Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[N+:11]([C:14]1[C:15]([CH3:29])=[C:16]2[C:21](=[C:22]([CH3:25])[C:23]=1[CH3:24])[O:20][C:19]([CH2:27][OH:28])([CH3:26])[CH2:18][CH2:17]2)([O-:13])=[O:12].C(N(CC)CC)C>C(Cl)Cl.O>[N+:11]([C:14]1[C:15]([CH3:29])=[C:16]2[C:21](=[C:22]([CH3:25])[C:23]=1[CH3:24])[O:20][C:19]([CH:27]=[O:28])([CH3:26])[CH2:18][CH2:17]2)([O-:13])=[O:12]
Reactant: Cc1c(C)c([N+](=O)[O-])c(C)c2c1OC(C)(CO)CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1c(C)c([N+](=O)[O-])c(C)c2c1OC(C)(C=O)CC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.8 %

Procedure:
Under a nitrogen flow at −60° C., 1.6 ml of oxalic acid dichloride was dissolved in 40 ml of methylene chloride and 3.1 ml of DMSO was added dropwise at −60° C., followed by stirring for 5 minutes. A solution prepared by dissolving 3.9 g of 6-nitro-2-hydroxymethyl-2,5,7,8-tetramethylchroman in 10 ml of methylene chloride was added dropwise under a nitrogen gas flow at −60° C., followed by stirring at −60° C. for 30 minutes. 12 ml of triethylamine was added at −60° C. and the temperature was gradually raised to room temperature, thereby to complete the reaction. After the completion of the reaction, the reaction solution was poured into water and then extracted with chloroform. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate. After removing magnesium sulfate by filtration and concentrating under reduced pressure, the residue was subjected to silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 3.4 g of the objective product as a crystal.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](F)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(F)c2ccccc12
Reactant: C1CCNC1
Product: CCOC(=O)c1ccc(N2CCCC2)c2ccccc12
Reaction time: 0.08 h
Yield: 70 %

Procedure:
154BG85-11 (156 mg, 0.7 mmol) was transferred to a Pyrex tube and pyrrolidine (1 mL) was added. The tube was capped and the reaction tube was exposed to microwave irradiation (100° C., 3 min). The microwave exposure was repeated for 5 min at 130° C. The pyrrolidine was evaporated and the reaction mixture was transferred to a separation funnel with ethyl acetate and washed with 2 M NaOH. The aqueous phase was acidified with 2 M HCl and extracted with ethyl acetate. The organic phases were collected, dried over Na2SO4, filtered and concentrated to yield 135 mg (70%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:4]=2[S:5][C:6]=1[CH2:7][OH:8]>C1(C)C=CC=CC=1.O=[Mn]=O>[Cl:1][C:2]1[C:3]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[CH:9][C:4]=2[S:5][C:6]=1[CH:7]=[O:8]
Reactant: COc1cc2sc(CO)c(Cl)c2cc1OC
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: COc1cc2sc(C=O)c(Cl)c2cc1OC
Reaction time: 12 h

