Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:41])[CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][N:32]=[C:31]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[Cl:41])[CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Clc1ccccc1-c1cc(Br)ccn1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4ccnc(-c5ccccc5Cl)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-bromo-2-(2-chloro-phenyl)-pyridine.
Reaction SMILES: CON(C)[C:4](=[O:24])[CH:5]([N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[C:8]1[CH3:23])[CH3:6].[CH3:26][Mg]Br>C1COCC1>[CH3:23][C:8]1[N:7]([CH:5]([C:4](=[O:24])[CH3:26])[CH3:6])[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[C:9]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2cccnc21
Solvent: C1CCOC1
Product: CC(=O)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2cccnc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
In a 50 mL round-bottom flask, under an atmosphere of N2, was added (±)-tert-butyl 1-(1-(methoxy(methyl)amino)-1-oxopropan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (0.630 g, 1.813 mmol) and THF (30 mL). The solution was cooled to 0° C. then methylmagnesium bromide (2.59 ml, 3.63 mmol) was added and the reaction was slowly warmed to ambient temperature while being monitored by LCMS. The reaction was done in 3 h at ambient temperature. Quenched with 50 mL 1N HCl, 50 mL brine, extracted with EtOAc, dried over Na2SO4, filtered, concentrated to provide (±)-tert-butyl 2-methyl-1-(3-oxobutan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate, which was used directly in the following reaction. LRMS (M+H) m/z: calcd 303.37. found 303.1.
Reaction SMILES: [C:1]([O:7][CH2:8][O:9][C:10]([CH:12]1[N:17]2[C:18](=[O:40])[C@@H:19]([NH:20][C:21](=[O:39])/[C:22](/[C:26]3[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=3)=[CH:23]\[CH2:24][CH3:25])[C@H:16]2[S:15][CH:14]=[C:13]1[Cl:41])=[O:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].ClC1C=CC=C(C(OO)=[O:50])C=1>ClCCl.C(=O)([O-])O.[Na+]>[C:1]([O:7][CH2:8][O:9][C:10]([C:12]1[N:17]2[C:18](=[O:40])[C@@H:19]([NH:20][C:21](=[O:39])/[C:22](/[C:26]3[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=3)=[CH:23]\[CH2:24][CH3:25])[C@H:16]2[S:15](=[O:50])[CH2:14][C:13]=1[Cl:41])=[O:11])(=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5]
Reactant: CC/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)C(Cl)=CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCOC(=O)C(C)(C)C)=C(Cl)CS(=O)[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Yield: 76.2 %

Procedure:
To a solution of 7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-chloro-2-cephem-4-carboxylic acid pivaloyloxymethyl ester (410 mg) in dichloromethane (3 ml) is added dropwise a solution of m-chloroperbenzoic acid (47.4 mg) in dichloromethane (1 ml) with stirring at 0° C. After stirring at the same temperature for 20 minutes, the reaction mixture is diluted with aqueous sodium hydrogen carbonate. The organic layer is separated, washed with water, dried, and concentrated. The resulting residue is purified by silica gel column chromatography to give 7beta-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoyl]amino-3-chloro-3-cephem-4-carboxylic acid 1-oxide pivaloyloxymethyl ester (135 mg) as crystals.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[F:6][C:7]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]2[C:8]=1[C:9](O)=[CH:10][C:11]([CH3:19])=[N:12]2.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[Cl:3][C:9]1[C:8]2[C:13](=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:7]=2[F:6])[N:12]=[C:11]([CH3:19])[CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(F)c2c(O)cc(C)nc12
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1ccc(F)c2c(Cl)cc(C)nc12
Temperature: 118 °C

