Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][O:23][CH3:24])[CH:17]=[C:16]([F:25])[C:15]=1B1OC(C)(C)C(C)(C)O1>>[F:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][CH2:22][O:23][CH3:24])[CH:17]=[C:16]([F:25])[C:15]=1[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12]
Reactant: COCCOc1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: COC(=O)c1ccc(F)c(Br)n1
Product: COCCOc1cc(F)c(-c2nc(C(=O)OC)ccc2F)c(F)c1
Yield: 95 %

Procedure:
Method 1 was followed using methyl 6-bromo-5-fluoropicolinate (1.0 equiv.) and 2-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.75 equiv.) at 80° C. for 1 hour to give methyl 6-(2,6-difluoro-4-(2-methoxyethoxy)phenyl)-5-fluoropicolinate in 95% yield. LC/MS=341.9 (M+H), Rt=0.89 min.
Reaction SMILES: [N:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:8]=2)[CH2:6][CH2:5]O[CH2:3][CH2:2]1.Br[C:27]1C2C(=CC=CC=2)N([Si](C(C)C)(C(C)C)C(C)C)C=1.N1CCCCC1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.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]>[N:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:8]=2)[CH2:6][CH2:5][CH2:27][CH2:3][CH2:2]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(N2CCOCC2)c2ccccc21
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(Br)c2ccccc21
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Solvent: C1CCNCC1
Solvent: ClC(Cl)Cl
Product: CC(C)[Si](C(C)C)(C(C)C)n1cc(N2CCCCC2)c2ccccc21

Procedure:
Following a method similar to 3-morpholin-4-yl-1-triisopropylsilanyl-1H-indole using 3-bromo-1-triisopropylsilanyl-1H-indole (0.70 g, 1.99 mmol), piperidine (0.26 g, 3.04 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (0.02 g, 0.05 mmol), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.05 g, 0.05 mmol) and 1N solution of lithium bis(trimethylsilyl)amide in THF (2.40 mL) to prepare the title compound. Purify by flash chromatography using 0 to 40% of EtOAc in hexanes to give the title compound (0.20 g, 29%): MS (ES) 357.1 (M+1)+.
Reaction SMILES: O[C:2]1([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[CH2:17][CH3:18])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[O:19]1[CH2:21][C@H:20]1[CH2:22][O:23][C:24]1[C:32]2[CH2:31][CH2:30][O:29][C:28]=2[CH:27]=[CH:26][CH:25]=1>CO>[O:29]1[CH2:30][CH2:31][C:32]2[C:24]([O:23][CH2:22][C@@H:20]([OH:19])[CH2:21][N:5]3[CH2:6][CH2:7][CH:2]([C:8]4[S:12][C:11]5[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=5[C:9]=4[CH2:17][CH3:18])[CH2:3][CH2:4]3)=[CH:25][CH:26]=[CH:27][C:28]1=2
Reactant: CCc1c(C2(O)CCNCC2)sc2ccccc12
Reactant: c1cc2c(c(OC[C@@H]3CO3)c1)CCO2
Solvent: CO
Product: CCc1c(C2CCN(C[C@H](O)COc3cccc4c3CCO4)CC2)sc2ccccc12
Yield: 35 %

