Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:17][CH2:16]1)=[O:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH:54]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[C:56]([C:63](O)=[O:64])=[CH:55]1>CN(C=O)C.O>[O:14]=[C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:29])[F:30])[CH2:19][CH2:20]1)[CH2:12][NH:11][C:63]([C:56]1[C:57]2[C:62](=[CH:61][CH:60]=[CH:59][CH:58]=2)[NH:54][CH:55]=1)=[O:64]
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 12.35 %

Procedure:
DIPEA (143 mg, 0.193 mL, 1.11 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (prepared by the method described above) (157 mg, 0.44 mmol) in DMF (2 mL). HOBT (60 mg, 0.44 mmol) and EDCI (85 mg, 0.44 mmol) were then added at room temperature. After 2 minutes, 1H-Indole-3-carboxylic acid (60 mg, 0.37 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to the residue. The residue was purified by preparative HPLC to afford 21.3 mg (12.35% yield) of 1H-Indole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 95.81%. 1H NMR (CDCl3): δ 9.1 (s, 1H), 8.1 (d, 1H), 7.9-7.5 (m, 4H), 7.4-7.1 (m, 4H), 4.4-4.2 (m, 2H), 4.1-3.8 (m, 2H), 3.8-3.4 (m, 4H), 3.4-3.1 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:23][CH:24]5[CH2:29][O:28][CH2:27][CH:26]([NH:30]C(=O)[O-])[CH2:25]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[ClH:34]>O1CCOCC1>[ClH:34].[NH2:30][CH:26]1[CH2:27][O:28][CH2:29][CH:24]([NH:23][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[NH:18][CH:19]=2)=[O:22])[CH2:25]1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4COCC(NC(=O)[O-])C4)c3n2)c2ccc(F)cc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4COCC(N)C4)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-tetrahydro-2H-pyran-3-ylcarbamate (120 mg, 0.24 mmol) in 10 mL of dioxane was bubbled HCl gas for 3 h. The reaction mixture was stirred overnight at room temperature. The formed precipitate was separated by filtration and the filter cake was washed with 10 mL of ether to give 30 mg of N-(5-amino-tetrahydro-2H-pyran-3-yl)-2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide hydrochloride. LCMS: (M+H)+=410.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Mg].[CH2:15]1[O:17][CH2:16]1.[Cl-].[NH4+]>C1COCC1.C(OCC)C.Cl>[C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:15][CH2:16][OH:17]
Reactant: C1CO1
Reactant: Brc1ccccc1-c1ccccc1
Agent: Cl
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCCc1ccccc1-c1ccccc1
Temperature: 0 °C
Yield: 49.9 %

Procedure:
2-Bromobiphenyl (20.0 g, 86 mmol) in THF (85 ml) was dropwise added to a refluxing suspension of magnesium (2.1 g, 86 mmol) in THF (15 ml). The reaction mixture was refluxed for 18 h and an extra batch of 2-bromobiphenyl (2.0 g, 8.6 mmol) was added. The reaction mixture was refluxed for 2 h and cooled to 0° C. on an icebath. Ethyleneoxide (14.0 g, 0.32 mol) was was added. The reaction mixture was refluxed for 18 h, cooled to 0° C. and a saturated solution of ammonium chloride (100 ml) was dropwise added at this temperature. The reaction mixture was diluted with diethyl ether (100 ml) and concentrated hydrochloric acid was added until pH 2. The organic phase was separated, dried (MgSO4) and concentrated in vacuo. The residue was submitted to column chromatography on silica gel (800 ml) using heptane and ethyl acetate (7:3) as eluent to give 8.5 g of 2-(biphenyl-2-yl)ethanol as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:18](=[O:19])[C:17]2[CH:21]=[C:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:23]=[CH:24][C:16]=2[I:15])[CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1cc(S(C)(=O)=O)ccc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.1 %

