Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:38]=[CH:39][C:40]=1[Cl:41])[C:5]([NH:7][C:8]1[CH:37]=[CH:36][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]C)=[O:21])=[CH:15][C:14]=2[CH2:24][NH:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[CH:10][CH:9]=1)=[O:6].[OH-].[Na+]>CO.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:38]=[CH:39][C:40]=1[Cl:41])[C:5]([NH:7][C:8]1[CH:37]=[CH:36][C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][C:14]=2[CH2:24][NH:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)(=[O:27])=[O:28])=[CH:10][CH:9]=1)=[O:6]
Reactant: COC(=O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(CNS(=O)(=O)c2ccc(F)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)Cc1ccc(Oc2ccc(NC(=O)c3ccc(Cl)c(Cl)c3)cc2)c(CNS(=O)(=O)c2ccc(F)cc2)c1
Reaction time: 1 h
Yield: 30.6 %

Procedure:
Methyl 2-(4-(4-(3,4-dichlorobenzamido)phenoxy)-3-((4-fluorophenyl-sulfonamido)methyl)phenyl)acetate (40 mg, 0.065 mmol) was diluted with MeOH (1 mL) followed by the addition of NaOH (0.32 mL, 1.3 mmol). After stirring for 1 hour, the reaction mixture was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a 0.5 mm preparative plate eluting with methylene chloride:MeOH:AcOH (90:9:1) to yield 12 mg of the title compound as a solid. 1H NMR (400 MHz, CDCl3/CD3OD) 8.1 (m, 1H), 7.85 (m, 1H), 7.8 (m, 2H), 7.7 (d, 1H), 7.6 (d, 1H), 7.25 (s, 1H), 7.2 (m, 3H), 6.85 (d, 2H), 6.7 (d, 1H), 4.15 (s, 2H), 3.55 (s, 2H).
Reaction SMILES: C(O[Si](OCC)(OCC)CCC[S:8][S:9][CH2:10][CH2:11][CH2:12][Si:13]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])C.[S]>>[CH2:15]([O:14][Si:13]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])[CH2:12][CH2:11][CH2:10][S:9][S:8][S:9][CH2:10][CH2:11][CH2:12][Si:13]([O:14][CH2:15][CH3:16])([O:17][CH2:18][CH3:19])[O:20][CH2:21][CH3:22])[CH3:16]
Reactant: CCO[Si](CCCSSCCC[Si](OCC)(OCC)OCC)(OCC)OCC
Agent: [S]
Product: CCO[Si](CCCSSSCCC[Si](OCC)(OCC)OCC)(OCC)OCC

Procedure:
47.5 g of bis-[γ-(triethoxysilyl)-propyl]-disulfide (0.1 mole) was heated together with 3.2 g of sulfur (0.1 mole) under a nitrogen gas atmosphere for about 15 hours at about 150°C, until all of the sulfur had dissolved and did not crystallize out again upon cooling. A dark red liquid was formed, which a thin-layer chromatogram showed to contain no free sulfur, and in which disulfides and tetrasulfides are dissolved as shown by mass spectrographic analysis.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([NH:27][CH2:28][C@@H:29]3[C@H:34]([CH3:35])[CH2:33][CH2:32][CH2:31][NH:30]3)=[N:24][C:23]=2[CH:36]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[O:26][C:25]([NH:27][CH2:28][C@@H:29]3[C@H:34]([CH3:35])[CH2:33][CH2:32][CH2:31][N:30]3[C:7]([C:6]3[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[C:11]3[CH:12]=[N:13][C:14]([CH3:17])=[CH:15][CH:16]=3)=[O:9])=[N:24][C:23]=2[CH:36]=1
Reactant: Cc1ccc(-c2ccc(C)nc2)c(C(=O)O)c1
Reactant: C[C@@H]1CCCN[C@@H]1CNc1nc2cc(Cl)ccc2o1
Product: Cc1ccc(-c2ccc(C)nc2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A1, using 5-methyl-2-(6-methylpyridin-3-yl)benzoic acid and 5-chloro-N-(((2S,3R)-3-methylpiperidin-2-yl)methyl)benzo[d]oxazol-2-amine. ESI-MS (m/z): 489 [M+1]+.
Reaction SMILES: [O:1]([CH3:10])[CH:2]1[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[CH2:3]1.[C:11]1([C:17](Cl)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CO>N1C=CC=CC=1>[C:17]([O:9][CH2:8][C@H:6]1[O:7][CH:2]([O:1][CH3:10])[CH2:3][C@@H:4]1[OH:5])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC1C[C@H](O)[C@@H](CO)O1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Solvent: CO
Product: COC1C[C@H](O)[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 11.2 g (0.07 mole) of methyl 2-deoxyribofuranoside (90% pure) in 60 ml of dry pyridine under a dry nitrogen atmosphere were added 19.0 g (0.07 mole) of triphenylmethyl chloride. The mixture was stirred at ambient temperature for three days. Methanol (35 ml) was then added. The solvents were then evaporated under reduced pressure. The residue was taken up in 200 ml of ethyl acetate, washed with 75 ml of 5% sodium bicarbonate followed by a 75 ml wash with DI (deionized) water. The organic layer was dried (Na2SO4), filtered and the solvent removed under vacuum affording a sticky, viscous oil. This crude methyl 2-deoxy-5-O-tritylriboruanoside compound was used without further purification in subsequent synthetic procedures.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](I)[C:5]([OH:9])=[CH:4][CH:3]=1.C(OC([N:17]1[C:25]2[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=2)[CH:19]=[C:18]1B(O)O)=O)(C)(C)C.C([O-])(O)=O.[Na+]>O1CCOCC1.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[N:7]=[C:6]([C:18]2[NH:17][C:25]3[C:20]([CH:19]=2)=[CH:21][C:22]([F:26])=[CH:23][CH:24]=3)[C:5]([OH:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)nc1I
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2cc(F)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Oc1ccc(Cl)nc1-c1cc2cc(F)ccc2[nH]1
Temperature: 100 °C
Yield: 58.2 %

