Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18](C(OCC2C=CC=CC=2)=O)[CH2:17]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.CC(O)=O.[Pd]>[NH:18]1[CH2:19][CH2:20][CH2:21][CH:16]([NH:15][C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]2[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1NC1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1NC1CCCNC1
Yield: 85.5 %

Procedure:
10% Pd/C (0.20 gm, 0.19 mmol) was added to a solution of benzyl 3-((1R,2R)-2-(tert-butoxycarbonylamino)cyclohexylamino)piperidine-1-carboxylate, (1.73 gm, 4.01 mmol) in MeOH (14.6 mL) and AcOH (1.46 mL). A H2 atmosphere was then introduced via balloon. After 1 h the reaction mixture was filtered through Celite. The catalyst was rinsed with MeOH and the filtrate was concentrated. The residue was partitioned between EtOAc and sat. NaHCO3. The aqueous phase was isolated and extracted with EtOAc. All organic phases were combined, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to give the product tert-butyl (1R,2R)-2-(piperidin-3-ylamino)cyclohexylcarbamate (1.02 gm, 3.43 mmol, 86% yield) as a white foam. Anal. Calcd. for C16H31N3O2 m/z 297.2, found: 298.2 (M+H)+. Crude product was used without purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:21])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)O)cn1
Reactant: NC1CCOCC1
Product: Cc1onc(-c2ccncc2)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 70 %

Procedure:
As described for example 12, 6-(5-methyl-3-pyridin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.64 mol) instead of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid was converted using 4-aminotetrahydropyran instead of 2,2,2-trifluoroethylamine to the title compound (trituration with tert-butylmethylether, 178 mg, 70%) which was obtained as a white solid. MS: m/e=395.2 [M+H]+.
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][NH:17][C:16](=[O:19])[NH:15][CH2:14]2)=[CH:9][C:8]=1[OH:20].[OH-].[Na+]>O.O1CCOCC1>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:14][NH:15][C:16](=[O:19])[NH:17][CH2:18]2)=[CH:9][C:8]=1[O:20][CH:2]([F:4])[F:3]
Reactant: COc1ccc(C2CNC(=O)NC2)cc1O
Reactant: FC(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C2CNC(=O)NC2)cc1OC(F)F
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Chlorodifluoromethane was bubbled into a solution of (102 mg, 0.459 mmol, 1.0 eq) of tetrahydro-5-(4-methoxy-3-hydroxyphenyl)-2(1H)-pyrimidinone and 64 mg (1.61 mmol, 3.5 eq) of NaOH in 3 ml of H2O and 3 ml of 1,4-dioxane. After 1 hour at room temperature, the reaction mixture was heated to 60° C. for 1.5 hours. Chlorodifluoromethane was bubbled in continuously. The reaction mixture was cooled to room temperature, poured into 150 ml of H2O and 75 ml of ethyl acetate, extracted twice with ethyl acetate. The ethyl acetate extracts were washed twice with 2N NaOH, once with brine, dried over Na2SO4, and concentrated to yield 13.5 mg of a white solid, which was recrystallized from ethyl acetate-hexane to afford 8.4 mg, 7%, of off-white crystals. M.P.: 215°-216° C. Elemental Analysis: Calc'd for C12 H14N2O3F2 : Calc'd: C, 52.95; H, 5.18; N, 10.29. Found: C, 52.88; H, 4.91; N, 10.13.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].O>CS(C)=O>[CH2:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCBr
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCn1ccc2ccccc21
Temperature: 60 °C

Procedure:
A solution of indole (1.0 g) in dry DMSO (1 ml) is dropped into a suspension of sodium hydride (60% suspension in mineral oil; 0.37 g) in dry DMSO (20 ml), heating to 60° C. for 1 h. After cooling at room temperature, the resulting solution is added dropwise with a solution of n-octyl bromide (2.82 ml) in dry DMSO (2.8 ml). After a night at room temperature, the reaction mixture is poured into water (200 ml) and extracted with ethyl acetate (2×50 ml). The combined organic phases are washed with a NaCl saturated solution, dried and evaporated to dryness. The resulting residue is purified by column chromatography (silica gel; eluent n-hexane) to obtain 1.86 g of 1-(n-octyl)indole as oil.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-:16].[Na+].[Na+].[Cl-].[C:22]1([S+:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.ClCCl>O>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:16])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:35]1([S+:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: O=S(=O)([O-])c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 4-trifluoromethylbenzenesulfonyl chloride (20.53 g, 83.9 mmol) in water (150 ml) containing sodium carbonate (9.43 g, 88.10 mmol) was heated at reflux for 22 hours. After cooling to room temperature, triphenylsulfonium chloride (50% aqueous solution, 50.00 g) was added over 15 minutes. After stirring the biphasic mixture for 30 minutes, dichloromethane (300 ml) was added and the mixture stirred at room temperature for 20 hours. The layers were separated and the organic layer washed with water (7×150 ml) until the washings were neutral (pH 7 ). After drying (MgSO4 ), removal of the solvent in vacuo gave a pale yellow foam which was further dried by heating at 80°-100° C. for 108 hours under vacuum. In this way, triphenylsulfonium 4 -trifluoromethylbenzenesulfonate was isolated as a pale yellow glass (36.77 g).
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[NH:4][CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:7]=1.O=P(Cl)(Cl)[Cl:15]>CN(C=O)C>[Cl:15][C:3]1[N:4]=[CH:5][C:6]([C:8]([O:10][CH3:11])=[O:9])=[N:7][C:2]=1[CH3:1]
Reactant: COC(=O)c1c[nH]c(=O)c(C)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(Cl)c(C)n1
Yield: 52 %

