Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][NH:13][C:12](=[O:15])[CH2:11][CH2:10]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O([CH2:34][C:35]([F:38])([F:37])[F:36])S(C(F)(F)F)(=O)=O>C1COCC1.CN1C(=O)CCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][N:13]([CH2:34][C:35]([F:38])([F:37])[F:36])[C:12](=[O:15])[CH2:11][CH2:10]1
Reactant: O=C1CCC(c2cccc(F)c2F)CN1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: O=C1CCC(c2cccc(F)c2F)CN1CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 5-(2,3-difluorophenyl)piperidin-2-one (8.88 g, 42 mmol) in THF (250 mL) and NMP (170 mL) at 0° C. was added lithium bis(trimethylsilyl)amide (1.0 M in THF, 48 mL, 48 mmol) over 5 min, keeping the internal temperature of the reaction mixture below 5° C. The resulting mixture was stirred at 0° C. for 15 min, then 2,2,2-trifluoroethyl triflate (11.2 g, 48 mmol) was added dropwise, keeping the internal temperature of the reaction mixture below 5° C. The reaction mixture was allowed to warm slowly to ambient temperature and stirring was continued for 3 h. The resulting mixture was partitioned between saturated aqueous sodium bicarbonate (800 mL) and EtOAc (1 L). The organic layer was removed and the aqueous phase was extracted further with EtOAc (500 mL). The combined organic extracts were washed with water, then brine, then dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=293.9 (M+1).
Reaction SMILES: ClC1C=C(SC2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)NC=2CCC(N)=O)C=C(Cl)C=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:42])[CH:40]=3)[NH:35][C:34]=2[C:43]([OH:45])=[O:44])=[CH:28][CH:27]=1.C(Cl)(=O)C(Cl)=O.C(O)C1C=CC=CC=1.N1C=CC=CC=1>C1COCC1>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([S:32][C:33]2[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:42])[CH:40]=3)[NH:35][C:34]=2[C:43]([O:45][CH2:19][C:15]2[CH:16]=[CH:17][CH:18]=[CH:13][CH:14]=2)=[O:44])=[CH:30][CH:31]=1
Reactant: Cc1ccc2[nH]c(C(=O)O)c(Sc3ccc(Cl)cc3)c2c1
Reactant: Cc1ccc2c(Sc3cc(Cl)cc(Cl)c3)c(CCC(N)=O)[nH]c2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: OCc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc2[nH]c(C(=O)OCc3ccccc3)c(Sc3ccc(Cl)cc3)c2c1
Yield: 37 %

Procedure:
Following the method used to prepare 24a, the use of 1b (0.23 mmol) and oxalyl chloride in THF followed by allowing the intermediate acid chloride to react with benzyl alcohol (35 μL, 0.34 mmol) in presence of pyridine (54 μL, 0.68 mmol) provided 35 mg (37%) of product 16 as a pale yellow foam. 1H NMR (300 MHz, DMSO-d6) δ 2.34 (s, 3H), 5.35 (s, 2H), 7.00 (d, J=9 Hz, 2H), 7.20 (d, J=9 Hz, 1H), 7.26 (d, J=9 Hz, 2H), 7.29-7.38 (m, 6H), 7.47 (d, J=9 Hz, 1H), 12.44 (s, 1H). LC-MS (CI): m/z 408.1 [(M+H)+ C23H18ClNO2S requires 407.6]. Purity (100%). Calcd for C23H18ClNO2S: C, 67.72; H, 4.45; N, 3.43; S, 7.86; Cl, 8.69. Found: C, 67.53; H, 4.55; N, 3.42; S, 8.09; Cl, 8.45.
Reaction SMILES: CO.C(B(CC)CC)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([CH:44]([CH3:46])[CH3:45])[N:20](/[CH:29]=[CH:30]/[C@@H:31]([OH:43])[CH2:32][C:33](=[O:42])[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21]=2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[CH:13][CH:12]=1.[BH4-].[Na+]>C1COCC1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([CH:44]([CH3:46])[CH3:45])[N:20](/[CH:29]=[CH:30]/[C@@H:31]([OH:43])[CH2:32][C@@H:33]([OH:42])[CH2:34][C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[C:21]=2[C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)=[CH:13][CH:12]=1
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@@H](O)CC(=O)CC(=O)OC(C)(C)C
Agent: CCB(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@@H](O)C[C@@H](O)CC(=O)OC(C)(C)C
Yield: 99.7 %

