Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=O)[CH2:7][CH:8]2[C:13](=O)[CH2:12][CH2:11][S:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:18][CH:19]([CH3:24])[CH2:20][N:21]([CH3:23])[CH3:22].[ClH:25]>Cl.C(O)C.CCOCC>[ClH:25].[CH3:22][N:21]([CH3:23])[CH2:20][CH:19]([N:18]1[C:6]([C:5]2[CH:16]=[CH:17][C:2]([Br:1])=[CH:3][CH:4]=2)=[CH:7][C:8]2[CH2:9][S:10][CH2:11][CH2:12][C:13]1=2)[CH3:24]
Reactant: O=C(CC1CSCCC1=O)c1ccc(Br)cc1
Reactant: CC(N)CN(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CC(CN(C)C)n1c(-c2ccc(Br)cc2)cc2c1CCSC2
Temperature: 5 °C

Procedure:
A solution of 5.5 g (0.017 mole) of 3-(4-bromophenacyl)-2,3,5,6-tetrahydrothiopyran-4-one [Example 2 (a)], 1.6 g of 2-amino-1-dimethylaminopropane, 16 ml. of ethanol, and one drop of concentrated hydrochloric acid is heated under reflux for 3 hours, cooled to 5°C, and filtered to provide a solid product. The resulting product is dissolved in ethanol, the solution is acidified with ethereal hydrogen chloride and diluted to the cloud point with ether. Upon standing, a solid separates. Recrystallization from ethanol gives off-white crystals of 1-(1-dimethylamino-2-propyl)-2-(4-bromophenyl)-1,4,6,7-tetrahydrothiopyrano[4,3-b]pyrrole hydrochloride, m.p. 237° to 238°C. dec.
Reaction SMILES: Br[C:2]1C(OCC2CC2)=NC=C(C=1)C(O)=O.[C:16]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)#[N:17].[CH:27]1([CH2:30][O:31][C:32]2[C:47](C3C=CC(F)=C(F)C=3)=[CH:46][C:35]([C:36]([NH:38][C@@H:39]3C[CH2:43][CH2:42][CH2:41][C@H:40]3[OH:45])=[O:37])=[CH:34][N:33]=2)[CH2:29][CH2:28]1>>[C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:47]2[C:32]([O:31][CH2:30][CH:27]3[CH2:28][CH2:29]3)=[N:33][CH:34]=[C:35]([CH:46]=2)[C:36]([NH:38][CH2:39][C@@:40]([CH:41]2[CH2:42][CH2:43]2)([OH:45])[CH3:2])=[O:37])=[CH:20][CH:19]=1)#[N:17]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: O=C(O)c1cnc(OCC2CC2)c(Br)c1
Reactant: O=C(N[C@@H]1CCCC[C@H]1O)c1cnc(OCC2CC2)c(-c2ccc(F)c(F)c2)c1
Product: C[C@](O)(CNC(=O)c1cnc(OCC2CC2)c(-c2ccc(C#N)cc2)c1)C1CC1

Procedure:
The title compound was synthesized from 5-bromo-6-cyclopropylmethoxy-nicotinic acid (example 31 a) by Suzuki reaction with 4-cyanophenyl-boronic acid (in analogy to 31 c) and amide coupling with (R)-α-(aminomethyl)-α-methyl-cyclopropanemethanol (WO 2006/106054) (in analogy to example 31 b), to give the title compound as a white solid, MS (ISP): 392.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1.[CH2:10]([O:12][C:13]([N:15]=[C:16]=[S:17])=[O:14])[CH3:11]>O1CCOCC1>[CH2:10]([O:12][C:13]([NH:15][C:16]([NH2:7])=[S:17])=[O:14])[CH3:11].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1
Reactant: CCOC(=O)N=C=S
Agent: COc1ccc(N)nc1
Solvent: C1COCCO1
Product: CCOC(=O)NC(N)=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 201.5 %

