Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9]Cl>C(#N)C>[CH3:1][N:2]([CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[C:6]([O:5][CH3:4])[CH:7]=1)[CH3:3]
Reactant: CNC
Reactant: COc1cccc(CCl)c1
Solvent: CC#N
Product: COc1cccc(CN(C)C)c1
Reaction time: 4 h

Procedure:
Four hundred grams of dimethylamine were added to 1.5 liters of acetonitrile previously cooled with an external ice/ethanol bath. To this solution were added 322.7 g. of 3-methoxybenzyl chloride in a dropwise fashion. When the addition was completed, the reaction was stirred for an additional four hours with cooling. The reaction was stirred an additional 20 hours at room temperature, heated to reflux for five hours, and then concentrated under reduced pressure. The residue was taken up in water, the aqueous solution was made strongly basic with aqueous sodium hydroxide, and the solution was then extracted with diethyl ether. The ether layer was first washed with water and then extracted with dilute hydrochloric acid. The acid layer was made basic with an aqueous sodium hydroxide solution and extracted with diethyl ether. The layer was dried over sodium sulfate and evaporated to dryness. The residue was vacuum distilled at 3 torr. The fraction between 88° and 92° C. afforded 257 g. of the desired title intermediate. NMR.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:46])[C@H:10]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH:11][C:12](=[O:38])[C@H:13]([CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[NH:14][C:15](=[O:26])[CH2:16][CH2:17][NH:18][C:19](OC(C)(C)C)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:47]([C:49]1[CH:50]=[CH:51][C:52](C(O)=O)=[N:53][CH:54]=1)#[N:48]>>[CH2:1]([O:8][C:9](=[O:46])[C@H:10]([CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[NH:11][C:12](=[O:38])[C@H:13]([CH2:27][C:28]([O:30][CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[NH:14][C:15](=[O:26])[CH2:16][CH2:17][NH:18][C:19]([C:52]1[CH:51]=[CH:50][C:49]([C:47]#[N:48])=[CH:54][N:53]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: CC(C)(C)OC(=O)NCCC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Product: N#Cc1ccc(C(=O)NCCC(=O)N[C@@H](CC(=O)OCc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)OCc2ccccc2)nc1

Procedure:
N-[3-[(Benzyloxy)carbonyl]-N-[N-(t-butoxycarbonyl)-β-alanyl]-L-alanyl]-3-phenyl-L-alanine benzyl ester was deprotected and coupled with 5-cyano-2-pyridinecarboxylic acid to give N-[3-[(benzyloxy)carbonyl]-N-[N-[(5-cyano-2-pyridyl)carbonyl]-β-alanyl]-L-alanyl]-3-phenyl-L-alanine benzyl ester, m.p. 157°-158° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[NH2:11])[C:5](O)=[O:6].S(Cl)([Cl:15])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:12])[C:10]=1[NH2:11])[C:5]([Cl:15])=[O:6]
Reactant: Nc1c(Cl)cc(C(=O)O)cc1Cl
Reactant: O=S(Cl)Cl
Product: Nc1c(Cl)cc(C(=O)Cl)cc1Cl
Reaction time: 1 h

Procedure:
The 3,5-dichloro-4-aminobenzoic acid is refluxed with 200 ml. of thionyl chloride. A solution forms in 1 hr. and heating is maintained for 2 additional hours, after which the reaction mixture is permitted to stand overnight. Excess thionyl chloride is removed by evaporation to leave a yellow-brown crystalline mass as a residue. This is recrystallized from a mixture of n-hexane/ethylene chloride (90/10 by volume) to produce a light tan crystalline product, m.p. = 155° C. A portion of this material is recrystallized from methylene chloride as pale yellow needles existing in round clusters. These needles are dissolved in methylene chloride and anhydrous hydrogen chloride is bubbled into the solution. The yellow color is discharged and off-white needles of 3,5-dichloro-4-aminobenzoyl chloride are obtained, m.p. = 165° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[OH:12])[C:5]([NH:7][NH2:8])=[O:6].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O>>[F:13][C:14]([F:23])([F:24])[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[N:8][NH:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][C:11]([OH:12])=[C:2]([OH:1])[CH:3]=1
Reactant: NNC(=O)c1ccc(O)c(O)c1
Reactant: O=Cc1cccc(C(F)(F)F)c1
Product: O=C(NN=Cc1cccc(C(F)(F)F)c1)c1ccc(O)c(O)c1