Procedure:
A solution of dry THF (16 ml) and dry methanol (4 ml) under nitrogen at room temperature was treated with a solution of triethyl borane (1.0M in THF, 2.32 ml). After 1 h the mixture was cooled to -78° and treated with a solution of 1,1-dimethyleth-1-yl (5S,E)-7-[4,5-bis-(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-5-hydroxy-3-oxo-6-heptenoate (1.075 g) in THF (4:1) (15 ml) plus washings (5 ml). After a further 1 h at -75° the mixture was treated with sodium borohydride (88 mg). After 21/2 h the mixture was quenched with saturated aqueous ammonium chloride solution (2 ml) and allowed to warm. The mixture was then diluted with water (100 ml) and extracted with ethyl acetate (3×70 ml). The combined extracts were dried and evaporated and the residue was azeotroped with methanol (3×30 ml). This gave a pale yellow solid (1.076 g) which was crystallised from ether-cyclohexane to give the title compound (739 mg) as white fluffy crystals, δ(CDCl3) 1.3-1.65 (m, 2H, CH(OH)CH2CH(OH)), 1.40 (d, J7 Hz, 6H, --CH(CH3)2), 1.46 (s, 9H, --C(CH3)3), 2.35 (d, J7 Hz, 2H, CH2CO2R), 3.15 (septet, J7 Hz, 1H, --CH(CH3)2), 3.77, 3.81 (2s, 2H, CH(OH)CH2CH(OH), 4.12 (m, 1H, CH(OH)CH2CO2), 4.42 (m, 1H, =CHCH(OH)CH2 --), 5.30 (dd, J14 and 7 Hz, 1H, N--CH=CH--), 6.67 (d, J14 Hz, 1H, N--CH=CH--), 6.90 and 7.09 (2t, J9 Hz each 2H, C-3 and C-5 protons of 4-fluorophenyls), 7.2-7.43 (m, 4H, C-2 and C-6 protons of 4-fluorophenyls).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C@@H:5]2[O:6][C:7](=[O:9])[CH2:8][C@@H:4]2[C@H:3]1/[CH:11]=[CH:12]/[C@@H:13]([OH:22])[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[O:23]1[CH:28]=[CH:27][CH2:26][CH2:25][CH2:24]1.[C:29](=[O:32])(O)[O-].[Na+]>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:16]1([CH2:15][CH2:14][C@H:13]([O:22][CH:4]2[CH2:3][CH2:2][CH2:10][CH2:29][O:32]2)/[CH:12]=[CH:11]/[C@@H:3]2[C@@H:4]3[C@@H:5]([O:6][C:7](=[O:9])[CH2:8]3)[CH2:10][C@H:2]2[O:1][CH:28]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1C[C@@H]2[C@@H](/C=C/[C@@H](O)CCc3ccccc3)[C@H](O)C[C@@H]2O1
Reactant: C1=COCCC1
Reactant: O=C([O-])O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C1C[C@@H]2[C@@H](/C=C/[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC3CCCCO3)C[C@@H]2O1
Reaction time: 2.5 h
Yield: 89.9 %

Procedure:
p-Toluenesulfonic acid monohydrate (0.3 g, 0.165 mmol) was added to a solution of (3aR,4R,5R,6aS)-hexahydro-5-hydroxy-4-((S,E)-3-hydroxy-5-phenylpent-1-enyl)cyclopenta[b]furan-2-one (10.0 g, 33.1 mmol) and 3,4-dihydro-2H-pyran (4.2 g, 49.7 mmol) in dichloromethane (100 mL) at room temperature and the mixture was stirred for 2.5 hr (TLC monitoring). Saturated aqueous solution of sodium bicarbonate (100 mL) was poured into the reaction mixture and the mixture was stirred for 5 minutes. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were dried over magnesium sulfate, the solid was filtered off and the filtrate was concentrated under reduced pressure to give 16.0 g of crude product. The crude product was purified by column chromatography and then concentrated under reduced pressure to provide 14.0 g of the title compound (89.9% yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1.[CH:14]1C=CC=C[CH:15]=1.C(O)C.S(=O)(=O)(O)O>O>[Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH2:14][CH3:15])=[O:10])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc(CCCBr)cc1
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(CCCBr)cc1
Reaction time: 23 h

