Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CO[C:8]23OCC[O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@H:17]([NH:28][C:29](=[O:31])[CH3:30])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])O1.C([C@@H]1C2[C@](C)(CCC(=[O:52])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[C:29]([NH:28][C@@H:17]1[CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:52])[CH2:19]2)[C@@H:25]2[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:12])[CH2:8][CH2:7]3)[CH2:16]1)(=[O:31])[CH3:30]
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: CC(=O)N[C@H]1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Product: CC(=O)N[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Yield: 96 %

Procedure:
The title compound II-bd was prepared in 96% yield from 3,3:17,17-bis(ethylendioxy)-6α-acetamidoandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 7.61 (d, 1H), 3.67 (m, 1H), 2.51-0.68 (m, 20H), 1.78 (s, 3H), 1.04 (s, 3H), 0.80 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[CH:4][C:5]2[C:9]([CH3:10])=[CH:8][S:7][C:6]=2[C:11]=1[Cl:12].Br[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].CC(=O)CC>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:13][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][C:5]2[C:9]([CH3:10])=[CH:8][S:7][C:6]=2[C:11]=1[Cl:12]
Reactant: CCOC(=O)CBr
Reactant: Cc1csc2c(Cl)c(Cl)c(O)cc12
Solvent: CN(C)C=O
Solvent: CCC(C)=O
Product: CCOC(=O)COc1cc2c(C)csc2c(Cl)c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
A mixture of 3.7 g of 6,7-dichloro-5-hydroxy-3-methylbenzo[b]thiophene, 4.3 g of ethyl bromoacetate and 20 ml of 2-butanone containing 5 ml of dimethylformamide is stirred at 60°-70° for 2 hours. The cooled mixture is diluted with ice-water and extracted 3 times with ether. The combined ether extract is dried over anhydrous magnesium sulfate and concentrated under vacuum to a brownish oil. Purification of the crude product is effected by column chromatography (alumina/ether). The purified ester is recrystallized from ether-pentane to give 4.3 g of ethyl [(6,7-dichloro-3-methylbenzo[b]thien-5-yl)oxy]acetate as fluffy needles, mp 115°-117°.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[CH3:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[C:10]=1[N:16]=[C:17]=[S:18].C(N(CC)CC)C>C(Cl)Cl>[CH3:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([CH3:8])[C:10]=1[N:16]1[C:5](=[O:7])[CH2:4][N:3]([CH2:1][CH3:2])[C:17]1=[S:18]
Reactant: CCNCC(=O)O
Reactant: Cc1cccc(C)c1N=C=S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2c(C)cccc2C)C1=S
Yield: 18.4 %

Procedure:
A mixture of N-ethyl glycine (9.2 g), 2,6-dimethylphenyl-isothiocyanate (8.2 g), triethylamine (10.1 g), and methylene chloride (150 mL) was heated at reflux for 3.5 hours. The mixture was evaporated to dryness. Purification was achieved through crystallization from ethanol. The title compound (2.3 g) was obtained as a white solid (2.3 g). m.p. 128°-131° C. Anal. Calcd. for. C13H16N2OS: C, 62.87; H, 6.49; N, 11.28. Found: C, 62.83; H, 6.50; N, 11.25. Mass spectrum (EI, M.+) m/z 248.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]=[C:4]([CH:8]=O)[CH2:3]1.O.[NH2:11][NH2:12]>CCCCO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]2[NH:11][N:12]=[CH:8][CH:4]2[CH2:3]1
Reactant: CN1CCC=C(C=O)C1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: CN1CCC2NN=CC2C1

Procedure:
3.2 g 1-Methyl-1,2,5,6-tetrahydro-pyridine-3-carbaldehyde was dissolved in 10 mL n-BuOH. Added were 2 equiv. of hydrazine hydrate, the mixture was refluxed for 24 hours and subsequently concentrated in vacuo. The residue was taken up in DCM and extracted with 2M NaOH, and the organic phase was dried over Na2SO4, filtrated and concentrated in vacuo to yield 1.78 g of a brown oil which was used without further purification in the subsequent step.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=O.Cl.[NH2:27][OH:28].C[O-].[Na+].CO.Cl>O1CCOCC1>[OH:28][NH:27][C:3]([C:5]1[S:9][C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:7][CH:6]=1)=[O:2]
Reactant: COC(=O)c1cnc(N2CCN(S(=O)(=O)c3ccc(F)cc3)CC2)s1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NO)c1cnc(N2CCN(S(=O)(=O)c3ccc(F)cc3)CC2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound (12m) (125 mg, 0.320 mmol) in 1,4-dioxane (2 mL) were added hydroxylamine hydrochloride (225 mg, 3.20 mmol) and a freshly prepared solution of sodium methoxide in methanol (110 mg, 4.80 mmol of sodium dissolved in 1 mL of methanol) under a N2 atmosphere. The reaction mixture was stirred at room temperature for 2 h (progress of the reaction was monitored by TLC analysis). The reaction mixture was acidified to pH˜6 with 1M HCl and the formed precipitates were filtered off. The filtrate was diluted with ethylacetate (5 mL) and water (2 mL) and the organic layer was separated. The aqueous layer was washed with ethylacetate (5 mL) and the combined organic layers were dried on sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 13m. HPLC: (Rt=3.89 min).
