Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:7](=[O:8])[C:6]([CH3:10])([CH3:9])[C:5](=[O:11])[CH2:4][C:3]1=[O:12].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:34][CH3:35])=[C:31]([Pb+3])[CH:32]=1.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>ClCCl.Cl>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:34][CH3:35])=[C:29]([CH:4]2[C:3](=[O:12])[C:2]([CH3:13])([CH3:1])[C:7](=[O:8])[C:6]([CH3:9])([CH3:10])[C:5]2=[O:11])[CH:28]=1
Reactant: CC1(C)C(=O)CC(=O)C(C)(C)C1=O
Reactant: CCc1ccc(Br)cc1[Pb+3]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCc1ccc(Br)cc1C1C(=O)C(C)(C)C(=O)C(C)(C)C1=O
Temperature: 80 °C
Yield: 63.9 %

Procedure:
To a mixture of 2,2,4,4-tetramethylcyclohexane-1,3,5-trione (0.6 g, 3.6 mmol), 5-bromo-2-ethylphenyllead triacetate (2.27 g, 4.00 mmol) and N,N-dimethylaminopyridine (2.22 g, 18 mmol) is added anhydrous chloroform (25 ml) and toluene (6.3 ml), and the reaction mixture is heated at 80° C. for 3 hours. The mixture is diluted with dichloromethane (50 ml) and 2M aqueous hydrochloric acid (100 ml), and filtered through diatomaceous earth to remove inorganic residues. The filter cake is washed with dichloromethane, and all organic fractions are combined, washed with brine, dried over anhydrous magnesium sulphate then filtered. The filtrate is concentrated in vacuo and the residue is purified by flash column chromatography to give 6-(5-bromo-2-ethylphenyl)-2,2,4,4-tetramethylcyclohexane-1,3,5-trione as a white solid (0.84 g).
Reaction SMILES: [N:1]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13][C@H:2]1[C:3]([O:5]N1C(=O)CCC1=O)=O.Cl.[C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1)#[N:25].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:24]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:3](=[O:5])[C@@H:2]2[CH2:13][CH2:14][CH2:15][N:1]2[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])=[CH:28][CH:27]=1)#[N:25]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O
Reactant: N#Cc1ccc(CN)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCc1ccc(C#N)cc1
Reaction time: 48 h
Yield: 90 %

Procedure:
276 g of Boc-Pro-OSu (0.88 mol) were introduced into 2 l of methylene chloride at 0° C. To this solution were added successively 163.9 g of 4-cyanobenzylamine hydrochloride (0.97 mol) and 230 ml of diisopropylethylamine (1.34 mol). The suspension was stirred in a melting ice bath for 48 h and then filtered. The filtrate was extracted with 20% strength NaHSO4 solution (4×), saturated NaHCO3 solution (3×) and saturated sodium chloride solution (2×), dried and evaporated in a rotary evaporator. Recrystallization of the residue from methyl tert-butyl ether resulted in isolation of 261 g (90%) of white crystals, m.p. 124°-125° C.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=O)[OH:5])[OH:3].[C:11](Cl)(=[O:15])[CH:12]([CH3:14])[CH3:13]>C1(C)C=CC=CC=1.CCOCC.CCCCCC>[O:10]=[C:1]1[C@H:2]([O:3][C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[C@@H:4]([O:5][C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])[C:6](=[O:8])[O:9]1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: CC(C)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)C(=O)O[C@H]1C(=O)OC(=O)[C@@H]1OC(=O)C(C)C
Reaction time: 22 h
Yield: 70.6 %

