Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].ClC1[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=1.[C]=O.[CH2:20](O)[CH3:21]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:17][C:14]([F:15])([F:16])[C:10]1[CH:11]=[C:12]([Cl:13])[C:2]([C:1]([O:4][CH2:20][CH3:21])=[O:3])=[N:8][CH:9]=1
Reactant: CC(=O)[O-]
Reactant: CCO
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: [Pd+2]
Agent: [C]=O
Agent: [Na+]
Product: CCOC(=O)c1ncc(C(F)(F)F)cc1Cl
Temperature: 80 °C
Reaction time: 5 h

Procedure:
The reaction was carried out in a 100 ml stainless steel autoclave equipped with a magnetic stirring bar. The reagents were charged in a teflon liner in the following order: (1) ethanol (20 ml), (2) sodium acetate (1.70 g, 20 mmol), (3) 2,3-dichloro-5-trifluoromethylpyridine (2.16 g [97 percent], 10 mmol), (4)1,1′-bis(diphenylphosphino)ferrocene (166 mg, 0.30 mmol [3 mol percent]), and (5) palladium acetate (12 mg, 0.05 mmol [0.5 mol percent]). The air in the autoclave was replaced with carbon monoxide and the pressure adjusted to 15 bar. The reaction mixture was then heated to 80° C. (jacket temperature) and the reaction was carried out with stirring. After 5 hours, the reaction mixture was cooled to room temperature, filtered through celite, GC analysis indicated that the mixture consisted of 98 percent of ethyl 5-trifluoromethyl-3-chloropyridine-2-carboxylate. The mixture was concentrated under vacuum and the product was isolated by flash chromatography on silica gel eluting with ethyl acetate/hexane (1:4) affording 2.34 g (92 percent, <99 percent GC area percent). Other data concerning the product was:
Reaction SMILES: [C:1]1([C:7]2[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=2[CH2:9][CH:10]([C:16]([O:18]CC)=[O:17])[C:11]([O:13]CC)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>O.C(O)C>[C:1]1([C:7]2[CH:24]=[CH:23][CH:22]=[CH:21][C:8]=2[CH2:9][CH:10]([C:16]([OH:18])=[O:17])[C:11]([OH:13])=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(Cc1ccccc1-c1ccccc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(Cc1ccccc1-c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A stirred solution of 149.0 g (0.456 mole) of diethyl (2-phenylbenzyl)malonate and 56.1 g (1.0 mole) of potassium hydroxide in 50 ml of water and 500 ml of ethanol was heated under reflux for 3 hours. The reaction mixture was allowed to cool to ambient temperature and stand for 60 hours. The ethanol was removed by distillation and the residue slurried in 400 ml of water. The mixture was extracted with one portion of 250 ml of diethyl ether. The aqueous phase was separated and acidified with concentrated hydrochloric acid, then extracted with two portions of 250 ml each of diethyl ether. The two extracts of the acidified aqueous phase were combined, dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give (2-phenylbenzyl)malonic acid as a pale yellow oil. The oil was used directly in the next step of this reaction sequence.
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[C:14]2[B:15]([OH:22])[O:16][CH:17]([CH2:18][N+:19]([O-:21])=[O:20])[C:13]=2[CH:12]=[CH:11][CH:10]=1)C.[OH-].[Na+]>CO.O>[OH:22][B:15]1[C:14]2[C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:23])=[O:3])=[CH:10][CH:11]=[CH:12][C:13]=2[CH:17]([CH2:18][N+:19]([O-:21])=[O:20])[O:16]1
Reactant: CCOC(=O)CCCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 4-(1-hydroxy-3-nitromethyl-1,3-dihydro-benzo[c][1,2]oxaborol-7-yloxy)-butyric acid ethyl ester (2.51 g, 7.78 mmol), 10% NaOH (17 mL), and 1:1 MeOH/H2O (70 mL) was stirred at rt for 5 h. The MeOH was removed in vacuo and the remaining aqueous layer was acidified to pH 1 using 2 M HCl. The aqueous layer was then extracted with EtOAc. The organic fractions were washed with brine, dried (MgSO4), and concentrated in vacuo to give the title compound as a pale yellow foam: yield 1.85 g (81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11].C(N([CH:19]([CH3:21])[CH3:20])C(C)C)C.[CH3:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>C(#N)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:30][C:23]2[CH:22]=[CH:21][C:19]([CH3:20])=[CH:25][CH:24]=2)[CH2:22][C:23]2[CH:30]=[CH:29][C:26]([CH3:27])=[CH:25][CH:24]=2)=[CH:5][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(N)cc1[N+](=O)[O-]
Reactant: Cc1ccc(CBr)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccc(N(Cc2ccc(C)cc2)Cc2ccc(C)cc2)cc1[N+](=O)[O-]
Reaction time: 16 h
Yield: 93 %

