Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10](#[N:13])[CH2:11][CH3:12].[O-2].[Ca+2].[OH-].C[N+](C)(C)C>O>[CH3:12][C:11](=[C:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:10]#[N:13]
Reactant: CCC#N
Reactant: CCCCCCC(C)=O
Agent: C[N+](C)(C)C
Agent: [Ca+2]
Agent: [O-2]
Solvent: O
Product: CCCCCCC(C)=C(C)C#N
Temperature: 103 °C

Procedure:
Into a 100 ml. flask, equipped with a magnetic stirrer, thermometer, condensor, and static nitrogen head, was placed 13.6 g. of 2-octanone, 11 g. of propionitrile, 61 g. of calcium oxide and 0.3 g. of 25% tetramethyl ammonium hydroxide in water. The mixture was held at reflux (103° C.) for 16 hours at which time gas chromatographic analysis showed 7% product nitrile relative to starting ketone.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: CSc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CSc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
1-Chloro-4-nitrobenzene (15 g, 95 mmol) and 4-(methylmercapto)phenol (13.3 g, 95 mmol) were dissolved in dimethylsulfoxide (100 mL). Potassium carbonate (15.8 g, 134 mmol) was added thereto, and the mixture was stirred for 12 h at 100° C. After completion of the reaction, excess water was added to precipitate a solid, which was then filtered and dried to give the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2.[OH-].[Na+].CN(C)[CH:20]=[O:21]>O>[Cl:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:20]=[O:21]
Reactant: CN(C)C=O
Reactant: Clc1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1c[nH]c2ccc(Cl)cc12
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 59 %

Procedure:
To stirred dimethylformamide (20 mL) at 0° C. was added dropwise phosphorus oxychloride (4.6 mL, 49 mmol). The mixture was stirred for 10 min and a solution of 5-chloroindole (5.0 g, 33 mmol) in dimethylformamide (5 mL) was added dropwise. The mixture was heated to 40° C. for 45 min, cooled to room temperature and then treated with a solution of sodium hydroxide (5.9 g, 148 mmol) in water (20 mL). The mixture was heated to 50° C. for 10 min, cooled to room temperature, poured onto crushed ice (100 mL) and filtered. The filter cake was recrystallised (methanol) to give the product as a white solid (3.5 g, 59%): mp 215-216° C.; Found: C, 60.13; H, 3.40; N, 7.75%. C9H6ClNO requires: C, 60.19; H, 3.37; N, 7.79%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([F:9])[C:7]=1F.O.Cl.[NH:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:9][C:6]1[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=[C:2]([F:1])[C:7]=1[N:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1
Reactant: O=C1CCNCC1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C1CCN(c2c(F)cc([N+](=O)[O-])cc2F)CC1
Yield: 94 %