Procedure:
To a solution of methyl 4,5-dihydro-6-methyl-5-oxo-2-pyrazine carboxylate (M. Mano, T. Seo, K. Imai, Chem. Pharm. Bull 10:3057-3063, 1980) in DMF (20 mL) was added POCl3 (20 mL). The reaction was refluxed for 0.5 h and then poured into ice. The aqueous layer was extracted with CHCl3 dried (MgSO4) and concentrated. The residue was chromatographed (SiO2, CHCl3) to provide the title compound (2.34 g, 52% yield); m.p. 49°-50° C.
Reaction SMILES: C([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([F:14])[CH:6]=1)(=O)C.B(F)(F)F.[CH3:19][CH2:20]OCC>C(O)C>[NH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH2:19][CH3:20])=[O:10])=[C:7]([F:14])[CH:6]=1
Reactant: CCOCC
Reactant: CC(=O)Nc1ccc(C(=O)O)c(F)c1
Agent: FB(F)F
Solvent: CCO
Product: CCOC(=O)c1ccc(N)cc1F

Procedure:
A solution of 10.0 g of 4-acetamido-2-fluorobenzoic acid, 100 ml of ethyl alcohol and 2.0 ml of boron trifluoride etherate is heated under reflux for 22 hours. The solvent is slowly removed by distillation as an equal amount of fresh ethyl alcohol is added. After 200 ml of solvent has been removed, the remainder is evaporated at reduced pressure. The residue is dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, dried and the solvent then evaporated to yield a solid. Recrystallization of the solid from ethanol-hexane yields ethyl 4-amino-2-fluorobenzoate.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.C(OC([NH:25][C@H:26]1[C@H:29]([CH2:30][CH3:31])[N:28]([S:32]([O-:35])(=[O:34])=[O:33])[C:27]1=[O:36])=O)(C)(C)C.ClCCl>C(O)=O>[NH2:25][C@H:26]1[C@H:29]([CH2:30][CH3:31])[N:28]([S:32]([OH:35])(=[O:33])=[O:34])[C:27]1=[O:36]
Reactant: CC[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1S(=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O=CO
Solvent: ClCCl
Product: CC[C@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Reaction time: 16 h
Yield: 34.7 %

Procedure:
(trans)-3-t-Butoxycarbonylamino-4-ethyl-2-oxo-1-azetidinesulfonic acid, tetrabutylammonium salt (6.75 g) in 40 ml of 98% formic acid is stirred for 3 hours at ambient temperature. Dichloromethane (60 ml) is added and the mixture is refrigerated for about 16 hours. The resulting precipitate is separated by filtration and then dried in vacuo to yield 0.85 g of the title compound, melting point 185° C., dec.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:7][CH:6]=1)(=[NH:4])=[O:3].[Br:19][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH:28]=1)[C:25](O)=[O:26]>>[Br:19][C:20]1[CH:28]=[C:24]([C:25]([N:4]=[S:2]([C:5]2[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:9][CH:10]=2)([CH3:1])=[O:3])=[O:26])[CH:23]=[N:22][CH:21]=1
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(S(C)(=N)=O)cc1
Product: CC(C)(C)OC(=O)Nc1ccc(S(C)(=O)=NC(=O)c2cncc(Br)c2)cc1
Yield: 74.6 %

