Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[CH:38]=[CH:37][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:34]=[CH:33][C:24]([CH2:25][CH:26]5[S:30][C:29](=[O:31])[NH:28][C:27]5=[O:32])=[CH:23][CH:22]=4)[N:16]([CH3:35])[C:15]=3[CH:36]=2)=[CH:8][CH:7]=1.C(N(CC)CC)C.[F:46][C:47]1[CH:52]=[C:51]([F:53])[CH:50]=[CH:49][C:48]=1[N:54]=[C:55]=[O:56]>CN(C)C=O>[F:46][C:47]1[CH:52]=[C:51]([F:53])[CH:50]=[CH:49][C:48]=1[NH:54][C:55]([NH:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]3[N:18]=[C:17]([CH2:19][O:20][C:21]4[CH:34]=[CH:33][C:24]([CH2:25][CH:26]5[S:30][C:29](=[O:31])[NH:28][C:27]5=[O:32])=[CH:23][CH:22]=4)[N:16]([CH3:35])[C:15]=3[CH:36]=2)=[CH:37][CH:38]=1)=[O:56]
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCN)cc3)cc21
Reactant: O=C=Nc1ccc(F)cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(CCNC(=O)Nc4ccc(F)cc4F)cc3)cc21
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 58.3 %

Procedure:
To a mixture of 5-[4-[6-[4-(2-aminoethyl)phenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (0.3 g), triethylamine (65 mg) and anhydrous N,N-dimethylformamide (5 ml) was added 2,4-difluorophenyl isocyanate (81 mg) and the mixture was stirred at room temperature for 4.5 hours and then allowed to stand for 2 days. The reaction mixture was concentrated and diluted with water and tetrahydrofuran and then extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. To the residue was added ethyl acetate and the precipitate was isolated by filtration and washed with ethyl acetate to afford the title compound (0.2 g, mp 161-164° C.).
Reaction SMILES: [OH:1][CH:2]([C:4]1([OH:27])[CH2:21][CH2:20][CH:19]2[CH:6]([C:7](=[O:26])[C:8]3[C:17]([CH2:18]2)=[C:16]([O:22][CH3:23])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=3[O:24][CH3:25])[CH2:5]1)[CH3:3]>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[C:2]([C:4]1([OH:27])[CH2:21][CH2:20][CH:19]2[CH:6]([C:7](=[O:26])[C:8]3[C:17]([CH2:18]2)=[C:16]([O:22][CH3:23])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]=3[O:24][CH3:25])[CH2:5]1)(=[O:1])[CH3:3]
Reactant: COc1c2c(c(OC)c3ccccc13)C(=O)C1CC(O)(C(C)O)CCC1C2
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: COc1c2c(c(OC)c3ccccc13)C(=O)C1CC(O)(C(C)=O)CCC1C2
Yield: 100.5 %

Procedure:
0.1 g of 1,2,3,4,4a,5,12,12a-octahydro-2-(1-hydroxyethyl)-2-hydroxy-6,11-dimethoxy-12-oxo -naphthacene, prepared as described in Example 12, in benzene was treated with 1 g of silver carbonate at refluxing temperature. After filtering off the inorganic solids and removing the solvent, 0.1 g of the title product was obtained.
Reaction SMILES: [CH3:1][C:2]12[CH2:7][CH:6]1[CH2:5][CH:4]([CH2:8][CH:9]=O)[C:3]2([CH3:12])[CH3:11].[CH:13](=[O:17])[CH2:14][CH2:15][CH3:16].[O-]CC.[Na+].[Na]>C(O)C>[CH2:15]([C:14](=[CH:9][CH2:8][CH:4]1[CH2:5][CH:6]2[C:2]([CH3:1])([CH2:7]2)[C:3]1([CH3:12])[CH3:11])[CH:13]=[O:17])[CH3:16]
Reactant: CC1(C)C(CC=O)CC2CC21C
Reactant: CCCC=O
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCC(C=O)=CCC1CC2CC2(C)C1(C)C
Yield: 37.7 %

