Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:15](=[O:30])[N:16]([CH2:18][C:19]3[C:20](C)=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=3)[N:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C(Cl)Cl.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CCOC(C)=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[CH:6]=[CH:5][N:4]3[C:15](=[O:30])[N:16]([CH2:18][C:19]4[CH:20]=[N:21][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:23][CH:24]=4)[N:17]=[C:3]3[C:2]=2[C:36]2[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(Br)c(-c3ccc(Cl)cc3)ccn2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2c(-c3ccc(Cl)cc3)ccn3c(=O)n(Cc4ccc(C(F)(F)F)nc4)nc23)cc1
Temperature: 90 °C
Yield: 65.6 %

Procedure:
Into a 5 dram vial at room temperature were placed a magnetic stirbar, 8-bromo-7-(4-chlorophenyl)-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (100 mg, 0.20 mmol), 4-methoxyphenylboronic acid (94 mg, 0.60 mmol), Pd(dppf)Cl2.CH2Cl2 (17 mg, 0.02 mmol), powdered anhydrous K3PO4 (133 mg, 0.60 mmol), and dry THF (3 mL). The vial was flushed with argon and then capped tightly. The vial was heated to 90° C. for 6 h while stirring. Analysis by HPLC/MS indicated that starting material was absent and one major new product had formed. The reaction mixture was diluted with EtOAc (20 mL) and water (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc. The combined organic extract was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was purified by automated silica gel chromatography (eluted with EtOAc/hexanes) to obtain the title compound (67 mg) as an oil. HPLC/MS: retention time=4.0 min, [M+H]+=511.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][C:22]1([CH3:27])[CH2:26][O:25][CH2:24][NH:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([N:23]3[C:22]([CH3:27])([CH3:21])[CH2:26][O:25][CH2:24]3)=[O:14])[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC1(C)COCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)COCN1C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 4,4-dimethyloxazolidine (CAN 51200-87-4) in the presence of TBTU and DIEA to obtain the title compound as white solid; MS (EI): m/e=368.5 [MH+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]3[C:17]4[CH2:28][CH2:27][NH:26][C:20]5([CH2:25][CH2:24]C[O:22][CH2:21]5)[C:18]=4[O:19][C:13]=3[CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.F[C:30]1C=C(S)C=CC=1.IC1C=CC2C3CCNC4(CCOC4C)C=3OC=2C=1>>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]3[C:17]4[CH2:28][CH2:27][NH:26][C:20]5([CH2:25][CH2:24][O:22][CH:21]5[CH3:30])[C:18]=4[O:19][C:13]=3[CH:12]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(S)c1
Reactant: O=S(=O)(c1cccc(F)c1)c1ccc2c3c(oc2c1)C1(CCCOC1)NCC3
Agent: CC1OCCC12NCCc1c2oc2cc(I)ccc12
Product: CC1OCCC12NCCc1c2oc2cc(S(=O)(=O)c3cccc(F)c3)ccc12

Procedure:
Prepared as described for 7-[(3-fluorophenyl)sulfonyl]-3,4,5′,6′-tetrahydro-2H,4′H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-pyran] (Example 22) starting from 3-fluorobenzenethiol and 7-iodo-2′-methyl-3,4,4′,5′-tetrahydro-2H-spiro[1-benzofuro[2,3-c]pyridine-1,3′-furan].
