Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CCCC)CCCC)CCC.[C]=O>CO.C1(P([Pd-](Cl)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:5][C:6]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Br)ccc21
Agent: Cl[Pd-]([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [C]=O
Solvent: CCCCN(CCCC)CCCC
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
A solution of 5-bromo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (4.0 g, 13.5 mmol), tributylamine and bis-triphenylphosphinopalladium(II) chloride (0.65 g, 0.926 mmol) in methanol was sealed in a Parr pressure apparatus and pressurized with 600 psi of carbon monoxide. The solution was heated at 100° C. for one week. The vessel was cooled to room temperature and the gas vented. The solution was filtered, and the solvent was evaporated in vacuo. The residue was purified by flash chromatography, on silica gel eluted with 10-40% ethyl acetate in hexane to give the product mixed with tributylamine, 2.5 g (67%). The product was used without further purification in the subsequent step.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].Cl.[NH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][N:30]2[CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31]2)[CH2:25][CH2:24]1.C(NC(C)C)(C)C>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:23]3[CH2:24][CH2:25][CH:26]([CH2:29][N:30]4[CH2:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH2:31]4)[CH2:27][CH2:28]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: c1ccc2c(c1)CN(CC1CCNCC1)C2
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: Cl
Solvent: CC(C)NC(C)C
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(CN2Cc3ccccc3C2)CC1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 2-piperidin-4-ylmethyl-2,3-dihydro-1H-isoindole, hydrochloride, 5 equivalent of diisopropylamine was added, praeparative HPLC (Method C) (63%, colourless crystals). HPLC-MS m/z=498.1 (M+1), Rt: 3.07 min.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:29]([O:31][CH3:32])=[O:30])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19](C(OC)=O)=[CH:18][C:17]4[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[OH-].Cl>CN(C=O)C>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:29]([O:31][CH3:32])=[O:30])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]=[CH:18][C:17]4[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)C1=Cc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC=Cc1ccccc1-3

Procedure:
To a stirred solution of dimethyl 13-cyclohexyl-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylate (2.6 g, 6.1 mmol) in DMF (60 mL) was added LiOH (1.45 g, 60 mmol) and the reaction mixture was heated at 60° C. for 2d. The reaction mixture was cooled internally with ice, acidified with 1M aqueous HCl (pH<2) and extracted with EtOAc (350 mL). The organics were washed with H2O (˜150 mL), brine (˜150 mL), dried (MgSO4), filtered and concentrated. The solids were triturated with Et2O/hexanes (1:2) and collected to yield methyl 13-cyclohexyl-7H-indolo[2,1-a][2]benzazepine-10-carboxylate, 6-carboxylic acid (2.06 g, 4.96 mmol. 81%) as a fluffy yellow solid. 1HNMR (500 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.88 (s, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.67-7.55 (m, 4H), 5.58 (br s, 1H), 4.15 (br s, 1H), 3.90 (s, 3H), 2.84-2.75 (m, 1H), 2.10-1.65 (m, 6H), 1.49-1.07 (m, 4H). LCMS: m/e 416 (M+H)+, ret time 1.47 min, column A, 2 minute gradient.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.C([N:50]1CC[O:53][CH2:52][CH2:51]1)C.NCCO.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([NH:50][CH2:51][CH2:52][OH:53])=[O:20])=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Reactant: CCN1CCOCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: NCCO
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NCCO)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 8 %

