Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][O:6][C:7]([C:9]1([S:12][C:13]2[CH:18]=[C:17]([NH:19][C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][NH:23]3)=[S:21])[C:16]([F:28])=[CH:15][C:14]=2[Cl:29])[CH2:11][CH2:10]1)=[O:8].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:29][C:14]1[C:13]([S:12][C:9]2([C:7]([O:6][CH3:5])=[O:8])[CH2:10][CH2:11]2)=[CH:18][C:17]([N:19]=[C:20]2[N:22]3[N:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[C:1](=[O:2])[S:21]2)=[C:16]([F:28])[CH:15]=1
Reactant: O=C(Cl)Cl
Reactant: COC(=O)C1(Sc2cc(NC(=S)N3CCCCN3)c(F)cc2Cl)CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)C1(Sc2cc(N=c3sc(=O)n4n3CCCC4)c(F)cc2Cl)CC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
While stirring at a temperature of from 0° to +10° C., 5.7 ml of a 20% solution of phosgene in toluene are added dropwise to a solution of 3.7 g of 1-[2-chloro-4-fluoro-5-(1-hexahydropyridazinyl-thiocarbonylamino)-phenylthio]-cyclopropanecarboxylic acid methyl ester and 4.6 ml of triethylamine in 100 ml of toluene. The reaction mixture is then stirred for 4 hours and then introduced into ice-water. The organic phase is then separated off and dried over sodium sulfate. Concentration by evaporation and subsequent chromatographic purification by means of silica gel chromatography yield 3.7 g of 9-[4-chloro-2-fluoro-5-(1-methoxycarbonyl-cyclopropylthio)-phenylimino]-8-thia-1,6-diazabicyclo[4.3.0]nonan-7-one, having a melting point of +149° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH2:13][O:12][C:11](=[O:14])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(COC)OC>[CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH2:13][O:12][C:11](=[O:14])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C=C(NCc2ccccc2)CO1
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: O=C1C=C(N(Cc2ccccc2)Cc2ccccc2)CO1
Temperature: 50 °C
Reaction time: 7 h
Yield: 63.4 %

Procedure:
6.3 g of 4-(benzylamino)furan-2(5H)-one (Example 16) are initially charged in 75 ml of dimethoxyethane at room temperature. Subsequently, 1.1 g of sodium hydroxide are added and, at 40° C., 4 g of benzyl chloride are metered in. The mixture is stirred at 50° C. for a further 7 h. The solvent is substantially removed under reduced pressure and the residue is admixed with 50 ml of water and 50 ml of methylene chloride. The organic phase is removed, and the aqueous phase is extracted once again with 50 ml of methylene chloride. The combined methylene chloride phases are dried over sodium sulphate and the solvent is removed under reduced pressure. 5.6 g of 4-(dibenzylamino)furan-2(5H)-one are obtained (this corresponds to 68% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:13]#[N:14])[CH:10]2[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:12][CH:4]1[CH2:5]3)[CH2:9]2.[C:15]([O:19][C:20](=[O:30])[C:21]1[CH:26]=[C:25]([Cl:27])[C:24](F)=[CH:23][C:22]=1[F:29])([CH3:18])([CH3:17])[CH3:16].CC(C)([O-])C.[K+]>CS(C)=O.C(OCC)(=O)C>[Cl:27][C:25]1[C:24]([O:1][CH2:2][C:3]2([C:13]#[N:14])[CH:4]3[CH2:12][CH:8]4[CH2:7][CH:6]([CH2:11][CH:10]2[CH2:9]4)[CH2:5]3)=[CH:23][C:22]([F:29])=[C:21]([CH:26]=1)[C:20]([O:19][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:30]
Reactant: N#CC1(CO)C2CC3CC(C2)CC1C3
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2(C#N)C3CC4CC(C3)CC2C4)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
To a solution of 2-(hydroxymethyl)adamantane-2-carbonitrile (0.369 g, 1.93 mmol) and tert-butyl-5-chloro-2,4-difluorobenzoate (0.96 g, 3.86 mmol) in dimethylsulfoxide (30 mL) was added potassium tert-butoxide (0.42 g, 3.76 mmol). The mixture was stirred at ambient temperature for 0.5 hour, then diluted with ethyl acetate (200 mL). The organic layer was washed with 1 M hydrochloric acid (200 mL), brine (2×150 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography with a gradient of 0-30% ethyl acetate in hexanes to afford the title compound (0.64 g, 79% yield) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J=7.6 Hz, 1H), 6.65 (d, J=11.7 Hz, 1H), 4.29 (s, 2H), 2.36-2.30 (m, 4H), 2.02 (br s, 1H), 1.91-1.74 (m, 9H), 1.56 (s, 9H); MS (ES−) m/z 420.1 (M+1).
Reaction SMILES: C(O[CH:5]([C:27]1[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)(=O)C.C(N(CC)CC)C.[H][H]>CN(C)C=O.[OH-].[Pd+2].[OH-]>[C:33]([C:30]1[CH:31]=[CH:32][C:27]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([O:12][C:13]3[C:22]4[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=4)[N:16]=[CH:15][CH:14]=3)=[CH:8][CH:7]=2)=[CH:28][CH:29]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: [H][H]
Reactant: COc1cc2nccc(Oc3ccc(C(OC(C)=O)c4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(Cc4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Yield: 78.6 %

