Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([C:18]([C:20]2[C:21]([CH2:32][CH:33]3OCC[O:34]3)=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[O:19])[N:9]=[CH:8]1.O>C(O)(=O)C>[F:45][C:2]([F:1])([F:46])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:44])([F:42])[F:43])[CH:40]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([C:18]([C:20]2[C:21]([CH2:32][CH:33]=[O:34])=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[O:19])[N:9]=[CH:8]1
Reactant: O=C(c1ncn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1)c1c(CC2OCCO2)noc1-c1ccccc1Cl
Solvent: CC(=O)O
Solvent: O
Product: O=CCc1noc(-c2ccccc2Cl)c1C(=O)c1ncn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Dissolve [1-(3,5-Bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-imidazol-4-yl]-[5-(2-chloro-phenyl)-3-[1,3]dioxolan-2-ylmethyl-isoxazol-4-yl]-methanone (0.23 g, 0.35 mmol) in acetic acid (4 mL) and add H2O (2 mL). Attach a reflux condenser and warm to 100° C. After 18 h., concentrate the solution under reduced pressure, neutralize with sat. aq. NaHCO3, and extract with CH2Cl2 and EtOAc (2×). Dry the combined organic layers over MgSO4, filter, and concentrate to give the title compound: MS (ES) 619.2 (M+1); TLC Rf=0.35 (5% MeOH/EtOAc).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Br)=[C:9]([NH2:12])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][CH3:21])[C:14]=2[F:22])[N:6]=1)=[O:4].[CH:23](/B(O)O)=[CH:24]\[CH3:25].[F-].[Cs+].O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:10](/[CH:23]=[CH:24]/[CH3:25])=[C:9]([NH2:12])[N:8]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([O:20][CH3:21])[C:14]=2[F:22])[N:6]=1)=[O:4]
Reactant: C/C=C/B(O)O
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: C/C=C/c1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC

Procedure:
6-Amino-5-bromo-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrimidine-4-carboxylic acid methyl ester (400 mg, 1.02 mmol), trans-propenyl boronic acid (2132 mg, 1.54 mmol), bis(triphenylphosphine)palladium(II) dichloride (72 mg, 0.1 mmol), and cesium fluoride (311 mg, 2.05 mmol) were combined in 1,2-dimethoxyethane (2 mL) and water (2 mL) and heated at 100° C. for 15 min in a CEM microwave reactor. The cooled reaction mixture was partitioned between ethyl acetate and water; and the organic phase was dried and concentrated. The product was purified by flash chromatography on silica gel (hexane/ethyl acetate gradient) then purified again by reverse phase HPLC to yield the title compound: mp 133-135° C.: 1H NMR (CDCl3) δ 7.63 (m, 1H), 7.22 (m, 1H), 6.43 (m, 1H), 6.12 (m, 1H), 5.35 (br s, 2H), 3.99 (d, 3H), 3.94 (s, 3H), 1.94 (dd, 3H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]3[C:13](=[O:16])[O:14][CH2:15][C:11]=3[CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.O=[CH:20][CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.C([BH3-])#N.[Na+].CC(O)=O>CO>[O:16]=[C:13]1[C:12]2[CH:17]=[CH:18][C:9]([CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][N:4]([CH2:20][CH2:21][C:22]4[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=4)[CH2:3][CH2:2]3)=[CH:10][C:11]=2[CH2:15][O:14]1
Reactant: N#Cc1ccc(CC=O)cc1
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccc(CCN2CCN(CCc3ccc4c(c3)COC4=O)CC2)cc1

Procedure:
A mixture of 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one (50 mg, 0.20 mmol), 4-(2-Oxoethyl)benzonitrile (30 mg, 0.20 mmol), Sodium Cyanoborohydride (13 mg, 0.20 mmol), and a drop of HOAc was stirred together in Methanol for 2 hours. LC showed formation of the desired product. The crude was diluted with EtOAc, washed with water, adsorbed onto silica gel, and purified by silica gel chromatography. LC-MS (IE, m/z): 376 [M+1]+. (0.30 μM)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].[OH-].[K+].[CH2:20](Br)[CH2:21][CH2:22][CH3:23]>CS(C)=O.O>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[CH2:21][CH2:22][CH3:23]
Reactant: Cc1ccccc1C(=O)Nc1cccc(O)c1
Reactant: CCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCOc1cccc(NC(=O)c2ccccc2C)c1
Reaction time: 3 h
Yield: 92.9 %

