Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#N.[CH2:9]([Mg]Br)[CH2:10][CH3:11].C(Br)CC.CC[O:20]CC>>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1](=[O:20])[CH2:9][CH2:10][CH3:11]
Reactant: CCC[Mg]Br
Reactant: CCOCC
Reactant: N#Cc1ccccn1
Solvent: CCCBr
Product: CCCC(=O)c1ccccn1
Temperature: 25 °C

Procedure:
A solution of 2-cyanopyridine (2.20 g, 21.13 mmol) in Et2O (35 mL) added over 10 min to a rapidly stirring solution of freshly prepared n-PrMgBr (from n-PrBr (2.71 g, 22.03 mmol) and Mg (0.62 g) in Et2O (35 mL). Once addition was completed, the reaction was heated to reflux in a warm water bath for 2.5 hours. The reaction was cooled to RT then placed in ice, quenched with 5 mL H2O followed by 60 mL 5N H2SO4. The ether phase was separated. The aqueous phase was heated in warm water for 15 minutes, then cooled in ice, basified with sat. K2CO3. The mixture was extracted with CHCl3 and dried over K2CO3. The solution was filtered, concentrated and purified on Biotage Horizon (10-100% A=Hex, B=2:1 Hex:EtOAc) to afford 1.16 g of 1-(pyridin-2-yl)butan-1-one as an oil: 1H NMR (400 MHz, CDCl3) δ ppm 8.67 (ddd, J=4.74, 1.71, 0.88 Hz, 1H), 8.03 (dt, J=7.83, 1.01 Hz, 1H), 7.82 (td, J=7.71, 1.77 Hz, 1H), 7.45 (ddd, J=7.52, 4.74, 1.14 Hz, 1H), 3.15-3.21 (m, 2H), 1.71-1.80 (m, J=7.43, 7.43, 7.43, 7.43, 7.43 Hz, 2H), 1.00 (t, J=7.33 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:11]2([CH3:18])[NH:16][C:15](=O)[CH2:14][O:13][CH2:12]2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([C@@:11]2([CH3:18])[NH:16][C:15](=[S:28])[CH2:14][O:13][CH2:12]2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: C[C@@]1(c2cc(Br)cc([N+](=O)[O-])c2)COCC(=O)N1
Product: C[C@@]1(c2cc(Br)cc([N+](=O)[O-])c2)COCC(=S)N1

Procedure:
(R)-5-(3-Bromo-5-nitro-phenyl)-5-methyl-morpholin-3-one (2.60 g, 7.84 mmol) and Lawesson's reagent (2.54 g, 6.27 mmol) were stirred at 80° C. for 2 hrs. Volatiles were removed under reduced pressure and the crude product mixture was purified by automated column chromatography (cyclohexane/ethyl acetate) yielding the title compound as yellow foam. 1H-NMR (360 MHz, DMSO-d6): 11.28 (1H, NH), 8.38 (s, 1H), 8.22 (s, 1H), 8.17 (s, 1H), 4.44 (m, 1H), 4.22 (d, 1H), 3.81 (m, 1H), 1.60 (s, 3H); MS: 331 [(M+H)+].
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[N:16]=[C:15]([O:17]C)[C:14]([CH2:19][N:20]([CH3:31])[C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23][CH2:22]2)=[C:13]([CH3:32])[N:12]=1)[CH3:2].CCO.Cl.[OH-].[Na+]>CCOC(C)=O>[CH2:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:11]1[N:16]=[C:15]([OH:17])[C:14]([CH2:19][N:20]([CH3:31])[C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24][CH2:23][CH2:22]2)=[C:13]([CH3:32])[N:12]=1)[CH3:10]
Reactant: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(OC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1cccc(CC)c1-c1nc(C)c(CN(C)[C@H]2CCCc3ccccc32)c(O)n1
Temperature: 90 °C

