Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]([CH2:47][CH2:48][NH:49]C(OC(C)(C)C)=O)[CH:9]1[CH2:12][CH:11]([CH2:13][C:14]([NH:16][C@H:17]([B:34]2[O:42]C3C(C)(C4CC(C3)C4(C)C)[O:35]2)[CH2:18][C:19]2[C:20](OC)=[C:21]([CH:29]=[CH:30][CH:31]=2)[C:22]([O:24]C(C)(C)C)=[O:23])=[O:15])[CH2:10]1)=O)(C)(C)C.B(Cl)(Cl)Cl>>[NH2:49][CH2:48][CH2:47][NH:8][CH:9]1[CH2:12][CH:11]([CH2:13][C:14]([NH:16][C@H:17]2[CH2:18][C:19]3[CH:31]=[CH:30][CH:29]=[C:21]([C:22]([OH:24])=[O:23])[C:20]=3[O:35][B:34]2[OH:42])=[O:15])[CH2:10]1
Reactant: COc1c(C[C@H](NC(=O)CC2CC(N(CCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: NCCNC1CC(CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)C1

Procedure:
Prepared from tert-butyl 3-((R)-2-(2-(3-(tert-butoxycarbonyl(2-(tert-butoxycarbonylamino)ethyl)amino)cyclobutyl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoate and BCl3 following the procedure described in Step 2 of Example 1. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 362 (MH)+.
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:18]([O:20][C:21](=[O:26])/[CH:22]=[CH:23]/[CH2:24]Br)[CH3:19]>CO>[CH2:18]([O:20][C:21](=[O:26])/[CH:22]=[CH:23]/[CH2:24][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:1]23[CH2:8][CH:7]4[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]4)[CH2:10]2)[CH2:2]3)=[CH:16][CH:15]=1)[CH3:19]
Reactant: Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: CCOC(=O)/C=C/CBr
Solvent: CO
Product: CCOC(=O)/C=C/COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1

Procedure:
Analogously to the procedure described in Example 5, the use of 11.4 g of 4-(1-adamantyl)-phenol and 14.5 g of 4-bromocrotonic acid ethyl ester as starting materials gives 4-[4-(1-adamantyl)-phenoxy]-crotonic acid ethyl ester of melting point 91°-93° C (from methanol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]1[CH2:13][CH2:12][C:11]([F:15])([F:14])[CH2:10][C@H:9]1[C:16]([OH:18])=O.F[P-](F)(F)(F)(F)F.[N:26]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)[C:30]2C=CC=C[C:29]=2[N:28]=N1.Cl.NCC#N.C(N(CC)CC)C>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]1[CH2:13][CH2:12][C:11]([F:14])([F:15])[CH2:10][C@H:9]1[C:16]([NH:28][CH2:29][C:30]#[N:26])=[O:18]
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: O=C(O)[C@@H]1CC(F)(F)CC[C@H]1c1ccccc1Br
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: N#CCNC(=O)[C@@H]1CC(F)(F)CC[C@H]1c1ccccc1Br
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A mixture of (1R,2R)-2-(2-bromophenyl)-5,5-difluorocyclohexanecarboxylic acid (820 mg, 2.58 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (1.49 g, 2.86 mmol) and aminoacetonitrile hydrochloride (530 mg, 5.73 mmol) in N, N-dimethylformamide (5.0 mL) was cooled to 0° C. and treated with triethylamine (1.26 mL, 9.04 mmol). The resulting slurry was stirred at room temperature for 2.5 hours and then poured into water and extracted with ethyl acetate (3×). The combined extracts were washed with brine and dried (Na2SO4). Concentration in vacuo and chromatography of the residue on silica eluting with 2/3 EtOAc/hexanes yielded (1R,2R)-2-(2-bromophenyl)-N-(cyanomethyl)-5,5-difluorocyclohexanecarboxamide as a faint-yellow foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][CH2:8][NH:7][C:6]=2[CH:16]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][CH2:8][N:7]([C:21]3[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=3)[C:6]=2[CH:16]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1NCC2
Reactant: Clc1ccc(I)cc1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc(Cl)cc1)CC2
Yield: 21.1 %

