Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]2[CH2:36][CH2:35][NH:34][C:33]2=[O:37])/[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:38][C@@H:39]1[C:70](=[O:71])[N:41]2[C:42]([C:54]([O:56][CH:57]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[O:55])=[C:43]([CH2:46][S:47][C:48]3[N:52]([CH3:53])[N:51]=[N:50][N:49]=3)[CH2:44][S:45][C@H:40]12.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]2[CH2:36][CH2:35][NH:34][C:33]2=[O:37])/[C:27]([NH:38][C@@H:39]2[C:70](=[O:71])[N:41]3[C:42]([C:54]([O:56][CH:57]([C:64]4[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=4)[C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)=[O:55])=[C:43]([CH2:46][S:47][C:48]4[N:52]([CH3:53])[N:51]=[N:50][N:49]=4)[CH2:44][S:45][C@H:40]23)=[O:28])[N:25]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)/C(=N\OC1CCNC1=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)/C(=N\OC3CCNC3=O)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59 %

Procedure:
3.25 g of (Z)-2-(2-tritylaminothiazol-4-yl)-2-[(2-pyrrolidon-3-yl)oxyimino]acetic acid are dissolved in 200 ml of tetrahydrofuran, and 3.14 g of benzhydryl 7β-amino-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylate, 1.03 g of 1-hydroxybenzotriazole and 1.57 g of dicyclohexylcarbodiimide are added thereto. The mixture is stirred at room temperature for 2 hours. Insoluble materials are filtered off, and the filtrate is concentrated to dryness under reduced pressure. The residue is dissolved in ethyl acetate, and washed with 1% hydrochloric acid, 5% aqueous sodium bicarbonate solution and an aqueous saturated sodium chloride solution, successively. The ethyl acetate solution is then dried and concentrated to dryness under reduced pressure. The residue thus obtained is purified by silica gel chromatography (solvent, ethyl acetate:benzene=5:2). 3.7 g of benzhydryl 7β-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-[(2-pyrrolidon-3-yl)oxyimino]acetamido}-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]- 3-cephem-4-carboxylate are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[C:14]([C:19](=[O:23])[N:20]([CH3:22])[CH3:21])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[F:31][C:32]([F:49])([F:48])[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[C:40]([C:45](Cl)=[O:46])=[CH:41][CH:42]=[CH:43][CH:44]=2)=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:45]([C:40]3[C:39]([C:36]4[CH:37]=[CH:38][C:33]([C:32]([F:31])([F:48])[F:49])=[CH:34][CH:35]=4)=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:46])=[C:14]([C:19](=[O:23])[N:20]([CH3:22])[CH3:21])[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2ccc(N)c(C(=O)N(C)C)c2)CC1
Reactant: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(c2ccc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)c(C(=O)N(C)C)c2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1-(4-Amino-3-dimethylcarbamoylphenyl)-piperidine-4-carboxylic acid ethyl ester was dissolved in toluene (5 mL), and triethylamine (1.87 mL) was added thereto. The solution was cooled down to 0° C., and 4′-trifluoromethylbiphenyl-2-carbonyl chloride (synthesized from the corresponding carboxylic acid 1.44 g) was added thereto. The mixture was stirred at room temperature overnight. The insoluble matter was filtered off. After removal of the insoluble material by filtration, the filtrate was concentrated and purified by column chromatography on silica gel (acetone:hexane=5:1, v/v) to give the title compound (1.287 g).
Reaction SMILES: [CH3:1][C@@H:2]1[C@:25]2([O:31][CH2:30][C@H:28]([CH3:29])[CH2:27][CH2:26]2)[O:24][C@H:4]2[CH2:5][C@@H:6]3[C@@:20]([CH3:21])([C@@H:3]12)[CH2:19][C:18](=[O:22])[C@H:17]1[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[C@:15]1([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:23])[CH2:11]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][C@@H:2]1[C@:25]2([O:31][CH2:30][C@H:28]([CH3:29])[CH2:27][CH2:26]2)[O:24][C@H:4]2[CH2:5][C@@H:6]3[C@@:20]([CH3:21])([C@@H:3]12)[CH2:19][C@H:18]([OH:22])[C@H:17]1[C@H:7]3[CH2:8][CH2:9][C@@H:10]2[C@:15]1([CH3:16])[CH2:14][CH2:13][C@H:12]([OH:23])[CH2:11]2
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4C(=O)C[C@]3(C)[C@H]1[C@@H]2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4[C@@H](O)C[C@]3(C)[C@H]1[C@@H]2C

