Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2].[C:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:14])[CH:12]=[CH2:13]>C(#N)C>[C:1]([NH:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:13][CH2:12][C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: C=CC(=O)OCc1ccccc1
Reactant: CC(=O)NC1CCNCC1
Solvent: CC#N
Product: CC(=O)NC1CCN(CCC(=O)OCc2ccccc2)CC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A stirred mixture of 4-acetamidopiperidine (1.82 g, 12.8 mmol) and benzyl acrylate (2.57 g, 15.4 mmol) in acetonitrile (50 mL) was stirred overnight under nitrogen and at 40° C. for 1 h. The mixture was evaporated to dryness and the residue was purified by silica gel chromatograph eluting with a gradient of 0% to 30% dichloromethane/methanol/NH4OH (10:1:0.1) and dichloromethane to give benzyl 3-(4-acetamidopiperidin-1-yl)propanoate as an oil (3.81 g, 98%).
Reaction SMILES: [N:1]([C:4]1[S:8][C:7]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:6]=2[C:5]=1[C:14]([O:16]C)=O)=[C:2]=[S:3].[CH3:18][C:19]1[N:20]=[CH:21][N:22]([CH2:24][CH2:25][CH2:26][NH2:27])[CH:23]=1>>[CH3:18][C:19]1[N:20]=[CH:21][N:22]([CH2:24][CH2:25][CH2:26][N:27]2[C:14](=[O:16])[C:5]3[C:6]4[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:7]=4[S:8][C:4]=3[NH:1][C:2]2=[S:3])[CH:23]=1
Reactant: COC(=O)c1c(N=C=S)sc2c1CCCCC2
Reactant: Cc1cn(CCCN)cn1
Product: Cc1cn(CCCn2c(=S)[nH]c3sc4c(c3c2=O)CCCCC4)cn1

Procedure:
The compound was synthesized starting from methyl 5,6,7,8-tetrahydro-2-isothiocyanato-4H-cyclohepta[b]thiophene-3-carboxylate (0.111 g. 0.42 mmol) and 3-(4-methyl-1H-imidazol-1-yl)propan-1-amine (9) (0.058 g, 0.42 mmol) as described above.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@@H:14]([OH:16])[CH2:13][C@@H:9]1[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.Cl.[CH2:28]([N:30]=[C:31]=NCCCN(C)C)C.CNC.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.C(Cl)(Cl)Cl.CN(C)C=O>[CH3:28][N:30]([CH3:31])[C:10]([C@H:9]1[CH2:13][C@@H:14]([OH:16])[CH2:15][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:11]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C[C@@H]1C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CN(C)C(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reaction time: 0.5 h
Yield: 98.1 %

Procedure:
A 25 mL N,N-dimethylformamide solution of 2.50 g of (4S)-1-(tert-butoxycarbonyl)-4-hydroxy-D-proline and 2.19 g of 1-hydroxybenzotriazole was stirred for 5 minutes under cooling, after which 2.49 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added, and the reaction mixture was stirred for 30 minutes at the same temperature. After this, 1.95 g of a 50% dimethylamine aqueous solution was added to the reaction solution, and the reaction mixture was stirred for 16 hours at room temperature. Then 100 mL of chloroform and 50 mL of a 5% potassium carbonate aqueous solution were added to the reaction solution, and liquid separation was performed, after which the aqueous layer was extracted with chloroform (30 mL×2), and the combined organic layer was washed with 30 mL of saturated brine and dried with magnesium sulfate, then the drying agent was then filtered off and the solvent was distilled off under reduced pressure. The residue thus obtained was subjected to column chromatography (silica gel 60, mobile phase: ethyl acetate) to obtain 2.74 g of the titled compound (pale yellow solid).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:20])=[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[N:6]=[N:7][CH:8]=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:4](=[O:20])[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)=[N:6][N:7]([S:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:29])=[O:28])[CH:8]=1
Reactant: COc1cnnc(-c2ccnn2-c2ccccc2)c1O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cn(S(=O)(=O)c2ccccc2)nc(-c2ccnn2-c2ccccc2)c1=O
Yield: 78.8 %