Procedure:
96 mmol (1.6 equivalents) of MnO2 are added at room temperature under an inert atmosphere to a suspension of 60.4 mmol of the compound obtained in Step C in 360 ml of toluene. After 6 hours' reaction at 80° C., 0.6 equivalent of MnO2 is added to the reaction mixture, followed six hours later by 0.6 equivalent of MnO2. The reaction mixture is then filtered while hot over Celite and rinsed with toluene. After 12 hours at room temperature, the filtrate precipitates. Filtration of the precipitate followed by rinsing with toluene and then with pentane enables 8.65 g of the expected product to be isolated.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[CH2:11]([O:13][C:14]([N:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][C:20]([O:31][CH3:32])=[C:21]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:22]=2)[CH:17]1[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=1)=[O:15])[CH3:12].C([O-])(=O)C.[K+]>ClCCl.O>[CH2:11]([O:13][C:14]([N:16]1[CH:25]=[C:24]([CH:3]=[O:4])[C:23]2[C:18](=[CH:19][C:20]([O:31][CH3:32])=[C:21]([O:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:22]=2)[CH:17]1[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[CH:35]=1)=[O:15])[CH3:12]
Reactant: CN(C)C=O
Reactant: CCCCOc1cc2c(cc1OC)C(Cc1cccc(OC)c1)N(C(=O)OCC)C=C2
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCOc1cc2c(cc1OC)C(Cc1cccc(OC)c1)N(C(=O)OCC)C=C2C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
To anhydrous N,N-dimethylformamide (0.102 mL, 1.32 mmol) at 0° C. was added phosphorus oxychloride (0.053 mL, 0.58 mmol) dropwise. The mixture was warmed to room temperature and stirred for 30 minutes. The mixture was cooled in an ice-bath, 6-butoxy-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (230 mg, 0.53 mmol) in dichloromethane (3 mL) was added dropwise. After addition was complete, the mixture was heated on an oil bath for 4 hrs at 80° C. The mixture was cooled to 0° C. and a solution of potassium acetate (154 mg, 1.56 mmol) in water (2 mL) was added slowly. The mixture was then heated at 80° C. for 20 minutes. The mixture was cooled, poured into water and diluted with dichloromethane (60 mL). The organic layer was washed water (2×20 mL), saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 6-butoxy-4-formyl-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (243 mg, 99% yield) as a yellow oil. The crude product was used without further purification.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:25]=[CH:24][C:17]([C:18]([NH:20][CH2:21][CH2:22][CH3:23])=[O:19])=[CH:16][N:15]=1)#[N:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:10]=[C:1]1[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[S:4][C:12]([C:14]2[CH:25]=[CH:24][C:17]([C:18]([NH:20][CH2:21][CH2:22][CH3:23])=[O:19])=[CH:16][N:15]=2)=[N:13]1
Reactant: COC(=O)c1ccccc1S
Reactant: CCCNC(=O)c1ccc(C#N)nc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCNC(=O)c1ccc(-c2nc(=O)c3ccccc3s2)nc1
Yield: 66.2 %

Procedure:
A mixture of methyl thiosalicylate (2.2 g, 13.3 mmol), 6-cyano-N-propylnicotinamide (1.2 g, 6.5 mmol), triethylamine (2.0 ml, 14.3 mmol) and toluene (4 ml) was refluxed for 5 hrs as described in Example 1. After cooling, the precipitated crystals were collected by filtration and recrystallized from diisopropylether-chloroform to give the titled compound (1.4 g, 67%) as crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].Cl.[CH3:23][O:24][C:25](=[O:28])[CH2:26][NH2:27].C(N(CC)CC)C.O1CCOCC1>C(OCC)(=O)C.O>[CH3:23][O:24][C:25]([CH2:26][NH:27][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20])=[O:28]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1ccc(F)c([N+](=O)[O-])c1
Reactant: COC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)CNc1ccc(N2C(=O)C3=C(CCCC3)C2=O)cc1[N+](=O)[O-]
Yield: 36.2 %

Procedure:
2-(4-Fluoro-3-nitrophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (5.8 g) was added to a mixture of glycine methyl ester hydrochloride (7.5 g), triethylamine (6 g) and 1,4-dioxane (50 ml), and the resultant mixture was heated under reflux for 4 hours, followed by addition of water and extraction with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was crystallized from methanol to give 2-(4-methoxycarbonylmethylamino-3-nitrophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (2.6 g). m.p., 220° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:20][CH2:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([NH:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1Oc1ccc(F)cc1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Product: COC(=O)c1ccc(CNC(=O)c2cc(Cl)ccc2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-chloro-2-(4-fluorophenoxy)benzoic acid (step 2) and methyl 4-(aminomethyl)benzoate hydrochloride: 1H-NMR (CDCl3) δ 8.24 (1H, d, J=2.8 Hz), 7.97–7.94 (3H, m), 7.36–7.32 (3H, m), 7.11–6.96 (4H, m), 6.74 (1H, d, J=8.8 Hz), 4.71 (2H, d, J=5.9 Hz), 3.90 (3H, s); MS (ESI) m/z 414 (M+H)+, 412 (M−H)−.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:11]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:24]3[C:25]([CH3:43])=[C:26]([NH:31][C:32]([C:34]4[CH:42]=[CH:41][C:37]5[O:38][CH2:39][O:40][C:36]=5[CH:35]=4)=O)[C:27]([CH3:30])=[C:28]([CH3:29])[C:23]=3[O:22][C:21]2([CH3:45])[CH3:44])=[CH:16][CH:15]=1)([CH3:13])[CH3:12].[OH-].[Na+]>O1CCCC1>[O:38]1[C:37]2[CH:41]=[CH:42][C:34]([CH2:32][NH:31][C:26]3[C:27]([CH3:30])=[C:28]([CH3:29])[C:23]4[O:22][C:21]([CH3:45])([CH3:44])[CH:20]([C:17]5[CH:16]=[CH:15][C:14]([CH:11]([CH3:13])[CH3:12])=[CH:19][CH:18]=5)[C:24]=4[C:25]=3[CH3:43])=[CH:35][C:36]=2[O:40][CH2:39]1
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc3c(c1)OCO3)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1NCc1ccc3c(c1)OCO3)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 39.6 %

