Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(N)(=O)=O.[N:6]1([S:10]([NH2:13])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1.[C:14]12([CH2:21][O:22][C:23]3[C:31]([CH:32]4[CH2:34][CH2:33]4)=[CH:30][C:26]([C:27](O)=[O:28])=[C:25]([F:35])[CH:24]=3)[CH2:20][CH:19]1[CH2:18][CH2:17][CH2:16][CH2:15]2>>[N:6]1([S:10]([NH:13][C:27](=[O:28])[C:26]2[CH:30]=[C:31]([CH:32]3[CH2:33][CH2:34]3)[C:23]([O:22][CH2:21][C:14]34[CH2:20][CH:19]3[CH2:18][CH2:17][CH2:16][CH2:15]4)=[CH:24][C:25]=2[F:35])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1
Reactant: NS(=O)(=O)N1CCC1
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CCCCC2C3)cc1F
Agent: CS(N)(=O)=O
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC23CCCCC2C3)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with azetidine-1-sulfonamide and to replace 4-(((1r,3r,5r,7r)-2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 4-(bicyclo[4.1.0]heptan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid, the title compound was obtained following purification by reverse-phase HPLC as a colorless powder (0.037 g, 37%): 1H NMR (300 MHz, DMSO-d6) δ 11.60 (br, s, 1H), 7.15 (d, J=8.3 Hz, 1H), 6.87 (d, J=13.0 Hz, 1H), 4.09-3.98 (m, 4H), 3.92-3.84 (m, 1H), 3.80-3.74 (m, 1H), 2.23-1.98 (m, 3H), 1.96-1.68 (m, 3H), 1.66-1.52 (m, 1H), 1.34-1.13 (m, 4H), 1.04-0.83 (m, 3H), 0.75-0.60 (m, 3H), 0.41-0.33 (m, 1H); MS (ES+) m/z 423.1 (M+1)
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.Cl[C:24]1[N:29]=[CH:28][C:27]([CH2:30][CH3:31])=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>>[CH2:30]([C:27]1[CH:26]=[N:25][C:24]([N:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:21])([F:22])[F:1])=[CH:20][CH:19]=2)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:29][CH:28]=1)[CH3:31]
Reactant: Oc1ccc(CCNCc2ccc(OC(F)(F)F)cc2)cc1
Reactant: CCc1cnc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cnc(N(CCc2ccc(O)cc2)Cc2ccc(OC(F)(F)F)cc2)nc1
Yield: 76.2 %

Procedure:
Condensation of 4-(2-{[4-(trifluoromethoxy)benzyl]amino}ethyl)phenol (500 mg; 1.61 mmol) with 2-chloro-5-ethyl-pyrimidine (0.19 ml; 1.54 mmol) as per general procedure E (conditions: 5 ml of DIEA, 200C, 16 hr) provided the title compound (490 mg; 76% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([NH:30][CH3:31])(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([NH:30][CH3:31])(=[O:28])=[O:29])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNS(=O)(=O)c1ccc(C)c(Br)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CNS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c1

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 3-bromo-N,4-dimethylbenzenesulfonamide (Combiblocks), the title compound was obtained as an orange sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([CH2:10][N:11]2[CH2:15][CH2:14][N:13]([C@@H:16]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]2=[O:28])[CH:7]=[CH:6][CH:5]=1)([CH3:3])=[CH2:2]>CO.[Pd]>[CH:1]([C:4]1[N:9]=[C:8]([CH2:10][N:11]2[CH2:15][CH2:14][N:13]([C@@H:16]([C:24]([CH3:25])([CH3:27])[CH3:26])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:12]2=[O:28])[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: C=C(C)c1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Agent: [Pd]
Solvent: CO
Product: CC(C)c1cccc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)n1
Reaction time: 2 h