Procedure:
The title compound was prepared from 3,4-dihydroxy-benzoic acid hydrazide and 3-trifluoromethyl-benzaldehyde by a procedure similar to Example 22. 1H NMR (DMSO-d6): 11.79 (s, 1H), 9.55 (s, 1H), 9.28 (s, 1H), 8.50 (s, 1H), 8.04 (s, 1H), 8.0 (d, J=7.8 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H), 7.38 (d, J=2.4 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](Cl)=[O:9])=[N:6][CH:7]=1.[C:26]([O:30][C:31]([N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([NH:42][CH2:43][CH3:44])=[N:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[C:26]([O:30][C:31]([N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]([N:42]([C:8]([C:5]2[C:4]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:24])([F:23])[F:25])[CH:16]=3)(=[O:13])=[O:14])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[O:9])[CH2:43][CH3:44])=[N:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCNc1nn(C(=O)OC(C)(C)C)c2ccccc12
Reactant: O=C(Cl)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Product: CCN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1nn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl chloride (100 mg, 0.24 mmol), 3-ethylamino-indazole-1-carboxylic acid tert-butyl ester (62.6 mg, 0.24 mmol), and TEA (0.64 mL) in THF (1 mL) was stirred at 60° C. for 2 hours and then purified by flash column to give 3-{[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-ethyl-amino}-indazole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:7][C@H:6]1[C:8]([OH:10])=O)=[O:4].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.CN1CCOCC1.[CH3:40][C@H:41]1[CH2:46][CH2:45][C@H:44]([NH2:47])[CH2:43][CH2:42]1>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:7][C@H:6]1[C:8](=[O:10])[NH:47][CH:44]1[CH2:45][CH2:46][CH:41]([CH3:40])[CH2:42][CH2:43]1)=[O:4]
Reactant: C[C@H]1CC[C@H](N)CC1
Reactant: COC(=O)[C@@H]1C[C@H]1C(=O)O
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@H]1C(=O)NC1CCC(C)CC1
Reaction time: 3 h
Yield: 95.6 %

Procedure:
Stir a solution of trans-cyclopropane-1,2-dicarboxylic acid monomethyl ester (Example 3a) (3.0 g, 20.8 mmol) and TOTU (8.5 g, 26 mmol) in DMF (300 mL) at ambient temperature for 20 min at which time add N-methylmorpholine (2.4 mL 22.9 mmol) and trans 4-methylcyclohexylamine 3.06 g, 27.0 mmol). After 3 h, remove the solvent and dissolve the residue in H2O/EtOAc. Extract the aqueous layer 3 more times with EtOAc and combine the extracts. Wash the extract with saturated NaHCO3 solution, brine and dry over MgSO4. Concentrate the solvent to afford the crude product, and purify by column chromatography over silica gel to give 4.76 g (95%) of colorless crystals, m/z=240 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][O:5][C:6]1[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10]([NH2:12])=[O:11])(=[O:3])[NH2:2].[NH3:21]>>[C:1]([CH2:4][O:5][C:6]1[CH:16]=[C:15]([S:17]([NH2:21])(=[O:19])=[O:18])[CH:14]=[CH:13][C:7]=1[O:8][CH2:9][C:10]([NH2:12])=[O:11])(=[O:3])[NH2:2]
Reactant: NC(=O)COc1ccc(S(=O)(=O)Cl)cc1OCC(N)=O
Reactant: N
Product: NC(=O)COc1ccc(S(N)(=O)=O)cc1OCC(N)=O
Reaction time: 16 h