Procedure:
To a degassed solution of 6-chloro-2-iodopyridin-3-ol (1.0 g, 3.91 mmol) and (1-(tert-butoxycarbonyl)-5-fluoro-1H-indol-2-yl)boronic acid (prepared using the method described in Example 1, 1.3 g, 4.66 mmol) in 1,4-dioxane-H2O (20 mL, 10:1), Pd(PPh3)2Cl2 (120 mg) and NaHCO3 (1.0 g, 11.90 mmol) were added under N2. The mixture was heated to 100° C. overnight. The reaction mixture was cooled to room temperature, filtered and washed with EtOAc. The filtrate was washed with H2O, brine, dried over Na2SO4. After concentrated, the residue was purified by column chromatography (PE:EA 5:1) to give the product of 6-chloro-2-(5-fluoro-1H-indol-2-yl)pyridin-3-ol (600 mg, yield: 58.2%). 1H-NMR (DMSO-d6, 400 MHz) δ 11.37 (br s, 1H), 11.03 (s, 1H), 7.51 (dd, J=8.8, 4.8 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.34 (dd, J=10.0, 2.4 Hz, 1H), 7.30 (d, J=1.2 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 6.94˜6.99 (m, 1H). MS (M+H)+: 263/265.
Reaction SMILES: [C:1]([C:3]1([O:9][CH3:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[CH3:10][O:9][C:3]1([CH2:1][NH2:2])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: COC1(C#N)CCOCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: COC1(CN)CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Under ice-cooling, a diethyl ether (5 ml) solution of 4-cyano-4-methoxytetrahydropyran (600 mg; Chemistry Letters, pp. 937-940, 1984) was added dropwise to a diethyl ether (10 ml) suspension of lithium aluminum hydride (242 mg) spending 20 minutes and, after completion of the dropwise addition, stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was ice-cooled, and sodium sulfate decahydrate was gradually added to the reaction mixture until foaming stopped. After completion of the addition, the insoluble matter was filtered, and the filtered solid was washed with diethyl ether. The filtrate and washed solution were combined and concentrated under a reduced pressure to obtain the title compound (597 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].C(=O)([O-])[O-].[Na+].[Na+].CCCCCC>COCCOC.O.[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.CCOC(C)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[C:16]([O:17][CH3:18])[CH:15]=2)=[N:3][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Brc1ccc(Br)nc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc(Br)cn2)cc1OC
Temperature: 75 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
To a degassed solution of 2,5-dibromopyridine 35 (0.50 g, 2.11 mmol), 3,4-dimethoxyphenylboronic acid 36 (0.50 g, 2.74 mmol) and sodium carbonate (0.67 g, 6.3 mmol) in ethyleneglycol dimethylether (7 mL) and H2O (2 mL) was added tetrakis(triphenylphosphine)-palladium(0) (0.16 g, 0.14 mmol) and the solution was stirred at 75° C. for 18 h. The reaction mixture was filtered, concentrated, diluted with AcOEt, washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography of the residue (eluent: 3:1 hexane:AcOEt) provided title compound 37 (0.47 g, 76% yield).
Reaction SMILES: Cl.[C:2]([NH2:7])(=[NH:6])[CH:3]([CH3:5])[CH3:4].C[O-].[Na+].C([O:13][C:14](=O)[CH:15]([S:19][CH3:20])[C:16]([CH3:18])=O)C>CO>[CH:3]([C:2]1[N:7]=[C:14]([OH:13])[C:15]([S:19][CH3:20])=[C:16]([CH3:18])[N:6]=1)([CH3:5])[CH3:4]
Reactant: CC(C)C(=N)N
Reactant: CCOC(=O)C(SC)C(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CSc1c(C)nc(C(C)C)nc1O
Reaction time: 4 h
Yield: 43.7 %