Procedure:
To 5-methoxypyridin-2-amine (5 g, 40 mmol) in dioxane (40 mL) was added ethoxycarbonyl isothiocyanate (5.23 mL, 44.3 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo to afford 5-methoxypyridin-2-amine ethoxycarbonyl thiourea (10.28 g, 40.3 mmol, 100% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 12.03 (1H, br. s.), 11.37 (1H, br. s.), 8.53 (1H, br. s.), 8.11 (1H, d, J=2.93 Hz), 7.50 (1H, dd, J=8.97, 3.11 Hz), 4.22 (2H, q, J=7.07 Hz), 3.84 (3H, s), 1.26 (3H, t, J=7.14 Hz). MS (LC/MS) R.T.=2.40; [M+H]+=256.1.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([Cl:8])=[C:4]2[NH:9][CH:10]=[N:11][C:3]=12.C(N(CC)CC)C.[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[CH:23][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:25][CH:26]=1>O1CCOCC1>[Cl:8][C:5]1[N:6]=[N:7][C:2]([N:30]2[CH2:31][CH2:32][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:34])([F:19])[F:33])=[CH:26][N:25]=3)[CH2:28][CH2:29]2)=[C:3]2[N:11]=[CH:10][NH:9][C:4]=12
Reactant: Clc1nnc(Cl)c2[nH]cnc12
Reactant: FC(F)(F)c1ccc(N2CCNCC2)nc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(N2CCN(c3nnc(Cl)c4[nH]cnc34)CC2)nc1
Temperature: 80 °C
Yield: 36.4 %

Procedure:
4,7-Dichloro-1H-imidazo[4,5-d]pyridazine (250 mg, 1.32 mmol) is combined with triethylamine (270 μL), dioxane (2 mL), and 1-(5-Trifluoromethyl-pyridin-2-yl)-piperazine (290 mg, 1.26 mmol). The reaction mixture is heated to 80° C. for 70 h. Concentrate in vacuo to remove dioxane. The residue is purified by flash chromatography on silica gel (MeOH/CH2Cl2) to afford the title compound (176 mg, 57%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:16]([CH3:19])([CH3:18])[CH3:17])=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:7]=1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:16]([C:5]1[CH:4]=[CH:3][C:2]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])=[CH:7][C:6]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1ccc(Oc2cc(Br)ccc2C(C)(C)C)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2cc(C#C[Si](C)(C)C)ccc2C(C)(C)C)cc1
Temperature: 75 °C

Procedure:
In a sealed tube vessel, a solution of 323 mg (1.0 mmol) of 5-bromo-2-tert-butyl-1-[(4′-methyl)phenoxy]benzene (Compound J) in 6 mL of triethylamine was sparged (with a stream of argon bubbled vigorously into the solution) for several minutes. To this solution was added 48 mg (0.25 mmol) of cuprous iodide and the resultant mixture was sparged with argon for several minutes. To this reaction mixture was then added 175 mg (0.25 mmol) of bis(triphenylphosphine)palladium(II) chloride. After sparging with argon for a couple of minutes, 1.1 mL (1.0 g, 10.1 mmol) of trimethylsilyl acetylene was added to the reaction mixture. The pressure tube was then sealed and heated in an oil bath (75° C.) for 4 days at which time an additional 178 mg (0.25 mmol) of bis(triphenylphosphine)palladium(II) chloride and 1.0 mL (0.9 g, 9.4 mmol) of trimethylsilyl acetylene were added. The reaction mixture was heated at 75° C. for days, filtered through celite and washed with ethyl ether (100 mL). The filtrate was extracted with water (3×75 mL-portions) and brine, dried over MgSO4, filtered and concentrated in vacuo to give a dark brown oil residue. Purification by flash chromatography (preabsorbed onto silica with 100% chloroform, eluted with 100% hexane) gave the title compound as a clear, colorless oil which solidified to a white solid. PMR (CDCl3): δ 0.19 (9 H, s), 1.39 (9 H, s), 2.34 (3 H, s), 6.84-6.91 (3 H, m), 7.10-7.17 (3 H, m), 7.29 (1 H, d, J=8.1 Hz).
Reaction SMILES: [H-].[Na+].[S:3]1[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7]=2[C:6](=[O:16])[CH:5]=[CH:4]1.[CH3:17]I>CCCCCC.CN(C)C=O>[CH3:17][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[C:15]2[S:3][CH:4]=[CH:5][C:6](=[O:16])[C:7]1=2
Reactant: CI
Reactant: O=c1ccsc2c1[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cn1c2ccccc2c2sccc(=O)c21
Reaction time: 3 h