Procedure:
2-Carbamoylmethoxy-4-chlorosulfonylphenoxyacetamide (Intermediate A65, 12.9 g, 0.040 mol) was dissolved in methanolic ammonia and stirred for 16 hr. The solvent was removed at aspirator pressure, and the residue was crystallized in water. The resulting solid was washed with hot water and several additional portions of water. The product, title compound weighed 8.6 g (71%).
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[C:15]([OH:22])[C:14]=2[CH2:23][CH2:24][CH3:25])=[CH:7][C:6]=1[O:26][CH2:27][CH3:28])C.[OH-].[Na+]>>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:8]2[CH:9]=[CH:10][C:5]([C:4]([OH:29])=[O:3])=[C:6]([O:26][CH2:27][CH3:28])[CH:7]=2)=[C:14]([CH2:23][CH2:24][CH3:25])[C:15]=1[OH:22])(=[O:21])[CH3:20]
Reactant: CCCc1c(OCc2ccc(C(=O)OCC)c(OCC)c2)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Product: CCCc1c(OCc2ccc(C(=O)O)c(OCC)c2)ccc(C(C)=O)c1O

Procedure:
4-[(4-Acetyl-3-hydroxy-2-propylphenoxy)methyl]-2-ethoxybenzoic acid ethyl ester was allowed to react with 1.0N sodium hydroxide according to the procedure of Example 70 and the product was purified by recrystallization from methanol to give 4[(4-acetyl-3-hydroxy-2-propylphenoxy) methyl]-2-ethoxybenzoic acid, the title compound, m.p. 145°-150° in 93% yield.
Reaction SMILES: [C:1]([N:4]1[CH2:26][C:12]2([CH2:17][CH2:16][N:15]([C:18]3([C:24]#N)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].C[Mg]Br>O1CCCC1>[CH3:24][C:18]1([N:15]2[CH2:14][CH2:13][C:12]3([C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:26]3)[CH2:17][CH2:16]2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC(=O)N1Cc2ccccc2C2(CCN(C3(C#N)CCCCC3)CC2)C1
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)N1Cc2ccccc2C2(CCN(C3(C)CCCCC3)CC2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The crude 1-(2-acetyl-2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)cyclohexanecarbonitrile 8a was dissolved in anhydrous tetrahydrofuran (1.0 mL) and treated with methylmagnesium bromide (1.0 mL 1.0 M solution in butyl ether, 1.0 mmol). The vial was flushed with nitrogen and stirred at room temperature for 3 hours. The reaction was diluted with ethyl acetate (5.0 mL), quenched with saturated aqueous ammonium chloride (1.0 mL) and stirred overnight at room temperature. The layers were separated, the organic layer concentrated under reduced pressure and purified by reverse-phase HPLC (1-25% CH3CN—H2O gradient, with 0.05% TFA, 15 min) to provide 1-(1′-(1-methylcyclohexyl) -1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-yl)ethanone. LC/MS m/z [M+H]+ 341.2 retention time 1.83 min (10-99% CH3CN—H2O gradient, with 0.05% TFA, 5 min).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:39])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[CH3:39][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=5)=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(-c5ccc(C(F)(F)F)cn5)cc4)CC3)n2CCS1
Agent: Cl
Solvent: CO
Product: CC1(CO)Cc2nnc(C3(c4ccc(-c5ccc(C(F)(F)F)cn5)cc4)CC3)n2CCS1
Yield: 67.5 %