Procedure:
To a flask containing (1S)-N-{[2-(2,6-diethylphenyl)-4-methoxy-6-methylpyrimidin-5-yl]methyl}-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine (3.5 g, 8.15 mmol) is added EtOH (50 mL) and HCl (12 N, 50 mL) and the solution is heated at 90° C. for 16 h. The solution is cooled to 0° C. and basified using 5N NaOH slowly, followed by addition of EtOAc (100 mL). The organic layer is washed with sat. NaHCO3 (100 mL), brine (100 mL) and dried over Na2SO4. Concentration and vacuum drying affords the title compound as a white gummy foam. [mass expected (415.57); mass found (415.33)]
Reaction SMILES: [CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[CH:34]([CH3:35])[CH:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH:27](C(OC)=O)[C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45]>N1C(C)=CC=CC=1C>[CH3:1][CH2:2][C:3]1[C:21]2=[N:22][C:5](=[CH:6][C:7]3[NH:11][C:10]([CH:12]=[C:13]4[C@@H:34]([CH3:35])[C@H:33]([CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])[C:15]([C:16]5[CH2:27][C:25](=[O:26])[C:24]6[C:17]=5[NH:18][C:19]([C:23]=6[CH3:32])=[CH:20]2)=[N:14]4)=[C:9]([CH3:42])[C:8]=3[CH:43]=[CH2:44])[C:4]=1[CH3:45]
Reactant: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4C(=O)OC)C(CCC(=O)OC)C3C
Solvent: Cc1cccc(C)n1
Product: C=Cc1c(C)c2cc3nc(c4c5[nH]c(cc6nc(cc1[nH]2)C(C)=C6CC)c(C)c5C(=O)C4)[C@@H](CCC(=O)OC)[C@@H]3C
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of methyl pheophorbide-a (100 g, 165 mmol) in 2,6-lutidine (4 L) was added distilled water (40 mL, 2.22 mol, 13 equiv., 1% v/v) and the mixture was refluxed under argon with stirring. The reaction was monitored by HPLC (hexane-acetone, 90:10-mobile phase, LiChrospherCN-column, detection at 425 and 410 nm). The HPLC of reaction aliquot after 90 min showed 99.5% of completion. The solution was cooled to room temperature after 120 min of reflux and solvent removed under reduced pressure with water bath at 45-50° C. Hexane (120 mL) was added and the solid was collected by filtration and rinsed with hexane to remove any traces of 2,6-lutidine. The solid was vacuum dried to give methyl pyropheophorbide-a (89.6 g, 99%).
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:29])[C:27]=4[Cl:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:30].C1COCC1.[N:36]1([CH2:41][CH2:42][C:43]2[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][CH:44]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1>CCOC(C)=O.CCCCCC>[O:30]=[C:4]1[C:3](=[CH:2][NH:49][C:46]2[CH:47]=[CH:48][C:43]([CH2:42][CH2:41][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)=[CH:44][CH:45]=2)[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:29])[C:27]=4[Cl:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5]1
Reactant: Nc1ccc(CCN2CCCC2)cc1
Reactant: Cn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)c1Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(CCN4CCCC4)cc3)c2)c1Cl
Temperature: 65 °C
Reaction time: 24 h
Yield: 29 %

