Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:36])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][O:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[O:24][CH2:23]2)[CH:17]([CH:37]([OH:39])[CH3:38])[C:16]3=[O:40])=[O:13])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:45].O>[Pd].O1CCOCC1>[Na+:45].[OH:39][CH:37]([CH:17]1[C:16](=[O:40])[N:15]2[CH:18]1[CH:19]([CH3:36])[C:20]([S:21][CH:22]1[CH2:26][CH:25]([CH2:27][O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[O:24][CH2:23]1)=[C:14]2[C:12]([O-:13])=[O:11])[CH3:38]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(COCc4ccccc4)C3)C(C)C12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SC3COC(COCc4ccccc4)C3)C(C)C12
Yield: 33 %

Procedure:
The title compound is prepared by the procedure of Example 18 using 0.170 g of product from Example 81, 0.0277 g of sodium bicarbonate, 1.2 ml of water, 6.8 ml of dioxane, and 0.055 g of 10% palladium/carbon to give 0.045 g of desired product.
Reaction SMILES: [Mg].[CH3:2][S:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][Mg]Cl)=[CH:6][CH:5]=1.CSC1C=CC(CCl)=CC=1.C(Cl)C1C=CC=CC=1.[F:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[C:37](=O)[CH:36]([CH3:42])[CH2:35]2>CCOCC.C1(C)C=CC=CC=1>[F:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[CH:37]([CH2:8][C:7]1[CH:11]=[CH:12][C:4]([S:3][CH3:2])=[CH:5][CH:6]=1)[C:36]([CH3:42])=[CH:35]2
Reactant: CSc1ccc(C[Mg]Cl)cc1
Reactant: CC1Cc2cc(F)ccc2C1=O
Agent: CSc1ccc(CCl)cc1
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: ClCc1ccccc1
Product: CSc1ccc(CC2C(C)=Cc3cc(F)ccc32)cc1
Temperature: 30 °C
Reaction time: 0.07 h

Procedure:
Twenty-five grams (1.04 moles) of magnesium turnings were placed in a dried flask under N2 with 400 ml. of ether. Ten ml. of 0.05 molar p-methylthiobenzyl magnesium chloride in ether is added and the mixture is warmed to 30°C. About 2-3% of 39.7 g. (0.23 moles) of p-methylthiobenzyl chloride in 75 ml. of toluene is added. After 3-5 minutes of stirring an exotherm to 32°-33°C occurs signifying initiation of the reaction. After aging for 5 minutes, the rest of the benzyl chloride is added dropwise over 90 minutes. The reaction is aged for 30 minutes with stirring. 5-Fluoro-2-methyl-1-indanone (32.6 g., 0.199 mole) is added dropwise over 45 minutes. After aging for 30 minutes, the milky supernatant mixture is decanted from the magnesium. The flask and residual magnesium are rinsed with toluene. The reaction is then quenched by the addition of 120 ml. of 3N sulfuric acid. The lower layer is discarded. To the organic layer is added 80 ml. of 1:10 concentrated sulfuric acid, acetic acid and the two-phase mixture, stirred vigorously for one hour and water (100 ml.) is added. The bottom layer is discarded and the organic layer is washed with 100 ml. of water and 200 ml. of 2N sodium hydroxide. After a final water wash the organic layer is concentrated to give 5-fluoro-2-methyl-1-(p-methylthiobenzyl)-indene. Similarly, when p-methylsulfinylbenzyl chloride is used in place of p-methylthiobenzyl chloride in the above example, the corresponding p-methylsulfinylbenzyl indene is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3([C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[O:22])[CH2:20][CH2:19]3)=[O:17])=[CH:11][C:10]=2[F:31])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.Cl[C:40](OC1C=CC=CC=1)=[O:41].FC(F)(F)C(O)=O.[CH3:56][O:57][CH:58]1[CH2:61][NH:60][CH2:59]1>O1CCCC1>[F:31][C:10]1[CH:11]=[C:12]([NH:15][C:16]([C:18]2([C:21]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)=[O:22])[CH2:20][CH2:19]2)=[O:17])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:40]([N:60]2[CH2:61][CH:58]([O:57][CH3:56])[CH2:59]2)=[O:41])[CH:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reactant: COC1CNC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC1CN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)C1
Reaction time: 1 h
Yield: 57.4 %