Procedure:
POCl3 (3.4 mL, 36 mmol) was added dropwise to 5-fluoro-8-methoxy-2-methyl-quinolin-4-ol (0.56 g, 2.7 mmol) at 0° C. The reaction vessel was equipped with a drying tube containing P4O10 and heated to 118° C. for 2 h. The reaction mixture was concentrated in vacuo and partitioned between DCM (30 mL), water (2 mL), and concentrated aqueous NH3 (2 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with EA/DCM 1:15) to give the title compound. MS (m/z): 226.5 [M+H+]
Reaction SMILES: [NH2:1][OH:2].[Br:3][C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=3[F:22])[N:13]=[C:12]([CH3:23])[C:11]=2[C:24]#[N:25])=[C:6]([CH3:26])[CH:5]=1>CO>[Br:3][C:4]1[N:8]([CH3:9])[C:7]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=3[F:22])[N:13]=[C:12]([CH3:23])[C:11]=2[C:24](=[N:1][OH:2])[NH2:25])=[C:6]([CH3:26])[CH:5]=1
Reactant: NO
Reactant: Cc1cc(Br)n(C)c1-c1c(C#N)c(C)nn1-c1ccc(O)cc1F
Solvent: CO
Product: Cc1cc(Br)n(C)c1-c1c(C(N)=NO)c(C)nn1-c1ccc(O)cc1F
Temperature: 150 °C
Reaction time: 0.33 h
Yield: 32.5 %

Procedure:
Hydroxylamine (16.3 M solution in water, 0.3 mL, 4.8 mmol) was added to 5-(5-bromo-1,3-dimethyl-1H-pyrrol-2-yl)-1-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (7 mg, 0.018 mmol) in MeOH (0.6 mL) and the reaction was stirred at 150° C. for 20 min in the microwave. The crude reaction was purified on preparative HPLC to give E9 5-(5-bromo-1,3-dimethyl-1H-pyrrol-2-yl)-1-(2-fluoro-4-hydroxyphenyl)-N′-hydroxy-3-methyl-1H-pyrazole-4-carboximidamide (2.47 mg, 33%). Identification of the title compound by 1H-NMR showed that the oxime product was a single isomer, but did not confirm whether the (E) or (Z) oxime isomer had been obtained. ES/MS m/z: 422.00, 424.00 (M+H), 420.09, 422.07 (M−H); 1H NMR (acetone-d6, 500 MHz): 8.11 (s, 1H), 7.20 (t, 1H, J=8.8 Hz), 6.86 (s, 1H), 6.70 (m, 1H), 6.62 (dd, 1H, J=2.6, 11.9 Hz), 3.41 (s, 3H), 2.39 (s, 3H) and 1.66 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]=[C:5]([OH:19])[C:6]1[C:7](=[C:11]([Cl:18])[C:12](Cl)=[C:13]([Cl:16])[C:14]=1[Cl:15])[C:8]([OH:10])=[O:9].[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+].Cl>O1CCCC1>[OH:1][CH2:2][CH2:3][N:4]=[C:5]([OH:19])[C:6]1[C:7](=[C:11]([Cl:18])[C:12]([S:27][C:24]2[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=2)=[C:13]([Cl:16])[C:14]=1[Cl:15])[C:8]([OH:10])=[O:9]
Reactant: Cc1ccc(S)cc1
Reactant: O=C(O)c1c(Cl)c(Cl)c(Cl)c(Cl)c1C(O)=NCCO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(Sc2c(Cl)c(Cl)c(C(O)=NCCO)c(C(=O)O)c2Cl)cc1

Procedure:
2 g (6.08 millimols) of tetrachlorophthalic acid N-2-hydroxyethylimide, 0.79 g (6.38 millimols) of p-thiocresol, 2.52 g (18.24 millimols) of potassium carbonate and 20 ml of tetrahydrofuran are stirred at 25° C. for 20 hours. The mixture is acidified with dilute HCl solution and extracted with methylene chloride and the extracts are dried over sodium sulfate. After recrystallisation from toluene, 1.41 g (56% of theory) of the title compound are obtained: melting point 205°-9° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][NH:9][C:10]([C:12]1[N:13]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=2)[C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([C:21]#[N:22])=[CH:16][CH:15]=2)=[O:11].BrC1C=C(C=CC=1)CBr.NCC(C)(C)CO.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:55][N:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>COCCOC>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][NH:9][C:10]([C:12]1[N:13]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N:59]3[CH2:60][CH2:61][N:56]([CH3:55])[CH2:57][CH2:58]3)[CH:25]=2)[C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([C:21]#[N:22])=[CH:16][CH:15]=2)=[O:11]
Reactant: CN1CCNCC1
Reactant: N#Cc1ccc2c(c1)cc(C(=O)NCC1CCCCC1O)n2Cc1cccc(Br)c1
Agent: BrCc1cccc(Br)c1
Agent: CC(C)(CN)CO
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Product: CN1CCN(c2cccc(Cn3c(C(=O)NC[C@@H]4CCCC[C@H]4O)cc4cc(C#N)ccc43)c2)CC1
Temperature: 100 °C
Yield: 8 %