Procedure:
A solution containing the product from Example 117B (0.038 g, 0.098 mmol) in methanol (1 mL) was treated with 10% Pd on carbon (0.005 g) and the reaction was stirred under an atmosphere of hydrogen (balloon pressure) for 2 hours. The reaction was filtered and the solvent was concentrated to give the title compound, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:17]3[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=3)[C:20]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.[CH3:33][N:34]([CH3:39])[CH2:35][C:36](O)=[O:37]>>[NH2:1][C:2]1[C:7]2=[C:8]([C:17]3[CH:18]=[C:19]([CH:30]=[CH:31][CH:32]=3)[C:20]([NH:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:36](=[O:37])[CH2:35][N:34]([CH3:39])[CH3:33])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CN(C)CC(=O)O
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3cccc(C(=O)NCc4ccccc4)c3)c12
Product: CN(C)CC(=O)N1CCC(c2cc(-c3cccc(C(=O)NCc4ccccc4)c3)c3c(N)ncnn23)CC1
Yield: 18 %

Procedure:
In a manner similar to the procedure described for the preparation of Example 342 and using 3-(4-amino-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-N-benzylbenzamide and N,N-dimethylglycine as starting material, 10 mg (18%) of the desired product was isolated. 1H NMR (400 MHz, CO3OD) δ 7.98 (s, 1H), 7.85 (d, 1H), 7.82 (s, 1H), 7.62 (d, 1H), 7.55 (t, 1H), 7.36-7.28 (m, 4H), 7.25-7.20 (m, 1H), 6.57 (s, 1H), 4.62-4.57 (m, 3H), 4.18-4.14 (m, 1H), 3.51-3.42 (m, 1H), 3.31-3.16 (m, 5H), 2.82-2.78 (m, 1H), 2.29 (s, 6H), 2.19-2.11 (m, 2H), 1.78-1.59 (m, 2H); 512.3, LC-MS m/z [M+H]+ 512.3, RT 1.96 min.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[C@H:6]([CH3:8])[NH2:7])[CH3:3].[CH2:10]([CH2:14][C:15](=O)[CH3:16])[C:11]([CH3:13])=O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:16][C:15]1[N:7]([CH:6]([CH3:8])[C:5]([O:4][CH2:2][CH3:3])=[O:9])[C:11]([CH3:13])=[CH:10][CH:14]=1
Reactant: CCOC(=O)[C@H](C)N
Reactant: CC(=O)CCC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(C)n1c(C)ccc1C
Yield: 59 %

Procedure:
Alanine ethyl ester hydrochloride (30.8g; 0.2 mole) was dissolved in 100 ml of acetic acid. Acetonylacetone (22.8 g; 0.2 mole) and then 16.4 g (0.2 mole) of sodium acetate were added to the solution, and the mixture heated under reflux for 5 hours. The acetic acid was distilled off under reduced pressure, and ethyl acetate added to the residue. The organic layer was washed with an aqueous solution of sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to afford 29.2 g of a crude product. The product was chromatographed on a column of silica gel using cyclohexane/ethyl acetate (4/1) as an eluent to afford ethyl 2-(2,5-dimethylpyrrol-1-yl)propionate (23.0 g, 0.118 mole, 59.0%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][C:14](I)=[CH:13][C:12]=3[Cl:19])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCO[CH2:28][CH2:27]1>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([Cl:17])=[CH:15][C:14]([CH:27]=[CH2:28])=[CH:13][C:12]=3[Cl:19])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: C1COCCO1
Reactant: Clc1cc(I)cc(Cl)c1-c1nc2ccnc(Cl)c2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=Cc1cc(Cl)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Temperature: 100 °C
Yield: 72 %