Procedure:
N-{4-[(2-Aminopyridin-4-yl)oxy]-3-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (75 mg) was dissolved in tetrahydrofuran (1.8 ml) under a nitrogen atmosphere, and triethylamine (0.074 ml) and phenyl chloroformate (0.0488 ml) were added dropwise at room temperature in this order, followed by stirring for 1 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a 1N aqueous solution of sodium hydroxide, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (1.8 ml). This solution was added to a mixture of a crude product of 3-methoxyazetidine trifluoroacetate (corresponds to 0.671 mmol) and triethylamine (0.247 ml), followed by stirring at room temperature overnight (for 11 hr). The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a 1N aqueous solution of sodium hydroxide, water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (eluent; heptane:ethyl acetate=1:2, ethyl acetate, then ethyl acetate:methanol=50:1). Fractions containing the target compound were concentrated. To the resultant residue (64.2 mg) was added diethyl ether:heptane=1:2 to suspend a solid. The solid was collected by filtration and washed with heptane. This was dried under aeration provide the titled compound as white powder (54.6 mg, 57.4%).
Reaction SMILES: CC1C=C(C=CC=1C(F)(F)F)[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[C:20]([C:27]([N:29]4[CH2:34][CH2:33][N:32]([CH2:35][C:36]5[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]([F:47])([F:46])[F:45])=[CH:38][CH:37]=5)[CH2:31][CH2:30]4)=[O:28])[N:21]3COC)=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)=O.[C:55]1(OC)[C:56](=[CH:59][CH:60]=[CH:61][CH:62]=1)OC.Cl.[CH3:66][OH:67]>>[CH3:5][N:7]([C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:23]=[C:22]3[C:18]([CH:19]=[C:20]([C:27]([N:29]4[CH2:30][CH2:31][N:32]([CH2:35][C:36]5[CH:37]=[CH:38][C:39]([O:42][CH2:43][C:44]([F:46])([F:45])[F:47])=[CH:40][CH:41]=5)[CH2:33][CH2:34]4)=[O:28])[NH:21]3)=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)[C:66](=[O:67])[C:61]1[CH:62]=[CH:55][C:56]([C:44]([F:47])([F:46])[F:45])=[CH:59][CH:60]=1
Reactant: COCn1c(C(=O)N2CCN(Cc3ccc(OCC(F)(F)F)cc3)CC2)cc2ccc(Oc3ccc(NC(=O)c4ccc(C(F)(F)F)c(C)c4)cn3)cc21
Reactant: COc1ccccc1OC
Reactant: CO
Agent: Cl
Product: CN(C(=O)c1ccc(C(F)(F)F)cc1)c1ccc(Oc2ccc3cc(C(=O)N4CCN(Cc5ccc(OCC(F)(F)F)cc5)CC4)[nH]c3c2)nc1

