Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2.[Cl:12][C:13]1[C:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:17][C:16](C2OC3(C)C(C)(C3)O2)=[CH:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:13]1[C:18]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:17][C:16]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][N:6]=3)=[CH:15][N:14]=1
Reactant: CC12CC1(C)OC(c1cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3)c1)O2
Reactant: Brc1cnc2ncccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(Nc1cc(-c2cnc3ncccc3c2)cnc1Cl)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 67.3 %

Procedure:
(Some starting materials may be obtained from Princeton Biomolecular Research, Inc., Monmouth Junction, N.J.) To a 50 mL round-bottomed flask was added 3-bromo-1,8-naphthyridine (73 mg, 351 μmol), N-(2-chloro-5-(1,5-dimethyl-2,4-dioxa-bicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (140 mg, 351 μmol), tetrakis(triphenylphosphine)palladium (41 mg, 35 μmol), sodium carbonate (351 μl, 702 μmol), dioxane (3 mL). The reaction mixture was stirred at 100° C. for 5 h. The mixture was cooled down to room temperature. The reaction mixture was diluted with water (1 mL) and extracted with CH2Cl2 (5×20 mL). The organic extract was washed with saturated NaCl (2 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 10% MeOH/CH2Cl2 to give N-(2-chloro-5-(1,8-naphthyridin-3-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (98 mg, 67% yield) as a white solid. MS (ESI pos. ion) m/z calc'd for C19H12ClFN4O2S: 414.0; found 415.0. 1H NMR (300 MHz, MeOD) δ ppm 7.30 (t, J=8.77 Hz, 2 H) 7.76 (dd, J=8.18, 4.38 Hz, 1 H) 7.89 (dd, J=8.99, 5.04 Hz, 2 H) 8.44 (d, J=2.34 Hz, 1 H) 8.62 (dd, J=8.18, 1.90 Hz, 1 H) 8.70 (d, J=2.34 Hz, 1 H) 8.79 (d, J=2.48 Hz, 1 H) 9.15 (dd, J=4.38, 1.90 Hz, 1 H) 9.39 (d, J=2.48 Hz, 1 H)
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][C:12]([OH:14])=[O:13])[CH:9]=2)[CH2:4][CH2:3]1.[OH-].[K+].[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO>[CH:17](=[C:3]1[C:2](=[O:1])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][C:12]([OH:14])=[O:13])[CH:9]=2)[CH2:4]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)CC2
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccc2c(c1)C(=O)C(=Cc1ccccc1)C2
Reaction time: 0.67 h

Procedure:
3-Oxo-5-indaneacetic acid (4.94 g, 0.026 mol) was added to a stirred solution of 85% KOH (3.43 g, 0.052 mol) in EtOH (73 ml) containing benzaldehyde (2.76 g, 0.026 mol) at 10° C. and stirred for 40 minutes. The potassium salt of the precipitated product was filtered off, dissolved in H2O (100 ml) was acidified with conc. HCl to give the title product, m.p. 202°-4° C. (EtOH).
Reaction SMILES: N[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([F:10])=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12].N([O-])=O.[Na+].[BrH:18]>[Cu](Br)Br>[Br:18][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([F:10])=[CH:4][C:3]=1[C:11](=[O:13])[CH3:12]
Reactant: Br
Reactant: COc1cc(F)cc(C(C)=O)c1N
Agent: Br[Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Product: COc1cc(F)cc(C(C)=O)c1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
1-(2-Amino-5-fluoro-3-methoxy phenyl)ethanone (2.66 g, 14.2 mmol), which had been obtained in Reference example 3(3b), was suspended in 10% aqueous hydrogen bromide solution (22 mL). Then, a 9% aqueous sodium nitrite solution (11 mL, 14.4 mmol) was slowly added dropwise thereto at 0° C. After stirring the mixture solution for 1 hour at 0° C., a solution in which copper bromide (I) (2.24 g, 15.7 mmol) is dissolved in 47% aqueous hydrogen bromide solution (15 mL) was added thereto, and the mixture was refluxed with heating at 110° C. for 2 hours. The reaction solution was cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (n-hexane/ethyl acetate=4/1) to give the title compound as a pale yellow solid (2.15 g, yield 61%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][N:8]=[C:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][C:16]=3[F:25])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.[CH3:26][N:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH:32]=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:26][N:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[CH2:32][N:1]1[CH2:6][CH2:5][CH:4]([O:7][N:8]=[C:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:17][C:16]=3[F:25])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1
Reactant: Cn1cccc1C=O
Reactant: CS(=O)(=O)c1ccc(N2CCC(=NOC3CCNCC3)CC2)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cccc1CN1CCC(ON=C2CCN(c3ccc(S(C)(=O)=O)cc3F)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 63a (24 mg, 0.065 mmol) in 1 mL of DCM, was added 1-methyl-1H-pyrrole-2-carbaldehyde (10.6 g, 0.098 mmol), triethylamine (27 μL, 0.19 mmol) and sodium triacetoxyborohydride (27.6 mg, 0.13 mmol). The mixture was stirred overnight at room temperature, concentrated and purified on preparative HPLC to give 66-1: LC-MS 463.0 (MH+).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]([NH:9][C:10]1[C:11]([CH3:16])=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:8])[CH3:7].COCC(NC1C=CC=CC=1)=O>C1C=CC=CC=1>[C:6]([NH:9][C:10]1[CH:15]=[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:13]=[CH:12][C:11]=1[CH3:16])(=[O:8])[CH3:7]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)Nc1ccccc1C
Agent: COCC(=O)Nc1ccccc1
Solvent: c1ccccc1
Product: CC(=O)Nc1cc(S(=O)(=O)Cl)ccc1C
Temperature: 10 °C
Reaction time: 24 h