Procedure:
(4-Tert-butylphenyl)-[4-(6,7-dimethoxy-4-quinolyloxy)phenyl]-methyl acetate (Compound 31) (26 mg) was dissolved in N,N-dimethylformamide (3 ml) to prepare a solution. Triethylamine (0.5 ml) and 20% palladium hydroxide (200 mg) were then added to the solution, and the mixture was stirred in a hydrogen atmosphere at room temperature for 2 hr. The reaction solution was filtered, water and ethyl acetate were added to the filtrate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and was dried over sodium sulfate. The solvent was removed by evaporation under the reduced pressure to give the title compound (18 mg, yield 79%).
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1[N:12]=[CH:13][C:14]([C:21]2[CH:31]=[CH:30][C:24]([C:25]([N:27]([CH3:29])[CH3:28])=[O:26])=[CH:23][CH:22]=2)=[N:15][C:16]=1[C:17]([NH:19][NH2:20])=[O:18].Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[NH2:10][C:11]1[N:12]=[CH:13][C:14]([C:21]2[CH:22]=[CH:23][C:24]([C:25]([N:27]([CH3:28])[CH3:29])=[O:26])=[CH:30][CH:31]=2)=[N:15][C:16]=1[C:17]1[O:18][C:33](=[O:35])[NH:20][N:19]=1
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(C(=O)NN)n2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3n[nH]c(=O)o3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
DIPEA (86.08 mg, 116.0 μL, 0.6660 mmol) was added to a solution of 4-(5-amino-6-(hydrazinecarbonyl)pyrazin-2-yl)-N,N-dimethylbenzamide (100 mg, 0.3330 mmol) in DCM (6.500 mL) under nitrogen. A solution of triphosgene (39.53 mg, 0.1332 mmol) in DCM (100.0 μL) was then added dropwise to the stirred solution. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was filtered and the solid obtained dried under vacuum to yield the product (106. g mg, 98% yield); 1H NMR (400.0 MHz, DMSO) d 2.96 (s, 3H), 3.00 (s, 3H), 7.33 (br s, 2H), 7.52 (d, 2H), 8.09 (d, 2H), 8.89 (s, 1H) and 12.98 (br s, 1H) ppm; MS (ES+) 327.12
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=2[N:3]=1.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH2:18].C(=O)(O)[O-].[Na+]>>[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][NH:18][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:4]=2[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]c(Cl)nc12
Reactant: CN(C)CCN
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C)CCNc1nc2c([N+](=O)[O-])cccc2[nH]1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-4-nitro-1H-benzimidazole (300 mg) and N,N-dimethylethylenediamine (2 ml) were stirred at 80° C. for 8 hours. The reaction mixture was poured into saturated sodium bicarbonate aqueous solution and extracted with a mixture of chloroform and methanol. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was washed with diisopropyl ether to give 2-[[2-(dimethylamino)ethyl]amino]-4-nitro-1H-benzimidazole (113 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[N:10]1.[OH:27][CH:28]1[CH2:32][NH:31][CH:30]([C:33]([OH:35])=[O:34])[CH2:29]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[NH:12][C:13]([CH2:20][N:31]2[CH2:32][CH:28]([OH:27])[CH2:29][CH:30]2[C:33]([OH:35])=[O:34])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)C1CC(O)CN1
Product: CCOC(=O)C1=C(CN2CC(O)CC2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 65 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.92 g, 3.81 mmol) was reacted with 4-hydroxypyrrolidine-2-carboxylic acid (0.5 g, 3.81 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (1.37 g, 65%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:37]=[CH:38][CH:39]=1)[C:12]([NH:14][C:15]1[CH:16]=[C:17]([CH:33]=[CH:34][C:35]=1[CH3:36])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:22]=1)=[O:19])=[O:13])C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:37]=[CH:38][CH:39]=1)[C:12]([NH:14][C:15]1[CH:16]=[C:17]([CH:33]=[CH:34][C:35]=1[CH3:36])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)[CH:22]=1)=[O:19])=[O:13]
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(O)c1
Reaction time: 12 h
Yield: 80.5 %