Procedure:
To a mixture of 3,4,5-trifluoronitrobenzene (3.894 g, 0.022 mol) and 4-piperidone hydrochloride monohydrate (3.072 g, 0.020 mol) in chloroform (24 ml), was added triethylamine (8.3 ml, 0.06 mol) under stirring. The resulting mixture was heated and stirred at 70° C. for 7 h. After completion of the reaction (TLC), the solvent was evaporated under reduced pressure and the residue diluted with water (10 ml). The separated solid was filtered, washed with water (8 ml) followed by hexane (5 ml) to obtain yellow crystalline solid as a product, 4.8 g, 94% yield M.P.: 130-132° C.; MS: M+1=257 (MH+ 100%) for M.F.: C11H10F2N2O3
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[C:15]([Cl:16])=[CH:14][C:13]([N:17]([C:22]2[C:41]([CH:42]3[CH2:44][CH2:43]3)=[CH:40][C:25]3[C:26]([C:36](=[O:39])[NH:37][CH3:38])=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[O:28][C:24]=3[CH:23]=2)[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[BrH:45]>C(#N)C.CCOC(C)=O.O.[Cu]Br>[Br:45][C:6]1[C:15]([Cl:16])=[CH:14][C:13]([N:17]([C:22]2[C:41]([CH:42]3[CH2:44][CH2:43]3)=[CH:40][C:25]3[C:26]([C:36](=[O:39])[NH:37][CH3:38])=[C:27]([C:29]4[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=4)[O:28][C:24]=3[CH:23]=2)[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(Cl)c(N)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(Cl)c(Br)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Sodium nitrite (0.17 g, 2.42 mmol) was added to a 0° C. solution of methyl 2-amino-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate (1.29 g, 2.20 mmol) in acetonitrile (7.3 ml) and 48% aqueous HBr (7.3 ml) at 0° C. and the reaction mixture was stirred at 0° C. for 30 mins, Copper(I) bromide (0.38 g, 2.64 mmol) was added and the solution was heated at 50° C. for 30 mins. The reaction mixture was cooled to RT, diluted with EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered, evaporated and purified by silica gel chromatography (0-50% EtOAc/hexanes) to afford the title compound (1.24 g, 86%) as a white foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.86-7.93 (m, 2H), 7.50-7.63 (m, 4H), 7.17-7.25 (m, 2H), 5.79 (br. s., 1H), 3.92 (s, 3H), 3.28 (s, 3H), 3.01 (d, J=4.88 Hz, 3H), 1.94-2.04 (m, 1H), 0.76-1.09 (m, 3H), 0.55 (br. s., 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:27])[CH2:22][CH2:21][CH2:20]2.N1C(C)=CC=CC=1C>ClCCl>[O:27]=[C:23]1[CH2:22][CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH:26]=[CH:25][C:24]1=2
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1CCCc2cc(O)ccc21
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Temperature: 0 °C
Yield: 91.8 %

Procedure:
Trifluoromethanesulfonic anhydride (1.7 mL, 10 mmol) was added slowly over 1 hour to a solution of 6-hydroxy-1-tetralone (1.62 g, 10 mmol) and 2,6-lutidine (1.28 mL, 10 mmol) in dry dichloromethane (10 mL) cooled to 0° C. After 1 hour the solution was diluted with dichloromethane (10 mL) and washed with 1 M hydrochloric acid (20 mL). The organic layer was re-extracted with dichloromethane (50 mL) and the combined organics washed with 1 M hydrochloric acid (10 mL). The organics were dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography (Silica gel, CH2Cl2) to provide 2.7 g of compound 2 (93%).
Reaction SMILES: Cl.Cl.Cl.[NH2:4][CH2:5][C@H:6]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)[C:7]([O:9][CH3:10])=[O:8].Cl.[CH3:26][C:27]1[CH:36]=[C:35]([CH2:37][O:38][C:39]2[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=2)[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1>>[F:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:14]2[CH2:13][CH2:12][N:11]([C@@H:6]([CH2:5][NH:4][S:45]([C:42]3[CH:43]=[CH:44][C:39]([O:38][CH2:37][C:35]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]=[C:27]([CH3:26])[CH:36]=4)=[CH:40][CH:41]=3)(=[O:46])=[O:47])[C:7]([O:9][CH3:10])=[O:8])[CH2:16][CH2:15]2)=[CH:23][CH:22]=1
Reactant: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Reactant: COC(=O)[C@H](CN)N1CCN(Cc2ccc(F)cc2)CC1
Agent: Cl
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1)N1CCN(Cc2ccc(F)cc2)CC1
Yield: 44.5 %

Procedure:
In a manner analogous to example 3.6, using 1.5 g (3.7 mmol) of methyl (S)-3-amino-2-[4-(4-fluorobenzyl)piperazin-1-yl]propanoate trihydrochloride and 1.6 g (4.1 mmol) of 4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride hydrochloride (prepared as described in 17.2), 1.0 g (46%) of methyl (S)-2-[4-(4-fluorobenzyl)piperazin-1-yl]-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoate is obtained in the form of a white solid.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:14]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH2:15].C([O-])([O-])=O.[Na+].[Na+].O>C(#N)C>[CH3:19][S:16]([CH2:14][CH2:15][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)(=[O:18])=[O:17]
Reactant: C=CS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(CCS(C)(=O)=O)CC1
Temperature: 25 °C
Yield: 93 %