Procedure:
Chlorosulfonic acid (500 g.) was taken in a three neck round bottom flask equipped with a guard tube and cooled it to 10° C. N-acetyl 2-toluidine (100 g.) was added in small portions maintaining temperature below 10° C. After complete addition of 2-methoxy acetanilide cooling is removed and reaction was brought to 25° C. Reaction mixture was stirred at 25° C. for further 24 hours. After the completion of reaction (TLC), the reaction mixture was poured on ice-water, and the resulting slurry was filtered on buchner funnel. Solid cake on funnel was washed with 500 mL of water and the resulting solid was dried on phosphorus pentoxide in a desiccator to obtain 113.5 grams off white solid. It was found to contain a mixture of two isomers as confirmed from NMR and HPLC; however the desired isomer was obtained by partial crystallization using benzene and used for further experimentation, after the thorough carectorisation.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[CH:20]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28])([CH3:22])[CH3:21]>O>[C:8]1([C:5]2[N:6]=[CH:7][C:2]([N:23]([CH2:24][CH2:25][CH2:26][CH2:27][OH:28])[CH:20]([CH3:22])[CH3:21])=[N:3][C:4]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)NCCCCO
Reactant: Clc1cnc(-c2ccccc2)c(-c2ccccc2)n1
Solvent: O
Product: CC(C)N(CCCCO)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Temperature: 190 °C
Reaction time: 10 h
Yield: 56.5 %

Procedure:
30 g of 2-chloro-5,6-diphenylpyrazine and 131.22 g of 4-(isopropylamino)-1-butanol were mixed and then heated with stirring at 190° C. for 10 hours. The reaction solution was air-cooled, poured into water, extracted with diethyl ether, dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography to obtain 22.96 g of the desired compound as a colorless crystal having a melting point of 102 to 103° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:56])[C:30]([CH3:55])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=3)=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:56])[C:30]([CH3:55])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][N:52]=[CH:51][CH:50]=3)=[C:42]([CH:46]=2)[C:43]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(N)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OCc3ccncc3)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OCc3ccncc3)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 32.1 %

