Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2](/[CH:4]=[C:5](/[C:16](=O)[C:17]([F:20])([F:19])[F:18])\[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])C.Cl.[NH:23]([CH:25]1[CH2:30][CH2:29][C:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])([CH3:31])[CH2:27][CH2:26]1)N.CCN(C(C)C)C(C)C>CCO>[CH2:36]([O:35][C:33](=[O:34])[CH2:32][C:28]1([CH3:31])[CH2:27][CH2:26][CH:25]([N:23]2[C:16]([C:17]([F:20])([F:19])[F:18])=[C:5]([C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:7])[CH:4]=[N:2]2)[CH2:30][CH2:29]1)[CH3:37]
Reactant: CN(C)/C=C(\C(=O)OCc1ccccc1)C(=O)C(F)(F)F
Reactant: CCOC(=O)CC1(C)CCC(NN)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)CC1(C)CCC(n2ncc(C(=O)OCc3ccccc3)c2C(F)(F)F)CC1
Reaction time: 8 h
Yield: 73.5 %

Procedure:
A solution of (Z)-benzyl 2-((dimethylamino)methylene)-4,4,4-trifluoro-3-oxobutanoate (2.018 g, 6.70 mmol) in EtOH (20 mL) was added dropwise to a solution of ethyl 2-(4-hydrazinyl-1-methylcyclohexyl)acetate hydrochloride (1.6 g, 6.38 mmol) and DIPEA (2.452 ml, 14.04 mmol) in EtOH (31.9 ml) at ambient temperature. The reaction was allowed to stir overnight. The solvent was removed and the residual oil was purified using a 40 g REDISEP™ Gold SiO2 column eluting with 0-25% EtOAc/hexane using the Gold resolution method. Fractions containing the desired product were combined and concentrated in vacuo to provide benzyl 1-(4-(2-ethoxy-2-oxoethyl)-4-methylcyclohexyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate (2.12 g, 4.69 mmol, 73.4% yield) as a mixture of isomers (colorless syrup). LCMS=453.4 (M+H)+.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4].[C:8]([O:12][C:13]([NH:15][NH:16][C:17](=[S:40])[C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:28][C@H:27]([CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[O:26][C:25]2=[O:38])=[CH:20][C:19]=1[F:39])=[O:14])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([O:12][C:13]([NH:15][N:16]=[C:17]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:28][C@H:27]([CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[O:26][C:25]2=[O:38])=[CH:20][C:19]=1[F:39])[S:40][CH:2]1[CH2:7][CH2:6][O:5][C:3]1=[O:4])=[O:14])([CH3:9])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc(C(=S)NNC(=O)OC(C)(C)C)c(F)c2)C(=O)O1
Reactant: O=C1OCCC1Br
Product: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc(C(=NNC(=O)OC(C)(C)C)SC3CCOC3=O)c(F)c2)C(=O)O1

Procedure:
Prepared from α-bromo-γ-butyrolactone (0.021 ml, 0.227 mmol) and N′-{4-[5(S)-(tert-butoxycarbonylaminomethyl)-2-oxo-oxazolidin-3-yl]-2-fluorothiobenzoyl}-hydrazinecarboxylic acid tert-butyl ester (0.100 g, 0.206 mmol) according to the procedure of Example 1, Intermediate II (0.95 g, 80%); MS (m/z): [M+H]+=569.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][NH:10][C:11]([NH2:13])=[S:12])([CH3:4])([CH3:3])[CH3:2].Br[CH:16]([CH3:20])[C:17](=O)[CH3:18].CCN(C(C)C)C(C)C>C(O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH2:9][NH:10][C:11]1[S:12][C:16]([CH3:20])=[C:17]([CH3:18])[N:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCNC(N)=S
Reactant: CC(=O)C(C)Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc(NCCNC(=O)OC(C)(C)C)sc1C