Procedure:
A solution of 8-bromo-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (50 mg, 0.17 mmol), 1-chloro-4-iodobenzene (82 mg, 0.34 mmol), Pd2(dba)3 (15 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (15 mg) and Cs2CO3 (110 mg, 0.34 mmol) in toluene (10 mL) was heated at 110° C. overnight. The reaction mixture was evaporated, water (10 mL) was added, extracted with ethyl acetate (20 mL), concentrated to give the crude product, which was purified by prep-TLC (DCM:MeOH=15:1) to afford 8-bromo-6-(4-chlorophenyl)-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (14 mg, yield 20%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[C:12]([CH3:17])[CH:11]=1)/[C:5](=[N:7]/C)/[CH3:6].Cl.NO>C(O)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([CH3:6])=[N:7][O:18][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[C:12]([CH3:17])[CH:11]=1)=[O:19]
Reactant: C/N=C(\C)C(C(=O)OC)C(=O)c1ccc(Br)c(C)c1
Agent: Cl
Agent: NO
Solvent: CC(=O)O
Product: COC(=O)c1c(C)noc1-c1ccc(Br)c(C)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
2-(4-Bromo-3-methyl-benzoyl)-3-[(E)-methylimino]-butyric acid methyl ester (40.0 mmol) and hydroxylamine hydrochloride (2.9 g, 41 mmol) were combined in acetic acid (100 mL) and stirred at 60° C. overnight. The mixture was concentrated, and the residue was partitioned between EtOAc and water. Saturated aqueous NaHCO3 was added to neutralize residual acetic acid, and the organic layer was separated and washed twice with water. The combined aqueous layers were back-extracted with EtOAc, and the combined organic layers were dried, filtered, and concentrated. The crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][C:6]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][NH:8][C:7]1=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][C:6]1([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:10][CH2:9][NH:8][C:7]1=[S:31]
Reactant: CCOC(=O)C1(Cc2ccc(F)c(F)c2)CCCNC1=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(Cc2ccc(F)c(F)c2)CCCNC1=S
Temperature: 100 °C
Reaction time: 8 h
Yield: 127.6 %

Procedure:
To a mixture of ethyl 3-(3,4-difluorobenzyl)-2-oxopiperidine-3-carboxylate (2.8 g) in toluene (50 ml) was added Lawesson's reagent (2.67 g) at room temperature, and the mixture was stirred at 100° C. overnight. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.64 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1.C([BH3-])#N.[Na+].[CH3:30][C:31]([CH3:33])=O.C(#N)C>C(Cl)(Cl)Cl.[B].C(O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:15]2[CH:16]=[CH:17][C:12]([O:11][C@@H:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:10][C@@H:2]3[NH:1][CH:31]([CH3:33])[CH3:30])=[CH:13][CH:14]=2)=[CH:20][CH:21]=1
Reactant: CC(C)=O
Reactant: N[C@H]1Cc2ccccc2[C@H]1Oc1ccc(Oc2ccc(F)cc2)cc1
Agent: [BH3-]C#N
Agent: [B]
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(C)N[C@H]1Cc2ccccc2[C@H]1Oc1ccc(Oc2ccc(F)cc2)cc1
Yield: 53 %