Procedure:
A mixture of 5-cyano-1-[3-bromobenzyl]-1H-indole-2-carboxylic acid (2-hydroxy-cyclohexylmethyl)amide (prepared using 3-bromobenzyl bromide and 3-amino-2,2-dimethyl-1-propanol in a manner similar to that described in Example 35) (0.250 g, 0.54 mmol), tris(dibenzylidineacetone)dipalladium (125 mg, 0.014 mmol), 2-(dicyclohexylphosphine) biphenyl (9.6 mg, 0.027 mmol), potassium phosphate (1.44 g, 0.82 mmol) and N-methylpiperazine (64 mg, 0.64 mmol) in 1,2-dimethoxyethane (3 ml) were heated in a sealed Reactavial at 100° C. under nitrogen for 30 h. After cooling to ambient temperature, the mixture was filtered through dicalite and the resulting filtrate evaporated to dryness. Purification was fulfilled by chromatography on silica using DCM:methanol (19:1) as eluent, affording the title compound (0.021 g, 8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1.[CH3:9][C:10]([CH3:12])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClC(Cl)C.[OH-].[Na+]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][CH:10]([CH3:12])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: Nc1ccc(Cl)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)Nc1ccc(Cl)nc1
Reaction time: 24 h
Yield: 76.3 %

Procedure:
To a solution of 2-chloro-5-aminopyridine (500 mg, 3.88 mmol) and acetone (250 μL, 4.27 mmol) in dichloroethane (13 mL) was added NaBH(OAc)3 (989 mg, 4.66 mmol) and AcOH (330 μL, 5.82 mmol). The reaction was stirred for 24 hours and was diluted with 1N NaOH. The aqueous solution was washed with CH2Cl2 (3×). The combined organic solutions were dried (Na2SO4), filtered and concentrated. Purification by medium pressure chromatography eluting with a solvent gradient (2% MeOH in CH2Cl2 to 5% MeOH in CH2Cl2) provided 505.2 mg of (6-chloro-pyridin-3-yl)-isopropyl-amine. 1H NMR (CD3OD) δ 7.64 (d, 1H), 7.10 (d, 1H), 6.99 (dd, 1H), 3.55 (m, 1H), 1.17 (d, 6H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:12]1([O:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>CCCCCCC.ClCCCl>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([C:15]1[CH:16]=[CH:17][C:12]([O:18][CH3:19])=[CH:13][CH:14]=1)=[O:5]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCCCCCC
Product: COc1ccc(C(=O)c2ccc(F)cc2F)cc1
Temperature: 0 °C
Yield: 80.6 %

Procedure:
Combine 2,4-difluorobenzoyl chloride (227.8 g, 1.29 mol), anisole (154.2 mL, 1.42 mol) and 1,2-dichloroethane (2.28 L) and cool (−3° C.) under a nitrogen atomosphere. Add aluminum chloride (209.8 g, 1.57 mol) over 45 minutes. The solution color turns from clear to yellow. Pour the reaction mixture over a mixture of ice (1700 g) and concentrated HCl (640 mL) over 2 minutes. The color of the mixture turns from yellow to clear. Separate layers and wash organic layer with 10% potassium carbonate (1600 mL), water (1600 mL), dry (MgSO4), filter and concentrate to give a solid. Stir the solid in heptane (960 mL) and filter to give the title compound as a white solid (258.1 g, 81% Yield): 1H NMR (CDCl3, 200 MHz) δ 3.9 (s, 3H), 6.95 (m, 4H), 7.55 (quar, 1H), 7.8 (d, 2H). Purity by LC/MS (APCl)=100% area, [M+H]+=248 m/e.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([N:15]1[C:21](=[O:22])[CH2:20][CH2:19][N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH2:17][CH2:16]1)[CH2:5][CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Li+].[BH4-]>>[CH2:8]([O:7][CH2:6][CH2:5][C@H:4]([N:15]1[C:21](=[O:22])[CH2:20][CH2:19][N:18]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:31])([F:32])[F:30])[CH:24]=2)[CH2:17][CH2:16]1)[CH2:3][OH:2])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: COC(=O)[C@H](CCOCc1ccccc1)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Agent: [BH4-]
Agent: [Li+]
Product: O=C1CCN(c2cccc(C(F)(F)F)c2)CCN1[C@H](CO)CCOCc1ccccc1
Yield: 94 %