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:7][CH2:6][CH:5]([CH2:8][CH:9]=[C:10]([C:19]2([C:22]([F:25])([F:24])[F:23])[CH2:21][CH2:20]2)[O:11][Si](CC)(CC)CC)[CH2:4][CH2:3]1.[Br:27]Br>ClCCl>[Br:27][CH:9]([CH2:8][CH:5]1[CH2:6][CH2:7][C:2]([F:26])([F:1])[CH2:3][CH2:4]1)[C:10]([C:19]1([C:22]([F:25])([F:24])[F:23])[CH2:21][CH2:20]1)=[O:11]
Reactant: CC[Si](CC)(CC)OC(=CCC1CCC(F)(F)CC1)C1(C(F)(F)F)CC1
Reactant: BrBr
Solvent: ClCCl
Product: O=C(C(Br)CC1CCC(F)(F)CC1)C1(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
{3-(4,4-Difluorocyclohexyl)-1-(1-trifluoromethylcyclopropyl)prop-1-enyloxy}triethylsilane (3.00 g, 7.53 mmol) obtained in step 4 was dissolved in dichloromethane (30 mL). Under ice-cooled condition, a dichloromethane solution (10 mL) of bromine (1.32 g, 8.28 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with hexane after adding a saturated sodium hydrogen carbonate aqueous solution, and a sodium thiosulfate aqueous solution. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10→80/20) to give 2-bromo-3-(4,4-difluorocyclohexyl)-1-(1-trifluoromethylcyclopropyl)propan-1-one (2.69 g, yield 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([S:13][C:14]([F:17])([F:16])[F:15])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.[N+:18]([O-:21])([OH:20])=[O:19]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([S:13][C:14]([F:15])([F:17])[F:16])=[CH:11][C:12]=2[N+:18]([O-:20])=[O:19])=[CH:6][CH:7]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10]([S:13][C:14]([F:16])([F:15])[F:17])=[C:11]([N+:18]([O-:21])=[O:19])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)Sc1ccc(-c2ccc(Cl)cc2)[nH]1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(-c2ccc(Cl)cc2)[nH]c1SC(F)(F)F
Product: O=[N+]([O-])c1cc(SC(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 2-(p-chlorophenyl)-5-[(trifluoromethyl)thio]pyrrole (1.0 g, 0.0036 mol) in acetic acid is cooled with an ice bath, treated with nitric acid (0.24 g, 0.00378 mol), stirred for two hours, poured into ice-water and stirred for one hour. The aqueous solution is filtered and the filter cake is washed with water and dried in a vacuum dessicator to obtain a tan solid. Flash chromatography of the solid using silica gel and a 1:10 ethyl acetate/hexanes solution gives 2-(p-chlorophenyl)-3-nitro-5-[(trifluoromethyl)thio]pyrrole as a yellow solid (0.45 g, mp 143°-145° C.) and 5-(p-chlorophenyl)-3-nitro-2-[(trifluoromethyl)thio]pyrrole as a yellow solid (0.17 g, mp 185°-193° C.). Both products are identified by 1HNMR, 19FNMR and 13CNMR spectral analyses.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[N:21]1[C:30]2[C:25](=[CH:26][C:27]([CH2:31][NH2:32])=[CH:28][CH:29]=2)[N:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:32][CH2:31][C:27]4[CH:26]=[C:25]5[C:30](=[CH:29][CH:28]=4)[N:21]=[CH:22][CH:23]=[N:24]5)[C:3]=3[CH2:11]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Reactant: NCc1ccc2nccnc2c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(NCc4ccc5nccnc5c4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (100 mg, 0.35 mmol) and quinoxalin-6-ylmethanamine (150 mg, 0.94 mmol) in acetonitrile (1 mL) and N,N-diisopropylethylamine (500 μL, 3 mmol) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by preparative HPLC (30-60% acetonitrile-water [10 mM DEA]) to afford a light yellow solid.