Procedure:
A solution of 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4-ol (100 mg) and benzenesulfonylchloride (79 mg) in pyridine (4.00 mL) was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting solid was washed with ethyl acetate and diethyl ether, and dried to give the title compound (120 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:38][S:39]([CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1)(=[O:41])=[O:40]>>[ClH:22].[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][S:39]([CH3:38])(=[O:40])=[O:41])[CH2:49][CH2:48]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazol-1-yl-]-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone hydrochloride was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 17) in an analogous manner as described in example 25. LR-MS: 685.3 [(M+H)+]
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]([CH2:20][C:21]2[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=2)[CH2:24][N:25]2[CH:29]([C:30](O)=[O:31])[CH2:28][CH2:27][S:26]2(=[O:34])=[O:33])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:6]([F:38])[C:5]([O:39][CH3:40])=[CH:4][CH:3]=1.[Cl:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][NH2:47])=[CH:44][CH:43]=1>>[Cl:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][NH:47][C:30]([CH:29]2[CH2:28][CH2:27][S:26](=[O:33])(=[O:34])[N:25]2[CH2:24][C:23]2[CH:35]=[CH:36][CH:37]=[C:21]([CH2:20][N:9]([CH2:8][C:7]3[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([O:39][CH3:40])[C:6]=3[F:38])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:22]=2)=[O:31])=[CH:44][CH:43]=1
Reactant: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)O)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Reactant: NCc1ccc(Cl)cc1
Product: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)NCc4ccc(Cl)cc4)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Yield: 37.1 %

Procedure:
2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1 dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (Intermediate 7, 0.085 g, 0.142 mmol) was reacted with 4-chlorobenzyl amine (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 43 μL, 0.355 mmol) to form 2-(3-{[(6-chloro-2-fluoro-3-methoxy-benzyl)-((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid 4-chloro-benzylamide (0.038 g, 37%). m/z=721 (M+1); HRMS: calcd for C36H48Cl2FN4O4S. Calc [M+H+] 721.2752. found 721.2755.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]1[N:11]=[CH:10][C:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[C:20]([O:22][CH:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[CH:21]=2)[NH:18][C:17]([C:29](=[S:31])[NH2:30])=[CH:16]3)=[CH:8][CH:7]=1)(=[O:4])=[O:3].[C:32]([O:37][CH2:38][CH3:39])(=[O:36])[C:33]#[C:34][CH3:35].C(P(CCCC)CCCC)CCC.CO>O1CCCC1.C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH2:38]([O:37][C:32](=[O:36])[CH2:33][CH:34]1[S:31][C:29]([C:17]2[NH:18][C:19]3[C:15]([CH:16]=2)=[CH:14][C:13]([O:12][C:9]2[CH:10]=[N:11][C:6]([CH2:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][CH:8]=2)=[CH:21][C:20]=3[O:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[N:30][CH2:35]1)[CH3:39]
Reactant: CS(=O)(=O)Cc1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=S)cc3c2)cn1
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(CS(C)(=O)=O)nc4)cc(OC4CCOCC4)c3[nH]2)S1
Temperature: 90 °C
Reaction time: 1 h
Yield: 61.5 %

Procedure:
To a solution of 5-({6-[(methylsulfonyl)methyl]pyridin-3-yl}oxy)-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-2-carbothioamide (2.25 g) in tetrahydrofuran (10 mL) and toluene (15 mL) were added ethyl 2-butynoate (1.37 g) and tri-n-butylphosphine (0.99 g), and the mixture was stirred at 90° C. for 1 hr. The reaction mixture was cooled, and concentrated under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (methanol:ethyl acetate:hexane=0:0:100 to 5:95:0, volume ratio) to give the title compound (1.72 g, yield 61%) as a yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][N:3]=1.Cl[C:11]1N=C(Cl)C(F)=CN=1>>[Cl:1][C:2]1[N:3]=[C:4]([CH3:11])[C:5]([F:9])=[C:6]([CH3:8])[N:7]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1nc(Cl)ncc1F
Product: Cc1nc(Cl)nc(C)c1F