Procedure:
A mixture of 19 g (0.15 mole) of isobutyramidine hydrochloride, 35 ml of methanol, 8.1 g (0.15 mole) of sodium methylate and 27 g (0.15 mole) of 2-methylmercaptoacetoacetic acid ethyl ester was stirred for 4 hours at 60°-70°C. The solvent was then distilled off under reduced pressure, the residue was dissolved in warm water and the solution was neutralized with acetic acid. The product which had crystallized out was filtered off. 13 g (44% of theory) of 2-isopropyl-4-hydroxy-5-methylmercapto-6-methylpyrimidine were obtained in the form of a colorless powder of melting point 156°C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:10]=3[C:9]=2[C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1>>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:10]=3[C:9]=2[C:18](=[O:27])[C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2c(-c3ccc(O)cc3)sc3cc(O)ccc23)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1ccc(O)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Temperature: 187.5 °C
Reaction time: 1.5 h
Yield: 86.6 %

Procedure:
A 250 mL, 3 neck, flask fitted with a thermometer, condenser, and stopper is charged 2-(4-hydroxyphenyl)-3-(4-methoxybenzoyl)-6-hydroxybenzo[b]thiophene (3.0 g, 7.97 mmol) and pyridine hydrochloride (18.5 g, 160 mmol). The contents are heated to 185-190° C. and held at this temperature for 90 minutes. The hot mixture is then poured into 250 mL of ice/water. A yellow solid formed with this addition. The material is extracted into 250 mL of ethyl acetate. The aqueous is then back-extracted with 100 mL of ethyl acetate. The combined organics are washed with 150 mL 1N hydrochloric acid and 150 mL brine. The solvent is removed in vacuo giving a viscous oil. To the oil is added 10 mL of 1:1 methylene chloride/hexanes which induced crystallization. The slurry is cooled to 0° C. and stirred at this temperature for 1 hour. The product is collected by vacuum filtration and washed with 25 mL of 4:1 hexanes/methylene chloride. Drying the solid at 100° C. for 5 hours afforded 2.5 g (86.2%) of a dark yellow solid containing approximately 3% monomethoxy starting material. An analytical sample is obtained by chromatography on silica gel (15:1 methylene chloride:methanol). mp 135° C. (dec); 1H NMR (300.1 MHz, DMSO-d6) δ 6.67 (d, 2H), 6.71 (d, 2H), 6.85 (dd, 1H), 7.17 (d, 2H), 7.25 (d, 1H), 7.32 (d, 1H), 7.57 (d, 2H), 9.73 (br s, 2H), 10.41 (br s, 1H); 13C NMR (75.5 MHz, DMSO-d6) d 107.1, 115.1, 115.4, 115.6, 123.4, 123.9, 128.4, 129.7, 129.9, 132.1, 132.4, 139.2, 140.0, 155.4, 157.8, 162.5, 192.4; MS (FD+) m/e 362 (100), 363 (24), 364 (7); HRMS m/e calc'd for C2H15O4S (M+1): 363.069106, found 363.06990.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:31])[N:9]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH:23]=[C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1)([O-])=[O:2].[Cl-].[NH4+]>O1CCCC1.O.[Zn]>[OH:2][NH:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8](=[O:31])[N:9]([CH2:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:20][CH:21]=[C:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH2:23][CH2:24]3)[C:10](=[O:14])[NH:11]2)=[CH:6][CH:5]=1
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)n1CCCCN1CC=C(c2ccccc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: O=c1[nH]c2cc(NO)ccc2c(=O)n1CCCCN1CC=C(c2ccccc2)CC1
Temperature: 32 °C
Reaction time: 2 h
Yield: 29.6 %