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH:3]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14]C)[CH:10]=2)[CH:5]=1.B(Br)(Br)Br.CO.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:27][C:2]([F:1])([F:26])[CH:3]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH3:25])=[O:23])[CH2:18][CH2:17]1)[C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:14])[CH:10]=2)[CH:5]=1
Reactant: COC(=O)C1CCN(C(c2ccc3cc(OC)ccc3c2)C(F)(F)F)CC1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1CCN(C(c2ccc3cc(O)ccc3c2)C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 48.2 %

Procedure:
To a solution of methyl 1-(2,2,2-trifluoro-1-(6-methoxynaphthalen-2-yl)ethyl)piperidine-4-carboxylate (500 mg, 1.3 mmol) in DCM (10 mL) was added BBr3 (3 N in DCM, 0.9 mL, 2.6 mmol, 2 eq) at 0° C. Then the reaction mixture was stirred at 0° C. for 5 h. Methanol (5 mL) was added into the mixture. The reaction was stirred at room temperature for another 2 h, and then was poured into the NaHCO3 aqueous solution, extracted with DCM (10 mL*3). The combined organic layers were washed with water (5 mL*3) and concentrated to give the crude product, which was purified by chromatography (Petroleum ether:ethyl acetate=1:1) to give methyl 1-(2,2,2-trifluoro-1-(6-hydroxynaphthalen-2-yl)ethyl)piperidine-4-carboxylate as a yellow solid (230 mg, yield: 47%). ESI-MS (M+1)+: 368.1. 1HNMR (400 MHz, CDCl3) δ: 7.69-7.67 (m, 2H), 7.60 (d, J=8.4 Hz, 1H), 7.37 (d, J=8.8 Hz, 1H), 7.09-7.05 (m, 2H), 4.13 (q, J=8.8 Hz, 1H), 3.59 (s, 3H), 2.97-2.90 (m, 2H), 2.39-2.37 (m, 1H), 2.19-2.17 (m, 2H), 1.72-1.59 (m, 4H).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][CH:9]([NH:24][C:25]([C:27]2[NH:28][C:29]3[C:34]([CH:35]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:26])[C:8]1=[O:36].[C:37]1(=[O:47])[NH:41][C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12.[K].CN(C)C=O>O>[C:37]1(=[O:47])[N:41]([CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:10][CH:9]([NH:24][C:25]([C:27]3[NH:28][C:29]4[C:34]([CH:35]=3)=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])[C:8]2=[O:36])[C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCOCCCl)C1=O)c1cc2ccccc2[nH]1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2N(CCOCCN2C(=O)c3ccccc3C2=O)C1=O)c1cc2ccccc2[nH]1
Temperature: 85 °C
Reaction time: 7 h
Yield: 105.3 %

Procedure:
A mixture of (3RS)-1-[2-(2-chloroethoxy)ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzo-diazepine-2-one (700 mg), potassium phthalimide (610 mg) and N,N-dimethylformamide (5 ml) was stirred for 7 hours at 80-90° C. The reaction mixture was poured into a cold water (100 ml) and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and evaporated to give (3RS)-1-[2-(2-phthalimidoethoxy) ethyl]-1,3-dihydro-3-(2-indolylcarbonylamino)-5-phenyl-2H-1,4-benzodiazepine-2-one (0.9 g).
