Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][S:3]2(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][Cl:20].O>CN(C=O)C.CCOC(C)=O>[Cl:20][CH2:19][CH2:18][N:6]1[CH2:7][C@@H:2]2[CH2:8][C@H:5]1[CH2:4][S:3]2(=[O:10])=[O:9]
Reactant: ClCCBr
Reactant: O=S1(=O)C[C@@H]2C[C@H]1CN2
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=S1(=O)C[C@@H]2C[C@H]1CN2CCCl
Temperature: 25 °C
Reaction time: 30 h
Yield: 32.6 %

Procedure:
To a solution of (1S,4S)-2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide, hydrobromide (0.5 g, 2.192 mmol) in DMF (25 mL) was added potassium carbonate (0.397 mL, 6.58 mmol) followed by 1-bromo-2-chloroethane (0.927 mL, 10.96 mmol). The reaction mixture was stirred at rt. After 30 h, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to viscous light brown oil. The crude material was loaded onto a silica gel column, eluted with 1:2 hex:EtOAc to give (1S,4S)-5-(2-chloroethyl)-2-thia-5-azabicyclo[2.2.1]heptane 2,2-dioxide (150 mg, 32.6% yield) of a clear glass material. LC/MS: m/e 210.0 (M+H)+, 0.240 min (method 3).
Reaction SMILES: N1C=CCN2C=CC=CC=12.[C:11]([C:14]1[CH:37]=[CH:36][C:17]([O:18][CH2:19][C:20]2[C:25]3=[N:26][CH:27]=[C:28]([C:31]4[NH:35][N:34]=[N:33][N:32]=4)[C:29](=[O:30])[N:24]3[CH:23]=[CH:22][CH:21]=2)=[C:16]([CH2:38][CH2:39][CH3:40])[C:15]=1[OH:41])(=[O:13])[CH3:12]>>[C:11]([C:14]1[CH:37]=[CH:36][C:17]([O:18][CH2:19][C:20]2[C:25]3=[N:26][CH:27]=[C:28]([C:31]4[NH:35][N:34]=[N:33][N:32]=4)[C:29](=[O:30])[N:24]3[CH:23]=[CH:22][CH:21]=2)=[C:16]([CH2:38][CH:39]=[CH2:40])[C:15]=1[OH:41])(=[O:13])[CH3:12]
Reactant: CCCc1c(OCc2cccn3c(=O)c(-c4nnn[nH]4)cnc23)ccc(C(C)=O)c1O
Agent: C1=CC2=NC=CCN2C=C1
Product: C=CCc1c(OCc2cccn3c(=O)c(-c4nnn[nH]4)cnc23)ccc(C(C)=O)c1O

Procedure:
The aqueous preparation of claim 1 in which the pyrido[1,2-a]pyrimidine compound is 9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy)methyl]-3-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]pyrimidin-4-one; the polyoxyethylene sorbitan fatty acid ester is polyoxyethylene sorbitan monooleate; and the polyethylene glycol has a molecular weight of 400.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[C:17](=O)[CH3:18])[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:26].[Na+]>CO.C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]2[CH:17]([NH2:26])[CH3:18])[CH:5]=[CH:6][CH:7]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc2ccccc2n1-c1cccc(F)c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(N)c1cc2ccccc2n1-c1cccc(F)c1
Temperature: 65 °C
Yield: 95.9 %