Procedure:
A solution of the compound (574 mg, 1.0 mmol) obtained in Example 42-1) and 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (311 mg, 68%) as a colorless solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[CH:29][C:28](=[O:32])[N:27]([CH:33]5[CH2:37][CH2:36][CH2:35][CH2:34]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:38]CCl>Cl.C(OCC)C>[ClH:38].[CH:33]1([N:27]2[C:25]3[N:26]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:15][N:16]=4)[N:22]=[CH:23][C:24]=3[C:30]([CH3:31])=[CH:29][C:28]2=[O:32])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: ClCCl
Reactant: Cc1cc(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cn3)ncc12
Agent: Cl
Solvent: CCOCC
Product: Cc1cc(=O)n(C2CCCC2)c2nc(Nc3ccc(N4CCNCC4)cn3)ncc12
Reaction time: 48 h
Yield: 90.9 %

Procedure:
4-[6-(8-Cyclopentyl-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylic acid tert-butyl ester (0.093 g, 0.184 mmol) was dissolved in dichloromethane (3 mL) to which 2 N HCl in diethyl ether (2 mL) was added and the resulting mixture was stirred for 2 days. Additional 2 N HCl was added and stirring was continued for 16 hours. The solvent was removed to give 8-cyclopentyl-5-methyl-2-(5-piperazin-4-yl-pyridin-2-ylamino)-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt as a yellow solid (0.080 g, 90.9%). 1H NMR δ(400 MHz, DMSO-d6) 9.92 (s, 2H), 8.85 (s, 1H), 8.02 (d, J=2.9 Hz, 1H), 7.91 (d, J=9.3 Hz, 1H), 7.78 (d, J=9.3 Hz, 1H), 6.33 (s, 1H), 5.79 (m, 1H), 3.40 (m, 4H), 3.22 (m, 4H), 2.39 (s, 3H), 2.20 (m, 2H), 1.91 (m, 2H), 1.74 (m, 2H), 1.56 (m, 2H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:18][CH3:19])[C:13]=2[Cl:17])[C:8]=1[Cl:20])(=O)=O.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[Cl:17][C:13]1[C:14]2[C:9](=[C:8]([Cl:20])[C:7]([C:28]3[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)=[CH:16][CH:15]=2)[CH:10]=[CH:11][C:12]=1[O:18][CH3:19]
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1ccc2c(Cl)c(OS(=O)(=O)C(F)(F)F)ccc2c1Cl
Product: COc1ccc(-c2ccc3c(Cl)c(OC)ccc3c2Cl)cc1

Procedure:
The title compound was prepared by 1,5-dichloro-6-methoxy-2-naphthyl trifluoromethanesulfonate (0.32 g, 0.85 mmol) with 4-methoxyphenyl boronic acid (0.18 g, 1.2 mmol) according to method A to yield 0.27 g (95%) of a white solid mp 146-149° C.;1H NMR (CDCl3): δ 3.88 (3H, s), 4.07 (3H, s), 7.02 (2H, d, J=8.73 Hz), 7.41 (1H, d, J=9.52 Hz), 7.46 (2H, d, J=8.83 Hz), 7.53 (1H, d, J=8.73 Hz), 8.19 (1H, d, J=8.73 Hz), 8.36 (1H, d, J=9.12 Hz);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:19](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:13]([CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH3:19])[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(Cl)cc(NC2CCCC2)c1C
Agent: [Cs+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)c1cc(Cl)cc(N(C)C2CCCC2)c1C
Temperature: 80 °C
Yield: 95.4 %