Procedure:
A solution 4-hydroxy-4-(3-ethylbenzo[b]thiophen-2-yl)piperidine (0.069 g, 0.281 mmol) and (S)-(+)-4-(oxiranylmethoxy)-2,3-dihydrobenzo[b]furan (0.054 g, 0.281 mmol) in methanol (3 mL) was heated at reflux for 18 hours, and then cooled and evaporated. The residue was purified using silica gel chromatography (dichloromethane/1% methanol in dichloromethane) to give the title compound as a clear colorless oil (0.043 g, 35%). FDMS m/e=438 (M++1). C26H31NO3S.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:11]=[CH:10][S:9][N:8]=1.[O:12]1[C:16]2([CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[O:15][CH2:14][CH2:13]1>CCCCCC.O1CCCC1>[CH3:6][C:7]1[CH:11]=[C:10]([C:19]2([OH:22])[CH2:20][CH2:21][C:16]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:17][CH2:18]2)[S:9][N:8]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Cc1ccsn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C2(O)CCC3(CC2)OCCO3)sn1
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
At −78° C., 1.5 M of n-butyllithium in hexane (6.7 mL) was slowly added to a solution of 3-methylisothiazole (1.0 g, 0.010 mol) in tetrahydrofuran (15 mL) over a period of 20 min. After being stirred for another 30 min, 1,4-dioxa-spiro[4.5]decan-8-one (1.56 g, 0.00999 mol) in tetrahydrofuran (5 mL) was added within 10 min. The reaction mixture was stirred for another 2 hour at −78° C. and allowed to warm up overnight to room temperature. After quenching with brine, the mixture was extracted with EtOAc. The organic layer was dried and concentrated. Chromatography on silica gel eluting with hexane/EtOAc (1:5˜1:1) provided 1.8 g (70.6%) of the title compound. MS (M+H)+ 256.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:17][CH:16]=2)=[O:13])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].ON1C2C=CC=CC=2N=N1.[C:38](O)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl.C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([C:38](=[O:45])[C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[CH2:24][CH2:23]3)=[CH:17][CH:16]=2)=[O:13])[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(OC2CCNCC2)cc1
Reactant: O=C(O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(OC2CCN(C(=O)c3ccccc3)CC2)cc1
Temperature: 22 °C
Reaction time: 19 h
Yield: 93.4 %

Procedure:
To an ice-cooled solution of 1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-[4-(piperidin-4-yloxy)-phenyl]-urea (82.2 mg, 0.22 mmol), 1-hydroxybenzotriazole (HOBt, 50.1 mg, 0.37 mmol), and benzoic acid (38.8 mg, 0.32 mmol) in dichloromethane-THF (1:1, 2 mL) is added DCC (52.0 mg, 0.25 mmol). The reaction mixture is stirred at 22° C. for 19 hours. The crude product is purified on a silica gel chromatography with ethyl acetate-hexanes to provide a white solid (97.7 mg, 93.4% yield, ES+(m/z) 476.1 [M+H]).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[C:13](=O)[NH:12][CH2:11]2)(=[O:5])=[O:4].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>C1(C)C(C)=CC=CC=1>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[C:13](=[S:25])[NH:12][CH2:11]2)(=[O:5])=[O:4]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CNS(=O)(=O)c1cccc2c1C(=O)NC2
Solvent: Cc1ccccc1C
Product: CNS(=O)(=O)c1cccc2c1C(=S)NC2
Yield: 84.8 %

Procedure:
A mixture of 0.68 g of N-methylisoindolin-1-one-7-sulfonamide, 0.61 g of Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide) and 15 ml of xylene was heated to reflux under nitrogen for 24 hours. The mixture was allowed to cool, the solid products collected, and recrystallized from isopropanol (carbon) to give 0.31 g of the title compound as a yellow solid, m.p. 231°-232° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:9]=[C:10](B(O)O)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:19][C:20]1[C:21](I)=[CH:22][C:23](=[O:44])[N:24]([CH2:26][CH2:27][C@@:28]([CH3:43])([S:39]([CH3:42])(=[O:41])=[O:40])[C:29]([NH:31][O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[O:30])[CH:25]=1>O1CCOCC1.O.[Pd]>[F:19][C:20]1[C:21]([C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([F:7])[CH:9]=2)=[CH:22][C:23](=[O:44])[N:24]([CH2:26][CH2:27][C@@:28]([CH3:43])([S:39]([CH3:42])(=[O:40])=[O:41])[C:29]([NH:31][O:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[O:30])[CH:25]=1
Reactant: COc1ccc(B(O)O)cc1F
Reactant: C[C@@](CCn1cc(F)c(I)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(=O)n(CC[C@](C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)cc2F)cc1F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Pd Encat™ (580 mg, 0.17 mmol) was added to a mixture of potassium carbonate (723 mg, 5.2 mmol), (3-fluoro-4-methoxyphenyl)boronic acid (318 mg, 2.1 mmol), and (2R)-4-(5-fluoro-4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide, T3, (900 mg, 1.7 mmol) in 1,4-dioxane:water (5:1, 24 mL). The reaction was heated to 80° C. and allowed to stir at this temperature overnight. The reaction was filtered through a pad of celite, which was washed with methanol (250 mL). The filtrate was concentrated under reduced pressure, and the resulting crude material was purified via flash chromatography using an eluent of EtOAc in heptanes (20-100%), then 10% methanol in EtOAc to provide the title compound as a light tan residue (800 mg, 99%). MS (LCMS) m/z 495.1 (M−1).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[C:13]([Br:14])=[CH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[C:9](=[O:19])[C:8]=2[CH:20]=1>O.CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[C:13]([Br:14])=[CH:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=3[CH:9]([OH:19])[C:8]=2[CH:20]=1
Reactant: O=c1c2ccccc2cc(Br)c2ccc(Cl)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OC1c2ccccc2C=C(Br)c2ccc(Cl)cc21