Procedure:
A solution of 4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 4) (90 mg, 0.211 mmol) in DMF (2 mL) was treated with EDC (48.5 mg, 0.253 mmol), HOBT hydrochloride (38.8 mg, 0.253 mmol) and N-ethylmorpholine (0.080 mL, 0.633 mmol) and after 3 min with 2-aminoethanol (0.025 mL, 0.422 mmol)). The resulting mixture was stirred at room temperature for 5 h then EDC (48.5 mg, 0.253 mmol), N-ethyl morpholine (0.080 mL, 0.633 mmol), HOBT (38.8 mg, 0.253 mmol) and further 2-aminoethanol (0.025 mL, 0.422 mmol) were added and the corresponding mixture was stirred for 16 h then concentrated in vacuo. The residue was partitioned between water and EtOAc and the layers were separated. The aqueous phase was extracted with EtOAc (×2) and the combined organic layers were washed with saturated aqueous NaHCO3 (×3), then brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by MDAP to give 4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-N-(2-hydroxyethyl)benzamide (8 mg, 8%) as a white solid. LCMS (HpH, 2 min), Rt=0.78 min, MH+=470.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:58]1([NH2:64])[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:64][N:58]5[CH2:63][CH2:62][O:61][CH2:60][CH2:59]5)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NN1CCOCC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NN2CCOCC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and morpholin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.41 (m, 2H) 1.59-1.86 (m, 8H) 2.94 (br. s., 4H) 3.31 (s, 3H) 3.67 (br. s., 4H) 3.94 (s, 3H) 4.16 (t, 2H) 4.38-4.54 (m, 1H) 7.45 (d, J=8.7 Hz, 1H) 7.48 (s, 1H) 8.14 (d, 1H) 8.23 (s, 1H) 8.57 (br. s., 1H) 9.57 (s, 1H). [M+H] calc'd for C26H33F2N7O4 546. found 546.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH2:12]1[CH2:17][O:16][CH:15]=[CH:14][CH2:13]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:15]1[CH2:14][CH2:13][CH2:12][CH2:17][O:16]1
Reactant: Cc1cc(Br)c2cn[nH]c2c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Br)c2cnn(C3CCCCO3)c2c1
Yield: 74.5 %

Procedure:
A mixture of 4-bromo-6-methyl-1H-indazole (1.05 g, 5 mmol), DHP (2.1 g, 25 mmol), and TsOH.H2O (96 mg, 0.5 mmol) in THF (50 ml) under nitrogen was heated at reflux overnight. The reaction mixture was concentrated in vacuo and to the residue was added DCM (300 mL) and water (50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography by using petroleum ether:EtOAc (100:1) as eluting solvents to afford 4-bromo-6-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole as light yellow oil (1.1 g, 90%) MS (ESI): m/z=295.1 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:32]([O:36][CH3:37])(=[O:35])[CH:33]=[CH2:34].C(N(CC)CC)C>C(#N)C.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:4][C:3]1[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:2]=1/[CH:34]=[CH:33]/[C:32]([O:36][CH3:37])=[O:35]
Reactant: Nc1cc(F)ccc1Br
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/c1ccc(F)cc1N
Temperature: 80 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a mixture of 2-bromo-5-fluoroaniline (35.00 g, 184 mmol, Aldrich), palladium (II) acetate (2.06 g, 9.18 mmol, Strem) and tri(o-tolyl)phosphine (5.60 g, 18.40 mmol; Strem) in acetonitrile (350 ml) at RT was added methyl acrylate (33.00 ml, 365 mmol, Aldrich) and triethylamine (64.00 ml, 460 mmol, Aldrich). The reaction was heated at 80° C. for 24 h. The reaction mixture was diluted with EtOAc (500 mL) and the resulting colorless crystalline solid was filtered and washed with EtOAc. The organic solution was concentrated to dryness and the solids were slurried in 10% EtOAc/hexane at 60° C. for 1 h. The slurry was cooled to RT and filtered. The solid was washed with 10% EtOAc/hexane and sucked dry with air to give 18.30 g (51%) of a light-yellow crystalline solid. m/z=195.9 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:7]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][C@@H:28]2[CH2:30][C@H:25]1[CH2:26][NH:27]2)=[O:23])([CH3:20])([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>[Cl-].[Na+].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].C1(C)C=CC=CC=1>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:7]=[C:2]([N:27]3[CH2:26][C@@H:25]4[CH2:30][C@H:28]3[CH2:29][N:24]4[C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[CH:3]=[N:4][CH:5]=2)=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: COc1ccc(Oc2cncc(Br)c2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(Oc2cncc(N3C[C@@H]4C[C@H]3CN4C(=O)OC(C)(C)C)c2)cc1