Procedure:
The condensation of 20.0 g (0.12 mol) of (1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)ethanal with 17.0 g (0.24 mol) of butyraldehyde catalyzed with sodium ethoxide prepared from 0.25 g of sodium in 35 ml of ethanol, according to Example 15, gave 9.98 g (38% yield) of 2-ethyl-4-(1,2,2-trimethylbicyclo[3.1.0]hex-3-yl)but-2-enal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][N:4]=1.[Li]C.[CH:15](N1CCCCC1)=[O:16]>C1COCC1.C(NC(C)C)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:6]([O:9][CH2:10][O:11][CH3:12])=[CH:5][N:4]=1)[CH:15]=[O:16]
Reactant: O=CN1CCCCC1
Reactant: COCOc1ccc(OC)nc1
Agent: [Li]C
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCOc1cnc(OC)cc1C=O
Temperature: -40 °C
Reaction time: 3 h
Yield: 42.3 %

Procedure:
To a solution of 2-methoxy-5-(methoxymethoxy)pyridine (20 g, 0.12 mol) in THF was added diisopropylamine (0.24 g, 2.4 mmol). The solution was cooled to −40° C. followed by addition of MeLi (3M/THF, 72 mL, 0.216 mol) slowly. The resulting mixture was warmed to 0° C., stirred at 0° C. for 3 h, cooled back down to −40° C. and added N-formylpiperidine (24 mL, 0.216 mol). After stirring at −40° C. for 2 h, the mixture was quenched with a mixed solution of HCl (37%, 120 mL) and THF (250 mL). The temperature was then raised to rt and diluted with water (200 mL) and EtOAc (200 mL). The pH of the mixture was adjusted to 8-9 with solid K2CO3 and extracted with EtOAc (300 mL) twice. The organic layer was combined, dried over Na2SO4, and concentrated. The residue was purified on silica gel with 25% EtOAc/hexanes as eluent to give 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (10 g, 42%) as a pale yellow oil. 1H NMR (400 MHz; CD3OD) 7.90 (s, 1H), 6.92 (s, 1H), 5.64 (s, 1H), 5.20 (s, 2H), 3.84 (s, 3H), 3.48 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:13])=[CH:5][C:6]=1[C:7](N(OC)C)=[O:8].[C:14]1([Mg]Br)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)C.[Cl-].[NH4+]>C1COCC1>[C:7]([C:6]1[CH:5]=[C:4]([Cl:13])[S:3][C:2]=1[Cl:1])(=[O:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CON(C)C(=O)c1cc(Cl)sc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(c1ccccc1)c1cc(Cl)sc1Cl
Temperature: -30 °C
Reaction time: 4 h
Yield: 56 %

Procedure:
To a stirred solution of 2,5-dichloro-N-methoxy-N-methyl-3-thiophenecarboxamide (350 mg, 1.46 mmol) in THF (5 mL) was added 3M solution of phenylmagnesium bromide in diethyl ether (1.2 mL, 3.6 mmol) at −78° C., and the mixture was stirred for 4 hours at −30° C. Saturated ammonium chloride solution was added, and the whole was extracted with ethyl acetate (60 mL×2). The combined organic layers were washed with saturated NaHCO3 solution, brine, dried over MgSO4, and concentrated in vacuo. The resulting residue was purified by flash chromatography eluting with hexane-ethyl acetate (12:1) to provide the title product as a yellow oil. (212 mg, 56% yield).
Reaction SMILES: C1(C)C=CC(S([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][N:13]([CH:17]=[O:18])[CH2:12]2)(=O)=O)=CC=1.[C:20]([O-])(=[S:22])[CH3:21].[K+]>CN(C)C=O>[C:20]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([CH:17]=[O:18])[CH2:12]1)(=[S:22])[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)OC2CCCN(C=O)C2)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=S)OC1CCCN(C=O)C1
Yield: 21 %