Procedure:
(3β,5α,25R)spirostan-3-ol-11-one (Aldrich Chemical Company, Milwaukee, Wisc. or Steraloids Inc., Wilton, N.H., or see preparation G13) was converted into the title compound via reduction with lithium aluminum hydride in THF at room temperature according to the procedure described in J. Am, Chem. Soc., 1951, 73, 1777.
Reaction SMILES: [CH3:1][CH:2]1[C:10]2[C:9](O)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][O:3]1.O=P(Cl)(Cl)[Cl:14]>C(#N)C>[Cl:14][C:9]1[C:10]2[CH:2]([CH3:1])[O:3][CH2:4][C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1OCc2ncnc(O)c21
Solvent: CC#N
Product: CC1OCc2ncnc(Cl)c21
Temperature: 25 °C
Yield: 96.5 %

Procedure:
To a suspension of 5-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-4-ol (1.2 g, 7.9 mmol) in acetonitrile (50 mL) was added via syringe POCl3 (3.6 g, 23.7 mmol) and the mixture heated to reflux for 3 hours. The mixture was allowed to cool to room temperature and then concentrated. The residue was diluted with EtOAc and quenched by pouring into saturated NaHCO3. The organic layer was separated and the aqueous layer extracted with EtOAc (3×100 mL). The combined organic layers were dried (MgSO4) and concentrated to give 4-chloro-5-methyl-5,7-dihydrofuro[3,4-d]pyrimidine (1.3 g, 96%) as a light brown oil which was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz) δ 8.89 (s, 1H), 5.46 (q, J=6.4 Hz, 1H), 5.15 (dd, J=14.4, 2.8 Hz, 1H), 5.02 (dd, J=14.4, 2.8 Hz, 1H), 1.62 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:19][CH2:20][CH3:21])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:14]([CH2:19][CH2:20][CH3:21])[C:11]=3[C:12]=2[CH3:13])=[CH:22][CH:23]=1
Reactant: CCCc1c(O)ccc2oc(Cc3ccc(OC)cc3)c(C)c12
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1c(OC(=O)OCC)ccc2oc(Cc3ccc(OC)cc3)c(C)c12
Yield: 79 %

Procedure:
A solution of 2-(p-methoxybenzyl)-3-methyl-4-propyl-5-hydroxybenzofuran (1.2 gm, 3.87 mmoles), ethyl chloroformate (0.1 mL) and triethylamine (1.0 mL) in tetrahydrofuran (15 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo. The residue was purified by chromatography on silica gel and eluted with 15% ethylacetate in hexane to yield 1.2 gm (79%) of 2-(p-methoxybenzyl)-3-methyl-4-propyl-5-ethoxycarbonyloxybenzofuran, mp. 51°-53° C.
Reaction SMILES: [O:1]1[CH:6]([C:7]([O-:9])=O)[CH2:5][NH:4][C:3]2[CH:10]=[CH:11][CH:12]=[CH:13][C:2]1=2.[Li+].[NH2:15][C@@H:16]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@H:17]([OH:32])[CH2:18][NH:19][C@@H:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([CH2:30][CH3:31])[CH:28]=2)[O:23][CH2:22][CH2:21]1>>[CH2:30]([C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[O:23][CH2:22][CH2:21][C@@H:20]2[NH:19][CH2:18][C@@H:17]([OH:32])[C@@H:16]([NH:15][C:7]([CH:6]1[O:1][C:2]2[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=2[NH:4][CH2:5]1)=[O:9])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH3:31]
Reactant: CCc1ccc2c(c1)[C@@H](NC[C@@H](O)[C@@H](N)Cc1ccccc1)CCO2
Reactant: O=C([O-])C1CNc2ccccc2O1
Agent: [Li+]
Product: CCc1ccc2c(c1)[C@@H](NC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)C1CNc3ccccc3O1)CCO2

