4-(3,4,5-trimethoxybenzoyl)piperazine-2-methanol (12.0 g), methyl iodide (21.3 g) and dimethyl formamide (50 ml) is added, under ice-cooling while stirring, in limited amounts, 60% sodium hydride (1.8 g). The mixture is stirred for 30 further minutes, and the reaction mixture is poured into ice-water, followed by extraction with ethyl acetate. The organic layer is dried and concentrated. The residue is purified by means of a silica gel column chromatography (eluent: dichloromethane-ethyl acetate=1:1) to afford 1-tert-butoxycarbonyl-2-methoxymethyl-4-(3,4,5-trimethoxybenzoyl)piperazine (12.5 g) as colorless crystals, m.p. 127° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[CH3:23])[CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.Br[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[CH3:23])[CH2:9][C:10]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([CH3:31])[CH:26]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1cc(Br)ccn1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccc(F)cc1C
Product: Cc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccc(F)cc2C)ccn1

Procedure:
In analogy to example 74, step 5, from 3-(4-bromophenyl)-3-(4-fluoro-2-methylphenyl)-N-methoxy-N-methylpropanamide and 4-bromo-2-methylpyridine was prepared the title compound as a white solid, MS (ESI+): m/z=414.07 [M+H]+.