Procedure:
A 22.7 g (0.1 mol) portion of 3'-hydroxy-2-methylbenzanilide was dissolved in 80 ml of dimethyl sulfoxide and to this solution was added a solution of 5.6 g (0.1 mol) of potassium hydroxide in 40 ml of water. The white mixture was cooled with water, and 30 ml of dimethyl sulfoxide containing 13.7 g (0.1 mol) of n-butylbromide was added dropwise to the solution with stirring. After the addition, the mixture was warmed and kept at 40° to 50° C for 3 hours. The reaction mixture was poured into 700 ml of water and the oily material formed was extracted with benzene. The benzene layer was washed with water, dehydrated over anhydrous sodium sulfate and the benzene was removed to obtain the product, which was recrystallized from a mixture of benzene and n-hexane (1 : 2) to obtain 26.3 g (92.9%) of greyish needle-like crystals having a melting point of 87° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH:15]([Sn](CCCC)(CCCC)CCCC)=[CH2:16]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:15]([C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1)=[CH2:16]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: OCc1cn(-c2cccc(Br)c2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: C=Cc1cccc(-n2cnc(CO)c2)c1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 49.9 %

Procedure:
Under an Ar atmosphere, a solution of [1-(3-bromo-phenyl)-1H-imidazol-4-yl]-methanol (3.0 g, 12 mmol) in DMF (90 ml) was successively treated with PdCl2(PPh3)2 (0.87 g, 0.1 mmol) and vinyltributylstannane (4.1 g, 13 mmol). The resulting mixture was heated to 60° C. for 8 h. After evaporation of the solvent the residue was stirred for 30 min with AcOEt (60 ml) and aqueous 10% KF solution. The organic phase was separated and the aqueous phase was extracted 3 times with AcOEt. The combined organic phases were dried (Na2SO4), concentrated and chromatographed [silica, elution with gradient CH2Cl2 to 40% (CH2Cl2/MeOH=9:1)] to yield the title compound as a colorless oil (1.2 g, 51%). MS: m/e=201 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1c(N)cccc1Cl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cccc(Cl)c2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
18.7 g of 3-chloro-2-methylaniline was dissolved in 120 mL of pyridine, and 22.9 g of p-toluene sulfonylchloride was added portionwise thereto over 30 minutes, followed by stirring at room temperature overnight. The reaction liquid was concentrated under reduced pressure, and to the obtained residue was added water, followed by extraction with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, saturated brine, an aqueous saturated sodium hydrogen carbonate solution, and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 34.6 g of N-(3-chloro-2-methylphenyl)-4-methylbenzenesulfonamide.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].C([Li])CCC.[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>O>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:20](=[NH:21])[C:19]1[CH:22]=[CH:23][C:16]([CH3:15])=[CH:17][CH:18]=1)[CH3:2]
Reactant: CCc1ccccc1N
Reactant: Cc1ccc(C#N)cc1
Agent: [Li]CCCC
Solvent: O
Product: CCc1ccccc1NC(=N)c1ccc(C)cc1
Reaction time: 8 h

Procedure:
Procedure as described for Amidine I using the following amounts: 6.18 mL of 2-ethylaniline (50.0 mmol); 25.0 mL of 2.0 M butyllithium (50.0 mmol), 5.86 g of 4-methylbenzonitrile (50.0 mmol). After refluxing overnight, the solution was dark brown. Addition of water yielded a yellow solution with suspended solid. Solution was filtered and taken to dryness. The residue was treated with 75 mL of pentane, stirred overnight, and filtered yielding 10.51 g (88%) of light yellow solid. 1H NMR (400 MHz, CDCl3): 7.79 (d, 2H), 7.25 (d, 3H), 7.17 (t, 1H), 7.02 (t, 1H), 6.86 (d, 1 H), 4.68 (s, 2H), 2.57 (q, 2H), 2.41 (s, 3H), 1.17 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[C:26]([F:37])[CH:25]=3)[CH:15]=2)=[C:9]([CH3:38])[CH:8]=1)[CH3:2].CO.[OH-].[Na+].Cl>O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[C:16]([CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[C:26]([F:37])[CH:25]=3)[CH:15]=2)=[C:9]([CH3:38])[CH:8]=1)[CH3:2]
Reactant: CCOCCOc1cc(C)c(-c2cc(COc3ccc(CCC(=O)OCC)c(F)c3)ccc2OC)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOCCOc1cc(C)c(-c2cc(COc3ccc(CCC(=O)O)c(F)c3)ccc2OC)c(C)c1
Yield: 19.9 %