Procedure:
A solution of (2-thioureido-ethyl)-carbamic acid tert-butyl ester [CAS 331779-96-5] (3.6 g), 3-bromo-2-butanone (2.45 g), and DIPEA (5.5 ml) in ethanol (100 ml) was stirred overnight at RT and refluxed 1 hour. The mixture was concentrated. Ethyl acetate was added. Insoluble parts were filtered off and the remaining solution was extracted with brine. The organic layer was dried, evaporated and purified by flash chromatography yielding after crystallization 0.86 g of white crystals. MS (ISP): 272.2 (MH+).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([CH:34]2[CH2:37][CH2:36][NH:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl>[C:28]1([CH:34]2[CH2:37][CH2:36][N:35]2[C:23]([C:22]2[CH:21]=[CH:20][C:19]([S:16]([N:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:8]3)(=[O:18])=[O:17])=[CH:27][CH:26]=2)=[O:24])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: c1ccc(C2CCN2)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1)N1CCC1c1ccccc1
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
Combine 4-(3-phenyl-indole-1-sulfonyl)-benzoic acid (125 mg, 0.33 mmol) and 2-phenyl-azetidine (100 mg, 0.75 mmol, excess) in dichloromethane (1.0 mL) and triethylamine (0.300 mL, 2.15 mmol, excess) and add benzotriazol-1-yloxytris(dimethylamino)phosphonium hexfluorophosphate (BOP Reagent) (0.150 mg, 0.33 mmol) at room temperature. Stir for 30 minutes, load entire reaction directly onto pre-packed silica gel column and purify by flash column chromatography (EtOAc/Hexanes) to yield 149 mg of (2-Phenyl-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone as a glassy solid (92%). LRMS: MH+ 493.08.
Reaction SMILES: [N:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[OH:9])=[N+:2]=[N-:3].N1C=CC=CC=1.[N+:16]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)([O-:18])=[O:17].[N+](C1C=CC(S(O)(=O)=O)=CC=1)([O-])=O>C(Cl)Cl>[N:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[O:9][S:25]([C:22]1[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:24][CH:23]=1)(=[O:26])=[O:27])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@@H]1CCC[C@H]1O
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: O=[N+]([O-])c1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: [N-]=[N+]=N[C@@H]1CCC[C@H]1OS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 84.2 %

Procedure:
A solution of (±)-trans-2-azido-cyclopentanol (1.27 g, 10.0 mmol) (Zhang, Z. da; Scheffold, R. Helv. Chim. Acta 1993, 76, 2602) in CH2Cl2 (14 mL) at 0° C. was treated successively with pyridine (0.88 mL, 10.9 mmol) and 4-nitro-benzenesulfonyl chloride (2.22 g, 10.0 mmol) and allowed to warm to room temperature slowly. The reaction was stirred for 4 d, during which additional pyridine (0.9 mL, 11 mmol) and 4-nitro-benzenesulfonic acid (2.2 g, 10 mmol) was added, and partitioned between CH2Cl2 and 1 N HCl. The aqueous phase was extracted with CH2Cl2 and the extracts were washed with saturated NaHCO3, dried and concentrated. Chromatography of the residue with 10:1–4:1 hexanes:EtOAc gave the product (2.63 g, 84%) as a yellow oil: 1H NMR δ 1.61–1.90 (m, 4H), 2.00–2.16 (m, 2H), 3.96 (m, 1H), 4.72 (m, 1H), 8.14 (m, 2H), 8.43 (m, 2H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([S:26][C:23]3[CH:24]=[CH:25][C:20]([CH3:19])=[CH:21][CH:22]=3)[O:3][C:4]=2[CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:8][CH:9]=1
Reactant: Cc1ccc(S)cc1
Reactant: O=C(O)CCc1oc(Cl)nc1-c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Sc2nc(-c3ccc(Cl)cc3)c(CCC(=O)O)o2)cc1
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 92.6 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-oxazolepropionic acid (1.43 g), 4-methylthiophenol (0.68 g), potassium carbonate (2.07 g) and N,N-dimethylformamide (20 ml) was stirred under a nitrogen atmosphere at 100° C. for 40 minutes. Water was added to the reaction mixture, which was then acidified with 2 N hydrochloric acid. The crystals thus precipitated were collected by filtration to obtain 4-(4-chlorophenyl)-2-(4-methylphenylthio)-5-oxazolepropionic acid (1.73 g, 93%). This was recrystallized from ethanol to give colorless needles. mp 160-161° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: Oc1ccccc1Cl
Product: Cc1cc(Nc2cc3ccccc3c(Oc3ccccc3Cl)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from 2-chloro-phenol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(2-chloro-phenoxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 352(MH+).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[CH3:15][O-:16].[Na+].O>CN(C)C=O>[CH3:15][O:16][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: CC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)=O)cc1C(F)(F)F
Temperature: 25 °C
Yield: 91.8 %

