Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[C:8]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[O:27][CH3:28])([F:19])[C:7]1=[O:29])=[O:5].[C:30]([O:34][P:35]([O-:42])([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])([CH3:33])([CH3:32])[CH3:31].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:30]([O:34][P:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])([O:42][CH2:2][O:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=2)[C@@:8]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[O:27][CH3:28])([F:19])[C:7]1=[O:29])=[O:5])=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Reactant: COc1ccc(Cl)cc1C1(F)C(=O)N(C(=O)OCI)c2cc(C(F)(F)F)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(C(=O)OCOP(=O)(OC(C)(C)C)OC(C)(C)C)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
To a 25 mL flask containing 3-(5-chloro-2-methoxy-phenyl)-3-fluoro-2-oxo-6-trifluoromethyl-2,3-dihydro-indole-1-carboxylic acid iodomethyl ester ((S)-XIV) (0.200 g, 0.368 mmol) was added 5 mL anhydrous tetrahydrofuran, and tetrabutylammonium di-t-butylphosphate (0.199 g, 0.441 mmol). The reaction was heated to reflux and allowed to stir for 1 hour. The reaction was then cooled to room temperature, and the solvent was evaporated in vacuo. The crude foam was purified by flash chromatography (silica gel 4:1 Hexanes: EtOAc) producing the title compound (0.110 g, 48%) as a clear colorless oil. 1H NMR (CDCl3 400 MHz): δ=8.35 (s, 1H), 7.78 (s, 1H), 7.48 (d, 1H, J=7 Hz), 7.34 (d, 1H, J=7 Hz), 7.30 (d, 1H, J=7 Hz), 6.76 (d, 1H, J=7 Hz), 5.90 (d, 1H, J=12.4 Hz), 3.53 (s, 3H), 1.50 (s, 18H).
Reaction SMILES: BrBr.O=[C:4]([CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1.[N:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[NH:23][C:24]([NH2:26])=[S:25]>O1CCOCC1>[CH3:16][C:4]1[N:26]=[C:24]([NH:23][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][N:17]=2)[S:25][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: CC(=O)Cc1ccc(S(N)(=O)=O)cc1
Reactant: NC(=S)Nc1cnccn1
Agent: BrBr
Solvent: C1COCCO1
Product: Cc1nc(Nc2cnccn2)sc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 60 °C
Yield: 28.1 %

Procedure:
Bromine (0.017 ml, 0.33 mmol) is added dropwise to a stirred solution of 4-(2-oxo-propyl)-benzenesulfonamide (prepared as described in European patent specification EP 91749 A2) (0.087 g, 4.1 mmol) in dioxan (10 ml) at 0° C. After 30 minutes the solvent is removed and the crude product is dissolved in ethanol (4.0 ml). Pyrazin-2-yl-thiourea (0.063 g, 0.41 mmol) is added and the stirred reaction mixture is heated at 60° C. for 3 hours. The solvent is removed and the residue is triturated with ethyl acetate to give the title compound as a pale orange solid (0.040 g). MH+ (AP+):
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH:36]([C@@H:38]1[CH2:42][CH2:41][CH2:40][N:39]1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=O.N1CCCCC1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[C:32]([C:33]#[N:34])=[CH:36][C@@H:38]3[CH2:42][CH2:41][CH2:40][N:39]3[C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
To a sealed tube was added 3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (507 mg, 1.07 mmol), tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (0.2, mL, 1.1 mmol), piperidine (0.05 mL, 0.54 mmol) and ethanol (3 mL). The tube was capped and heated to 100° C. for 16 hrs. The reaction was not complete so an additional amount of tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (732 mg, 3 eq) was added and heating was continued for 4 hrs at 110° C. The reaction was cooled and concentrated then dissolved in DCM (50 mL) and washed with water (50 mL) and brine. The organic layer was dried (MgSO4), filtered and concentrated. The resulting material was purified by Isolera (250 g column; 2%-3% MeOH/DCM) to provide 403 mg (57%) of tert-butyl (2S)-2-[3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-2-cyano-3-oxo-prop-1-enyl]pyrrolidine-1-carboxylate as a solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=1)[O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[C:19]1([C:18]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[C:8]([CH:15]=[CH:16][CH:17]=2)[O:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)COc1cccc(CCCCO)c1
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(CCCCOC(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of methyl 3-(4-hydroxybutyl)phenoxyacetate (174 mg) in dimethylformamide (8.0 ml) was added successively trityl chloride (223 mg) and N,N-dimethylaminopyridine (88 mg). After stirred overnight at room temperature, the mixture was quenched by addition of water and extracted with ether. The extract was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by flash silica gel chromatography (n-hexane:ethyl acetate=4:1) to give the title compound (228 mg) having the following physical data.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:21]([NH2:23])=[N:20][CH:19]=[N:18][C:17]=3[NH:16][CH:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH:26]([S:29](Cl)(=[O:31])=[O:30])([CH3:28])[CH3:27].O>CN(C)C=O>[CH:26]([S:29]([N:16]1[C:17]2[N:18]=[CH:19][N:20]=[C:21]([NH2:23])[C:22]=2[C:14]([C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)=[CH:15]1)(=[O:31])=[O:30])([CH3:28])[CH3:27]
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: CC(C)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)n1cc(-c2ccc(Oc3ccccc3)cc2)c2c(N)ncnc21