Procedure:
A small screw cap test tube was charged with 5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 328, 100 mg, 0.2365 mmol) and THF (2.5 mL). To the resulting solution was added 4-(2-Pyrrolidin-1-yl-ethyl)-phenylamine (45 mg, 0.236 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and diluted with EtOAc (˜5 mL) and Hexane (˜50 mL). The precipitate that formed was collected by filtration and washed with acetone (˜15 mL) to afford the title compound in 29% yield (0.041 g, 0.0689 mmol).
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.BrC[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1.[F:24][C:25]1[CH:26]=[C:27]([CH2:32][OH:33])[CH:28]=[CH:29][C:30]=1[F:31]>>[F:22][C:19]1[CH:20]=[C:21]([CH:16]=[CH:17][C:18]=1[F:23])[CH2:11][N:7]1[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=[C:2]([O:33][CH2:32][C:27]3[CH:28]=[CH:29][C:30]([F:31])=[C:25]([F:24])[CH:26]=3)[CH:12]=[C:6]12
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Reactant: OCc1ccc(F)c(F)c1
Reactant: Fc1ccc(CBr)cc1F
Product: O=c1nc(OCc2ccc(F)c(F)c2)cc2n1CCCN2Cc1ccc(F)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for E2 starting from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one, 4-(bromomethyl)-1,2-difluorobenzene and (3,4-difluorophenyl)methanol.
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH2:22])[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[F:24][C:25]1[CH:26]=[C:27]2[C:32](=[C:33]([F:35])[CH:34]=1)[CH2:31][C:30](=O)[CH2:29][CH2:28]2>>[CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH:22][CH:30]2[CH2:29][CH2:28][C:27]3[C:32](=[C:33]([F:35])[CH:34]=[C:25]([F:24])[CH:26]=3)[CH2:31]2)[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: Diast #1 (RT 12 min) 14.2, 19.5, 2.9, 26.0, 28.2, 28.9, 29.7, 36.5, 52.9, 55.5, 58.9, 60.9, 67.5, 68.9, 101.1, 104.5, 110.7, 131.2, 137.4, 172.4; MS m/z 490.3 (M+1). Diast#2 (RT 18 min)14.2, 19.6, 25.9, 26.0, 28.3, 28.9, 29.6, 36.5, 52.5, 55.5, 58.8, 60.4, 67.5, 68.9, 101.1, 104.5, 110.6, 131.2, 137.3, 172.2; MS m/z 490.3 (M+1). Chiral sep using a Kromasil TBB column, elute 95/5, heptane/IPA, flow rate 85 ml/min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([O:9][CH2:10][CH3:11])[N:3]=1.C(N(CC)CC)C.C(O)C.O.[NH2:23][NH2:24]>O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:23][NH2:24])[N:5]=[C:4]([O:9][CH2:10][CH3:11])[N:3]=1
Reactant: CCOc1nc(Cl)cc(Cl)n1
Reactant: NN
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOc1nc(Cl)cc(NN)n1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
A mixture of 50.0 g of 95 percent purity (0.246 mol) 4,6-dichloro-2-ethoxypyrimidine, 26.9 g (0.266 mol) of triethylamine, 200 mL of ethanol, and 200 g of water was prepared and cooled to 5° C. To this was added 13.4 g (0.266 mol) of hydrazine hydrate over a 15-min period with stirring and cooling at about 5° C. The mixture was stirred and allowed to warm to ambient temperature overnight. It became very thick, but approximately 10 percent of the starting material remained. Another 1.3 g (0.026 mol) of hydrazine hydrate was added and stirring was continued for another 4 hours. The solids that formed were recovered by vacuum filtration and were washed twice with 100 mL portions of water and then with 100 mL of acetonitrile. The title compound, which was obtained as a white powder melting at 170°-173° C., amounted to 43.9 g (88 percent of theory).
Reaction SMILES: CN1CCOCC1.Cl.[OH:9][CH2:10][CH2:11][CH2:12][CH2:13][C@@H:14]([C:16]([O:18][CH3:19])=[O:17])[NH2:15].[C:20]1(=[O:41])[N:24]([NH:25][C@H:26]([C:33](O)=[O:34])[CH2:27][C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)[C:23](=[O:36])[C:22]2=[CH:37][CH:38]=[CH:39][CH:40]=[C:21]12.OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C)C=O>[C:23]1(=[O:36])[N:24]([NH:25][C@H:26]([C:33]([NH:15][C@H:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:13][CH2:12][CH2:11][CH2:10][OH:9])=[O:34])[CH2:27][C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)[C:20](=[O:41])[C:21]2=[CH:40][CH:39]=[CH:38][CH:37]=[C:22]12
Reactant: O=C(O)[C@H](Cc1cccs1)NN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)[C@@H](N)CCCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CCCCO)NC(=O)[C@H](Cc1cccs1)NN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N-Methylmorpholine (1.51 ml., 14.5 mmol.) was added to a solution of 6-hydroxy-L-norleucine, methyl ester, hydrochloride (8.53 mmol.) in methylene chloride (34 ml)/dimethylformamide (9 ml.) at room temperature under argon. The resulting mixture was cooled to 0° C. and N-phthalimido-3-(2-thienyl)-L-alanine (2.57 g., 8.54 mmol.), hydroxybenzotriazole (1.19 g., 8.80 mmol.) and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (1.80 g., 9.4 mmol.) were added sequentially. After stirring at 0° C. for 30 minutes, the mixture was warmed to room temperature and stirred for 1.5 hours. The volatiles were evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was washed successively with 0.5 N hydrochloric acid, water, saturated sodium bicarbonate, and brine, and the organic layer was dried (sodium sulfate), filtered, and concentrated. The residue was flash chromatographed (Merck silica gel) eluting with 2:1 ethyl acetate/hexane to give 3.13 g. of title compound as a white foam. TLC (5% acetic acid in ethyl acetate) Rf =0.68.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH3:10])=[CH:4][C:3]=1[S:12]([NH:15][CH2:16][CH2:17][OH:18])(=[O:14])=[O:13].S1C=CN=C1.ClC1C=CC(CC(=O)C)=CC=1S(N)(=O)=O.ClC1C=CC(C2SC(NC3C=NC=CN=3)=NC=2C)=CC=1S(N)(=O)=O.[NH:63]1[CH:67]=[CH:66][C:65]([NH:68][C:69]([NH2:71])=[S:70])=[N:64]1>>[OH:18][CH2:17][CH2:16][NH:15][S:12]([C:3]1[CH:2]=[CH:7][CH:6]=[C:5]([C:8]2[S:70][C:69]([NH:68][C:65]3[CH:66]=[CH:67][NH:63][N:64]=3)=[N:71][C:9]=2[CH3:10])[CH:4]=1)(=[O:14])=[O:13]
Reactant: NC(=S)Nc1cc[nH]n1
Reactant: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)NCCO)c1
Agent: CC(=O)Cc1ccc(Cl)c(S(N)(=O)=O)c1
Agent: Cc1nc(Nc2cnccn2)sc1-c1ccc(Cl)c(S(N)(=O)=O)c1
Agent: c1cscn1
Product: Cc1nc(Nc2cc[nH]n2)sc1-c1cccc(S(=O)(=O)NCCO)c1

