Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[CH:23][N:24]([CH2:26][CH2:27][C:28](=[O:30])[CH3:29])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:31][Mg]Br.[NH4+].[Cl-]>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[CH:23][N:24]([CH2:26][CH2:27][C:28]([OH:30])([CH3:31])[CH3:29])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[Mg]Br
Reactant: CC(=O)CCn1cnc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn(CCC(C)(C)O)cn1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-1-(3-oxobutyl)-1H-imidazole-4-carboxamide (100 mg, 1.18 mmol) in dry THF (3 ml) was added to 3.0 M methylmagnesium bromide solution in ether (0.39 ml) at 30-40° C. Thereafter the reaction mixture was stirred at 45° C. for 3 h. The cooled reaction mixture was poured into saturated NH4Cl solution. Solvents were evaporated and the product was extracted into ethyl acetate. The combined organic layers were washed with water, dried and concentrated. The crude product was purified by flash chromatography on silica gel by using EtOAc-MeOH (9:1) as an eluent. The final purification was made by preparative HPLC to obtain the title compound. 1H NMR (400 MHz, CDCl3): 1.22 (3H, d), 1.30 (6H, s), 1.97 (2H, m), 4.14 (2H, m), 4.28 (1H, distorted dd), 4.41 (1H, distorted dd), 4.56 (1H, m), 6.60 (1H, d), 7.48 (2H, m), 7.56 (1H, d), 7.61 (1H, distorted d), 7.79 (1H, distorted dd), 7.86 (1H, d), 8.17 (1H, d).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[N:10]([O-])=O.[Na+]>S(=O)(=O)(O)O>[N:1]1[C:2]2[S:3][CH:4]=[CH:5][C:6]=2[C:7](=[O:8])[NH:9][N:10]=1
Reactant: O=N[O-]
Reactant: NC(=O)c1ccsc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=c1[nH]nnc2sccc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 18.5 %

Procedure:
To an ice cold solution (0° C.) of 2-aminothiophene-3-carboxamide (5 g, 35.21 mmol) in concentrated sulfuric acid (40 mL) was added a cold (0° C.) solution of sodium nitrite (2.5 g, 35.21 mmol) in concentrated sulfuric acid (30 mL) for 30 min (while adding, the temperature should keep between −5-0° C.). After addition, the mixture was stirred at the same temperature (0° C.) for 3 h. The mixture was poured into crushed ice slowly with stirring for 15 min and stirred at the same temperature for 15 min. The solution was extracted with ethyl acetate (4×200 mL) and the combined EtOAc layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using chloroform-methanol (95:5) as eluents to give the product as a pale red color solid (1.0 g, 18%), mp 175-176° C. 1H NMR (400 MHz, DMSO-d6): δ 15.18 (1H, s), 8.16 (1H, d, J=5.6 Hz), 7.64 (1H, d, J=5.6 Hz); 13C NMR (100 MHz, DMSO-d6): δ 159.1, 153.8, 132.0, 126.1, 121.2; LC-MS (negative ion mode): m/z 152 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=1)=O.C(#N)C.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>C(OC)(C)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][C:3]=1[CH2:9][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=1
Reactant: CCOc1ccc(C(=O)c2cc(I)ccc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CC#N
Product: CCOc1ccc(Cc2cc(I)ccc2Cl)cc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A jacketed 1 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged with crude (2-chloro-5-iodophenyl)(4-ethoxyphenyl)methanone (30.13 g, 77.93 mmol), acetonitrile (300 mL, KF=0.004 wt % water) and the suspension was set stirring under nitrogen and was cooled to about 5° C. Then triethylsilane (28 mL, 175.30 mmol, 2.25 equiv) was added followed by boron trifluoride-diethyletherate (24 mL, 194.46 mmol, 2.50 equiv) which was added over about 30 seconds. The reaction was warmed to ambient over 30 min and was stirred for 17 hours. The reaction was diluted with methyl tert-butyl ether (150 mL) followed by saturated aq sodium bicarbonate (150 mL) which was added over about 1 minutes. Mild gas evolution was noticed and the biphasic solution was stirred at ambient for 45 minutes. The upper organic phase was washed with saturated aq. sodium bicarbonate (100 mL), and with saturated aq. sodium chloride (50 mL). The washed extract was concentrated on a rotary evaporator to about one half of its original volume and was diluted with water (70 mL). Further concentration in vacuo at 45° C. was done until white prills formed which were allowed to cool to ambient while stirring. After about 30 minutes at ambient, the suspended solids were isolated by filtration, washed with water (30 mL), and were dried in vacuo at 45° C. After about 2.5 hours, this afforded 1-chloro-2-(4-ethoxybenzyl)-4-iodobenzene as a slightly waxy white granular powder (28.28 g, 98.2 area % by HPLC at 220 nm, 97.4% “as-is” yield).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([O:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[C:13]([N+:26]([O-:28])=[O:27])[CH:12]=[CH:11][C:10]=1[CH:29](C(OC(C)(C)C)=O)[C:30]([O:32]C(C)(C)C)=[O:31]>ClCCl.C(OCC)(=O)C.O>[F:8][C:9]1[C:14]([O:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)=[C:13]([N+:26]([O-:28])=[O:27])[CH:12]=[CH:11][C:10]=1[CH2:29][C:30]([OH:32])=[O:31]
Reactant: CC(C)(C)OC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(Oc2cccc3ccccc23)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(O)Cc1ccc([N+](=O)[O-])c(Oc2cccc3ccccc23)c1F
Temperature: 45 °C
Yield: 100 %