Procedure:
To a solution of rac-3-Methyl-piperazine-1-carboxylic acid tert-butyl ester (350 mg, 1.75 mmol) in dimethylformamide (3 ml) were added 2-Iodo-5-methanesulfonyl-benzoic acid (540 mg, 1.67 mmol), N-ethyldiisopropylamine (1.8 ml, 10.5 mmol), and TBTU (630 mg, 1.92 mmol). The reaction mixture was then allowed to stir at room temperature for 16 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by column chromatography (SiO2, 20 g, Heptane/EtOAc 0-100%) to give the title compound (400 mg, 45%). MS (m/e): 526.2 (M+NH4+).
Reaction SMILES: N[C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:13].N([O-])=[O:15].[Na+]>S(=O)(=O)(O)O>[OH:15][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:13]
Reactant: Cc1ccc2c(=O)[nH]ccc2c1N
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1ccc2c(=O)[nH]ccc2c1O
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 69.1 %

Procedure:
5-Amino-6-methylisoquinolin-1(2H)-one (2.00 g, 11.48 mmol) was dissolved in sulfuric acid (24.3 mL, 287 mmol) (75%, 35 mL). The solution was cooled to 0° C. then a solution of sodium nitrite (12.1 mmol) in sulfuric acid (5 mL) was added dropwise over 15 min. The resulting solution was stirred at 0° C. for 45 min and then the reaction mixture was heated to 70° C. and stirred for 16 h. The reaction mixture was cooled in an ice bath for 15 min, then 100 g of ice was added. The mixture was filtered. The filter cake was washed with water for 4 times until the filtrate became neutral by pH paper. The filter cake was air dried to give 5-hydroxy-6-methylisoquinolin-1(2H)-one as a dark gray solid (1.39 g, 69% yield). MS (ESI, pos. ion) m/z: 176 [M+H]+
Reaction SMILES: C([O:5][C:6](=[O:23])[CH2:7][N:8]([C:14](=[O:22])[CH:15]([CH3:21])[CH2:16][S:17][C:18](=[O:20])[CH3:19])[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)(C)(C)C.C[Si](Cl)(C)C.[I-].[Na+].O>C(#N)C>[C:18]([S:17][CH2:16][CH:15]([CH3:21])[C:14]([N:8]([CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)[CH2:7][C:6]([OH:23])=[O:5])=[O:22])(=[O:20])[CH3:19]
Reactant: CC(=O)SCC(C)C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)SCC(C)C(=O)N(CC(=O)O)C1CCCC1

Procedure:
A mixture containing 80.1 g (0.23 mol) of N-(3-acetylthio-2-methyl-propanoyl)-N-cyclopentyl glycine t-butyl ester, 37.9 g (0.35 mol) of trimethysilyl chloride, and 52.5 g (0.35 mol) of sodium iodide in 300 ml of acetonitrile was heated between 45°-50° C. for 30 minutes. Following the addition of 50 ml of water, the mixture was concentrated in vacuo. The residue was rendered basic with 400 ml of saturated aqueous NaHCO3, washed three times with ethyl acetate, acidified with concentrated HCl, and extracted three times with ethyl acetate. These later organic extracts were combined, dried over MgSO4, filtered, and concentrated in vacuo to afford 60 g (91%) of the crude product. Purification via high pressure liquid chromatography (HPLC) [ethyl acetate/hexane/acetic acid (60/40/2)] afforded N-(3-acetylthio-2-methylpropanoyl)-N-cyclopentyl glycine as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH3:31])[CH:25]=3)=[CH:22][N:21](CC3C=CC(OC)=CC=3)[N:20]=2)[CH:14]=1)(=[O:11])=[O:10]>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[C:23]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH3:31])[CH:25]=3)=[CH:22][NH:21][N:20]=2)[CH:14]=1)(=[O:10])=[O:11]
Reactant: CNc1cc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2)ccn1
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc(-c2c[nH]nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2)ccn1
Temperature: 70 °C
Reaction time: 4 h
Yield: 20.1 %

Procedure:
300 mg (0.53 mmol) of 2,5-difluoro-N-(3-{1-(4-methoxybenzyl)-4-[2-(methylamino)-pyridin-4-yl]-1H-pyrazol-3-yl}phenyl)benzenesulfonamide were dissolved in 10 ml of trifluoroacetic acid and the mixture heated at 70° C. under stirring for 4 hours. The solvent was then removed in vacuo, the residue partitioned between dichloromethane and a saturated aqueous solution of sodium hydrogenocarbonate. The organic layer was dried over sodium sulphate and evaporated to dryness. The crude was finally purified by flash-chromatography on a silica gel column (CH2Cl2-CH3COCH3; from 9/1 to 8/2), giving 47 mg (20%) of the title compound.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].I[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1.CN(C)C=O>[CH:13]1([S:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: IC1CCCC1
Reactant: COC(=O)c1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1SC1CCCC1
Yield: 96.6 %