Procedure:
The title compound was prepared using a procedure analogous to that described in Example 35, wherein (±)-lithium 3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate was coupled with (2R,3S)-3-amino-1-((S)-6-ethylchroman-4-ylamino)-4-phenylbutan-2-ol to afford the title compound (a 1:1 mixture of epimers at the benzooxazine stereocenter) as a white solid. MS m/z: 502 (M+1).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[OH:11][C@H:12]([CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH2:13][N:14]1[CH2:19][CH2:18][C:17]2[NH:20][CH:21]=[C:22]([CH3:23])[C:16]=2[C:15]1=[O:24]>ClCCl>[OH:11][C@H:12]([CH2:25][N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[CH2:13][N:14]1[CH2:19][CH2:18][C:17]2[NH:20][C:21]([CH:8]=[O:9])=[C:22]([CH3:23])[C:16]=2[C:15]1=[O:24]
Reactant: CN(C)C=O
Reactant: Cc1c[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Temperature: 25 °C
Yield: 74.9 %

Procedure:
Phosphorus oxychloride (674 μL, 4.04 mmol) and N,N-dimethylformamide (963 μL, 12.32 mmol) were dissolved in 21.18 mL of dichloromethane under stirring at room temperature, and the reaction solution was stirred for 15 minutes while maintaining the temperature at −10° C. in an ice-water bath. (R)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 1e (790 mg, 2.7 mmol) was dissolved in 10 mL of dichloromethane under stirring, and the solution was then added dropwise to the above reaction system. Upon completion of the addition, the ice-water bath was removed, and the reaction system was allowed to warm up to room temperature and stirred for another 2 hours. The reaction was completed until TLC showed the disappearance of starting materials, and the reaction system was quenched with iced water and stirred for 15 minutes. The mixture was adjusted to pH about 12 with 10N sodium hydroxide solution and extracted with the solvent mixture of dichloromethane and methanol (V:V=20:1, 100 mL ×8). The combined organic extracts were washed with saturated brine (150 mL), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure to give the crude product (800 mg). The crude product was purified by silica gel column chromatography to give the title compound (R)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 1f (650 mg, yield 75%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21.C[Si](C)(C)[C:28]([F:31])([F:30])[F:29].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:25])[C:28]([F:31])([F:30])[F:29])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of 9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (640 mg, 1.54 mmol) in tetrahydrofuran (8 mL) was added trimethyl(trifluoromethyl)silane (0.683 mL, 4.62 mmol) and tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 0.308 mL, 0.308 mmol) at 0° C. After the mixture was stirred at 0° C. for 30 min and at room temperature for 1 h, to the mixture was added 1N hydrochloric acid (2 mL) at 0° C., and the reaction mixture was stirred at room temperature for 30 min. The mixture was quenched with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-70% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (329 mg, 0.678 mmol, 44%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[C:19]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[O:10])[S:6][CH:7]=1.[CH3:26][O:27][C:28](=[O:35])[CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>>[CH3:26][O:27][C:28](=[O:35])[CH2:29][CH2:30][S:31](=[O:33])(=[O:32])[NH:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[C:19]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[O:10])[S:6][CH:7]=1
Reactant: COC(=O)CCS(=O)(=O)Cl
Reactant: Cc1ccc(NC(=O)Nc2nc(CN)cs2)c(C(=O)C2CCCC2)c1
Product: COC(=O)CCS(=O)(=O)NCc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Yield: 91.2 %

Procedure:
3-({2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl}-sulfamoyl)-propionic acid metyl ester (116 mg, 91%) was prepared from 1-(4-aminomethyl-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (90 mg, 0.25 mmol) and 3-chlorosulfonyl-propionic acid methyl ester (47 mg, 0.25 mmol) following the general procedure T.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:15].[CH3:16][S:17]([C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:18]>N1C=CC=CC=1>[S:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[N:15]([S:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:21]=1)(=[O:28])=[O:27])[S:26]([C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:21]=1)(=[O:28])=[O:27]
Reactant: Nc1cccc2cc(C3=NCCS3)[nH]c12
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: c1ccncc1
Product: CS(=O)(=O)c1cccc(S(=O)(=O)N(c2cccc3cc(C4=NCCS4)[nH]c23)S(=O)(=O)c2cccc(S(C)(=O)=O)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.8 %