Procedure:
To a stirred solution of 7-nitro-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione (2.1 g) in 50% aqueous tetrahydrofuran (210 ml) was added ammonium chloride (2.68 g) in water (27 ml). To this mixture was added zinc dust (1.65 g) by five portions over a period of 3 hours. The temperature was raised at 32° C. during the reaction. After additional stirring for 2 hours, the precipitated materials were filtered, washed with water and extracted with dimethylformamide (100 ml) under nitrogen. The organic extract was filtered and the filtered cake was washed with dimethylformamide (20 ml). The combined organic solution was diluted with water (24 ml), cooled in a refrigerator, and then treated with active charcoal (1.05 g) and silica gel (2.1 g). The charcoal and silica gel were filtered off and washed with 80% aqueous dimethylformamide (5 ml). To the combined solution was added dropwise cold water (96 ml) with stirring on an ice bath and the precipitated crystals were collected, washed with water, and then suspended in methanol (50 ml). To this mixture was added 10% hydrogen chloride in methanol (50 ml) and the mixture was stirred for 1 hour. The precipitated crystals were collected, washed with methanol, stirred with water, and then filtered and dried to give 7-hydroxyamino-3-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl]-1,2,3,4-tetrahydroquinazoline-2,4-dione (0.60 g).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:9]3[C:14]([C:15]=2[CH:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CN(C=O)C>[Cl:23][CH2:22][CH2:21][CH2:20][N:8]1[C:7]2[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:16][C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: CC(=O)c1ccc2[nH]c3ccccc3c2c1
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)c1ccccc1n2CCCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-Acetylcarbazole (1.0 g, 0.0048 mol) was dissolved in dry DMF (20 mL) and NaH (50% in oil) (0.13 g, 0.0053 mol) was added. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was added dropwise to a solution of 1-bromo-3-chloropropane (0.83 g, 0.0053 mol) in DMF (20 mL). The resulting mixture was stirred under a N2 atmosphere for 60 h. The solvent was removed in vacuo, and the residue was purified on a silica gel column (Eluent: CH2Cl2). This afforded the title comoound 0.70 g (51%) as a solid. M.p. 109-111° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.C(N(CC)CC)C.[C:26]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[C:26]([C:30]1[CH:31]=[CH:32][C:33]([C:34]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9](=[O:18])[C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[O:35])=[CH:37][CH:38]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(C(=O)Nc2ccccc2O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccc2OC(=O)c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Yield: 69.8 %

Procedure:
A solution of N-(2-hydroxyphenyl)-4-methoxybenzamide (0.486 g, 2.00 mmol) in methylene chloride (35 mL) was cooled to 0° C. Triethylamine (0.281 mL, 2.00 mmol) was added followed by the dropwise addition of a solution of 4-tert-butylbenzoyl chloride (0.393 mL, 2.00 mmol) in methylene chloride (15 mL). The reaction mixture was allowed to warm to room temperature over 16 h and washed with cold water, dried (magnesium sulfate), filtered, and concentrated in vacuo. Crystallization of the residue from diethyl ether provided 0.563 g (70%) of the title compound.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[CH:20]=[CH:21]C=2O)=[O:16])=[CH:10][CH:9]=1)#[N:7].Cl>O1CCCC1.N1C=CC=CC=1>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[C:19]1[CH:20]=[CH:21][C:5]2[O:4][C:2](=[O:3])[N:14]([C:11]3[CH:10]=[CH:9][C:8]([C:6]#[N:7])=[CH:13][CH:12]=3)[C:15](=[O:16])[C:17]=2[CH:18]=1
Reactant: N#Cc1ccc(NC(=O)c2cc(-c3ccc(F)cc3F)ccc2O)cc1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: N#Cc1ccc(-n2c(=O)oc3ccc(-c4ccc(F)cc4F)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 22 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 10 (1.4 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 22.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][C@@H:5]([CH3:8])[CH2:4][NH:3]1.[S:9](N)([NH2:12])(=[O:11])=[O:10]>O1CCOCC1>[CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][N:3]1[S:9]([NH2:12])(=[O:11])=[O:10]
Reactant: NS(N)(=O)=O
Reactant: C[C@@H]1CN[C@@H](C)CN1
Solvent: C1COCCO1
Product: C[C@@H]1CN(S(N)(=O)=O)[C@@H](C)CN1
Yield: 35.5 %