Procedure:
To a mixture of ethyl 3-(4-{[4′-(2-ethoxyethoxy)-6-methoxy-2′,6′-dimethylbiphenyl-3-yl]methoxy}-2-fluorophenyl)propanoate (0.45 g, 0.86 mmol), methanol (4.5 mL) and tetrahydrofuran (9 mL) was added 1 N aqueous sodium hydroxide solution (1.7 mL) at room temperature with stirring and the mixture was stirred at the same temperature for 2 hrs. The reaction mixture was neutralized with 1 N hydrochloric acid and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with water and saturated brine, dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1-hexane/ethyl acetate=1/2) to give the title compound (85 mg, yield 20%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH2:18])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[CH3:19][CH2:20][O:21][C:22]([CH:24]1[C:29](=O)[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23]>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:25]2[CH2:26][CH2:27][CH2:28][CH2:29][C:24]=2[C:22]([O:21][CH2:20][CH3:19])=[O:23])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CC(C)OC(=O)c1cc(NC(N)=O)c(F)cc1Cl
Reactant: CCOC(=O)C1CCCCC1=O
Product: CCOC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(Cl)cc2F)CCCC1

Procedure:
using isopropyl 2-chloro-4-fluoro-5-ureidobenzoate and ethyl cyclohexanone-2-carboxylate there is obtained isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-cyclohexen-1-yl]ureido}-benzoate, m.p. 129°-130° C.,
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[H-].[Na+].[CH3:19]N(C=O)C.IC>O>[CH3:19][NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:11])([F:12])([F:13])([F:10])[F:9])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: CN(C)C=O
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CNc1ccc(S(F)(F)(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-amino-3-nitro-phenyl sulfur pentafluoride (2.0 g), 60% sodium hydride (oil) (310 mg) and DMF (15 ml) was added dropwise iodomethane (447 μL) while ice-cooling. After that, the mixture was stirred at room temperature for 3 hours. To the reaction mixture was poured water, and the precipitated solid was collected by filtration. The solid was washed with water and dried to give methyl-(2-nitro-4-pentafluorosulfanyl-phenyl)-amine (2.0 g).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]1([CH2:38]O)[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31][CH2:30]1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:38][CH:29]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:31][CH2:30]3)[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: OCC1CCc2ccccc21
Product: FC(F)(F)c1cccc2c(-c3cccc(OCC4CCc5ccccc54)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 69, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenol and indan-1-yl-methanol. MS (ESI) m/z 510.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=O)[CH:10]=[N:9]1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:26]2[CH2:31][CH2:30][CH:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH2:28][CH2:27]2)=[C:22]([CH:25]=1)[C:23]#[N:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH3:13])=[C:11]([C:14]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:26]3[CH2:31][CH2:30][CH:29]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)[CH2:28][CH2:27]3)=[C:22]([C:23]#[N:24])[CH:25]=2)=[O:16])[CH:10]=[N:9]1
Reactant: Cc1c(C(=O)O)cnn1-c1ccccc1Cl
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccccc1Cl
Yield: 37.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(2-chlorophenyl)-5-methylpyrazole-4-carboxylic acid (1.0 g) and 5-amino-2-(4-morpholinopiperidin-1-yl)benzonitrile (1.2 g), the title compound (0.79 g) was obtained, melting point: 218° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])/[CH:4]=[C:5](\[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=1)/[CH3:6].[C:18](#[N:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3]([C:4]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:25][N:7]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH3:16])=[CH:12][CH:13]=2)[C:5]=1[CH3:6])=[O:17]
Reactant: N#Cc1ccccc1
Reactant: CCOc1ccc(N/C(C)=C\C(=O)OC)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: CCOc1ccc(-n2nc(-c3ccccc3)c(C(=O)OC)c2C)cc1