Procedure:
To a solution of 1,1-dimethylethyl 1-piperazinecarboxylate (72.8 g, 390 mmol) in acetonitrile (1.4 L) was added methyl vinyl sulfone (50 g, 470 mmol) and Na2CO3 (124 g, 1170 mmol) and the mixture was refluxed overnight. Then the mixture was cooled to rt, and poured into H2O and extracted with EtOAc. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure to give the title compound (106 g, 93% yield). 1H NMR (400 MHz, CDCl3) δ ppm 1.41-1.57 (m, 9H), 2.39-2.51 (m, 4H), 2.88 (t, J=8.4 Hz, 2H), 3.02 (s, 3H), 3.14 (t, J=8.4 Hz, 2H), 3.35-3.50 (m, 4H).
Reaction SMILES: [CH2:1]=[O:2].[F:3][CH:4]([C:9]([O:11][CH3:12])=[O:10])[C:5]([O:7][CH3:8])=[O:6]>C(=O)(O)[O-].[K+]>[OH:2][CH2:1][C:4]([F:3])([C:9]([O:11][CH3:12])=[O:10])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(F)C(=O)OC
Reactant: C=O
Agent: O=C([O-])O
Agent: [K+]
Product: COC(=O)C(F)(CO)C(=O)OC
Reaction time: 2 h
Yield: 89.8 %

Procedure:
48 g (0.48 mol) of potassium bicarbonate were dissolved in 535 g (6.59 mol) of aqueous formaldehyde solution (37% strength by weight) in a 4-liter glass flask. 841 g (5.6 mol) of dimethyl α-fluoromalonate were added dropwise to this solution., with stirring, in the course of 31/2 hours; the temperature was kept meanwhile within the range from 20° to 25° C. Stirring was continued for 2 hours at the same temperature, and during this time dimethyl α-hydroxymethyl-α-fluoromalonate was precipitated in the form of a colorless solid. 2,500 g of an aqueous, saturated solution of ammonium sulfate were then added to the reaction mixture, which was then extracted with methylene dichloride. The extraction solution was dried by means of anhydrous sodium sulfate. 906 g (90% of theory) of dimethyl a-hydroxymethyl-α-fluoromalonate were obtained after removing the methylene dichloride by distillation (bath temperature 40° C., 25 mbar).
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9]CC)=[O:8])[N:6]=1.[OH-].[Na+].Cl>C(O)C.O>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1csc(Br)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1csc(Br)n1
Temperature: 35 °C
Reaction time: 0.5 h