Procedure:
The titled compound was prepared from N-(2-hydroxy-ethyl)-3-(2-oxo-propyl)-benzenesulfonamide (43b) following the two-step procedure (bromination, thiazole formation) described for the conversion of 2-chloro-5-(2-oxo-propyl)-benzene-sulfonamide (33a) to 2-chloro-5-[4-methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonamide (33c) replacing pyrazin-2-yl-thiourea (1a) in the final step with (1H-pyrazol-3-yl)-thiourea (35a).
Reaction SMILES: C(N(CC)C(C)C)(C)C.O(P(O[C:27]1[CH2:28][C@@H:29]2[C@@H:39]([C@H:40]([OH:42])[CH3:41])[C:38](=[O:43])[N:30]2[C:31]=1[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH2:44]([O:47][C:48]([N:50]1[CH2:54][C@@H:53]([SH:55])[CH2:52][C@H:51]1[CH2:56][CH:57]1[CH2:61][CH2:60][NH:59][C:58]1=[O:62])=[O:49])[CH:45]=[CH2:46].C(OCC)(=O)C>C(#N)C>[CH2:44]([O:47][C:48]([N:50]1[CH2:54][C@@H:53]([S:55][C:27]2[CH2:28][C@@H:29]3[C@@H:39]([C@H:40]([OH:42])[CH3:41])[C:38](=[O:43])[N:30]3[C:31]=2[C:32]([O:34][CH2:35][CH:36]=[CH2:37])=[O:33])[CH2:52][C@H:51]1[CH2:56][CH:57]1[CH2:61][CH2:60][NH:59][C:58]1=[O:62])=[O:49])[CH:45]=[CH2:46]
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1CC1CCNC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](CC3CCNC3=O)N(C(=O)OCC=C)C2)C[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reaction time: 1 h
Yield: 76.7 %

Procedure:
N,N-diisopropylethylamine (0.13 ml, 0.76 mmol) was dropwise added to a solution of allyl (5R,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (369 mg, 0.76 mmol) and (2R,4S)-N-allyloxycarbonyl-4-mercapto-2-(2-pyrrolidon-3-ylmethyl)pyrrolidine (216 mg, 0.76 mmol) in acetonitrile (5.6 ml) under cooling with ice. The reaction mixture solution was stirred at the same temperature for one hour and further stirred at 5° C. for 16 hours. Ethyl acetate (60 ml) was added to the reaction solution. The mixture was washed sequentially with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel flash column chromatography (Wakogel™ C-300, 40 ml, acetone-ethyl acetate 2:3). The fraction containing the desired product was concentrated to obtain allyl (5R,6S)-2-[(2R,4S)-N-allyloxycarbonyl-2-(2-pyrrolidon-3-ylmethyl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-carbapen-2-em-3-carboxylate (303 mg, yield: 76.7%) in the form of foam.
Reaction SMILES: [O:1]([C:9]1[CH:10]=[C:11]([C@H:23]([OH:28])[CH2:24][N+:25]([O-])=O)[CH:12]=[CH:13][C:14]=1[O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[H][H]>CO.[Pd]>[O:1]([C:9]1[CH:10]=[C:11]([C@H:23]([OH:28])[CH2:24][NH2:25])[CH:12]=[CH:13][C:14]=1[O:15][Si:16]([C:19]([CH3:21])([CH3:20])[CH3:22])([CH3:18])[CH3:17])[Si:2]([C:5]([CH3:8])([CH3:6])[CH3:7])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@H](O)C[N+](=O)[O-])cc1O[Si](C)(C)C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H](O)CN)cc1O[Si](C)(C)C(C)(C)C
Yield: 93.3 %