Procedure:
5-(4-Phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (1.57 g) was dissolved in dry dimethylformamide (30 ml) and then sodium hydride (0.22 g of a 60% dispersion in mineral oil) was added with stirring. The mixture was stirred for 30 minutes and then isopropylsulphonyl chloride (0.74 g) was added and the mixture was stirred at ambient temperature for 18 hours. Water was added to the mixture until no further precipitation occurred. The solid was collected by filtration and purified by flash column chromatography on silica using dichloromethane/methanol (9:1) as the mobile phase to give a solid which was further purified by flash column chromatography on silica using ethyl acetate as the mobile phase to give 7-isopropylsulphonyl-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p. 162-162.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:31])[CH2:18][CH2:17][C:16]([CH2:29][NH2:30])([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:30][CH2:29][C:16]1([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:31])[CH2:14][CH2:15]1)=[O:6]
Reactant: NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and C-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=467.0, tR (minutes, Method E)=0.83
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.Cl[CH2:15][CH2:16][N:17]([CH2:19][CH2:20]Cl)[CH3:18].C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH3:18][N:17]1[CH2:19][CH2:20][N:1]([C:2]2[C:3]([OH:12])=[CH:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:15][CH2:16]1
Reactant: CN(CCCl)CCCl
Reactant: Nc1cc2ccccc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CN1CCN(c2cc3ccccc3cc2O)CC1
Reaction time: 48 h

Procedure:
3-Aminonaphthalen-2-ol (5 g, 31.4 mmol) is brought to the reflux point of 1-butanol (100 ml) in the presence of 2-chloro-N-(chloroethyl)-N-methylethanamine hydrochloride (6.05 g, 31.4 mmol) and sodium carbonate (1.7 g, 16 mmol). After 48 h, the reaction mixture is concentrated and impregnated onto silica and then purified by flash chromatography with a mixture (93/7/1) of dichloromethane/methanol/aqueous ammonia.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[N:8]=N/N2CCCC2)=[CH:4][CH:3]=1.[Li]C(CC)C.[CH3:20][C:21]([CH3:23])=[O:22]>CCOCC>[NH2:8][C:5]1[CH:4]=[CH:3][C:2]([C:21]([OH:22])([CH3:23])[CH3:20])=[CH:7][CH:6]=1
Reactant: CC(C)=O
Reactant: Brc1ccc(/N=N/N2CCCC2)cc1
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CC(C)(O)c1ccc(N)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
To a −78° C. solution of compound 134 (1 g, 3.95 mmol) in ether (20 mL) was added sec-BuLi (1.4 M in hexanes, 0.62 g, 9.67 mmol). The resulting solution was stirred for 30 min at −78° C., followed by addition of acetone (0.91 g, 15.81 mmol) dropwise at −78° C. The reaction mixture was warmed to room temperature overnight. The reaction mixture was partitioned between water and ether and the layers were separated. The aqueous layer was re-extracted with ether. The ether layers were the combined and concentrated in vacuo to yield crude 135 (0.33 g, 55.9%) which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([O:9][CH3:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Br:11]Br>C(O)(=O)C>[Br:11][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([O:9][CH3:10])[C:2]=1[F:1]
Reactant: BrBr
Reactant: COc1c(N)cccc1F
Solvent: CC(=O)O
Product: COc1c(N)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3-fluoro-2-methoxyaniline (2.8 g, 20 mmol) in 10 mL of acetic acid was added bromine (0.82 mL, 16 mmol) in acetic acid (10 mL) dropwise. The reaction mixture was stirred at rt. for 30 min. Solid was filtered and washed with acetic acid to give the HBr salt. It was then dissolved in water, basified by addition of KOH, extracted with ethyl acetate. The organic layer was dried and concentrated to give a white solid (2.8 g, 80%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 3.93 (s, 3H) 6.42 (dd, J=8.6, 1.8 Hz, 1H) 7.01 (dd, J=8.6, 7.1 Hz, 1H). [M+H] calc'd for C7H7BrFNO, 222. found 222.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][N:5]([C:7]([C:9]1[C:18]2[C:13](=[C:14]([S:21][C:22]([F:25])([F:24])[F:23])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=O)[CH3:6].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:28].O.S>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][N:5]([C:7]([C:9]1[C:18]2[C:13](=[C:14]([S:21][C:22]([F:25])([F:24])[F:23])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)=[S:28])[CH3:6]
Reactant: COC(=O)CN(C)C(=O)c1cccc2c(SC(F)(F)F)c(OC)ccc12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: S
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)CN(C)C(=S)c1cccc2c(SC(F)(F)F)c(OC)ccc12
Yield: 73.4 %