Procedure:
Ethyl 2-bromothiazole-4-carboxylate (600 mg, 2.54 mmol) was suspended in ethanol (15 mL). Sodium hydroxide (7.5 mL, 1 M) was added and the reaction mixture was stirred at 35° C. for 0.5 hours. The reaction mixture was acidified to pH ˜3 with 1 M HCl, then diluted with water (100 mL) and extracted with ethyl acetate (2×50 mL). The organic extracts were combined, washed with brine (100 mL), dried (sodium sulfate), filtered and concentrated to provide the title compound. MS (APCI) m/z=208/210 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([OH:7])([CH3:6])[CH2:3][CH2:4][OH:5].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.O>N1C=CC=CC=1>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:5][CH2:4][CH2:3][C:2]([OH:7])([CH3:6])[CH3:1])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CC(C)(O)CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-methylbutane-1,3-diol (2.13 mL, 20 mmol) in pyridine (20 mL) at 0° C. was added para-toluenesulfonyl chloride (3.8 g, 20 mmol) in pyridine (10 mL) drop-wise over 15 minutes. This mixture stirred at ambient temperature for 3 hours and 35 mL H2O was added and the mixture was extracted with ethyl acetate (2×50 mL). The combined organics were washed with H2O (2×50 mL), dried over MgSO4, filtered, concentrated under reduced pressure and dried under vacuum (˜1 mm Hg) to afford the title compound. MS (ESI) m/z 276 (M+18)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:15])[C:6]1[CH:14]=[CH:13][CH:12]=[C:8]([C:9](Cl)=[O:10])[CH:7]=1.[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:5]([C:6]2[CH:14]=[CH:13][CH:12]=[C:8]([C:9](=[O:10])[C:21]3[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=3)[CH:7]=2)=[O:15])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccc(F)cc1)c1cccc(C(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
Anhydrous aluminum chloride (160.0 g, 1.20 mol) was added to a stirred solution of isophthaloyl chloride (101.5 g, 0.50 mol) dissolved in fluorobenzene (480.5 g, 5.0 mol) over a five to ten minute period. The mixture was stirred at room temperature for one hour and then maintained at 70°-80° C. for four hours. After cooling, the reaction mixture was poured onto approximately 2000 g of ice containing 100 mL of concentrated hydrochloric acid. The resulting suspension was separated by decantation and washed several times with water. The organic layer was distilled to remove excess fluorobenzene and the solid residue was collected by filtration, washed with water, and dried at 100° C. The crude solid was recrystallized from approximately 1000 mL of toluene to afford 130.5 g (81% yield) of 1,3-bis(4-fluorobenzoyl)benzene; m.p. 177.5°-178.5° C.; 1H NMR (CDCl3) δ 6.8-8.3 (m, 12H, aromatic). Anal. Calcd. for C20H12F2O2 : C, 74.53%; H, 3.75%; F, 11.79%. Found: C, 74.33%; H, 3.59%; F, 11.42%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])#[N:2].[BH4-].[Na+].[CH2:16]1[CH2:20]OC[CH2:17]1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH:16]([CH3:20])[CH3:17])[C:6]([O:8][CH3:9])=[O:7])#[N:2]
Reactant: C1CCOC1
Reactant: COC(=O)c1ccc(O)c(C#N)c1
Agent: [BH4-]
Agent: [Na+]
Product: COC(=O)c1ccc(OC(C)C)c(C#N)c1
Reaction time: 0.17 h
Yield: 99 %