Procedure:
To a solution of 4′-fluoro-3′-trifluoromethylacetophenone (25.0 g) in N,N-dimethylformamide (70 ml) was added under ice-cooling sodium methoxide (7.21 g), and the mixture was stirred under ice-cooling for 2 hr and further at room temperature for 1 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (24.3 g) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.N1C=CC=CC=1.[CH3:23][C:24]1[C:25](B(O)O)=[N:26][CH:27]=[CH:28][CH:29]=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.CN(C)C=O>[Br:1][C:2]1[C:3]([O:16][C:25]2[C:24]([CH3:23])=[CH:29][CH:28]=[CH:27][N:26]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2
Reactant: Cc1cccnc1B(O)O
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)N1c2ccc(Br)c(Oc3ncccc3C)c2CC[C@@H]1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
A 100-mL, round-bottom flask equipped with a balloon filled with air was charged with (S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.200 g, 0.70 mmol), pyridine (1 mL), copper (II) acetate (0.382 g, 2.10 mmol), 3-methylpyridin-2-ylboronic acid 0.190 g, 1.39 mmol) and N,N-dimethylformamide (8 mL). The resulting mixture stirred at 90° C. overnight. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluting with 1:8, ethyl acetate/petroleum ether) to afford (S)-1-(6-bromo-2-methyl-5-(3-methylpyridin-2-yloxy)-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.129 g, 49%) as yellow oil. MS (ESI, pos. ion) m/z 375, 377 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[OH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N+:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)([O-:10])=[O:9]
Reactant: Oc1cccnc1
Reactant: O=[N+]([O-])c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(Oc2cccnc2)c1
Yield: 72.7 %