Procedure:
N-[[6-Methoxy-5-(trifluoromethylthio)-1-naphthalenyl]carbonyl]-N-methylglycine methyl ester (2.0 g, 5.4 mmoles) was dissolved in dry pyridine (40 ml). Phosphorus pentasulfide (2.37 g, 10.7 mmoles) was added to the pyridine solution. The mixture was heated at refluxed for 4 hr and then poured into warm water at 50° to 80° C. (caution: evolution of copious quantities of H2S). The mixture was extracted with ethyl acetate. The extract was washed successively with 3 N aqueous HCl, water, a saturated aqueous solution of NaHCO3, water and brine, dried (MgSO4) and concentrated to dryness. The residue was recrystallized from ethanol-water to give 1.6 g of the title compound; mp 121°-123° C.; NMR (CDCl3) δ 3.00 (s, 3H), 3.75 (s, 3H), 4.00 (s, 3H), 4.35 and 4.5 (d, 2H), 7.0-8.5 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]([OH:12])=[O:11])[C:5](O)=[N:6][C:7]=1[CH3:8].C1(P(Cl)([Cl:21])=O)C=CC=CC=1>O>[Cl:21][C:5]1[C:4]([C:10]([OH:12])=[O:11])=[CH:3][C:2]([Cl:1])=[C:7]([CH3:8])[N:6]=1
Reactant: Cc1nc(O)c(C(=O)O)cc1Cl
Reactant: O=P(Cl)(Cl)c1ccccc1
Solvent: O
Product: Cc1nc(Cl)c(C(=O)O)cc1Cl
Temperature: 135 °C
Reaction time: 1 h

Procedure:
To 5 g (0.027 mole) of 5-chloro-2-hydroxy-6-methyl-3-pyridinecarboxylic acid was added 35 g of phenylphosphonic dichloride. The mixture was heated to 135° C. for 1.5 hr. After cooling, the reaction solution was poured carefully into 250 ml of water and stirred for 1 hr. The water was extracted with 3×100 ml of methylene chloride. The combined organic extracts were washed with 2×100 ml of water, dried over sodium sulfate, filtered, concentrated by rotary evaporation, taken up in toluene, charcoaled, and concentrated by rotary evaporation. The crude residue was crystallized from hexane to give 1.7 g (31%) of beige analytically pure crystals, m.p. 123°-38° C. with decomposition.
Reaction SMILES: [Na].[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH2:3][CH2:4][CH3:5].Cl.[CH:15]([N:18]([CH2:22][CH2:23]Cl)[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16]>C(O)C>[CH2:2]([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:23][CH2:22][N:18]([CH:19]([CH3:21])[CH3:20])[CH:15]([CH3:17])[CH3:16])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCOc1ccccc1O
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCCCOc1ccccc1OCCN(C(C)C)C(C)C
Temperature: 0 °C