Procedure:
To a solution of 3 (3.0 g, 10.8 mmol) in THF e H (10 mL/10 mL) was slowly added NaBH4 (407 mg, 10.8 mmol). The mixture was stirred for 10 min, quenched by saturated NH4Cl and partitioned between EtOAc and H2O. The organic layer was washed with sat NaHCO3 and brine, dried over Na2SO4, filtered and concentrated to give 4 (3.0 g, 99%), which was used without further purification. LRMS (M+H+) m/z 281.0.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[CH:19][C:18]([C:21]3[S:22][C:23]4[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:24]=4[N:25]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C.C(Cl)Cl>C(Cl)Cl.C1COCC1>[F:1][C:2]([F:7])([F:6])[C:3]([NH:30][C:28]1[CH:27]=[CH:26][C:24]2[N:25]=[C:21]([C:18]3[CH:19]=[N:20][C:15]([N:12]4[CH2:11][CH2:10][N:9]([CH3:8])[CH2:14][CH2:13]4)=[CH:16][CH:17]=3)[S:22][C:23]=2[CH:29]=1)=[O:4]
Reactant: CN1CCN(c2ccc(-c3nc4ccc(N)cc4s3)cn2)CC1
Reactant: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(c2ccc(-c3nc4ccc(NC(=O)C(F)(F)F)cc4s3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
A mixture of 2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,3-benzothiazol-6-amine trifluoroacetate (0.12 g, 0.27 mmol), ethyl chloroformiate (36 μL, 0.38 mmol) and diisopropylethylamine (0.238 mL, 1.44 mmol) in DCM/THF (1:1, 7 mL) was stirred at r.t. overnight. Additional DCM was added before washing the sol. with sat. sodium hydrogencarbonate and then brine. The sol. was then dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by prep. HPLC, to give intermediate 2,2,2-trifluoro-N-{2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]-1,3-benzothiazol-6-yl}acetamide (43 mg). MS m/z (M+H) 422, (M−H) 420. To this intermediate (43 mg) in THF (5 mL) was added lithium aluminium hydride (12 mg, 0.3 mmol). The r.m. was refluxed for 1.5 h then allowed to come to r.t. Two drops of sat. Na2SO4, followed by ethyl acetate was added and the mixture was stirred for a few minutes. The organic layer was washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by prep. HPLC to yield the title compound (25 mg) as a pale yellow solid. 1H NMR (MeOH-D4) δ 8.59 (d, 1H) 7.97 (dd, 1 H) 7.60 (d, 1 H) 7.11 (d, 1 H) 6.75-6.87 (m, 2 H) 3.80 (q, 2 H) 3.55-3.70 (m, 4 H) 2.50-2.61 (m, 4 H) 2.33 (s, 3 H); MS m/z (M+H) 408, (M−H) 406.
Reaction SMILES: [CH3:1][N:2]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1)[C:3](=[O:19])[CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:16])([CH3:15])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1>[OH-].[Na+]>[CH3:1][N:2]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=1)[C:3](=[O:19])[CH2:4][C:5]1[CH:14]=[CH:13][C:12]2[C:11]([CH3:15])([CH3:16])[CH2:10][CH2:9][C:8]([CH3:18])([CH3:17])[C:7]=2[CH:6]=1
Reactant: COC(=O)c1ccc(N(C)C(=O)Cc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: CN(C(=O)Cc1ccc2c(c1)C(C)(C)CCC2(C)C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.8 g (4.6 mmol) of the ester obtained above in (a), 100 ml of 2N methanolic sodium hydroxide and 50 ml of TMF are introduced into a round-bottomed flask. The mixture is stirred at room temperature for one hour and evaporated to dryness, the residue is taken up with water, the mixture is extracted with ethyl ether and the aqueous phase is separated after settling has taken place. The aqueous phase is acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated. 1.6 g (94%) of the expected acid, having a melting point of 192°-193° C., are collected.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Yield: 97.7 %

Procedure:
4-Fluoro-2-methyl-1-nitrobenzene (2 g), piperazine-1-carboxylic acid tert-butyl ester (4.8 g), potassium carbonate (3.57 g) and dimethyl sulfoxide (20 ml) were heated together at 80° C. under nitrogen for 15 hours. The mixture was then cooled, diluted with ethyl acetate (200 ml), washed with 2M aqueous hydrochloric acid (200 ml), dried (MgSO4), and concentrated to give the sub-title compound (4.05 g).
Reaction SMILES: Br[CH:2]([C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=1)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:18][C:19]([NH2:21])=[S:20].C(OCC)C>O1CCCC1>[NH2:21][C:19]1[S:20][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[N:17])[CH:11]=2)[N:18]=1
Reactant: CCOC(=O)C(Br)C(=O)c1cccc(C#N)c1
Reactant: NC(N)=S
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1sc(N)nc1-c1cccc(C#N)c1
Temperature: 65 °C
Reaction time: 16 h
Yield: 102.7 %