Procedure:
To a mixture of 2-(4,5-dihydro-1,3-thiazol-2-yl)-1H-indole-7-amine (100 mg) and pyridine (3 mL) was added 3-(methylsulfonyl)benzenesulfonyl chloride (140 mg) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:1) to give the title compound (41 mg, yield 14%) as pale-yellow crystals. M+1=654.
Reaction SMILES: [K+].[C:2]([C:4]1[C:13]([F:14])=[CH:12][C:7]2[N:8]=[C:9]([S-:11])[S:10][C:6]=2[CH:5]=1)#[N:3].[K].S[C:17]1SC2C(N=1)=NC=C(C(OCC)=O)C=2>>[F:14][C:13]1[C:4]([C:2]#[N:3])=[CH:5][C:6]2[S:10][C:9]([S:11][CH3:17])=[N:8][C:7]=2[CH:12]=1
Reactant: CCOC(=O)c1cnc2nc(S)sc2c1
Reactant: N#Cc1cc2sc([S-])nc2cc1F
Agent: [K+]
Agent: [K]
Product: CSc1nc2cc(F)c(C#N)cc2s1

Procedure:
5-Fluoro-2-(methylthio)benzo[d]thiazole-6-carbonitrile was synthesized as an orange solid (1.2 g, 86%) using a procedure analogous to that described in Step 2 of Example 114, substituting 6-cyano-5-fluorobenzo[d]thiazole-2-thiolate potassium salt from the previous step for ethyl 2-mercaptothiazolo[4,5-b]pyridine-6-carboxylate potassium salt used in Example 114. 1H NMR (300 MHz, DMSO-d6) δ 8.67 (d, J=6.4 Hz, 1H), 8.01 (d, J=10.5 Hz, 1H), 2.84 (s, 3H); LCMS (ESI) m/z 225 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:25]([OH:27])=[O:26])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:28](=[O:30])[CH3:29])=[C:20]([C:25]([OH:27])=[O:26])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1ccc(-c2nc(-c3ccc(O)c(C(=O)O)c3)cs2)cc1OCC
Product: CCOc1ccc(-c2nc(-c3ccc(OC(C)=O)c(C(=O)O)c3)cs2)cc1OCC

Procedure:
A solution of 1 g of 2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-hydroxyphenyl)thiazole in 5 ml of acetic anhydride was stirred at 100° C. for 4 hours with heating. The solvent was distilled off. The residue was dissolved in 50 ml of ethyl acetate. To the solution was added 10 ml of a saturated sodium hydrogencarbonate solution, and phase separation was conducted. The ethyl acetate layer was made acidic with 10% hydrochloric acid, washed with 10 ml of a saturated aqueous sodium chloride solution, dried and subjected to distillation to remove the solvent. The residue was recrystallized from ethyl acetate to obtain 145 mg of 2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-acetyloxyphenyl)thiazole.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:21]=[C:22]([CH3:24])[CH:23]=1)[C:5]([N:7]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9][C@@H:8]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6].[H-].[Na+].Cl[C:28]1[N:32]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[C:31]2[CH:41]=[CH:42][CH:43]=[CH:44][C:30]=2[N:29]=1>CN(C)C=O>[CH3:24][C:22]1[CH:21]=[C:4]([CH:3]=[C:2]([CH3:1])[CH:23]=1)[C:5]([N:7]1[CH2:12][CH2:11][C@H:10]([O:13][C:28]2[N:32]([CH2:33][C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)[C:31]3[CH:41]=[CH:42][CH:43]=[CH:44][C:30]=3[N:29]=2)[CH2:9][C@@H:8]1[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:6]
Reactant: Fc1ccc(Cn2c(Cl)nc3ccccc32)cc1
Reactant: Cc1cc(C)cc(C(=O)N2CC[C@H](O)C[C@@H]2Cc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)cc(C(=O)N2CC[C@H](Oc3nc4ccccc4n3Cc3ccc(F)cc3)C[C@@H]2Cc2ccccc2)c1
Yield: 64.7 %