Procedure:
To a stirred solution of 5.00 g (29.7 mmol) 4-methoxy-3-nitro-phenylamine in 60 ml acetonitrile at 0° C. were added 10.2 ml (59.5 mmol) N-ethyldiisopropylamine and 11.6 g (62.4 mmol) 4-methylbenzyl bromide. Stirring was continued at room temperature for 16 h and then the mixture was diluted with ethyl acetate and washed with 0.5 N hydrochloric acid and then with brine. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford 10.4 g (93%) (4-methoxy-3-nitro-phenyl)-bis-(4-methyl-benzyl)-amine as an orange oil. ES-MS m/e (%): 399 (M+Na+, 18), 377 (M+H+, 100).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]=O.[C:19]1([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:10]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[O:9][CH2:17][N:25]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Reactant: C=O
Product: c1ccc(CN(Cc2ccccc2)OCN(c2ccccc2)c2ccccc2)cc1

Procedure:
The procedure of Example I s repeated using 21.33 g of dibenzylhydroxylamine, 9.46 g of aqueous formaldehyde (37%) solution and 16.92 g of diphenylamine, to afford the title compound as a colorless liquid with a mass spectrum, NMR and IR consistent with the desired structure.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8]([O:10][CH3:11])[N:7]=[C:6]([CH3:12])[N:5]=1.[C:13](=O)(OC1C=CC=CC=1)[O:14]C1C=CC=CC=1.[NH2:29][S:30]([C:33]1[CH:42]=[C:41]([I:43])[CH:40]=[CH:39][C:34]=1[C:35]([O:37][CH3:38])=[O:36])(=[O:32])=[O:31].Cl>CC(N(C)C)=O>[CH3:11][O:10][C:8]1[N:7]=[C:6]([CH3:12])[N:5]=[C:4]([NH:3][C:13]([NH:29][S:30]([C:33]2[CH:42]=[C:41]([I:43])[CH:40]=[CH:39][C:34]=2[C:35]([O:37][CH3:38])=[O:36])(=[O:32])=[O:31])=[O:14])[N:9]=1
Reactant: COC(=O)c1ccc(I)cc1S(N)(=O)=O
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: COc1nc(C)nc(N)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(I)cc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Temperature: 0 °C