Procedure:
p-Methoxyaniline (0.078 g, 0.639 mmol), triethylamine (0.066 g, 0.639 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.108 g, 0.639 mmol) were added to a methylene chloride solution (10 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-(4-pyridylmethyloxy)benzoic acid (0.135 g, 0.318 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=9:1) and then recrystallized from ether to obtain the titled compound (0.054 g, 0.102 mmol, 32%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][N:53]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH2:22]2)[C:13]([NH:51][C:52]2[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][N:53]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)O)cc1Cl
Reactant: Nc1ccc(Cl)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)Nc2ccc(Cl)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.2 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid (prepared as in Example 60, 300 mg, 0.84 mmol) and triphenylphosphine (288 mg, 1.09 mmol) in methylene chloride (6.0 mL) cooled to 0° C. was treated with N-bromosuccinimide (192 mg, 1.09 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The bright orange reaction mixture was then treated with 2-amino-5-chloropyridine (220 mg, 1.68 mmol) and 2,6-lutidine (0.42 mL, 3.36 mmol). The resulting reaction mixture was stirred at 25° C. for 4 h. The reaction mixture was then diluted with methylene chloride (25 mL) and was successively washed with a 10% aqueous hydrochloric acid solution (1×20 mL), a saturated aqueous sodium bicarbonate solution (1×20 mL) and water (1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 65/35 hexanes/ethyl acetate to 1/1 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyridin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (265 mg, 67%) as a white foam: [α]23589=−35.71° (c=0.35, chloroform); EI-HRMS m/e calcd for C21H22Cl2N2O4S (M+H)+ 469.0750, found 469.0754.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.C([Li])CCC.[Cl-].[CH3:14][O:15][CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>O1CCCC1.CCCCCC>[CH3:14][O:15][CH:16]=[C:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1
Reactant: O=C1CCOCC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC=C1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tetrahydro-4H-pyran-4-one (5.00 g, 50 mmol) was dissolved in tetrahydrofuran (250 ml) and cooled in an ice-water bath. To this solution was added n-butyl lithium (24 ml of a 2.5M solution in hexane, 60 mmol) and the reaction mixture was then allowed to warm to room temperature and stirred for 1 hour. This was then cooled to 0° C. and a solution of (methoxymethyl)triphenyl phosphonium chloride (25.6 g, 75 mmol) in tetrahydrofuran (10 ml) was added and the reaction stirred for 30 minutes. The reaction mixture was then concentrated under reduced pressure and the residue triturated with diethyl ether (10×), decanting the supernatant each time. The combined supernatants were then evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using an elution gradient of pentane:ethyl acetate (95:5 to 90:10) to provide the title compound, 1.80 g.
Reaction SMILES: O=[O+][O-].C=[C:5]1[CH2:10][N:9]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:8][N:7]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:6]1.C(=O)=[O:36].CC(C)=O.CSC>O=O.CC(C)=O>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([S:11]([N:9]2[CH2:10][C:5](=[O:36])[CH2:6][N:7]([S:23]([C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH2:8]2)(=[O:13])=[O:12])=[CH:15][CH:16]=1)([O-:22])=[O:21]
Reactant: O=C=O
Reactant: C=C1CN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Agent: O=O
Agent: O=[O+][O-]
Solvent: CSC
Solvent: CC(C)=O
Product: O=C1CN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)CN(S(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.08 h
Yield: 83 %