Procedure:
The title compound was prepared in a similar manner to Example 31 from (±) cis-2-amino-1-[4-(4-fluorophenoxy)phenoxy]indane (70 mg, 0.2 mmol), sodium cyanoborohydride (25 mg, 0.4 mmol), acetone (0.29 ml, 4 mmol) and acetonitrile (10 ml). After subjecting the crude product to column chromatography on silica gel eluting with 5% ethanol in chloroform, residual boron impurities were removed by dissolving the product in hexanes and filtering. Removal of the hexanes in vacuo afforded the title compound (40 mg) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([OH:15])=O)[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:44][C:45]1[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([NH:44][C:45]3[CH:50]=[CH:49][N:48]=[CH:47][CH:46]=3)=[O:15])[CH2:7][C@@H:6]3[CH2:16][O:17][CH2:18][CH2:19][N:5]3[C:4]=2[N:3]=1
Reactant: O=C(O)CN1C[C@@H]2COCCN2c2nc(Cl)ncc21
Reactant: Nc1ccncc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CN1C[C@@H]2COCCN2c2nc(Cl)ncc21)Nc1ccncc1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x26 using (R)-2-(2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetic acid (PREPARATION x25, 50 mg, 0.176 mmol), HATU (87 mg, 0.228 mmol), 4-aminopyridine (25 mg, 0.263 mmol) and triethylamine (0.073 mL, 0.527 mmol) in DMF (2 mL). ESI-MS m/z [M+H]+ calc'd for C16H17ClN6O2, 361.12; found 361.2.
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[CH:12]([C:31]2[CH:36]=[CH:35][C:34](Cl)=[C:33]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[CH:41][CH:40]=3)[CH:32]=2)[N:11]([CH3:48])[CH:10]1[CH2:49][O:50]CC1C=CC=CC=1)C1C=CC=CC=1>CO.C(O)(=O)C.[Pd]>[CH2:46]([O:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][C:33]2[CH:32]=[C:31]([C@H:12]3[C@H:13]([OH:23])[C@@H:14]([OH:15])[C@H:9]([OH:8])[C@@H:10]([CH2:49][OH:50])[N:11]3[CH3:48])[CH:36]=[CH:35][CH:34]=2)=[CH:40][CH:41]=1)[CH3:47]
Reactant: CCOc1ccc(Cc2cc(C3[C@H](OCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)C(COCc4ccccc4)N3C)ccc2Cl)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCOc1ccc(Cc2cccc([C@H]3[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)N3C)c2)cc1
Yield: 24.2 %

Procedure:
Compound from step E (50 mg) in methanol and acetic acid (25 uL) was treated 5% wet Pd—C (10 mg) under H2 atmosphere for 4 h. The reaction mixture was filtered through a pad of celite and concentrated. Chromatography on silica gel (10 to 100% acetonitrile containing 0.1% ammonium acetate/water gradient) provided (2S,3S,4R,5R,6R)-2-[3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-1-methyl-piperidine-3,4,5-triol (6 mg, 70%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[CH3:9].[OH:10][C@H:11]1[CH2:15][NH:14][C:13](=[O:16])[CH2:12]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:14]2[CH2:15][C@H:11]([OH:10])[CH2:12][C:13]2=[O:16])=[CH:4][C:3]=1[CH3:9]
Reactant: O=C1C[C@@H](O)CN1
Reactant: Cc1cc(I)ccc1Br
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Cc1cc(N2C[C@H](O)CC2=O)ccc1Br
Temperature: 110 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
A mixture of 2-bromo-5-iodotoluene (500 mg, 1.68 mmol), (R)-4-hydroxy-pyrrolidinone (204 mg, 2.02 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (58.5 mg, 0.101 mmol), tris(dibenzylideneacetone)-dipalladium(0)-chloroform adduct (35.0 mg, 0.034 mmol) and cesium carbonate (769 mg, 2.36 mmol) in 1,4-dioxane (degassed, 5 ml) was stirred at 110° C. overnight in a nitrogen stream. The reaction mixture was treated with H2O and extracted with AcOEt (×2). The organic layers were combined and sequentially washed with H2O and saturated brine, and then dried over Na2SO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (n-hexane/AcOEt) to give (R)-1-(4-bromo-3-methyl-phenyl)-4-hydroxy-pyrrolidin-2-one as a pale brown solid (173 mg, 38%).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([NH:16][CH:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][C:8]3[C:9](I)=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.CC1(C)C2C=[CH:37][CH:36]=[C:35](P(C3C=CC=CC=3)C3C=CC=CC=3)[C:34]=2[O:33]C2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[Pd](Cl)Cl.C(O)CCC>[Br:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([NH:16][CH:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:7][C:8]3[C:9]([CH:34]([CH:35]4[CH2:37][CH2:36]4)[OH:33])=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Reactant: CC(Nc1nc2c(I)c[nH]c(=O)c2c2cc(Br)ccc12)C(C)(C)C
Agent: Cl[Pd]Cl
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CC(Nc1nc2c(C(O)C3CC3)c[nH]c(=O)c2c2cc(Br)ccc12)C(C)(C)C
Temperature: 100 °C