Procedure:
In a sealed pressure tube under a argon atmosphere, 3-bromo-5-(4-methoxyphenoxy)pyridine (2.37 g, 1.20 mmol), (1S,4S)-N-(tert-butoxycarbonyl)-2,5-diazabicyclo[2.2.1]heptane (0.21 g, 1.00 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.02 g, 0.02 mmol, 2,2′-bis(diphenylphosphino)-1,1′-binapthyl (0.025 g, 0.04 mmol), sodium tert-butoxide (0.20 g, 2.0 mmol) and toluene (12 mL) was stirred at 80° C. for 24 h. The reaction mixture was dissolved in saturated aqueous sodium chloride solution (20 mL) and then extracted with diethyl ether (3×30 mL). The combined diethyl ether extracts were washed with saturated aqueous sodium chloride solution (20 mL), dried (Na2SO4), filtered and concentrated to a brown oil (0.37 g, 93%). The material was used without further purification.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:19])C=1>C(Cl)Cl>[N+:1]1([O-:19])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2ncccc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1cccc2ccccc21
Reaction time: 24 h
Yield: 90 %

Procedure:
To a 100 mL round bottom flask containing a solution of quinoline (12.2 mmol) in 50 mL DCM was added 5.3 g of m-CPBA (30.6 mmol). The reaction mixture was stirred for 24 h. The reaction mixture was then diluted DCM (100 mL), washed with 5% NaOH (2×100 mL), dried (MgSO4), filtered, and concentrated in vacuo to give solid quinoline-N-oxide (90-95% yield).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14]>>[Cl:6][C:7]1[CH:12]=[C:11]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:10]=[CH:9][C:8]=1[O:13][CH3:14]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccccc1Cl
Product: COc1ccc(S(=O)(=O)Cl)cc1Cl
Temperature: 55 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
Under N2 atmosphere, 41.25 mL chlorosulfonic acid was cooled in an ice bath, and under stirring 22.26 mL 2-chloroanisole was added dropwise. The mixture was heated to 55° C.; after 10 min. the heat source was removed and the mixture was stirred overnight at room temperature. The mixture was poured into ice water and extracted twice with DCM. The combined organic layers were dried over MgSO4 and evaporated to dryness. The residue was purified by flash chromatography (PA/EA 9:1) to give 24.94 g (50%) of a beige oil. 1H NMR (400 MHz, CDCl3) δ 4.03 (s, 3H), 7.08 (d, J=8.73 Hz, 1H), 7.94 (dd, J=9.03, 2.41 Hz, 1H), 8.06 (d, J=2.41 Hz, 1H).
Reaction SMILES: [CH2:1]([N:8](C)[CH:9]1[CH2:15][O:14][CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10]1)C1C=CC=CC=1.C(O)=O>CO.[Pd]>[CH3:1][NH:8][CH:9]1[CH2:15][O:14][CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10]1
Reactant: CN(Cc1ccccc1)C1COCCN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CNC1COCCN(C(=O)OC(C)(C)C)C1
Reaction time: 22 h

Procedure:
A solution of tert-butyl 6-(benzyl(methyl)amino)-1,4-oxazepane-4-carboxylate (0.795 g (2.48 mmol) 107.2 in MeOH (20 mL) was treated with 5% Pd/C (0.26 g) and HCO2H (1 mL). The black suspension was stirred under a 60 PSI H2 atmosphere for 22 hr. The catalyst was removed by filtration through celite and the filtrate was concentrated in vacuo to remove volatiles. The residue was diluted with EtOAc and washed with sat′d NaHCO3, dried over MgSO4, filtered, and concentrated to yield 0.tert-butyl 6-(methylamino)-1,4-oxazepane-4-carboxylate (0.17 g) 107.3 as a clear viscous oil that was used without further purification. 1H NMR (400 MHz, CHLOROFORM-d) δ 3.82-3.60 (m, 5H), 3.59-3.48 (m, 1H), 3.47-3.33 (m, 3H), 3.26 (dd, J=6.5, 14.6 Hz, 1H), 2.93-2.82 (m, 2H), 2.46 (s, 3H), 1.48 (s, 9H); LCMS (ESI) m/z: 231.10 [M+H]−.
Reaction SMILES: [CH2:1]([CH:3]([CH2:15][CH3:16])[CH2:4][NH:5][CH2:6][C:7]1[S:11][C:10](B(O)O)=[CH:9][CH:8]=1)[CH3:2].Br[C:18]1[CH:19]=[C:20]2[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=1)[NH:23][CH:22]=[C:21]2[CH:30]1[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([CH:3]([CH2:15][CH3:16])[CH2:4][NH:5][CH2:6][C:7]1[S:11][C:10]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:31][CH2:32][N:33]([S:36]([CH2:39][CH3:40])(=[O:37])=[O:38])[CH2:34][CH2:35]2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CCC(CC)CNCc1ccc(B(O)O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCC(CC)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Temperature: 150 °C
Reaction time: 0.13 h