Procedure:
2-Chloro-5-fluoro-4,6-dimethylpyrimidine was prepared in a manner analogous to Intermediate 55, substituting 2,4,6-trichloro-5-fluoropyrimidine for 2,4-dichloro-5-fluoropyrimidine. 1H NMR (500 MHz, CDCl3): 2.50 (d, J=2.7 Hz, 6H).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]1[CH2:17][CH2:16][N:15]([C:18]([CH2:20][C:21]#[N:22])=[O:19])[CH2:14][CH2:13]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:19]=[C:18]([N:15]1[CH2:16][CH2:17][CH2:12][CH2:13][CH2:14]1)[CH:20]=[C:21]1[NH:22][C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4]1
Reactant: N#CCC(=O)N1CCCCC1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C1NC(=CC(=O)N2CCCCC2)Sc2ccccc21
Yield: 25 %

Procedure:
Methyl thiosalicylate (1.7 g, 10.1 mM) and 1-cyanoacetylpiperidine (2.0 g, 13.1 mM) were dissolved in toluene (5 ml), and triethylamine (2 ml, 14.4 mM) was added to the solution. After heating for 30 hours under reflux, the reaction solution was concentrated to give crude crystals. The crude crystals were recrystallized from ethanol to give the title compound as needles (730 mg, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([N:6]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[CH:17]=1)[C:7]1[S:8][C:9](C)=[C:10]([C:12](O)=[O:13])[N:11]=1)=[O:5].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl>ClCCl>[Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[C:4]([N:6]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[CH:17]=1)[C:7]1[S:8][CH:9]=[C:10]([C:12]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:13])[N:11]=1)=[O:5]
Reactant: COc1cc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc(C(=O)O)c(C)s2)ccc1Cl
Reactant: C1CCNC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COc1cc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc(C(=O)N3CCCC3)cs2)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.2 %

Procedure:
A mixture of 400 mg (0.85 mmol) 2-[(2,4-dichloro-benzoyl)-(4-chloro-3-methoxy-phenyl)-amino]-5-methyl-thiazole-4-carboxylic acid, 105 μL (1.27 mmol) pyrrolidine and 179 mg (1.10 mmol) 1,1′-carbonyldiimidazole in 12 mL dichloromethane was stirred for 16 h at room temperature. The mixture was poured onto 0.5 N hydrochloric acid and extracted with dichloromethane. Organic phases were pooled, washed with water and brine and dried with MgSO4. Volatiles were removed in vacuo and the residue was purified by silica gel chromatography (n-heptane/ethyl acetate 1:1) to yield 270 mg (60%) of the title compound as colorless solid. MS (m/e): 524.1, 526.1 (MH+)
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.B1C2CCCC1CCC2.[N:17]1[C:26]2C(=CC=CC=2)N=C[CH:18]=1.C([O-])([O-])=O.[K+].[K+].B([O-])[O-].C([O-])(O)=O.[Na+]>CN(C=O)C.O>[N:3]1[C:2]2[C:1](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:26]=[N:17][CH:18]=1
Reactant: C=C1CCCCN1
Reactant: c1ccc2nccnc2c1
Agent: B1C2CCCC1CCC2
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2ncncc2c1
Temperature: 65 °C