Procedure:
A mixture of p-(3-bromopropyl)benzoic acid (100.8 g.; 0.41 mole), benzene (290 ml.), ethanol (60 ml.) and concentrated sulfuric acid (1.4 ml.) is heated under reflux under a Dean and Stark constant water separator until the evolution of water ceases. The time required is 23 hours.
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([O:9][CH:10]2[CH2:13][CH:12]([NH2:14])[CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.Cl[C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1.CCN(C(C)C)C(C)C.O>CN1C(=O)CCC1>[Br:2][C:3]1[C:4]([O:9][CH:10]2[CH2:11][CH:12]([NH:14][C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:13]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: NC1CC(Oc2ncccc2Br)C1
Reactant: Clc1nc2ccccc2s1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Brc1cccnc1OC1CC(Nc2nc3ccccc3s2)C1
Temperature: 180 °C
Yield: 60 %

Procedure:
A mixture of 3-((3-bromopyridin-2-yl)oxy)cyclobutanamine hydrochloride (242 mg, 1 mmol), 2-chloro-benzothiazole (169 mg, 1 mmol) and DIEA (286 mg, 2 mmol) in NMP (10 mL) was heated to 180° C. for 2 hours in microwave. The reaction mixture was added water, extracted with EtOAc (40 mL), washed with brine and dried over Na2SO4. The organic layers were concentrated and purified by column chromatography to give N-(3-((3-bromopyridin-2-yl)oxy)cyclobutyl)benzo[d]thiazol-2-amine (225 mg, 0.6 mmol, yield 60%). ESI-MS (M+1): 376 calc. for C16H14BrN3OS 375.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:16][CH3:17])(=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12].N1CCCCC1.C(O)(=O)C>C1(C)C=CC=CC=1>[CH:1](=[C:10]([C:9]([O:16][CH3:17])=[O:15])[C:11]([O:13][CH3:14])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)CC(=O)OC
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COC(=O)C(=Cc1ccccc1)C(=O)OC

Procedure:
Into a one-liter three-necked conical flask are introduced in succession 60 g (565.39 mmol) of benzaldehyde, 77 g of dimethyl malonate (565.32 mmol), 3.85 g of piperidine (45.21 mmol), 130 ml of toluene and 2.71 g (45.16 mmol) of acetic acid.
Reaction SMILES: [C:1](Cl)(=[O:3])C.[O:5]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[C:17]([CH3:21])[C:16]=3[CH:22]([O:25][Si](C)(C)C)[C:23]#N)=[CH:14][C:9]=2[CH2:8][CH2:7][CH2:6]1.C[OH:31]>>[O:5]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[C:17]([CH3:21])[C:16]=3[CH:22]([OH:25])[C:23]([O:3][CH3:1])=[O:31])=[CH:14][C:9]=2[CH2:8][CH2:7][CH2:6]1
Reactant: Cc1nn(C)c(-c2ccc3c(c2)CCCO3)c1C(C#N)O[Si](C)(C)C
Reactant: CC(=O)Cl
Reactant: CO
Product: COC(=O)C(O)c1c(C)nn(C)c1-c1ccc2c(c1)CCCO2
Reaction time: 0.33 h
Yield: 55 %