Procedure:
To a solution of M-methyl-N-[6-(1-methoxymethyl-2-{4-[4-(2,2,2-trifluoroethoxy)benzyl]piperazine-1-carbonyl}-1H-indol-6-yloxy)pyridin-3-yl]-4-trifluoromethylbenzamide (0.24 g, 0.31 mmol) in MeOH (12 mL) were added veratrole (0.43 g, 3.1 mmol) and 2 M HCl (6 mL), and the mixture was stirred under reflux for 7 hours. The solvent was evaporated in vacuo, and the residue was extracted with AcOEt. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (AcOEt) to give 0.34 g of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]#[N:28])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.[N-:29]=[N+:30]=[N-:31].[Na+].[NH4+].[Cl-]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]4[NH:31][N:30]=[N:29][N:28]=4)[CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(-c2nc3ccc(C#N)cc3nc2-c2ccc(OC)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3ccc(-c4nnn[nH]4)cc3nc2-c2ccc(OC)cc2)cc1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Into a 20-mL sealed tube, was placed a solution of 2,3-bis(4-methoxyphenyl)quinoxaline-6-carbonitrile (200 mg, 0.51 mmol, 1.00 equiv, 93%) in N,N-dimethylformamide (7 mL), NaN3 (500 mg, 7.69 mmol, 15.18 equiv), NH4Cl (147.9 mg, 2.79 mmol, 5.00 equiv). The resulting solution was stirred for 4 h at 100° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 8×50 mL of dichloromethane/MeOH (10:1) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The resulting mixture was washed with methanol. This resulted in 47 mg (23%) of 2,3-bis(4-methoxyphenyl)-6-(1H-tetrazol-5-yl)quinoxaline as a yellow solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].C([N:13]1[CH2:27][CH2:26][C:25]2[C:16](=[N:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[C:24]=2[Cl:28])[CH2:15][CH2:14]1)C>C(Cl)Cl.CCOCC>[C:5]1([O:4][C:2]([N:13]2[CH2:27][CH2:26][C:25]3[C:16](=[N:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[C:24]=3[Cl:28])[CH2:15][CH2:14]2)=[O:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCN1CCc2nc3ccccc3c(Cl)c2CC1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(Oc1ccccc1)N1CCc2nc3ccccc3c(Cl)c2CC1
Reaction time: 8 h

Procedure:
A solution of 1.2 gm (7.7 millimols) of phenyl chloroformate in 20 ml of methylene chloride was added dropwise to a mixture of 2 gm (7.7 millimols) of 3-ethyl-11-chloro-1,2,4,5-tetrahydro-3H-azepino[4,5-b]quinoline and 15 ml of methylene chloride at 5° C. After standing overnight, the resulting mixture was diluted with ether to double its volume and was then suction-filtered. The filter cake was recrystallized from acetone.
Reaction SMILES: [CH3:1][C:2]([NH:16]C(=O)OCC1C=CC=CC=1)([CH2:4][CH2:5][S:6]([CH2:9][CH:10]([OH:15])[CH:11]([OH:14])[CH2:12][OH:13])(=[O:8])=[O:7])[CH3:3].[H][H]>CO.[Pd]>[NH2:16][C:2]([CH3:3])([CH3:1])[CH2:4][CH2:5][S:6]([CH2:9][CH:10]([OH:15])[CH:11]([OH:14])[CH2:12][OH:13])(=[O:8])=[O:7]
Reactant: CC(C)(CCS(=O)(=O)CC(O)C(O)CO)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(N)CCS(=O)(=O)CC(O)C(O)CO
Reaction time: 3.5 h

Procedure:
A solution of benzyl 2-methyl-4-(2,3,4-trihydroxybutylsulfonyl)butan-2-ylcarbamate (172.1 mg, 0.4418 mmol) in methanol (5 ml) was purged with nitrogen and palladium on carbon (10%, 40 mg) was added. The suspension was put under a blanket of hydrogen (1.3 atmospheres) and stirred for 3.5 hours. The suspension was filtered through a 0.45 um PTFE filter and concentrated in vacuo to afford the title compound which was used without further purification. LRMS (ESI/APCI) m/z 256 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[C:39]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:37]=[CH:36][C:3]=1[CH2:4][N:5]([CH2:22][CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:11]=1.IC.[CH:46](N(C(C)C)CC)(C)C.[CH3:55][S:56]([OH:59])(=[O:58])=[O:57]>CN(C=O)C.C(Cl)Cl>[CH3:55][S:56]([OH:59])(=[O:58])=[O:57].[Cl:1][C:2]1[C:39]([C:40]([F:41])([F:43])[F:42])=[CH:38][CH:37]=[CH:36][C:3]=1[CH2:4][N:5]([CH2:22][CH:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH2:17][CH2:18][N:19]([CH3:46])[CH2:20][CH2:21]2)[CH:11]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: FC(F)(F)c1cccc(CN(CCCOc2cccc(N3CCNCC3)c2)CC(c2ccccc2)c2ccccc2)c1Cl
Agent: CS(=O)(=O)O
Solvent: CI
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1CCN(c2cccc(OCCCN(Cc3cccc(C(F)(F)F)c3Cl)CC(c3ccccc3)c3ccccc3)c2)CC1
Temperature: 50 °C

