Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(CC)CC.[CH3:37][N:38]=[C:39]=[S:40].O>C(#N)C>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:39](=[S:40])[NH:38][CH3:37])[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN=C=S
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CNC(=S)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 101.5 %

Procedure:
To a solution of the compound (0.20 g) obtained in Example 1 and Et3N (0.16 ml) in acetonitrile (10 ml), methyl isothiocyanate (0.083 g) was added, and the reaction mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous 10% citric acid solution and saturated brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was isolated and purified by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain the title compound as colorless oil (0.22 g, 99%).
Reaction SMILES: [CH2:1]([C:7]1[CH:16]=[CH:15][C:14]2[C:13]([CH3:18])([CH3:17])[CH2:12][CH2:11][C:10]([CH3:20])([CH3:19])[C:9]=2[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Br:21]Br>C(Cl)(Cl)(Cl)Cl.[Fe]>[Br:21][C:16]1[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:8][C:9]2[C:10]([CH3:19])([CH3:20])[CH2:11][CH2:12][C:13]([CH3:18])([CH3:17])[C:14]=2[CH:15]=1
Reactant: CCCCCCc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: BrBr
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCc1cc2c(cc1Br)C(C)(C)CCC2(C)C
Temperature: 0 °C
Reaction time: 4 h
Yield: 89.7 %

Procedure:
A solution of 2-hexyl-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalene (from Example 2.1, 12.1 g) in 80 ml of carbon tetrachloride, containing 327 mg of pulverised iron powder, was cooled to 0° C. and treated dropwise with a solution of 7.84 g of Br2 in 8 ml of carbon tetrachloride. The mixture was stirred at 0° C. for 4 hours. The reaction mixture was filtered and then poured into 200 ml ice/water. Extraction of the biphasic mixture with 3 portions of 100 ml of methylene chloride was followed by a washing of the combined organic extracts with 100 ml of saturated aqueous sodium bicarbonate solution and 100 ml water. The organic phase was dried over MgSO4 and concentrated in vacuo, giving a yellow oil. The crude product was distilled under vacuum, yielding 14 g of a pale yellow oil. B.p. 148° C. at 0.09 bar.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([F:11])[C:4]([F:10])([F:9])[S:5]([O-:8])(=[O:7])=[O:6].C([O:18][C:19]1[CH:24]=[CH:23][C:22]([S+:25]([C:37]2[CH:42]=[CH:41][C:40]([O:43]CCCC)=[CH:39][CH:38]=2)[C:26]2[CH:31]=[CH:30][C:29]([O:32]CCCC)=[CH:28][CH:27]=2)=[CH:21][CH:20]=1)CCC.FC(F)(F)C(F)C(F)(F)S(O)(=O)=O>C(O)C>[F:13][C:2]([F:1])([F:12])[CH:3]([F:11])[C:4]([F:9])([F:10])[S:5]([O-:8])(=[O:6])=[O:7].[OH:18][C:19]1[CH:24]=[CH:23][C:22]([S+:25]([C:37]2[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=2)[C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[CH:21][CH:20]=1
Reactant: CCCCOc1ccc([S+](c2ccc(OCCCC)cc2)c2ccc(OCCCC)cc2)cc1
Agent: O=S(=O)(O)C(F)(F)C(F)C(F)(F)F
Agent: O=S(=O)([O-])C(F)(F)C(F)C(F)(F)F
Solvent: CCO
Product: Oc1ccc([S+](c2ccc(O)cc2)c2ccc(O)cc2)cc1
Yield: 100 %

Procedure:
A solution of 56.8 g (0.08 mol) of tris-(4-butoxyphenyl) sulfonium 3,3,3,2,1,1-hexafluoropropane sulfonate and 1.86 g (0.008 mol) of 3,3,3,2,1,1-hexafluoropropane sulfonic acid in 200 ml of ethanol was refluxed for 8 hours with stirring. After evaporation of the solvent, the obtained crude product of tris-(4-hydroxyphenyl) sulfonium 3,3,3,2,1,1-hexafluoropropane sulfonate (yield about 100%) was dissolved in 160 g of N,N-dimethylformamide and reacted with 55.4 g (0.40 mol) of anhydrous potassium carbonate and 60.3 g (0.40 mol) of t-butyl chloroacetate at 80° C. for 3 hours. The cooled reaction mixture was poured into 700 ml of water and extracted with dichloromethane. The organic phase was washed with water and dried. The solvent was removed. The oily residue was purified by column chromatography on silica gel using a dichloromethane and methanol as the eluent. The white product was collected to yield 31.8 g (yield 45%) of analytically pure tris-(4-t-butoxycarbonylmethoxyphenyl) sulfonium 3,3,3,2,1,1-hexafluoropropane sulfonate. The melting point of the product was 78° C. The 1H-NMR spectrum gave the following signals (CDCl3): δ=1.45 (s, 27H), 4.56 (s, 6H), 5.20-5.56 (d[m], 1H), 7.10-7.13 (d, 6H), 7.55-7.60 (d, 6H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][C@H:10]([OH:12])[C@@H:9]([NH:13][C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:12][C@H:10]1[CH2:11][N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8][C@@H:9]1[NH:13][C:14](=[O:29])[CH2:15][NH:16][C:17](=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CN(C2CCCCC2)C[C@@H]1O
Reactant: BrCc1ccccc1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@H]1CN(C2CCCCC2)C[C@@H]1OCc1ccccc1

Procedure:
The title compound was prepared by alkylation of compound of Example 1 with benzyl bromide following the procedure described in Example 2. MS calculated (M+H)+ 504. found 504.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[C:3]=1[CH2:14]O.[Br:16]P(Br)Br>ClCCl>[Br:16][CH2:14][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:8][N:9]([CH2:12][CH3:13])[CH2:10][CH3:11]
Reactant: CCN(CC)Cc1cccc(Cl)c1CO
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: CCN(CC)Cc1cccc(Cl)c1CBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To {2-chloro-6-[(diethylamino)methyl]phenyl}methanol (3.0 g, 13.2 mmol) in anhydrous dichloromethane (80 mL) was added dropwise tribromophosphane (2.5 mL, 26.4 mmol). The mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was dried in vacuo, affording {[2-(bromomethyl)-3-chlorophenyl]methyl}diethylamine. The product was used without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:21])=[C:4]([CH3:20])[C:5]2[O:10][C:9]([CH3:17])([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH2:8][C:7](=[O:18])[C:6]=2[CH:19]=1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].N1C=CN=C1.O>CN(C=O)C>[CH3:26][C:25]([Si:22]([CH3:24])([CH3:23])[O:1][C:2]1[C:3]([CH3:21])=[C:4]([CH3:20])[C:5]2[O:10][C:9]([CH3:17])([CH2:11][CH2:12][CH:13]=[C:14]([CH3:15])[CH3:16])[CH2:8][C:7](=[O:18])[C:6]=2[CH:19]=1)([CH3:28])[CH3:27]
Reactant: CC(C)=CCCC1(C)CC(=O)c2cc(O)c(C)c(C)c2O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCCC1(C)CC(=O)c2cc(O[Si](C)(C)C(C)(C)C)c(C)c(C)c2O1
Reaction time: 18 h
Yield: 71.7 %

Procedure:
A mixture of 2,3-dihydro-6-hydroxy-2,7,8-trimethyl-2-(4-methylpent-3-enyl )-4H-1-benzopyran-4-one (9.4 q, 34.3 mmole), tert-butyldimethylsilyl chloride (7.75 g, 51.5 mmole), and imidazole (6.99 g, 0.1 mole) were dissolved in 50 mL of dry DMF. The solution was stirred under nitrogen for about 18 hours, poured into water and extracted with ether. The organic layers were dried (brine, MgSO4) and concentrated in vacuo. The crude material was purified by flash chromatography (gradient 20:1 to 10:1 hexanes:ether) to give the title compound as a colorless oil (9.9 g, 24.6 mmole, 72%): 1H NMR (CDCl3) δ 0.20 (s, 6H), 1.0 (s, 9H), 1.37 (s, 3H), 1.55 (s, 3H), 1.55-1.60 (m, 1H), 1.65 (s, 3H), 1.74-1.84 (m, 1H), 2.0-2.1 (m, 2H), 2.14 (s, 3H), 2.16 (s, 3H), 2.63 (ABq, J=16.5 Hz, 2H), 5.07 (t, J=7.0 Hz, 1H), 7.09 (s, 1H); MS m/e 403 (MH+).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH2:13]([CH2:15][NH2:16])[OH:14].C(N(CC)C(C)C)(C)C>O1CCCC1>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:16][CH2:15][CH2:13][OH:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=S(=O)(NCCO)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-(Bromomethyl)benzenesulfonyl chloride (5.0 g, 18.6 mmol) was dissolved in tetrahydrofuran. Ethanolamine (1.1 mL, 18.6 mmol) and N,N-diisopropylethylamine (3.9 mL, 22.3 mmol) were added, and the reaction was allowed to stir at ambient temperature for 30 minutes. The reaction was concentrated to an oil that was partitioned between water and ethyl acetate and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over Na2SO4, and filtered. The resulting filtrate was concentrated to an oil that was a mixture of the title compound and 4-chloromethyl N-(2-hydroxyethyl)benzenesulfonamide. The resulting oil was dried in vacuo (3.7 g, 68%). ES-MS m/z 250 (M+H) and 294 (M+H).
Reaction SMILES: [CH2:1]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]3[CH:18]=[CH:19][C:20]([NH:22][C:14]=3[CH:13]=2)=[O:21])[CH2:5][CH2:4][N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[Cl:30])[CH2:2]1.C(N(CC)CC)C.[CH2:38]([N:40]([CH2:44][CH3:45])[C:41](Cl)=[O:42])[CH3:39]>O1CCCC1>[CH2:38]([N:40]([CH2:44][CH3:45])[C:41](=[O:42])[O:21][C:20]1[CH:19]=[CH:18][C:15]2[C:14](=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]3[CH2:5][CH2:4][N:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=4[Cl:30])[CH2:2][CH2:1]3)=[CH:17][CH:16]=2)[N:22]=1)[CH3:39]
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Reactant: CCN(CC)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)Oc1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2n1
Temperature: 100 °C

Procedure:
A mixture of dehydro-aripiprazole (1.50 g, 3.36 mmol), triethylamine (1.03 mL, 7.39 mmol), diethyl carbamoyl chloride (1.02 mL) were combined in tetrahydrofuran (30 mL). This was then heated to 100° C. for 6 hours by microwave. The reaction was quenched with water (50 mL) and extracted with dichloromethane (2×100 mL). The combined organics were dried (MgSO4) and concentrated. The crude product was purified by column chromatrography on silica eluting with ethyl acetate to 20% tetrahydrofuran/ethyl acetate to give the product. The product was then triturated with heptane to remove aliphatic impurities and then dried to give Compound-334 (1.54 g) as a light brown oil.
