Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:17]=2[CH:18]=[O:19])[C:5]([Cl:8])=[N:6][CH:7]=1.[BH4-].[Na+].O>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:17]=2[CH2:18][OH:19])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: O=Cc1c(-c2cc(Br)cnc2Cl)nc2ccccn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OCc1c(-c2cc(Br)cnc2Cl)nc2ccccn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.6 %

Procedure:
To a solution of 2-(5-bromo-2-chloropyridin-3-yl)imidazo[1,2-a]pyridine-3-carbaldehyde (100 mg, 0.29 mmol) in MeOH (5 mL), NaBH4 (20 mg, 0.53 mmol) was added at 0° C. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was added water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using PTLC (eluted with dichloromethane:MeOH=30:1) to provide (2-(5-bromo-2-chloropyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)methanol (30 mg, yield: 29%). 1H-NMR (DMSO, 400 MHz) δ 8.66 (d, J=2.4 Hz, 1H), 8.49 (d, J=6.8 Hz, 1H), 8.25 (d, J=2.4 Hz, 1H), 7.64 (d, J=9.2 Hz, 1H), 7.35˜7.40 (m, 1H), 7.03˜7.07 (m, 1H), 5.33 (t, J=5.2 Hz, 1H), 4.75 (d, J=5.2 Hz, 2H). MS (M+H)+: 338/340.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>OS(O)(=O)=O>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: CCOC(=O)c1ccc(Br)s1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Br)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 5-bromothiophene-2-carboxylate (1.5 g, 6.38 mmol) in aqueous conc. H2SO4 (6 ml) cooled to 0° C., aqueous 65% HNO3 (2 ml) was added, and the reaction was left to warm to RT and stirred for 1 hour. The mixture was poured into ice-water and extracted with EtOAc (×3); the combined organic layers were dried over sodium sulfate and the solvent was removed affording ethyl 5-bromo-4-nitrothiophene-2-carboxylate (Int. 40) which was used without any additional purification (550 mg, 1.964 mmol).
Reaction SMILES: [CH:1]([C:4]1[O:8][C:7]([CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)=[N:6][N:5]=1)([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH:1]([C:4]1[O:8][C:7]([CH2:9][CH2:10][NH2:11])=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nnc(CCNC(=O)OC(C)(C)C)o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1nnc(CCN)o1

Procedure:
4.00 g (15.67 mmol) tert-butyl [2-(5-isopropyl-[1,3,4]oxadiazol-2-yl)-ethyl]-carbamate and 20 ml trifluoroacetic acid are stirred in 200 ml dichloromethane for 24 hours at ambient temperature. Then the mixture is evaporated down, the residue is made basic and extracted with ethyl acetate. The organic phase is dried and evaporated to dryness.
Reaction SMILES: [C:1]([C:4]1[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=1[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1)([OH:3])=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>C1(C)C=CC=CC=1.FC(F)(F)S(O)(=O)=O>[O:3]=[C:1]1[C:4]2[CH:21]=[CH:20][CH:19]=[CH:18][C:5]=2[CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][C:9]1=2
Reactant: O=C(O)Cc1ccc(OCc2ccccc2C(=O)O)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Temperature: 75 °C
Yield: 73.1 %

Procedure:
To a suspension of 4-(2-carboxybenzyloxy)phenylacetic acid (Olo-IM1) (300.09 g, 1.04 mol; assay: 99.0%) and trifluoromethane sulfonic acid (4.77 g, 0.03 mol; assay: 98.0%) in toluene (1122 g) was added slowly trifluoroacetic anhydride (255.18 g, 1.20 mol; assay: 99.0%) at 20-35° C. The brown solution was stirred after complete addition of trifluoroacetic anhydride for 1 hour at 20-25° C. and the mixture was then hydrolyzed with water (99.0 g). Afterwards, the mixture was distilled under normal pressure until the steam temperature was 105-110° C. (1191 g two-phase distillate). The residue was diluted with toluene (261 g) and the suspension was heated to reflux. The dark solution was then cooled to 75° C. and seeded with crystals of 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid (Olo-IM2). The suspension was stirred after cooling to 20-25° C. for additional 1-2 hours at this temperature. The product was filtered off, washed with cyclohexane (600 g) and water (390 g) and dried under vacuum (20 h, 50° C.) to give 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid (Olo-IM2) (yield: 203.21 g, 0.76 mol, 73.0%; HPLC assay >99.5%, HPLC purity: 99.62%). This product was then recrystallized from a mixture of cyclohexane (700 g) and toluene (1892 g). After filtration the wet product was washed with cyclohexane (466 g) and dried under vacuum (15 h, 70° C.) to give slightly gray colored 6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-acetic acid (Olo-IM2) (yield: 198.4 g, 0.74 mol, 97.6%; HPLC assay >99.5%, HPLC purity: 99.90%; overall yield: 71.3%).