Procedure:
To 750 ml of absolute ethanol was added gradually 13.8 g (0.60 mole) of metallic sodium cut into pieces. After all the sodium had reacted 49.8 g (0.30 mole) of o-butoxyphenol was added. The solution was cooled down in ice-water whereupon a solution of 60.0 g (0.30 mole) of diisopropylaminoethylchloride hydrochloride in 150 ml of absolute ethanol was added rapidly with stirring. The reaction mixture was then boiled under reflux for 5 hours.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2([C:13]([O:15]C)=[O:14])[CH2:12][CH2:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>C1COCC1.O>[C:1]1([NH:7][C:8]([C:10]2([C:13]([OH:15])=[O:14])[CH2:11][CH2:12]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)C1(C(=O)Nc2ccccc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1(C(=O)Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
Methyl 1-(phenylcarbamoyl)cyclopropanecarboxylate (0.607 g, 2.77 mmol) was dissolved in a mixture of THF (3.5 mL) and water (3.50 mL), lithium hydroxide monohydrate (0.349 g, 8.31 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The THF was removed under reduced pressure and additional water (20 mL) was added. The solution was acidified to ˜pH 4 with 2 M HCl and the off white solid that precipitated was collected by suction filtration and washed with additional water to give 1-(phenylcarbamoyl)cyclopropanecarboxylic acid (0.482 g, 85% yield). MS (ESI) m/z: 206.0 (M+H+)
Reaction SMILES: COC([NH:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8][C:7]1=[O:16])=O.C[Si](I)(C)C>C(#N)C.C(OCC)(=O)C>[NH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][NH:8][C:7]1=[O:16]
Reactant: COC(=O)NC1C(=O)NCc2ccccc21
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: NC1C(=O)NCc2ccccc21
Temperature: 65 °C

Procedure:
Step D—Removal of the Methoxyoxycarbonyl Group (MOC): To the 4-methoxycarbonylamino-1,2,3,4-tetrahydroisoquinoline-3-one (3.4 mmoles) in 30 mL of acetonitrile was added 2 mole equivalents of trimethylsilyliodide (TMSI). The reaction mixture was heated to 50-80° C. for 3 hrs and then cooled and poured into a separatory funnel. The reaction mixture was diluted with ethyl acetate and washed with 1 molar K2CO3 and then with 5% NaHSO3. The organic layer was dried over Na2SO4 and filtered. The solvent was removed under reduced pressure to give the 4-amino-1,2,3,4-tetrahydroisoquinoline-3-one derivative. Typical yields range from 50-87%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.[C:16]1([C@@H:22]([CH2:24]O)[NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]23[O:15][CH2:24][C@H:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:23]2[C:12](=[O:14])[CH2:11][CH2:10][CH2:9]3)=[CH:6][CH:7]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: O=C(O)CCCC(=O)c1ccc(F)cc1
Solvent: Cc1ccccc1
Product: O=C1CCC[C@@]2(c3ccc(F)cc3)OC[C@H](c3ccccc3)N12
Yield: 68 %

Procedure:
5-(4-Fluoro-phenyl)-5-oxo-pentanoic acid (1 g, 5.10 mmol) and (S)-(+)-2-phenylglycinol (0.839 g, 6.12 mmol) in toluene (15 mL) together with 4 Å molecular sieves was heated at 140° C. under Dean-Stark conditions for 20 hours. The reaction mixture was filtered through Celite®, evaporated and the residue dissolved in ethyl acetate then re-evaporated. The crude material was purified by column chromatography eluting with 20-40% ethyl acetate in cyclohexane to afford (3S,8aS)-8a-(4-fluoro-phenyl)-3-phenyl-hexahydro-oxazolo[3,2-a]pyridin-5-one (1.08 g).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[C:5]1[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(Cl)cc1Cl
Yield: 65.6 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 2,4-dichlorophenylboronic acid (available from Combi-Blocks Inc.; 76 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′,4′-dichloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (65 mg, 65%). 1H NMR (400 MHz, DMSO-d6) δ 13.15 (br s, 1H), 8.55 (s, 1H), 8.49 (s, 1H), 8.34 (s, 1H), 8.29 (d, J=7.8 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.78 (d, J=8.3 Hz, 1H), 7.70 (s, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.36-7.43 (m, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:10]1[CH:11]=[CH:12][C:13]2[CH:28]3[CH2:29][C:15]4([CH2:19][N:18]([CH2:20][CH:21]5[CH2:25][CH2:24][CH2:23][CH2:22]5)[CH2:17][CH:16]4[C:26]4[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=43)[C:14]=2[CH:34]=1)(=[O:9])[CH3:8]>CCOCC>[OH:9][CH:7]([C:10]1[CH:11]=[CH:12][C:13]2[CH:28]3[CH2:29][C:15]4([CH2:19][N:18]([CH2:20][CH:21]5[CH2:25][CH2:24][CH2:23][CH2:22]5)[CH2:17][CH:16]4[C:26]4[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=43)[C:14]=2[CH:34]=1)[CH3:8]
Reactant: CC(=O)c1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(O)c1ccc2c(c1)C13CC2c2ccccc2C1CN(CC1CCCC1)C3
Yield: 60.5 %