Procedure:
A mixture of 3-(3-benzyloxybenzamido)-4-methyl-N-(3-morpholinophenyl)benzamide (4.49 g), 10% palladium-on-carbon (0.5 g) and ethyl acetate was stirred under an atmosphere of hydrogen gas for 12 hours. The resultant mixture was filtered through diatomaceous earth and the separated solids were washed with warm DMF (200 ml). The combined filtrates were concentrated to a volume of about 20 ml and water (50 ml) was added. The resultant solid was dried under vacuum at 55° C. There was thus obtained the title compound as a solid (2.99 g); NMR Spectrum: (DMSOd6) 2.25 (s, 3H), 3.07 (t, 4H), 3.72 (t, 4H), 6.67 (m, 1H), 6.97 (m, 1H), 7.18 (t, 1H), 7.36 (m, 6H), 7.78 (m, 1H), 7.92 (s, 1H), 9.68 (s, 1H), 9.89 (s, H), 10.01 (s, 1H); Mass Spectrum: M+H+ 432.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:10][C:11](=[O:40])[CH:12]([CH2:35][S:36][C:37](=[O:39])[CH3:38])[CH2:13][C:14]1[CH:15]=[N:16][C:17]([N:20](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:18][CH:19]=1)[CH3:9]>C(Cl)Cl>[CH2:8]([O:10][C:11](=[O:40])[CH:12]([CH2:35][S:36][C:37](=[O:39])[CH3:38])[CH2:13][C:14]1[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=1)[CH3:9]
Reactant: CCOC(=O)C(CSC(C)=O)Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(CSC(C)=O)Cc1cnc(N)nc1
Reaction time: 2 h
Yield: 132 %

Procedure:
TFA (1.5 mL) was added to a solution of 2-acetylsulfanylmethyl-3-(2-[N,N-bis(tert-butoxycarbonyl)amino]-pyrimidin-5-yl)-propionic acid ethyl ester (225 mg, 0.46 mmol) in methylene chloride (1.5 mL). The reaction was stirred for 120 min and concentrated under reduced pressure to give the title compound (172 mg, 94%) as the TFA salt.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH3:11])[N+:3]=1[O-].[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([CH2:11][O:16][C:13](=[O:15])[CH3:14])[N:3]=1
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)[n+]1[O-]
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCc1ccc([N+](=O)[O-])c(Cl)n1
Temperature: 60 °C