Procedure:
A stream of ozone in oxygen was bubbled into a solution of hexahydro-5-(methylene)-1,3-bis(4-nitrobenzenesulfonyl)pyrimidine (0.6 g, 1.3 mmol) in 150 mL acetone at −78° C. (dry ice-acetone bath) until a blue color persisted for 5 minutes. The reaction was stirred for 15 minutes under a nitrogen atmosphere. Next, 2.0 mL of dimethyl sulfide was added. After stirring for 10 minutes, the solvent was removed and the solid dried under reduced pressure to give 0.5 g (83%) of tetrahydro-1,3-bis(4-nitrobenzenesulfonyl)pyrimidin-5(4H)-one. [1H NMR (acetone-d6): δ3.95 (s, 4H), 5.25 (s, 2H), 8.20, 8.48 (AB q, J=9.0 Hz, 8H); 13C NMR (DMSO-d6): δ53.8, 58.8, 124.8, 129.3, 141.9, 150.4, 196.2].
Reaction SMILES: [CH3:1]OC1C=C(OC)C=CC=1C(Cl)=O.[Cl:14][C:15]1[CH:21]=[C:20]([O:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25]N=2)[CH:19]=[CH:18][C:16]=1[NH2:17].[CH3:37][O:38][C:39]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:40]=1[C:47]([N:49]=[C:50]=[S:51])=[O:48]>C1(C)C=CC=CC=1.C(O)C>[CH3:37][O:38][C:39]1[CH:44]=[C:43]([O:45][CH3:46])[CH:42]=[CH:41][C:40]=1[C:47]([N:49]=[C:50]=[S:51])=[O:48].[Cl:14][C:15]1[CH:21]=[C:20]([O:22][C:23]2[C:32]3[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=3)[N:26]=[CH:25][CH:1]=2)[CH:19]=[CH:18][C:16]=1[NH:17][C:50]([NH:49][C:47](=[O:48])[C:40]1[CH:41]=[CH:42][C:43]([O:45][CH3:46])=[CH:44][C:39]=1[O:38][CH3:37])=[S:51]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Agent: COc1ccc(C(=O)N=C=S)c(OC)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2Cl)c(OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
2,4-Dimethoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-dimethoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Chloro-4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2,4-dimethoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (40 mg, yield 48%).
Reaction SMILES: C(O[C:4](=[O:35])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16]([C:24]([F:27])([F:26])[F:25])=[N:17]3)[CH2:8][C@@H:7]1[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)C.[CH2:36]([NH2:38])[CH3:37]>C1COCC1>[CH2:28]([C@H:7]1[CH2:8][N:9]([C:12]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]3[C:13]=2[CH:14]=[CH:15][C:16]([C:24]([F:26])([F:25])[F:27])=[N:17]3)[CH2:10][CH2:11][N:6]1[CH2:5][C:4]([NH:38][CH2:36][CH3:37])=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCOC(=O)CN1CCN(c2ccc(OC)c3nc(C(F)(F)F)ccc23)C[C@@H]1Cc1ccccc1
Reactant: CCN
Solvent: C1CCOC1
Product: CCNC(=O)CN1CCN(c2ccc(OC)c3nc(C(F)(F)F)ccc23)C[C@@H]1Cc1ccccc1

Procedure:
The title compound was prepared by the method outlined for Example 117 using [(S)-2-Benz yl-4-(8-methoxy-2-trifluoromethyl-quinolin-5-yl)-piperazin-1-yl]-acetic acid ethyl ester and a 2 M THF solution of ethylamine. The title compound was isolated as a yellow solid (68 mg, 63%). LC/MS (Method B) 2.82 min, [M+1]+ 486.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:5]=1)([O-:3])=[O:2]
Reactant: CCCCCCBr
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCn1ccc([N+](=O)[O-])n1
Reaction time: 16 h
Yield: 67.2 %

Procedure:
3-Nitro-1H-pyrazole (prepared in example 3, 100 mg, 0.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL) and a 60% dispersion of sodium hydride in mineral oil (42 mg, 1.06 mmol) was added while stirring under nitrogen. After the effervescence ceased and the reaction stirred for an additional 10 min before 1-bromo-hexane (150 μL, 1.06 mmol) was added. The reaction continued to stir under nitrogen for 4 h. The reaction was stored at −25° C. for 16 h. The solution was diluted with ethyl acetate (30 mL), washed with water (2×10 mL), saturated aqueous brine solution (10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 25% ethyl acetate/hexanes to 75% ethyl acetate/hexanes) afforded 3-nitro-1-hexyl-1H-pyrazole (118 mg, 56%) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[CH2:12]([O:14][C:15](=[O:23])[CH2:16][C:17]1[N:18]=[C:19]([NH2:22])[S:20][CH:21]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:23])[CH2:16][C:17]1[N:18]=[C:19]([NH:22][C:9]([NH:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[CH3:11])=[S:10])[S:20][CH:21]=1)[CH3:13]
Reactant: Cc1ccc(Cl)cc1N=C=S
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NC(=S)Nc2cc(Cl)ccc2C)n1
Yield: 39.9 %

