Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].[C:33]([O-:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([O-:38])=[O:37]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37].[CH3:28][S:29]([NH:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[CH2:5][N:6]1[CH2:7][CH2:8][N:9]([CH:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH2:11]1)(=[O:31])=[O:30]
Reactant: Nc1cccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)c1
Reactant: CS(=O)(=O)Cl
Reactant: O=C([O-])/C=C/C(=O)[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Nc1cccc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)c1
Product: O=C(O)/C=C/C(=O)O

Procedure:
To a solution of 1-(3-aminobenzyl)-4-benzhydrylpiperazine (1.43 g) in a mixture of pyridine (3.2 g) and chloroform (20 ml) was dropwise added methanesulfonylchloride (0.31 ml) at 5° to 6° C. with stirring. The mixture was stirred at the same temperature for 30 minutes and at ambient temperature for 2 hours. The reaction mixture was concentrated and the resultant was extracted with ethyl acetate. The extract was washed with water, dried and evaporated in vacuo to give a residue. According to a conventional manner, the residue was converted to fumarate, which was recrystallized from ethanol to afford 1-(3-methanesulfonylaminobenzyl)-4-benzhydrylpiperazine fumarate (0.65 g) as yellow crystals. mp: 213°-215° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:32][O:33][C:34](=[O:44])[C:35]1[CH:40]=[CH:39][C:38]([CH:41](Br)[CH3:42])=[CH:37][CH:36]=1>C1COCC1>[CH3:32][O:33][C:34](=[O:44])[C:35]1[CH:40]=[CH:39][C:38]([CH:41]([CH3:42])[CH:10]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:21])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:18])([CH3:20])[CH3:19])=[CH:13][CH:12]=2)=[CH:37][CH:36]=1
Reactant: CC(C)(C)c1ccc(CC(=O)OCc2ccccc2)cc1
Reactant: COC(=O)c1ccc(C(C)Br)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)C(C(=O)OCc2ccccc2)c2ccc(C(C)(C)C)cc2)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of (4-tert-butyl-phenyl)acetic acid benzyl ester (Step C, 1.8 g, 6.38 mmol) in anhydrous THF (15 mL) was added LiHMDS (9.57 mL, 9.57 mmol, 1.0 M solution in toluene) at −78° C. The reaction mixture was stirred for 1.5 h at −78° C., and then 4-(1-bromo-ethyl)-benzoic acid methyl ester (1.7 g, 7.02 mmol, in THF 5.0 mL) was added dropwise, stirred for 2 h at −78° C. and then allowed to warm to rt for 1 h. After completion of the reaction quenched with saturated NH4Cl solution (20 mL) and stirred for 10 min. The reaction mixture was extracted with ethyl acetate (100 mL) and the organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was recrystallization from minimum amount of EtOAc and hexane at room temperature to afford 4-[2-benzyloxycarbonyl-2-(4-tert-butyl-phenyl)-1-methyl-ethyl]-benzoic acid methyl ester as a mixture of diastereomers (2.3 g, 80%), d/r (2:1): 1H NMR (300 MHz, CDCl3): δ 8.02 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.30-7.38 (m, 7H), 7.06 (d, J=6.9 Hz, 2H), 5.11 (dd, J=6.0, 12.9 Hz, 2H), 3.92 (s, 3H), 3.75 (d, J=7.5 Hz, 1H), 3.49-3.46 (m, 1H), 1.29 (s, 9H), 1.24 (d, J=6.9, Hz, 3H); TLC conditions: Uniplate silica gel, 250 microns; mobile phase=ethyl acetate-hexanes (1:4); Rf=0.6.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]2[CH2:18][CH2:19][CH2:20][C:13]=2[N:12]=1.[CH3:21][O:22][C:23]([C:25]1([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:28][CH2:27][CH2:26]1)=[O:24]>C(O)C>[CH3:21][O:22][C:23]([C:25]1([C:29]2[CH:30]=[CH:31][C:32]([NH:35][C:15]3[C:14]4[CH2:18][CH2:19][CH2:20][C:13]=4[N:12]=[C:11]([Cl:10])[N:16]=3)=[CH:33][CH:34]=2)[CH2:26][CH2:27][CH2:28]1)=[O:24]
Reactant: COC(=O)C1(c2ccc(N)cc2)CCC1
Reactant: Clc1nc(Cl)c2c(n1)CCC2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COC(=O)C1(c2ccc(Nc3nc(Cl)nc4c3CCC4)cc2)CCC1
Temperature: 10 °C
Yield: 61.8 %