Procedure:
1-fluoro-3-nitrobenzene (1 g, 7 mmol, 1 eq), 3-hydroxypyridine (674 mg, 7.09 mmol, 1.00 eq), K2CO3 (1.18 g, 8.54 mmol, 1.20 eq) and DMF (10 mL) were added to a microwave vial and microwaved at 200° C. for 30 minutes. The reaction was filtered and concentrated on silica gel (5 g). The silica gel was loaded on top a fresh bed of silica gel and washed with 50% ethyl acetate/hexane. The solvents were removed in vacuo and the crude mixture was purified by flash chromatography on silica gel afforded 1.1 g (72%) of the title compound as a brown oil: 1H NMR (400 MHz, DMSO-d6) 8.49 (d, J=2.8 Hz, 1H), 8.46 (d, J=4.6 Hz, 1H), 8.02 (dd, J=8.2, 2.0 Hz, 1H), 7.78 (t, J=2.3 Hz, 1H), 7.70 (t, J=8.2 Hz, 1H), 7.60 (m, 1H), 7.54 (dd, J=8.3, 2.4 Hz, 1H), 7.49 (dd, J=8.4, 4.6 Hz, 1H); ES-MS [M+1]+: 217.2
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(OCCC1N(CCC2C=CC=CC=2)C(SC2C=C(F)C=C(F)C=2)=C(C(C)C)N=1)(=O)N.[CH2:40]([O:47][CH2:48][C:49](Cl)=[O:50])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:49](=[O:50])[CH2:48][O:47][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH3:3]
Reactant: O=C(Cl)COCc1ccccc1
Reactant: CCOC(=O)CN
Agent: CC(C)c1nc(CCOC(N)=O)n(CCc2ccccc2)c1Sc1cc(F)cc(F)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
In 50 ml of methylene chloride was added 15.0 g (35.8 mmol) of glycine ethyl ester hydrochloric acid, followed by addition of 9.2 9 (75.3 mmol) of 4-dimethylaminopyridine under ice-cooling. After stirring for 10 minutes, 6.5 ml (39.4 mmol) of benzyloxyacetylchloride was added dropwise under ice-cooling over 30 minutes. The temperature was raised up to room temperature, and the mixture was stirred for 12 hours. To the mixture, 20 ml of methylene chloride was added, and filtered. To the filtrate, 5% hydrochloric acid was added, and the mixture was extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and 9.0 g of N-benzyloxyacetylglycine ethyl ester was obtained (yield 100%).
Reaction SMILES: [NH:1]([C:3]1[N:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]3([NH:23]C(=O)OC(C)(C)C)[CH2:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=1)[C:9]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:8]2)[NH2:2].C1N=CN([C:42](N2C=NC=C2)=[O:43])C=1>O1CCOCC1.CCOC(C)=O>[NH2:23][C:19]1([C:16]2[CH:15]=[CH:14][C:13]([C:10]3[C:9]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:8][C:7]4[CH:6]=[CH:5][N:4]5[C:42](=[O:43])[NH:2][N:1]=[C:3]5[C:12]=4[N:11]=3)=[CH:18][CH:17]=2)[CH2:22][CH2:21][CH2:20]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(NN)nccc4cc3-c3ccccc3)cc2)CCC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NC1(c2ccc(-c3nc4c(ccn5c(=O)[nH]nc45)cc3-c3ccccc3)cc2)CCC1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
A mixture of tert-butyl {1-[4-(8-hydrazino-3-phenyl-1,7-naphthyridin-2-yl)phenyl]cyclobutyl}carbamate (7-5) (30.0 mg, 0.0620 mmol) and CDI (40.4 mg, 0.249 mmol) in 1,4-dioxane (2 mL) was stirred at 100° C. for 15 h and then cooled to room temperature. The mixture was diluted with EtOAc, washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel. The residue was treated with HCl in MeOH and the mixture was heated in a microwave reactor at 80° C. for 5 min. The solvent was evaporated and the residue was purified by reverse phase (H2O/0.1% TFAaq.-MeCN/0.1% TFAaq.) HPLC to give 9-[4-(1-aminocyclobutyl)phenyl]-8-phenyl[1,2,4]triazolo[4,3-h]-1,7-naphthyridin-3(2H)-one (7-6) as a colorless solid.
Reaction SMILES: [C:1]([C:3]([C:20](=[O:28])[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]([O:17]CC)=[O:16])[CH:6]=1)#[N:2].[OH-].[Na+]>C1COCC1.O>[C:1](/[C:3](/[C:20](=[O:28])[NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[CH:4]\[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]([OH:17])=[O:16])[CH:6]=1)#[N:2]
Reactant: CCOC(=O)Cn1cc(C=C(C#N)C(=O)Nc2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#C/C(=C\c1cn(CC(=O)O)c2ccccc12)C(=O)Nc1ccccc1

Procedure:
A stirred solution of crude ethyl [3-(2-cyano-2-phenylcarbamoyl-vinyl)-indol-1-yl]-acetate (0.079 mmol) in THF (0.8 ml) is treated with 0.2N aqueous NaOH (0.4 ml, 0.08 mmol) at rt for 10 min. The yellow reaction mixture is diluted with water (2 ml) and washed twice with diethyl ether (2 ml). The aqueous phase is acidified to pH 1 by adding conc. HCl and extracted with dichloromethane. The solvent is evaporated and the residue is recrystallized from acetonitrile yielding pure title compound.
Reaction SMILES: [NH2:1][C:2]([CH3:9])=[C:3]([Cl:8])[C:4](OC)=[O:5].[CH:10]([NH2:12])=O.C[O-].[Na+]>CO>[Cl:8][C:3]1[C:4]([OH:5])=[N:12][CH:10]=[N:1][C:2]=1[CH3:9]
Reactant: NC=O
Reactant: COC(=O)C(Cl)=C(C)N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ncnc(O)c1Cl