Reaction SMILES: ClC1C=CC2SC=[C:8]([CH2:9][N:10]3[CH2:14][CH2:13][N:12](C4SC(C(O)=O)=C(C)N=4)C3=O)[C:4]=2[CH:3]=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44](O)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.N1C=CC=CC=1CN>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH:12][CH2:13][C:14]4[CH:3]=[CH:4][CH:8]=[CH:9][N:10]=4)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:48][CH:49]=1
Reactant: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1ccccn1
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccccn1
Yield: 54 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-2-ylmethanamine, the title compound was obtained as a colorless solid in 54% yield: mp 183-185° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.60-8.56 (m, 2H), 7.85-7.80 (m, 1H), 7.45-7.23 (m, 6H), 4.55 (d, J=6.0 Hz, 2H), 4.49 (s, 2H), 4.07 (t, J=9.0 Hz, 2H), 3.52 (t, J=9.0 Hz, 2H) 2.55 (s, 3H); MS (ES+) m/z 426.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][NH:7][C:8]([C:10]1([CH2:23][CH2:24][CH2:25][CH2:26]Br)[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[O:4].[N:28]1([C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]([CH2:5][CH2:6][NH:7][C:8]([C:10]1([CH2:23][CH2:24][CH2:25][CH2:26][N:31]2[CH2:32][CH2:33][N:28]([C:34]3[CH:43]=[CH:42][C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:35]=3)[CH2:29][CH2:30]2)[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])=[O:4]
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Reactant: COC(=O)CCNC(=O)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: COC(=O)CCNC(=O)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2-methoxycarbonyl-ethyl)-amide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:16])[CH3:15])[C:5]2[O:9][CH:8]([CH2:10][NH2:11])[CH2:7][C:6]=2[C:12]=1[CH3:13].C(N(C(C)C)CC)(C)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>>[CH2:30]([O:29][C:27](=[O:28])[NH:11][CH2:10][CH:8]1[CH2:7][C:6]2[C:12]([CH3:13])=[C:2]([Cl:1])[CH:3]=[C:4]([CH:14]([CH3:16])[CH3:15])[C:5]=2[O:9]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1c(Cl)cc(C(C)C)c2c1CC(CN)O2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)cc(C(C)C)c2c1CC(CNC(=O)OCc1ccccc1)O2
Yield: 81.3 %

Procedure:
Treatment of (±)-1-(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methanamine (3.41 g, 12.3 mmol) with diisopropylethylamine (1.99 g, 14.2 mmol) and benzyl chloroformate (2.42 g, 14.2 mmol) generally according to the procedure described for Intermediate 12 gave 3.74 g (81%) of (±)-benzyl(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a colorless oil. Anal. calcd. for C21H24ClNO3 C, 67.46; H, 6.47; N, 3.75. Found C, 67.01; H, 6.52; N, 3.56. Chiral HPLC separation of (±)-benzyl(5-chloro-7-isopropyl-4-methyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate (Chiralpak AD, ethanol) provided two fractions.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[N:6]=1.[H-].[Na+].Cl[C:18]([O:20][CH2:21][CH2:22]Cl)=[O:19].O>O1CCCC1>[O:19]=[C:18]1[N:1]([C:2]2[S:3][CH:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=3)[N:6]=2)[CH2:22][CH2:21][O:20]1
Reactant: O=C(Cl)OCCCl