Procedure:
Diisopropylethylamine (45.9 mL, 264.55 mmol) was added slowly to a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopentapyrimidine (10 g, 52.91 mmol) and 1-(4-amino-phenyl)-cyclobutanecarboxylic acid methyl ester (13.015 g, 63.49 mmol) in anhydrous ethanol (100 mL) under stirring at 10° C. Thereafter, the mixture was heated at reflux for 48 hours and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel) to afford the title compound as a light yellow solid (11.7 g, 62% yield).
Reaction SMILES: N(C[C:5]([O:7]CC)=[O:6])=C=O.[N:10]([CH:13]([CH2:23][C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:25])[C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:15])=C=O>CN(C=O)C.CS(C)=O.O>[C:5](=[O:6])([OH:7])[NH2:10].[NH2:10][C@H:13]([C:14]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:15])[CH2:23][C:24]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:25]
Reactant: CCOC(=O)CN=C=O
Reactant: CCCCCCOC(=O)CC(N=C=O)C(=O)OCCCCCC
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCOC(=O)C[C@H](N)C(=O)OCCCCCC
Product: NC(=O)O
Reaction time: 1 h

Procedure:
2.7 g (i.e., 50 mmol of hydroxyls) of dextran with a weight-average molar mass of approximately 10 kg/mol (Bachem) are dissolved in a DMF/DMSO mixture. The mixture is brought to 130° C. with stirring and 3.2 g (25 mmol) of ethyl isocyanatoacetate and then 3.9 g (8 mmol) of dihexyl 2-isocyanatobutanedioate are gradually introduced. After reacting for 1 h, the medium is diluted in water and purified by diafiltration through a 5 kD PES membrane against 0.1N NaOH, 0.9% NaCl and water. The final solution is quantitatively determined by dry extract, in order to determine the concentration of polymer. A fraction of solution is lyophilized and analyzed by 1H NMR in D2O in order to determine the degree of conversion of the hydroxyls to N-(sodium methylcarboxylate) carbamate and the degree of the functionalization of the hydroxyls to give dihexyl aspartate carbamate.
Reaction SMILES: CS(O[CH2:6][C:7]1([C:12]#[N:13])[CH2:10][C:9](=[CH2:11])[CH2:8]1)(=O)=O.[C-]#N.[K+].[CH3:17][N:18](C)C=O>O>[C:17]([CH2:6][C:7]1([C:12]#[N:13])[CH2:10][C:9](=[CH2:11])[CH2:8]1)#[N:18]
Reactant: CN(C)C=O
Reactant: C=C1CC(C#N)(COS(C)(=O)=O)C1
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: C=C1CC(C#N)(CC#N)C1
Temperature: 65 °C

Procedure:
A mixture of (1-cyano-3-methylenecyclobutyl)methyl methanesulfonate (0.41 g, 0.0020 mol) and potassium cyanide (0.66 g, 0.010 mol) in N,N-dimethylformamide (5 mL, 0.06 mol) was heated at 65° C. overnight. After diluting with water, the resulting mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, dried and evaporated to dry. The residue was used directly in next step.
Reaction SMILES: [CH2:1]([N:3]([CH2:38][CH3:39])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:48]1N=N[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][C:49]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.NC1C=CC=CC=1>CN(C=O)C>[CH2:38]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([F:37])[C:35]=2[CH3:36])[C:30]([NH:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:39]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: Nc1ccccc1
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)Nc3ccccc3)cc(F)c2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-5-fluoro-4-methylbenzoic acid (30 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and aniline (7.51 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (14.1 mg, 42%). LC-MS m/z 615 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.ClC(Cl)(O[C:20](=[O:26])OC(Cl)(Cl)Cl)Cl.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl.C(N(CC)CC)C>[N:28]1([C:20]([N:2]2[CH2:3][CH2:4][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:6][CH2:7]2)=[O:26])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)N2CCCCC2)CC1
Reaction time: 2 h
Yield: 100.3 %