Procedure:
A mixture of 4-chloro-2-(2,6-dichloro-4-iodo-phenyl)-thiazolo[5,4-c]pyridine (0.30 g, 0.68 mmol), vinyl borane pinacol ester (0.105 g, 0.68 mmol), PdCl2(PPh3)2 (0.029 g, 0.04 mmol) and sodium carbonate (0.288 g, 2.70 mmol) in water (0.4 mL) and dioxane (4 mL) was degassed with nitrogen and heated at 100° C. for 2 hours. The reaction mixture was cooled to room temperature and then partitioned between EtOAc and water. The organic layer was separated, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 0-8% EtOAc in pentane to give the desired compound as an off-white solid (0.168 g, 72% yield). 1H NMR (300 MHz, CDCl3): δ 8.51 (d, J=5.6 Hz, 1H), 7.98 (d, J=5.6 Hz, 1H), 7.53-7.45 (m, 2H), 6.69-6.62 (m, 1H), 5.91 (d, J=17.5 Hz, 1H), 5.52 (d, J=10.9 Hz, 1H).
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:25]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[N:24][N:23]([CH2:34][CH2:35]O)[C:22](=[O:37])[CH:21]=2)=[CH:16][CH:15]=1.[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.[K+].[Br-]>N1C=CC=CC=1.O>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:25]([C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)=[N:24][N:23]([CH2:34][CH2:35][N:42]3[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]3)[C:22](=[O:37])[CH:21]=2)=[CH:18][CH:19]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(-c2cc(=O)n(CCO)nc2-c2ccc(OC)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(-c2cc(=O)n(CCN3CCN(C)CC3)nc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of para-toluenesulfonyl chloride (357 mg, 4 eq) in pyridine (0.5 ml), a solution of 5,6-bis(4-methoxyphenyl)-2-(2-hydroxyethyl)-2H-pyridazin-3-one (165 mg, 0.47 mmol) in pyridine (1.0 ml) was added, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The organic layer was washed successively with water and a brine, and was then dried over anhydrous sodium sulfate. The solvent was distilled off, and N-methylpiperazine (0.15 ml, 3 eq) was added to the residue. The resulting mixture was stirred at 90-100° C. for 2 hours. After water was added to the reaction mixture, the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and a brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and ethanol was added to the residue. The resulting mixture was azeotropically boiled three times with ethanol to drive off water. The thus-obtained residue (256 mg) was separated and purified by chromatography on a silica gel column [silica gel: 8 g, chloroform/methanol (20/1)], whereby a yellow oil (165 mg, 81%) was obtained. The oil was left over in a refrigerator. Precipitated crystals were washed with a mixed solvent of methanol and diethyl ether, whereby the title compound (65 mg, 32%) was obtained as pale yellow prisms. Melting point: 109.7-110.8° C. 1H-NMR (CDCl3) δ: 2.29(3H,s), 2.46(4H,brs), 2.64(4H,brs), 2.87(2H,t,J=6.83 Hz), 3.80(3H,s), 3.81(3H,s), 4.40(2H,t,J=6.84 Hz), 6.79(2H,d,J=9.03 Hz), 6.81(2H,d,J=8.78 Hz), 6.87(1H,s), 7.02(2H,d,J=8.79 Hz), 7.12(2H,d,J=9.03 Hz). IR (KBr) cm−1: 1659,1608,1513,1295,1250,1177,1013.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][OH:8])[CH2:3][CH2:4][OH:5].[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.[H-].[Na+].[Cl-].[NH4+]>O1CCOCC1.O>[Br:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][OH:8]
Reactant: BrCCCCCCBr
Reactant: CC(CCO)CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: O
Product: CC(CCO)CCOCCCCCCBr
Yield: 65.1 %