Procedure:
To a CEM microwave tube containing the crude (5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)boronic acid (48 mg, 0.199 mmol) was added a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol) in dioxane (1.75 mL), a solution of K2CO3 (130 mg, 0.942 mmol) in H2O (0.25 mL), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The reaction was heated in a CEM microwave for 30 min at 150° C. The reaction mixture was filtered through a 2 g SCX cartridge (pre-equilibrated with 3 mL MeOH), eluting in sequence with MeOH (3 mL) and a 2 M solution of NH3/MeOH (9 mL). The NH3/MeOH fraction was dried under a stream of nitrogen at 50° C., and the crude product was taken up in dimethyl sulfoxide (1.1 mL) and purified on an Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2×100 mm) eluting at 20 mL per min for 1 min with 10% CH3CN/H2O (0.1% TFA) then a linear gradient of 10% CH3CN/H2O (0.1% TFA) to 95% CH3CN/H2O (0.1% TFA) over 8 min and holding at the final concentration for 30 sec. The fractions containing product were filtered through a 2 g Pharmasil CHQAX column (polymer bound ammonium hydroxide; United Chemical Technologies) to remove TFA and concentrated under a stream of nitrogen at 50° C. to give impure title compound. The impure title compound was repurified on an Agilent MDAP and free based with the ammonium hydroxide column as shown above to give 8.5 mg of the title compound (10%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.N1C2C=CC=CC=2N=C1CN(C1C2N=CC=CC=2CCC1)CC1C=CC(CN)=CC=1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1ncccc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 151.9 %

Procedure:
Using General Procedure B: To a stirred solution of 2-methyl-pyridine-3-carbaldehyde (75 mg, 0.62 mmol), N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (246 mg, 0.62 mmol) and AcOH (40 uL, 0.62 mmol) in THF (6.2 mL) was added NaBH(OAc)3 (394 mg, 1.86 mmol) and the mixture was stirred at room temperature overnight. Purification of the crude white foam (280 mg) by column chromatography on silica gel (200:3:1—CH2Cl2:MeOH:NH4OH) afforded the desired product (116 mg, 37%) as a colorless syrup.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].[CH2:12]([SH:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl>[OH-].[Na+]>[CH2:12]([S:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C(O)CCCCCCCBr
Reactant: CCCCCCCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCSCCCCCCCC(=O)O
Temperature: 100 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
At room temperature, a commercially available reagent of 8-bromo-octanoic acid (97% content, 1.74 g, 7.56 mmol) was dissolved in an aqueous solution (15 mL) of 18% sodium hydroxide, and a commercially available reagent of heptane-1-thiol (1.0 g, 7.56 mmol) was added dropwise. The mixture was then warmed to 100° C., and stirred for 2.0 hours while maintaining the temperature at 100° C. The mixture was cooled to room temperature, and then neutralized to pH 6.0 with concentrated hydrochloric acid. After filtration, solid was washed with dichloromethane, and the filtrate was extracted. The aqueous layer was then washed with ethyl acetate. To the organic layer was added 150 mL of ethyl acetate and the organic layer was washed with water, dried over anhydrous sodium sulfate, and filtered. After the solvent was distilled off, the filtrate was dried under reduced pressure to obtain 8-heptylsulfanyl-octanoic acid (No. 6804237; 2.04 g, 98% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[C:14]1[N:15]2[N:21]=[C:20]([O:22][CH3:23])[C:19]([NH:24][CH2:25][CH2:26][CH3:27])=[C:16]2[S:17][CH:18]=1.Cl.Cl[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1.CC(C)([O-])C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+].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>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].O.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][CH3:11])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[C:14]1[N:15]2[N:21]=[C:20]([O:22][CH3:23])[C:19]([N:24]([CH2:25][CH2:26][CH3:27])[C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[C:16]2[S:17][CH:18]=1
Reactant: Clc1ccncc1
Reactant: CCCNc1c(OC)nn2c(-c3c(OC)cc(COC)cc3OC)csc12
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: O
Solvent: C1COCCO1
Product: CCCN(c1ccncc1)c1c(OC)nn2c(-c3c(OC)cc(COC)cc3OC)csc12
Temperature: 100 °C
Reaction time: 7 h
Yield: 58.7 %