Procedure:
A suspension of 1.0 g of tert-butyl piperidin-4-ylcarbamate hydrochloride and 0.6 ml of triethylamine in 15 ml of methylene chloride was added to a solution of 418 mg of triphosgene in 10 ml of methylene chloride under cooling with ice-water bath. The reaction mixture was stirred for 2 hours with ice cooling, and then a solution of 358 mg of piperidine and 0.6 ml of triethylamine in 5 ml of methylene chloride was added thereto and stirred at room temperature for 15 hours. Aqueous 10% citric acid solution was added to the reaction mixture, and this was extracted with EtOAc. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The resulting solid was washed with ether to obtain 440 mg of tert-butyl [1-(piperidine-1-carbonyl)piperidin-4-yl]carbamate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]34[CH2:20][CH2:19][C:16]([C:21](O)=[O:22])([CH2:17][CH2:18]3)[CH2:15][CH2:14]4)[O:10][N:9]=2)=[CH:4][CH:3]=1.[F:24][C:25]([F:37])([F:36])[C:26]1[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=1[C:28]([NH:30][NH2:31])=O.[Cl-].ClC1N(C)CC[NH+]1C.C(N(CC)CC)C>ClCCl.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]34[CH2:20][CH2:19][C:16]([C:21]5[O:22][C:28]([C:27]6[CH:32]=[CH:33][CH:34]=[CH:35][C:26]=6[C:25]([F:24])([F:36])[F:37])=[N:30][N:31]=5)([CH2:15][CH2:14]3)[CH2:17][CH2:18]4)[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: NNC(=O)c1ccccc1C(F)(F)F
Reactant: O=C(O)C12CCC(c3nc(-c4ccc(F)cc4)no3)(CC1)CC2
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Fc1ccc(-c2noc(C34CCC(c5nnc(-c6ccccc6C(F)(F)F)o5)(CC3)CC4)n2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of the acid (7-C) (138.9 mg, 0.439 nmol) and 2-(trifluoromethyl)benzoic hydrazide (7-D) (89.7 mg, 0.439 mmol) was first co-evaporated with toluene three times. Dichloromethane (7 mL) was added to the mixture as solvent. To the resulting suspension was added 2-chloro-1,3-dimethylimidazolinium chloride (743 mg, 4.39 mmol) followed by triethylamine (1.2 mL, 8.78 mmol). The mixture was allowed to stir at room temperature under nitrogen for 48 h to ensure the completion of the reaction. The reaction mixture was then diluted with dichloromethane, washed with water, 1N HCl, saturated sodium bicarbonate aqueous solution, and lastly brine. The organics were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography using hexane/ethyl acetate (3/1) as eluent to give 3-(4-fluorophenyl)-5-(4-{5-[2-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}bicyclo[2.2.2]oct-1-yl)-1,2,4-oxadiazole (7-E) as a white solid. 1H NMR (500 MHz, CDCl3) δ 2.25 (s, 12H), 7.21 (t, J=8.7 Hz, 2H), 7.74-7.76 (m, 2H), 7.91 (m, 1H), 8.11-8.15 (m, 3H) ppm. ESI-MS m/z (M+H) 485.2.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=O)=[CH:6][C:5]=1[C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:24])[NH:19][CH:18]=[CH:17]2.C(OC)(=O)C.[CH2:30](Br)[CH:31]=[CH2:32].[CH:34]1([NH2:37])[CH2:36][CH2:35]1.C([Mg]Cl)(C)C>C1COCC1.CN(C=O)C>[CH2:30]([N:19]1[CH:18]=[CH:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([C:5]3[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=3[CH3:3])[C:8]([NH:37][CH:34]3[CH2:36][CH2:35]3)=[O:10])[CH:15]=2)[C:20]1=[O:24])[CH:31]=[CH2:32]
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(C)c(-c2ccc3c(=O)[nH]ccc3c2)c1
Reactant: C=CCBr
Agent: CC(C)[Mg]Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COC(C)=O
Solvent: C1CCOC1
Product: C=CCn1ccc2cc(-c3cc(C(=O)NC4CC4)ccc3C)ccc2c1=O
Reaction time: 0.25 h