Reactant: N#Cc1ccc(-c2csc(N)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2csc(N3CCOC3=O)n2)cc1
Reaction time: 1 h
Yield: 10 %

Procedure:
4-(2-Amino-thiazol-4-yl)-benzonitrile (1.5 g, 7.4 mmol), prepared in the previous step, in dry tetrahydrofuran (10 mL) was added dropwise to a suspension of sodium hydride (0.6 g, ˜15 mmol, 60% in oil) in dry tetrahydrofuran (10 mL) at room temperature. After 1 h, 2-chloroethyl chloroformate (0.83 mL, 8 mmol) was added dropwise and the mixture heated under reflux. After 16 h, the mixture was cooled, poured carefully into water, which was extracted with ethyl acetate. The organic layer was separated, dried (anhydrous Na2SO4), evaporated and the residue purified by silica gel column chromatography (ethyl acetate:hexane, 3:7) to afford the crude product. Recrystallization from ethanol gave the title compound (0.2 g, 10%), MS (ES) m/z 272 [M+H]+. HPLC 99.5% @ 210-370 nm, 99.3% @ 240 nm; RT=8.3 min, the Xterra® RP18 column, 3.5μ, 4.6×150 mm column 1.2 mL/min, 85/15-5/95 (Phos Buff. pH=2.1/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][N:12]3[C:16](=[O:17])[CH2:15][S:14][C:13]3=[O:18])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:19](=O)[CH2:20][CH2:21][CH3:22].N1CCCCC1>C(O)C>[CH:19](=[C:15]1[S:14][C:13](=[O:18])[N:12]([CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:16]1=[O:17])[CH2:20][CH2:21][CH3:22]
Reactant: CCCC=O
Reactant: O=C1CSC(=O)N1CSc1cccc2nccn12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCCC=C1SC(=O)N(CSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.41 g (5.1 mmol) of 3-(imidazo[1,2-a]pyridin-5-ylthio)methylthiazolidine-2,4-dione and 0.46 ml (5.1 mmol) of n-butyraldehyde in 30 ml of ethanol, 0.06 ml (0.6 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=1/2) to yield 1.26 g (74.8%, yellow oily substance) of the desired product.
Reaction SMILES: C[C@]1(NC2C=NC(C(F)(F)F)=CN=2)CCC[C@@H]1NC(C1C(N2N=CC=N2)=CC=CN=1)=O.[CH3:32][C@:33]1([NH:39][C:40]2[CH:45]=[N:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][N:41]=2)[CH2:37][CH2:36][CH2:35][C@@H:34]1[NH2:38].[Cl:50][C:51]1[CH:52]=[CH:53][C:54]([N:60]2[N:64]=[CH:63][CH:62]=[N:61]2)=[C:55]([CH:59]=1)[C:56](O)=[O:57]>>[Cl:50][C:51]1[CH:52]=[CH:53][C:54]([N:60]2[N:64]=[CH:63][CH:62]=[N:61]2)=[C:55]([CH:59]=1)[C:56]([NH:38][C@H:34]1[CH2:35][CH2:36][CH2:37][C@:33]1([CH3:32])[NH:39][C:40]1[CH:45]=[N:44][C:43]([C:46]([F:49])([F:47])[F:48])=[CH:42][N:41]=1)=[O:57]
Reactant: O=C(O)c1cc(Cl)ccc1-n1nccn1
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Agent: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1
Product: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1cc(Cl)ccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 77) from (1S,2S)-1-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 25; 90 mg, 0.35 mmol) and 5-chloro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 38a; CAS number 1293284-54-4; 93 mg, 0.42 mmol) except this was purified by column chromatography (silica, 0-50% ethyl acetate/petrol) followed by recrystallisation from diethyl ether/pentane to afford the title compound.