Procedure:
(Step 1) A solution of methyl 2-sulfanylbenzoate (7.0 g), iodocyclopentane (10.6 g) and potassium carbonate (7.48 g) in tetrahydrofuran-N,N-dimethylformamide (100 ml+10 ml) was stirred at 70° C. for 3 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The reaction mixture was washed successively with 1N hydrochloric acid and saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel chromatography (ethyl acetate:hexane=1:4) to give methyl 2-(cyclopentylsulfanyl)benzoate (9.5 g) as an oil. The obtained methyl 2-(cyclopentylsulfanyl)benzoate (5.0 g) was dissolved in ethyl acetate (150 ml), and m-chloroperbenzoic acid (11.5 g, containing water: Wako Pure Chemical Industries, Ltd.) was added at 0° C. The mixture was stirred at room temperature for 0.5 hr, and quenched with aqueous sodium thiosulfate solution. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=1:4) to give methyl 2-(cyclopentylsulfonyl)benzoate (4.11 g).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[N:4][CH:3]=[N:2]1.C(=O)(O)[O-].[Na+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][S:21]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:23])=[O:22])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: NCCCn1cncn1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(NCCCn1cncn1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of 1.26 g of 1H-1,2,4-triazole-1-propanamine in 30 ml of dichloromethane containing an excess of saturated sodium bicarbonate solution was added, all at once at room temperature, a solution of 1.27 ml of benzenesulfonyl chloride in 15 ml of dichloromethane. The mixture was stirred at room temperature for 16 hours. The layers were separated. The dichloromethane layer was evaporated in vacuo and gave the compound of the Example as a colorless oil.
Reaction SMILES: BrC1C=CC=CC=1C(Cl)=O.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[Br:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([N:42]=[C:43]=[S:44])=[O:41]>C1(C)C=CC=CC=1.C(O)C>[Br:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([N:42]=[C:43]=[S:44])=[O:41].[Br:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]([NH:42][C:43]([NH:30][C:29]1[CH:31]=[CH:32][C:26]([O:25][C:16]2[C:15]3[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=3)[N:19]=[CH:18][CH:17]=2)=[CH:27][CH:28]=1)=[S:44])=[O:41]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccccc1Br
Agent: O=C(N=C=S)c1ccccc1Br
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4Br)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
2-Bromo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2-bromo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml). A solution of 2-bromo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (85 mg, yield 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][CH:11]2[CH2:17][CH2:16][N:15]([C:18]3[N:19]([CH3:26])[N:20]=[CH:21][C:22]=3[N+:23]([O-])=O)[CH2:14][CH2:13][CH:12]2[OH:27])=[CH:5][CH:4]=1.[C:28]([O:32][C:33]([NH:35][C:36]1[S:40][C:39]([C:41]2[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:42]=2[F:48])=[N:38][C:37]=1[C:49](O)=[O:50])=[O:34])([CH3:31])([CH3:30])[CH3:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CCO.O.CN(C=O)C.[Fe]>[F:48][C:42]1[CH:43]=[CH:44][CH:45]=[C:46]([F:47])[C:41]=1[C:39]1[S:40][C:36]([NH:35][C:33](=[O:34])[O:32][C:28]([CH3:30])([CH3:29])[CH3:31])=[C:37]([C:49](=[O:50])[NH:23][C:22]2[CH:21]=[N:20][N:19]([CH3:26])[C:18]=2[N:15]2[CH2:16][CH2:17][CH:11]([O:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:12]([OH:27])[CH2:13][CH2:14]2)[N:38]=1
Reactant: COc1ccc(COC2CCN(c3c([N+](=O)[O-])cnn3C)CCC2O)cc1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Agent: [Fe]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COC2CCN(c3c(NC(=O)c4nc(-c5c(F)cccc5F)sc4NC(=O)OC(C)(C)C)cnn3C)CCC2O)cc1
Temperature: 100 °C
Reaction time: 66 h