Procedure:
In analogy to the procedure described in example 2, (S)-4-benzyloxy-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-butyric acid methyl ester (example 5B) and LiBH4 gave the title compound in 94% yield as light yellow oil. MS: 437.2 (MH+).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=2[S:4][CH:3]=1.[CH:20]1(B(O)O)[CH2:22][CH2:21]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.CC(C)([O-])C.[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[CH:20]1([C:2]2[C:11]3[O:10][CH:9]([CH3:12])[CH2:8][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:6][C:5]=3[S:4][CH:3]=2)[CH2:22][CH2:21]1
Reactant: CC1CN(C(=O)OC(C)(C)C)Cc2scc(Br)c2O1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC1CN(C(=O)OC(C)(C)C)Cc2scc(C3CC3)c2O1
Temperature: 80 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
A suspension of tert-butyl 8-bromo-2-methyl-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (348 mg) obtained in Example 6, steps 1-6, cyclopropylboronic acid (129 mg), palladium acetate (11.2 mg), tricyclohexylphosphine (28 mg), potassium tert-butoxide (337 mg) and toluene (5 mL) was stirred at 80° C. for 16 hr under an argon atmosphere. The reaction solution was cooled to room temperature, and filtered through celite. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→10% ethyl acetate/hexane) to give the title compound (266 mg, 86%) as a pale-yellow oil.
Reaction SMILES: [Cl-].[NH4+].[OH-].[K+].[CH2:5]([C:7]1([CH2:38][CH3:39])[C@H:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:22])[CH2:19][O:20][CH3:21])=[CH:14][CH:13]=2)[N:9]([C:23]([NH:25][C@H:26]([CH2:34][CH:35]=[CH2:36])[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[O:24])[C:8]1=[O:37])[CH3:6].C([BH3-])#N.[Na+]>CO>[CH2:38]([C:7]1([CH2:5][CH3:6])[C@H:10]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([OH:22])[CH2:19][O:20][CH3:21])=[CH:14][CH:13]=2)[N:9]([C:23]([NH:25][C@H:26]([CH2:34][CH:35]=[CH2:36])[C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[O:24])[C:8]1=[O:37])[CH3:39]
Reactant: C=CC[C@@H](NC(=O)N1C(=O)C(CC)(CC)[C@@H]1Oc1ccc(C(=O)COC)cc1)c1ccc(C)cc1
Agent: [BH3-]C#N
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: C=CC[C@@H](NC(=O)N1C(=O)C(CC)(CC)[C@@H]1Oc1ccc(C(O)COC)cc1)c1ccc(C)cc1
Reaction time: 0.5 h
Yield: 32.8 %