Procedure:
Prepared using Method B from 4.5 g (24.5 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 4.56 g (24.5 mmol) of 2-(2-amino-thiazol-4-yl)-acetic acid ethyl ester to give 3.62 g of title compound as a white solid (40% yield, m.p. 177-179° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12](=O)[C:13]([F:16])([F:15])[F:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH2:18]CC1C=C(C=CC=1)CN.O>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([NH2:18])[C:13]([F:16])([F:15])[F:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C(c1cc(Cl)cc(C(F)(F)F)c1)C(F)(F)F
Reactant: NCc1cccc(CN)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: NC(c1cc(Cl)cc(C(F)(F)F)c1)C(F)(F)F
Reaction time: 12 h
Yield: 65.9 %

Procedure:
To a solution of 24.5 g of 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethanone (88 mmol, 1 eq) in 200 ml of toluene were added 13.6 g of m-(aminomethyl)benzylamine (100 mmol, 1.13 eq). After the addition of a catalytic amount of p-TsOH.H2O (˜100 mg), the mixture was refluxed on a water separator for 12 h (approx. 5 ml of water were removed). Thereafter, another 5.5 g of m-(aminomethyl)benzylamine (40 mmol) were added and the mixture was boiled for a further 11 h. Subsequently, the toluene was distilled off (760 Torr). The resulting crude product was distilled under high vacuum (30-105° C. at 0.5 Ton). Further distillation by means of a Vigreux column (b.p. 105-108° C. at 25 Torr) gives 16.0 g of 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethanamine (58 mmol, 65%) as a clear liquid.
Reaction SMILES: C([N:3]([CH2:15][CH3:16])[C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[CH3:13])C.C([Li])(C)(C)C.CCCCC.[Cl:27][C:28]1[CH:29]=C([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])C#N>C1COCC1>[Cl:27][C:28]1[CH:29]=[C:16]([C:15]2[N:3]=[C:4]([OH:14])[C:5]3[C:6]([CH:13]=2)=[CH:7][C:8]([O:11][CH3:12])=[CH:9][CH:10]=3)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37]
Reactant: COc1ccc(C#N)cc1Cl
Reactant: CCN(CC)C(=O)c1ccc(OC)cc1C
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: COc1ccc2c(O)nc(-c3ccc(OC)c(Cl)c3)cc2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.1 %

Procedure:
To a solution of N,N-diethyl-4-methoxy-2-methylbenzamide (1 g, 4.52 mmol) in THF (9 ml) at −78° C. was added dropwise tert-butyllithium 1.7 M in pentane (3.19 ml, 5.42 mmol) and the solution was stirred for 0.5 h before addition of 3-chloro-4-methoxybenzonitrile (0.757 g, 4.52 mmol) in THF (9 ml). The resulting solution was warmed to rt and stirred for 16 h. The reaction mixture was quenched with water, neutralized with 1 N HCl. The precipitated solid was collected and washed with water to give 3-(3-chloro-4-methoxyphenyl)-6-methoxyisoquinolin-1-ol (1.2 g, 84% yield) as a solid after drying. MS: MS m/z 316.1 (M++1).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1/[CH:21]=[CH:22]/[C:23]#N.CO.S(=O)(=O)(O)[OH:28]>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1/[CH:21]=[CH:22]/[CH:23]=[O:28]
Reactant: O=S(=O)(O)O
Reactant: COc1cccc(OC)c1/C=C/C#N
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cccc(OC)c1/C=C/C=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
Add 355 mL of a 1M solution of diisobutylaluminium hydride (DIBAL-H) (355 mmol) in toluene to a solution of 61 g (322 mmol) of (2E)-3-(2,6-dimethoxyphenyl)acrylonitrile in 600 mL of anhydrous toluene under argon and cooled to 0° C., maintaining the temperature at 0° C. Then bring the reaction mixture to room temperature (RT) and stir for 3 h. Then add 13 mL (322 mmol) of methanol and then, dropwise, 170 g (174 mmol) of an aqueous solution of sulphuric acid at 10 wt. %. Stir the suspension for one hour, then filter on a celite bed. Wash the filtrate with 500 mL of water then dry over Na2SO4 and concentrate under reduced pressure. Take up the residue obtained in 500 mL of DCM and filter in a silica column, eluting with DCM. After concentration under reduced pressure, we obtain 37 g of (2E)-3-(2,6-dimethoxyphenyl)acrylaldehyde in the form of colourless oil.