Procedure:
25.9 g (0.17 mol) of methyl 3-amino-2-chloro-2-butenoate are reacted with 11.7 g (0.26 mol) of formamide and 51 ml of sodium methylate solution in 20 ml of methanol and worked up in analogy to Example 9 (reaction time 20 h). Yield: 16.6 g (67.5%)
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([C:25]3[CH2:26][CH2:27][O:28][CH2:29][CH:30]=3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1)=[O:11].C([O-])=O.[NH4+]>C1COCC1.CO.[Pd]>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[C:24]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:23][CH:22]=[CH:21][N:20]=2)=[CH:16][CH:17]=1)[OH:11]
Reactant: O=C(c1ccc(Oc2ncccc2C2=CCOCC2)cc1)c1nc2ccccc2[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: OC(c1ccc(Oc2ncccc2C2CCOCC2)cc1)c1nc2ccccc2[nH]1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A 350 ml heavy-walled vessel was charged with (1H-benzo[d]imidazol-2-yl)(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)methanone (1.2 g, 3.02 mmol) and ammonium formate (5.71 g, 91 mmol) in THF (20 mL) and MeOH (20.00 mL). The reaction was evacuated 2× and treated with palladium on carbon 10% (0.321 g, 0.302 mmol) under nitrogen. The vessel was capped and the mixture was heated to 70° C. After 6 hours, the reaction was allowed to cool down to RT and filtered through celite. The filtrate was reduced under vacuum and the resulting residue was partition with DCM and water. The DCM layer was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The organic layer was then dried with sodium sulfate and purified by column chromatography on silica gel using a gradient of 2 to 12% MeOH in DCM to give (1H-benzo[d]imidazol-2-yl)(4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)methanol as a white solid. MS (ESI, pos. ion) m/z: 401.9 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:27])=[C:10]([C:13]3[CH:18]=[C:17]([CH:19]=C)[CH:16]=[CH:15][C:14]=3[O:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:11]=2)[C:6]([CH3:29])([CH3:28])[CH2:5][C:4]1=[O:30])[CH3:2].CSC.B.[OH-:35].[Na+].OO>C1COCC1>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:27])=[C:10]([C:13]3[CH:18]=[C:17]([CH2:19][OH:35])[CH:16]=[CH:15][C:14]=3[O:21][CH2:22][C:23]([F:24])([F:25])[F:26])[CH:11]=2)[C:6]([CH3:28])([CH3:29])[CH2:5][C:4]1=[O:30])[CH3:2]
Reactant: [OH-]
Reactant: C=Cc1ccc(OCC(F)(F)F)c(-c2cc3c(cc2C)C(C)(C)CC(=O)N3CC)c1
Agent: B
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CSC
Product: CCN1C(=O)CC(C)(C)c2cc(C)c(-c3cc(CO)ccc3OCC(F)(F)F)cc21
Reaction time: 8 h

Procedure:
To a solution of Compound 55A (0.24 mmol, 0.1 g) in 2 mL THF was added a solution of borane dimethylsulfide in THF (0.36 mmol, 0.03 mL) at 0° C. and the reaction mixture was stirred overnight. A solution of 2M NaOH (1 mL) was then added followed by a dropwise addition of hydrogen peroxide (30%, 1 mL). The solution was stirred at r.t. for 3 h. It was extracted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated. The LCMS indicated the presence of the desired product (m/z found 436) and a byproduct where the amide carbonyl group was reduced to a methylene group (m/z found 422). The residue was purified by column chromatography (3:1 hexane/EtOAc followed by 1:1 hexane/EtOAc) to obtain 1-ethyl-7-[5-hydroxymethyl-2-(2,2,2-trifluoro-ethoxy)-phenyl]-4,4,6-trimethyl-3,4-dihydro-1H-quinolin-2-one as a colorless oil (0.073 g).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[CH2:31]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:27][C:28]3[CH:29]=[C:30]4[C:34](=[CH:35][CH:36]=3)[NH:33][C:32](=[O:37])[CH2:31]4)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Cc2cc(NC(=O)C(=O)N3CCC(Cc4ccc(F)cc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67.5 %