Procedure:
A suspension of 755 mg (14.1mmol) of ammonium chloride and 213 mg (3.8 mmol) of potassium hydroxide in 5 mL of dry methanol was treated with 520 mg (1.08 mmol) of 3,3-diethyl-1-[(R)-α-(allyl)-4-(methyl)benzylaminocarbonyl]-4-(S)-[4-(1-oxo-2-methoxyethyl) phenoxy]azetidin-2-one. After 30 min, 205 mg (3.26 mmol) of sodium cyanoborohydride was added and the mixture stirred for 14 hr, at which point 1 gm of 3A molecular sieves was added. After 3 days, the mixture was diluted with methanol, filtered through Celite, concentrated in vacuo, filtered again (rinsing with ethyl acetate), concentrated in vacuo, and the residue purified by flash chromatography on 50 gm of silica eluting with 800 mL of 67:33 hexanes: ethyl acetate, then sequentially 1 L of 99:1 methylene chloride: methanol, 500 mL of 98.5: 1.5 methylene chloride: methanol, and 1 L of 97:3 methylene chloride: methanol to give 170 mg of 3,3-Diethyl-1-[(R)-α-(allyl)-4-(methyl)benzylaminocarbonyl]-4-(S)-[4-(1-(RS)-hydroxy-2-methoxyethyl)phenoxy]azetidin-2-one as well as impure product. The latter was purified by flash chromatography on 43 g of silica eluting with 97.5:2.5:0.3 methylene chloride: methanol: ammonia water to provide the product as an oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH2:23][C:24](=[O:35])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:11][N:10]=1)(C)(C)C.Cl.CCO>CCOC(C)=O.O1CCOCC1>[NH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([CH2:23][C:24]([NH:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[O:35])=[CH:11][N:10]=1
Reactant: COc1ccc(CNC(=O)Cc2cnc(CNC(=O)OC(C)(C)C)c3cc(OC)c(OC)cc23)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1COCCO1
Product: COc1ccc(CNC(=O)Cc2cnc(CN)c3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {6,7-dimethoxy-4-[(4-methoxy-benzylcarbamoyl)-methyl]-isoquinolin-1-ylmethyl}-carbamic acid tert-butyl ester (64 mg, 0.13 mmol) in 1.5 mL of EtOAc was added 3 mL of a 4 M solution of HCl in dioxane. After stirring at room temperature for 1 h, 1 mL of EtOH was added to facilitate solution. The reaction was stirred for 48 hours and the precipitated HCl salt was collected by filtration (58 mg, >100%). H1-NMR (DMSO): 9.00 (m, 1H), 8.79 (br s, 3H), 8.35 (s, 1H), 7.62 (s, 1H), 7.46 (s, 1H), 7.12 (d, J=8.5 Hz, 2H), 6.80 (d, 2H, J=8.3 Hz), 4.75 (br s, 2H), 4.18 (d, J=5.4 Hz, 2H), 4.02 (s, 3H), 4.00 (s, 2H), 3.82 and 3.68 (s, 3H); MS: APCI (M+H) calc'd for C22H25N3O4+H 396.5; found 396.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)([CH2:11][CH2:12][CH2:13]Cl)[C:9]#[N:10])=[N:6][CH:7]=1.CC(C[AlH]CC(C)C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[CH2:11][CH2:12][CH2:13][NH:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: COc1cccc(C(C#N)(CCCCl)c2ccc(Br)cn2)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cccc(C2(c3ccc(Br)cn3)CCCNC2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.5 %

Procedure:
To a solution of 2-(5-bromo-pyridin-2-yl)-5-chloro-2-(3-methoxy-phenyl)-pentanenitrile (0.54 g, 1.43 mmol) in CH2Cl2 (3 mL) at −78° C. was added DIBAL in CH2Cl2 (1M, 3.2 mL). The reaction mixture was stirred at −78 for 1 h and at room temperature for 4 h. The solution was poured to a saturated aqueous solution of Rochelle's salt (10 mL) and the resulting mixture was stirred vigorously for 16 h. The aqueous layer was washed with CH2Cl2 (3×10 mL), and the combined extracts were dried over Na2SO4 and concentrated. Purification by flash chromatography with CH2Cl2/MeOH (10:1) yielded 0.36 g of 5-bromo-3′-(3-methoxy-phenyl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,3′]bipyridinyl. 1HNMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 7.63 (dd, 1H), 7.24-7.18(m, 1 H), 6.91 (d, 1H) 6.81-6.67 (comp, 3H), 3.96-3.90 (m, 1H), 3.75 (s, 3H), 3.09-3.00 (comp, 2H), 2.82-2.74 (m, 1H), 2.54-2.48 (m, 1H), 2.41-2.34 (m, 1H), 1.64-1.60 (m, 1H), 1.38-1.31 (m, 1H); MS (M+1) 347.1, 349.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:36][CH2:37][CH3:38])=[C:5]([CH:28]=[CH:29][C:30]=1[C:31]1[N:32]=[CH:33][S:34][CH:35]=1)[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]2[CH2:15][CH2:16][CH:17]([C:19]([O:21]C)=[O:20])[O:18][C:13]=2[C:12]=1[CH2:25][CH2:26][CH3:27].CO.C1COCC1.C(OCC)(=O)C>[OH-].[Li+]>[CH3:1][O:2][C:3]1[C:4]([CH2:36][CH2:37][CH3:38])=[C:5]([CH:28]=[CH:29][C:30]=1[C:31]1[N:32]=[CH:33][S:34][CH:35]=1)[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]2[CH2:15][CH2:16][CH:17]([C:19]([OH:21])=[O:20])[O:18][C:13]=2[C:12]=1[CH2:25][CH2:26][CH3:27]
Reactant: CCCc1c(OCCCOc2ccc(-c3cscn3)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCOc2ccc(-c3cscn3)c(OC)c2CCC)ccc2c1OC(C(=O)O)CC2