Procedure:
To a solution of 5-((4-methoxyphenyl)methoxy)-1-(2-methyl-4-nitro-pyrazol-3-yl)azepan-4-ol (0.80 g, 2.18 mmol) in EtOH (30 mL) and water (3 mL) was added iron powder (0.90 g, 16.11 mmol) The reaction mixture was heated at 100° C. for 2 hr, cooled to room temperature, filtered through Celite® and the filtrate concentrated under reduced pressure. The residue was dissolved in DCM (50 mL) and washed with water (50 mL). The aqueous layer was re-extracted with DCM (50 mL) and the combined organic layers passed through a phase separation cartridge and concentrated under reduced pressure to give a pale orange gum. To a solution of this gum (0.55 g, 1.60 mmol) in DMF (5 mL) was added 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (0.62 g, 1.76 mmol), HATU (0.85 g, 2.40 mmol) and DIPEA (0.56 mL, 3.20 mmol). The reaction mixture was stirred at room temperature for 66 hr, quenched with a saturated aqueous NaHCO3 (200 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (100 mL), separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-10% MeOH/EtOAc) gave tert-butyl N-(2-(2,6-difluorophenyl)-4-((5-(4-hydroxy-5-((4-methoxyphenyl)methoxy)azepan-1-yl)-1-methyl-pyrazol-4-yl)carbamoyl)thiazol-5-yl]carbamate as a pale pink solid (530 mg, 35% over two steps). 1H NMR (400 MHz, CDCl3) δ 10.44 (s, 1H), 9.02 (s, 1H), 7.91 (s, 1H), 7.38-7.28 (m, 1H), 7.25 (d, J=8.2 Hz, 2H), 7.00 (t, J=8.7 Hz, 2H), 6.92-6.84 (m, 2H), 4.61 (d, J=11.1 Hz, 1H), 4.40 (d, J=11.1 Hz, 1H), 3.91 (t, J=8.6 Hz, 1H), 3.81 (s, 3H), 3.73 (s, 3H), 3.55 (td, J=8.4, 3.4 Hz, 1H), 3.34-3.13 (m, 4H), 3.10 (s, 1H), 2.22-2.14 (m, 2H), 1.93-1.77 (m, 2H), 1.62-1.50 (m, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH2:16](Br)[CH:17]([CH3:19])[CH3:18]>>[CH2:16]([N:13]1[CH:14]=[C:10]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[N:11]=[C:12]1[CH3:15])[CH:17]([CH3:19])[CH3:18]
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: CC(C)CBr
Product: Cc1cc(C#Cc2cn(CC(C)C)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=254.2 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and isobutylbromide.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1(Br)[CH:14]=[C:13]([O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:24][CH3:25])[CH:11]=2)[NH:6]1)=[O:4].[CH3:27][N:28]1[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:12]2[C:7](=[C:8]([N:31]3[CH2:32][CH2:33][CH2:34][N:28]([CH3:27])[CH2:29][CH2:30]3)[CH:9]=[C:10]([O:24][CH3:25])[CH:11]=2)[N:6]=1)=[O:4]
Reactant: CN1CCCNCC1
Reactant: COC(=O)C1(Br)C=C(OCOCC[Si](C)(C)C)c2cc(OC)ccc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(OCOCC[Si](C)(C)C)c2cc(OC)cc(N3CCCN(C)CC3)c2n1
Temperature: 25 °C
Yield: 92.6 %