Procedure:
Sodium hydride (75 mg, 60% in oil) was added to a stirred mixture of 4-methyl-3-(1-oxo-1,2-dihydro-isoquinolin-6-yl)-benzoic acid, methyl ester (Intermediate 3) (250 mg), methyl acetate (0.5 mL) and DMF (5 mL). The mixture was stirred for 15 minutes. Allyl bromide (0.5 mL) was added via syringe and the mixture was stirred for 30 minutes, then quenched with sat. aqueous NH4Cl solution and extracted into ethyl acetate. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to give crude ester. The ester was treated with THF (5 mL) and cyclopropylamine (0.3 mL). A solution of isopropylmagnesium chloride (2M, 0.4 mL) in THF was added dropwise. The reaction mixture was stirred for 10 minutes, quenched with sat. aqueous NH4Cl solution and extracted into ethyl acetate. The phases were separated, the organic phase was dried (Na2SO4), filtered and concentrated in vacuo to give crude product (380 mg). A sample (80 mg) of crude product was purified by HPLC to give an analytical sample of the title compound as a solid (45 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[N:12]=[C:11]([N:13]([CH3:15])[CH3:14])[C:10]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:9][N:8]=2)=[CH:4][CH:3]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH:56]1[C:65]2[C:60](=[CH:61][CH:62]=[CH:63][CH:64]=2)[CH:59]=[CH:58][C:57]=1[C:66](O)=[O:67]>CN(C=O)C.O>[CH3:14][N:13]([CH3:15])[C:11]1[C:10]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:9][N:8]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:66]([C:57]3[CH:58]=[CH:59][C:60]4[C:65](=[CH:64][CH:63]=[CH:62][CH:61]=4)[CH:56]=3)=[O:67])=[CH:22][CH:21]=2)[N:12]=1
Reactant: COC(=O)Cc1cnc(Cc2ccc(N)cc2)nc1N(C)C
Reactant: O=C(O)c1ccc2ccccc2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cnc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1N(C)C
Reaction time: 3 h

Procedure:
A solution containing methyl [2-(4-aminobenzyl)-4-(dimethylamino)pyrimidin-5-yl]acetate (0.090 g, 0.30 mmol) and PyBOP (0.187 g, 0.36 mmol) in anhydrous DMF (1 mL) at room temperature was treated with 2-naphthoic acid (0.062 g, 0.36 mmol). The reaction mixture was stirred for 3 hours before diluting with water. The thus quenched reaction mixture was extracted with EtOAc and the combined organic extracts was washed sequentially with 0.5N HCl, saturated NaHCO3, and brine, dried over anhydrous MgSO4, filtered, and concentrated to dryness to give the crude product methyl {4-(dimethylamino)-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate.
Reaction SMILES: [C:1]([CH2:3][CH2:4][P:5]([CH:10]([O:15][CH2:16][CH2:17][CH3:18])[O:11][CH2:12][CH2:13][CH3:14])(=[O:9])[O:6][CH2:7][CH3:8])#[N:2].N>[Ni].C(O)C>[NH2:2][CH2:1][CH2:3][CH2:4][P:5]([CH:10]([O:15][CH2:16][CH2:17][CH3:18])[O:11][CH2:12][CH2:13][CH3:14])(=[O:9])[O:6][CH2:7][CH3:8]
Reactant: CCCOC(OCCC)P(=O)(CCC#N)OCC
Agent: [Ni]
Agent: N
Solvent: CCO
Product: CCCOC(OCCC)P(=O)(CCCN)OCC

Procedure:
A mixture of 4,35 g of ethyl 2-cyanoethyl(di-n-propyloxymethyl)phosphinate,10 g of ammonia and 2.3 g of Raney-Nickel :n 170 ml of ethanol is hydrogenated for 10.5 hours. The catalyst is filtered off and the solvent is removed by evaporation. The crude oil is purified by distillation to yield ethyl 3-aminopropyl(di-n-propyloxymethyl)phosphinate as a colourlessoil.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:15](OC)=[O:16])[O:7][CH2:6]1)[CH2:2][CH3:3].[OH-].[Na+].O=S(Cl)[Cl:26]>CO.O>[ClH:26].[CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[C:15]([Cl:26])=[O:16])[O:7][CH2:6]1)[CH2:2][CH3:3]
Reactant: CCCN(CCC)C1COc2cccc(C(=O)OC)c2C1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCN(CCC)C1COc2cccc(C(=O)Cl)c2C1
Product: Cl
Yield: 80 %

Procedure:
3-Dipropylamino-5-methyloxychroman (Example 2; 400 mg, 1.37 mmol) was dissolved in 10 ml methanol and NaOH (60 mg, 1.5 mmol) in 2 mL H2O was added. The mixture was refluxed for 5 hours, cooled, filtered through Celite and evaporated to dryness. The residue was refluxed in SOCl2 (5 mL, 68 mmol) for 30 minutes. The excess SOCl2 was then removed in vacuo to give 3-dipropylamino-5-chloroformylchroman-HCL as a gum. The pale brown gum was dissolved in CH2Cl2 (50 mL), and a stream of NH3 (g) was introduced during 2 minutes. The solution was washed with aqueous NaHCO3, dried with Na2SO4 and evaporated to dryness. The oil was purified by flash chromatography (silica gel) by elution with ethyl acetate/hexane 1:4. Yield 80%, 13C-NMR: 172.0 154.9 136.5 126.9 120.4 119.1 118.6 67.8 53.0 52.6 26.1 22.4 21.9 14.1 11.7.
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][NH:10][C:9](=[O:19])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]>>[O:19]=[C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][N:10]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)CCCCCCCBr
Reactant: O=c1nc(-c2ccccc2)c(-c2ccccc2)c[nH]1
Product: COC(=O)CCCCCCCn1cc(-c2ccccc2)c(-c2ccccc2)nc1=O