Procedure:
98 mg of (S)-1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol obtained in example 10 was dissolved in 10 ml of methanol, and 10 mg of 10% Pd/C was added to the solution, after which the mixture was reacted at 20° C. under the hydrogen pressure of 0.3 MPa for 5 hours, so as to obtain 85 mg of the intended compound.
Reaction SMILES: Cl.[C:2]1([NH:12]N)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1CC=O)([O-:16])=[O:15].Cl.[C:27](O)(=O)[CH3:28]>>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:8]1[CH:9]=[CH:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[C:3]1[C:2]=2[NH:12][CH:28]=[CH:27]1)([O-:16])=[O:15]
Reactant: CC(=O)O
Reactant: O=CCc1ccccc1[N+](=O)[O-]
Reactant: NNc1cccc2ccccc12
Agent: Cl
Product: O=[N+]([O-])c1ccccc1-c1ccc2c(ccc3cc[nH]c32)c1
Yield: 32 %

Procedure:
A suspension of 4.24 g (22.5 mmol) of 1-naphthylhydrazine hydrochloride in acetic acid (35 ml) was slowly boiled and a solution of 3.4 g (20.6 mmol) of 2-nitrophenylacetaldehyde in acetic acid (15 ml) was dropped thereinto under stirring. After the completion of the dropping, the obtained mixture was heated under reflux for 1 hour. Then 20 ml of a mixture of 1 N hydrochloric acid with acetic acid was further added thereto and the obtained mixture was heated under reflux for additional 1 hour. After distilling off the solvent, the residue was dissolved by adding ethyl acetate thereto. The organic layer was washed successively with an aqueous solution of sodium hydrogencarbonate, water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography to thereby give 1.91 g (yield: 32%) of 7-(2-nitrophenyl)benz[g]indole. Then the obtained product was dissolved in ethyl acetate (60 ml) and 200 mg of platinum (IV) oxide was added thereto. Then catalytic reduction was effected under atmospheric pressure in a hydrogen atmosphere at room temperature to thereby give 1.7 g (yield: 99%) of 7-(2-aminophenyl)benz[g]indole.
Reaction SMILES: CC(P(C(C)(C)C)[C:6]1[C:11]([C:12]2C=CC=C[CH:13]=2)=[CH:10][CH:9]=[CH:8][CH:7]=1)(C)C.[C:22]1([C:28]#[C:29][P:30](=[O:35])([OH:34])[O:31][CH2:32][CH3:33])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(C1CCCCC=1)#C>[Au].ClC(Cl)C>[CH2:32]([O:31][P:30]1(=[O:34])[CH:29]=[C:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:13]=[C:12]([C:11]2[CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=2)[O:35]1)[CH3:33]
Reactant: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Reactant: CCOP(=O)(O)C#Cc1ccccc1
Agent: [Au]
Agent: C#CC1=CCCCC1
Solvent: CC(Cl)Cl
Product: CCOP1(=O)C=C(c2ccccc2)C=C(C2=CCCCC2)O1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
A gold (Ag(I)) catalyst {[Au(JohnPhos)NCCH3]+SbF6—} [JohnPhos:(2-biphenyl)di-tert-butylphosphine] (11.3 mg, 0.015 mmol) was put into a reaction container, and dichloroethane (0.4 mL) was added thereto. After stirring at room temperature for 5 minutes, ethyl hydrogen phenylethynylphosphonate (63.0 mg, 0.3 mmol) diluted with 0.5 mL of dichloroethane was added thereto. Then 1-ethynylcyclohex-1-ene (63.6 mg, 0.6 mmol) was put thereinto, followed by stirring at 30° C. for 18 hours, and when all of the starting materials disappeared in the TLC, the reaction was allowed to be completed. After the solvent was removed under low atmospheric pressure, the product was separated by chromatography to obtain 2-ethoxy-4-phenyl-6-1-cyclohexenyl-1,2-oxaphosphorin 2-oxide (58.8 mg, 62%) which is a title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[CH:9](O)[CH:8]([CH:11]([CH3:13])[CH3:12])[S:7][C:6]=2[C:14]=1[Cl:15].B(F)(F)F.CCOCC.[OH-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[C:3]([O:16][CH3:17])=[CH:4][C:5]2[CH:9]=[C:8]([CH:11]([CH3:12])[CH3:13])[S:7][C:6]=2[C:14]=1[Cl:15]
Reactant: COc1cc2c(c(Cl)c1Cl)SC(C(C)C)C2O
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOCC
Product: COc1cc2cc(C(C)C)sc2c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35.8 %