Reaction SMILES: C([O:8][C:9]([C:11]1[O:12][C:13]([CH:16]=[CH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:14][CH:15]=1)=[O:10])C1C=CC=CC=1>CO.[Pd]>[C:21]([O:20][C:18]([CH2:17][CH2:16][C:13]1[O:12][C:11]([C:9]([OH:10])=[O:8])=[CH:15][CH:14]=1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C(=O)OCc2ccccc2)o1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)CCc1ccc(C(=O)O)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
5-(2-tert-Butoxycarbonylethenyl)furan-2-carboxylic acid benzyl ester (0.97 g, 2.80 mmol) was dissolved in methanol (50 mL), 10% palladium/carbon (0.1 g) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. After completion of the reaction, palladium/carbon was removed by celite filtration, and the solvent was evaporated under reduced pressure to give the title compound (0.66 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:20][CH:19]3[CH2:21][CH2:22][CH2:23][CH:18]3[CH:17]2[CH2:24][OH:25])=[O:15])=[CH:4][CH:3]=1.Cl[C:27]1[O:28][C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>>[O:28]1[C:29]2[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=[C:27]1[O:25][CH2:24][CH:17]1[CH:18]2[CH2:23][CH2:22][CH2:21][CH:19]2[CH2:20][N:16]1[C:14]([C:9]1[N:10]=[C:11]([CH3:13])[S:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:15]
Reactant: Cc1nc(C(=O)N2CC3CCCC3C2CO)c(-c2ccc(F)cc2)s1
Reactant: Clc1nc2ccccc2o1
Product: Cc1nc(C(=O)N2CC3CCCC3C2COc2nc3ccccc3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared following the same general protocol as described for Example 80 using (5-(4-fluorophenyl)-2-methylthiazol-4-yl)(1-(hydroxymethyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone and 2-chlorobenzoxazole. MS (ESI) 478.2 (M+H).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:22]([O:24][CH3:25])=[O:23])[CH:2]=C.[O:26]=[O+][O-]>C(Cl)Cl.CO>[CH2:15]([O:14][C:13]1[C:4]([CH2:1][CH:2]=[O:26])=[C:5]([C:22]([O:24][CH3:25])=[O:23])[CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=[O+][O-]
Reactant: C=CCc1c(OCc2ccccc2)cc(C(=O)OC)cc1C(=O)OC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(OCc2ccccc2)c(CC=O)c(C(=O)OC)c1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of dimethyl 4-allyl-5-(benzyloxy)isophthalate (3.5 g, 10.28 mmol) in CH2Cl2 and methanol was cooled to −78° C. and treated with ozone until the solution appeared blue (20 min). Nitrogen was bubbled through the solution until the blue color dissipated. Dimethylsulfide (1.0 mL) was added and the cold-bath was removed allowing the reaction mixture to warm to room temperature overnight. Concentration of the solution under vacuum provided an oil which was purified by column chromatography on silica gel eluted with 10-30% EtOAc in hexanes to afford the aldehyde (3.0 g, 98%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.90 (s, 3 H) 3.95 (s, 3 H) 4.29 (s, 2 H) 5.14 (s, 2 H) 7.31-7.56 (m, 5 H) 7.81 (d, J=1.32 Hz, 1 H) 8.29 (d, J=1.51 Hz, 1 H) 9.75 (s, 1 H); MS (ESI, pos): 343.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)C(=O)C(F)(F)F)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[CH:38]=[C:37]([OH:39])[CH:36]=[C:35]([OH:40])[CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:11][CH2:10][N:9]1[C:32](=[O:41])[C:33]1[CH:34]=[C:35]([OH:40])[CH:36]=[C:37]([OH:39])[CH:38]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cc(O)cc(O)c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(c1cc(O)cc(O)c1)N1CC[C@H](NCc2ccnc3ccccc23)C[C@H]1Cc1ccccc1

Procedure:
0.097 g (0.172 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dihydroxybenzoyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine is reacted with 0.026 g (0.688 mmol) of sodium borohydride in analogy to Example 2. The title compound ##STR73## is obtained (0.023 g, 29%) as white foam. TLC: methylene chloride/methanol/conc. ammonia (350:50:1) Rf =0.57, FD-MS: M+ =467.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[CH2:5]2.CO[CH:16]1[CH2:20][CH2:19][CH:18](OC)O1.Cl.ClC1C=CN=CC=1>O1CCOCC1>[N:1]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8](=[O:12])[NH:7][C:6](=[O:13])[CH2:5]3)[CH:16]=[CH:20][CH:19]=[CH:18]1
Reactant: Nc1ccc2c(c1)CC(=O)NC2=O
Reactant: COC1CCC(OC)O1
Agent: Cl
Agent: Clc1ccncc1
Solvent: C1COCCO1
Product: O=C1Cc2cc(-n3cccc3)ccc2C(=O)N1
Yield: 66.9 %

Procedure:
A mixture of 6-amino-4H-isoquinoline-1,3-dione (1 g, 5.68 mmol), 2,5-dimethoxytetrahydrofuran (0.736 mL, 5.68 mmol), 4-chloropyridine hydrochloride (0.417 g, 2.78 mmol) in dioxane (20 mL) is heated at 70° C. for 2 h [Ref: J. Heterocyclic Chem. 35, 1313, (1998)] After cooling, the solid is filtered, washed successively with water, ether and hexane to yield 0.86 g (67%) of the title compound as a light brown solid, mp 212-213° C.; HRMS (ESI) m/z calcd for C13H10N2O2 227.08151. found 227.08151 (M+H)+1. Analysis for C13H10N2O2 (0.5H2O): Calcd: C, 66.37; H, 4.71; N, 11.91. Found: C, 66.19; H, 4.56; N, 11.09.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7]CCO.[CH2:11]([O:13][C:14](=[O:42])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37]S(C)(=O)=O)[CH3:12]>C1(C)C=CC=CC=1>[CH2:11]([O:13][C:14](=[O:42])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][O:7][CH2:6][CH2:5][O:4][CH3:3])[CH3:12]
Reactant: COCCOCCO
Reactant: CCOC(=O)CCCCCOCCOCCOCCOCCOCCOCCS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCOCCOCCOCCOCCOCCOCCOCCOC
Temperature: 0 °C
Reaction time: 4 h
Yield: 62.6 %

Procedure:
NaH (88 mg of a 60% dispersion in oil, 2.2 mmol) was suspended in anhydrous toluene (3 ml) under N2 and chilled to 0° C. Monodispersed diethylene glycol monomethyl ether (0.26 ml, 0.26 g, 2.2 mmol) that had been dried via azeotropic distillation with toluene was added. The reaction mixture was allowed to warm to room temperature and stirred for four hours, during which time the cloudy gray suspension became clear and yellow and then turned brown. Mesylate 5 (0.50 g, 1.0 mmol) in 2.5 ml dry toluene was added. After stirring at room temperature over night, the reaction was quenched by the addition of 2 ml of methanol and the resultant solution was filtered through silica gel. The filtrate was concentrated in vacuo and the FAB MS: m/e 499 (M+H), 521 (M+Na). Additional purification by preparatory chromatography (silica gel, 19/3 chloroform/methanol) provided the monodispersed compound 6 as a clear yellow oil (0.302 g 57%). FAB MS: m/e 527 (M+H), 549 (M+Na).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([C:12]#[N:13])=[CH:6][CH:5]=[CH:4][C:3]1=2>CC1C=CC(C(C)C)=CC=1.CC1C=CC(S([N-][C@@H]([C@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1.Cl[Ru+].CCN(CC)CC>[OH:1][C@@H:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([C:12]#[N:13])=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: N#Cc1cccc2c1CCCC2=O
Agent: Cl[Ru+]
Agent: Cc1ccc(S(=O)(=O)[N-][C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccc(C(C)C)cc1
Product: N#Cc1cccc2c1CCC[C@H]2O
Temperature: 30 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