Procedure:
According to AVV A, (Z-3-(4-ethoxyphenylamino)-but-2-enoic acid methylester (235.3 mg, 1.0 mmol, 1.0 equiv.) was stirred with Cu(OAc)2 (544.9 mg, 3.0 mmol, 3.0 equiv.) into benzonitrile (3.0 ml, 29.4 mmol, 29.4 equiv.) for 14 hours at 120° C. The olive-green oily raw product (490.3 mg) was purified by means of column chromatography (silica gel (50 g), pentane/EtOAc 95:5→0:100). The desired product was obtained in the form of a white solid (291.0 mg, 0.87 mmol, 87%).
Reaction SMILES: [Cl:1]CC([NH:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:9]([S:17]([N:20]=CN(C)C)(=[O:19])=[O:18])[C:8]=1[OH:25])=O>C(O)C.Cl>[ClH:1].[NH2:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([CH3:15])([CH3:16])[CH3:14])[CH:10]=[C:9]([S:17](=[O:18])(=[O:19])[NH2:20])[C:8]=1[OH:25]
Reactant: CN(C)C=NS(=O)(=O)c1cc(C(C)(C)C)cc(CNC(=O)CCl)c1O
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(CN)c(O)c(S(N)(=O)=O)c1

Procedure:
3 g (0.008 mole) of 2-chloro-N-[5-(1,1-dimethylethyl)-3-dimethylaminomethyleneaminosulfonyl-2-hydroxybenzyl]-acetamide in a mixture of 30 ml of ethanol and 3 ml of concentrated hydrochloric acid are heated under reflux for 2 hours. The solvent is removed in vacuo and the residue is crystallized from methanol/ether.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:19]([O-:21])=[O:20])=[C:4]([C:9]([C:13]2[N:17]=[C:16]([CH3:18])[O:15][N:14]=2)=[CH:10][C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:22]([N:24]([CH2:28][CH3:29])[C:25](Cl)=[O:26])[CH3:23].N1C=CC=CC=1.Cl>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:22]([N:24]([CH2:28][CH3:29])[C:25]([O:12][C:11]1[CH:10]=[C:9]([C:13]2[N:17]=[C:16]([CH3:18])[O:15][N:14]=2)[C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([N+:19]([O-:21])=[O:20])[C:2]=1[OH:1])=[O:26])[CH3:23]
Reactant: COC(=O)c1c(-c2noc(C)n2)cc(O)c(O)c1[N+](=O)[O-]
Reactant: CCN(CC)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)Oc1cc(-c2noc(C)n2)c(C(=O)OC)c([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 3,4-dihydroxy-6-(5-methyl-[1,2,4]-oxadiazol-3-yl)-2-nitrobenzoate (compound 1-5) (50 mg), diethylcarbamoyl chloride (0.024 mL), 4-dimethylaminopyridine (4 mg) and pyridine (2 mL) was stirred at room temperature for 3 hours. After addition of ethyl acetate, the mixture was acidified with 2 mol/L hydrochloric acid. The separated organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 20%-100% ethyl acetate/hexane, gradient elution) to give the title compound (31 mg). The structural formula was illustrated in table 13.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.CN(C=O)C.[F:17][C:18]([F:22])([F:21])[CH2:19][NH2:20]>CCOCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:20][CH2:19][C:18]([F:22])([F:21])[F:17])[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2occc2n1
Reactant: NCC(F)(F)F
Solvent: CCOCC
Solvent: CN(C)C=O
Product: FC(F)(F)CNc1nc(Cl)nc2ccoc12
Temperature: 120 °C
Yield: 71.4 %

Procedure:
To a flask was added 2,4-dichlorofuro[3,2-d]pyrimidine (0.80 g, 4.23 mmol, ArkPharm) and DMF (3.0 mL). 2,2,2-Trifluoroethanamine (1.05 g, 10.58 mmol, Acros) was added. The mixture was heated in a microwave at about 120° C. for about 15 min. The mixture was diluted with Et2O (100 mL). The mixture was washed with water (3×25 mL). The combined aqueous layer was extracted with Et2O (2×50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was transferred neat and was purified by preparative TLC eluting with 3:1 hexanes/EtOAc to give 2-chloro-N-(2,2,2-trifluoroethyl)furo[3,2-d]pyrimidin-4-amine (0.76 g, 71%): LC/MS (Table 2, Method h) Rt=1.85 min; MS m/z: 252, 254 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[CH:3]([OH:5])[CH3:4].[C:8](O)(=[O:12])/[CH:9]=[CH:10]/[CH3:11]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:4][CH:3]([O:5][C:8](=[O:12])[CH:9]=[CH:10][CH3:11])[CH:2]([CH3:1])[CH2:6][CH3:7]
Reactant: CCC(C)C(C)O
Reactant: C/C=C/C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC=CC(=O)OC(C)C(C)CC
Reaction time: 3.5 h
Yield: 66.6 %