Reaction SMILES: [C:1]([O:7][CH:8]([C:13]([Cl:16])([Cl:15])[Cl:14])[CH:9]=[C:10]([CH3:12])[CH3:11])(=[O:6])[CH2:2]C(C)=O.C(N(CC)CC)C.S([N:34]=[N+:35]=[N-])(C1C=CC(C)=CC=1)(=O)=O.[OH-].[Na+]>C(#N)C>[N+:34](=[CH:2][C:1]([O:7][CH:8]([C:13]([Cl:16])([Cl:15])[Cl:14])[CH:9]=[C:10]([CH3:12])[CH3:11])=[O:6])=[N-:35]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(=O)CC(=O)OC(C=C(C)C)C(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)=CC(OC(=O)C=[N+]=[N-])C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 3-methyl-1-trichloromethyl-2-butenyl acetoacetate (5.75 g, 0.02 mole) and triethylamine (2.02 g, 0.02 mole) in 50 ml of acetonitrile was added a solution of tosyl azide (3.94 g, 0.02 mole, prepared according to the method of Organic Synthesis Collective Volume V, page 179 A) in acetonitrile dropwise over a period of 10 minutes. The resultant mixture, containing the thus produced 3-methyl-1-trichloromethyl-2-butenyl-2-diazoacetoacetate, was stirred at room temperature for two hours and then poured into 60 ml (0.06 mole) of 1 N aqueous sodium hydroxide. The resulting mixture was stirred at room temperature for 30 minutes and then extracted with about 100 ml of ether. After phase separation, the aqueous layer was extracted with an additional 150 ml portion of ether, and the ether extracts were combined. The ethereal solution was then washed ten times with 50 ml portions of 3% aqueous potassium hydroxide containing sodium chloride and then three times with 50 ml portions of saturated aqueous sodium chloride. The washed ethereal solution was dried over magnesium sulfate, and the ether was removed by evaporation, affording a brown oily residue. The residue was purified by column chromatography on silica gel using benzene as the eluant, to give 3-methyl-1-trichloromethyl-2-butenyl diazoacetate (4.63 g, 85% yield).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[Br:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Br-:21].[OH:10][C:9]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([CH2:8][CH2:7]1)[CH2:2][CH2:3]2
Reactant: OC(c1cccs1)(c1cccs1)C12CCN(CC1)CC2
Reactant: BrCCc1ccccc1
Product: OC(c1cccs1)(c1cccs1)C12CC[N+](CCc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 48.7 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct -4-yl(di-2-thienyl)methanol (0.0658 g, 0.215 mmol) and (2-bromoethyl)benzene (0.050 mL, 0.366 mmol) in 1MeOH/1CHCl3 (4.0 mL) were reacted to give the desired product (0.0514 g, 48.9%). ELMS m/z 410(M+) Rt (1.83 min).
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]2=[C:6]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]=1[C:23]([O:25]CC)=O)(=O)[CH3:2].O.[NH2:29][NH2:30]>C(O)(=O)C>[CH2:16]([O:15][C:6]1[C:5]2[C:23](=[O:25])[NH:30][N:29]=[C:1]([CH3:2])[C:4]=2[N:8]2[CH2:9][CH2:10][N:11]([CH3:14])[C:12](=[O:13])[C:7]=12)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NN
Reactant: CCOC(=O)c1c(OCc2ccccc2)c2n(c1C(C)=O)CCN(C)C2=O
Solvent: O
Solvent: CC(=O)O
Product: Cc1n[nH]c(=O)c2c(OCc3ccccc3)c3n(c12)CCN(C)C3=O

Procedure:
A solution of ethyl 6-acetyl-8-(benzyloxy)-2-methyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]-pyrazine-7-carboxylate (0.44 g,1.2 mmol; see Example 7, Step 7), and hydrazine monohydrate (0.37 mL, 11.9 mmol) in glacial acetic acid (2 mL) was heated in a microwave oven at 180° C. for 20 minutes. The reaction mixture was concentrated under vacuum and the residue partitioned between dichloromethane and aqueous sodium bicarbonate. The organic extract was dried over MgSO4, filtered, and concentrated to provide the titled dione.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[CH3:15][O:16][C:17](=[O:22])[CH:18]([CH2:20][OH:21])[NH2:19].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:15][O:16][C:17](=[O:22])[CH:18]([NH:19][C:11](=[O:13])[C@H:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH3:10])[CH2:20][OH:21]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)C(N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(CO)NC(=O)[C@@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.9 %

Procedure:
A round-bottomed flask was charged with Boc-D-alanine (600 mg, 3.17 mmol) and DL-serine methyl ester hydrochloride (691 mg, 4.44 mmol). DMF (12 ml) was added followed by N,N-diisopropylethylamine (1.5 ml, 8.6 mmol) and HATU (1.33 g, 3.49 mmol). The yellow reaction mixture was stirred at room temperature for 48 h then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated to afford 422 mg (41%) of 2-((R)-2-tert-butoxycarbonylamino-propionylamino)-3-hydroxy-propionic acid methyl ester as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][C:4](=[O:13])[CH:3]=1.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:22]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH2:33][CH2:34][NH:35][C:36](=[O:38])[CH3:37])[CH3:23]>>[CH2:22]([C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH:14]([C:3]1[C:4](=[O:13])[CH2:5][CH:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:2]=1[OH:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:27]2[CH2:33][CH2:34][NH:35][C:36](=[O:38])[CH3:37])[CH3:23]
Reactant: O=Cc1ccccc1
Reactant: O=C1C=C(O)C(c2ccccc2)C1
Reactant: CCc1ccc2[nH]cc(CCNC(C)=O)c2c1
Product: CCc1ccc2[nH]c(C(C3=C(O)C(c4ccccc4)CC3=O)c3ccccc3)c(CCNC(C)=O)c2c1

Procedure:
Using general procedure C, 3-hydroxy-4-phenyl-cyclopent-2-enone (Lit. 17) was reacted with benzaldehyde and N-[2-(5-ethyl-1H-indol-3-yl)-ethyl]-acetamide (Lit. 6) to give the title compound as an orange solid. MS: 493.4 ([M+H]+).
Reaction SMILES: [NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[C:4]([CH2:12][C:13]2OC=[CH:16][CH:17]=2)[CH:3]1[NH:18][C:19]([NH:21][C:22]([O:24][CH3:25])=[O:23])=[S:20].[OH-].[Na+].[CH3:28]I.C[C:31](C)=[O:32]>O>[NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[C:4]([CH2:12][C:13]2[CH:17]=[CH:16][O:32][CH:31]=2)[CH:3]1[NH:18][C:19](=[N:21][C:22]([O:24][CH3:25])=[O:23])[S:20][CH3:28]
Reactant: CI
Reactant: CC(C)=O
Reactant: CCCSC1=C(Cc2ccco2)C(NC(=S)NC(=O)OC)C(=N)C=C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCSC1=C(Cc2ccoc2)C(NC(=NC(=O)OC)SC)C(=N)C=C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.7 %

Procedure:
To a suspension of 1-imino-(2-furylmethyl)-2-(3-carbomethoxythioureido)-4-propylthiobenzene (3.77 g; 0.01 mole) in acetone (45 ml) and water (15 ml) there is added 50% aqueous sodium hydroxide (0.79 g; 0.01 mole). Within 15 min. after addition a solution forms and is stirred at room temperature for 30 min. To the solution there is added methyl iodide (1.42 g; 0.01 mole). The mixture is stirred at room temperature for 13/4 hrs. and the suspension that forms is vacuum filtered. The filter cake is air dried to afford 1-imino-(3-furylmethyl)-2-(3-carbomethoxy-S-methylisothioureido)-4-propylthiobenzene (2.65 g; 67.7%), m.p. 96°-98° C.
