Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([NH:6][C:7](=[O:16])[C:8](=[O:15])[N:9]2[OH:14])=[CH:4][CH:3]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C.P([O-])([O-])([O-])=O>[CH2:17]([O:14][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[C:11]=2[C:12]#[N:13])[NH:6][C:7](=[O:16])[C:8]1=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1c(Cl)ccc2[nH]c(=O)c(=O)n(O)c12
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Product: N#Cc1c(Cl)ccc2[nH]c(=O)c(=O)n(OCc3ccccc3)c12
Reaction time: 20 h
Yield: 98.1 %

Procedure:
To a solution of 2,0 g (~8,4 mmol) 7-chloro-8-cyano-1-hydroxyquinoxaline-2,3(1H,4H)-dione in a mixture of 150 ml ethanol and 175 ml 0,1M phosphate buffer pH 7.4 was added 3.0 g (~17,4 mmol) of benzylbromide. Stirring was continued for 20 h at 24° C. The precipitate was filtered off to give the title compound (2.7 g; 98%), m.p. 227°-229° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([N:24]([CH2:40][CH3:41])[CH2:25][CH2:26][N:27]([CH2:29][C:30]1[N:35]=[C:34]2[CH2:36][O:37][C:38](=O)[C:33]2=[CH:32][CH:31]=1)[CH3:28])[CH3:23].Cl>C1COCC1>[CH2:40]([N:24]([CH2:22][CH3:23])[CH2:25][CH2:26][N:27]([CH2:29][C:30]1[N:35]=[C:34]2[CH2:36][O:37][C:38](=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[C:33]2=[CH:32][CH:31]=1)[CH3:28])[CH3:41]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCN(CC)CCN(C)Cc1ccc2c(n1)COC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN(CC)CCN(C)Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.6 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (125 mg, 0.83 mmol.) in THF (4 mL) is treated with a solution of lithium bis(trimethylsilyl)amide (1.66 mL of a 1M solution in THF, 1.66 mmol) dropwise. The resulting solution is stirred for 20 min at room temperature. A solution of 2-{[(2-diethylamino-ethyl)-methyl-amino]-methyl}-7H-furo[3,4-b]pyridin-5-one (115 mg, 0.41 mmol) in THF (1.5 mL) is added dropwise to the reaction mixture. The resulting solution is stirred at room temperature for 4 h and then poured into 10% aqueous HCl solution (30 mL) previously cooled to 0° C. The ice bath is removed and the solution is stirred at room temperature for 16 h. The yellow solution is then cooled and solid NaHCO3 is carefully added to adjust the solution to pH=8. The aqueous layer is extracted with EtOAc. The combined organic extracts are dried with anhydrous Na2SO4 and concentrated. The solid residue is broken up in isopropyl alcohol to give a yellow solid. The yellow solid is collected by filtration to give the title compound (102 mg, 61%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11](=[NH:14])[NH:12][NH2:13])=[N:9][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:5]2=[N:6][CH:7]=1.[CH3:24][C:25]([CH3:36])([C:30](=O)[C:31](OC)=[O:32])[C:26]([O:28][CH3:29])=[O:27]>>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[N:13][C:30]([C:25]([CH3:36])([CH3:24])[C:26]([O:28][CH3:29])=[O:27])=[C:31]([OH:32])[N:14]=3)=[N:9][N:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)C(=O)C(C)(C)C(=O)OC
Reactant: COc1ccc(Cn2nc(C(=N)NN)c3cc(F)cnc32)cc1
Product: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3ccc(OC)cc3)c3ncc(F)cc23)nc1O