Procedure:
118 g (1.0 mol) of 3-methyl-1,5-pentanediol and 317 g (1.3 mol) of 1,6-di-bromohexane in 2.5 l of dioxan were treated at room temperature with 28 g (1.1 mol) of 95 percent sodium hydride and subsequently heated under reflux for 24 h. After cooling the reaction mixture was treated with 400 ml of water, neutralized with saturated ammonium chloride solution and subsequently extracted three times with 1 l of tert-butyl methyl ether each time. The combined organic extracts were washed with saturated ammonium chloride solution, dried over magnesium sulphate and concentrated on a rotary evaporator. Starting material and byproducts were removed by distillation in a vacuum at 150° C. bath temperature and 0.09 mbar. As the distillation residue there were obtained 183 g of 66 percent 12-bromo-3-methyl-6-oxadodecan-1-ol (43%), which is sufficiently pure for the further reactions.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[NH:12][C:13]([CH3:34])=[C:14]([C:17]2[NH:18][C:19]3[CH:25]=[C:24]([C:26](=[O:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH:23]=[CH:22][C:20]=3[N:21]=2)[C:15]=1[CH3:16])=[O:10])=[O:5])C.[OH-].[Na+].Cl>O1CCCC1.C(O)C>[C:4]([CH2:6][CH2:7][NH:8][C:9]([C:11]1[NH:12][C:13]([CH3:34])=[C:14]([C:17]2[NH:18][C:19]3[CH:25]=[C:24]([C:26](=[O:33])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:23]=[CH:22][C:20]=3[N:21]=2)[C:15]=1[CH3:16])=[O:10])([OH:5])=[O:3]
Reactant: CCOC(=O)CCNC(=O)c1[nH]c(C)c(-c2nc3ccc(C(=O)c4ccccc4)cc3[nH]2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1[nH]c(C(=O)NCCC(=O)O)c(C)c1-c1nc2ccc(C(=O)c3ccccc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
The N-(2-ethoxycarbonylethyl)-4-(5-benzoylbenzimidazol-2-yl)-3,5-dimethylpyrrole-2-carboxamide (300 mg) obtained in Example 19 was dissolved in tetrahydrofuran (5 ml) and ethanol (5 ml), and a 4 N sodium hydroxide aqueous solution (10 ml) was added to the solution and stirred at room temperature for 1 hour. The reaction mixture was neutralized with a 4 N hydrochloric acid solution, and then the precipitate was collected by filtration. The solid was dried in vacuo to afford N-(2-carboxyethyl)-4-(5-benzoylbenzimidazol-2-yl)-3,5-dimethylpyrrole-2-carboxamide (211 mg, 75%) as a purple solid.
Reaction SMILES: CN(CC1[C:6]([OH:24])=[CH:7][C:8]2[CH2:9][CH2:10][C@@H:11]3[C@@H:20]([C:21]=2[CH:22]=1)[CH2:19][CH2:18][C@@:16]1([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]1=[O:23])C.[OH-].[K+].C[CH2:28][O:29][CH2:30][CH3:31]>>[OH:24][C:6]1[C:31]([CH2:30][O:29][CH3:28])=[CH:22][C:21]2[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:23])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]=2[CH:7]=1
Reactant: CCOCC
Reactant: CN(C)Cc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: [K+]
Agent: [OH-]
Product: COCc1cc2c(cc1O)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 20 h
Yield: 88 %

Procedure:
To a suspension of 2-dimethylaminomethyl-3-hydroxyestra-1,3,5(10)-trien-17-one (72, 2.0 g, 6.1 mmol) in Et2O (200 mL) was added iodemethane (10 mL, 161 mmol) and stirred for 20 h at room temperature. The precipitate was collected by filtration and washed with Et2O. The solid was dissolved in MeOH (50 mL) and added potassium hydroxide (5.0 g, 85%, 76 mmol), and stirred for 3 h at reflux condition. After the reaction mixture was cooled to room temperature, solvent was evaporated at reduced pressure until half volume. The reaction mixture was acidified with 5 N HCl at 0° C., and extracted with Et2O. The combined organic layers were washed with H2O, saturated aqueous NaCl, and then dried (Na2SO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using CHCl3 :EtOAc (15:1→10:1, v/v) to afford 1.34 g of 74 (88% yield) mp: 149-151° C.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:14][C:13]([F:16])([F:15])[CH2:12][CH2:11][N:10]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][C:19]=2[O:26][CH3:27])[C:9]1=[O:28])(C)(C)C.Cl.O1CCOCC1.CCN(C(C)C)C(C)C.[Cl:46][C:47]1[CH:48]=[CH:49][C:50]([S:53](Cl)(=[O:55])=[O:54])=[N:51][CH:52]=1>ClCCl>[CH3:27][O:26][C:19]1[CH:20]=[C:21]([O:24][CH3:25])[CH:22]=[CH:23][C:18]=1[CH2:17][N:10]1[CH2:11][CH2:12][C:13]([F:15])([F:16])[CH2:14][C@@H:8]([NH:7][S:53]([C:50]2[CH:49]=[CH:48][C:47]([Cl:46])=[CH:52][N:51]=2)(=[O:55])=[O:54])[C:9]1=[O:28]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cn1
Reactant: COc1ccc(CN2CCC(F)(F)C[C@@H](NC(=O)OC(C)(C)C)C2=O)c(OC)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN2CCC(F)(F)C[C@@H](NS(=O)(=O)c3ccc(Cl)cn3)C2=O)c(OC)c1