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].N[C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][C:7]=1[Cl:15].Cl>O>[Cl:15][C:7]1[CH:8]=[C:9]([C:12](=[O:14])[CH3:13])[CH:10]=[CH:11][C:6]=1[N+:1]([O-:3])=[O:2]
Reactant: O=N[O-]
Reactant: CC(=O)c1ccc(N)c(Cl)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=O)c1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
A solution of sodium nitrite (1.63 g) in water (4.3 ml) was added dropwise to a solution of 4'-amino-3'-chloroacetophenone (2.5 g) and concentrated hydrochloric acid (5.5 ml) in water (5.5 ml) at 0° to 3° C., and the solution was stirred for 15 minutes at 0° C. The resulting solution was added portionwise to a mixture of sodium nitrite (7.3 g) and cuprous oxide (0.76 g) in water (32 ml) at -5° to 0° C. The mixture was stirred for 1 hour at 0° C. and for 1 hour at room temperature, and extracted with chloroform. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (60 g) eluting with chloroform. The fractions containing the desired compound were combined and concentrated under reduced pressure to give pale yellow crystals of 3'-chloro-4'-nitroacetophenone (2.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.C([Li])(CC)C.C1CCCCC1.C[O:45][B:46]([O:48]C)F>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([F:10])([F:11])[F:12])=[C:6]([B:46]([OH:48])[OH:45])[CH:7]=1
Reactant: COB(F)OC
Reactant: FC(F)(F)Oc1ccc(Cl)cc1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: OB(O)c1cc(Cl)ccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the 4-chloro(trifluoromethoxy)benzene (2.0 g, 10.18 mmol) in dry tetrahydrofuran (THF, 30 ml) at −78° C., was added ethylenediaminetetraacetic acid (EDTA, 1.24 g, 10.7 mmol) followed by a 1.3 M solution of sec-butyllithium in cyclohexane (7.63 ml, 10.7 mmol) and the reaction stirred for 2 hours under nitrogen. To this reaction mixture at −78° C., was then added dropwise the preformed dimethoxyfluoroborane mixture. The reaction was stirred at −78° C. for 30 minutes, warmed to room temperature for 30 minutes, and then quenched with water (10 ml). The reaction mixture was extracted with diethyl ether (4×50 ml). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. To purify, the residue was dissolved in diethyl ether (10 ml) and washed with an aqueous solution of 10% NaOH (50 ml). The aqueous layer was acidified and extracted with ethyl acetate (3×40 ml). The combined ethyl acetate extracts were dried over MgSO4 and concentrated in vacuo to afford a mixture of the title compound and its corresponding regioisomer as a white solid (0.862 g).
Reaction SMILES: [C:1]1(=[O:8])O[C:5](=[O:6])[CH:4]=[C:2]1[CH3:3].[CH3:9][C:10]1([CH3:19])[C@H:15]2[CH2:16][C@@H:11]1[CH2:12][CH2:13][C@H:14]2CN.[N:20]1C=CC=C[CH:21]=1>>[CH3:19][C:10]1([CH3:9])[CH:11]2[CH2:16][CH:15]1[CH2:14][CH:13]([CH2:21][N:20]1[C:5](=[O:6])[CH:4]=[C:2]([CH3:3])[C:1]1=[O:8])[CH2:12]2
Reactant: c1ccncc1
Reactant: CC1(C)[C@H]2CC[C@@H](CN)[C@@H]1C2
Reactant: CC1=CC(=O)OC1=O
Product: CC1=CC(=O)N(CC2CC3CC(C2)C3(C)C)C1=O
Temperature: 90 °C

Procedure:
A solution of citraconic anhydride (0.1 M) in pyridine (20 ml)was treated with (−)-cis-myrtanylamine (0.1 M). The reaction mixture was heated to 90° C. for six hours. The reaction mixture was then concentrated in vacuo and the residue was extracted into ethyl acetate. The ethyl acetate layer was washed with water and with cold aqueous hydrochloric acid, then dried over sodium sulphate and finally concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([C:8](=[N:16][OH:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].O>CN(C)C=O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:8](=[N:16][O:17][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)CBr
Reactant: ON=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CON=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.45 g., 80% w/w suspension in mineral oil) was added gradually to a stirred solution of 4,4'-dichlorobenzophenone oxime (4.0 g.) in dry dimethylformamide (20 ml.) keeping the temperature below 30° C. After 30 minutes, ethyl bromoacetate (1.7 ml.) was added to the stirred solution and the temperature was allowed to rise to 30° C. After 16 hours stirring at ambient temperature the mixture was poured into water (100 ml.) and the subsequent mixture was extracted with ether. The combined extracts were washed with water, dried (MgSO4) and evaporated to give ethyl di-(4-chlorophenyl)methyleneamino-oxyacetate, as an oil (3.8 g.), essentially pure and having a characteristic ester absorption at 1740-1760 cm-1 in the infra-red spectrum.
Reaction SMILES: C(OC([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:28])[CH:14]([NH:16][C:17](=[O:27])[C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=1)[CH3:15])=O)(C)(C)C.[O:29]=[C:30]1[O:34][CH:33]([O:35][CH2:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40]C=2)[CH:32]([NH:44][C:45](C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=[O:46])[CH2:31]1>>[CH2:36]([O:35][CH:33]1[CH:32]([NH:44][C:45]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:28])[CH:14]([NH:16][C:17](=[O:27])[C:18]2[CH:23]=[CH:22][C:21]([N:24]([CH3:25])[CH3:26])=[CH:20][CH:19]=2)[CH3:15])=[O:46])[CH2:31][C:30](=[O:29])[O:34]1)[C:37]1[CH:38]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Reactant: CC(NC(=O)c1ccc(N(C)C)cc1)C(=O)N1CCCC1C(=O)OC(C)(C)C
Product: CC(NC(=O)c1ccc(N(C)C)cc1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Yield: 45 %

Procedure:
Prepared from 1-(2-(4-dimethylamino-benzoylamino)-propionyl]-pyrrolidine-2-carboxylic acid tert-butyl ester and syn-(2-benzyloxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester according to the procedure used to prepare 98a to afford 60 mg (45% yield). 1H-NMR (500 MHz, CDCl3): δ 1.04 (d, 0.75H), 1.35 (d, 2.25H), 1.80-2.50 (m, 5H), 2.75-3.20 (m, 8H), 3.45-3.75 (m, 2H), 4.05-4.20 (m, 0.5H), 4.30-4.80 (m, 3.5H), 4.80-4.95 (m, 1.5H), 5.52 (d, H), 5.75-6.00 (m, 0.5H), 6.60-6.90 (m, 3H), 7.10-7.50 (m, 4H), 7.50-7.80 (m, 2H); retention time on analytical HPLC: 10.46 min; LC-MS: m/z=523 (M+H+).