Procedure:
4.89 g (15.557 mmol) of the compound from Example 32A were reacted analogously to the procedure of Example 28A with 4.391 g (23.336 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate (described in J. Am. Chem. Soc. 124(14), 3680-3691; 2002). After the reaction had gone to completion, a solid was filtered off, which was washed with ethanol and then dried under high vacuum. This gave 6.04 g (85% of theory) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])=[CH:7][CH:6]=1)=[O:4].[N:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1>C(#N)C>[N:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:31][CH2:32][N:33]([CH2:2][C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][S:14]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)(=[O:16])=[O:15])=[CH:7][CH:6]=3)=[O:4])[CH2:34][CH2:35]2)=[CH:26][CH:25]=1
Reactant: c1cc(N2CCNCC2)ccn1
Reactant: Cc1ccc(S(=O)(=O)NCCc2ccc(C(=O)CBr)cc2)cc1
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)NCCc2ccc(C(=O)CN3CCN(c4ccncc4)CC3)cc2)cc1
Reaction time: 18 h

Procedure:
A solution of N-(2-[4-bromoacetylphenyl]ethyl)-4-methylphenylsulphonamide (485 mg) in acetonitrile (10 ml) was added to a stirred solution of 1-(4-pyridyl)piperazine (400 mg) in acetonitrile (10 ml) and the mixture was stirred for 18 hours. The solvent was evaporated in vacuo and the residue purified by flash chromatography on silica, eluting with 10% v/v methanol/dichloromethane. On evaporation of the eluant fraction crystallisation occured. These crystals on filtration and washing with dichloromethane gave the title compound, 230 mg, as an off-white solid: m.p. 133°-135° C.; NMR(d6DMSO) δ8.14(2H,bd), 7.90(2H,d), 7.65(2H,d), 7.59(1H,t), 7.35(2H,d), 7.29(2H,d), 6.81(2H,d), 3.37(2H,s), 3.33(4H,t), 2.98(2H,q), 2.76(2H,t), 2.63(4H,t), 2.38(3H,s); m/e 479(M+H)+ ; calculated for C26H30N4O3S: C, 65.2; H, 6.3; N, 11.7; found. C 65.0; H, 6.3; N, 11.4%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[CH2:15][C:16]#[N:17])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:4]([N+:18]([O-])=O)[CH:3]=1.C([O-])(O)=O.[Na+].CCOC(C)=O>CC(O)=O.O.[Fe]>[NH2:17][C:16]1[CH2:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[N:18]=1
Reactant: CCOC(=O)/C(=C/c1ccc(Br)cc1[N+](=O)[O-])CC#N
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2ccc(Br)cc2N=C(N)C1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 90.5 %

Procedure:
A mixture of (E)-ethyl 3-(4-bromo-2-nitrophenyl)-2-(cyanomethyl)acrylate (20.0 g, 59.0 mmol) in AcOH (380 mL) was heated to 80° C. To this mixture iron (19.8 g, 354 mmol) was added portionwise over 1 h keeping the internal temperature below 100° C. After completion of addition of iron, the reaction mixture was heated for additional 2.5 h at 80-85° C. until the starting material disappeared on HPLC. The reaction mixture was cooled to room temperature and filtered through a GF/F filter packed with Celite rinsing with AcOH. The filtrate was concentrated under reduced pressure to give the crude material which was diluted with water (150 mL). The aqueous mixture was treated with sat'd NaHCO3 (200 mL) until it became basic (pH>8). To the suspension was added additional EtOAc (350 mL). The whole mixture was filtered through a filter packed with Celite. The solids filtered off were diluted with EtOAc (300 mL), stirred for 15 min, and filtered again. This process with the solids filtered off was repeated one more time. All of the organic layers were combined and washed with sat'd aq NaHCO3 (300 mL) followed by brine (300 mL), dried over MgSO4, filtered while rinsing with EtOAc, and concentrated under reduced pressure to give the crude material that was triturated with ether (100 mL) to afford 16.5 g (91%) of (1E,4E)-ethyl 2-amino-8-bromo-3H-benzo[b]azepine-4-carboxylate.
Reaction SMILES: C[Si](C)(C)[O:3][CH:4]([CH:9]1[CH2:18][CH2:17][C:12]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:11][CH2:10]1)[C:5]([F:8])([F:7])[F:6].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:8][C:5]([F:6])([F:7])[CH:4]([CH:9]1[CH2:10][CH2:11][C:12]2([O:13][CH2:14][CH2:15][O:16]2)[CH2:17][CH2:18]1)[OH:3]
Reactant: C[Si](C)(C)OC(C1CCC2(CC1)OCCO2)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(C1CCC2(CC1)OCCO2)C(F)(F)F
Reaction time: 2 h