Procedure:
A solution of 1-formyl-3-piperidinyl p-toluenesulfonate (1.12 g., 0.007 mole) and potassium thioacetate (0.91 g., 0.008 mole) in 10 ml. dimethylformamide was heated at 70° C. under nitrogen for 20 hours. The reaction mixture was diluted with 150 ml. ethyl acetate and the resulting solution was washed with four 50 ml. portions of water and 50 ml. brine, dried over anhydrous sodium acetate and concentrated in vacuo. The residue was chromatographed on silica gel (125 g.) eluting with 4:1 ethyl acetate-hexane to yield 0.16 g. (21% yield) of the title compound. NMR (CDCl3): 1.13-2.3 (c) and 2.32 (s) (total 7H); 2.84-4.0 (c, 5H); and 7.9 (d, 1H)ppm.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[S:11][CH:12]=[C:13]([CH3:20])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C(Cl)(Cl)Cl>[NH2:9][C:10]1[S:11][C:12]([Br:1])=[C:13]([CH3:20])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(C)csc1N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(N)sc(Br)c1C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
N-Bromosuccinimide (1.78 g) was added portion-wise to a solution of ethyl 2-amino-4-methylthiophene-3-carboxylate (1.71 g) in chloroform (25 ml) at 0° C. After 1 hour, the mixture was diluted with chloroform (20 ml) and washed with a mixture of brine and saturated aqueous sodium hydrogen carbonate (100 ml, 1:1). The organic phase was dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane (0-20%) to give ethyl 2-amino-5-bromo-4-methylthiophene-3-carboxylate (1.32 g) as a bright yellow solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:5]2[N:6]([C:10]([CH:14]=[O:15])=[C:11]([CH3:13])[N:12]=2)[CH:7]=[CH:8][CH:9]=1.[CH3:16][O:17][C:18]([NH:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23]Br)=[O:19].Cl>O1CCCC1>[CH:14]([C:10]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:4]([NH:3][CH2:23][C:22]3[C:25]([CH3:29])=[CH:26][CH:27]=[CH:28][C:21]=3[NH:20][C:18]([O:17][CH3:16])=[O:19])[C:5]2=[N:12][C:11]=1[CH3:13])=[O:15]
Reactant: COC(=O)Nc1cccc(C)c1CBr
Reactant: Cc1nc2c(N)cccn2c1C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Nc1cccc(C)c1CNc1cccn2c(C=O)c(C)nc12
Temperature: 50 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
A suspension of 400 mg of commercial 80% sodium hydride in 10 ml of dry tetrahydrofuran is added to a solution of 2 g of 8-amino-3-formyl-2-methylimidazo[1,2-a]pyridine in 40 ml of dry tetrahydrofuran at RT. Brief heating at 50° C. is followed by vigorous evolution of gas. After the evolution of gas is complete, the mixture is cooled to 0° C., and a solution of 3.9 g of 2-methoxycarbonylamino-6-methylbenzyl bromide in 40 ml of dry tetrahydrofuran is added dropwise. The mixture is again heated to 50° C. and kept at this temperature for 3 h. It is then poured into ice-water, neutralized with a little dilute hydrochloric acid and extracted four times with ethyl acetate. The collected organic phases are washed with water and dried over sodium sulfate. The solvent is stripped off in vacuo, and the dark brown viscous residue is chromatographed on silica gel (ethyl acetate:petroleum ether=1:1 as eluent). Recrystallization from isopropanol results in 2.5 g of the title compound of m.p. 188°-190° C. (dec.).
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[C:13]([CH:14]([CH3:16])[CH3:15])=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8]O)[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Br:43])C(=O)C1>ClCCl>[CH2:1]([O:3][CH2:4][O:5][C:6]1[C:13]([CH:14]([CH3:16])[CH3:15])=[CH:12][CH:11]=[CH:10][C:7]=1[CH2:8][Br:43])[CH3:2]
Reactant: CCOCOc1c(CO)cccc1C(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOCOc1c(CBr)cccc1C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a stirred solution of 2-(ethoxymethoxy)-3-isopropylbenzyl alcohol (Ic) (2.04 g, 9.09 mmol) and PPh3 (3.82 g, 14.6 mmol) in dichloromethane (45 mL) was added NBS (2.59 g, 14.6 mmol) in portions at 0° C. The reaction was stirred at 0° C. for 30 min. The reaction was quenched by the addition of water (50 mL). The product was extracted with CH2Cl2 (3×50 mL). The combined organic extracts were washed with water (50 mL), and brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification of the crude product by flash column chromatography (hexanes/ethyl acetate=10:1, v/v) provided the title compound (2.27 g, 86%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([C:21]3[CH2:26][CH2:25][N:24]([S:27]([CH2:30][C:31](OCC)=O)(=[O:29])=[O:28])[CH2:23][CH:22]=3)=[CH:17][C:15]=2[N:16]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C1C[O:45][CH2:44]C1>>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[O:13][C:14]2[CH:20]=[CH:19][C:18]([C:21]3[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:44][OH:45])(=[O:28])=[O:29])[CH2:23][CH:22]=3)=[CH:17][C:15]=2[N:16]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)CS(=O)(=O)N1CC=C(c2ccc3oc(-c4ccc(S(C)(=O)=O)cc4F)nc3c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CS(=O)(=O)c1ccc(-c2nc3cc(C4=CCN(S(=O)(=O)CCCO)CC4)ccc3o2)c(F)c1
Reaction time: 1.5 h