Procedure:
To a stirred solution of methyl 5-chloro-3-(cyclopentylamino)-2-methylbenzoate (0.5 g, 1.86 mmol) in acetonitrile (5 mL) was added cesium carbonate (1.22 g, 3.7 mmol) and methyl iodide (1.32 g, 9.33 mmol). The resulting mixture was heated at 80° C. for 12 h. On completion, the mixture was cooled to room temperature and filtered, the residue was washed with ethyl acetate and the filtrate was concentrated and then purified by column chromatography to afford methyl 5-chloro-3-(cyclopentyl(methyl)amino)-2-methylbenzoate (0.5 g, 95%).
Reaction SMILES: [CH3:1][CH:2]([NH:10][C:11](=[O:13])[CH3:12])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH2:16][CH2:15]1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:11]([NH:10][CH:2]([CH3:1])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:8][CH:9]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)NC(C)Cc1ccccc1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)NC(C)Cc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a one l., three necked, creased flask provided with a stirrer, thermometer, condenser topped with a drying tube and a short length of Gooch tubing connected to a small Erlenmeyer flask was placed 18.7 g (0.106 moles) of N-(alpha-methylphenethyl) acetamide, 15.9 g (0.159 moles) of succinic anhydride and 500 ml of dry methylene chloride. The flask and contents were cooled to 0°-5°, and from the Erlenmeyer flask through the Gooch tubing, 55.5 g (0.424 moles) of anhydrous aluminum chloride was added in small portions over a period of approximately 0.5 hour. A sharp exotherm occurred after each of the first additions, but the temperature was not allowed to exceed 8°. During the addition, the succinic anhydride slowly dissolved and gradually a grayish green gum was deposited. After five hours at 0°-5°, the cooling bath was removed, and the stirred mixture allowed to warm to room temperature (19°-22°), then stirred for another twenty-four hours. At the end of this time, the reaction mixture consisted of a reddish orange gum and a pale-colored solvent. The mixture was cooled in an ice bath, and with vigorous stirring 200 ml of 3 N hydrochloric acid added at 20°. The mixture was stirred until the color of the viscous red gum became grayish white. The stirrer was then stopped, the layers allowed to separate, and the lower methylene chloride layer removed by suction from the reaction vessel. Another 300 ml of methylene chloride was added to the flask, the contents stirred for five minutes, then allowed to settle and the lower layer drawn off as before.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)[CH:11]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:28]/[CH:29]=[CH:30]/[C:31]#[C:32][Si:33]([CH3:36])([CH3:35])[CH3:34].OC(C=C)C#C[Si](C)(C)C.C[Si](C#C)(C)C.C(C=C)=O.CS(Cl)(=O)=O.[Br-].C[NH+](C)C>CN(C)C=O.O.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:1]([N:3]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)[CH:11]=1)[CH2:28]/[CH:29]=[CH:30]/[C:31]#[C:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH3:2]
Reactant: CCNCCOCCOc1cccc(-c2ccsc2)c1
Reactant: C[Si](C)(C)C#C/C=C/CBr
Agent: C#C[Si](C)(C)C
Agent: C=CC(O)C#C[Si](C)(C)C
Agent: C=CC=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(C/C=C/C#C[Si](C)(C)C)CCOCCOc1cccc(-c2ccsc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
1.9 g of N-ethyl-2-[2-[3-(3-thienyl)phenoxy]ethoxy]ethylamine and 2.7 g of potassium carbonate were dissolved in 15 ml of dimethylformamide, and a dimethylformamide solution (5 ml) of 1.43 g of (E)-5-bromo-3-penten-1-ynyl(trimethyl)silane [synthesized by mesylating 3-hydroxy-4-penten-1-ynyl(trimethyl)silane, prepared from trimethylsilylacetylene and acrolein, with methanesulfonyl chloride and triethylamine, and subsequently treating the mesylated product with trimethylammonium bromide] was added dropwise. The mixture was stirred at room temperature for 30 minutes, and then ethyl acetate and water were added. The organic layer separated was worked up in a customary manner, and the product was purified by silica gel column chromatography [methylene chloride / methanol=20/1] to give 2.3 g of (E)-N-ethyl-N-(5-trimethylsilyl-2-penten-4-ynyl)-2-[2-[3-(3-thienyl) phenoxy]ethoxy]ethylamine as a colorless oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11]Br)=[CH:9][CH:8]=1)#[N:6]>O.CN(C=O)C.C1(C)C=CC=CC=1>[C:5]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11][N:1]=[N+:2]=[N-:3])=[CH:9][CH:8]=1)#[N:6]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN=[N+]=[N-])cc1