Procedure:
3-Methyl-pentan-2-ol (400 g), crotonic acid (CH3CH═CHCOOH) (445.5 g), toluene (400 mL), and para-toluenesulfonic acid (PTSA) (4 g) were charged into to 2-L reaction flask fitted with a mechanical stirrer, a thermocouple, a condenser, and a Bidwell-Sterling trap. The reaction mixture was heated to reflux. Water was collected and removed via the Bidwell-Sterling trap. The reaction mixture was aged for about 3.5 hours. The resulting reaction mixture was then cooled and washed sequentially with water, aqueous sodium hydroxide (NaOH) (10%), and brine. The aqueous and organic layers were split. The organic layer was fractional distilled to provide but-2-enoic acid 1,2-dimethyl-butyl ester (444 g) with a boiling point of 106° C. at 34 mmHg.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH2:1]([NH:8][C:9]1[C:14]2[N:15]=[C:16]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nc(N2CCOCC2)c2ncnc(NCc3ccccc3)c2n1
Reactant: C1CNCCN1
Product: c1ccc(CNc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 118 from 8-benzylamino-2-chloro-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 139°-141° C.) and piperazine.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]3[N:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:11][C:8]2=[N:9][CH:10]=1)(=[O:4])=[O:3].[H-].[Na+].[CH:22]1([CH2:28]Br)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH:22]1([CH2:28][N:11]2[C:8]3=[N:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=[C:7]3[CH:13]=[C:12]2[C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: BrCC1CCCCC1
Reactant: CS(=O)(=O)c1cnc2[nH]c(-c3ncccn3)cc2c1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1cnc2c(c1)cc(-c1ncccn1)n2CC1CCCCC1
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a suspension of 5-methanesulfonyl-2-(2-pyrimidinyl)-1H-pyrrolo[2,3-b]pyridine (150 mg) in N,N-dimethylformamide (5.5 ml), 60% sodium hydride (32.8 mg) was added at 0° C. under nitrogen atmosphere and the mixture was stirred at the same temperature for 30 minutes. Subsequently, to the mixture was added cyclohexylmethyl bromide (154 mg) at 0° C. and the mixture was stirred at 60° C. for 2 hours, followed by addition of cyclohexylmethyl bromide (77 mg) and stirring of the mixture at the same temperature for 1 hour. Further, to the mixture was added cyclohexylmethyl bromide (77 mg) and the mixture was stirred at 60° C. for 15 hours. Subsequently, the reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (methanol:chloroform=1:20) and further recrystallized, (chloroform/hexane) to obtain 109 mg of the desired product as a white needle-like crystal.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[N:3]=1.C(N(CC)CC)C.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:3]=[C:2]([N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CN1CCNCC1
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCN(c2ncnc(Nc3ccc(P(C)(C)=O)cc3)n2)CC1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (0.072 mmol) in 1.5 mL of ethanol is added 10 L of triethylamine and 1-Methyl piperazine (7.2 mg, 0.072 mmol). The mixture can be microwaved at 120 degrees until formation of the desired compound. The reaction mixture is filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:12])[CH2:9][C:10]#[N:11].F[C:14]1C=CC=CC=1C(=O)C>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([OH:12])([CH3:14])[CH2:9][C:10]#[N:11]
Reactant: N#CCC(O)c1ccccc1F
Reactant: CC(=O)c1ccccc1F
Product: CC(O)(CC#N)c1ccccc1F

Procedure:
3-(2-Fluoro-phenyl)-3-hydroxy-butyronitrile was prepared by the same procedure of 3-(2-fluoro-phenyl)-3-hydroxy-propionitrile from 1-(2-fluoro-phenyl)-ethanone in example 6.