Procedure:
In a manner similar to that described in Example 480 (step 6), tert-Butyl [4-(S-methylsulfonimidoyl)phenyl]carbamate (0.141 g, 0.522 mmol) and 5-bromonicotinic acid (0.104 g, 0.522 mmol), were converted to the title compound (0.177 g, 75%).
Reaction SMILES: C[Al](C)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1.[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C:50]3[CH:55]=[C:54]([F:56])[CH:53]=[CH:52][C:51]=3[CH3:57])[N:48]=[CH:49][C:42]=12)[C:36](OC)=[O:37])([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Si:13]([O:30][CH2:31][CH2:32][O:33][CH2:34][C@H:35]([O:40][C:41]1[N:46]=[CH:45][N:44]=[C:43]2[N:47]([C:50]3[CH:55]=[C:54]([F:56])[CH:53]=[CH:52][C:51]=3[CH3:57])[N:48]=[CH:49][C:42]=12)[C:36]([NH:12][C:9]1[CH:8]=[CH:7][C:6]([Cl:5])=[CH:11][N:10]=1)=[O:37])([C:26]([CH3:27])([CH3:28])[CH3:29])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: COC(=O)[C@H](COCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ncnc2c1cnn2-c1cc(F)ccc1C
Agent: C[Al](C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1-n1ncc2c(O[C@@H](COCCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C(=O)Nc3ccc(Cl)cn3)ncnc21
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 72.7 %

Procedure:
Trimethylaluminium (2M in toluene) (0.556 mL, 1.11 mmol) was added dropwise to a stirred solution of 5-chloropyridin-2-amine (143 mg, 1.11 mmol) in toluene (10 mL), under nitrogen at 0° C. The resulting solution was allowed to stir at this temperature for a further 20 minutes. (2S)-methyl 3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-2-(1-(5-fluoro-2-methylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (Intermediate AK4) (466 mg, 0.74 mmol) in toluene (5 mL) was added slowly to the mixture at 0° C. The reaction mixture was then heated to 100° C. and was stirred for 6 hours using the microwave. The reaction mixture was allowed to cool to ambient temperature, then evaporated to afford a gum. This was dissolved in EtOAc (75 mL), and washed sequentially with Rochelle's solution (20 mL), and water (20 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 10 to 30% EtOAc in isohexane to afford the product (390 mg, 72.6%). 1H NMR (400 MHz, DMSO) δ 0.88 (9H, s), 2.03 (3H, s), 3.82-3.67 (4H, m), 4.05 (1H, m), 4.15 (1H, m), 6.00 (1H, m), 7.45-7.31 (8H, m), 7.50 (1H, t), 7.60 (4H, m), 7.87 (1H, dd), 8.02 (1H, d), 8.40 (1H, d), 8.51 (1H, s), 8.56 (1H, s), 11.25 (1H, s); m/z (ES+) (M+H)+=725; HPLC tR=3.63 min.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH:6]=[CH:7][S:8][CH3:9])[C:3](O)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.O>C(OCC)(=O)C>[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:3](=[O:4])[C:2]([CH3:10])([CH3:1])[CH:6]=[CH:7][S:8][CH3:9])=[CH:26][CH:25]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CSC=CC(C)(C)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CCOC(C)=O
Product: CSC=CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Reaction time: 16 h
Yield: 32.1 %