Procedure:
To a stirring solution of (2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(3-piperazin-1-yl-phenoxy)-propyl]-amine (150 mg, 2.46 mmol) in anhydrous DMF (20 ml) was added iodomethane (16.8 uL, 2.71 mmol) and diisopropylethylamine (86 uL, 4.93 mmol). The resulting solution was heated at 50° C. for 4 hours and then concentrated. Purification by flash silica gel chromatography (silica gel 60, EM science; 3% MeOH and 0.5% NH2OH in CH2Cl2) afforded the N-methylated product. The amine was dissolved in CH2Cl2 and methansulfonic acid (2 equivalents) was added. The methylene chloride solution was concentrated and the resulting bis-methanesulfonate salt was dried under vacuum to yield the title compound as a solid, 56 mg (37%). MS(ES) m/e 622.4 (M+).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Sn](C)(C)C)=[CH:9][CH:8]=2)[CH2:5][C@H:4]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:3]1.Br[C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH2:33][CH:32]([CH2:34][OH:35])[O:31][N:30]=2)=[N:27][CH:28]=1.O1C=CC=C1P(C1OC=CC=1)C1OC=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.C(Cl)(Cl)Cl.[Pd].[Pd]>[OH:35][CH2:34][CH:32]1[O:31][N:30]=[C:29]([C:26]2[CH:25]=[CH:24][C:23]([C:10]3[CH:11]=[CH:12][C:7]([N:6]4[CH2:5][C@H:4]([CH2:17][NH:18][C:19](=[O:21])[CH3:20])[O:3][C:2]4=[O:1])=[CH:8][CH:9]=3)=[CH:28][N:27]=2)[CH2:33]1
Reactant: OCC1CC(c2ccc(Br)cn2)=NO1
Reactant: CC(=O)NC[C@H]1CN(c2ccc([Sn](C)(C)C)cc2)C(=O)O1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NOC(CO)C4)nc3)cc2)C(=O)O1
Temperature: 90 °C
Yield: 26.8 %

Procedure:
N-({(5S)-2-Oxo-3-[4-(trimethylstannyl)phenyl]-1,3-oxazolidin-5-yl}methyl)acetamide (300 mg, 0.76 mM), [3-(5-bromopyridin-2-yl)-4,5-dihydroisoxazol-5-yl]methanol (194 mg, 0.76 mM), tris(dibenzylideneacetone)dipalladium (0)-chloroform adduct (78 mg, 0.076 mM) and tri-2-furylphosphine (35 mg, 0.152 mM) were placed in a flask. The solids were degassed and placed under nitrogen. Anhydrous dioxane (5 ml) was added and the suspension was heated at 90° C. for 15 hours. The reaction mixture was cooled and the solvent was evaporated. The residue was chromatographed on silica gel eluting with 5% methanol in dichloromethane to give the title compound (83 mg).
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:18]([C:20]2[NH:21][N:22]=[N:23][CH:24]=2)=[O:19])[CH2:9][C@:10]([CH2:15][OH:16])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH2:52]1[C:60]2[C:55](=[CH:56][C:57](O)=[CH:58][CH:59]=2)[CH2:54][CH2:53]1.CN1CCOCC1>C(Cl)Cl>[CH2:52]1[C:60]2[C:55](=[CH:56][C:57]([O:12][C:11](=[O:13])[C@@:10]([CH2:15][OH:16])([CH3:14])[CH2:9][C@H:8]([NH:17][C:18]([C:20]3[NH:21][N:22]=[N:23][CH:24]=3)=[O:19])[CH2:7][C:4]3[CH:5]=[CH:6][C:1]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:2][CH:3]=3)=[CH:58][CH:59]=2)[CH2:54][CH2:53]1
Reactant: Oc1ccc2c(c1)CCC2
Reactant: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@@](CO)(C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cnn[nH]1)C(=O)Oc1ccc2c(c1)CCC2
Reaction time: 0.25 h
Yield: 0.9 %