Procedure:
2-Chloro-3-nitro-6-picoline-N-oxide (1,6 g, 8.5 mmol) was dissolved in acetic anhydride (5 mL) and the solution was heated in a 60° C. oil bath for 3 hours. The solvents were removed under vacuum and the dark residue was partitioned between methylene chloride (30 mL) and saturated aqueous potassium carbonate (100 mL). The aqueous layer was re-extracted with more methylene chloride (2×40 mL) and the combined methylene chloride layers were dried with magnesium sulfate, filtered and evaporated under vacuum. The crude solid was dissolved in methylene chloride (SmL) and was loaded onto a silica gel column (E. Merck 60, 230-400 mesh, 2.5×24 cm). The column was eluted with methylene chloride collecting 8 mL fractions. Fractions 11-26 were combined and evaporated to give the title compound (0.42 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])=[N:4][CH:5]=[N:6][C:7]=1[CH:8](O)[CH3:9].C(N(S(F)(F)[F:28])CC)C>ClCCl>[Cl:1][C:2]1[C:3]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])=[N:4][CH:5]=[N:6][C:7]=1[CH:8]([F:28])[CH3:9]
Reactant: CSc1ccc(C(C)Nc2ncnc(C(C)O)c2Cl)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CSc1ccc(C(C)Nc2ncnc(C(C)F)c2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 80 ml of dichloromethane was dissolved 4.7 g of 5-chloro-6-(1-hydroxyethyl)-4-[1-(4-methylthiophenyl)ethylamino]pyrimidine, and to the mixture was added dropwise 2.6 g of diethylaminosulfur trifluoride under ice cooling. The mixture was stirred at room temperature for 1 hour.
Reaction SMILES: [C:1]1(=[O:21])[N:5]([CH2:6][CH2:7][CH2:8][S:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[C:4](=[O:16])[C:3]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:2]12.[BH4-].[Na+]>C(O)C>[OH:21][CH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=1)=[O:16]
Reactant: O=C1c2ccccc2C(=O)N1CCCSc1ccncc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(NCCCSc1ccncc1)c1ccccc1CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 78.2 %

Procedure:
To a solution of 5.97 g (20.0 mmol) of 4-(3-phthalimidopropylthio)pyridine in 300 ml of ethanol, 7.57 g (200 mmol) of sodium borohydride was added, and stirred at room temperature for 24 hours. The solvent was distilled off and saturated saline was added to the residue. The mixture was extracted with chloroform and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:10) to give 4.73 g of the desired compound (78.2% yield, colorless crystals), mp. 110°-111° C.
Reaction SMILES: [CH:1]([Si:4](OS(C(F)(F)F)(=O)=O)([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Br:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([CH3:39])([CH3:38])[CH2:34][NH:35]2)=[CH:31][C:30]=1[F:40]>C(Cl)Cl>[Br:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([CH3:38])([CH3:39])[CH2:34][N:35]2[Si:4]([CH:1]([CH3:2])[CH3:3])([CH:5]([CH3:6])[CH3:7])[CH:8]([CH3:9])[CH3:10])=[CH:31][C:30]=1[F:40]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: CC1(C)CNc2cc(Br)c(F)cc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[Si](C(C)C)(C(C)C)N1CC(C)(C)c2cc(F)c(Br)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
Triisopropylsilyltrifluoromethanesulfonate (3.5 mL, 13.0 mmol) and DIPEA (3.2 mL, 19.5 mmol) were added to a solution of 6-bromo-5-fluoro-3,3-dimethyl-2,3-dihydro-1H-indole (1.5 g, 6.5 mmol) in DCM (50 mL). The reaction mixture was stirred at room temperature overnight then quenched with saturated aqueous NaHCO3 and extracted with DCM (×3). The organic phase was dried (MgSO4), filtered and concentrated. The crude material was purified by SiO2 chromatography (10% EtOAc in petrol) to give the title compound (1.8 g) as a white solid. 1H NMR (DMSO-d6): 7.07 (1H, d), 6.65 (1H, d), 3.44 (2H, s), 1.64-1.33 (3H, m), 1.33-1.17 (6H, m), 1.10 (18H, d).
Reaction SMILES: Cl.Cl[CH:3]([CH2:6][NH2:7])[C:4]#N.[OH-:8].[Ca+2:9].[OH-:10]>O>[NH:7]1[CH2:6][CH:3]1[C:4]([O-:10])=[O:8].[Ca+2:9].[NH:7]1[CH2:6][CH:3]1[C:4]([O-:10])=[O:8]
Reactant: [OH-]
Reactant: N#CC(Cl)CN
Agent: Cl
Agent: [Ca+2]
Solvent: O
Product: O=C([O-])C1CN1
Temperature: 60 °C