Procedure:
Methylene piperidine ED.8 (243 mg, 1.23 mmol) is combined with 9-BBN (2.46 mL, 0.5 M in THF) and heated to 65° C. for 1 h. Then the mixture is cooled to 20° C., quinoxaline D*.5 (300 mg, 1.23 mmol), Pd(dppf) (50 mg, 10 mol %) and K2CO3 (195 mg, 1.41 mmol) are placed in DMF/H2O (1.2 mL, 5:1) and slowly the freshly prepared boronate is added dropwise. The reaction mixture is heated to 60° C. for 2 h, cooled, combined with NaHCO3 and extracted with DCM (3×10 mL). The solvent is removed, the residue is purified by chromatography (45:55 to 90:10 in 6 min CH3CN/H2O) and quinoxaline D.51 (250 mg, 50%) is obtained.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:24][C:25]([F:29])([F:28])[S:26]Cl>CCOCC>[C:12]1([C:11]2[CH:10]=[C:9]([S:26][C:25]([F:29])([F:28])[F:24])[NH:8][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: FC(F)(F)SCl
Reactant: c1ccc(-c2cc[nH]c2-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: FC(F)(F)Sc1cc(-c2ccccc2)c(-c2ccccc2)[nH]1
Temperature: 25 °C

Procedure:
In glassware flamed out, under nitrogen, and fitted with a dry ice condenser, were placed 11 g (0.05 mole) 2,3-diphenylpyrrole, 6.4 g (0.06 mole) anhydrous sodium carbonate and 200 ml ether. The mixture was chilled to -30° and 7.6 g (0.055 mole) trifluoromethanesulfenyl chloride was added as a gas from a tared trap. The reaction was stirred at -30° one-half hour, then allowed to warm to room temperature for two hours. The inorganic salts were removed by filtration and the ether filtrate was concentrated. The residue was chromatographed on 300 g Silic AR CC-7 eluting with hexane containing 5-10% toluene. The product was obtained as a white solid, 15.4 g (96%), m.p. 58°-9°.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:26][N:27]([CH:36]=[O:37])[O:28]CC2C=CC=CC=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][N:11]2[CH3:25])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[OH-].[OH-].[Pd+2]>[CH:1]1([CH2:6][C@H:7]([CH2:26][N:27]([CH:36]=[O:37])[OH:28])[C:8]([N:10]2[C@H:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[O:16])[CH2:13][CH2:12][N:11]2[CH3:25])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CC[C@@H](C(=O)Nc2ccc(F)cn2)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CN1CC[C@@H](C(=O)Nc2ccc(F)cn2)N1C(=O)[C@H](CC1CCCC1)CN(O)C=O
Reaction time: 2 h
Yield: 57.9 %

Procedure:
(3S)-2-[(2R)-3-Cyclopentyl-2 ({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-N-(5-fluoro-2-pyridinyl)-1-methyl-3-pyrazolidinecarboxamide (84 mg, 0.164 mmol) was dissolved in methanol (9.66 ml). To this mixture was added 20% palladium hydroxide on carbon (23.06 mg, 0.033 mmol). The reaction mixture was degassed and placed under 1 atm of H2. After 2 h, the reaction mixture was filtered and concentrated. The residue was purified by RP-HPLC to afford (3S)-2-((2R)-3-cyclopentyl-2-{[formyl(hydroxy)amino]methyl}propanoyl)-N-(5-fluoro-2-pyridinyl)-1-methyl-3-pyrazolidinecarboxamide (40 mg, 0.095 mmol, 57.8% yield) as white foam solid. LC-MS (ES) m/e 422.1 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:21][C:10]2=[C:11]3[C:16](=[C:17]([CH3:19])[CH:18]=[C:9]2[CH2:8]1)[NH:15][C:14](=[O:20])[CH:13]=[CH:12]3)(=O)=O.[I:22]([O-])(=O)=O.[Na+]>CN(C)C=O>[I:22][CH2:6][CH:7]1[O:21][C:10]2=[C:11]3[C:16](=[C:17]([CH3:19])[CH:18]=[C:9]2[CH2:8]1)[NH:15][C:14](=[O:20])[CH:13]=[CH:12]3
Reactant: [O-][I+2]([O-])[O-]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(COS(C)(=O)=O)C2
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CI)C2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methanesulfonyloxymethyl-5-methyl -2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (931 mg) in dimethylformamide (20 ml), sodium iodate (4.5 g) was added, and the mixture was stirred at 100° C. for 2 hours. After completion of the reaction, the solvent was distilled off, and the residue was purified by silica gel column chromatography (eluent: chloroform) to obtain 1 g (assayed quantitatively) of the target compound as a light yellow powder.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH3:13])=[C:7]([N+:14]([O-])=O)[CH:6]=1)(=[O:4])=[O:3]>CC(O)=O.[Fe]>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH3:13])=[C:7]([CH:6]=1)[NH2:14])(=[O:3])=[O:4]
Reactant: C/C=C/c1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: C/C=C/c1ccc(S(C)(=O)=O)cc1N
Temperature: 90 °C
Reaction time: 0.42 h
Yield: 81.4 %