Procedure:
To 28.4 g of 6,7-dichloro-2,3-dihydro-3-hydroxy-2-isopropyl-5-methoxybenzo[b]thiophene in 139 ml of glacial acetic acid is added 35 ml of boron trifluoride etherate. The reaction is heated on a steam bath for 10 minutes and allowed to stir at room temperature for 90 min. The reaction is poured into a mixture of 250 ml of 10% sodium hydroxide solution and 150 ml of ice. The mixture is basified with 50% sodium hydroxide solution, diluted with 600 ml of water and extracted with four 300 ml-portions of ether. The combined ether extracts are washed with one 350 ml-portion of water, one 150 ml-portion of saturated sodium chloride solution and dried over magnesium sulfate to give 26.4 g of a clear, brown oil of high purity by thin-layer chromatography. A 10 g-portion of the oil is chromatographed on 500 ml of silica gel with ether:hexane (1:2) to give 9.55 g of 6,7-dichloro-2-isopropyl-5-methoxybenzo[b]thiophene as a clear, colorless oil which solidified to a low melting solid, mp <37°, pure thin-layer chromatography (silica gel, 1:1, ether-hexane or carbon tetrachloride).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:19])[NH:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:20]1([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(#N)C>[C:1]1([NH:7][C:8](=[O:19])[NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([N:23]3[CH2:22][CH2:21][N:20]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][CH2:24]3)=[O:16])=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Nc1ccccc1)Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(NC(=O)Nc3ccccc3)cc2)CC1
Yield: 67.1 %

Procedure:
To a solution of 4-(3-phenylureido)benzoic acid (13.5 g, 52.68 mmol) in acetonitrile (250 mL) at room temperature was added tert-butyl piperazine-1-carboxylate (11.8 g, 63.22 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (21.1 g, 156.5 mmol, HOBT) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (30 g, 156.5 mmol, EDCl). The mixture was stirred at reflux temperature for 16 hours and was then concentrated under vacuum. The residue was submitted to silica chromatography (0-5% ethyl acetate in n-hexanes as eluant) to give the title compound (15.0 g). MS (ESI) m/z 425.1 [M+H]+
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][NH:10][CH2:11][CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1.S1CCCS[CH2:19]1.Cl>C(COC)OC>[CH:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([CH2:9][N:10]2[CH2:19][C:17]3[CH:16]=[CH:15][S:14][C:13]=3[CH2:12][CH2:11]2)[CH:5]=1.[ClH:1]
Reactant: C1CSCSC1
Reactant: Clc1ccccc1CNCCc1cccs1
Agent: Cl
Solvent: COCCOC
Product: Clc1ccccc1CN1CCc2sccc2C1
Temperature: 10 °C
Yield: 62.7 %

Procedure:
N-[(2-chlorophenyl-methyl)]-2-(2-thienyl)ethylamine HCl (14.4 g) is suspended into 50 ml of dimethoxyethane. 1,3-Dithiane (9 g) and 0.12 ml of 37% hydrochloride acid are added. The reaction mixture is refluxed for 24 hours. Thereafter, the mixture is cooled to 10° C. and the crystalline precipitate is filtered and washed twice with 5 ml of dimethoxyethane. The product is dried at 60° C. under vacuum to yield 9.4 g (62.7%) of ticlopidine hydrochloride having the same physico-chemical characteristics as reported in Example 1.