Procedure:
(±)-cis-1-(3,5-dimethylbenzoyl)-2-(phenylmethyl)-4-piperidinol (2.6 g) dissolved in N,N-dimethylformamide (100 ml) was stirred under N2. Sodium hydride (60%) (0.36 g) was added and the mixture was stirred at 40° C. for 1 hour. 2-Chloro-1-[(4-fluorophenyl)-methyl]-1H-benzimidazole (2.6 g) was added and the mixture was stirred at 60° C. for 20 hours. The solvent was evaporated and the residue was taken up in water and CH2Cl2. The organic layer was separated, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH 97/3). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE, yielding 2.85 g (65%) of (±)-cis-1-(3,5-dimethylbenzoyl)-4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]oxy]-2-(phenylmethyl)piperidine (comp. 70; mp. 154.1° C.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([F:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:11]([F:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(F)cc1[N+](=O)[O-]
Reactant: C1CCNC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(F)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (5-chloro-4-fluoro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B6) (5.81 g, 20 mmol) and pyrrolidine (8.27 mL, 100 mmol) in DMSO (40 mL) at 23° C. according to the general procedure C. Obtained as a yellow solid (6.42 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C:6]1([NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([S:18]([NH:17][C:6]2([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:32])[CH2:9][NH:8][CH2:7]2)(=[O:20])=[O:19])=[CH:26][CH:25]=1)[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCc1ccc(S(=O)(=O)NC2(CC(=O)OCC)CN(C(=O)OC(C)(C)C)C2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCc1ccc(S(=O)(=O)NC2(CC(=O)OCC)CNC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.5 %

Procedure:
tert-Butyl 3-(2-ethoxy-2-oxoethyl)-3-(4-pentylphenylsulfonamido)azetidine-1-carboxylate (79 mg, 0.169 mmol) was dissolved into DCM (4 mL). The solution was treated with TFA (0.3 mL). The mixture was stirred at room temperature for 4 h. DCM was removed under vacuum. Ethyl acetate (25 mL) was added and the solution was washed with saturated sodium bicarbonate (2×5 mL), water (10 mL), brine (10 mL), dried over MgSO4 and concentrated to afford the title compound as a white powder (52 mg, 84%). 1H NMR (400 MHz, CDCl3) δ 7.79 (d, 2H, J=8 Hz), 7.31 (d, 2H, J=8 Hz), 4.05 (q, 2H, J=7.2 Hz), 3.94 (d, 2H, J=8.8 Hz), 3.36 (d, 2H, J=8.8 Hz), 3.01 (s, 2H), 2.68 (t, 2H, J=8 Hz), 1.66 (m, 2H), 1.34 (br, 4H), 1.22 (t, 3H, J=7.2 Hz), 0.90 (t, 3H, J=6.8 Hz); MS ESI 369.1 [M+H]+, calcd for [C18H28N2O4S+H]+ 369.18.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: OCCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1OCCc1ccccn1

Procedure:
7.05 g (50 mmol) of 2-fluoronitrobenzene, 6.77 g (50 mmol) of 2-(2-hydroxyethyl)pyridine and 16.62 g (50 mmol) of cesium carbonate in 30 mL of dimethyformamide were stirred at room temperature for 7 days. The mixture was then filtered, and the filtrate was subjected to fractional distillation. The solvent and unreacted 2-fluoronitribenzene distilled below 100° C. at 8 to 4 mbar. The product distilled in a bulb tube still at 170 to 180° C. of furnace temperature under a vacuum of 3 mbar.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH2:9][C:10]#[N:11])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[BrH:12].[OH-].[Na+]>C1(C)C=CC=CC=1>[NH2:11][C:10]1[CH:9]=[C:8]2[C:3](=[C:1]([Br:12])[N:2]=1)[N:4]=[CH:5][CH:6]=[CH:7]2
Reactant: Br
Reactant: N#CCc1cccnc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Nc1cc2cccnc2c(Br)n1

Procedure:
Through a stirred solution of 2-Cyano-3-pyridylacetonitrile (3.6 g, 0.025 mol) in toluene (80 ml) is bubbled HBr for 5 h. Then, 4N NaOH is carefully added and the suspension stirred vigorously. The mixture is filtered and the product washed with water and dried. Crystallisation from toluene affords the title compound. Mass M+H 225. Melting point 188° C., decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:31][CH:32]1[CH2:36][CH2:35][CH:34]([CH3:37])[NH:33]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:33]4[CH:34]([CH3:37])[CH2:35][CH2:36][CH:32]4[CH3:31])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Reactant: CC1CCC(C)N1
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1C(C)CCC1C

Procedure:
In the same manner as Example 117, 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide. (0.51 mmol.) was reacted with 2,5-dimethylpyrrolidine (1.02 mmol., 101 mg.) in dimethylformamide. The crude product was also purified via chromatography as Example 117, leaving 214 mg. (82%) of the yellow product: mp 110-113° C.