Procedure:
To a suspension of aluminum chloride (847 mg, 6.35 mmol) in tetrahydrofuran (10 ml) was gradually added under ice cooling lithium aluminum hydride (240 mg, 6.35 mmol) and the resulting mixture was stirred at the same temperature for 10 minutes. To this mixture was added N-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-1,3-benzodioxol-5-carboxamide (0.60 g, 1.27 mmol) and the mixture was refluxed with heating for 3 hours. The reaction mixture was poured into ice water and neutralized with an 8 N aqueous solution of sodium hydroxide. The product was extracted twice with ethyl acetate. The combined organic layers were washed with water, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was crystallized from methanol to obtain 0.23 g (40% yield) of the title compound. Melting point: 100-102° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH:14]([N:17]=[C:18]=S)([CH3:16])[CH3:15]>C(OCC)(=O)C>[Br:8][C:7]1[C:2]2[NH:1][C:18]([NH:17][CH:14]([CH3:16])[CH3:15])=[N:13][S:10](=[O:12])(=[O:11])[C:3]=2[CH:4]=[C:5]([Br:9])[CH:6]=1
Reactant: Nc1c(Br)cc(Br)cc1S(N)(=O)=O
Reactant: CC(C)N=C=S
Solvent: CCOC(C)=O
Product: CC(C)NC1=NS(=O)(=O)c2cc(Br)cc(Br)c2N1

Procedure:
The title compound was prepared from 2-amino-3,5-dibromobenzenesulfonamide and isopropyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 306-311° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 1.19 (d, 6H, CH(CH3)2), 3.90 (m, 1H, CH(CH3)2), 7.82 (d, 1H, ArH), 7.92 (br.d, 1H, NH), 8.16 (d, 1H, ArH), 9.65 (br.s, 1H, NH); MS: m/e 395/397/399 (M+); (C10H11N3Br2O2S1) calc. C, 30.25; H, 2.79; N, 10.58; found C, 30.34; H, 2.77; N, 10.48.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18]3[N:19]=[C:20]4[N:24]([CH:25]=3)[N:23]=[C:22](Br)[S:21]4)[O:17][C:13]=2[CH:12]=[C:11]([O:27][CH3:28])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O-:30].[Na+]>ClCCl.CO>[CH2:1]([O:8][C:9]1[C:14]2[CH:15]=[C:16]([C:18]3[N:19]=[C:20]4[N:24]([CH:25]=3)[N:23]=[C:22]([O:30][CH3:29])[S:21]4)[O:17][C:13]=2[CH:12]=[C:11]([O:27][CH3:28])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OCc2ccccc2)c2cc(-c3cn4nc(Br)sc4n3)oc2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OCc2ccccc2)c2cc(-c3cn4nc(OC)sc4n3)oc2c1
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution of 6-(4-(benzyloxy)-6-methoxybenzofuran-2-yl)-2-bromoimidazo[2,1-b][1,3,4]thiadiazole (Example 1F, 2.30 g, 5.04 mmol) in a mixture of dichloromethane (180 mL) and methanol (45 mL) was treated at 22° C. with 4.2 mL of a 25 wt. % solution of sodium methoxide in methanol (0.2 mmol) added in one portion. More methanol (45 mL) was added and the mixture was stirred for 1 h. The reaction mixture was quenched by the addition of 25 mL of 1N hydrochloric acid followed by 20 ml of saturated sodium bicarbonate. The solvent was evaporated under reduced pressure and the residue was diluted with dichloromethane (400 mL), washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. Chromatography of the residue on silica gel (3×10 cm, elution with dichloromethane-ethyl acetate 0-4%) gave 1.70 g (83% yield) of the title compound as a white solid. This material was recrystallized from ethyl acetate (30 mL per gram, 80% recovery) to give white needles. LC (Method D): 2.293 min. HRMS (ESI) calcd for C21H18N3O4S [M+H]+ m/z 408.1013, found 408.1024. 1H NMR (CDCl3, 600 MHz) δ 3.81 (s, 3H), 4.18 (s, 3H), 5.16 (s, 2H), 6.37 (d, J=1.75 Hz, 1H), 6.67 (broad s, 1H), 7.07 (s, 1H), 7.31 (broad t, 1H), 7.37 (broad t, 2H), 7.45 (broad d, 2H), 7.81 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]3[N:13]([C:18]4[CH:23]=[CH:22][C:21](B5OC(C)(C)C(C)(C)O5)=[CH:20][CH:19]=4)[C:14](=[O:17])[NH:15][N:16]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.Br[C:34]1[CH:39]=[CH:38][C:37]([N:40]2[CH:44]=[CH:43][CH:42]=[CH:41]2)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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].ClCCl>[CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]3[N:13]([C:18]4[CH:23]=[CH:22][C:21]([C:34]5[CH:35]=[CH:36][C:37]([N:40]6[CH:41]=[CH:42][CH:43]=[CH:44]6)=[CH:38][CH:39]=5)=[CH:20][CH:19]=4)[C:14](=[O:17])[NH:15][N:16]=3)[CH2:7]2)=[O:5])[CH2:2][CH2:3]1
Reactant: Brc1ccc(-n2cccc2)cc1
Reactant: CC1(C)OB(c2ccc(-n3c(C[C@@H]4CCN(C(=O)C5CC5)C4)n[nH]c3=O)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc(-n4cccc4)cc3)cc2)C1
Temperature: 25 °C
Yield: 42 %