Procedure:
0.084 g of sodium hydride (60% pure in paraffin oil) was added to a suspension of 0.23 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine in 3 ml of dimethylacetamide (DMA) at room temperature to form a mixture. The mixture was stirred until the evolution of gas ended. A solution of 0.44 g of diphenyl carbonate in 1 ml of DMA was then slowly added dropwise at about 5° C., and the resulting mixture therefrom was stirred for 10 minutes. A solution of 0.68 g of methyl 2-aminosulfonyl-4-iodobenzoate (92.5% pure) in 2 ml of DMA was slowly added dropwise, to the resulting mixture, while cooled in an ice bath, to form a reaction mixture. When the reaction ended, the reaction mixture was then introduced into a solution of 30 ml of ice-water and 0.25 ml of concentrated hydrochloric acid, whereby a crude product separated out. The crude product which separated out was then purified by washing with a little water, methanol and diisopropyl ether and drying. The yield was 0.47 g (46% of theory).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:12])([CH3:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[I:13][CH2:14][CH2:15][CH2:16]I>>[I-:13].[I:13][CH2:14][CH2:15][CH2:16][N+:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]([CH3:12])([CH3:11])[C:2]=1[CH3:1]
Reactant: CC1=Nc2ccccc2C1(C)C
Reactant: ICCCI
Product: CC1=[N+](CCCI)c2ccccc2C1(C)C
Product: [I-]
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a 50 mL round bottom flask is added 2,3,3-trimethylindolenine (14.4 mmol) and 1,3-diiodopropane (72.7 mmol) and the mixture is stirred at 60° C. under an atmosphere of nitrogen for 16 hours. The resulting solid is recrystallized from ethanol to give 1-[3-iodopropyl]-2,3,3-trimethyl-3H-indolium iodide (40) as crystals.
Reaction SMILES: O.O.[Sn](Cl)Cl.[Cl:6][C:7]1[C:16]([Cl:17])=[N:15][C:14]2[C:9](=[CH:10][C:11]([Cl:22])=[C:12]([Cl:21])[C:13]=2[N+:18]([O-])=O)[N:8]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[NH2:18][C:13]1[C:12]([Cl:21])=[C:11]([Cl:22])[CH:10]=[C:9]2[C:14]=1[N:15]=[C:16]([Cl:17])[C:7]([Cl:6])=[N:8]2
Reactant: O=[N+]([O-])c1c(Cl)c(Cl)cc2nc(Cl)c(Cl)nc12
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1c(Cl)c(Cl)cc2nc(Cl)c(Cl)nc12
Yield: 83.7 %

Procedure:
Tin(II) chloride dihydrate (346.3 g, 1.54 mol) was added to a solution of 2,3,6,7-tetrachloro-5-nitroquinoxaline (96.2 g, 0.31 mol) in ethyl acetate (1.8 liters). The mixture was heated under reflux for 4 hours, cooled and poured cautiously into an excess of aqueous saturated sodium bicarbonate solution. The mixture was filtered through CELITE (trade mark) filter aid washing well with ethyl acetate. The filter cake was macerated with further ethyl acetate and the solid material filtered off. The combined ethyl acetate phases were dried (MgSO4) and concentrated under reduced pressure to give 5-amino-2,3,6,7-tetrachloroquinoxaline (73.4 g, 84%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccc(C)c2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)c1
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(3-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 2) 30.0 mg (0.071 mmol) in 3 ml of EtOH and 2 ml of THF was added 28.0 mg (0.70 mmol, 0.7 ml) of NaOH (1.0 M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ 7.90 (2H, d, J=8.5 Hz), 7.59 (2H, d, J=8.5 Hz), 7.46 (2H, s), 7.32-7.13 (4H, m), 7.10 (1H, s), 6.98 (1H, t, J=4.5 Hz), 2.34 (3H, s), 2.31 (2H, d, J=4.5 Hz), 1.30 (6H, s).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:4]=1.C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:4]=1)[C:25](=[O:27])[CH3:26]
Reactant: CNc1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(C)c1ccc([N+](=O)[O-])c(N2CCCCC2)c1
Reaction time: 8 h
Yield: 71 %