Procedure:
To a solution of ethyl 2-bromo-3-(3-cyanophenyl)-3-oxopropionate (4.0 g, 13.5 mmol) in 100 mL of tetrahydrofuran was added thiourea (1.03 g, 13.5 mmol). The resulting mixture was stirred at 65° C. for 16 h. The reaction was allowed to cool and the solvent was evaporated in vacuo. The residue was triturated with ether, taken up in ethyl acetate, washed with saturated aq Na2CO3 and brine, dried (MgSO4) and concentrated in vacuo to yield a solid. Trituration with ethyl ether left the title compound as an off-white solid (3.79 g, 98%).
Reaction SMILES: [S-:1][C:2]#[N:3].[CH3:4][N:5]([C+:7]([N:9]([CH3:11])[CH3:10])Cl)[CH3:6].[CH3:12][N-:13][CH3:14].[Li+]>C(#N)C>[S-:1][C:2]#[N:3].[CH3:4][N:5]([CH3:6])[C:7](=[N+:13]([CH3:14])[CH3:12])[N:9]([CH3:11])[CH3:10]
Reactant: C[N-]C
Reactant: CN(C)[C+](Cl)N(C)C
Agent: N#C[S-]
Agent: [Li+]
Solvent: CC#N
Product: CN(C)C(N(C)C)=[N+](C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.9 %

Procedure:
1.00 g (5.16 mmol) of bis(dimethylamino)chlorocarbenium thiocyanate and 0.26 g (5.10 mmol) of lithium dimethylamide are dissolved in 10 ml of acetonitrile under a protective-gas atmosphere (argon). The reaction mixture is stirred for 5 hours at room temperature, and LiCl is subsequently filtered off. The salt LiCl is washed with 2 ml of acetonitrile, and the organic phases are combined. The solvent is distilled off, and the residue is dried under reduced pressure at 7 Pa and 50° C., giving 0.99 g of hexamethylguanidinium thiocyanate as an oil, corresponding to a yield of 94.8%.
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[N:15][C:16]([C:20]4[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][N:21]=4)=[CH:17][CH:18]=3)[N:13]=[C:12]([CH2:30][O:31][CH3:32])[C:11]=2[C:33]([O:35]C)=[O:34])=[CH:5][CH:4]=1.O[Li].O.C1COCC1.O>C(O)(=O)C>[F:38][C:2]([F:1])([F:37])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[N:15][C:16]([C:20]4[C:25]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:23]=[CH:22][N:21]=4)=[CH:17][CH:18]=3)[N:13]=[C:12]([CH2:30][O:31][CH3:32])[C:11]=2[C:33]([OH:35])=[O:34])=[CH:5][CH:4]=1
Reactant: COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(Nc2ccc(C(F)(F)F)cc2)c1C(=O)OC
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(Nc2ccc(C(F)(F)F)cc2)c1C(=O)O

Procedure:
Stir a solution of methyl 4-[(4-trifluoromethylphenyl)amino]-7-(3-trifluoromethylpyridin-2-yl)-2-methoxymethyl-[1,8]naphthyridine-3-carboxylate (114 mg, 0.212 mmol), LiOH.H2O (45.0 mg, 1.06 mmol), THF (2 mL) and water (0.1 mL) for 18 hours at room temperature. Add water (20 mL) and acidify with acetic acid. Extract the solution with EtOAc (3×25 mL). Wash the combined organic extracts with brine and dry over Na2SO4. Remove the solvent under reduced pressure to yield the title compound. MS 523.18 (M+1). 1H NMR δ (CDCl3) 11.50 (1H, br s), 8.89 (1H, s), 8.19 (2H, d), 7.88 (1H, dd), 7.67 (2H, m), 7.59 (1H, dd), 7.51 (2H, d), 7.22 (1H, br s), 5.30 (2H, s), 3.65 (3H, s).
Reaction SMILES: N([O-])=[O:2].[Na+].[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](N)=[O:11])#[N:6]>S(=O)(=O)(O)O>[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:2])=[O:11])#[N:6]
Reactant: O=N[O-]
Reactant: N#Cc1cccc(C(N)=O)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N#Cc1cccc(C(=O)O)c1
Yield: 91.2 %

Procedure:
Sodium nitrite (2.07 g) was dissolved in a 70 wt. % aqueous sulfuric acid solution (100 ml), and m-cyanobenzamide (2.92 g) was added to the resultant solution. The mixture was allowed to react at 40° C. for one hour with stirring. The precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 2.68 g of m-cyanobenzoic acid (yield 92%). The m-cyanobenzoic acid obtained had a purity of 99% or more.