Procedure:
Trifluoroacetic acid (30 mL, 389 mmol) was added to a solution of bis(1,1-dimethylethyl) [2-fluoro-3-(1-naphthalenyloxy)-4-nitrophenyl]propanedioate (22.89, g, 46 mmol) in dichloromethane (250 mL). the mixture was heated under a reflux condenser at 45° C. for 4 hrs. The reaction mixture was cooled to room temperature and diluted with ethyl acetate and water. The organic layer was dried over sodium sulfate and concentrated to give the title compound (15.70 g, 100%). 1H NMR (400 MHz, chloroform-d) δ ppm 8.91 (br. s., 1H), 8.30-8.44 (m, 1H), 7.82-7.91 (m, 2 H), 7.51-7.62 (m, 3H), 7.21-7.35 (m, 2H), 6.58 (d, 1H), 3.82 (d, 2H). ES MS: m/z 340 (M−1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([F:8])[CH:3]=1.[Br-].[S:10]1[CH:14]=[CH:13][N:12]=[C:11]1[Zn+].C1COCC1>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:8][C:4]1[CH:3]=[C:2]([C:11]2[S:10][CH:14]=[CH:13][N:12]=2)[CH:7]=[CH:6][N:5]=1
Reactant: Fc1cc(Br)ccn1
Reactant: [Zn+]c1nccs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Fc1cc(-c2nccs2)ccn1
Reaction time: 3.5 h
Yield: 61 %

Procedure:
To a 2 dram vial equipped with a stir bar was added 4-bromo-2-fluoropyridine (132 mg, 0.750 mmol) and Pd(dppf)Cl2 (27 mg, 0.038 mmol). The vial was sealed with a septum screwcap and then was placed under N2 atmosphere. To the vial was added thiazol-2-ylzinc(II) bromide in THF (3.0 mL, 1.5 mmol). The vial was placed in a 60° C. heating block with stirring for 3.5 h. The reaction solution was transfered to a 125 mL separatory funnel and was diluted with EtOAc (50 mL). The solution was washed with water:brine (25 mL:25 mL); then brine (50 mL). The organic solution was dried over MgSO4; filtered; then concentrated in vacuo. The residue was subjected to silica gel chromatography (hexanes:EtOAc) to afford 2-(2-fluoropyridin-4-yl)thiazole as a white solid (83 mg, 61%). 1H-NMR (400 MHz, CDCl3) δ 8.32 (d, J=5.3 Hz, 1H), 8.00 (d, J=3.3 Hz, 1H), 7.73 (dt, J=5.3, 1.6 Hz, 1H), 7.53 (d, J=3.3 Hz, 1H), 7.51-7.50 (m, 1H): MS: MS m/z 181.0 (M++1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[O:21]=[C:2]1[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)CBr
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Temperature: 25 °C
Yield: 62.9 %