Procedure:
To a 1,4-dioxane (0.7 mL) solution of 3-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-6-methoxy-N-propylpyrazolo[5,1-b][1,3]thiazole-7-amine (70 mg, 0.179 mmol) were added 4-chloropyridine hydrochloride (32.2 mg, 0.215 mmol), sodium tert-butoxide (20.6 mg, 0.215 mmol), potassium phosphate tribasic (64.6 mg, 0.304 mmol), tris(dibenzylideneacetone)dipalladium (8.2 mg, 0.009 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (7.77 mg, 0.0134 mmol), and the mixture was stirred at 100° C. for seven hours. After the reaction mixture was returned to room temperature, water was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by medium pressure amino silica gel column chromatography (n-heptane/ethyl acetate: 10% then 80%) to obtain the title compound (49.4 mg, 0.105 mmol).
Reaction SMILES: [F:1][C:2]1[C:7]([S:8][CH3:9])=[CH:6][C:5]([CH3:10])=[CH:4][C:3]=1[O:11][CH3:12].C[OH:14]>O>[F:1][C:2]1[C:7]([S:8]([CH3:9])=[O:14])=[CH:6][C:5]([CH3:10])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: CO
Reactant: COc1cc(C)cc(SC)c1F
Solvent: O
Product: COc1cc(C)cc(S(C)=O)c1F
Temperature: 25 °C

Procedure:
To a mixture of 2-fluoro-1-methoxy-5-methyl-3-(methylsulfanyl)benzene (557.4 mg), MeOH (20 mL) and water (4 mL) was added NaIO4 (960 mg) at 0° C. The mixture was stirred at room temperature over weekend. The mixture was diluted with water. The precipitate was filtered off, and the filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (486 mg).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C@@H:8]([NH:13][C:14]1[S:15][CH:16]=[C:17]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[N:18]=1)[C:9]([F:12])([F:11])[F:10]>C1COCC1>[CH3:7][C@@H:8]([NH:13][C:14]1[S:15][CH:16]=[C:17]([C:19]2[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=2)[N:18]=1)[C:9]([F:10])([F:12])[F:11]
Reactant: C[C@@H](Nc1nc(-c2ccc(C#N)cc2)cs1)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H](Nc1nc(-c2ccc(CN)cc2)cs1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
Add a solution of 1M lithium aluminum hydride in THF (12 mL, 12 mmol) dropwise to an ice-cooled solution of (R)-4-[2-(1-methyl-2,2,2-trifluoroethylamino)-thiazol-4-yl]-benzonitrile in anhydrous THF (10 mL). Heat to reflux for 1 h, cool to room temperature, quench by slow addition of water (12 mL), ether (50 mL), 1N NaOH (12 mL) and additional water (36 mL). Add EtOAc (50 mL), stir vigorously for 20 min and filter over a bed of Celite®. Dry the organic phase over MgSO4, filter and concentrate in vacuo to obtain the title compound (765 mg, 64%). MS (ES+) m/z: 302 (M+H)+.