Procedure:
A solution of 20.23 g (0.31 mol) sodium azide in 50 ml water was added to 49.15 g (251 mmol) 4-cyanobenzyl bromide in 200 ml DMF at ambient temperature. An exothermic reaction took place and after 1.5 h the reaction mixture was diluted with 200 ml toluene(caution: In order to avoid separation of potentially explosive azide compounds it is adviceable to add the toluene to the rection mixture before addition of the water) and 500 ml water. The aqueous phase was extracted with an additional 2×50 ml toluene. The combined organic extracts were washed with 2×50 ml water and brine and finally dried (MgSO4) and filtered. The solution was used as such in the next step.
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH2:8](O)[CH3:9]>>[CH2:8]([O:7][CH2:1][C:2]1[O:6][CH:5]=[CH:4][CH:3]=1)[CH3:9]
Reactant: CCO
Reactant: OCc1ccco1
Product: CCOCc1ccco1
Reaction time: 2.5 h

Procedure:
Six batches of ethylfurfuryl ether comprising liquid were prepared as follows. A feed mixture of 120 grams ethanol and 110 grams furfuryl alcohol (molar ratio ethanol/furfuryl alcohol of 2.5) was added to 10 grams acidic ZSM-5 particles with a silica-alumina ratio of 30. The mixture was contracted with the catalyst for 2.5 hours at 125° C. under stirring.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([N:25](CC3C=CC(OC)=CC=3OC)[C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[CH:19][CH:20]=2)[NH:15][CH2:14][CH2:13]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[N:12]1[C:21]2[C:16](=[CH:17][C:18]([S:22]([NH:25][C:26]3[S:30][N:29]=[CH:28][N:27]=3)(=[O:23])=[O:24])=[CH:19][CH:20]=2)[NH:15][CH2:14][CH2:13]1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(c2)NCCN3c2ccc(C(F)(F)F)cc2Cl)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ncns1)c1ccc2c(c1)NCCN2c1ccc(C(F)(F)F)cc1Cl
Reaction time: 0.17 h

Procedure:
1-(2-Chloro-4-(trifluoromethyl)phenyl)-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide (INTERMEDIATE V, 0.068 g, 0.108 mmol) was dissolved in 1 mL of DCM and TFA (0.1 mL, 1.298 mmol) was added. The reaction was stirred for 10 minutes. The material was concentrated, dissolved in acetonitrile and loaded onto an ion exchange column (pre-wetted with acetonitrile). The column was flushed several times with acetonitrile, then the product was liberated by flushing the column several times with about 1M HCl solution in MeOH/EtOAc (made by adding acetyl chloride to a MeOH/EtOAc mixture). The second filtrate was concentrated to afford 1-(2-chloro-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1,2,3,4-tetrahydroquinoxaline-6-sulfonamide as a purple solid. 1H NMR (400 MHz, DMSO-d6) δ=8.42 (s, 1 H), 7.99 (s, 1 H), 7.80 (d, J=8.1 Hz, 1 H), 7.63 (d, J=8.0 Hz, 1 H), 7.01 (d, J=2.1 Hz, 1 H), 6.80 (dd, J=1.9, 8.3 Hz, 1 H), 6.08 (d, J=8.4 Hz, 1 H), 3.61 (t, J=4.0 Hz, 2 H), 3.40 (t, J=4.4 Hz, 2 H). m/z (ESI) 475.8 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:19]=[O:20])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:21])[CH:3]=1.C([Sn](CCCC)(CCCC)[CH2:27][O:28][CH2:29][O:30][CH3:31])CCC>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:19]([OH:20])[CH2:27][O:28][CH2:29][O:30][CH3:31])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:21])[CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)COCOC
Reactant: O=Cc1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Product: COCOCC(O)c1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carbaldehyde 10f is treated with tributyl-methoxymethoxymethyl-stannane according to the procedure described in Example 42, Step A to yield compound 10l. MS APCI (+) m/z 444, 446 (M+, Br pattern) detected.