Procedure:
To a suspension of L-tartaric acid (5.0 g, 33.3 mmol) in toluene (60 mL) was added isobutyryl chloride (11.3 mL, 107 mmol). The resulting suspension was heated to reflux and stirred for 22 h at reflux temperature. The reaction mixture was then concentrated in vacuo to afford a crystalline solid, which was suspended in a mixture of ether and hexane (1:3), filtered, washed with hexane and dried to afford the desired compound (27) as a white crystalline solid (6.4 g, 71%). 1H-NMR (400 MHz, CDCl3): δ 1.25 (d, J=6.8 Hz, 12H), 2.72 (hept, J=6.8 Hz, 2H), 5.63 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C:12]2([CH2:22][OH:23])[CH2:21][CH2:20][C:15]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH2:13]2)=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH:24]([O-])([O-])OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[N:11]1([C:12]2([CH2:22][OH:23])[CH2:21][CH2:20][C:15]3([O:16][CH2:17][CH2:18][O:19]3)[CH2:14][CH2:13]2)[C:3]2=[C:4]3[S:10][CH:9]=[CH:8][C:5]3=[N:6][CH:7]=[C:2]2[N:1]=[CH:24]1
Reactant: CCOC([O-])[O-]
Reactant: Nc1cnc2ccsc2c1NC1(CO)CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: OCC1(n2cnc3cnc4ccsc4c32)CCC2(CC1)OCCO2
Temperature: 85 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
A mixture of {8-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]-1,4-dioxaspiro[4.5]dec-8-yl}methanol (90.0 mg, 0.268 mmol), ethyl orthoformate (112 μL, 0.671 mmol), and p-toluenesulfonic acid monohydrate (5.1 mg, 0.027 mmol) in toluene (3.0 mL) was stirred at 85° C. overnight. The mixture was diluted with EtOAc, then washed with sat. sodium bicarbonate and brine. The organic layer was dried (Na2SO4), filtered and concentrated to give 50 mg (50%) of the desired product. LCMS calculated for C17H20N3O3S (M+H)+: m/z=346.1. Found: 346.0.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([F:23])=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([F:23])=[CH:19][CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(F)ccc(Br)c3O2)cc1
Reactant: OB(O)c1ccccc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3c(F)ccc(-c4ccccc4)c3O2)cc1
Yield: 53.9 %

Procedure:
Treatment of (±)-(7-bromo-4-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.0 g, 4.98 mmol) with phenyl boronic acid (0.91 g, 7.22 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.392 g, 0.498 mmol), and potassium carbonate (1.72 g, 12.46 mmol) acording to the procedure described for Intermediate 37 gave 1.07 g (54%) of (±)-(4-fluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Rf=0.46 (silica, ethyl acetate:hexanes 1:4); 1H NMR (DMSO-d6) δH 7.70 (d, 2H); 7.53 (d, 2H); 7.40 (t, 2H); 7.32 (m, 4H); 6.77 (t, 1H); 5.15 (m, 1H); 4.31 (dd, 1H); 4.22 (dd, 1H); 3.30 (dd, 1H, obscured by H2O peak); 3.01 (dd, 1H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[CH:41]=[CH:40][C:19]2[N:20]3[C:24]([CH2:25][NH:26][CH2:27][C:18]=2[CH:17]=1)=[N:23][N:22]=[C:21]3[CH:28]1[CH2:33][CH2:32][N:31]([C:34]2[N:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:30][CH2:29]1.[N:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH:48]=O.N>C(O)(=O)C.ClCCl>[Cl:15][C:16]1[CH:41]=[CH:40][C:19]2[N:20]3[C:24]([CH2:25][N:26]([CH2:48][C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][N:42]=4)[CH2:27][C:18]=2[CH:17]=1)=[N:23][N:22]=[C:21]3[CH:28]1[CH2:33][CH2:32][N:31]([C:34]2[N:35]=[CH:36][CH:37]=[CH:38][N:39]=2)[CH2:30][CH2:29]1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ncccn4)CC3)n1-2
Reactant: O=Cc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Clc1ccc2c(c1)CN(Cc1ccccn1)Cc1nnc(C3CCN(c4ncccn4)CC3)n1-2
Temperature: 5 °C
Reaction time: 18 h
Yield: 54.3 %