Procedure:
A mixture of 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]2′(1′H)-one (0.28 g, 1.00 mmol), ethyl 2-bromoacetate (0.17 g, 1.00 mmol) and cesium carbonate (0.98 g, 3.00 mmol) in acetone (20.0 mL) was stirred at reflux for 5 hours. After cooling down to ambient temperature, the mixture was filtered. The filtrate was evaporated under reduced pressure and the residue was subjected to column chromatography to give the title compound (0.23 g, 63%) as a white solid: MS (ES+) m/z 366.4 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)[C:9]([Cl:21])=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][OH:7].[F:22][C:23]([F:27])([F:26])[CH2:24]O>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH3:20])=[CH:17][CH:18]=2)[C:9]([Cl:21])=[CH:8][C:3]=1[O:4][CH2:5][CH2:6][O:7][CH2:24][C:23]([F:27])([F:26])[F:22]
Reactant: CCc1ccc(Cc2cc(Br)c(OCCO)cc2Cl)cc1
Reactant: OCC(F)(F)F
Solvent: ClCCl
Product: CCc1ccc(Cc2cc(Br)c(OCCOCC(F)(F)F)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-bromo-5-chloro-4-(4-ethylbenzyl)phenoxy)ethanol (AU) (0.53 g, 1.4 mmol) in anhydrous CH2Cl2 (4 mL), was added 2,2,2-trifluoroethanol (0.43 g, 4.3 mmol) and triphenylphosphine polystyrene resin (0.57 g, 2.2 mmol). The resulting mixture was stirred overnight at room temperature, after which it was heated for 2 h at 45° C. The mixture was absorbed onto Celite and purified using silica gel column chromatography eluting with a gradient of EtOAc in hexanes to give intermediate BR. 1H-NMR (CDCl3, 300 MHz) δ 7.36 (s, 1H), 7.14 (m, 4H), 6.94 (s, 1H), 4.17-4.01 (m, 8H), 2.67 (q, J=7.5 Hz, 2H), 1.27 (t, J=7.5 Hz, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:25])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:1]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[N+:12]=2[O-:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(-c2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2ccccc2)[n+]1[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 9.9 %

Procedure:
To a solution of methyl 6-phenylpyridine-2-carboxylate (509 mg, 6.24 mmol) in dichloromethane (5 mL) was added m-chloroperbenzoic acid (purity: 69-75%, 2.87 g, 12.5 mmol), and the mixture was stirred at room temperature for 3 days. Saturated sodium thiosulfate aqueous solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate/hexane=1/2→1/1) to give the title compound (142 mg, 10%) as a colorless oil.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27]([C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][S:37]([C:34]3[CH:35]=[CH:36][C:31]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:32][CH:33]=3)(=[O:39])=[O:38])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: CC(C)(C)c1ccc(S(=O)(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)cc1

Procedure:
The title compound, white solid (92 mg, 70%), MS (ISP) m/z=523.6 [(M+H)+], mp 171° C., was prepared in accordance with the general method of example 36 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-tert-butyl-benzenesulfonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[C:13]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[N:14][C:15]3[C:20]([N:21]=1)=[CH:19][C:18]([C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=3)[CH2:7][CH2:6][CH2:5]2.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[C:13]([C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[N:14][C:15]3[C:20]([N:21]=1)=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][CH:16]=3)[CH2:7][CH2:6][CH2:5]2
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(F)ccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(F)ccc43)nc2c1
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To a solution of methyl 3-(6-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (88 mg, 0.18 mmol) in methanol (25 mL) and water (1 mL) was added sodium hydroxide (24.5 mg, 0.61 mmol) with stifling overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (10 mL), adjusted to pH 4 with hydrochloric acid (3 N) to give the precipitation, which was collected by filtration to afford 3-(6-fluoro-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a yellow solid (63 mg, 79%).
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])(C1C=CC(C)=CC=1)(=O)=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH2:36][OH:37])[CH:31]=[C:32]([CH2:34][OH:35])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:35][CH2:34][C:32]1[CH:33]=[C:28]([NH:27][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:29]=[C:30]([CH2:36][OH:37])[CH:31]=1
Reactant: COC(=O)CCOCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: Nc1cc(CO)cc(CO)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCOCCOCCOCCNc1cc(CO)cc(CO)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 25.7 %