Procedure:
A mixture of 1-[1-(3-fluorophenyl)-1H-indol-2-yl]ethanone (0.40 g, 1.6 mmol) and ammonium acetate (1.22 g, 15.8 mmol) in methanol (5.0 mL) and acetonitrile (5.0 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling to room temperature, sodium cyanoborohydride (0.20 g, 3.2 mmol) was added to the resultant mixture. The reaction was heated at 65° C. overnight. The reaction was cooled to room temperature and quenched with saturated NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over MgSO4 and concentrated to give crude product (0.39 g, 97%), which was used directly in the next step. LCMS calculated for C16H13FN (M-NH2)+: m/z=238.1. Found: 238.1.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH:11](=O)[CH:12]([CH3:14])[CH3:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH2:11]([NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)C=O
Reactant: COC(=O)c1ccsc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccsc1NCC(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 2-aminothiophene-3-carboxylate (2.0 g, 12.7 mmol) in dichloromethane (40 mL) and glacial acetic acid (0.72 mL) were added isobutyraldehyde (0.87 g, 12.1 mmol) and sodium triacetoxyborohydride (4.0 g, 18.9 mmol). The reaction mixture was stirred for 18 h at room temperature and concentrated. The residue was dissolved in ethyl acetate, washed with aqueous sodium bicarbonate solution and with water, dried over anhydrous sodium sulfate and concentrated. The residual oil was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate-hexane to afford the title compound as a slightly yellow oil (2.19 g, 81% yield). 1H NMR (400 MHz, CDCl3): δ 7.00 (d, 1H), 6.18 (d, 1H), 3.80 (s, 3H), 3.20 (m, 2H), 1.68 (m, 1H), 1.00 (d, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][NH:10][CH2:9][CH2:8][N:7]([CH3:12])[C:6]=2[CH:13]=1.COC(O)C.Cl[C:20]1[N:25]=[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:23]([Cl:38])=[CH:22][N:21]=1.Cl.O1CCOCC1.N>CO.ClCCl>[Cl:38][C:23]1[C:24]([NH:26][C@@H:27]2[CH2:32][CH2:31][CH2:30][CH2:29][C@H:28]2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[N:25][C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][NH:10][CH2:9][CH2:8][N:7]([CH3:12])[C:6]=3[CH:13]=2)=[N:21][CH:22]=1
Reactant: CN1CCNCc2ccc(N)cc21
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: COC(C)O
Agent: Cl
Agent: N
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCNCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)cc21
Temperature: 25 °C
Yield: 73.4 %

Procedure:
To 40 ml sure-seal reaction vial, 8-Amino-1-methyl-1,2,3,4-tetrahydrobenzo[e][1,4]diazepine (0.33 g, 2 mmoles), methoxy ethanol (6 ml), and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (0.51 g, 1.1.5 mmole), 4M HCl in dioxane (1 ml, 4 mmoles) were added. The reaction was heated to reflux for 3 hours. Upon cooling to room temperature, the solvent was then removed under vacuum to afford a yellow solid. The product (0.53 g, 74% yield) was isolated via column chromatography with dichloromethane and ammonia in methanol (2% to 30% ammonia in methanol) as eluant. NMR 1H-(DMSO)-δ-9.02 (bs, 1H), 7.93 (s, 1H), 7.32 (d, 1H, J=8.59 Hz), 7.16 (bs, 2H), 6.93 (d, 1H, J=7.58), 6.67 (d, 1 h, J=7.58 Hz), 3.80-3.90 (bm, 1H), 3.64 (s, 2H), 3.30-3.40 (bm, 1H), 3.17 (d, 1H, 5.2 Hz), 2.92 (s, 3H), 2.83-2.90 (m, 4H), 2.82 (s, 3H), 1.95-2.12 (m, 2H), 1.65-1.75 (m, 2H), 1.15-1.48 (m, 4H). LCMS (ESI+) 480.13 (M+H); MP=153-206° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:17]2[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC3C=CC(OC)=CC=3)CC3C=CC(OC)=CC=3)[N:18]=2)[C:5]([NH:8][C:9]2[CH:10]=[N:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:51]2[CH2:56][CH2:55][N:54](C(OC(C)(C)C)=O)[CH2:53][CH:52]=2)O1>>[CH3:16][O:15][C:12]1[N:11]=[CH:10][C:9]([NH:8][C:5]2[C:4]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:3][C:2]([C:51]3[CH2:56][CH2:55][NH:54][CH2:53][CH:52]=3)=[CH:7][N:6]=2)=[CH:14][CH:13]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: COc1ccc(Nc2ncc(C3=CCNCC3)cc2-c2nc(C)nc(N)n2)cn1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 247 using 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate, and was isolated as a bright yellow amorphous solid (13%). m/z (ESI, +ve ion) 391.1 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.74 (1H, br. s.); 8.81 (1H, br. s.); 8.54 (1H, br. s.); 8.40 (1H, br. s.); 8.17 (1H, br. s.); 7.88 (1H, br. s.); 7.73 (1H, br. s.); 6.83 (1H, br. s.); 6.17 (1H, d, J=1.0 Hz); 3.84 (3H, s); 2.93 (2H, br. s.); 2.44 (4H, br. s.); 1.56 (4H, s).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:2]1.[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[N+:15]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[C:3]2[C:10]([O:12][CH2:13][CH3:14])=[O:11])([O-:17])=[O:16]
Reactant: CCOC(=O)c1n[nH]c2ccccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1n[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
Ethyl indazole-3-carboxylate (73.7 mmol) was dissolved in 20 mL concentrated sulfuric acid and the reaction mixture was cooled to 0° C. A mixture of concentrated sulfuric acid (12 mL) and 70% nitric acid (12 mL) was added dropwise over the course of 1 h. The mixture was stirred for an additional 1 h at 0° C. and was poured onto of crushed ice (200 g). The solid was collected by vacuum filtration, washed with several portions of water and dried in vacuo. The dried solid was suspended in 250 mL acetonitrile and the mixture was heated at reflux for 2 h. The mixture was allowed to cool to room temperature and the solid was collected and dried in vacuo to provide ethyl 5-nitroindazole-3-carboxylate (53%) as a colorless solid. The acid, obtained by basic hydrolysis, was coupled with the bicyclobase according to procedure A.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:36][CH2:37][CH2:38][OH:39])=[N:12][N:13](CC4C=CC=CC=4)[C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1.[H][H]>C(O)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([O:36][CH2:37][CH2:38][OH:39])=[N:12][NH:13][C:14]=3[NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:26])[CH3:27])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: [H][H]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCO)nn2Cc2ccccc2)cc1
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2[nH]nc(OCCO)c2-c2ccc3c(c2)OCO3)cc1
Reaction time: 8 h