Procedure:
Acetyl chloride (0.35 mL, 4.96 mmol) was added to anhydrous methanol (3 mL) at 0° C. under nitrogen atmosphere. The mixture was stirred for 20 minutes before adding 2-[5-(3,4-dihydro-2H-1-benzopyran-6-yl)-1,3-dimethyl-1H-pyrazol-4-yl]-2-[(trimethylsilyl)oxy]acetonitrile (27b) (147 mg, 0.41 mmol). The mixture was stirred at room temperature for 1 hour then at 50-60° C. for 5 hours. The solution was concentrated in vacuo. A saturated solution of sodium hydrogencarbonate (10 mL) was added to the residue. The aqueous layer was extracted with ethyl acetate (2×10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (dichloromethane/ethyl acetate 40/60) to provide the desired hydroxyl-ester (27c) (72 mg, 0.227 mmol, 55%) as a colorless oil.
Reaction SMILES: [O:1]([CH2:5][CH3:6])[C:2]([S-])=[S:3].[K+].Br[NH:9][C:10](=[NH:15])[C:11]([Cl:14])([Cl:13])[Cl:12]>O.C(Cl)Cl>[Cl:12][C:11]([Cl:14])([Cl:13])[C:10]1[N:15]=[C:2]([O:1][CH2:5][CH3:6])[S:3][N:9]=1
Reactant: CCOC(=S)[S-]
Reactant: N=C(NBr)C(Cl)(Cl)Cl
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CCOc1nc(C(Cl)(Cl)Cl)ns1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
32 g (0.2 mole) of potassium ethyl xanthate was dissolved in 175 ml of water. This was stirred rapidly while a solution of 48 g (0.2 mole) of N-bromotrichloroacetamidine in 150 ml of methylene chloride was added over 15 minutes. Then, the mixture was stirred one hour at room temperature. The dark methylene chloride layer was separated and the water layer extracted with 100 ml of methylene chloride. The combined methylene chloride fractions were dried over magnesium sulfate and filtered. Next, the solvent was evaporated and then the crude product was distilled at 75° C. under a vacuum of 0.9mm to give 26 g of 3-trichloromethyl-5-ethoxy-1,2,4-thiadiazole.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[C:15]1([CH3:29])[CH:20]=[CH:19][CH:18]=[C:17]([C:21]2[S:22][CH:23]=[CH:24][C:25]=2[C:26](O)=[O:27])[CH:16]=1>>[F:13][C:10]([F:12])([F:11])[C:9]([NH:8][CH2:7][C@H:2]1[N:3]([C:26]([C:25]2[CH:24]=[CH:23][S:22][C:21]=2[C:17]2[CH:16]=[C:15]([CH3:29])[CH:20]=[CH:19][CH:18]=2)=[O:27])[CH2:4][C@H:5]2[C@@H:1]1[CH2:6]2)=[O:14]
Reactant: Cc1cccc(-c2sccc2C(=O)O)c1
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)C(F)(F)F
Product: Cc1cccc(-c2sccc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)C(F)(F)F)c1

Procedure:
prepared by reaction of N-[(1S,2S,5R)-1-(3-Aza-bicyclo[3.1.0]hex-2-yl)methyl]-2,2,2-trifluoro-acetamide with 2-m-tolyl-thiophene-3-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[C:17]2[O:16][CH:15]([CH2:18][NH:19][C:30](=[O:31])[O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cccc(C)c1-c1cccc2c1OC(CN)C2
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1-c1cccc2c1OC(CNC(=O)OCc1ccccc1)C2
Yield: 87.2 %

Procedure:
Treatment of (±)-1-[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (0.947 g, 3.73 mmol) with diisopropylethylamine (0.725 g, 5.60 mmol) followed by benzyl chloroformate (0.765 g, 4.48 mmol) generally according to the procedure described for Intermediate 12 provided 1,26 g (87%) of (±)-benzyl {[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a colorless oil. Anal. calcd. for C25H25NO3: C, 77.49; H, 6.5; N, 3.61. Found: C, 77.42; H, 6.57; N, 3.62. Chiral HPLC separation of (±)-benzyl {[7-(2,6-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (Chiralcel OJ, methanol:carbon dioxide 4:6) provided two fractions. Fraction 1 (Rt=3.12 min, Chiralcel OJ, methanol:carbon dioxide 4:6); Fraction 2 (Rt=4.28 min, Chiralcel OJ methanol:carbon dioxide 4:6).
Reaction SMILES: CN(C)C=O.[C:6]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][CH:18]=[C:19]([C:22]([CH3:24])=O)[C:20]=2[OH:21])=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].[NH:25]([C:27]([NH:29][C:30]1[S:34][C:33]([C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:31]=1)=[S:28])[NH2:26]>Cl.O>[C:6]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][CH:18]=[C:19]([C:22](=[N:26][NH:25][C:27]([NH:29][C:30]3[S:34][C:33]([C:35]([O:37][CH3:38])=[O:36])=[CH:32][CH:31]=3)=[S:28])[CH3:24])[C:20]=2[OH:21])=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: COC(=O)c1ccc(NC(=S)NN)s1
Reactant: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(NC(=S)NN=C(C)c2csc(-c3ccc(C(C)(C)C)cc3)c2O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
Dimethylformamide (1.3 ml) and conc. hydrochloric acid (1 drop) were added to 2-(4-t-butylphenyl)-3-hydroxy-4-methylcarbonylthiophene (70 mg, 0.26 mmol) synthesized in Reference Synthetic Example 33 and methyl 5-hydrazinocarbonothioylamino-2-thiophenecarboxylate (59 mg, 0.26 mmol) synthesized in Reference Synthetic Example 57, and the mixture was stirred overnight at room temperature. Water was added, and the precipitated solid was filtered. The obtained solid was extracted with chloroform, dried over anhydrous sodium sulfate. The organic layer was concentrated, and purified with a silica gel column chromatography (chloroform/methanol=95/5) to obtain the desired product as a pale yellow solid (112 mg, yield 90%).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1C(O)=O.[C:9]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[N:10].[CH2:19]([N:26]1[C:30](=[O:31])[CH:29]=[CH:28][C:27]1=[O:32])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[CH2:19]([N:26]1[C:30](=[O:31])[CH:29]2[CH:15]([C:14]3[CH:17]=[CH:18][C:11]([C:9]#[N:10])=[CH:12][CH:13]=3)[N:1]3[CH:2]([CH:28]2[C:27]1=[O:32])[CH2:6][CH2:7][CH2:8]3)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: O=C1C=CC(=O)N1Cc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Product: N#Cc1ccc(C2C3C(=O)N(Cc4ccccc4)C(=O)C3C3CCCN32)cc1
Temperature: 80 °C
Yield: 32 %