Procedure:
A solution of 5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (0.252 mmol) in dioxane (1.5 mL) was treated with 1-(4-bromophenyl)-1H-pyrrole (0.252 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (10 mg), and 2M aq potassium carbonate (0.756 mmol). The reaction mixture was purged with nitrogen, sealed, and irradiated in a microwave (Biotage Initiator) at 150° C. for 15 min. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). The aqueous layer was acidified to pH˜4 using 1N aq HCl and was extracted with dichloromethane. The resulting organic phase was treated with Si-Thiol (Silicycle, 20 mg), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (35-65% acetonitrile/water+0.1% NH4OH). The resulting product was purified by silica gel chromatography (0-8% methanol/dichloromethane) to afford the title compound as an amorphous white solid (42%). MS(ES)+ m/e 454.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[CH:21][C:20]([CH2:23][C:24]([NH2:26])=[O:25])=[C:19]([NH:27][CH2:28][C:29]4[CH:34]=[C:33]([F:35])[CH:32]=[C:31]([F:36])[CH:30]=4)[CH:18]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.C(=O)([O-])[O-].[K+].[K+].O.[CH3:44][NH2:45].C(O)C>>[F:35][C:33]1[CH:34]=[C:29]([CH:30]=[C:31]([F:36])[CH:32]=1)[CH2:28][NH:27][C:19]1[CH:18]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:45][CH3:44])[CH2:5][CH2:6]3)=[CH:15][CH:14]=2)[N:22]=[CH:21][C:20]=1[CH2:23][C:24]([NH2:26])=[O:25]
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCN(CCCl)CC3)cc2)cc1NCc1cc(F)cc(F)c1
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CNCCN1CCN(c2ccc(Nc3cc(NCc4cc(F)cc(F)c4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
42 mg of 6-({4-[4-(2-chloroethyl)piperazin-1-yl]phenyl}amino)-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide (the compound of Example 250) was dissolved in a 30% methylamine-ethanol solution, to which 23 mg of potassium carbonate was added, and stirred at 80° C. for 8 hours. After cooling, water was added to the reaction mixture, extracted with chloroform, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel thin layer chromatography (chloroform:ammonia methanol=10:1), and crystallized by adding ether to obtain 8 mg (15%) of the title compound as a slight yellow solid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]([N:15]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[S:16]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:33][C@@H:34]([CH2:36][OH:37])[CH3:35]>CN1C(=O)CCC1>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([N:15]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[S:16]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH:12]=[C:11]([NH:33][C@H:34]([CH3:35])[CH2:36][OH:37])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](N)CO
Reactant: C[Si](C)(C)CCOCN(c1cc(Cl)nc(SCc2ccccc2)n1)S(=O)(=O)N1CCCC1
Solvent: CN1CCCC1=O
Product: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(=O)(=O)N2CCCC2)nc(SCc2ccccc2)n1