Procedure:
N-[4-(1,3-benzodioxol-5-yl)-1-benzyl-3-(2-hydroxyethoxy)-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide (Example 78) (15.8 g) was dissolved in acetic acid (500 ml). Under an atmosphere of nitrogen, Pearlmann's catalyst (JM type 91, 1.6 g) was added and the reaction was stirred for 48 h under 4 bars of hydrogen at 50° C. The reaction mixture was filtered on a short pad of Celite® and concentrated under reduced pressure. To the oily residue was added water (300 ml) and dichloromethane (300 ml). The phases were separated, the organic phase washed with a 5% aqueous solution of sodium bicarbonate (2×150 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was dissolved in methanol (300 ml), solid potassium carbonate (8 g) was added in one portion and the reaction mixture was stirred overnight and then concentrated under reduced pressure. Water (500 ml) was added to the resulting solid and the mixture as extracted with dichloromethane (3×500 ml). The organic fraction was dried on sodium sulfate and concentrated under reduced pressure. The red-yellow solid was re-crystallised in ethyl acetate yielding the title compound as a white solid (7.2 g)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[NH:22]C(=O)C(C)(C)C)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCCCO.Cl>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[NH2:22])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1C1(O)CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: CCCCO
Product: Nc1ccc(Cl)cc1C1=CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Yield: 47.2 %

Procedure:
A suspension of N-[2-(1-benzyl-4-hydroxy-piperidin-4-yl)-4-chloro-phenyl]-2,2-dimethyl-propionamide (6.00 g) in n-BuOH (50 ml) and 6N HCl (120 ml) was heated to reflux temperature for 5 days. The solution was then poured into ice water, made acidic with conc. HCl and extracted with ethyl acetate. The water layer was made basic and extracted three times with CH2Cl2, dried over sodium sulfate and concentrated in vacuo. The residue was subjected to silica gel chromatography (hexane:ethyl acetate:triethyl amine 49:49:2) to afford 2-(1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-4-chloro-phenylamine (2.11 g; viscous oil; Retention Time HPLC 1.81 min; MS (ES+) 299 (M+H+)) and 4-(2-amino-5-chloro-phenyl)-1-benzyl-piperidin-4-ol (2.11 g; viscous oil; Retention Time HPLC 1.58 min; MS (ES+) 317 (M+H−).
Reaction SMILES: C([N:7]1[C:10](=[O:11])[C@H:9]([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[C@H:8]1[CH2:23][C:24](=[O:30])[CH2:25][C:26]([O:28][CH3:29])=[O:27])(C(OC)=O)=O>CO>[O:30]=[C:24]([CH2:23][C@@H:8]1[C@@H:9]([N:12]2[C:13](=[O:22])[C:14]3=[CH:21][CH:20]=[CH:19][CH:18]=[C:15]3[C:16]2=[O:17])[C:10](=[O:11])[NH:7]1)[CH2:25][C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)CC(=O)C[C@@H]1[C@@H](N2C(=O)c3ccccc3C2=O)C(=O)N1C(=O)C(=O)OC
Solvent: CO
Product: COC(=O)CC(=O)C[C@H]1NC(=O)[C@@H]1N1C(=O)c2ccccc2C1=O
Yield: 64.9 %