Procedure:
To a solution of (2R,5S)-2,5-dimethylpiperazine (2 g) in dioxane (100 ml) was added sulfamide (2.5 g) and the reaction mixture was then heated at reflux in dioxane (100 ml) for 72 h. The reaction mixture was partitioned between EtOAc (150 ml) and H2O (150 ml) and the aqueous re-extracted with EtOAc (2×150 ml). Organics were collected, dried and reduced in vacuo to give (2S,5R)-2,5-dimethylpiperazine-1-sulfonamide as a white solid (1.2 g). A mixture of (2S,5R)-2,5-dimethylpiperazine-1-sulfonamide (0.38 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.43 g) and, 4-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product from example 35 step i), 0.4 g) in dioxane (20 mL) was heated at reflux in a microwave at 100° C., 300 W, open vessel with cooling for 4 h. The reaction mixture was then reduced in vacuo and the residue partitioned between DCM (150 ml) and H2O (150 ml). The organics were separated and the aqueous layer was re-extracted with DCM (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give a yellow solid. This residue was then purified by prep HPLC to give the title compound as a white solid. Yield: 9 mg
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][CH:22]([CH2:27][CH2:28][CH3:29])[CH2:21][C:20]=3[NH:19][C:18]([CH3:30])=[C:17]2[C:31]#[N:32])[CH:5]=[C:6]([O:13][CH2:14][CH3:15])[C:7]=1[O:8]S(C)(=O)=O.F[C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][CH:22]([CH2:27][CH2:28][CH3:29])[CH2:21][C:20]=3[NH:19][C:18]([CH3:30])=[C:17]2[C:31]#[N:32])[CH:5]=[C:6]([O:13][CH2:14][CH3:15])[C:7]=1[O:8][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OS(C)(=O)=O)c(OCC)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(Oc2ccc([N+](=O)[O-])cc2)c(OCC)c1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of the product of step b (0.20 g), 1-fluoro-4-nitrobenzene (53 μL) and cesium carbonate (0.22 g) was dissolved in dimethyl sulfoxide (1 mL) and stirred at 80° C. for 16 h. Dichloromethane was added and the reaction mixture was washed with a solution of 1% hydrochloric acid in water and with saturated brine. The organic phase was concentrated and the title compound was obtained after flash column chromatography (silica gel, heptane/ethyl acetate).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([C:24]([F:27])([F:26])[F:25])[C:8]2[CH:9]=[C:10]([Br:13])[CH:11]=[CH:12][C:7]=2[N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[C:5](=[O:23])[O:4]1.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](O)=[O:34])=[CH:31][CH:30]=1.O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>O.CN(C=O)C>[Br:13][C:10]1[CH:11]=[CH:12][C:7]2[N:6]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:5](=[O:23])[O:4][C:3]([CH2:2][NH:1][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=3)([C:24]([F:26])([F:27])[F:25])[C:8]=2[CH:9]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: COc1ccc(CN2C(=O)OC(CN)(C(F)(F)F)c3cc(Br)ccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(CN2C(=O)OC(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
While stirring a solution of DMF (50 mL) containing 4-(aminomethyl)-6-bromo-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (13.67 g, 30.7 mmol), 4-fluorobenzoic acid (4.73 g, 33.8 mmol), hydroxybenzotriazole monohydrate (4.7 g, 30.7 mmol) and triethylamine (4.69 mL, 33.8 mmol) at 0° C., 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.47 g, 33.8 mmol) was added little by little thereto. After the reaction solution was stirred overnight at room temperature, water was slowly added thereto. After a solid began to precipitate, further excess water was added thereto, and the mixture was stirred at room temperature for 2 hours. The solid was collected by filtration and washed with water and then dried under reduced pressure, whereby the objective compound (15.6 g, 90%) was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[NH:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:31]([OH:33])=O)(=[O:27])=[O:26]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N:22]([CH3:23])[C:31](=[O:33])[C:30]1[CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=[C:28]([S:25]([CH3:24])(=[O:26])=[O:27])[CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNc1cnccc1-c1ccc(F)cc1OCc1ccccc1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Product: CN(C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1)c1cnccc1-c1ccc(F)cc1OCc1ccccc1

Procedure:
The title compound was prepared in analogy to example 90, from 4-(2-(benzyloxy)-4-fluorophenyl)-N-methylpyridin-3-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 18 hours at room temperature. The compound was purified by silica gel chromatography on a 50 g column using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Light brown foam (637 mg, 69%). MS (ESI): m/z=559.131 [M+H]+.