To a stirred solution of 5-oxo-5,6,7,8-tetrahydronaphthalene-1-carbonitrile INT-1 (3.0 g, 17.5 mmol) in 5:1 HCO2:NEt3 (24 mL) was added RuCl(p-cymene)[(R,R)-Ts-DPEN] (0.13 g, 0.26 mmol). The mixture was stirred at 30° C. for 15 h then partitioned between EA and H2O. The combined organic layers were dried over Na2SO4 and chromatographed (EA/hex) to provide 2.99 g (99%) of (R)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-1-carbonitrile INT-2 as a white solid. LCMS-ESI (m/z) calculated for C11H11NO: 173.2; found 174.1 [M+H]+, 156.1 [M−NH4]+, tR=2.60 min. 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=7.8 Hz, 1H), 7.54 (dt, J=8.7, 4.4 Hz, 1H), 7.34-7.26 (m, 1H), 4.85-4.71 (m, 2H), 3.48 (s, 1H), 3.13-2.96 (m, 1H), 2.90 (ddd, J=17.7, 7.8, 5.6 Hz, 1H), 2.15-1.95 (m, 2H), 1.97-1.76 (m, 2H). Chiral HPLC: (R)-5-hydroxy-5,6,7,8-tetrahydronaphthalene-1-carbonitrile was eluted with 5% IPA/hexane: 99.1% ee, tR=15.3 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[F:20])[CH2:6][CH2:5]2.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:46]1[C:54]2[C:49](=[N:50][CH:51]=[N:52][C:53]=2[NH2:55])[N:48]([CH3:56])[N:47]=1.C([O-])(O)=O.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[F:20][C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[CH2:12][C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:46]3[C:54]4[C:49](=[N:50][CH:51]=[N:52][C:53]=4[NH2:55])[N:48]([CH3:56])[N:47]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)=[O:21]
Reactant: O=C(Cc1cc(F)ccc1F)N1CCc2cc(Br)ccc21
Reactant: Cn1nc(Br)c2c(N)ncnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(F)ccc2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
To a mixture of 5-bromo-1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indole (160 mg, 0.454 mmol), bis(pinacolato)diboron (127 mg, 0.500 mmol), and potassium acetate (134 mg, 1.363 mmol) was added 1,4-dioxane (6 mL), and the mixture was degassed with N2 for 10 minutes. PdCl2(dppf)-CH2Cl2 adduct (18.55 mg, 0.023 mmol) was added, and the reaction mixture was stirred for 3 hours at 100 C in a sealed vessel. The reaction was cooled down to room temperature. 3-bromo-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (104 mg, 0.454 mmol) and sat. aq. NaHCO3 (2 mL) were added, and N2 gas was bubbled through the mixture for 10 minutes. PdCl2(dppf)-CH2Cl2 adduct (18.55 mg, 0.023 mmol) was added, the vessel was sealed, and the reaction mixture was stirred overnight at 100 C (LCMS:N13207-34suzu). The mixture was allowed to cool to room temperature and poured onto water (˜150 mL). The resulting mixture was filtered, and the resulting solid was triturated with Et2O. To the solid in the filter was added a 90:10 mixture of CHCl3:CH3OH (˜7 mL), and the resulting mixture was filtered. The filtrate was injected into a 90 g SiO2 columns. Flash chromatography on SiO2 (gradient: 100% CHCl3 to 90:10:1 CHCl3:CH3OH:NH4OH) provided the title compound 3-{1-[(2,5-difluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (160 mg) as a brown solid. 1H NMR (400 MHz, DMSO-d6) δ 3.29 (t, J=8.34 Hz, 2H), 3.94 (s, 3H), 3.97 (s, 2H), 4.30 (t, J=8.46 Hz, 2H), 7.14-7.31 (m, 3H), 7.44 (d, J=8.34 Hz, 1H), 7.53 (s, 1H), 8.14 (d, J=8.34 Hz, 1H), 8.25 (s, 1H)
Reaction SMILES: C[O:2][C:3]([C@@H:5]([NH:7][C:8](=[O:33])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][CH2:18][C@H:17]([NH:20][C@@H:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH2:16]2)=[CH:11][CH:10]=1)[CH3:6])=O.[BH4-].[Li+].[Cl-].[NH4+].C(Cl)(Cl)Cl>C1COCC1>[OH:2][CH2:3][C@@H:5]([NH:7][C:8](=[O:33])[C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:19][CH2:18][C@H:17]([NH:20][C@@H:21]([C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=[CH:25][CH:24]=3)[CH3:22])[CH2:16]2)=[CH:13][CH:14]=1)[CH3:6]