Procedure:
Sodium triacetoxyborohydride (277 mg, 1.31 mmol) was added to a mixture of the amine from example 12 (250 mg, 0.65 mmol), 2-pyridine carboxaldehyde (105 mg, 0.98 mmol), and acetic acid (3 drops) in dichloromethane (5 ml), cooled to 5° C., and the reaction mixture was then stirred at room temperature for 18 hours. 0.88 Ammonia was added to the reaction mixture, the phases were separated and the organic layer was dried over magnesium sulphate and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol (95:5) as eluant, to afford the title compound (167 mg)
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:34])/[CH:16]=[CH:17]/[C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:20][C:19]=2[CH3:33])=[CH:11][C:10]=1[CH3:35])C1C=CC=CC=1>C(O)C.O1CCOCC1.[OH-].[Pd+2].[OH-]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:34])[CH2:16][CH2:17][C:18]2[S:22][C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[N:20][C:19]=2[CH3:33])=[CH:11][C:10]=1[CH3:35]
Reactant: Cc1cc(C(=O)/C=C/c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1cc(C(=O)CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)ccc1O

Procedure:
To a solution of (2E)-1-[4-(benzyloxy)-3-methylphenyl]-3-{4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}prop-2-en-1-one (intermediate 9, 0.77 g) in ethanol (30 ml) and 1,4-dioxane (10 ml) was added to 20% palladium hydroxide (0.31 g) and hydrogenated at 21° C. for 18 hours. The reaction was filtered through Celite and the filtrate evaporated to give material which was further purified by flash column chromatography using cyclohexane:ethyl acetate (3:1) as eluent to give the title compound as a colourless oil.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[C:14]([O:18][C:19]([NH:21][C:22]1[CH:27]=[C:26]([CH2:28][OH:29])[CH:25]=[CH:24][N:23]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(OCC)(=O)C>CN(C)C=O>[C:14]([O:18][C:19]([NH:21][C:22]1[CH:27]=[C:26]([CH2:28][O:29][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH:25]=[CH:24][N:23]=1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)Nc1cc(CO)ccn1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(CO[Si](C)(C)C(C)(C)C)ccn1
Yield: 96 %

Procedure:
Imidazole (2.1 g, 31 mmol) and tert-butyldimethylsilyl chloride (4.4 g, 29 mmol) were added to a solution of (2-tert-butoxycarbonylaminopyridin-4-yl)methanol (Reference compound No. 4-1, 6.2 g, 28 mmol) in N,N-dimethylformamide (120 mL) at room temperature, and the mixture was stirred for 2 hours. Ethyl acetate (300 mL) was added to the reaction mixture, then the mixture was washed with water (750 mL) and brine (200 mL), and then the mixture was dried over anhydrous magnesium sulfate. The organic layer was evaporated under reduced pressure to give 9.0 g of the title reference compound as a colorless solid. (Yield 96%)
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]([CH3:28])[C:8]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:12][C:13]([CH2:16]OS(C)(=O)=O)=[N:14][CH:15]=1)=[O:9].[CH3:38][NH:39][CH3:40].O>C(Cl)Cl.C(O)C>[F:34][C:32]([F:33])([F:35])[C:30]1[CH:29]=[C:5]([CH:4]=[C:3]([C:2]([F:36])([F:1])[F:37])[CH:31]=1)[CH2:6][N:7]([CH3:28])[C:8]([C:10]1[C:11]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[N:12][C:13]([CH2:16][N:39]([CH3:40])[CH3:38])=[N:14][CH:15]=1)=[O:9]
Reactant: CNC
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(COS(C)(=O)=O)nc1-c1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CN(C)Cc1ncc(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c(-c2ccccc2)n1
Reaction time: 16 h
Yield: 90 %

Procedure:
To a solution of 0.40 g (0.73 mmol) methanesulfonic acid 5-[(3,5-bis-trifluoromethyl-benzyl)-methyl-carbamoyl]-4-phenyl-pyrimidin-2-ylmethyl ester in 5 ml CH2Cl2 1 ml 5.6 m dimethylamin-solution in ethanol were added. The reaction mixture was stirred for 16 hrs. at RT. The reaction mixture was poured into H2O and extracted three times with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH 20:1) to give 0.33 g (90%) 2-dimethylaminomethyl-4-phenyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a colorless oil, MS (ISP): 497.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.[CH3:12][C:13](OC(C)=O)=[O:14]>N1C=CC=CC=1>[C:8]([C:7]1[C:2]([NH:1][C:13](=[O:14])[CH3:12])=[N:3][C:4]([S:10][CH3:11])=[N:5][CH:6]=1)#[N:9]
Reactant: CSc1ncc(C#N)c(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CSc1ncc(C#N)c(NC(C)=O)n1
Temperature: 80 °C
Reaction time: 23 h
Yield: 48 %