Procedure:
To a solution of trimethyl(2,2,2-trifluoro-1-(1,4-dioxaspiro[4.5]decan-8-yl)ethoxy)silane (792 mg, 2.54 mmol, prepared in the previous step) in THF (10 mL) was added a TBAF (2.6 mL, 2.6 mmol, 1 M in THF) dropwise. After the complete addition, the reaction mixture was at room temperature 2 hours and then concentrated in vacuo. The residue purified by flash chromatography (silica gel, 0-100% ethyl acetate/heptane) to afford the product.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][CH:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[CH:22]=[CH:23][C:24]4[N:25]([C:27]([N:30]5[C@H:35]([CH3:36])[CH2:34][CH2:33][CH2:32][C@@H:31]5[CH3:37])=[N:28][N:29]=4)[CH:26]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:38]2[CH:39]=[N:40][N:41]([CH2:43][CH2:44][OH:45])[CH:42]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:46][S:47](Cl)(=[O:49])=[O:48].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][CH:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[CH:22]=[CH:23][C:24]4[N:25]([C:27]([N:30]5[C@H:31]([CH3:37])[CH2:32][CH2:33][CH2:34][C@@H:35]5[CH3:36])=[N:28][N:29]=4)[CH:26]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:38]2[CH:39]=[N:40][N:41]([CH2:43][CH2:44][O:45][S:47]([CH3:46])(=[O:49])=[O:48])[CH:42]=2)[N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(OC3CCC(NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCO)c4)CC3)cn12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(OC3CCC(NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCOS(C)(=O)=O)c4)CC3)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
A mixture of Intermediate 17b (0.75 g, 1.21 mmol), methanesulfonyl chloride (140 μL, 1.81 mmol) and DIPEA (0.63 mL, 3.62 mmol) in DCM (15 mL) was stirred at RT for 1 h. The reaction mixture was partitioned between DCM and water. The organic layer was washed with brine, separated through a phase separating cartridge and concentrated in vacuo to afford the title compound (0.82 g, 97%). LCMS (Method 3): Rt 3.59 min, m/z 697 [MH+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=4)[CH:15]=3)[N:10]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][O:24]3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH:38]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C)C=O>[CH3:22][N:20]1[CH:21]=[C:17]([C:14]2[CH:15]=[C:16]3[C:8]([C:6]4[N:7]=[C:2]([C:37]5[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH:38]=5)[CH:3]=[CH:4][CH:5]=4)=[N:9][N:10]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[C:11]3=[CH:12][N:13]=2)[CH:18]=[N:19]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cn1cc(-c2cc3c(-c4cccc(Cl)n4)nn(C4CCCCO4)c3cn2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc3c(-c4cccc(C5=CCN(C(=O)OC(C)(C)C)CC5)n4)nn(C4CCCCO4)c3cn2)cn1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
In a high-pressure vial was placed 3-(6-chloropyridin-2-yl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine ((84.1 mg, 0.21 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (197.5 mg, 0.64 mmol), cesium carbonate (346.979 mg, 1.06494 mmol;), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloro-methane (1:1) (17.4 mg, 0.021 mmol), and N,N-Dimethylformamide (2.5 mL). Nitrogen was passed through the mixture for 15 minutes and the vessel was sealed. The reaction mixture was stirred at 90° C. under N2 for 4 days, cooled to RT, and diluted with EtOAc. The reaction mixture was filtered through a pad of Celite®. The organic layer was washed with water and brine, dried over Na2SO4, filtered, and evaporated in vacuo. The crude product was purified using both flash chromatography (Si-PPC gradient elution, solvent: 0-20% methanol in ethyl acetate) and reverse phase HPLC purification to give tert-butyl 4-(6-(5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate as an oil (40.4 mg, 35.0%). 1H NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 8.72 (s, 1H), 8.08 (d, J=7.8 Hz, 1H), 7.98 (s, 1H), 7.93 (s, 1H), 7.75 (t, J=7.8 Hz, 1H), 7.39 (d, J=7.7 Hz, 1H), 6.79 (s, 1H), 5.87 (dd, J=8.5, 2.0 Hz, 1H), 4.23 (d, J=2.6 Hz, 2H), 4.07-3.96 (m, 1H), 3.98 (s, 3H), 3.85-3.72 (m, 3H), 2.87 (s, 2H), 2.66-2.52 (m, 1H), 2.17 (d, J=9.2 Hz, 2H), 1.90-1.67 (m, 3H), 1.52 (s, 9H). LC/MS: m/z 542.4 [M+1].
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH3:29][NH:30][CH2:31][CH:32]([CH3:34])[CH3:33]>>[CH3:29][N:30]([CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2)[CH2:31][CH:32]([CH3:34])[CH3:33]
Reactant: CNCC(C)C
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN(C)CC(C)C)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with N,2-dimethylpropan-1-amine via General Procedure E to give 10.1 mg of 285 following reverse phase purification. MS (Q1) 449.2 (M)+
Reaction SMILES: COC1C=CC([CH2:7][N:8](C)[CH:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[CH2:11][C:10]2([CH3:22])[CH3:21])=CC=1>CO.[OH-].[OH-].[Pd+2]>[CH3:7][NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[CH2:11][C:10]1([CH3:22])[CH3:21]
Reactant: COc1ccc(CN(C)C2CCN(c3ccncc3)CC2(C)C)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CNC1CCN(c2ccncc2)CC1(C)C
Reaction time: 5 h
Yield: 92 %