Procedure:
To a clear, light brown solution of 2-bromo-6-methoxy-4-(2-trimethylsilanyl-ethoxymethoxy)-quinoline-2-carboxylic acid methyl ester (1.01 g, 2.28 mmol), N-methylhomopiperazine (0.32 mL, 2.57 mmol), and 4 Å sieves in 30 mL anhydrous toluene was added Pd2(dba)2 (43.8 mg, 0.048 mmol) and BINAP (169.8 mg, 0.27 mmol). The resulting wine colored solution was treated with cesium carbonate (1.124 g, 3.45 mmol). The reaction mixture was heated at reflux under nitrogen for 21 hours. The pea green reaction mixture was cooled to room temperature and concentrated. The crude mixture was purified by flash chromatography on silica gel using a gradient of 95:5 to 40:60 methylene chloride:methanol to afford the desired product as a yellow foam (1.004 g, 92%). 1H NMR (300 MHz, DMSO, d6) δ 7.67 (s, 1H, ArH3), 6.94 (d, 1H, Jm=2.4 Hz, ArH5), 6.66 (d, 1H, Jm=2.4 Hz, ArH7), 5.60 (s, 2H, OCH2O), 3.94 (s, 3H, CO2CH3), 3.88 (s, 3H, OCH3), 3.82 (t, 2H, J=8.0 Hz, OCH2CH2Si), 3.75 (bs, 4H, ArNCH2CH2CH2NCH3 & ArNCH2CH2N—CH3), 3.45 (bs, 2H, ArNCH2CH2NCH3), 3.31 (bs, 2H, ArNCH2CH2CH2NCH3), 2.83 (s, 3H, NCH3), 2.28 (bs, 2H, ArNCH2CH2CH2NCH3), 0.92 (t, 2H, J=8.0 Hz, OCH2CH2Si), 0.04 (s, 9H, Si(CH3)3; Mass Spec.: calc. for [C24H37N3O5Si+H]+ Theor. m/z=476; Obs. 476.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:34][O:35][CH2:36][CH2:37][NH:38][CH2:39][CH2:40][O:41][CH3:42]>>[CH3:34][O:35][CH2:36][CH2:37][N:38]([CH2:39][CH2:40][O:41][CH3:42])[C:1](=[NH:2])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18](=[O:20])(=[O:19])[NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)=[O:33])[CH:4]=1
Reactant: COCCNCCOC
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: COCCN(CCOC)C(=N)c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Yield: 11 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1.1 equivalents of bis(2-methoxyethyl)amine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [CH:1]([N:4]([CH2:20][CH2:21][CH:22]=O)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[C:9]=1[O:18][CH3:19])(=[O:7])=[O:6])([CH3:3])[CH3:2].[CH3:24][NH:25][CH2:26][CH2:27][C:28]1[CH:37]=[CH:36][C:33]([O:34][CH3:35])=[C:30]([O:31][CH3:32])[CH:29]=1>C(O)C.O=[Pt]=O>[CH3:32][O:31][C:30]1[CH:29]=[C:28]([CH2:27][CH2:26][N:25]([CH3:24])[CH2:22][CH2:21][CH2:20][N:4]([CH:1]([CH3:2])[CH3:3])[S:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[C:9]=2[O:18][CH3:19])(=[O:6])=[O:7])[CH:37]=[CH:36][C:33]=1[O:34][CH3:35]
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: COc1ccc(S(=O)(=O)N(CCC=O)C(C)C)c(OC)c1OC
Agent: O=[Pt]=O
Solvent: CCO
Product: COc1ccc(CCN(C)CCCN(C(C)C)S(=O)(=O)c2ccc(OC)c(OC)c2OC)cc1OC

Procedure:
N-isopropyl-N-(3-oxopropyl)-2,3,4-trimethoxybenzenesulfonamide prepared in the previous paragraph (7.50 g, 0.0384 m), N-methyl-homoveratrylamine (6.83 g, 0.350 m) in absolute ethanol (100 ml) containing PtO2 (0.5 g) was shaken under hydrogen all day. The crude product (8.01 g) obtained from this procedure after chromatography gave the pure title compound, a white gum (5.71 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: C1CCNCC1
Reactant: Clc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Product: Clc1ccc(-c2nsc3cc(OCCCCN4CCCCC4)ccc23)cc1

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-chloro-phenyl)-benzo[d]isothiazole and Piperidine were converted to yield 3-(4-Chloro-phenyl)-6-(4-piperidin-1-yl-butoxy)-benzo[d]isothiazole, MS: 401 (MH+, 1Cl).
Reaction SMILES: C([O:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][C@@H:14]2[CH2:18][CH2:17][NH:16][C:15]2=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO.C(Cl)Cl>[OH:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][C@@H:14]2[CH2:18][CH2:17][NH:16][C:15]2=[O:19])=[CH:11][CH:10]=1
Reactant: O=C1NCC[C@H]1Oc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: O=C1NCC[C@H]1Oc1ccc(O)cc1
Reaction time: 20 h

Procedure:
A mixture of (R)-3-(4-benzyloxy-phenoxy)-pyrrolidin-2-one (61 g), MeOH/DCM (2:1, 2 L) and Pd (10% on carbon, 6 g) was shaken under an atmosphere of hydrogen for 20 hours. The catalyst was removed by filtration and the filtrate concentrated to provide the subtitle compound. MS ESI+: m/z=194 [M+H]+.