Procedure:
14.1 g of alpha-chloro-beta-aminopropionitrile hydrochloride was dissolved in 160 g of water, and with stirring, 12 g of calcium hydroxide was gradually added. Then, the reaction mixture was heated to 60° C., and reacted at 60° to 65° C. for 8 hours. After the reaction, the excess of calcium hydroxide was removed by filtration. The residue was analyzed by high-speed liquid chromatography in the same way as in Example 1. The yield of calcium aziridine-2-carboxylate formed was 92.5%.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:22]=[CH:21][C:20]([CH2:23][CH2:24][CH3:25])=[CH:19][N:18]=3)[CH2:13][CH2:12]2)[CH:7]=[CH:6][N:5]1[C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:28][CH:27]=1.[CH3:39]I>CN(C=O)C>[CH3:39][N:32]([C:29]1[CH:28]=[CH:27][C:26]([N:5]2[CH:6]=[CH:7][C:8]([O:10][CH:11]3[CH2:16][CH2:15][N:14]([C:17]4[N:22]=[CH:21][C:20]([CH2:23][CH2:24][CH3:25])=[CH:19][N:18]=4)[CH2:13][CH2:12]3)=[CH:9][C:4]2=[O:3])=[CH:31][CH:30]=1)[C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: CI
Reactant: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(NC(=O)C(C)(C)C)cc4)c(=O)c3)CC2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1cnc(N2CCC(Oc3ccn(-c4ccc(N(C)C(=O)C(C)(C)C)cc4)c(=O)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.2 %

Procedure:
To a stirring suspension of sodium hydride (9.1 mg, 0.23 mmol), N-(4-(2-oxo-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)pyridin-1(2H)-yl)phenyl)pivalamide (15 mg, 0.030 mmol) in DMF (2 mL) was added Methyl iodide (10 μL, 0.16 mmol). The reaction was stirred at room temperature for 1.5 h. The reaction was quenched with H2O and extracted with EtOAc. The organic layer was concentrated in vacuo to a white solid. The solid was purified by flash chromatography (SiO2, 0 to 100% EtOAc in CH2Cl2) to yield 10 mg of the desired product as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.19 (s, 2H), 7.39-7.48 (m, 2H), 7.32-7.39 (m, 2H), 7.26 (d, J=2.01 Hz, 1H), 5.98-6.09 (m, 2H), 4.55-4.64 (m, 1H), 4.16-4.28 (m, 2H), 3.59-3.71 (m, 2H), 3.27 (s, 3H), 2.43 (t, J=7.40 Hz, 2H), 1.98-2.22 (m, 2H), 1.74-1.98 (m, 2H), 1.53-1.66 (m, 2H), 1.12 (s, 9 H), 0.96 (t, J=7.28 Hz, 3H). MS (ESI) 504 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.O[N:12]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH2:12])=[O:10])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(N)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 162.6 %

Procedure:
A mixture of 6-aminopyridine-3-carboxylic acid (8.36 g), N-hydroxybenzotriazole (10.2 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12.8 g) and 4-dimethylaminopyridine (8.12 g) in N,N-dimethylformamide (300 ml) was stirred at 0° C. for 15 minutes. (2E,4E)- and (2Z,4E)-4-methyl-2,4-heptadien-1-ylamine (7.7 g) was added to the mixture. The solution was stirred at 0° C. for 2 hours and then at room temperature overnight. The mixture was evaporated in vacuo and the residue was diluted with water. The resulting precipitate was filtered and washed with water to give N-[(2E,4E)- and (2Z-4E)-4-methyl-2,4-heptadien-1-yl]-6-amino-3-pyridinecarboxamide (13.5 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[SH:11].[C:12]1([CH3:20])[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1>N1C=CC=CC=1>[CH3:20][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:11][C:3]3[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=3[N:1]=2)=[CH:14][CH:13]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: Nc1cc([N+](=O)[O-])ccc1S
Solvent: c1ccncc1
Product: Cc1ccc(-c2nc3cc([N+](=O)[O-])ccc3s2)cc1
Temperature: 100 °C