Procedure:
A solution of N-(4-methoxybenzyl)-N,3,3-trimethyl-1-(pyridin-4-yl)piperidin-4-amine (320 mg, 0.944 mmol, 1 eq) in MeOH (6 ml) was degassed for 15 min with nitrogen, then Pd(OH)2 (320 mg) was added and hydrogenation was carried out for 5 h at RT under balloon pressure (H2). After monitoring by thin-layer chromatography, the reaction mixture was filtered off over Celite and the filtrate was concentrated under reduced pressure. The crude product so obtained was used in the next stage without being purified further. Yield: 92% (190 mg, 0.867 mmol).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[C:4]=1[C:12]([OH:14])=O)[CH3:2].S(Cl)([Cl:17])=O>>[CH2:1]([C:3]1[S:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[C:4]=1[C:12]([Cl:17])=[O:14])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCc1sc2ccccc2c1C(=O)O
Product: CCc1sc2ccccc2c1C(=O)Cl
Yield: 91 %

Procedure:
Into a quarter-litre flask equipped with a condenser were introduced 27.2 g (0.128 mol) of 2-ethyl-3-carboxy-benzo[b]thiophene and 100 ml of thionyl chloride. The solution was refluxed for 3 hours and the excess of thionyl chloride was then eliminated by distillation. The residue was distilled and 27.1 g of 2-ethyl-3-chlorocarbonyl-benzo[b]thiophene were obtained representing a yield of 91%; b.p. 110/120° C (0.05 mm/Hg).
Reaction SMILES: C([Li])CCC.I[C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:14][OH:15].B(OC)(OC)OC.C(=O)([O-])[O-].[Na+].[Na+].[C:29]([O:33][C:34](=[O:55])[NH:35][C:36]([C:38]1[S:39][C:40]([S:53][CH3:54])=[C:41]([S:43]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48](Br)[CH:47]=2)(=[O:45])=[O:44])[CH:42]=1)=[NH:37])([CH3:32])([CH3:31])[CH3:30]>CCOCC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[C:29]([O:33][C:34](=[O:55])[NH:35][C:36]([C:38]1[S:39][C:40]([S:53][CH3:54])=[C:41]([S:43]([C:46]2[CH:47]=[C:48]([C:7]3[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=3[CH2:14][OH:15])[CH:49]=[CH:50][CH:51]=2)(=[O:45])=[O:44])[CH:42]=1)=[NH:37])([CH3:32])([CH3:31])[CH3:30]
Reactant: Cc1cccc(CO)c1I
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Agent: [Pd]
Agent: COB(OC)OC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2CO)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.3 %