Reaction SMILES: COC1[CH:11]=[C:10]2[C:6](CNC2)=[CH:5][C:4]=1[OH:12].[CH3:13][O:14][C:15](=[O:27])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1.[Na].BrCCCC[CH2:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])(C)[CH3:36]>O1CCCC1.C(OCC)C.O>[CH3:13][O:14][C:15](=[O:27])[CH:16]([CH2:11][CH2:10][CH2:6][CH2:5][CH2:4][O:12][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:36])[CH3:34])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1
Reactant: COC(=O)Cc1ccc(OC)c(OC)c1
Reactant: COc1cc2c(cc1O)CNC2
Reactant: CC(C)(C)[Si](C)(C)CCCCCBr
Agent: [Na]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(CCCCCO[Si](C)(C)C(C)(C)C)c1ccc(OC)c(OC)c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution, -78° C. under argon, of 2 38 g of 3,4-dimethoxyphenyl acetic acid methyl ester in 30 ml of tetrahydrofuran is added 12.45 ml of 1.0M sodium hexamethylsidilazide. The solution is stirred at -78° C. for 5 minutes and then warmed to 0° C. for 1 hour. To this solution is added 3.5 g of (5-bromopentyl)(1,1-dimethylethyl)dimethyl silane. The reaction mixture is allowed to warm to room temperature and stirred for 12 hours. The mixture is diluted with diethyl ether and water, the layers are separated and the organic layer is washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel: hexane/ethyl acetate,5/1) to give 2.6 g of the desired product as a clear oil.
Reaction SMILES: CN([CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([F:14])[CH:12]=2)[NH:7][CH:6]=1)C.[C-:15]#[N:16].[K+].CI>CO.O>[F:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:4][C:15]#[N:16]
Reactant: [C-]#N
Reactant: CN(C)Cc1c[nH]c2ccc(F)cc12
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CO
Product: N#CCc1c[nH]c2ccc(F)cc12
Temperature: 20 °C

Procedure:
A mixture of 38 g of 3-dimethylaminomethyl-5-fluoroindole (0.198 mole; cf. Hoffman et al. J. Heterocyclic Chem. 2, 298 [1965]; of the 5-fluorogramine therein) in 500 ml of methanol was prepared. Then a solution of 25.7 g of KCN (0.396 mole) in 50 ml of water was added, with stirring. The stirred mixture was cooled to 20° C. and 34.6 ml of methyl iodide (0.556 mole) was added over a 20 minute period. The mixture was then stirred about 20° C. for 16 hours. The solvent was removed by evaporation and the residue was partitioned between ether and water. The ether portion was washed with water, 5% HCl, saturated NaHCO3 solution, water, and brine, dried over MgSO4 and evaporated to leave a liquid residue. This residue was distilled at reduced pressure in a Kugelrohr apparatus. The fraction distilling at 134°-140° C. and 0.3 to 0.1 Torr was collected and crystallized from ethyl acetate-petroleum ether, mp. 58°-59°, yield 5.3 g (44% theory).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:17]3[C:16]([CH3:18])=[N:15][NH:14][C:13]=3[C:12](=[O:19])[N:11]2[C:20]2[CH:21]=[C:22]([CH3:30])[C:23]3[N:24]([C:26]([CH3:29])=[N:27][N:28]=3)[CH:25]=2)=[CH:6][CH:5]=1.I[CH2:32][CH3:33]>CN(C=O)C.CCOCC>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:17]3[C:13](=[N:14][N:15]([CH2:32][CH3:33])[C:16]=3[CH3:18])[C:12](=[O:19])[N:11]2[C:20]2[CH:21]=[C:22]([CH3:30])[C:23]3[N:24]([C:26]([CH3:29])=[N:27][N:28]=3)[CH:25]=2)=[CH:6][CH:5]=1
Reactant: CCI
Reactant: Cc1n[nH]c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCn1nc2c(c1C)C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