Procedure:
Example 59 (200 mg, 0.42 mmol) was dissolved in DCM (30 ml) and added TFA (1.5 ml, 9.2 mmol). This mixture was stirred at rt for 3 h and DCM was removed on rotavapour to obtain a residue. Residue was co-distilled with diethyl ether to obtain 2-(2-fluoro-4-(methyl sulfonyl)phenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (210 mg). 2-(2-fluoro-4-(methylsulfonyl)phenyl)-5-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (200 mg, 0.4 mmol) was dissolved in DCM (10 ml) and added TEA (0.46 ml, 3.3 mmol). This mixture was stirred at rt for 30 mins. After 30 mins reaction mixture cooled to 0° C. and added ethyl 3-(chlorosulfonyl)propanoate (164 mg, 0.4 mmol). This reaction continued for 30 mins at rt. Work up (H2O/DCM) followed by column purification on combiflash using a gradient mixture of EtOAc and Petether (45:55) as eluent afforded ethyl 2-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridin-1(2H)-ylsulfonyl)acetate (120 mg). Ethyl 2-{4-[2-(2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazol-5-yl}-5,6-dihydropyridin-1(2H)-ylsulfonyl)acetate (100 mg, 0.19 mmol) was dissolved in THF (5 ml) and added Lithiumaluminium hydride (14 mg, 0.38 mmol) at 0° C. This mixture was stirred at same temperature for 90 mins. After completion of the reaction, reaction mass quenched with 1N HCl (7 ml). Work up (DCM/H2O) followed by purification on combiflash using a gradient mixture of EtOAc and Petether (80:20) as eluent afforded the titled compound (40 mg) as a white solid. M.P.: 184-186° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.48 (t, J 8.1, 1H), 8.06 (dd, J 1.6, 10.1, 1H), 8.00-7.94 (m, 2H), 7.84 (d, J 8.6, 1H), 7.63 (dd, J 1.8, 8.5, 1H), 6.29 (s, 1H), 4.64 (t, J 5.3, 1H), 3.94 (d, J 2.9, 2H), 3.50-3.42 (m, 4H), 3.36 (s, 3H), 3.18-3.10 (m, 2H), 2.70-2.62 (m, 2H), 1.88-1.80 (m, 2H).
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[NH2:17][C:18]1[CH:33]=[C:32]([F:34])[C:21]2[N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:23]=[N:24][C:20]=2[C:19]=1[CH3:35]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:28]([O:27][C:25]([N:22]1[C:21]2[C:32]([F:34])=[CH:33][C:18]([N:17]=[C:8]=[S:9])=[C:19]([CH3:35])[C:20]=2[N:24]=[CH:23]1)=[O:26])([CH3:30])([CH3:31])[CH3:29]
Reactant: Cc1c(N)cc(F)c2c1ncn2C(=O)OC(C)(C)C
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(N=C=S)cc(F)c2c1ncn2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of di-2-pyridyl thionocarbonate (0.393 mg) and 4-dimethylaminopyridine (0.01 g) in methylene chloride (100 mL) is added dropwise over 30 minutes a solution of 5-amino-1-tert-butoxycarbonyl-7-fluoro-4-methylbenzimidazole (0.409 g) in methylene chloride (70 mL). The mixture is stirred at room temperature for 3 hours then rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 10% ethyl acetate/hexane to afford 1-tert-butoxycarbonyl-7-fluoro-4-methyl-5-benzimidazolylisothiocyanate as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[CH:25]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:27]=[C:28]4[C:32]=3[N:31]([CH3:33])[N:30]=[CH:29]4)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][O:22][CH2:23][C:24]3[CH:25]=[C:26]([C:34]([F:35])([F:36])[F:37])[CH:27]=[C:28]4[C:32]=3[N:31]([CH3:33])[N:30]=[CH:29]4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cn1ncc2cc(C(F)(F)F)cc(COCC3(c4ccc(F)cc4)CCN(C(=O)OC(C)(C)C)CC3)c21
Solvent: O=C(O)C(F)(F)F
Product: Cn1ncc2cc(C(F)(F)F)cc(COCC3(c4ccc(F)cc4)CCNCC3)c21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
tert-Butyl 4-(4-fluorophenyl)-4-(((1-methyl-5-(trifluoromethyl)-1H-indazol-7-yl)methoxy)methyl)piperidine-1-carboxylate (66 mg, 0.127 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 2 mL) and stirred at room temperature for 15 min. The reaction was concentrated, and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 53.5 mg (100%) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 8.00 (s, 1H), 7.94 (s, 1H), 7.30 (s, 1H), 7.15 (m, 2H), 6.87 (m, 2H), 4.68 (s, 2H), 3.99 (s, 3H), 3.44 (s, 2H), 2.82 (m, 2H), 2.67 (m, 2H), 2.04 (m, 2H), 1.60-1.95 (m, 3H); 13C-NMR (CDCl3, 126 MHz) δ 162.2, 160.2, 139.8, 139.4, 133.9, 128.6, 128.5, 124.8, 124.6 (q, J=272 Hz), 124.5 (q, J=2.9 Hz), 122.6 (q, J=33 Hz), 121.2, 119.7 (q, J=4.8 Hz), 115.0, 114.8, 79.0, 70.5, 42.6, 41.3, 38.3, 33.9. Mass spec.: 422.08 (MH)+. Accurate mass spec.: m/z 422.1837 [MH]+, Δ=4.4 ppm.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.C(O)(=O)C.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[N:22]1[CH:26]=[CH:25][CH:24]=[CH:23]1>C(O)C>[CH3:21][O:20][C:18]1[CH:19]=[C:14]2[C:15](=[CH:16][CH:17]=1)[N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:5]1([CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1)[NH:13]2
Reactant: COc1ccc(-n2cccc2)c(N)c1
Reactant: CN1CCC(=O)CC1
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2c(c1)NC1(CCN(C)CC1)c1cccn1-2