Procedure:
To a suspension of 4-amino-2-methylsulfanyl-pyrimidine-5-carbonitrile (5.45 g) in pyridine (66 mL) was added Ac2O (31 mL) at RT. The reaction mixture was stirred at 80° C. for 23 h, then was cooled to RT and evaporated under reduced pressure. The residue was dissolved in DCM (150 mL) and washed with NaHCO3 (sat'd aq) and brine. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (from 0 to >50% EtOAc/Hexane in 20 min.) to give 3.25 g (48% yield) of N-(5-cyano-2-methylsulfanyl-pyrimidin-4-yl)-acetamide as a yellow solid. MS=167 [M−C2H3O+1]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[NH:11][C:12](=[O:23])[C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=1.O[CH2:26][CH2:27][CH2:28][O:29][N:30]=[CH:31][C:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:26][CH2:27][CH2:28][O:29]/[N:30]=[CH:31]/[C:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:34]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:33]=2)=[CH:6][C:5]=1[NH:11][C:12](=[O:23])[C:13]1[CH:14]=[CH:15][C:16]([C:19]([CH3:20])([CH3:21])[CH3:22])=[CH:17][CH:18]=1
Reactant: OCCCON=Cc1cn(Cc2ccccc2)c2ccccc12
Reactant: COC(=O)c1ccc(O)cc1NC(=O)c1ccc(C(C)(C)C)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(OCCCO/N=C/c2cn(Cc3ccccc3)c3ccccc23)cc1NC(=O)c1ccc(C(C)(C)C)cc1
Temperature: 0 °C
Yield: 55.3 %

Procedure:
To a solution of 2-(4-tert-butyl-benzoylamino)-4-hydroxy-benzoic acid methyl ester (0.313 g, 0.96 mmol) in tetrahydrofuran (14 mL) was added 1-benzyl-1H-indole-3-carbaldehyde O-(3-hydroxy-propyl)-oxime (0.303 g, 0.98 mmol) and triphenyl phosphine (0.327 g, 1.26 mmol). The reaction was cooled to 0° C., diisopropyl azodicarboxylate (0.240 mL, 1.22 mmol) was added and warmed to room temperature overnight. It was poured into brine and extracted with ethyl acetate. The combined organics were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography using ethyl acetate/hexanes (10/90) to afford 4-[3-({[(1E)-(1-benzyl-1H-indol-3-yl)methylidene]amino}oxy)-propoxy]-2-[(4-tert-butylbenzoyl)amino]benzoic acid methyl ester (0.328g, 55 %) as a white solid. (+ES, M+H) m/z 618. 1H NMR (400 MHz, DMSO-d6); δ 11.95 (s, 1H), 8.42 (d, 1H), 8.38 (s, 1H), 7.98 (m, 2H), 7.88 (d, 2H), 7.82 (s, 1H) 7.62 (d, 2H), 7.47 (d, 1H), 7.29 (m, 2H), 7.21 (m, 4H), 7.08 (m, 1H), 6.81 (dd, 1H), 5.43 (s, 2H), 4.24 (m, 4H), 3.88 (s, 3H), 2.19 (m, 2H), 1.32 (s, 9H). Elemental analysis: Calcd. for C38H39N3O5: C, 73.88; H, 6.36; N, 6.8. Found: C, 73.40; H, 6.44; N, 6.37.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([C:9]([OH:11])=O)[CH:3]=1.[CH:12]1([N:15]2[CH:19]=[N:18][N:17]=[C:16]2[C:20]2[N:25]=[C:24]([NH2:26])[CH:23]=[CH:22][CH:21]=2)[CH2:14][CH2:13]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([C:9]([NH:26][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:16]3[N:15]([CH:12]4[CH2:14][CH2:13]4)[CH:19]=[N:18][N:17]=3)[N:25]=2)=[O:11])[CH:3]=1
Reactant: Cc1cnc(C(=O)O)cc1Cl
Reactant: Nc1cccc(-c2nncn2C2CC2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cnc(C(=O)Nc2cccc(-c3nncn3C3CC3)n2)cc1Cl
Yield: 47 %