Reaction SMILES: C(O)(=O)C.[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([O:14]CC(Cl)(Cl)Cl)=[O:13])[N:9]2[C:20](=[O:31])[CH:21]([NH:22][C:23](=[O:30])[CH2:24][C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[C@H:8]2[S:7]1>CN(C)C=O.[Zn]>[CH3:5][CH:6]1[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[N:9]2[C:20](=[O:31])[CH:21]([NH:22][C:23](=[O:30])[CH2:24][C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[C@H:8]2[S:7]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S1
Yield: 92.6 %

Procedure:
Acetic acid (3 ml) and zinc powder (2.4 g) were added under stirring and ice-cooling to a solution of 2,2,2-trichloroethyl 2-methyl-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylate (1.8 g) in anhydrous dimethyl-formamide (10 ml), and the mixture was stirred for 1 hour at the same temperature. After the reaction, zinc powder was filtered off, and the filtrate was extracted by pouring into a mixture of 5% hydrochloric acid (50 ml) and ethyl acetate (40 ml). The ethyl acetate layer was washed with water and dried. After the solvent was distilled off, the residue was dissolved in ether and allowed to stand, after which the precipitating crystals were collected by filtration and dried to give 2-methyl-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylic acid (1.2 g), mp 175° C. (dec.).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH2:7]([O:9][C:10]([C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:15]2[CH:28]=[CH:29][S:30][C:14]=2[C:13]=1O)=[O:11])[CH3:8].CN(C=O)C>C(Cl)Cl>[CH2:7]([O:9][C:10]([C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:15]2[CH:28]=[CH:29][S:30][C:14]=2[C:13]=1[Cl:4])=[O:11])[CH3:8]
Reactant: CCOC(=O)c1c(O)c2sccc2n(Cc2ccc(OC)cc2)c1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1c(Cl)c2sccc2n(Cc2ccc(OC)cc2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
Oxalyl chloride (4.8 mL, 55 mmol) was added to a solution of 7-hydroxy-4-(4-methoxybenzyl)-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester (54) (9.87 g, 27 mmol) in dry CH2Cl2 at 0° C. After adding anhydrous DMF (0.5 mL), the solution was allowed to come at room temperature and was further stirred at room temperature for 24 h. Excess solvent was evaporated to yield 7-chloro-4-(4-methoxybenzyl)-5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid ethyl ester as off white solids. Yield 85%; 1H NMR (400 MHz, DMSO-d6) δ 1.30 (t, J=7.2 Hz, 3H), 3.70 (s, 3H), 5.36 (s, 2H), 6.88 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 7.53 (d, J=5.6 Hz, 1H), 8.20 (d, J=5.6 Hz, 1H ppm; MS m/z=378 amu (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[NH2:25][C@@H:26]1[CH2:30][CH2:29][N:28]([C:31](=[O:35])[C@H:32]([OH:34])[CH3:33])[CH2:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:34][C@H:32]([CH3:33])[C:31]([N:28]1[CH2:29][CH2:30][C@@H:26]([NH:25][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:19]=2)=[O:21])[CH2:27]1)=[O:35]
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: C[C@@H](O)C(=O)N1CC[C@@H](N)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](O)C(=O)N1CC[C@@H](NC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(Cl)cc4s2)n3C)C1
Yield: 28.8 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [(R)-1-((R)-2-hydroxy-propionyl)-pyrrolidin-3-yl]amide (20 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (50 mg), (R)-1-((R)-3-amino-pyrrolidin-1-yl) 2-hydroxy-propan-1-one (100 mg), HBTU (150 mg), and DIEA (100 uL) in DMF (1 mL). LC/MS: m/z 498.6.