Procedure:
9-bromo-4-iodo-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one (50 mg, 0.100 mmol), palladium(II) chloride (0.355 mg, 1.999 μmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (1.157 mg, 1.999 μmol), triethylamine (18.11 μl, 0.130 mmol) and 1-butanol (1000 μl) were combined in a 40 mL vial and sparged with nitrogen for 5 minutes. The cap on the vial was removed and the atmosphere changed to carbon monoxide by pressurizing to 30 psi and releasing the pressure 3 times inside a stainless steel pressure vessel. Then, the pressure of CO was adjusted to 100 psi and heated to 100° C. for 5 h. Then, the reaction was cooled to room temperature, the reaction was then poured into ethyl acetate, washed with saturated NaHCO3, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA, to afford the title compound as a white solid. 1H NMR (500 MHz, C2D6SO) δ 11.68 (d, 1H, J=6.0 Hz), 10.04 (d, 1H, J=2.0 Hz), 8.50 (d, 1H, J=9.0 Hz), 7.83 (d, 1H, J=7.0 Hz), 7.78 (d, 1H, J=7.5 Hz), 7.68 (d, 1H, J=8.5 Hz), 4.81 (m, 1H), 4.22 (m, 2H), 1.68 (m, 2H), 1.37 (m, 2H), 1.17 (m, 6H), 0.93 (s, 9H). LRMS (ESI) calc'd for (C23H29BrN3O3) [M+H]+ 476.1; found 476.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:6][C@:5]([C:8]2[S:12][C:11]([S:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[N:10][CH:9]=2)([CH3:7])[CH2:4][O:3]1.Cl.[NH2:25][OH:26]>>[CH3:1][C:2]1([CH3:23])[O:6][C@:5]([C:8]2[S:12][C:11]([S:13][C:14]3[CH:19]=[CH:18][C:17](/[C:20](=[N:25]/[OH:26])/[CH3:21])=[CH:16][CH:15]=3)=[N:10][CH:9]=2)([CH3:7])[CH2:4][O:3]1
Reactant: NO
Reactant: CC(=O)c1ccc(Sc2ncc([C@@]3(C)COC(C)(C)O3)s2)cc1
Agent: Cl
Product: C/C(=N\O)c1ccc(Sc2ncc([C@@]3(C)COC(C)(C)O3)s2)cc1
Yield: 82 %

Procedure:
Using an analogous procedure to that described in Example 68, 4'-{5-[(4R)-2,2,4-trimethyl-1,3-dioxolan-4-yl]thiazol-2-ylthio}acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-{5-[(4R)-2,2,4-trimethyl-1,3-dioxolan-4-yl]thiazol-2-ylthio}acetophenone oxime in 82% yield as a gum.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1C(=O)C2C(=CC=CC=2)C1=O)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].CC(O)C.NN>C1COCC1>[CH2:6]([O:5][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(CCCCCN1C(=O)c2ccccc2C1=O)OCC
Agent: NN
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CCOP(=O)(CCCCCN)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.8 %