Procedure:
A solution of 4-chloro-5-methylpicolinic acid (159 mg, 0.924 mmol), 6-(4-Cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridin-2-ylamine (169 mg, 0.840 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (383 mg, 1.01 mmol), and N-methylmorpholine (11 μL, 1.01 mmol) in N,N-dimethylformamide was stirred at 65° C. for 12 hours. The solvent was removed under reduced pressure, the residue was suspended in acetonitrile, and the solid product was isolated by filtration, washed with water (80 mL), acetonitrile (80 mL), diethyl ether (80 mL), and dried under vacuum to afford 4-chloro-N-(6-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridin-2-yl)-5-methylpicolinamide as a white powder (140 mg, 47% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@@H:4]([NH:8][C:9](=O)[CH:10]([NH:13][C:14]([C:16]1[C:17]2[CH:24]=[N:23][N:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:18]=2[CH:19]=[N:20][CH:21]=1)=[O:15])[CH2:11][CH3:12])[C@H:5]([OH:7])[CH3:6].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[CH3:1][O:2][C:3]([C@@H:4]1[C@H:5]([CH3:6])[O:7][C:9]([CH:10]([NH:13][C:14]([C:16]2[C:17]3[CH:24]=[N:23][N:22]([C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)[C:18]=3[CH:19]=[N:20][CH:21]=2)=[O:15])[CH2:11][CH3:12])=[N:8]1)=[O:33]
Reactant: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C(=O)N[C@H](C(=O)OC)[C@@H](C)O
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: CCC(NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)C1=N[C@H](C(=O)OC)[C@H](C)O1

Procedure:
To a solution of (2S,3R)-2-(2-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]amino}-butyrylamino)-3-hydroxy-butyric acid methyl ester (0.900 g, 1.96 mmol) in THF (20.0 mL) was added Burgess reagent (0.586 g, 2.46 mmol). The mixture was warmed at reflux for 23 hours. The mixture was then concentrated in vacuo, dissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography eluting with a gradient of 0-10% methanol in ethyl acetate to afford (4S,5S)-2-(1-{[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]-amino}-propyl)-5-methyl-4,5-dihydro-oxazole-4-carboxylic acid methyl ester as white foam.
Reaction SMILES: II.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(N(CC)CC)C.[CH2:29]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][C@H:40]1[C:45]([NH:47][NH:48][C:49](=O)[CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:46])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH2:29]([O:36][C:37]([N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][C@H:40]1[C:45]1[O:46][C:49]([CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)=[N:48][N:47]=1)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cc1ccccc1)NNC(=O)[C@@H]1CCCCN1C(=O)OCc1ccccc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCCC[C@H]1c1nnc(Cc2ccccc2)o1
Reaction time: 0.17 h
Yield: 25.2 %