Reactant: COC(=O)[C@H](C)NC(=O)c1ccc(N2CC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: C[C@@H](CO)NC(=O)c1ccc(N2CC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.2 %

Procedure:
In 1 ml of THF was dissolved 31.9 mg of N—[(S)-1-methoxycarbonylethyl]-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzamide, 3.0 mg of lithium borohydride was added thereto, and the mixture was stirred at room temperature for 1 day. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and chloroform was added to the mixture and the mixture was stirred and then the liquids were separated. The organic layer was dried and evaporated, and then, the residue was purified by NH silica gel thin-layer chromatography (chloroform:methanol=95:5) to obtain 14.7 mg of N—[(S)-1-hydroxypropan-2-yl]-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzamide (the following Table X, Example 12.003).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([C@@H:15]1[C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:17][C:16]1=[O:24])[CH2:12][CH2:13][CH3:14].[CH2:25]([O:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1>[CH2:11]([C@@:15]1([C:33]([O:32][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:34])[C@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:17][C:16]1=[O:24])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCC[C@H]1OC(=O)[C@@H]1CCCC
Reactant: O=C(Cl)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCC[C@@H]1OC(=O)[C@]1(CCCC)C(=O)OCc1ccccc1
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 76.2 %

Procedure:
To a −78° C. solution of NaHMDS (1.2 equiv, 0.91 mmol, 45 μL, 2M in THF) in 5 mL THF was added 150 mg (0.73 mmol) of β-lactone 3a dissolved in 2.5 mL THF. After 1.5 h, benzylchloroformate (1.1 equiv, 0.833 mmol, 120 μL) was added at one time and stirred for an additional 3 h. This solution was warmed to 23° C. over 1 h and worked up as described above for β-lactone 8b. Flash chromatography on SiO2 (5% Et2O:hexanes) gave β-lactone 8c (185 mg, 74% yield) as a colorless oil: Rf 0.48 (15% Et2O:Hexanes); IR (thin film) 1824, 1757, 1716 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.40 (m, 5H), 5.27, 5.22 (AB q, J=12.0, 2H), 4.52 (dd, J=4.8, 8.4 Hz, 1H), 2.50-2.56 (m, 1H), 2.22-2.30 (m, 2H), 1.71-1.85 (m, 1H), 1.44-1.60 (m, 4H), 1.15-1.39 (m, 8H), 0.81-0.92 (m, 6H); 13C NMR (500 MHz, CDCl3) 14, 14.6, 14.7, 23.1, 23.3, 23.6, 24.9, 25.8, 26.9, 29.4, 30.4, 31.1, 31.9, 32.3, 40.4, 71.6, 79.8, 121.7, 129.2, 129.4, 129.5, 129.8, 133.1, 152.7, 163.7, 167.3; ESI LRMS Calcd. for C20H28LiO4+[M+Li]: 339. Found: 338.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:27](Cl)([Cl:29])=[O:28]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:27]([Cl:29])=[O:28])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cl)OC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
1-Benzyloxycarbonyl-4-hydroxypiperidine (15 g., 0.0638 mole) and N,N-diisopropylethylamine (12.3 ml., 9.13 g., 0.0707 mole) were dissolved in toluene (150 ml.), and the solution was added over 30 min. to a solution of phosgene (12.63 g., 0.128 mole) in toluene (150 ml.). The reaction mixture was protected from atmospheric moisture (drying tube), stirred magnetically, and kept at ambient temperature in a water bath during the addition. When the addition was complete the mixture was filtered and the solid residue washed with toluene (ca. 50 ml.). The solvent in the combined filtrate and washings was evaporated in vacuo (1 mm. pressure, solid CO2 cold finger condenser) to give 1-benzyloxycarbonyl-4-chlorocarbonyloxypiperidine, I.R. λmax 1775 cm.-1 and 1700 cm.-1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[NH:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.O[CH2:22][CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(P(CCCC)CCCC)CCC.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1.C([O-])(O)=O.[Na+]>[CH2:27]([O:26][C:25]([NH:24][CH2:23][CH2:22][O:1][C:2]1[CH:3]=[C:4]([CH:8]2[NH:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1)=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(NCCO)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNC(c2cccc(O)c2)C1