Procedure:
[5-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pentyl]-phosphonic acid diethyl ester (0.300 g, 0.849 mmol) was dissolved in THF [2 mL], IPA [4 mL]. Hydrazine (0.081 g, 2.540 mmol) was added to this solution and stirred at room temperature for 18 hours. The white precipitate was filtered and washed with dichloromethane. Removal of the solvent in vacuo yielded the title compound (0.136 g, 72%) 1H-NMR (CDCl3): δ 4.07 (m, 4H), 2.68 (t, 2H, J=6.74 Hz), 1.72 (m, 2H), 1.60 (m, 2H), 1.43 (m, 4H), 1.31 (m, 6H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:30][O:31][C:32](=[O:52])[C@@H:33]([N:39]1[C:51]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:45]2[C:40]1=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:34][CH2:35][CH2:36][CH2:37][NH2:38]>C1COCC1>[CH3:30][O:31][C:32](=[O:52])[C@@H:33]([N:39]1[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][C:45]=2[C:46]2[C:51]1=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:25](=[O:27])[C:24]1[CH:23]=[CH:22][C:21]([C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)[C@H](CCCCN)n1c2ccccc2c2ccccc21
Reactant: O=C(O)c1ccc(C(=O)c2ccccc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCCCNC(=O)c1ccc(C(=O)c2ccccc2)cc1)n1c2ccccc2c2ccccc21
Reaction time: 1 h
Yield: 55.9 %

Procedure:
Carbonyldiimidazole (0.162 g, 1.0 mmol) was added to a solution of 4-benzoyl benzoic acid (0.226 g, 1.0 mmol) in dry THF (10 mL) under nitrogen atmosphere at room temperature and the resulting mixture was stirred for 1 h at the same conditions. Then, (S)-methyl 6-amino-2-carbazol-9-yl-hexanoate 4 (0.310 g, 1.0 mmol) in dry THF (5 mL) was added dropwise by syringe into the reaction mixture. The reaction mixture was allowed to stir for additional 3 h at room temperature. After completion of the reaction (monitored by TLC), the solvent was removed under reduced pressure and the crude product was dissolved in ethyl acetate (50 mL) washed with brine (20 mL×2), and finally dried over anhydrous Na2SO4. Filtration followed by removal of the solvent under reduced pressure provided a gummy colorless residue, which was purified by column chromatography over silica gel using dichloromethane:methanol (98:2) as eluent to afford (S)-6-(4-benzoyl-benzoylamino)-2-carbazol-9-yl-hexanoic acid methyl ester 6 (0.290 g, 56%) as a white solid.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:11]=2[CH:12]([CH3:14])[CH3:13])[C:3]1=[O:22].[F:23][C:24]([F:31])([F:30])[C:25]1[N:26]=[CH:27][NH:28][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:10]2[C:11]([CH:12]([CH3:14])[CH3:13])=[C:7]([N:4]3[CH2:5][CH2:6][CH:2]([N:28]4[CH:29]=[C:25]([C:24]([F:31])([F:30])[F:23])[N:26]=[CH:27]4)[C:3]3=[O:22])[CH:8]=[N:9]2)=[CH:16][CH:17]=1
Reactant: CC(C)c1c(N2CCC(Br)C2=O)cnn1-c1ccc(F)cc1
Reactant: FC(F)(F)c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1c(N2CCC(n3cnc(C(F)(F)F)c3)C2=O)cnn1-c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
A mixture of 3-bromo-1-[1-(4-fluorophenyl)-5-isopropyl-pyrazol-4-yl]pyrrolidin-2-one (0.020 g, 0.055 mmol), 4-(trifluoromethyl)-1H-imidazole (0.024 g, 0.17 mmol) and K2CO3 (0.030 g, 0.22 mmol) in DMF (0.6 mL) was stirred at 60° C. for 1 hr. The mixture was then cooled to room temperature, quenched with water (30 mL) and extracted with EtOAc (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to yield the title compound (0.022 g, TFA salt, 75%); 1H NMR (TFA salt) (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.59 (s, 1H), 7.51 (s, 1H), 7.39 (dd, J=8.4, 4.8 Hz, 2H), 7.20 (dd, J=8.6, 8.6 Hz, 2H), 5.06 (dd, J=10.8, 8.8 Hz, 1H), 3.90 (m, 1H), 3.83 (m, 1H), 2.98 (m, 2H), 2.54 (m, 1H), 1.21 (d, J=7.2 Hz, 3H), 1.20 (d, J=7.2 Hz, 3H); MS: (ES) m/z calculated for C20H19F4N5O (free form) [M+H]+ 422.1. found 422.1.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)[CH:12]=[C:13]([C:15](=O)[NH:16][CH2:17][CH3:18])[CH:14]=1)=[O:8].[Si](Cl)(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[CH:12]=[C:13]([C:15]2[N:16]([CH2:17][CH3:18])[N:3]=[N:2][N:1]=2)[CH:14]=1)=[O:8]
Reactant: [N-]=[N+]=[N-]
Reactant: CCNC(=O)c1cc(C(=O)OC)cc(-c2ccc(C)cc2)c1
Agent: Cl[Si](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCn1nnnc1-c1cc(C(=O)OC)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.6 %