Procedure:
In a similar manner, a solution of 1.7 grams of sodium borohydride in 20 milliliters of water was added dropwise to a solution of 3-chloro-11-bromo-5H-dibenzo[a,d]cyclohepten-5-one in 100 milliliters of boiling methanol and the resulting mixture refluxed for 1.5 hours to obtain a 3-chloro-11-bromo-5H-dibenzo[a,d]cyclohepten-5-ol intermediate which was recovered by evaporating the mixture to dryness in vacuo, then washing with water, filtering and drying under reduced pressure at about 60° C.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].[Na][Na].Cl[C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:29])[CH:25]=2)[N:20]=1.C1C=CC([O-])=CC=1.[Na+]>CS(C)=O.O>[F:29][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:12][CH:13]=1)[CH:28]=[CH:27]2
Reactant: Fc1ccc2nc(Cl)ccc2c1
Reactant: CC(Oc1ccc(O)cc1)C(=O)O
Agent: [Na+]
Agent: [Na][Na]
Agent: [O-]c1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: CC(Oc1ccc(Oc2ccc3cc(F)ccc3n2)cc1)C(=O)O
Temperature: 125 °C

Procedure:
2-(4-Hydroxyphenoxy)propionic acid (2.5 gm, 0.0127 mole) was dissolved in 50 ml of DMSO. A solution of sodium hydroxide (1.04 gm, 0.026 mole) in 3.0 ml of water was added and the mixture was stirred for a few minutes to insure complete conversion to the disodium salt. 2-Chloro-6-fluoroquinoline (2.5 gm, 0.0137 mole) was dissolved in 45.0 ml of DMSO and then added all at once to the sodium phenate solution. The reaction mixture was then heated to 125° C. and stirred under nitrogen at this temperature for 1.5 hr. At the end of this time it was cooled and poured into 400 ml of cold water. The aqueous mixture was washed with methylene chloride to remove a small amount of insolubles present and the aqueous layer was separated and acidified to pH 1 with concentrated hydrochloric acid. The phenoxy acid liberated was extracted with methylene chloride. Removal of the solvent left the crude product which was taken up in hot toluene, dried with sodium sulfate and decolorized with "Norite". After removal of about two-thirds of the volume of toluene and addition of hexane, the product, 2-(4-((6-fluoro-2-quinolinyl)oxy)phenoxy)propionic acid, precipitated as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[O:11][N:10]=1.C(O[CH:24](N(C)C)[N:25]([CH3:27])[CH3:26])(C)(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH:18]=[CH:24][N:25]([CH3:27])[CH3:26])[O:11][N:10]=1
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: COC(=O)c1c(-c2c(F)cccc2Cl)noc1C
Solvent: Cc1ccccc1
Product: COC(=O)c1c(-c2c(F)cccc2Cl)noc1C=CN(C)C