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]1[CH2:21][O:20][C:11]2([CH2:16][CH2:15][CH:14]([C:17]([O-:19])=O)[CH2:13][CH2:12]2)[O:10]1.[Na+].C(N(CC)CC)C.Cl.[CH2:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][NH2:41])=[CH:36][CH:35]=1)[CH3:32]>O1CCCC1.O>[CH2:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][NH:41][C:17]([CH:14]2[CH2:13][CH2:12][C:11]3([O:10][CH2:9][CH2:21][O:20]3)[CH2:16][CH2:15]2)=[O:19])=[CH:36][CH:35]=1)[CH3:32]
Reactant: O=C([O-])C1CCC2(CC1)OCCO2
Reactant: CCOc1ccc(NN)cc1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOc1ccc(NNC(=O)C2CCC3(CC2)OCCO3)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
At -40° C., 1.65 ml of isobutyl chloroformate are added to a mixture of 2.63 g of sodium 4,4-ethylenedioxycyclohexanoate in 20 ml of tetrahydrofuran followed by 1.8 ml of triethylamine. The reaction mixture is stirred for 2 hours at 0° C., then at -20° C., 2.4 g of 4-ethoxyphenylhydrazine hydrochloride are added; the reaction mixture is stirred for 2 hours at 0° C. then 100 ml of water are added and it is extracted with ethyl acetate. The organic phases are washed successively with water, with a solution of potassium bisulfate (pH=2), with a saturated potassium carbonate solution, dried over magnesium sulfate and evaporated off. The expected product is obtained after crystallisation from diethyl ether; M.p.=158° C.
Reaction SMILES: [C:1](Cl)(=O)C.[O:5]=[C:6]1[CH2:11][CH2:10][C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:12]([OH:14])=[O:13])[CH2:8][CH2:7]1.C(=O)([O-])O.[Na+]>CO>[O:5]=[C:6]1[CH2:11][CH2:10][C:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:12]([O:14][CH3:1])=[O:13])[CH2:8][CH2:7]1
Reactant: CC(=O)Cl
Reactant: O=C1CCC(C(=O)O)(c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(c2ccccc2)CCC(=O)CC1
Temperature: 45 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
Acetyl chloride (0.46 mL, 0.50 g, 6.4 mmol) was added to a solution of 4-oxo-1-phenylcyclohexanecarboxylic acid (Description 2, 0.94 g, 4.3 mmol) in methanol (5 mL) and the mixture was heated under reflux for 20 hours. The mixture was cooled, poured into aqueous sodium hydrogen carbonate (saturated, 100 mL) and extracted with ethyl acetate (2×50 mL). The combined organic fractions were dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (2 mL), acetic acid (6 mL) and water (2 mL) were added and the mixture was stirred at 45° C. for 2 hours. The mixture was cooled, the solvent was evaporated under reduced pressure and aqueous sodium hydrogen carbonate (saturated, 100 mL) was added. The mixture was extracted with ethyl acetate (2×50 mL), the combined organic fractions were dried (Na2SO2) and the solvent was evaporated under reduced pressure to give the tide compound (0.98 g, 98%). 1H NMR (250 MHz, CDCl3) δ 7.45-7.26 (5H, m), 3.72 (3H, s), 2.77 (2H, m), 2.61-2.38 (4H, m), and 2.25 (2H, m).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[C:5]([CH3:16])[CH:4]=1.C(N(CC)CC)C.[CH:24]1([C:29](Cl)=[O:30])[CH2:28][CH:27]=[CH:26][CH2:25]1.O>ClCCl>[Cl:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:9][CH2:10][N:11]([C:29]([CH:24]3[CH2:28][CH:27]=[CH:26][CH2:25]3)=[O:30])[CH2:12][CH2:13]2)=[C:5]([CH3:16])[CH:4]=1
Reactant: Cc1cc(Cl)ccc1OC1CCNCC1
Reactant: O=C(Cl)C1CC=CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(Cl)ccc1OC1CCN(C(=O)C2CC=CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
4-(4-Chloro-2-methylphenoxy)piperidine hydrochloride (28.6 g) and triethylamine (45.5 mL) were stirred in dichloromethane (100 mL) and cyclopent-3-ene-1-carbonyl chloride (14.26 g) in dichloromethane (100 mL) was added dropwise. When addition was complete, the reaction mixture was stirred at room temperature for 2 h. Water (250 mL) was added to the reaction mixture and product was extracted with dichloromethane. The dichloromethane was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was filtered through a plug of silica eluting with diethyl ether to give the subtitle compound (29.5 g).