Procedure:
4.B)f) A mixture of L-proline (20 mmol), 4-cyano-benzaldehyde (20 mmol) and N-benzylmaleimide (20 mmol) in DMF (20 ml) was heated to 80° C. for 5 hours. The solvent was removed in a high vacuum and the residue was separated chromatographically over silica gel (eluent hexane:ethyl acetate=1:1+1% triethylamine). (3aRS,4SR,8aRS,8bSR)-4-(2-Benzyl-1,3-dioxo-decahydro-pyrrolo[3,4-a]pyrrolizin-4-yl)-benzonitrile was isolated in 32% yield as colourless crystals. M.p.: 191°-193° C. (methanol). EI-MS: 371 ([M]+, 7); 184 (100); 156 (11); 91 (12)
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][CH2:12][C:13]1[C:17](=[O:18])[O:16][CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](OC(=O)C)(=O)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(O)(=O)C>[C:15]([NH:14][CH:13]([CH2:12][CH2:11][CH2:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:17](=[O:18])[CH3:25])(=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1OC(c2ccccc2)N=C1CCCNC(=O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: CC(=O)C(CCCNC(=O)c1ccccc1)NC(=O)c1ccccc1
Reaction time: 1 h

Procedure:
A mixture of 4-(3-benzamidopropyl)-2-phenyl-5-oxazolone (1.0 g, 3.1 m.mol), 4-dimethylaminopyridine (0.016 g), acetic anhydride (0.62 ml) and triethylamine (0.62 ml) was stirred for one hour. Acetic acid (4.7 ml) was added and the solution was set aside overnight and evaporated to dryness. The residue was dissolved in chloroform and washed with dilute NaOH, dilute HCl and then dried over MgSO4. Concentration gave the crude product which could be purified by dry-column chromatography on alumina with ethyl acetate as solvent to give 3,6-dibenzamidohexan-2-one.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C([Li])CCC.[N:18]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[N:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].CO>O1CCCC1>[CH3:11][C:8]1([CH3:12])[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([N:18]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH:10]=2)[CH:6]=[CH:7]1.[CH3:11][C:8]1([CH3:12])[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([N:18]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[NH:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH:10]=2)[CH2:6][CH2:7]1
Reactant: CC1(C)CCc2ccc(Br)cc21
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(c1)C(C)(C)C=C2
Product: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1ccc2c(c1)C(C)(C)CC2
Temperature: 25 °C
Yield: 37.2 %