Procedure:
(2S,4R)-5-Biphenyl-4-yl-2-hydroxymethyl-2-methyl-4-[(3H-[1,2,3]triazole-4-carbonyl)-amino]-pentanoic acid (118 mg, 290 μmol), HOBt (118 mg, 871 μmol), and EDCI (154 μL, 871 μmol) were dissolved into DCM and stirred for 15 minutes. 5-Indanol (310 mg, 2.3 mmol) and 4-methylmorpholine (128 μL, 1.2 mmol) were added and the resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with water and the DCM layer was separated and concentrated. AcOH was added and the product was purified by preparative HPLC to yield the title compound (1.4 mg; purity 95%). MS m/z [M+H]+ calc'd for C31H32N4O4, 525.24. found 5254.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:14]3N=C(CSC4C=CC=CC=4)S[CH:18]=3)[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[NH2:27][C:28](=[S:41])[C:29]([CH3:40])([CH3:39])[S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31]>CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:14]3[N:27]=[C:28]([C:29]([CH3:39])([S:30]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)(=[O:32])=[O:31])[CH3:40])[S:41][CH:18]=3)[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cc(-c3csc(CSc4ccccc4)n3)c(=O)[nH]c2c1
Reactant: CC(C)(C(N)=S)S(=O)(=O)c1ccccc1
Solvent: CO
Product: COc1ccc2cc(-c3csc(C(C)(C)S(=O)(=O)c4ccccc4)n3)c(=O)[nH]c2c1
Temperature: 120 °C

Procedure:
This compound was prepared according to the procedure described for Example 8836(c) by employing 3-(2-bromo-acetyl)-7-methoxy-1H-quinolin-2-one (Example 8741, 250 mg, 0.84 mmol) and 2-amino-1,1-dimethyl-1-(phenylsulfonyl)ethane-2-thione (Step b, 1.7 mL, 1.0 mmol) in 3.5 mL of anhydrous MeOH was heated at 120° C. for 3×5 min by microwave synthesizer. The reaction mixture was cooled to RT. The precipitates were collected by filtration and washed with MeOH and CH2Cl2 to provide the title compound as a white solid. MS m/z: 441 (M+1).
Reaction SMILES: [CH3:1][O:2][CH:3](Cl)Cl.[Br:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17]C)[CH:13]=2)[CH:8]=1.Cl>ClCCl.Cl[Ti](Cl)(Cl)Cl>[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([CH:12]=[O:17])=[C:3]([O:2][CH3:1])[CH:11]=[CH:10]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: COc1ccc2cc(Br)ccc2c1C=O
Temperature: 25 °C

Procedure:
9.7 ml of TiCl4 (2.1 eq) and 4.2 ml of dichloromethyl methyl ether (1.1 eq) are dissolved in 20 ml of dichloromethane at 0° C. A solution of 10 g of 2-bromo-6-methoxynapthalene (1 eq) is added dropwise in such a way that the temperature does not exceed 5° C. The reaction mixture is stirred at RT over night, followed by the addition of 300 ml of 1% HCl. The organic and aqueous phases are separated, and the aqueous phase is extracted with dichloromethane. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness on a rotary evaporator to obtain the desired product in quantitative yield (11 g).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)(=[O:21])=[O:20])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:28][CH:29]1[CH2:34][CH2:33][N:32]([CH:35]([CH3:37])[CH3:36])[CH2:31][CH2:30]1.[Cl:38][C:39]1[CH:44]=[C:43](B(O)O)[CH:42]=[CH:41][N:40]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:14][CH2:15][N:16]([S:19]([N:22]4[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]4)(=[O:21])=[O:20])[CH2:17][CH2:18]3)=[O:12])[N:8]2[C:43]2[CH:42]=[CH:41][N:40]=[C:39]([Cl:38])[CH:44]=2)=[CH:4][C:3]=1[O:28][CH:29]1[CH2:30][CH2:31][N:32]([CH:35]([CH3:37])[CH3:36])[CH2:33][CH2:34]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(S(=O)(=O)N5CCCCC5)CC4)[nH]c3cc2Br)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(S(=O)(=O)N5CCCCC5)CC4)n(-c4ccnc(Cl)c4)c3cc2Br)CC1
Temperature: 35 °C
Reaction time: 18 h
Yield: 47.5 %