NaH (21.18 mg, 0.529 mmol) was added to a stirred solution of 4-(4-chlorophenyl)-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 98) (160 mg, 0.407 mmol) in DMF (4 mL) at 0° C. and the resulting mixture was stirred at 0° C. for 30 min. Iodoethane (0.039 mL, 0.489 mmol) was added and the reaction mixture was stirred at RT for 30 min. The reaction was quenched with water, diluted with EtOAc and both phases were separated. The aq. layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by preparative achiral SFC (column NH2, gradient 19-24% in 6 min, total 11 min) to afford, after trituration in Et2O, 31 mg, 0.074 mmol, 18% yield) as white solid. tR: 0.88 min (LC-MS 2); ESI-MS: 421 [M+H]+ (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (t, J=7.2 Hz, 3H) 2.13 (s, 3H) 2.46 (s, 3H) 2.63 (s, 3H) 4.20 (q, J=7.2 Hz, 2H) 6.49 (s, 1H) 7.33-7.40 (m, 5H) 8.46 (s, 1H).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([O:18][CH3:19])=[N:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([F:17])[CH:10]=2)=[O:5])C.C[Al](C)C.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.CCOC(C)=O.CCCCCC>C1(C)C=CC=CC=1>[F:17][C:11]1[CH:10]=[C:9]2[C:14]([C:15]([CH3:16])=[C:6]([C:4]([NH:30][CH2:29][C:28]3[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=3)=[O:5])[C:7]([O:18][CH3:19])=[N:8]2)=[CH:13][CH:12]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1c(OC)nc2cc(F)ccc2c1C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1nc2cc(F)ccc2c(C)c1C(=O)NCc1ccc(F)cc1
Temperature: 110 °C
Yield: 30.9 %

Procedure:
To a stirred solution of 400 mg (1.52 mmol) 7-fluoro-2-methoxy-4-methylquinoline-3-carboxylic acid ethyl ester in toluene (10 ml) were added 3.04 ml (2M solution in toluene, 6.1 mmol) Me3Al at RT followed by the addition of 700 μl (6.1 mmol) 4-fluorobenzylamine. The reaction mixture was heated at 110° C. for 16 h. Then the reaction was quenched with water (10 ml) and extracted with EtOAc (3×20 ml). The combined organic layers were washed with water (20 ml), brine (20 ml), dried over Na2SO4 and concentrated in vacuum. After CC (EtOAc/hexane 1:4) of the residue, 160 mg (0.47 mmol, 31%) 7-fluoro-N-[(4-fluorophenyl)-methyl]-2-methoxy-4-methyl-quinoline-3-carboxylic acid amide (example 46) were obtained. MS: m/z 343.1 [M+H]+.
Reaction SMILES: [ClH:1].Cl.Cl.N1C=C(CN2C3C=CC(C4C=NC=CC=4)=CC=3CN(C(=O)C(F)(F)F)C(CC3C=CC=CC=3)C2)N=[CH:5]1.CCN(C(C)C)C(C)C.S(Cl)(Cl)(=O)=O.C([C:56]1[CH:57]=[CH:58][C:59]2[N:65](CC3N=CN(C(OC(C)(C)C)=O)C=3)[CH2:64][C@@H:63]([CH2:79][C:80]3[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=3)[N:62]([S:86]([CH3:89])(=[O:88])=[O:87])[CH2:61][C:60]=2[CH:90]=1)#N>C(Cl)Cl>[Cl:1][C:56]1[CH:57]=[CH:58][C:59]2[NH:65][CH2:64][C@@H:63]([CH2:79][C:80]3[CH:81]=[CH:82][CH:83]=[CH:84][CH:85]=3)[N:62]([S:86]([CH:89]=[CH2:5])(=[O:88])=[O:87])[CH2:61][C:60]=2[CH:90]=1
Reactant: CC(C)(C)OC(=O)n1cnc(CN2C[C@@H](Cc3ccccc3)N(S(C)(=O)=O)Cc3cc(C#N)ccc32)c1
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Reactant: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: C=CS(=O)(=O)N1Cc2cc(Cl)ccc2NC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4.4g (16.1 mmol) of Compound B of Example 347 in 75 ml of methylene chloride, at -78° C. and under argon, was added dropwise approximately one-half of a solution of 2.5 ml (24.2 mmol) of 2-chlorosulfonyl chloride in 15 ml of methylene chloride. Then was added rapidly dropwise 5 ml of DIPEA, followed by the remaining sulfonyl chloride solution and an additional 2.4 ml of DIPEA (total 7.4 ml, 40.3 mmol). The resulting pale yellow solution was stirred at -78° C. for 0.5 hr, allowed to warm to rt and reduced to one-half volume. The solution of crude Compound A was used directly.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:44])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([NH2:43])[N:37]=2)[CH:31]=1)=O)(C)(C)C>>[NH2:43][C:38]1[N:37]=[C:36]([C:32]2[CH:31]=[C:30]([C:28]3[CH2:27][C:26](=[O:44])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[CH:41]=[C:40]([CH3:42])[N:39]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)nc(N)n1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)nc(N)n1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (145 mg, 0.5 mmol) and 3-[3-(2-amino-6-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K45) (180 mg, 0.55 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (64 mg).