Procedure:
A mixture of 3.2 g (12 mmol) of [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid, 1.4 ml (10 mmol) of triethylamine, 1.5 g (10 mmol) of 5-amino-1,3-dihydro-indol-2-one [Tetrahedron, 24, 1376. (1957)] 3.8 g (10 mmol) of HBTU [O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (Advanced Chem. Tech.)] and 100 ml of dimethylformamide is stirred at room temperature for 24 hours. The reaction mixture is concentrated. Then 150 ml of 8% sodium hydrogencarbonate solution and 150 ml of chloroform is added to the mixture. The organic layer is separated and the water phase is extracted three times with 25 ml of chloroform. The combined organic layers are dried over sodium sulfate, concentrated and the residue is purified by column chromatography using Kieselgel 60 as adsorbent (Merck) and chloroform:methanol=19:1 as eluent to yield 2.67 g (68%) of the title compound. Melting Point: 195-197° C. (diethylether)
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[CH3:11][S:12](Cl)(=[O:14])=[O:13]>N1C=CC=CC=1.CCOC(C)=O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][S:12]([CH3:11])(=[O:14])=[O:13])=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCc1cc(Br)ccc1N
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCc1cc(Br)ccc1NS(C)(=O)=O
Reaction time: 15 h
Yield: 79.6 %

Procedure:
4-Bromo-2-ethyl-aniline (2 mL, 14 mmol) dissolved in anhydrous pyridine (35 mL) at room temperature was treated with methylsulfonyl chloride (1.3 mL, 16.8 mmol). The reaction was stirred at that temperature for 15 hours before it was diluted with EtOAc. The mixture was washed with H2O, brine and dried over MgSO4. The solvent was removed in vacuo and the residue was purified with flash chromatography (SiO2, 5-30% EtOAc in hexanes) to afford the desired product (3.1 g, 81% yield). 1H NMR (300 MHz, CDCl3): δ 1.25 (t, J=7.5 Hz, 3 H), 2.61-2.68 (m, 2 H), 3.02 (s, 3 H), 6.36 (s, 1 H), 7.36-7.39 (m, 3 H).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH2:12][CH:13]1[C:34](=[O:35])[N:15]2[CH:16]([C:21]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)=[O:22])[C:17]([CH3:20])([CH3:19])[S:18][C@H:14]12.F[C:37]1[NH:38][CH:39]=[CH:40][N:41]=1>C(#N)C>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[CH3:19][C:17]1([CH3:20])[CH:16]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[N:15]2[C:34](=[O:35])[CH:13]([NH:12][C:37]3[NH:38][CH:39]=[CH:40][N:41]=3)[C@H:14]2[S:18]1
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: Fc1ncc[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Product: CC1(C)S[C@@H]2C(Nc3ncc[nH]3)C(=O)N2C1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 3 h

Procedure:
A mixture of p-nitrobenzyl 6-amino-2,2-dimethylpenam-3-carboxylate toluene-p-sulphonate (523 mg.) and 2-fluoroimidazole (100 mg.) in acetonitrile (2 ml.) was stirred at 50° for 3 hours. The resulting solution was evaporated to dryness and the residue obtained was triturated with ether to give p-nitrobenzyl 2,2-dimethyl-6-(imidazol-2-yl)aminopenam-3-carboxylate toluene-p-sulphonate as a 50% pure solid (572 mg.) which was used without further purification.