Procedure:
To a solution of methyl-(4-nitro-3-piperidin-1-yl-phenyl)-amine (80 mg, 0.34 mmol, as prepared in the previous step) and triethylamine (118 μL, 0.850 mmol)) in 4 mL of CH2Cl2 was added acetic anhydride (320 μL, 3.40 mmol) via microsyringe and the reaction was allowed to stir overnight. At this time it was diluted with CHCl3 (50 mL), washed with satd aq NaHCO3 (2×50 mL), and dried (Na2SO4). Concentration of the solvent in vacuo and purification of the crude material using preparative TLC (4% MeOH—CHCl3) afforded 67 mg (71%) of the title compound as an oil. Mass spectrum (ESI, m/z): Calcd. for C14H19N3O3, 278.1 (M+H), found 278.1.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:15]=[C:14]([C:16]([OH:25])([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])[CH:13]=[C:5]3[CH2:6][CH2:7][CH2:8][N:9]([C:10](=[O:12])[CH:11]=1)[C:4]=23.O.O.O.C([O-])(=O)C.[Na+]>[Pd].C(O)(=O)C>[F:24][C:21]([F:22])([F:23])[C:16]([C:14]1[CH:13]=[C:5]2[C:4]3[N:9]([CH2:8][CH2:7][CH2:6]2)[C:10](=[O:12])[CH:11]=[CH:2][C:3]=3[CH:15]=1)([OH:25])[C:17]([F:20])([F:19])[F:18]
Reactant: O=c1cc(Cl)c2cc(C(O)(C(F)(F)F)C(F)(F)F)cc3c2n1CCC3
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=c1ccc2cc(C(O)(C(F)(F)F)C(F)(F)F)cc3c2n1CCC3

Procedure:
A mixture of 0.7 g. of 7-chloro-2,3-dihydro-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1H,5H-benzo[ij]quinolizin-5-one, 150 ml. of glacial acetic acid, 5 g. of sodium acetate trihydrate, and 0.5 g. of 10% palladium on charcoal is hydrogenated in a Parr shaker apparatus for 4 hours at an initial pressure of 3 atm. The catalyst is removed by filtration, solvent is removed by evaporation, and the residue is triturated with water. The insoluble material is filtered off, dried and recrystallized to give 2,3-dihydro-9-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1H,5H-benzo[ij]quinolizin-5-one, m.p. 295°-296°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[CH3:19][C:20]1[O:21][CH:22]=[C:23]([C:25](O)=[O:26])[N:24]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][CH:22]=3)=[O:26])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: Cc1nc(C(=O)O)co1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: Cc1nc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OCC3(F)F)c2)co1