Procedure:
A solution of methyl 4-[(2R,3R)-1-methoxalyl-4-oxo-3-phthalimidoazetidin-2-yl]-3-oxobutanoate (68 mg) in methanol (4 ml) was stirred at room temperature for 16 hours and heated at 55°-60° C. for two hours. The resultant solution was evaporated, and the residue was chromatographed on a silica gel plate (developing solvent: 20% acetone in dichloromethane) to afford methyl 3-oxo-4-[(2R,3R)-4-oxo-3-phthalimidoazetidin-2-yl]butanoate (35 mg) as an amorphous solid. Crystallization from a mixture of ethyl acetate and ether gave crystals (26 mg), mp 120°-124° C.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[N:7][N:8]([CH2:10][CH2:11][NH2:12])[CH:9]=1)([O-:4])=[O:3].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O>O1CCCC1>[N+:2]([C:5]1[CH:6]=[N:7][N:8]([CH2:10][CH2:11][NH:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH:9]=1)([O-:4])=[O:3]
Reactant: NCCn1cc([N+](=O)[O-])cn1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)NCCn1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-nitro-1H-pyrazol-1-yl)ethanamine hydrochloride (1.0 g) obtained in Step B of Example 348 in tetrahydrofuran (30 mL) were added triethylamine (2.2 mL) and methanesulfonyl chloride (0.60 mL) in an ice bath, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized (hexane/ethyl acetate) to give the title compound (880 mg).
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([O:13][CH3:14])=[C:7]2[C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=1)[C:6]2=O.C([SnH](CCCC)CCCC)CCC.[F-].[K+]>C1C=CC=CC=1>[CH3:12][O:11][C:10]1[CH:2]=[C:3]2[C:7](=[C:8]([O:13][CH3:14])[CH:9]=1)[CH2:6][N:5]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][C:24]([F:26])([F:27])[F:25])=[CH:21][CH:22]=1)[CH2:4]2
Reactant: COc1cc(OC)c2c(c1Br)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Agent: CCCC[SnH](CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: c1ccccc1
Product: COc1cc2c(c(OC)c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 25 °C
Yield: 66.7 %

Procedure:
To a solution of 4-bromo-5,7-Dimethoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1 one (0.200 g, 0.45 mmol) in benzene under N2 atmosphere was added 2,2′-azobis(2-methyl propionitrile) AIBN (5.0 mg), followed by tributyl tin hydride (0.238 mL, 0.9 mmol). The resulting mixture was refluxed in an oil bath for 2 h. The reaction was monitored by GC-MS for the disappearance of starting material. The reaction mixture was cooled to room temperature and stirred with potassium fluoride (200 mg) for 45 min. The solids were filtered and the filtrate was concentrated. The resulting material was purified using column chromatography (typically 40% ethyl acetate in hexanes) to give 5,7-Dimethoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-lone (0.106 g, 64%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.82 (s, 3H), 3.95 (s, 3H), 4.17 (s, 2H), 4.72 (s, 2H), 6.43 (d, 2H), 7.16 (d, 2H), 7.32 (d, 2H). GC-MS: m/z 367 (M)+, 349 (M−18)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[C:32]1([C:38]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[SH:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[CH3:52][C:53]([CH3:78])([O:55][C:56]([N:58]1[CH2:63][CH2:62][N:61]2[CH:64]=[C:65]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=3[O:73][CH3:74])[N:66]=[C:60]2[CH:59]1[CH2:75][CH2:76]O)=[O:57])[CH3:54]>C1COCC1>[CH3:54][C:53]([CH3:78])([O:55][C:56]([N:58]1[CH2:63][CH2:62][N:61]2[CH:64]=[C:65]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=3[O:73][CH3:74])[N:66]=[C:60]2[CH:59]1[CH2:75][CH2:76][S:39][C:38]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:57])[CH3:52]
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccccc1-c1cn2c(n1)C(CCO)N(C(=O)OC(C)(C)C)CC2
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccccc1-c1cn2c(n1)C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)N(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 111 %