Procedure:
6-Bromo-1,1-dimethyl-indan (prepared by using a well-known method: patent application WO2005066115) 4a (4.32 g, 19.27 mmol) was dissolved in 40 mL of tetrahydrofuran and then butyllithium (15.67 mL, 1.6 M, 25.05 mmol) was added dropwise at −78° C. After the reaction mixture was reacted for 40 minutes, a solution of di-tert-butyl azodicarboxylate (5.32 g, 23.12 mmol) in 30 mL of tetrahydrofuran was then added. The reaction mixture was reacted for another 3 hours at −78° C. The reaction mixture was added with 5 mL of methanol, then warmed up to room temperature and filtered by silica gel. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography to obtain the title compound di-tert-butyl 1-(3,3-dimethyl-1H-inden-5-yl)hydrazine-1,2-dicarboxylate 4b (2.70 g, yield 37.2%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:20]3[N:19]=[CH:18][CH:17]=[N:16][C:15]=3[C:14]([C:21]([OH:23])=[O:22])=[CH:13][CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.OS(O)(=O)=O.[CH3:29][CH2:30]O>>[CH2:29]([O:22][C:21]([C:14]1[C:15]2[N:16]=[CH:17][CH:18]=[N:19][C:20]=2[C:11]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=2)=[CH:12][CH:13]=1)=[O:23])[CH3:30]
Reactant: CCO
Reactant: COc1cc(OC)cc(-c2ccc(C(=O)O)c3nccnc23)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2)c2nccnc12

Procedure:
A mixture of 8-(3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (Step 1.2) (10 g), H2SO4 conc. (3 mL) and EtOH (500 mL) was stirred at reflux for 7 h, allowed to cool and concentrated. The residue was diluted in EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried (Na2SO4), filtered and concentrated to afford 10.1 g of the title compound as a beige solid. Title compound: ESI-MS: 339.2 [M−H]−; tR=4.72 min (System 1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[O:18][CH2:19][CH:20]1[CH2:22][CH2:21]1.C1C(=O)N([Br:30])C(=O)C1>C(Cl)(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:18][CH2:19][CH:20]2[CH2:22][CH2:21]2)=[CH:4][C:5]([CH:8]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][C:7]=1[Br:30]
Reactant: CCOC(=O)C(CC(C)C)c1ccc(N)c(OCC2CC2)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)C(CC(C)C)c1cc(Br)c(N)c(OCC2CC2)c1
Temperature: 25 °C
Yield: 72.3 %

Procedure:
To a stirred solution of ethyl 2-(4-amino-3-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (1.65 g, 5.4 mmol) in dry CCl4 (60 mL), NBS (0.96 g, 5.4 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 at room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents was dried over Na2SO4, filtered and concentrated in vacuo. The crude reaction mixture was purified by column chromatography to yield ethyl 2-(4-amino-3-bromo-5-(cyclopropylmethoxy)phenyl)-4-methylpentanoate (1.5 g) as a yellow solid.
Reaction SMILES: O1CCOCC1.[F:7][C:8]1[C:16]([F:17])=[C:15]([F:18])[C:14]([F:19])=[CH:13][C:9]=1[C:10](Cl)=[O:11].[CH3:20][N:21]([CH3:28])[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[O:25]>C(N(CC)CC)C>[CH3:20][N:21]([CH3:28])[CH:22]=[C:23]([C:10](=[O:11])[C:9]1[CH:13]=[C:14]([F:19])[C:15]([F:18])=[C:16]([F:17])[C:8]=1[F:7])[C:24]([O:26][CH3:27])=[O:25]
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Reactant: COC(=O)C=CN(C)C
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)C(=CN(C)C)C(=O)c1cc(F)c(F)c(F)c1F
Reaction time: 0.5 h
Yield: 50.7 %

Procedure:
To dioxane (80 ml) solution of 2,3,4,5-tetrafluorobenzoyl chloride (21.25 g) was added dioxane (25 ml) solution of methyl 3-dimethylaminoacrylate (12.92 g) with ice-cooling, and triethylamine (14.46 ml) was added thereto with ice-cooling. The mixture was stirred for 30 minutes at the same temperature, then for 3 hours at room temperature, and then for one hour at 50° to 60° C. The mixture was concentrated under reduced pressure, then dissolved in methylene chloride (200 ml), washed with water (200 ml) and brine (100 ml) in order, then dried with sodium sulfate and concentrated under reduced pressure to obtain a syrup product. The syrup product was subjected to column chromatography with silica gel and eluted with a mixed liquid of methanol/methylene chloride (3/97, V/V) to obtain methyl 3-dimethylamino-2-(2,3,4,5-tetrafluorobenzoyl)acrylate (15.47 g) as a syrup product.