Procedure:
A suspension of 0.15 g (0.25 mmol) [6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-[4-(piperidine-1-sulfonyl)-piperazin-1-yl]-methanone (example 1), 119 mg (0.76 mmol) 2-chloropyridine-4-boronic acid, 91 mg (0.50 mmol) copper(II) acetate and 80 μL (78 mg, 1.0 mmol) pyridine in 4 ml chloroform was stirred 18 h at 35° C. The volatile components were evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel with a gradient of dichloromethane:methanol (100:0 to 50:50 v/v) as eluant to afford 84 mg (47%) of the title compound as a light-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([NH2:14])[CH:3]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>C(O)(C)C>[ClH:1].[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:3][C:4]([NH2:14])=[N:5]2)=[CH:10][CH:9]=1
Reactant: COc1ccc2c(Cl)cc(N)nc2c1
Reactant: C1CCNC1
Solvent: CC(C)O
Product: COc1ccc2c(N3CCCC3)cc(N)nc2c1
Product: Cl
Temperature: 60 °C
Yield: 18.6 %

Procedure:
A solution of 319 mg (0.92 mmol) of 4-chloro-7-methoxy-quinolin-2-ylamine in 20 ml of isopropanol was treated with 130 mg (1.83 mmol) of pyrrolidine and heated at 60° C. for 6 h. The reaction mixture was cooled to RT, concentrated in vacuo. The residue was applied to a silica gel column with hexane/AcOEt (1:1) as eluent. The purified fractions were combined and concentrated in vacuo upon which the desired product crystallized out. The crystals were filtered off and dried in a high vacuum to give 48 mg (21%) of 7-methoxy-4-pyrrolidin-1-yl-quinolin-2-ylamine hydrochloride as a light brown solid. EI mass spectrum, m/e: 243.2 (M calculated for C14H17N3O: 243).
Reaction SMILES: [CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:23])[N:14]([CH2:19][C:20]([OH:22])=O)[C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[N:26]1[NH:27][CH:28]=[C:29]2[C:34]=1[CH2:33][CH2:32][CH:31]([NH2:35])[CH2:30]2.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[CH2:1]([S:8]([NH:11][C:12]1[C:13](=[O:23])[N:14]([CH2:19][C:20]([NH:35][CH:31]2[CH2:32][CH2:33][C:34]3[C:29](=[CH:28][NH:27][N:26]=3)[CH2:30]2)=[O:22])[C:15]([CH3:18])=[CH:16][CH:17]=1)(=[O:9])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCc2n[nH]cc2C1
Reactant: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: Cc1ccc(NS(=O)(=O)Cc2ccccc2)c(=O)n1CC(=O)NC1CCc2n[nH]cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.6 %

Procedure:
To a solution of 2-[3-[(benzylsulfonyl)amino]-6-methyl-2-oxo-1(2H)-pyridinyl]acetic acid (94.1 mg, 0.28 mmol) and 4,5,6,7-tetrahydro-2H-indazol-5-ylamine dihydrochloride (58.8 mg, 0.28 mmol) in 1 mL of DMF was added HOBt (42.8 mg, 0.28 mmol). The pH of the solution was adjusted to 8 with N-methylmorpholine and EDC (53.7 mg, 0.28 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and ethylacetate and saturated NaHCO3 solution were added to the residue. The water phase was extracted with ethyl acetate three times, and the combined organic phases were washed with saturated NaCl solution, dried over MgSO4, filtered and the solvent evaporated under reduced pressure. The product was purified by column chromatography (silicagel, eluant CH2Cl2/MeOH=9/1) to give 48 mg (38%) of a white solid compound.