Procedure:
n-Butyllithium (2.5M) [4.03 mL] was added to a solution of (2-iodo-3-methyl-phenyl)-methanol (1.00 g, 4.04 mL) [example 213, step a] in ether [20 mL] at −78° C. and stirred for 0.5 hours. Trimethyl borate [1.13 mL, 10.1 mmol) was added and the solution was stirred for 2 hours at room temperature, followed by evaporation. The crude residue was dissolved in ethanol/toluene (1/2) [30 mL] and 2M sodium carbonate [16.2 mL]followed by addition of {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.49 g, 1.01 mmol) [example 27, step c]. The solution was bubbled with argon and then tetrakis (triphenylphosphine) palladium (0) (0.18 g, 0.15 mmol) was added. The reaction was refluxed for 3 hours and then cooled to room temperature. Ethyl acetate was added and the crude reaction was washed with brine, dried over magnesium sulfate and evaporated. Column chromatography (50% EtOAc in hexanes) of the residue yielded the title compound (0.40 g, 74%) as a solid. ESI-MS (m/z): Calcd. for C25H28N2O5S3: 532.12; found: 532.7.
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[N:7]=1)=O.[OH-].[Na+]>>[F:18][C:15]([F:16])([F:17])[CH2:14][O:13][CH2:12][C:8]1[N:7]=[C:6]([NH2:5])[CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(COCC(F)(F)F)n1
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccc(COCC(F)(F)F)n1

Procedure:
This material was prepared in analogy to example 86 step B] from 2,2-Dimethyl-N-[6-(2,2,2-trifluoro-ethoxymethyl)-pyridin-2-yl]-propionamide (0.726 g) and 3M aqueous NaOH (5 mL) as a brown liquid (0.4 g). MS (EI): 206.1 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:26])=[CH:4][C:5]2[CH:6]3[CH2:24][N:23]([CH3:25])[CH2:22][CH2:21][CH:7]3[N:8]([CH2:11][C:12](O)([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH3:13])[C:9]=2[CH:10]=1.[OH-].[K+]>S(Cl)(Cl)=O.O>[Cl:1][C:2]1[C:3]([Cl:26])=[CH:4][C:5]2[C:6]3[CH2:24][N:23]([CH3:25])[CH2:22][CH2:21][C:7]=3[N:8](/[CH:11]=[C:12](\[C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)/[CH3:13])[C:9]=2[CH:10]=1
Reactant: CN1CCC2C(C1)c1cc(Cl)c(Cl)cc1N2CC(C)(O)c1ccncc1
Agent: [K+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: O
Product: C/C(=C/n1c2c(c3cc(Cl)c(Cl)cc31)CN(C)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
7,8-Dichloro-5-(2-hydroxy-2-(pyridin-4-yl)propyl)-2-methyl-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (500 mg, 1.2 mmol) in thionylchloride (5 mL) was stirred at RT for 5 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in N-methyl-2-pyrrolidone (5 mL) and the solution was stirred for 5 min. at RT. Powdered KOH (482 mg, 8.5 mmol) was added and the reaction mixture was heated at 100° C. for 1 h. The progress of reaction was monitored by TLC and NMR. The reaction mixture was cooled at RT, diluted with water and extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure and the residue purified by HPLC. 1H NMR (CD3OD, formate salt) δ (ppm): 8.30 (d, 2H), 7.50 (s, 1H), 7.20 (s, 1H), 7.05 (d, 2H), 6.95 (s, 1H), 3.70 (m, 2H), 2.85 (m, 2H), 2.70 (m, 2H), 2.58 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.CN.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>O1CCCC1>[CH3:1][NH:3][S:18]([C:15]1[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)CC
Agent: CN
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(OC)cc1
Reaction time: 1 h
Yield: 91.7 %