Procedure:
3.48 g (0.03 mole) of 1-methyl-4-piperidone and 3 ml. of glacial acetic acid are added to a solution of 5.65 g (0.03 mole) of 1-(2-amino-4-methoxy-phenyl) pyrrole in 100 ml. of absolute ethanol. The solution is refluxed for 15 hours and concentrated, and the residue is dissolved in water. The solution is filtered and basified. A solid precipitates and is filtered, dried and recrystallized from ethanol to give 4,5-dihydro-7-methoxy-1'-methylspiro[pyrrolo(1,2-a)quinoxaline-4,4'-piperidine], m.p. 124°-125° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Reactant: Clc1ncccn1
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1ncccn1
Temperature: 100 °C

Procedure:
A mixture of (RS) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (1.28 g) and 2-chloropyrimidine was heated at 100° C. for 48 hours. After cooling to room temperature the mixture was column chromatographed (silica gel, 0-10% (9:1 methanol/ammonia) in dichloromethane eluant) to give the title compound (0.42 g) as an oil.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:66](=[O:67])[N:6]2[C:7]([C:53]([O:55]CC3C=CC([N+]([O-])=O)=CC=3)=[O:54])=[C:8]([S:11][C@@H:12]3[CH2:16][N:15](C(OCC4C=CC([N+]([O-])=O)=CC=4)=O)[C@H:14]([C:30]([N:32]4[CH2:35][CH:34]([N:36](C(OCC5C=CC([N+]([O-])=O)=CC=5)=O)[C:37](=[NH:39])[CH3:38])[CH2:33]4)=[O:31])[CH2:13]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[H][H]>O1CCCC1.O.[Pd]>[C:37]([NH:36][CH:34]1[CH2:33][N:32]([C:30]([C@@H:14]2[CH2:13][C@H:12]([S:11][C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:66](=[O:67])[N:6]4[C:7]=3[C:53]([OH:55])=[O:54])[CH2:16][NH:15]2)=[O:31])[CH2:35]1)(=[NH:39])[CH3:38]
Reactant: [H][H]
Reactant: CC(=N)N(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: CC(=N)NC1CN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2)C1
Yield: 35.3 %