Procedure:
[(R)-1-(2,4-Dimethoxy-benzyl)-5,5-difluoro-2-oxo-azepan-3-yl]-carbamic acid tert-butyl ester (0.46 g, 1.0 mmol) was dissolved in 20 ml dichloromethane. 4 M HCl/1,4-dioxan (20 ml) were added dropwise and the mixture was allowed to react for 1 h. The reaction mixture was concentrated under reduced pressure and concentrated once from acetonitrile. To the resultant hydrochloride salt was added CH2Cl2 (15 ml) followed by the dropwise addition of Hünig's base (0.44 ml, 2.5 mmol). A solution of 5-chloropyridine-2-sulfonyl chloride (0.33 g, 1.1 mmol) in CH2Cl2 (5 ml) was added and the reaction mixture (pH 8) was stirred for a further 1.5 h. The reaction mixture was purified over silica gel (heptane-ethylacetate, 95:5-0:100): white solid 0.37 g (76%);
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:19][NH:20][CH3:21])=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[N:8]=[C:7]([O:15]C)[C:6]([O:17]C)=[N:5]2.[ClH:22]>O1CCOCC1>[ClH:22].[CH3:1][C:2]1[C:3]([CH2:19][NH:20][CH3:21])=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[C:6](=[O:17])[NH:5]2
Reactant: CNCc1c(C)c([N+](=O)[O-])cc2nc(OC)c(OC)nc12
Agent: Cl
Solvent: C1COCCO1
Product: CNCc1c(C)c([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12

Procedure:
To a solution of 6-methyl-5-methylaminomethyl-7-nitro-2,3-dimethoxy-quinoxaline (0.028 g, 0.095 mmol) in dioxane (1 mL) was added aqueous HCl (1 mL). The reaction was heated to reflux for 4 hours, cooled, and filtered. The pale yellow solid was filtered and washed with methanol.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]([CH3:32])([CH2:21][N:22]1[CH:31]=[C:25]2[N:26]=[CH:27][C:28]([Br:30])=[CH:29][C:24]2=[N:23]1)[C:19]#[N:20]>C1COCC1>[Br:30][C:28]1[CH:27]=[N:26][C:25]2=[CH:31][N:22]([CH2:21][C:18]([NH:17][C:12](=[O:13])[C:11]3[CH:15]=[CH:16][C:8]([O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:9][CH:10]=3)([C:19]#[N:20])[CH3:32])[N:23]=[C:24]2[CH:29]=1
Reactant: CC(N)(C#N)Cn1cc2ncc(Br)cc2n1
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2ncc(Br)cc2n1)NC(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 4-phenoxybenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-3-(6-bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (0.075 mmole, described in Example 182) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (6.7 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=476, RT=0.63 min.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[S:16][CH:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1.N>C(Cl)(Cl)Cl>[CH3:23][N:20]1[CH2:19][CH2:18][CH:17]([S:16][C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([OH:6])[CH:8]=3)[NH:12][CH:11]=2)[CH2:22][CH2:21]1
Reactant: COc1ccc2[nH]cc(SC3CCN(C)CC3)c2c1
Agent: BrB(Br)Br
Agent: N
Solvent: ClC(Cl)Cl
Product: CN1CCC(Sc2c[nH]c3ccc(O)cc23)CC1
Reaction time: 3 h
Yield: 10.5 %