Procedure:
Sodium hydride (2.3 g of 50% suspension in mineral oil, 0.05 mole) is washed with hexane and suspended in 25 ml of dimethylformamide (DMF). Thiopyrano [3,2-b]indol-4(5H)-one, 10.0 g (0.05 mole) in 130 ml of DMF is added and the mixture stirred for 3 hours. Methyl iodide (14.2 g, 0.1 mole) is added and the mixture stirred for 3 hours and then poured over ice. The white precipitate is filtered, dried and recrystallized from hexane to give 9.3 g of product, mp 113°-114° C.
Reaction SMILES: N(C(OC(C)(C)C)=O)[C@H:2]([C:12]([NH:14][C@H:15]([C:26]([NH:28][C@H:29]([C:42]([O:44][CH3:45])=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:36])=[O:27])[C@@H:16]([CH3:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:53]([C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[C@H:54]([C:59]([NH:61][C@H:62]([C:67]([NH:69]N)=[O:68])[CH2:63][CH:64]([CH3:66])[CH3:65])=[O:60])[CH2:55][C:56](=[O:58])[NH2:57]>>[NH:53]([C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[C@H:54]([C:59]([NH:61][C@H:62]([C:67]([NH:69][C@H:2]([C:12]([NH:14][C@H:15]([C:26]([NH:28][C@H:29]([C:42]([O:44][CH3:45])=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][NH:34][C:35]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:36])=[O:27])[C@@H:16]([CH3:25])[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:68])[CH2:63][CH:64]([CH3:66])[CH3:65])=[O:60])[CH2:55][C:56](=[O:58])[NH2:57]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)C(=O)NN
Reactant: COC(=O)[C@H](CCCCNC(=O)CCC(=O)O)NC(=O)[C@@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1
Product: COC(=O)[C@H](CCCCNC(=O)CCC(=O)O)NC(=O)[C@@H](NC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)OC(C)(C)C)[C@@H](C)OCc1ccccc1
Yield: 71.4 %

Procedure:
By using 3.60 g of Boc-Ser(Bzl)-Thr(Bzl)-Lys(CO-CH2CH2COOH)-OCH3 and 2.21 g of Boc-Asn-Leu-NHNH2, and the same procedure as in Reference Example 7 was repeated to obtain 3.37 g (yield: 71.4%) of the above-mentioned objective product.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH3:13][O:14][C:15]1[C:16]2[C:21]([C:22]([O:33][CH3:34])=[C:23]3[C:28]=1[CH:27]=[C:26]([S:29](Cl)(=[O:31])=[O:30])[CH:25]=[CH:24]3)=[CH:20][CH:19]=[CH:18][CH:17]=2.O1CCCC1>C(N(CC)CC)C>[CH3:13][O:14][C:15]1[C:16]2[C:21]([C:22]([O:33][CH3:34])=[C:23]3[C:28]=1[CH:27]=[C:26]([S:29]([O:1][N:2]1[C:3](=[O:12])[C:4]4=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]4[C:6]1=[O:7])(=[O:31])=[O:30])[CH:25]=[CH:24]3)=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: COc1c2ccccc2c(OC)c2cc(S(=O)(=O)Cl)ccc12
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1c2ccccc2c(OC)c2cc(S(=O)(=O)ON3C(=O)c4ccccc4C3=O)ccc12