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[N+:13]([C:16]1[CH:17]=[CH:18][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:20][CH:21]=1)([O-:15])=[O:14]>CN(C=O)C.C(O)C.CO>[CH2:9]([O:8][C:7]1[C:6](=[O:11])[C:5](=[O:12])[C:4]=1[N:25]1[CH2:26][CH2:27][N:22]([C:19]2[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:21][N:20]=2)[CH2:23][CH2:24]1)[CH3:10]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)nc1
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOc1c(N2CCN(c3ccc([N+](=O)[O-])cn3)CC2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.7 %

Procedure:
To 3,4-diethoxycyclobut-3-ene-1,2-dione (1.20 mL, 8.10 mmol) in anhydrous DMF (10.0 mL) at room temperature was added a solution of 1-(5-nitropyridin-2-yl)piperazine (B-8) (1.926 g, 9.26 mmol) in anhydrous DMF (14.0 mL). The reaction mixture was stirred at room temperature for 3 h, and then diluted with absolute ethanol (40 mL) and methanol (30 mL). The yellow precipitate formed was filtered and washed with methanol (25 mL). The alcoholic filtrate was discarded, and the solid residue was dissolved in methylene chloride. The solution obtained was concentrated to give 3-ethoxy-4-(4-(5-nitropyridin-2-yl)piperazin-1-yl)cyclobut-3-ene-1,2-dione (C-9) as a yellow solid (1.93 g, 72% yield). MS (M+1): m/e 333. Nota: The presence of 1 equivalent 2-fluoroaniline or 2,6-dichloroaniline in the reaction mixture does not affect the course of the reaction in those conditions.
Reaction SMILES: [F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([CH:6]=[C:7](F)[CH:8]=1)[NH2:5].[C:13]([O-:16])([O-])=O.[Cs+].[Cs+].[OH:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.O>CS(C)=O>[F:1][C:2]1[C:3]([N+:10]([O-:12])=[O:11])=[C:4]([NH:5][CH:13]=[O:16])[CH:6]=[C:7]([O:19][C:20]2[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=2)[CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(O)cc1
Reactant: Nc1cc(F)cc(F)c1[N+](=O)[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=CNc1cc(Oc2ccc(C=O)cc2)cc(F)c1[N+](=O)[O-]
Yield: 37.8 %

Procedure:
A solution of the 3,5-difluoro-2-nitroaniline (0.348 g, 2.0 mmol), Cs2CO3 (1.63 g, 5 mmol), and 4-hydroxybenzaldehyde (0.268 g, 2.2 mmol) in dimethylsulfoxide (2 mL) was heated to 80 degrees Centigrade for 1 hour and then cooled. Water was added and the organics extracted using ethyl acetate (2×50 mL). The combined organics were then washed once in brine and dried (Na2SO4), filtered and concentrated. Chromatography on silica gel (gradient of 20%-60% ethyl acetate/hexanes) eluted the product and the fractions were concentrated. The residue was refluxed in 96% formic acid (4 mL) until the reaction was complete conversion of the aniline was observed by TLC (−1.5 h) and then cooled and poured onto ice-water. The organics were extracted with ethyl acetate (2×25 mL) and the combined organics washed once in water, once in brine, dried (Na2SO4), filtered and concentrated to give 0.230 g of the {3-fluoro-5-[(4-formylphenyl)oxy]-2-nitrophenyl}formamide as a solid.