Procedure:
Part A: To a mixture of 50 mL of tetrahydrofuran, 15 mL (108 mmol) of triethylamine and 10 mL (116 mmol) of a 40% aqueous methylamine solution at 0 C, was added 15.0 g (72.6 mmol) of 4-methoxy-benzenesulfonyl chloride over a 15 minutes. After 1 hour, the solvents were removed in vacuo, 5% aqueous KHSO4 and ethyl acetate added, the organic layer separated, washed with saturated aqueous sodium bicarbonate, brine, dried with sodium sulfate, filtered and stripped to afford a white solid. This was recrystallized from hot ethyl acetate/hexane to afford 13.4 g of N-methyl-4-methoxybenzenesulfonamide, m/e=202 (M+H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]([CH2:10][CH2:11][OH:12])[C:6]([CH3:9])=[CH:7][CH:8]=1.Cl[CH2:14][C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].Cl>O1CCCC1.O>[CH3:3][C:4]1[N:5]([CH2:10][CH2:11][O:12][CH2:14][C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:6]([CH3:9])=[CH:7][CH:8]=1
Reactant: Cc1ccc(C)n1CCO
Reactant: CCOC(=O)CC(=O)CCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)COCCn1c(C)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
32 g of sodiumhydride (60% oil dispersion) was added to 500 ml of tetrahydrofuran, and 56 g (0.4 mol) of 2-(2,5-dimethylpyrrole-1-yl)ethanol obtained in Preparation Example 1 was added thereto, followed by stirring at room temperature for 1 hour. The reaction mixture was cooled to 0° C., and a solution obtained by dissolving 65.84 g (0.4 mol) of ethyl 4-chloroacetoacetate in 200 ml of tetrahydrofuran was added thereto dropwise over 2 hours. The mixture was stirred at room temperature for 16 hours and then adjusted to pH 6 to 7 with 3N hydrochloric acid. A sufficient amount of water was added to dissolve solid precipitates formed, and the reaction mixture was extracted two times with 600 ml and 100 ml of ethyl acetate, respectively. Combined ethyl acetate extract was dried over anhydrous magnesium sulfate, treated with decolorizing carbon, and then, the solvent was distilled off under a reduced pressure, to obtain 96.2 g of the titled compound as a pale yellow oil (yield: 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[O:22])[CH:16]=1.[Li+].CC([N-]C(C)C)C.O>C1COCC1.C(OCC)(=O)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:2]([Cl:1])[C:7]=1[CH:21]([C:17]1[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=1)[OH:22]
Reactant: O=Cc1cccnc1
Reactant: Clc1cc(Cl)c(-c2ccccc2)nn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: OC(c1cccnc1)c1c(Cl)nnc(-c2ccccc2)c1Cl
Temperature: -78 °C
Reaction time: 3 h
Yield: 123.4 %

Procedure:
To a solution of 4,6-dichloro-3-phenyl-pyridazine (2.27 g, 0.01 mol) in dry THF (30 mL) was added pyridine-3-carbaldehyde (1.3 g, 0.012 mol). The reaction mixture was cooled down to −78° C. and a solution of LDA (2 N, 22 mL) was added dropwise, keeping the internal temperature below −50° C. The reaction mixture was stirred for 3 h, then water and ethyl acetate were added. Phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried (phase separator cartridge) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, isohexane/ethyl acetate 9:1 to 8:2) yielding the title compound as a solid (4.1 g).