Procedure:
A solution of 4-(methylsulfonyl)-2-nitro-1-[(1E)-prop-1-en-1-yl]benzene (Intermediate 59; 1.10 g; 4.56 mmol) in AcOH (7 ml) was treated with powdered iron (3.82 g; 68.4 mmol) and the reaction mixture was stirred at 90° C. for 25 min. Further AcOH was added (20 mL), the solid was filtered off and rinsed with EtOAc. The solvents were removed under reduced pressure, the residue was taken up in EtOAc and washed with saturated NaHCO3 solution twice the with brine. The organic phase was dried on MgSO4, filtered and concentrated under reduced pressure to give the title compound as a brown oil (784 mg, 81%).
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7]1)=[O:5])C.[OH-].[Na+]>C(O)(=O)C>[C:4]([CH:6]1[C:15](=[O:16])[C:14]2[C:9](=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7]1)([OH:5])=[O:3]
Reactant: CCOC(=O)C1C=Nc2c(cccc2[N+](=O)[O-])C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=C(O)C1C=Nc2c(cccc2[N+](=O)[O-])C1=O
Temperature: 25 °C
Yield: 93 %

Procedure:
A mixture of 3-ethoxycarbonyl-8-nitro-4-oxo-3,4-dihydro-quinoline (12 g) and 2M sodium hydroxide solution (100 ml) was stirred at reflux for 1 hour. The mixture was cooled to ambient temperature and acidified to pH 5 with glacial acetic acid. The mixture was filtered and the solid so obtained washed with water to give 3-carboxy-8-nitro-4-oxo-3,4-dihydroquinoline in 93% yield, mp 263-265° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[CH:9]=2)[O:4][C:3]=1[C:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)=[O:26].C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C>>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:7]1[N:6]=[C:5]2[O:4][C:3]([C:25]([C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[O:26])=[C:2]([NH:1][C:37](=[O:36])[CH2:38][OH:39])[C:10]2=[CH:9][C:8]=1[C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1
Reactant: Nc1c(C(=O)c2cccnc2)oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc12
Reactant: CC(=O)OCC(=O)Cl
Product: O=C(CO)Nc1c(C(=O)c2cccnc2)oc2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)cc12

Procedure:
Using the general acylating procedure described in Example 18, the product of Example 157 was reacted with acetoxyacetyl chloride and then subjected to the general ester hydrolysis procedure described in Example 25 to afford the title compound. HPLC/MS: 518.0 (M+1), 520.0 (M+3); Rt=3.52 min.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:38][CH:39]([CH3:41])[CH3:40])=[C:34]([CH:37]=1)[C:35]#[N:36].O>CN(C=O)C>[C:35]([C:34]1[CH:37]=[C:30]([CH:31]=[CH:32][C:33]=1[O:38][CH:39]([CH3:41])[CH3:40])[CH2:29][O:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH:13]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1)#[N:36]
Reactant: CC(C)(C)OC(=O)CC1CCn2c1cc1cc(O)ccc12
Reactant: CC(C)Oc1ccc(CCl)cc1C#N
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(COc2ccc3c(c2)cc2n3CCC2CC(=O)OC(C)(C)C)cc1C#N
Temperature: 60 °C
Yield: 65.4 %