Procedure:
A solution of 0.5 g of 2,2-dimethyl-4-methylthio-3-butenoic acid in 20 mL of ethyl acetate was treated with 0.6 g of carbonyldiimidazole, and the solution was heated for 10 minutes at reflux. After the solution had cooled, 0.65 g of p-chloroaniline was added and heating continued for 16 hours. The solution was then cooled, poured into water and extracted into ethyl acetate. The organic layer was washed with 50 mL of 1N HCl, dried over MgSO4, and concentrated. The residual solid was recrystallized from CHCl3 /hexane to give 0.27 g of N-(4-chlorophenyl)-2,2-dimethyl-4-(methylthio)-3-butenamide, m.p. 105°-106° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1[NH2:8].O.[NH2:11][NH2:12]>CCO>[Cl:9][C:5]1[N:4]=[N:3][C:2]([NH:11][NH2:12])=[C:7]([NH2:8])[CH:6]=1
Reactant: Nc1cc(Cl)nnc1Cl
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1nnc(Cl)cc1N
Temperature: 100 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
To a stirred suspension of 3,6-dichloropyridazin-4-amine (Step 112.1) (1.49 g, 9.09 mmol) in EtOH (15 mL) was added hydrazine hydrate (11.04 mL, 227 mmol) and the resulting mixture was heated up and stirred at 100° C. for 3 hr. The reaction was cooled down to RT and concentrated under reduced pressure. The crude product was triturated with water (25 mL) to afford the title product (478 mg, 3 mmol, 33% yield) as yellow solid. tR: 0.24 min (LC-MS 2); ESI-MS: 160 [M+H]+ (LC-MS 2); ESI-MS: 158 [M−H]− (LC-MS 2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[N:9]/[S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.Br[Mg][C:18]#[CH:19]>C(Cl)Cl.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:9][S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[C:18]#[CH:19])=[CH:6][CH:7]=1
Reactant: C#C[Mg]Br
Reactant: CC(C)(C)S(=O)/N=C/c1ccc(Br)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: C#C[C@@H](NS(=O)C(C)(C)C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2.8 g (9.7 mmol) N-[(1E)-(4-bromophenyl)methylidene]-2-methylpropane-2-sulfinamide in 30 ml CH2Cl2 at −78° C. was added 49 mL (24 mmol) 0.5M bromo(ethynyl)magnesium in THF. The reaction mixture was warmed slowly to room temperature. After 24 h at room temperature, the reaction mixture was quenched with saturated ammonium chloride, extracted three times with methylene chloride, and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, linear gradient 0-100% EtOAc:hexane) afforded N-[(1R)-1-(4-bromophenyl)prop-2-ynyl]-2-methylpropane-2-sulfinamide. 1H NMR (CDCl3, 400 MHz) 7.52-7.45 (m, 2H); 7.41-7.38 (m, 2H); 5.19 (dd, 1H, J=2.38 Hz, 6.05 Hz); 3.66 (br d, 1H, J=6.04 Hz); 2.64 (d, 1H, J=2.38 Hz); 1.20 (s, 9H). ESMS+1=316.0.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[Br:23][C:20]1[CH:19]=[CH:18][C:17]([S:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)(=[O:16])=[O:15])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
4-(4-Bromo-benzenesulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (500 mg, 1.23 mmol) was dissolved in a mixture of dichloromethane (5 mL) and trifluoroacetic acid (5 mL) and stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo and then dissolved in dichloromethane and washed with saturated sodium bicarbonate solution and then water. The organic layer was then dried over magnesium sulfate and concentrated in vacuo to yield the product as a white solid (329 mg, 88%). 1H NMR (CDCl3) δ 1.77 (s, 1H), 2.96 (m, 4H), 3.01 (m, 4H), 7.64 (dt, 2H, J=2.1, 8.7 Hz), 7.69 (dt, 2H, J=2.1, 8.7 Hz).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[C:6](/P(OCC)(OCC)=O)=[CH:7]\[CH3:8])=[O:5].[K].C([O-])(C)(C)C.[Br:23][C:24]1[N:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][CH:25]=1.C(OCC)C>O1CCCC1>[CH2:2]([O:3][C:4](=[O:5])/[CH:6]=[CH:7]/[CH:8]=[CH:30]/[C:28]1[CH:27]=[CH:26][CH:25]=[C:24]([Br:23])[N:29]=1)[CH3:1]
Reactant: O=Cc1cccc(Br)n1
Reactant: C/C=C(\C(=O)OCC)P(=O)(OCC)OCC
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C=C/c1cccc(Br)n1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
A solution of 5.88 g of 4-phosphonocrotonic acid triethyl ester in 60 ml of tetrahydrofuran is mixed in portions with 2.5 g of potassium-tert-butanolate with stirring and under argon atmosphere at -20° C. After 30 minutes, a solution of 2.6 g of 6-bromopyridine-2-aldehyde is instilled at -20° C. and the mixture is stirred at this temperature for another hour. The reaction mixture is poured on ice, shaken out with diethyl ether, the organic phase is washed with saturated common salt solution, dried on sodium sulfate and concentrated by evaporation. The residue is chromatographed on silica gel with hexane/ethyl acetate=95/5. 2.66 g of 5-(6-bromo-2-pyridyl)-(E,E)-2,4-pentadienoic acid ethyl ester is obtained as crude product.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1)=[O:5])[CH3:2].[IH:30].CO>C(OCC)C>[IH:30].[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cn1c(NC2CCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Agent: I
Solvent: CCOCC
Solvent: CO
Product: CCOC(=O)Cn1c(NC2CCNCC2)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Combine (1-(ethoxycarbonylmethyl)-1H-benzimidazol-2-yl)(1-(t-butoxycarbonyl)piperidin-4-yl)amine (0.405 g, 1.00 mmol), aqueous hydriodic acid (0.29 mL, 57%), and methanol (15 mL). Heat to reflux. After 2 hour, cool to ambient temperature and add diethyl ether (100 mL) and stir to give a solid. After 1 hour, collect the solid by filtration, dissolve in methanol and add diethyl ether (100 mL) to give a solid. Collect the solid by filtration and dry in vacuo to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3[C:16]4[CH2:24][CH2:23][C:22]5[C:18](=[CH:19][N:20]([CH2:25][CH2:26]O)[N:21]=5)[C:17]=4[S:28][C:14]=3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:49]>C(Cl)Cl>[Br:49][CH2:26][CH2:25][N:20]1[CH:19]=[C:18]2[C:22]([CH2:23][CH2:24][C:16]3[C:15]4=[C:10]([NH:9][C:4]5[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=5)[N:11]=[CH:12][N:13]=[C:14]4[S:28][C:17]=32)=[N:21]1
Reactant: BrC(Br)(Br)Br
Reactant: OCCn1cc2c(n1)CCc1c-2sc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(Nc2ncnc3sc4c(c23)CCc2nn(CCBr)cc2-4)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 30.5 %