Procedure:
At 25° C., iodine (3.21, 12.64 mmol) was added to the PPh3 solution in CH2Cl2 (40 mL). After 10 minutes, triethylamine (1.5 mL) was added, followed by compound 71 (2.5 g, 6.32 mmol). After 20 hours, the solution was concentrated and passed through a pad of silica gel (100 mL). The crude oil was purified by column chromatography (25-30% EtOAc in hexanes), affording 600 mg (25%) of the desired product as a solid. 1.6 g of compound 71 was recovered.
Reaction SMILES: C1(O)C=CC=CC=1.[OH-].[Na+].[CH3:10][NH:11][CH2:12][C:13]1[N:14]=[C:15]([CH:18]([CH3:20])[CH3:19])[S:16][CH:17]=1.[O:21]([C:28]([NH:30][C@H:31]([C:35]([OH:37])=[O:36])[CH:32]([CH3:34])[CH3:33])=O)C1C=CC=CC=1>C1COCC1>[CH3:10][N:11]([C:28]([NH:30][C@H:31]([C:35]([OH:37])=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:21])[CH2:12][C:13]1[N:14]=[C:15]([CH:18]([CH3:20])[CH3:19])[S:16][CH:17]=1
Reactant: CNCc1csc(C(C)C)n1
Reactant: CC(C)[C@H](NC(=O)Oc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: Oc1ccccc1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Temperature: 15 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
To a solution of phenol (2.18 g, 23.2 mmol) in THF (25 mL) was added 50% NaOH solution (1.86 g, 23.2 mmol) at ambient temperature. After the exotherm subsided, N-methyl-N-((2-isopropyl-4-thiazolyl)methyl)amine (3.95 g, 23.2 mmol) was added. The solution was cooled to 15° C., and then a solution of N-phenoxycarbonyl-L-Valine (5.0 g, 21.1 mmol) dissolved in 25 mL of THF was added slowly. An ice bath was used to maintain the temperature between 15 and 20° C. Following a 5 mL THF rinse, the reaction was allowed to warm to ambient temperature. After three hours, an additional aliquot of 50% NaOH solution (90 mg, 2.3 mmol) was added. After 19 hours, the reaction was quenched by the addition of 100 mL of water and the THF removed under reduced pressure. The remaining aqueous phase was washed with MTBE (3×60 mL), toluene (70 mL) was added, and the pH was adjusted to 3.7 with 4 N HCl. The layers were separated, and the aqueous phase was extracted with two additional aliquots (70 mL) of toluene. The combined toluene extracts were concentrated in vacuo. The resulting oil was crystallized using toluene and heptane to give the title compound (5.1 g, 78%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:11])[CH2:9][O:10][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(CO)c1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(CO[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.7 %

Procedure:
To a solution of 73B (2.34 g, 10.9 mmol) in 30 mL DMF, was added imidazole (1.11 g, 16.3 mmol) and tert-butyldimethylsilyl chloride (1.97 g, 13.1 mmol). The mixture was stirred at rt for 3 h, then was diluted with hexanes. The organic phase washed with H2O (2×) and brine, dried (Na2SO4) and concentrated. The product was purified by flash chromatography (0 to 10% EtOAc/hexanes gradient) to afford 2.00 g of 73C as a colorless oil. MS (ESI) m/z 197.1 (M-OTBS)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:29])[NH:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C:23]4=[O:28])=[CH:18][CH:17]=3)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[CH:39]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14](=[O:29])[NH:15][C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][C:23]4=[O:28])=[CH:20][CH:21]=3)[N:10]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([O:44][CH3:45])[CH:39]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cccc2[nH]c(C(=O)Nc3ccc(N4CCOCC4=O)cc3)nc12
Reactant: COc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc2c1nc(C(=O)Nc1ccc(N3CCOCC3=O)cc1)n2Cc1cccc(OC)c1
Reaction time: 4 h

Procedure:
366.5.0 mg (0.929 mmol) 2-[4-(3-Oxo-morpholin-4-yl)-phenylcarbamoyl]-1H-benzoimidazole-4-carboxylic acid methyl ester were dissolved in 15 mL DMF. Sequentially 192.6 mg (1.394 mmol) K2CO3 and 156.1 μl (1.394 mmol) 1-bromomethyl-3-methoxy-benzene were added and the resulting mixture was stirred for 4 h at 80°. The mixture was diluted with 300 mL toluene and washed with 50 mL of a saturated NaHCO3-solution. The product was not completely soluble in toluene, so ethyl acetate had to be added. The organic layer was washed with brine, dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by preparative HPLC (CH3CN/H2O gradient+0.05% formic acid) (separation of isomers) to give 1-(3-Methoxy-benzyl)-2-[4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-1H-benzoimidazole-4-carboxylic acid methyl ester as a light brown amorphous solid.