Procedure:
To a mixture of methyl 3-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)propanoate (263a) (250 mg, 0.640 mmol) and (5-amino-1,3-phenylene)dimethanol (26)(108 mg, 0.704 mmol) in anhydrous DMF (1.4 ml) was added potassium carbonate (133 mg, 0.960 mmol). The reaction stirred for 18 hours at 80° C. and then was allowed to cool to room temperature. The mixture was quenched with water and extracted two times with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (5% Methanol/methylene chloride) yielded methyl 3-(2-(2-(2-(3,5-bis(hydroxymethyl)phenylamino)ethoxy) ethoxy) ethoxy)propanoate (264a) (61 mg, 25%); 1H NMR (400 Hz, CDCl3): δ 6.58 (s, 1H), 6.47 (s, 2H), 4.49 (s, 4H), 3.67 (t, J=6.4 Hz, 2H), 3.62 (s, 3H), 3.64-3.54 (m, 10H), 3.21 (t, J=5.2 Hz, 2H), 2.51 (t, J=6.4 Hz, 2H); MS (m/z): found 394.3 (M+Na)+.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29]Cl)[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1.[CH3:34][NH:35][CH2:36][CH:37]([C:39]1[S:40][CH:41]=[CH:42][CH:43]=1)[OH:38].O>CN(C=O)C>[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29][N:35]([CH2:36][CH:37]([OH:38])[C:39]4[S:40][CH:41]=[CH:42][CH:43]=4)[CH3:34])[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1
Reactant: CNCC(O)c1cccs1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1)CC(O)c1cccs1
Temperature: 90 °C
Yield: 62.6 %

Procedure:
N,N-Diisopropylethylamine (0.14 mL) and N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2, 0.150 g) were added to a solution of rac-2-(methylamino)-1-thien-2-ylethanol (Preparation 46, 0.130 g) in DMF (10 mL). The reaction mixture was heated to 90° C. for 1 h. The mixture was allowed to cool to room temperature and was poured into water (25 mL). The suspension was filtered and the resulting solid was purified by column chromatography (CH2Cl2/methanol; 99/1, 98/2) followed by recrystallization from ethyl acetate to yield 0.125 g of the title compound as a white solid. Physical characteristics. M.p. 145-147° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.65, 8.54, 7.41-7.32, 6.97-6.93, 6.87, 6.42, 5.52, 4.984.93, 4.55, 3.91, 3.76, 2.70-2.60, 2.30; 13C NMR (100 MHz, CDCl3) δ 168.9, 159.9, 148.3, 145.6, 140.3, 136.2, 132.4, 127.9, 124.1, 123.8, 121.8, 119.8, 119.0, 112.0, 109.9, 101.8, 61.3, 59.6, 49.2, 37.7, 37.0, 32.9; MS (ESI+) m/z 486 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10](O)=[O:11].[CH3:25][S:26]([NH2:29])(=[O:28])=[O:27].Cl>S(Cl)(Cl)=O>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([NH:29][S:26]([CH3:25])(=[O:28])=[O:27])=[O:11]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: O=S(Cl)Cl
Product: CS(=O)(=O)NC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid (2 gm) is heated under reflux in excess of thionyl chloride (20 ml) for 90 minutes. The excess thionyl chloride is removed under vacuum. The residual product is mixed with at least 1.5 mole equivalent CH3SO2NH2, heated slowly in an oil bath to about 110° C. The reaction temperature is slowly raised to about 150° C. and kept at that temperature for at least 30 minutes or till the HCl ceases to evolve. The reaction mixture is cooled and the residue is crystallized from isopropanol to give 5-(2chloro-4-trifluoromethylphenoxy)-2-nitro-N-methansulphonyl benzamide, m.p. 201° C. In a similar way, but using the appropriate sulphonamide in place of methanesulphonamide, the corresponding nitrobenzoic acid sulphonamides are obtained, giving the following melting points 162° C., 179° C., 185° C., 170° C., 101° C., from the reaction with ethyl, propyl, butyl, hexyl and trifluoromethanesulphonamide respectively.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].O=[C:6]1[CH:10]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[CH2:9][CH2:8][CH:7]1[C:21](OCC)=[O:22].O>CO>[F:19][C:17]([F:18])([F:20])[C:14]1[N:13]=[CH:12][C:11]([CH:10]2[C:6]3[N:1]=[C:2]([OH:3])[N:4]=[C:21]([OH:22])[C:7]=3[CH2:8][CH2:9]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)C1CCC(c2ccc(C(F)(F)F)nc2)C1=O
Reactant: NC(N)=O
Solvent: O
Solvent: CO
Product: Oc1nc(O)c2c(n1)C(c1ccc(C(F)(F)F)nc1)CC2
Reaction time: 8 h
Yield: 45.1 %