Procedure:
To a solution of 0.1 g (0.3708 mmol) methyl 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carboxylate in 10 mL dry toluene, was added 0.15 mL (0.7417 mmol) tert-Butoxy-bis(dimethylamino)methane. The reaction mixture was heated under reflux for 6 h.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH:23](OC)[O:24]C)[C:20]([O:28][CH3:29])=[CH:19][C:18]=3[N+:30]([O-:32])=[O:31])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.Cl>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH:23]=[O:24])[C:20]([O:28][CH3:29])=[CH:19][C:18]=3[N+:30]([O-:32])=[O:31])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc([N+](=O)[O-])c(Nc2nc(-c3cccc(Cl)c3)c(C(N)=O)s2)cc1C(OC)OC
Agent: Cl
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])c(Nc2nc(-c3cccc(Cl)c3)c(C(N)=O)s2)cc1C=O
Temperature: 0 °C
Yield: 77 %

Procedure:
A mixture of 0.200 g (0.42 mmole) of 4-(3-chloro-phenyl)-2-(5-dimethoxymethyl-4-methoxy-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.46a), 6 mL of acetonitrile, 2 mL of 6 M hydrochloric acid heated at reflux for 2 hours. The mixture was diluted with 200 mL of ice-water and the purple precipitate was collected by filtration, washed with water, and air dried to give 0.140 g of 4-(3-chloro-phenyl)-2-(5-formyl-4-methoxy-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.46b).
Reaction SMILES: [CH2:1]([CH:4]([CH2:8][CH2:9][CH3:10])[C:5]([OH:7])=O)[CH2:2][CH3:3].C(Cl)(=O)[C:12]([Cl:14])=O.[N+](=C)=[N-].Cl.O1CCOCC1>ClCCl.CN(C=O)C>[Cl:14][CH2:12][C:5](=[O:7])[CH:4]([CH2:1][CH2:2][CH3:3])[CH2:8][CH2:9][CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCC(CCC)C(=O)O
Agent: C=[N+]=[N-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCC(CCC)C(=O)CCl
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To 2-propylpentanoic acid (156.6 μl, 1.00 mmol) dissolved in anhydrous dichloromethane (2 mL) was added DMF (3 μL, 4 mole %), and the solution was cooled to 0° C. under a nitrogen atmosphere. To the solution was added oxalyl chloride (94.3 μL, 1.08 mmol) dropwise over a few minutes. The reaction was stirred 18 hours while warming to ambient temperature. The mixture was cooled to 0° C. and excess ˜0.3 M ethereal diazomethane solution was added. The reaction mixture was stirred 18 hours while warming to ambient temperature. The reaction mixture was washed with 1 M aqueous sodium carbonate solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in ether (2 mL) and cooled to 0° C. under a nitrogen atmosphere. Hydrogen chloride as a 4 N solution in dioxane (275 μL, 1.10 mmol) was added dropwise over a few minutes. The reaction was stirred 18 hours while warming to ambient temperature. The reaction mixture was concentrated under reduced pressure and the residual oil was used in the next step without further purification.
Reaction SMILES: Cl.C(OC([NH:9][C:10]1[C:15](B(O)O)=[CH:14][CH:13]=[CH:12][N:11]=1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].Br[C:26]1[C:27]([C:41]#[N:42])=[N:28][N:29]([CH2:38][CH2:39][CH3:40])[C:30]=1[CH2:31][CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH2:38]([N:29]1[C:30]([CH2:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[C:26]2[C:27]([C:41]([NH2:42])=[N:9][C:10]3[N:11]=[CH:12][CH:13]=[CH:14][C:15]=32)=[N:28]1)[CH2:39][CH3:40]
Reactant: CC(C)(C)OC(=O)Nc1ncccc1B(O)O
Reactant: CCCn1nc(C#N)c(Br)c1CC1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCCn1nc2c(N)nc3ncccc3c2c1CC1CCOCC1
Temperature: 80 °C
Yield: 24.3 %