Procedure:
tert-Butyl 2-(7-hydroxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (0.287 g, 1.000 mmol), cesium carbonate (0.489 g, 1.500 mmol) and 5-(chloromethyl)-2-isopropoxybenzonitrile (0.315 g, 1.500 mmol) were taken up in DMF (2.0 mL) and heated to 60° C. for 16 h in a 20 mL sealed scintillation vial. The reaction was cooled down to room temperature and poured into water and extracted into ether (2×5 mL). The organic layers were combined and washed with water (3×5 mL), saturated NaCl (1×5 mL), dried over MgSO4, and filtered by vacuum filtration through a glass fiber paper. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.301 g) as a light yellow solid. LCMS m/z=461.5 [M+H]+.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1>C(Cl)Cl>[Br:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc(Br)cc1
Temperature: 0 °C

Procedure:
A mixture of 22.5 1 of methylene chloride and 3030 ml of tert-butylamine is cooled to 0° C. Then a solution of 3 kg of 4-bromo-benzoyl chloride in 15 1 of methylene chloride is added in portions. The mixture is cooled to 0°-5° C. and then stirred over night at room temperature. The reaction mixture is filtered and the filtrate washed with 5 1 of methylene chloride, three times with 5 1 of 3 N HCl, twice with 4 1 of NaHCO3 and twice with 2 l of brine. The organic layer is dried over Na2SO4 and evaporated. The crude crystals are stirred with 8 l of ether for 30 minutes and the mixture is cooled to 0° C. and filtered. Thus 4-bromo-N-tert-butyl-benzamide is obtained in form of white crystals, m.p.133°-134° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[Cl:10])[C:5]#[N:6].[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:11][C:8]1[C:9]([Cl:10])=[C:2]([NH:1][C:13](=[O:12])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: N#Cc1cc(N)c(Cl)c(Br)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(C#N)cc(Br)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.9 %

Procedure:
To a solution of 3-amino-5-bromo-4-chlorobenzonitrile (0.88 g, 3.80 mmol) in DCM (25 mL) was added TEA (1.590 mL, 11.41 mmol), BOC2O (1.059 mL, 4.56 mmol) and DMAP (0.464 g, 3.80 mmol). The mixture was stirred at RT for 16 h. The reaction mixture was concentrated, the crude product was purified using ISCO silica gel column (24 g, EtOAc/hexane=0-30%) to give 0.667 g of tert-butyl 3-bromo-2-chloro-5-cyanophenylcarbamate as white solid
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]=[CH:6][C:7]1[S:11][C:10]([NH:12][C:13](=[O:31])[C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=[C:16]([O:27][CH:28]([CH3:30])[CH3:29])[CH:15]=2)=[N:9][CH:8]=1)[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][CH2:6][C:7]1[S:11][C:10]([NH:12][C:13](=[O:31])[C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:17]=[C:16]([O:27][CH:28]([CH3:29])[CH3:30])[CH:15]=2)=[N:9][CH:8]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1cnc(NC(=O)c2cc(Oc3ccccc3)cc(OC(C)C)c2)s1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCc1cnc(NC(=O)c2cc(Oc3ccccc3)cc(OC(C)C)c2)s1
Yield: 90 %

Procedure:
3-[2-(3-Isopropoxy-5-phenoxybenzoylamino)-thiazol-5-yl]-propionic acid ethyl ester was prepared in 90% yield from the reduction of 3-[2-(3-isopropoxy-5-phenoxybenzoylamino)-thiazol-5-yl]-acrylic acid ethyl ester in methanol (10 mL) using hydrogen (60 psi) over Pd/C (200 mg).