Procedure:
To a melt of urea (748 mg, 12.45 mmol) at 150° C. was added ethyl 2-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)cyclopentanecarboxylate (750 mg, 2.49 mmol) dropwise. The reaction was stirred overnight. The reaction mixture was cooled and the resulting solid mass was broken up and suspended in MeOH. The mixture was diluted with a large excess of water and cooled in an ice bath. The suspension was filtered and the residue was washed with water and dried to afford the semi-pure product, 7-(6-(trifluoromethyl)pyridin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diol (334 mg, 1.124 mmol, 45.1% yield). LC-MS (M+H)+=298.0.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43](O)=[O:44])=[CH:31][CH:32]=2)[N:27]=1.C(N(CC)C(C)C)(C)C.[CH:55]1[C:64]2[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=2)[CH:58]=[CH:57][C:56]=1[C@H:65]([NH2:67])[CH3:66]>CN(C)C=O>[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43]([NH:67][C@@H:65]([C:56]3[CH:57]=[CH:58][C:59]4[C:64](=[CH:63][CH:62]=[CH:61][CH:60]=4)[CH:55]=3)[CH3:66])=[O:44])=[CH:31][CH:32]=2)[N:27]=1
Reactant: C[C@@H](N)c1ccc2ccccc2c1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1ccc2c(N3CCN(C)CC3)nc(N)nc2c1)c1ccc2ccccc2c1
Reaction time: 0.17 h
Yield: 48.6 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (40 mg, 0.1 mmol) was added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (20 mg, 0.07 mmol) in N,N-dimethylformamide (1 mL) and N,N-diisopropylethylamine (24 μL, 0.14 mmol). The reaction mixture was stirred for 10 minutes, and then (1R)-1-(2-naphthyl)ethanamine (24 mg, 0.14 mmol) was added. The crude reaction mixture stirred for 18 h. at r.t. and then was purified on RP-HPLC (pH=2) to afford the title product (15 mg, 27%) as a TFA salt as an off white amorphous solid. 1H NMR (300 MHz, DMSO): δ 1.52 (d, 3H), 2.82 (s, 3H), 3.22 (m, 2H), 3.65 (m, 4H), 4.65 (m, 2H), 5.32 (m, 1H), 7.44 (m, 2H), 7.54 (dd, 1H), 7.76-7.86 (m, 5H), 7.92 (d, 1H), 8.02 (d, 1H); Analytic LCMS (M+H)+: m/z=441.2.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:5]([NH2:6])=[CH:4][C:3]=1[C:10]1[C:14]([Cl:15])=[C:13]([C:16]([F:19])([F:18])[F:17])[N:12]([CH3:20])[N:11]=1.C([O-])(=O)C.[Na+].[Br:26]Br>C(O)(=O)C>[Br:26][C:4]1[C:3]([C:10]2[C:14]([Cl:15])=[C:13]([C:16]([F:17])([F:18])[F:19])[N:12]([CH3:20])[N:11]=2)=[C:2]([F:1])[CH:8]=[C:7]([Cl:9])[C:5]=1[NH2:6]
Reactant: Cn1nc(-c2cc(N)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cn1nc(-c2c(F)cc(Cl)c(N)c2Br)c(Cl)c1C(F)(F)F
Reaction time: 8 h

Procedure:
28 g (0.086 mol) of 4-fluoro-6-chloro-3-(4-chloro-5-trifluoromethyl-1-methyl-1H-pyrazol-3-yl)aniline (described in EP-A 0791571) were dissolved in 200 ml of acetic acid and admixed with 35 g (0.42 mol) of sodium acetate. 13.7 g (0.086 mol) of bromine were added dropwise to this mixture. The mixture was stirred overnight, the volatile components were removed under reduced pressure and the residue was taken up in 200 ml of dichloromethane. This solution was washed with 2 N aqueous NaOH and dried over MgSO4, and the residue obtained after concentration of the solution was chromatographed on silica gel using cyclohexane/ethyl acetate (4/1 v/v). This gave 20 g of the title compound IVc.1.