Procedure:
A solution of boron tribromide (6.3 ml) in chloroform (16 ml) is added dropwise to a solution of 5-methoxy-3-[(1-methylpiperidin-4-yl)thio]-1H-indole (8 g, prepared in Example 41) in chloroform (105 ml) at 0° C. After 3 hours at room temperature, the reaction mixture is poured onto ice and rendered basic with aqueous ammonia. The organic phase is dried over sodium sulfate and concentrated. The oily residue is chromatographed on silica gel (eluent: CH2Cl2 /EtOH/iPrNH2 79/20/1) to give 3-[(1-methylpiperidin-4-yl)thio]-1H-indol-5-ol (0.8 g), which is recrystallized from xylene.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)[CH2:3][OH:4].C(N(CC)CC)C.[CH:22]([Si:25](Cl)([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23].O>CN(C)C=O.C(OCC)(=O)C>[OH:1][CH:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:9][CH:10]=1)[CH2:3][O:4][Si:25]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OCC(O)c1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)[Si](OCC(O)c1ccc(C(F)(F)F)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
1-(1,2-Dihydroxyethyl)-4-(trifluoromethyl)benzene (81.0 mg, 0.393 mmol) and triethylamine (57.6 μL, 0.413 mmol) were dissolved in N,N-dimethylformamide (1.6 mL). To this, triisopropylsilyl chloride (87.2 μL, 0.413 mmol) was added under a nitrogen atmosphere at 0° C. and the mixture was stirred at room temperature for 2 hours. After water was added to the reaction mixture, extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to give 1-(1-hydroxy-2-triisopropylsiloxyethyl)-4-(trifluoromethyl)benzene (Compound CM) (117 mg, yield: 82%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1F)[C:5]1[C:10]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]4[N:25]([CH:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)[C:24]5[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=5[N:22]=4)[CH:17]=3)[N:12]=2)=[CH:9][C:8]([O:39][CH3:40])=[CH:7][CH:6]=1.COC(C1C=C[C:52]2[N:53](C3CCCCC3)[C:54](C3C=C4C(=CC=3)N=C(C3C=C(OC)C=CC=3Br)C=C4)=NC=2C=1)=O.CN(C)C1C=CC(B(O)O)=CC=1>>[CH:26]1([N:25]2[C:24]3[CH:32]=[CH:33][C:34]([C:36]([OH:38])=[O:37])=[CH:35][C:23]=3[N:22]=[C:21]2[C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([C:10]2[C:5]([C:4]4[CH:41]=[CH:42][C:43]([N:53]([CH3:54])[CH3:52])=[CH:2][CH:3]=4)=[CH:6][CH:7]=[C:8]([O:39][CH3:40])[CH:9]=2)[CH:20]=[CH:19]3)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COc1ccc(-c2ccc(F)c(Cl)c2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Reactant: COC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(OC)ccc4Br)ccc3c1)n2C1CCCCC1
Agent: CN(C)c1ccc(B(O)O)cc1
Product: COc1ccc(-c2ccc(N(C)C)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c1
Yield: 26 %

Procedure:
Following the full procedure and workup for Compound 366, Compound 365b (100 mg, 0.175 mmol) was reacted with 4-dimethylaminophenylboronic acid (44 mg, 0.2625 mmol) to produce the title compound (27 mg, 26% yield).
Reaction SMILES: S1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:3][CH2:2]1.O[O:22][S:23]([O-:25])=O.[K+].[OH-].[Na+]>CO.O>[O:22]=[S:23]1(=[O:25])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)=[CH:3][CH2:2]1
Reactant: COC(=O)c1ccc(C2=CCSc3ccccc32)cc1
Reactant: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C2=CCS(=O)(=O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Methyl 4-(2H-1-benzothiopyran-4-yl)benzoate from reaction 33b (0.77 g, 2.75 mmol) was dissolved in methanol (30 mL) cooled to 0° C. and Oxone® (6.76 g, 11.1 mmol) in water (7 mL) was added. The reaction was stirred for 1 h at 0° C. and then allowed to warm to room temperature and stir for another hour. The reaction was diluted with water, pH adjusted to pH=8 with 1 N sodium hydroxide. This was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over magnesium sulfate and concentrated to give methyl 4-(1,1-dioxido-2H-1-benzothiopyran-4-yl)benzoate (0.784 g, 91%) as a solid.