Procedure:
The compound of Example 11 (27 mg, 50 mmol) was combined with 2 mL of 4:1 methanol/THF and 0.1 mL of IN lithium hydroxide, and the mixture was allowed to react at room temperature for 3 hr (another 0.05 mL LiOH was added after 1.5 hr). The reaction mixture was poured into ethyl acetate/0.5 M hydrochloric acid, and the ethyl acetate layer was washed with brine, dried over sodium sulfate and concentrated under vacuum to give the product. High resolution mass spectrum, m/e 481.2281 (calculated for C28H35SO4N (M-CO2), 481.2287).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:25]=[CH:24][C:9]([CH2:10][NH:11][C:12]2[O:13][C:14]3[C:19]([C:20](=[O:23])[C:21]=2[CH3:22])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:7]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C>ClCCl>[CH3:22][C:21]1[C:20](=[O:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:13][C:12]=1[NH:11][CH2:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][O:1][S:32]([C:29]2[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=2)(=[O:34])=[O:33])=[CH:25][CH:24]=1
Reactant: Cc1c(NCc2ccc(CCCCO)cc2)oc2ccccc2c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCCCc2ccc(CNc3oc4ccccc4c(=O)c3C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.5 %

Procedure:
To a solution of 2-[4-(4-hydroxy-butyl)-benzylamino]-3-methyl-chromen-4-one (100 mg, 0.30 mmol) in dichloromethane (37 mL) was added p-toluenesulfonylchloride (68 mg, 0.36 mmol), dimethylaminopyridine (43.4 mg, 0.36 mmol), and triethylamine (62 μL, 0.44 mmol) in a 0° C. ice bath. The reaction slurry stirred overnight under N2 atmosphere, warming to room temperature slowly overnight. The next day, the reaction mixture was concentrated and purified by flash column chromatography (3:1→1:1 Hexane:ethyl acetate →100% ethyl acetate) to obtain the product as an oil (45 mg, 31% yield). 1H NMR (600 MHz, CDCl3): δ 8.19 (dd, 1H, J=1.5 and 7.9 Hz), 7.76 (d, 2H, J=8.3 Hz), 7.76 (m, 1H), 7.32 (d, 2H, J=7.9 Hz), 7.29 (d, 2H, J=8.1 Hz), 7.26 (d, 2H, J=8.0 Hz), 7.13 (d, 2H, J=8.0 Hz), 4.90 (t, 1H, J=5.1 Hz), 4.64 (d, 2H, J=5.6 Hz), 4.02 (t, 2H, J=5.9 Hz), 2.57 (t, 2H, J=7.3 Hz), 2.43 (s, 3H), 1.96 (s, 3H), 1.65 (m, 4H); 13C NMR (150 MHz, CDCl3): δ 174.9, 160.2, 152.8, 144.7, 141.5, 135.4, 133.1, 131.4, 129.8, 128.9, 127.9, 127.7, 125.9, 124.6, 122.8, 116.2, 93.4, 70.3, 45.5, 34.7, 28.4, 27.1, 21.6, 7.6.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl[C:28]([O:30][CH3:31])=[O:29].[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36]>C(Cl)Cl.C(O)C>[C:32]([OH:39])(=[O:38])/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36].[F:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH:17][C:28](=[O:29])[O:30][CH3:31])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NCCN1CCC(c2noc3cc(F)ccc23)CC1
Reactant: COC(=O)Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)NCCN1CCC(c2noc3cc(F)ccc23)CC1
Reaction time: 1 h

Procedure:
A mixture of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethylamine (2.0 gm, 7.6 mmol) and triethylamine (1.0 gm, 10 mmol) in DCM (50 ml) was treated with methyl chloroformate (860 mg, 9.12 mmol) dropwise at room temperature. The mixture was stirred for 1 hr. The reaction mixture was diluted with DCM and washed with brine. The organic solution was dried over MgSO4 and concentrated to a crude oil. The purification was done by flash chromatography over a silica gel columns(28 gm of Sorbsil C-30, eluted with DCM and MeOH/DCM). The pure oil thus obtained weighed 2.34 gm. It was converted to a fumarate salt by treatment with fumaric acid (840 mg, 1.0 eq) in ethanol. Crystallization was induced by adding drops of isopropyl ether, yield: 2.31 gm, m.p.=163°-165° C.