Procedure:
The subtitle compound was prepared as a yellow oil by the method of Example 43 step ii) by reacting the subtitle product of step ii) (8.26 g) with (R)-alaninol (3.61 g) in NMP (60 ml). Yield: 7.6 g.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:7][CH2:6]1.[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.O>C(O)C>[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:14][CH2:13][CH2:12][CH2:11][N:8]2[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:20][C:19]3[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=3)[CH2:10][CH2:9]2)=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: NCCCN1CCN(CCCN)CC1
Solvent: O
Solvent: CCO
Product: Fc1ccc(CNCCCN2CCN(CCCNCc3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1,4-bis(3-aminopropyl)piperazine (0.51 mL, 2.5 mmol) and 4-fluorobenzaldehyde (0.59 mL, 5.5 mmol) in absolute ethanol (20 mL), 3 Å molecular sieves are added. After stirring the mixture at room temperature for 5 h, NaBH (0.47 g, 12.5 mmol) was added portionwise and the mixture was stirred for 12 h at room temperature. The reaction was quentched by dropwise addition of water (20 mL) and ethanol was removed under reduced pressure. The aqueous residue was extracted with CH2Cl2 (3×30 mL). Combined organic layers were extracted with HCl 1M. The combined aqueous layers were neutralized with NaOH 1M and extracted with CH2Cl2. Combined organic layers were dried over MgSO4. Crude compound is purified thick-layer chromatography (acetone/NH4OH:90/10).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([OH:18])=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[C:15]([C:24]#[N:25])=[N:14]1.N1C=CC=CC=1.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34](Cl)=[O:35]>ClCCCl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([O:18][C:34](=[O:35])[C:33]([CH3:38])([CH3:37])[CH3:32])=[C:16]([S:19][C:20]([F:23])([F:21])[F:22])[C:15]([C:24]#[N:25])=[N:14]1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(O)c1SC(F)(F)F
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)C(=O)Oc1c(SC(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 20 h
Yield: 28.6 %

Procedure:
To the solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfenyl-5-hydroxypyrazole (7.00 g, 16.6 mmol) and pyridine (4.91 g, 62.1 mmol) in 1,2-dichloroethane at room temperature was added trimethylacetyl chloride (4.37 g, 36.2 mmol) dropwise. Ice bath was used to maintain the temperature of the reaction. After 20 hr at room temperature, the organic layer was washed five times with aqueous KHSO4 till the aqueous solution was at pH 1. The organic layer was then dried (MgSO4) and concentrated to give a solid residue. Upon chromatographic purification via silica gel column of the solid residue, after trituration with pentane, a off-white solid (2.403 g, 28.6% yield, 97.0% HPLC purity) was provided as the desired product, m. p. 82-83 C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:19]([O:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[CH2:37][O:38][C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:32]Br)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:20]1([C:19]([O:27][CH2:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[CH2:37][O:38][C:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:46])[CH2:32][O:1][C:2]2[CH:3]=[C:4]([C:8]3[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1ccc(-c2cccc(O)c2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1ccc(-c2cccc(OCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)c2)nc1

Procedure:
In a manner similar to that of Example 1(i), by reaction of 277 mg (1.1 mmol) of ethyl 6-(3-hydroxyphenyl)nicotinate with 500 mg (1.1 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide and 166 mg (1.2 mmol) of potassium carbonate. The desired product is obtained in the form of white crystals (m.p.=118-120° C.; m=500 mg; Y=73%).
Reaction SMILES: [C:1]1([C:7]2([CH2:16][C:17]([OH:19])=O)[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl.[NH3:32]>CCOCC>[C:1]1([C:7]2([CH2:16][C:17]([NH2:32])=[O:19])[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CC1(c2ccccc2)Oc2ccccc2O1
Reactant: N
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: c1ccccc1
Product: NC(=O)CC1(c2ccccc2)Oc2ccccc2O1
Reaction time: 12 h

Procedure:
To 22 g. of (2-phenyl-1,3-benzodioxol-2-yl)-acetic acid in 300 cc. of anhydrous benzene, in the cold, 18.1 g. of PCl5 are added. After leaving the mixture for 2 hours to allow the reaction to be completed a cold solution of NH3 in anhydrous ether is added to the mixture, in drops and with shaking. After 12 hours, the mixture is poured onto ice. The organic phase is separated, washed with H2O until neutral, and finally dried with Na2SO4. The solvent is removed under vacuum and the residue is recrystallised from benzene, m.p. 114°-15°C.