Procedure:
Hydrochloric acid (10 mL of 1M) was added to a solution of 2-tert-butoxycarbonylamino-3-pyridylboronic acid (2.59 g, 10.9 mmol), and the resulting mixture was heated at 80° C. for 45 minutes and allowed to cool to room temperature. Potassium carbonate (3.87 g, 27.95 mmol) was added with stirring, and then DME (20 mL), 4-bromo-1-propyl-5-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazole-3-carbonitrile (1.70 g, 5.44 mmol), and dichlorobis(triphenylphosphine)palladium(II) (190 mg, 0.27 mmol) were added. The flask was placed under vacuum and back-filled with nitrogen three times. The reaction was heated under a nitrogen atmosphere at 95° C. overnight. The reaction was allowed to cool to room temperature, and the volatiles were removed under reduced pressure. The residue was dissolved in chloroform (100 mL), and the resulting solution was washed with water (100 mL), dried over magnesium sulfate, filtered, and concentrated to yield a light yellow solid. The crude product was purified by automated flash chromatography (eluting with 0% to 30% CMA in chloroform) followed by recrystallization from acetonitrile (30 mL). The crystals were washed with cold acetonitrile and dried overnight in a vacuum oven at 60° C. to provide 0.43 g of 2-propyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-2H-pyrazolo[3,4-c][1,8]naphthyridin-4-amine as white needles, mp 252-255° C.
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[NH:10][CH:9]=1)=O.CO.[CH3:21][NH:22][CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[CH3:21][N:22]([CH2:1][C@@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[NH:10][CH:9]=1)[CH3:23]
Reactant: CNC
Reactant: N#Cc1ccc2[nH]cc([C@@H]3CCC[C@H]3C=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C[C@@H]1CCC[C@H]1c1c[nH]c2ccc(C#N)cc12
Reaction time: 0.5 h
Yield: 64.1 %

Procedure:
Trans-3-(2-formyl-cyclopentyl)-1H-indole-5-carbonitrile (200 mg, 0.84 mMol) was stirred in THF (5 mL) and methanol (30 mL) with dimethylamine (0.84 mL, 2M in THF, 1.68 mMol) for 5 min. Sodium triacetoxyborohydride (530 mg, 2.52 mMol) was added and the reaction was stirred a further 30 min. The solvent was evaporated in vacuo and the residue was dissolved in 1N sodium hydroxide (20 mL). The reaction was extracted with ethyl acetate (3×10 mL), dried with magnesium sulfate, and evaporated to a white powder. The material was purified by precipitation from hot methylene chloride to provide the product (144 mg, 64%). 1H NMR (400 MHz, CDCl3) δ 8.32 (1H, brs), 8.00 (1H, s), 7.39 (2H, m), 7.12 (1H, d, J=1.8 Hz), 2.90 (1H, m), 2.17 (6H, s), 2.06–2.33 (5H, m), 1.66–1.90 (3H, m), 1.49 (1H, m); MS m/e 268.2 (M+H).
Reaction SMILES: [O:1]([CH2:13][CH2:14][CH2:15][CH3:16])[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].C[C:18](=[O:21])[CH2:19][CH3:20]>>[C:18]([O:12][CH2:11][C@H:9]1[O:10][C@@H:2]([O:1][CH2:13][CH2:14][CH2:15][CH3:16])[C@H:3]([OH:4])[C@@H:5]([OH:6])[C@@H:7]1[OH:8])(=[O:21])[CH2:19][CH2:20][CH2:2][CH2:3][CH2:5][CH2:7][CH3:9]
Reactant: CCC(C)=O
Reactant: CCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Product: CCCCCCCC(=O)OC[C@H]1O[C@@H](OCCCC)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 25 %

Procedure:
The title compound was prepared according to the method described in example 26 using n-butyl β-D-glucopyranoside (1.0 g, 4.2 mmol) in 2-butanone (50 ml) in a 25% yield after 24 hours: 1H NMR (400MHZ, CDCl3) δ: 0.90 (m, 6H); 1.29 (M, 8H); 1.37 (m, 2H); 1.61 (m, 4H); 2.35 (m, 2H); 3.35 (m, 2H); 3.50 (m, 3H); 3.85 (m, 1H); 4.27 (d, J=8 HZ, 1H); 4.28 (m, 1H); 4.38 (m, 1H).
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15](Cl)(=[O:20])[CH2:16][CH:17]([CH3:19])[CH3:18].C(N(CC)CC)C>O1CCCC1>[CH3:18][CH:17]([CH3:19])[CH2:16][C:15]([NH:14][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[C:9]=2[CH:1]=1)=[O:20]
Reactant: CC(C)CC(=O)Cl
Reactant: NC1CCc2oc3ccccc3c2C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)CC(=O)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 42.4 %