Procedure:
A mixture of 0.98 g of N-hydroxyphthalimide, 2.02 g of 9,10-dimethoxyanthracene-2-sulfonyl chloride and 40 ml of tetrahydrofuran was stirred on an ice bath, and 0.34 g of triethylamine was added.
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH3:8])[CH2:3][NH:4][CH2:5][CH2:6][NH2:7].[NH:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1>>[NH:10]1[CH2:15][CH2:14][CH:13]([NH:7][CH2:6][CH2:5][NH:4][CH2:3][C:2]([NH2:1])([CH3:9])[CH3:8])[CH2:12][CH2:11]1
Reactant: O=C1CCNCC1
Reactant: CC(C)(N)CNCCN
Product: CC(C)(N)CNCCNC1CCNCC1

Procedure:
In a manner analogous to that described immediately hereinabove, by reacting N-(2-amino-2-methylpropyl)-1,2-ethanediamine with piperidin-4-one, it is reductively alkylated to yield N-(4-piperidyl)-N'-(2-amino-2-methyl-propyl)-1,2-ethanediamine; and, 2,2,6,6-piperidin-4-one is reductively alkylated to yield N-(2,2,6,6-tetramethyl-4-piperidyl)-N'-(2-amino-2-methylpropyl)-1,2-ethanediamine having the structure: ##STR15##
Reaction SMILES: IC.[Cl:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:7]=[C:6]([CH:15]2[CH2:17][CH2:16]2)[C:5]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25].[C:26](=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Cl:3][C:4]1[C:9]([O:10][CH3:26])=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:7]=[C:6]([CH:15]2[CH2:16][CH2:17]2)[C:5]=1[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[F:25]
Reactant: COC(=O)c1cc(C2CC2)c(-c2ccc(F)cc2F)c(Cl)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C2CC2)c(-c2ccc(F)cc2F)c(Cl)c1OC
Yield: 69.4 %

Procedure:
Iodomethane (1.04 g) was added at room temperature to a mixture of methyl 2-chloro-6-cyclopropyl-2′,4′-difluoro-3-hydroxybiphenyl-4-carboxylate (1.66 g), potassium carbonate (1.36 g), and DMF (30 mL), and the resultant mixture was stirred at 60° C. for 3 hours in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.20 g).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:30])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][C:20]=1[O:27][CH2:28][CH3:29])[CH3:16]>>[CH2:15]([O:17][C:18](=[O:30])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])=[CH:21][C:20]=1[O:27][CH2:28][CH3:29])[CH3:16]
Reactant: CCOC(=O)c1ccc(CBr)cc1OCC
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Product: CCCc1c(OCc2ccc(C(=O)OCC)c(OCC)c2)ccc(C(C)=O)c1O

Procedure:
1-(2,4-dihydroxy-3-propylphenyl)ethanone was allowed to react with 4-(bromomethyl)-2-ethoxybenzoic acid ethyl ester according to the procedure of Example 69 and the product was purified by HPLC to give 4-[(4-acetyl-3-hydroxy-2-propylphenoxy)methyl]-2-ethoxybenzoic acid ethyl ester, the title compound, m.p. 92°-94° in 83% yield.
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.CS([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[O:20])[CH2:14][CH2:13]1)(=O)=O>>[CH:1]1([S:4]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=3)=[O:20])[CH2:14][CH2:13]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: CS(=O)(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)NC1CCN(S(=O)(=O)C2CC2)CC1
Yield: 54.1 %