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 2-methyl-oxazole-4-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=369.1 [M+H]+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:9]=[CH2:10])[C:5]([F:8])=[N:6][CH:7]=1.CO[CH2:13][CH2:14][O:15]C.B(F)(F)F.CC[O:23]CC.C(ON=O)(C)(C)C>CCCCC.C(Cl)Cl>[C:14]([O:15][C:2]1[CH:3]=[C:4]([CH:9]=[CH2:10])[C:5]([F:8])=[N:6][CH:7]=1)(=[O:23])[CH3:13]
Reactant: C=Cc1cc(N)cnc1F
Reactant: CCOCC
Reactant: COCCOC
Agent: CC(C)(C)ON=O
Agent: FB(F)F
Solvent: CCCCC
Solvent: ClCCl
Product: C=Cc1cc(OC(C)=O)cnc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a stirred solution of the 5-amino-2-fluoro-3-ethenylpyridine from a above (3.00 g, 21.7 mmol) in 3:1 DME:CH2Cl2 (50 mL) at −10° C. was slowly added borontrifluoride etherate (5.60 mL, 45.6 mmol). t-Butylnitrite (3.10 mL, 26.0 mmol) was added over the course of 15 min, keeping the reaction temperature below −5° C. The reaction mixture was warmed to 0° C. and stirred for 30 min. Pentane (500 mL) was added and the solid tetrafluoroborate diazonium salt was collected by filtration. The diazonium salt was dissolved in acetic anhydride (40 mL) and heated at 95 OC for 2 h —N2 evolution was noted at 85° C. The solvent was evaporated, the residue was dissolved in Et2O (250 mL), and washed with saturated, aqueous NaHCO3 (2×150 mL). The combined aqueous phases were extracted with Et2O (2×150 mL). The combined organic phases were washed with brine (50 mL), dried (MgSO4), and concentrated. The crude product was purified by column chromatography (silica gel; EtOAc/hexane, 4:6) to afford the desired product as a yellow oil (1.51 g, 40%): 1H NMR (CDCl3, 300 MHz) δ 2.35 (s, 3H), 5.54 (d, J=11.0 Hz, 1H), 5.90 (d, J=18.0 Hz, 2H), 6.75 (m, 1H), 7.66 (dd, J=2.0, 5.0 Hz, 1H) MS (CI/NH3) m/z 182 (M+H)+, 199 (M+NH4)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][NH:3][C:2]1=[O:6].[Cl-].[Al+3].[Cl-].[Cl-].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](Cl)=[O:17]>[N+](C1C=CC=CC=1)([O-])=O>[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]([C:5]1[NH:1][C:2](=[O:6])[NH:3][CH:4]=1)=[O:17]
Reactant: O=c1[nH]cc[nH]1
Reactant: O=C(Cl)c1ccco1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(c1c[nH]c(=O)[nH]1)c1ccco1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 50 ml of nitrobenzene is added 4.2 g of 1,3-dihydro-2H-imidazol-2-one, 13.3 g of aluminum chloride and 7.2 g of furanoyl chloride. The mixture is stirred at 60° C. for 3 hours and poured over ice water. The solids are filtered, washed with ether and recrystallized twice from ethanol-water to afford the title compounds. M.P. 318°-321° C.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[SiH](CC)(CC)CC.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:21]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[CH:2]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)c1ccc(Cn2ccc3ccccc32)cc1
Agent: CC[SiH](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2cc(Cc3ccccc3)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-((1H-indol-1-yl)methyl)benzoate 1 (0.250 g, 0.94 mmol) and benzaldehyde (96 μL, 0.94 mmol) in DCM (10 mL) at 0° C. was added SiEt3H (0.45 mL, 2.83 mmol) followed by trifluoroacetic acid (0.14 mL, 1.88 mmol). The reaction was stirred at 0° C. for 1 h. The reaction was then adjusted to pH 10 with 2 N NaOH and the organic products were extracted with DCM (3×15 mL). The combined organic fractions were washed with brine (15 mL), dried with Na2SO4, filtered and concentrated in vacuo. The title compound was isolated using automated column chromatography method 1 (0.262 g, 78%). 1H NMR (400 MHz, CDCl3): δ 7.97 (d, J=8.0 Hz, 2H), 7.56 (d, J=8.0 Hz, 1H), 7.32-7.27 (m, 4H), 7.23-7.10 (m, 6H), 6.87 (s, 1H), 5.33 (s, 2H), 4.15 (s, 2H), 3.91 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 166.8, 143.0, 141.2, 136.8, 130.1, 129.5, 128.7, 128.4, 128.3, 126.6, 126.5, 126.0, 122.1, 119.5, 119.3, 115.4, 109.6, 52.2, 49.7, 31.6.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:16])=[C:4]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.[N:29](OC(C)(C)C)=O.C1OCCOCCOCCOCCOCCOC1>C(Cl)(Cl)Cl>[F:15][C:12]([F:13])([F:14])[C:10]1[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]2[CH:16]=[N:29][NH:1][C:2]=2[CH:11]=1
Reactant: COC(=O)c1cc(C(F)(F)F)cc(N)c1C
Reactant: CC(C)(C)ON=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc(C(F)(F)F)cc2[nH]ncc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 90 %

Procedure:
To a stirred solution of methyl 3-amino-2-methyl-5-(trifluoromethyl)benzoate (1 equiv.) in chloroform (13 mL per 1 mmol), potassium acetate (1.05 equiv.) and acetic anhydride (2 equiv.) were added and reaction mixture stirred at room temperature for 12 h. After this time, tert-butyl nitrite (4 equiv.) and 18-crown-6 (0.35 equiv.) were added and reaction stirred again at 65° C. for 3 h. On completion, the reaction mixture was cooled to room temperature, diluted with chloroform (500 mL) and washed with sat. sodium bicarbonate solution. the organic layer was dried over sodium sulfate and concentrated to afford title the compound (yield 90-95%).
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[Cl:8][C:9]1[C:14]([S:15][CH3:16])=[C:13]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[N:10]=1>C1COCC1>[Cl:8][C:9]1[C:14]([S:15][CH3:16])=[C:13]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:6]([NH2:5])=[O:7])=[CH:25][CH:24]=2)[N:10]=1
Reactant: CSc1c(Cl)nc(-c2ccc(N)cc2)nc1N1CCOCC1
Reactant: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Product: CSc1c(Cl)nc(-c2ccc(NC(N)=O)cc2)nc1N1CCOCC1
Yield: 31.2 %