Procedure:
Following the procedure for Example 1, tetrahydro-dibenzofuran-2-ylamine (1.1 g, 6.0 mmol), isovaleryl chloride (0.82 g, 6.6 mmol), and triethylamine (2.6 mL, 18 mmol) in tetrahydrofuran (11 mL) provided 3-methyl-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-butyramide (0.69 g) after recrystallization from t-butyl methyl ether. Mp 154-157° C.; Anal. Calcd. for C17H21NO2: C, 75.25; H, 7.80; N, 5.16; Found: C, 75.20; H, 7.87; N, 5.26.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[F-].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:15][O:16][C:17]1[CH:22]=[C:21]([C:2]2[C:7]3[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[NH:10][C:6]=3[CH:5]=[CH:4][N:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(=O)c1cc2c(Cl)nccc2[nH]1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: COC(=O)c1cc2c(-c3cccc(OC)c3)nccc2[nH]1
Temperature: 100 °C
Yield: 85.7 %

Procedure:
Intermediate A1, Methyl 4-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (500 mg, 2.374 mmole), 3-methoxyphenylboronic acid (469 mg, 3.09 mmole), Pd(OAc)2 (32.0 mg, 0.142 mmole), X-Phos (113 mg, 0.237 mmole), and KF (414 mg, 7.12 mmole) were combined in 1,4-dioxane (10 mL). The mixture was degassed (3× pump/N2) then heated to 100° C. After 2 hr the mixture was cooled to RT, diluted with EtOAc, filtered through a pad of Celite washing with EtOAc, and concentrated. Flash column (Biotage-SNAP-50 g SiO2, 50% EtOAc/hexanes) gave the title compound (574 mg, 86%) as an off-white solid. 1H NMR (399 MHz, CDCl3): δ 9.26 (bs, 1 H); 8.51 (d, J=5.8 Hz, 1 H); 7.58-7.51 (m, 3 H); 7.50-7.40 (m, 1 H); 7.30 (d, J=5.9 Hz, 1 H); 7.03 (dd, J=8.2, 2.6 Hz, 1 H); 3.97 (s, 3 H); 3.91 (s, 3 H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][N:18]([CH2:19][C:20]([N:22]3[CH2:27][C@@H:26]([CH3:28])[O:25][C@@H:24]([CH3:29])[CH2:23]3)=[O:21])[C:12]2=[N:11][C:10]=1[C:30]1[S:31][C:32]([CH2:35][C:36]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:37]=2[C:38]([NH2:40])=O)=[CH:33][N:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CN(C=O)C.O=P(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][N:18]([CH2:19][C:20]([N:22]3[CH2:27][C@@H:26]([CH3:28])[O:25][C@@H:24]([CH3:29])[CH2:23]3)=[O:21])[C:12]2=[N:11][C:10]=1[C:30]1[S:31][C:32]([CH2:35][C:36]2[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:37]=2[C:38]#[N:40])=[CH:33][N:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN(C(=O)Cn2ccn3c(=O)c(OCc4ccccc4)c(-c4ncc(Cc5ccc(F)cc5C(N)=O)s4)nc23)C[C@H](C)O1
Solvent: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: C[C@@H]1CN(C(=O)Cn2ccn3c(=O)c(OCc4ccccc4)c(-c4ncc(Cc5ccc(F)cc5C#N)s4)nc23)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 20 h
Yield: 40.8 %

Procedure:
To a solution of the product of example 117 (15 mg, 0.024 mmol) in DMF (0.5 ml), POCl3 (0.1 ml) was added drop-wise. The mixture was stirred at room temperature for 20 hours, after which water was added, and then extracted with CH2Cl2. The extracts were combined, washed with brine, and then dried over sodium sulfate. The product was purified by column chromatography (CH2Cl2/EA/MeOH=8/2/1) to give the desired product (6 mg, 40% yield).