Procedure:
To a stirred solution of 153.2 g (0.9 mole) of 2-amino-4-nitrothiophenol in pyridine is added 108.1 g (0.9 mole) of 4-tolualdehyde, and the reaction is heated at 100° C. until the starting materials are consumed. After cooling to room temperature, the mixture is acidified with cold 2N HCl, and the intermediate benzthiazoline is collected by filtration. The benzthiazoline is dissolved in methanol, then ferric chloride is added, and the solution is warmed at 40° C. for about 2 hours until oxidation to the benzthiazole is complete. The product is recrystallized from ethanol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C@@H:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C@H:8]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:30]>ClCCl>[O-:30][N+:1]1[CH:6]=[CH:5][C:4]([C@@H:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][C@H:8]2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:3][CH:2]=1
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1ccncc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1cc[n+]([O-])cc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a dichloromethane solution (0.1 M) of trans-1-(1,1-dimethylethyl) 3-ethyl 4-(4-pyridinyl)-1,3-piperidinedicarboxylate (1 eq.) from the previous step was added 3-chloroperoxybenzoic acid (1 eq.). The resulting colorless solution was stirred at RT for 13 h. The reaction was then quenched with sat. aq. NaHSO3 and 1 N aq. NaOH. The aqueous layer was separated and back-extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over Na2SO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a white solid.
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]([F:15])=[C:11]([Cl:16])[CH:10]=2)[CH:3]=1.[OH:17][CH2:18][CH2:19][N:20]([C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1)[CH3:21]>>[Cl:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[F:15])[NH:8][C:4]1[CH:3]=[C:2]([NH:26][C:25]2[CH:24]=[CH:23][C:22]([N:20]([CH2:19][CH2:18][OH:17])[CH3:21])=[CH:28][CH:27]=2)[N:7]=[CH:6][N:5]=1
Reactant: CN(CCO)c1ccc(N)cc1
Reactant: Fc1ccc(Nc2cc(Cl)ncn2)cc1Cl
Product: CN(CCO)c1ccc(Nc2cc(Nc3ccc(F)c(Cl)c3)ncn2)cc1
Yield: 10 %

Procedure:
Using an analogous reaction procedure to that described in Example 6, 6-chloro-4-(3'-chloro-4'-fluoroanilino)pyrimidine (0.258 g) was reacted with 4-[N-(2-hydroxyethyl)-N-methylamino]aniline (0.166 g). The product so obtained was recrystallised from a mixture of methylene chloride, methanol and hexane to give 4-[3'-chloro-4'-fluoroanilino]6-[4'-{N-(2-hydroxyethyl) -N-methylamino}anilino]pyrimidine in 10% yield;
Reaction SMILES: [CH2:1]([O:3][CH:4]=[CH2:5])[CH3:2].[Br:6][CH:7]([CH3:17])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:9]>C1(C)C=CC=CC=1.C(O)(C(F)(F)F)=O>[Br:6][CH:7]([CH3:17])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:1]([O:3][CH2:4][CH3:5])[CH3:2])=[CH:12][CH:11]=1)=[O:9]
Reactant: C=COCC
Reactant: CC(Br)C(=O)c1ccc(O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(C)Oc1ccc(C(=O)C(C)Br)cc1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 103.9 %

Procedure:
Ethoxyethene (3.148 g, 43.655 mmol) and TFA (0.249 g, 2.183 mmol) was added to a suspension of 2-bromo-1-(4-hydroxyphenyl)propan-1-one (5.000 g, 21.827 mmol) in toluene (50 ml) at rt. The reaction mixture was stirred at 30° C. for 2 h and 30 min. The solvent was evaporated to yield the product as an oil (6.83 g, 100%).