Procedure:
Cyclopropylsulfonyl chloride (75 mg, 0.536 mmol) was reacted with ITU (70 mg, 0.268 mmol) as the same manner as the synthesis of 1-(1-(methylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea yielding the final product (53 mg, 0.145 mmol, 54.1% yield). 1H NMR (d6-DMSO, 300 Mhz): δ 8.20 (s, 1H), 7.26 (d, J=6.9 Hz, 2H), 7.07 (d, J=7.5 Hz, 2H), 6.14 (d, J=7.8 Hz, 1H), 3.59 (m, 1H), 3.52 (d, J=12.8 Hz, 2H), 2.98 (t, J=11.4 Hz, 2H), 2.79 (m, 1H), 2.57 (m, 1H), 1.90 (d, J=12.3 Hz, 2H), 1.42 (m, 2H), 1.15 (d, J=6.6 Hz, 6H), 0.95 (m, 4H).
Reaction SMILES: ClC1C=CC=[C:4]([C:8](OO)=[O:9])C=1.C([C@H:15]1[NH:18][C:17](=[O:19])[C@H:16]1[C@H:20]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH3:21])(=O)C.C(=O)([O-])[OH:31].[Na+].CSC>C(OCC)(=O)C>[C:8]([O:19][C@H:17]1[NH:18][C:15](=[O:31])[C@H:16]1[C@H:20]([O:22][Si:23]([C:26]([CH3:27])([CH3:28])[CH3:29])([CH3:24])[CH3:25])[CH3:21])(=[O:9])[CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C([O-])O
Reactant: CC(=O)[C@H]1NC(=O)[C@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: [Na+]
Solvent: CSC
Solvent: CCOC(C)=O
Product: CC(=O)O[C@H]1NC(=O)[C@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
m-Chloroperbenzoic acid (0.5 g) is added to a solution of the object compound of Example 22 (0.08g) in ethyl acetate (8 ml), and the mixture is stirred at room temperature for 3 days and then poured into a mixture of ethyl acetate (50 ml), aqueous sodium hydrogen carbonate (20 ml) and dimethyl sulfide (0.4 ml). The mixture is stirred at room temperature for 30 minutes. The organic layer is separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (eluent: 15% ethyl acetate-85% hexane) to give 0.045 g of (3S,4R)-4-acetoxy-3-[(R)-1-(tert-butyldimethylsilyloxy)ethyl]-2-azetidinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:38](Cl)([O:40][C:41](=[O:47])OC(Cl)(Cl)Cl)Cl.[CH3:49][C:50]1[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][C:51]=1[S:57][CH:58](C)[CH2:59]O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:47])[O:40][CH2:38][CH2:59][CH2:58][S:57][C:51]2[CH:52]=[C:53]([CH3:56])[CH:54]=[CH:55][C:50]=2[CH3:49])=[CH:18][CH:17]=1
Reactant: Cc1ccc(C)c(SC(C)CO)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OCCCSc4cc(C)ccc4C)cc3)c2cc1OC
Temperature: 25 °C
Yield: 39.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (70 mg) was added to toluene/triethylamine=10/1 (7 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (105 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-[(2,5-dimethylphenyl)sulfanyl]-1-propanol (78 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (48 mg, yield 37%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16](O)[CH3:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15].P(Br)(Br)[Br:20].O>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:16]([Br:20])[CH3:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:15]
Reactant: CC(O)c1ccc(CC2CCCCC2=O)c(Cl)c1
Reactant: BrP(Br)Br
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1ccc(CC2CCCCC2=O)c(Cl)c1
Reaction time: 1 h

Procedure:
Forty (40) grams of 1-[3-chloro-4-(2-oxocyclohexane-1-yl methyl)phenyl]ethanol were dissolved in 300 ml of carbon tetrachloride and then incorporated dropwise with 44.7 g of phosphorus tribromide at a temperature of -15° to -10° C., after which the whole was stirred at said temperature for 30 minutes, withdrawn from the ice bath and then further stirred for one hour. After the completion of the reaction, the reaction mixture was water washed, dried and then freed of the solvent at a reduced pressure to obtain a residue. The residue was adhered to a silica gel-packed column and then eluted with isopropyl ether-hexane (1/2), after which the eluate was freed of the solvent thereby to obtain 46.5 g of 1-[3-chloro-4-(2-oxocyclohexane-1-yl methyl)phenyl]ethylbromide.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.[Cl:11][C:12]1[CH:13]=[C:14]([S:19](Cl)(=[O:21])=[O:20])[CH:15]=[C:16]([Cl:18])[CH:17]=1>N1C=CC=CC=1.O>[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[S:19]([C:14]1[CH:13]=[C:12]([Cl:11])[CH:17]=[C:16]([Cl:18])[CH:15]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cc(Cl)cc(Cl)c1
Reaction time: 19 h
Yield: 87.9 %