Procedure:
Triphenylphosphine (4.08 g, 15.5 mmol) was dissolved in THF (25 ml), cooled to about 0° C. under N2 and Diethylazodicarboxylate (2.45 ml, 15.54 mmol) was added at a dropwise rate so that the reaction temperature was maintained at about <3° C. Stirring was continued for about ½ hour at 0° C. A mixture of the triphenylmethanethiol (4.30 g, 15.54 mmol) and the product from Step 13.e. (2.90 g, 7.77 mmol) in THF (25 ml) was added at a dropwise rate. The resulting mixture was stirred for about 1 hour at about 0° C. and then allowed to warn to room temperature. The mixture was concentrated under reduced pressure and the residue dissolved in ether (40 ml) and allowed to stand overnight. The solid was filtered off and the filtrate was concentrated then purified by flash chromatography on silica gel using 4:1/hexanes:EtOAc and then 4:1/hexanes:EtOAc as eluants. The product fractions were combined and concentrated under reduced pressure to obtain a pale yellow foam (5.49 g, 111%) which was used without further purification. Mass spec. 632.4 MH+.
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([C:14](=[O:22])[NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:44]2[C@H:45]([CH3:68])[C@H:46]3[C@@H:63]([C@H:64]([OH:66])[CH3:65])[C:62](=[O:67])[N:47]3[C:48]=2[C:49]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=2)=[O:50])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[C:16]1([NH:15][C:14]([C:12]2[N:13]=[C:9]([N:7]3[CH2:8][CH:5]([S:4][C:44]4[C@H:45]([CH3:68])[C@@H:46]5[C@@H:63]([C@H:64]([OH:66])[CH3:65])[C:62](=[O:67])[N:47]5[C:48]=4[C:49]([O:51][CH2:52][C:53]4[CH:58]=[CH:57][C:56]([N+:59]([O-:61])=[O:60])=[CH:55][CH:54]=4)=[O:50])[CH2:6]3)[S:10][CH:11]=2)=[O:22])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Reactant: CC(=O)SC1CN(c2nc(C(=O)Nc3ccccc3)cs2)C1
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(C(=O)Nc5ccccc5)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.4 %

Procedure:
To a solution of 3-acetylthio-1-(4-phenylcarbamoyl-1,3-thiazol-2-yl)azetidine (893 mg, 2.68 mmol) (obtained as described in Reference Example 32) in dimethylformamide (40 ml) was added hydrazine acetate (296 mg, 3.21 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.59 g, 3.21 mmol) in acetonitrile (53 ml) was added dropwise to the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (1.87 ml, 10.7 mmol). The mixture was stirred overnight while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate and ethyl acetate: methanol (9:1) as the eluant to afford p-nitrobenzyl (1R,5S,6S)-2-[1-(4-phenylcarbamoyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (1.2 g, yield 71%) as a pale yellow solid.
Reaction SMILES: C([O:4][CH2:5][C:6](=[O:18])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([OH:16])=[C:9]([OH:17])[CH:8]=1)(=O)C>C(O)C.Cl>[OH:4][CH2:5][C:6]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([OH:16])=[C:9]([OH:17])[CH:8]=1)=[O:18]
Reactant: CC(=O)OCC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Product: O=C(CO)c1cc(O)c(O)c([N+](=O)[O-])c1

Procedure:
A suspension of 2.6 g of (3,4-dihydroxy-5-nitrobenzoyl)methyl acetate in 20 ml of ethanol and 20 ml of 1N hydrochloric acid is heated to boiling under reflux for 5 hours. The reaction mixture is then evaporated, the residue is distilled with toluene and then recrystallized from ethanol. There is obtained 2,3',4'-trihydroxy-5'-nitroacetophenone of m.p. 208°-210°.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[CH:7]([NH:27]C=O)[CH2:6][CH:5]1[CH3:30])(=[O:3])[CH3:2].Cl>C(O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:27])[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(CN4CCCCC4)cc3)cc2C(NC=O)CC1C
Agent: Cl
Solvent: CCO
Product: CC(=O)N1c2ccc(-c3ccc(CN4CCCCC4)cc3)cc2[C@H](N)C[C@@H]1C
Temperature: 85 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
{1-Acetyl-2-methyl-6-[4-(1-piperidinylmethyl)phenyl]-1,2,3,4-tetrahydro-4-quinolinyl}formamide (for a preparation see Intermediate 15) (4.784 g, 11.80 mmol) was dissolved in ethanol (115 mL) and treated with HCl (5N in water, 7.08 ml, 35.4 mmol). The resulting mixture was stirred at 85° C. for 16 h, at room temperature for 16 h then most of the ethanol was removed in vacuo. The aqueous residue was basified to pH 9 with a saturated NaHCO3 aqueous solution (100 mL) then partitioned between water (150 mL) and AcOEt (200 mL). The layers were separated and the aqueous layer was extracted with AcOEt (5×100 mL). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give (cis)-1-acetyl-2-methyl-6-[4-(1-piperidinylmethyl)phenyl]-1,2,3,4-tetrahydro-4-quinolinamine (4.36 g, 10.62 mmol, 90%) as a pale yellow solid which was used in the next step without further purification.