Procedure:
To a suspension of 0.5 g of lithium aluminum hydride in 25 ml of ether was added dropwise a solution of 2.3 g of 5-acetyl-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]-pyrrole in 10 ml of ether. The reaction mixture was heated at reflux overnight and then excess lithium aluminum hydride was destroyed by the dropwise addition of a saturated aqueous sodium sulfate solution. The suspension was filtered with the aid of diatomaceous earth, and the filtrate was evaporated to dryness. The residue was dissolved in methylene chloride, and the solution was washed with water, dried over potassium carbonate and concentrated in vacuo to give 1.4 g of 5-(α-hydroxyethyl)-2-cyclopentylmethyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole as an oil; nmr spectrum; δ 1.0-4.0 (m, 19); 1.3 (d, 3); 3.0-4.0 (m, 1); 4.7 (t, 1); 6.8-7.4 (m, 7).
Reaction SMILES: [Cl-].[CH3:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8]([O-:10])=O.C1COCC1.[CH3:16][NH2:17]>C(OCC)(=O)C>[CH3:16][NH:17][C:8]([C:7]1[CH:6]=[CH:5][S:4][C:3]=1[CH3:2])=[O:10]
Reactant: CN
Reactant: Cc1sccc1C(=O)[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccsc1C
Yield: 71.8 %

Procedure:
2-Methyl-3-thiophenecarboxylate chloride (60.5 g)/THF (300 ml) solution was added dropwise to a 40% aqueous solution of methylamine (400 ml) at 0° C. Ethyl acetate (2 l) was added thereto, and then the organic layer was washed sequentially with water, a 5N aqueous solution of hydrochloric acid, an aqueous solution of saturated sodium bicarbonate, water and brine, dried and evaporated. The resulting residue was crystallized from n-hexane, to give the title compound as a white powder (43.5 g, yield; 71.8%).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:55](=[O:56])[N:6]2[C:7]([C:42]([O:44]CC3C=CC([N+]([O-])=O)=CC=3)=[O:43])=[C:8]([S:11][C@@H:12]3[CH2:16][N:15]([CH3:17])[C@H:14]([C:18]([N:20]4[CH2:25][CH2:24][N:23]([C:26](=[NH:41])[NH:27]C(OCC5C=CC([N+]([O-])=O)=CC=5)=O)[CH2:22][CH2:21]4)=[O:19])[CH2:13]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[H][H]>O1CCCC1.O.[Pd]>[C:26]([N:23]1[CH2:24][CH2:25][N:20]([C:18]([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:55](=[O:56])[N:6]4[C:7]=3[C:42]([OH:44])=[O:43])[CH2:16][N:15]2[CH3:17])=[O:19])[CH2:21][CH2:22]1)(=[NH:27])[NH2:41]
Reactant: [H][H]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C(=N)NC(=O)OCc5ccc([N+](=O)[O-])cc5)CC4)N(C)C3)[C@H](C)[C@H]12
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C(=N)N)CC4)N(C)C3)[C@H](C)[C@H]12

Procedure:
500 ml of 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-{(2S,4S) -1-methyl-2-[4-(4-nitrobenzyloxycarbonylamidino)piperazin-1-ylcarbonyl]-pyrrolidin-4-yl-thio}-1-carbapen-2-em-3-carboxylate [prepared as described in step (1) above] were dissolved in 75 ml of a 1:1 by volume mixture of tetrahydrofuran and water, and 2400 mg of a 10% w/w palladium-on-carbon catalyst were added to the resulting solution. The mixture was then hydrogenated in an atmosphere of hydrogen at 28° C. for 1 hour. At the end of this time, the catalyst was removed by filtration, and the filtrate was washed with diethyl ether. The filtrate was then concentrated to 20 ml by evaporation under reduced pressure. The solution was then subjected to reverse phase silica gel column chromatography (Cosmosil 75C18 -prep, manufactured by Nacalai Tesque, 100 ml), eluted with mixtures of acetonitrile and water in proportions of 0:100, 2:98, 4:96, 6:94 and 8:92 by volume, in that order. The fractions containing the desired compound were collected, concentrated to 3 ml by evaporation under reduced pressure, and cooled to precipitate colorless needle-like crystals. The crystals were filtered off and dried to obtain 435 mg of the title compound as crystals, melting at 218°-220° C. (with decomposition).