Procedure:
To a stirring solution of 2-{6-[(3-chloro-4-fluorophenyl)amino]-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-2-yl}ethanol (11.4 g, 27.4 mmol) in CH2Cl2 (240 mL) were added triphenylphosphine (13.5 g, 48.0 mmol) and carbon tetrabromide (17.0 g, 48 mmol). The mixture was stirred at room temperature for 1.5 h, and the solvent was then removed under reduced pressure. The crude residue was purified via flash chromatography (1:1 hexanes/EtOAc) to afford the desired product (4.0 g, 30%) as an off-white solid. 1H-NMR (CDCl3) δ 3.05 (t, 2H), 3.27 (t, 2H), 3.66 (s, 2H), 4.40 (t, 2H), 6.93 (s, 1H), 7.05 (t, 1H), 7.34-7.40 (m, 1H), 7.44 (s, 1H), 7.78 (dd, 1H), 8.40 (s, 1H); LCMS RT=3.81 min; [M+H]+=478.2, 480.2.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=3)[C:10]([CH2:19][C:20]([OH:22])=[O:21])=[C:9]2[CH3:23])=[O:7])=[CH:4][CH:3]=1.[SH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[N:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[CH2:27][S:26][O:21][C:20](=[O:22])[CH2:19][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:8]([C:6](=[O:7])[C:5]2[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[CH3:23]
Reactant: SCc1ccccn1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Product: COc1ccc2c(c1)c(CC(=O)OSCc1ccccn1)c(C)n2C(=O)c1ccc(Cl)cc1

Procedure:
6.5 g. (0.018 mol.) of 1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indol acetic acid are dissolves in 60 ml. of chloroform. After the addition of 2.9 g. (0.023 mol.) of 2-mercaptomethylpyridine and 4.9 g. (0.023 mol.) of N,N'-dicyclohexyl carbodiimide, the reaction mixture is stirred for 24 hours with the exclusion of moisture. The precipitated material is filtered off and the solvent of the resulting solution is distilled in a vacuum. The resulting residue is subjected to chromatography over a silicic acid gel column using a 1:1-mixture of chloroform and hexane as eluant.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:11]>C(OCC)C>[CH2:18]([CH:15]1[CH2:14][CH2:13][N:12]([C:10](=[O:11])[CH2:9][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccccc1
Reactant: O=C(CCl)N1CCC(Cc2ccccc2)CC1
Solvent: CCOCC
Product: O=C(CNc1ccccc1)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from aniline and 2-chloro-1-(4-benzyl-piperidin-1-yl)-ethanone (Example 200a) according to the method described in Example 206. Melting Point: 107-109° C. (diethylether)
Reaction SMILES: [F:1][C:2]([F:22])([F:21])/[C:3](/[NH:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)=[CH:4]\[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:23](/[C:25](=[CH:31]/[C:32]1[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=1)/[C:26]([O:28][CH2:29][CH3:30])=[O:27])#[N:24].N12CCCN=C1CCCCC2>O1CCOCC1>[NH2:24][C:23]1[N:10]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=2)[C:3]([C:2]([F:1])([F:21])[F:22])=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:31]([C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=2)[C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)/C=C(/Nc1cncc(C(F)(F)F)c1)C(F)(F)F
Reactant: CCOC(=O)/C(C#N)=C\c1ccc(C#N)cc1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1=C(N)N(c2cncc(C(F)(F)F)c2)C(C(F)(F)F)=C(C(=O)OCC)C1c1ccc(C#N)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Under Argon, the compound of Example 29A (180 mg, 0.40 mmol) and the compound of Example 28A (90.36 mg, 0.40 mmol) are dissolved in dioxane (5 ml). 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (6.08 mg, 0.04 mmol) is added, and the resulting solution is stirred at 85° C. overnight. The crude mixture is cooled to room temperature and purified directly by preparative HPLC.