Procedure:
0.77 g of 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-{3-[N(4-nitrobenzyloxycarbonyl)-N-acetimidoylamino]azetidin-1-ylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate [prepared as described in step (1) above] was dissolved in 15 ml of a 2:1 by volume mixture of tetrahydrofuran and water. 0.77 g of a 10% w/w palladium-on-carbon catalyst was then added to the resulting solution, after which the mixture was hydrogenated at room temperature for 2 hours in a hydrogen atmosphere. At the end of this time, the catalyst was removed by filtration, and the filtrate was washed with diethyl ether. The aqueous layer was then concentrated by evaporation under reduced pressure, and the resulting residue was subjected to reverse phase column chromatography (Cosmosil 75C18 -prep, manufactured by Nacalai Tesque, 100 ml). The fraction containing the title compound and obtained by elution with 4% by volume aqueous acetonitrile was concentrated by evaporation under reduced pressure and freeze-dried, to give 0.13 g of the title compound as a powder.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(CC)CC.[O:23]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC#N>[O:23]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])(=[O:38])=[O:37])=[CH:32][CH:31]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCCCCNS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.7 %

Procedure:
To a solution of 6-(Boc-amino)hexylamine (4.95 g, 23 mmol) and Et3N (2 eq, 6.4 ml, 46 mmol) in 25 ml CH3CN was added dropwise 4-phenoxybenzenesulfonyl chloride solution (1 eq, 6.16 g, 23 mmol) in 15 ml CH3CN. The reaction was stirred for 2 days at room temperature. The precipitate was filtered and the solvent was evaporated. The residue was purified by silica gel chromatography [eluent: CH2Cl2/1-2% MeOH] to yield 6.68 g (64%) a colorless oil, which solidified to a white solid, m.p.=77-78° C.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6](OC)=[O:7])=[C:2]=[S:3].O.[NH2:15][NH2:16]>C1COCC1>[NH2:15][N:16]1[C:6](=[O:7])[C:5]2[C:4](=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:1][C:2]1=[S:3]
Reactant: NN
Reactant: COC(=O)c1ccccc1N=C=S
Solvent: O
Solvent: C1CCOC1
Product: Nn1c(=S)[nH]c2ccccc2c1=O
Temperature: 25 °C
Yield: 95.5 %

Procedure:
Methyl 2-isothiocyanatobenzoate (5.00 g, 25.9 mmol) was dissolved in THF (125 mL), followed by addition of hydrazine monohydrate (2.51 mL, 51.8 mmol). The reaction mixture was refluxed for 1 h, cooled to RT and the precipitate was collected by filtration. The precipitate was washed with water and dried in vacuo to give pure title compound (4.78 g, 96%).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][S:9]C1C=CC(O)=CC=1>>[CH3:8][S:9][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7]
Reactant: CSc1ccc(O)cc1
Reactant: Oc1ccccc1
Product: CSc1ccccc1O
Yield: 221.7 %

Procedure:
Phenol (12.5 g, 0.13 moles), methyl disulfide (8.4 g, 0.089 moles), and H ELZ-20 (2.5 g) were combined and heated under nitrogen at reflux for 3 hours during which the temperature increased to 180° C. and GC analysis indicated no further increase in the amount of ortho-(methylthio)phenol. Methyl mercaptan was allowed to escape continuously. The mixture was cooled to room temperature and filtered. The catalyst was washed several times with ether and allowed to dry leaving solid weighing 3.2 g. The filtrate and ether washings were combined, and volatiles were removed on a rotary flash evaporator leaving 15.2 g of liquid. GC analysis indicated the presence of phenol (5.3 g, 43% recovered), ortho-(methylthio)phenol (5.1 g, 41% yield), para-(methylthio)phenol (2.3 g), and di(methylthio)phenols (2.2 g).