Procedure:
Sodium azide (145.8 mg, 16.2 mmol) was added into a solution of 5-ethylcarbamoyl-4′-methyl-biphenyl-3-carboxylic acid methyl ester (210 mg, 0.7 mmol) and SiCl4 (0.62 mL, 5.4 mmol) in dry acetonitrile (14 mL). After the reaction was stirred at room temperature for 24 hours, the reaction mixture was poured into cold saturated aqueous Na2CO3 solution. This mixture was extracted with ethyl acetate and dried with anhydrous Na2SO4. Solvent was removed under reduced pressure to afford 200 mgs of 5-(1-ethyl-1H-tetrazol-5-yl)-4′-methyl-biphenyl-3-carboxylic acid methyl ester (yield 89%). MS (M+H)=323.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:4][C:3]=1[N+:17]([O-])=O>[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]2)=[CH:4][C:3]=1[NH2:17]
Reactant: CC1(C)OB(c2ccc(F)c([N+](=O)[O-])c2)OC1(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2ccc(F)c(N)c2)OC1(C)C
Reaction time: 2 h
Yield: 100 %

Procedure:
A 500-mL Parr reactor bottle was purged with nitrogen and charged with 13 (6.92 g, 25.9 mmol), ethyl acetate (150 mL) and 10% palladium on carbon (50% wet, 150 mg dry weight). The bottle was attached to Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 2 h. After this time the hydrogen was evacuated and nitrogen charged into the reactor. The catalyst was removed by filtration through a pad of Celite 521 and the filter cake washed with methylene chloride (400 mL). The resulting solution was concentrated under reduced pressure to afford 14 in 100% yield (6.34 g) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.22 (dd, 1H, J=8.5, 1.0 Hz), 7.16 (m, 1H), 6.97 (dd, 1H, J=11.5, 8.0 Hz), 3.68 (br s, 2H), 1.33 (m, 12H); MS (ESI+) m/z 238.2 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([OH:19])=O)[N:12]=2)[CH:4]=1)[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:19])[N:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2cccc(C(=O)O)n2)c(C)[nH]c1=O
Reactant: C1CCNC1
Product: CCc1cc(-c2cccc(C(=O)N3CCCC3)n2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-6-carboxylic acid and pyrrolidine to afford the title compound. MS: m/e=312 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:33])[C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=3)[CH2:14][CH2:13]2)[C:11](=[O:34])[NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35]I>>[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:33])[C:19]3[CH:20]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:22]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:24]=3)[CH2:14][CH2:13]2)[C:11](=[O:34])[N:10]([CH3:35])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2Cc1ccccc1
Reactant: CI
Product: CN1CN(Cc2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=500.3 (M+H+), was prepared in accordance with the general method of example 71 from 1-benzyl-8-(3,5-bis-trifluoromethyl-benzoyl)-1,3,8-triaza-spiro[4.5]decan-4-one and methyliodide.