Procedure:
Trimethylsilyl isocyanate (136 mg, 5 eq.) was added to a stirred solution of 4-(4-Chloro-5-methylsulfanyl-6-morpholin-4-yl-pyrimidin-2-yl)-phenylamine (80 mg, 0.237 mmol.) in THF (2.0 ml) and the mixture was reacted to reflux for 16 hrs. The reaction mixture was extracted with EA and washed with brine. The crude was purified by Chromatography (Hexane/EtOAc 1:1) to give a product 28.1 mg (31.2%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].C(#N)C.[S:8](Cl)([Cl:11])(=[O:10])=[O:9].[NH:13]1[CH:17]=[CH:16][N:15]=[CH:14]1>C(OCC)(=O)C>[ClH:11].[N:13]1([S:8]([N:1]=[N+:2]=[N-:3])(=[O:10])=[O:9])[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: [N-]=[N+]=[N-]
Reactant: c1c[nH]cn1
Reactant: O=S(=O)(Cl)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cl
Product: [N-]=[N+]=NS(=O)(=O)n1ccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium azide (13.0 g) and acetonitrile (200 mL) were mixed. To the mixture was added dropwise sulfuryl chloride (16.1 mL) at ice temperature. The mixture was stirred at RT overnight, and then to the mixture was added imidazole (25.9 g) at ice temperature. The mixture was stirred at RT for 4 hr, and then to the mixture was added ethyl acetate. The mixture was washed with water (400 mL×2) and saturated aqueous sodium bicarbonate (400 mL×2), then dried over magnesium sulfate. The magnesium sulfate was filtered off. To the filtrate was added a solution of hydrochloric acid in ethyl acetate at ice temperature. The precipitated solid was collected on a filter to give the title compound (27.7 g).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:12]1[N:21]=[C:20](Cl)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=2)[N:13]=1.[OH2:25]>O1CCCC1>[CH2:1]([O:8][C:12]1[N:21]=[C:20]([O:25][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:23][CH3:24])[CH:18]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: O
Reactant: COc1ccc2nc(Cl)nc(Cl)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2nc(OCc3ccccc3)nc(OCc3ccccc3)c2c1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
3 ml of benzyl alcohol was dissolved in 50 ml of tetrahydrofuran, followed by the addition of 1.0 g of sodium hydride. The obtained mixture was stirred at 40 to 50° C. for 30 minutes, followed by the addition of 2.50 g (0.0109 mol) of 2,4-dichloro-6-methoxyquinazoline. The obtained mixture was heated under reflux for several hours, followed by the addition of water. The obtained mixture was extracted with chloroform and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under a reduced pressure to remove the solvent. The obtained crystalline residue was recrystallized from chloroform/n-hexane to give 3.84 g of the title compound as a yellow crystal.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19](Cl)[N:18]=[C:17]([N:31]3[CH2:36][CH2:35][N:34]([CH:37]=[O:38])[CH2:33][CH2:32]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:39]([OH:43])[CH2:40][CH2:41][OH:42]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:42][CH2:41][CH2:40][CH2:39][OH:43])[N:18]=[C:17]([N:31]3[CH2:36][CH2:35][N:34]([CH:37]=[O:38])[CH2:33][CH2:32]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OCCCO
Reactant: COc1ccccc1Oc1c(Cl)nc(N2CCN(C=O)CC2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(N2CCN(C=O)CC2)nc1OCCCO

Procedure:
The procedure described in Synthesis Example 3 was repeated by use of 4-t-butyl-N-[6-chloro-2-(4-formylpiperazinyl)-5-(2-methoxyphenoxy)-4-pyrimidinyl]benzenesulfonamide and 1,3-propanediol, to thereby obtain the title compound as a pale yellow solid.