Procedure:
L-Proline methyl ester hydrochloride (2.68 g, 16.2 mmol) was dissolved in pyridine (20 mL), 3,5-dichlorophenylsulfonyl chloride (3.57 g, 14.6 mmol) was added and the mixture was stirred for 19 hr. Water (5 mL) was added and the mixture was stirred for 45 min before diluting with water (200 mL). The mixture was extracted with Et2O (2×150 mL) and the combined extracts were washed with water (3×100 mL), 1N HCl (150 mL) and saturated aq NaHCO3 (150 mL), then dried (MgSO4), filtered and evaporated in vacuo to give 3,5-dichlorophenyl-sulfonyl-L-proline methyl ester as an oil (4.34 g, 88%).
Reaction SMILES: NC(N)=[S:3].[ClH:5].Cl.[CH2:7]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][Cl:24])[CH2:17][CH2:16]1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.[OH-].[Na+]>O.C(O)C>[ClH:24].[ClH:5].[CH2:7]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][SH:3])[CH2:17][CH2:16]1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC(N)=S
Reactant: ClCCCN1CCN(CCc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: SCCCN1CCN(CCc2ccccc2)CC1
Yield: 81.6 %

Procedure:
The procedure described in Example 1(b) was followed, using 15.2 g of thiourea, 32.6 g of 1-phenethyl-4-(3-chloropropyl)piperazine dihydrochloride, 20.0 g of triethylamine and 250 ml of reagent ethanol The hydrolysis was effected with 10.0 g of sodium hydroxide in 40 ml of water. Work-up, as described above, gave 26.4 g (79% of theory) of 3-(4-phenethylpiperazin-1-yl)propanethiol dihydrochloride as an off-white crystalline solid, M.p. 269°-272° C.
Reaction SMILES: N[C:2]1SC=C(/C(=N/OC)/C(O)=O)N=1.O.ON1C2C=CC=CC=2N=N1.C1(N=[C:32]=[N:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)CCCCC1>CN(C)C=O>[CH3:2][N:33]([CH3:32])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 254 %

Procedure:
A mixture of 1.00 g (5.00 mmol) of (Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetic acid, 0.76 g (5.00 mmol) of 1-hydroxy-1H-benzotriazole hydrate, 1.14 g (5.50 mmol) of dicyclohexylcarbodiimide and 20 ml of N,N-dimethylformamide was stirred at room temperature for 2 hours. The obtained white solid was filtered and the filtrate was cooled to 0° C. The filtrate was added to mixed solution of 2.5 g (5.00 mmol) of 7-amino-3-(2,3-cyclopenteno-4-carbamoyl-1-pyridinium)methyl-3-cephem-4-carboxylate hydroiodic acid obtained in Preparation Example 24, 10 ml of N,N-dimethylformamide and 1.6 ml (12.70 mmol) of N,N-dimethylaniline. The mixture was stored at room temperature overnight and the precipitate was removed therefrom. The residue was dropped into 500 ml of diethylether with stirring. The precipitate was filtered, triturated with 100 ml of acetone and filtered again. The crude product thus obtained was dissolved in 100 ml of water and insoluble material was discarded by filtration. The resultant was freeze-dried to obtain 1.0 g of the same compound as obtained in Method a (yield: 37%).
Reaction SMILES: [CH:1]12[CH2:8][CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][NH:2]2.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[OH-].[Na+]>[C:9]([N:2]1[CH2:3][CH:4]2[CH2:7][CH2:8][CH:1]1[CH:6]=[CH:5]2)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C1=CC2CCC1CN2
Agent: [Na+]
Agent: [OH-]
Product: O=C(c1ccccc1)N1CC2C=CC1CC2
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 2-azabicyclo[2,2,2]-oct-5-ene (M. P. Cava et al, J. Org. Chem., 30, 3772 (1965)) (3.3 g) in aqueous 2.5N sodium hydroxide (50 ml) was added benzoyl chloride (6 ml) and the mixture stirred vigourously for 1 hour. Extraction into ether (2×100 ml), drying (Na2SO4) and concentration afforded the 2-benzoyl-2-azabicyclo[2,2,2]oct-5-ene (D1a) (3.7 g, 55%).