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C([O-])O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCNC(c2cccc(OCCNC(=O)OCc3ccccc3)c2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(+) or (−)-tert-butyl 3-(3-hydroxyphenyl)piperazine-1-carboxylate (tr=9.7 min) (Biological Example 2.1) (300 mg, 1.078 mmol) and benzyl 2-hydroxyethylcarbamate (210 mg, 1.078 mmol) were dissolved in THF (10 ml). Tributylphosphine (0.404 ml, 1.617 mmol) was added, and after cooling to 0° C., DEAD 40% in toluene (0.640 ml, 1.617 mmol) was added dropwise. The reaction was stirred for 2 h at 0° C., then overnight at rt. The reaction mixture was diluted with aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with AcOEt. The organic phase dried over MgSO4 and concentrated in vacuum. The crude residue was purified by preparative HPLC (Macherey-Nagel Nucleosil 100-10 C18, CH3CN/H2O (0.1% TFA)) to give the title compound. MS (ESI+) m/z 455.2 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.O>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH:24][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(=O)c1ccc2ccnc(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2ccnc(NCc3ccc(OC)cc3)c2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
To a solution of ethyl 1-chloroisoquinoline-7-carboxylate (548 mg, 2.32 mmol) in N,N-dimethylformamide (9.3 mL) was added 4-methoxy-benzylamine (4.6 mL, 35 mmol) and potassium carbonate (5.14 g, 37.2 mmol). The reaction was heated to 70° C. and stirred overnight. The reaction was cooled to room temperature and was diluted with ethyl acetate and water. The layers were separated and the aqueous was extracted twice with ethyl acetate. The combined organics were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. Purification by flash column chromatography (0-35% ethyl acetate/heptanes) gave the title compound (430 mg, 55%) as a greenish oil. 1H NMR (400 MHz, CDCl3, δ): 8.49 (s, 1H), 8.16 (dd, J=8.6, 1.6 Hz, 1H), 8.09 (d, J=5.9 Hz, 1H), 7.69 (d, J=8.6 Hz, 1H), 7.33-7.40 (m, 2H), 6.96 (d, J=5.9 Hz, 1H), 6.87-6.93 (m, 2H), 5.67 (br. s., 1H), 4.76 (d, J=5.1 Hz, 2H), 4.41 (q, J=7.2 Hz, 2H), 3.81 (s, 3H), 1.37-1.43 (m, 3H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12]C)=[O:11])=[CH:9][C:4]=2[CH:3]=[N:2]1.[OH-].[Na+]>CO>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[CH:3]=[N:2]1
Reactant: COC(=O)c1ccc2sncc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2sncc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.8 %

Procedure:
61 mg of methyl benzo[d]isothiazole-5-carboxylate was dissolved in 1.26 mL methanol and treated with 1.26 mL 10% aqueous sodium hydroxide. The mixture was stirred 18 h at room temperature. The reaction mixture was concentrated, and then diluted with water. Acidified to pH ˜3 and collected the precipitate by filtration. The filtercake was washed with water. The solid was then dried under high vacuum to yield 48 mg of benzo[d]isothiazole-5-carboxylic acid as a white solid. 1H NMR (400 MHz, DMSO-d6) δδ ppm 8.08 (dd, J=8.49, 1.46 Hz, 1 H) 8.31 (d, J=8.58 Hz, 1 H) 8.79 (s, 1 H) 9.24 (d, J=0.78 Hz, 1 H).