Procedure:
Reaction of 4,5-diphenyl-2(1H)-pyrimidinone and methyl 8-bromooctanoate according to the procedure of Example 1 provided the title compound, m.p. 80°-83° C.
Reaction SMILES: [Mg+2].[Cl-].[Cl-].[CH2:4](N(CC)CC)C.C(OC)(=O)CC(OC)=O.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32])[C:25](Cl)=[O:26].Cl>C1(C)C=CC=CC=1>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:25](=[O:26])[CH3:4])[CH:28]=[CH:29][C:30]=1[N+:31]([O-:33])=[O:32]
Reactant: CCN(CC)CC
Reactant: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: COC(=O)CC(=O)OC
Solvent: Cc1ccccc1
Product: COc1cc(C(C)=O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.1 %

Procedure:
A suspension of MgCl2 (932 mg, 9.8 mmol) in toluene (13 mL) was treated with triethylamine (4.65 mL, 33.4 mmol), dimethyl malonate (1.9 mL, 16.6 mmol), stirred for 1.5 hours, and treated portionwise over 30 minutes with 3-methoxy-4-nitrobenzoyl chloride (3 g, 13.9 mmol). The reaction mixture was stirred for 45 minutes, then carefully treated with concentrated HCl (4 mL). The layers were separated and the organic phase was dried (Na2SO4), filtered, and concentrated. The, residue was dissolved in DMSO (11.5 mL) and water (0.5 mL), heated to reflux overnight, cooled to room temperature, and partitioned between water and ethyl acetate. The organic phase was washed sequentially with saturated NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated to provide 1.63 g (60% yield) of the desired product. MS (ESI(−)) m/e 194 (M−H)−.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Cl:11][C:12]1[CH:20]=[CH:19][C:18]2[C:14](=[CH:15][N:16]([CH3:21])[N:17]=2)[C:13]=1[CH2:22][OH:23].C(N(CC)CC)C>ClCCl>[Cl:11][C:12]1[CH:20]=[CH:19][C:18]2[C:14](=[CH:15][N:16]([CH3:21])[N:17]=2)[C:13]=1[CH:22]=[O:23]
Reactant: Cn1cc2c(CO)c(Cl)ccc2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cc2c(C=O)c(Cl)ccc2n1
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
To a solution of dimethyl sulfoxide (5.70 mL, 80.0 mmol) in dichloromethane (100 mL) was added oxalyl chloride (3.51 mL, 40.1 mmol) at −78° C., and the mixture was stirred for 30 min. To the reaction mixture was added a solution of (5-chloro-2-methyl-2H-indazol-4-yl)methanol (2.63 g, 13.4 mmol) in dichloromethane (34 mL), and the mixture was stirred for 2 hr. To the reaction mixture was added triethylamine (16.9 mL, 120 mmol) at −78° C., and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/4) to give the title compound (2.20 g, yield 85%).
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][C:14]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH2:25][CH3:26])[N:17]=[CH:16][N:15]=2)=[CH:7][CH:6]=1.ClC1C=CC=C(C(OO)=[O:35])C=1.[OH-].[Na+]>C(Cl)Cl>[CH3:1][S:2]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][C:14]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH2:25][CH3:26])[N:17]=[CH:16][N:15]=2)=[CH:7][CH:6]=1)=[O:35]
Reactant: CCOC(=O)c1c(CC)ncnc1NCCc1ccc(CCSC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)c1c(CC)ncnc1NCCc1ccc(CCS(C)=O)cc1
Yield: 76.6 %

Procedure:
A solution of ethyl 4-(2-(4-(2-methylthioethyl)phenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (0.25 g, 0.67 mmol) in methylene chloride (20 ml) was stirred under ice-cooling. 80% m-Chloroperbenzoic acid (0.16 g, 0.74 mmol) was added to the solution. The mixture was stirred under ice-cooling for 20 minutes, and then a 1N aqueous solution (20 ml) of sodium hydroxide was added. The mixture was extracted with methylene chloride and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel eluting with ethyl acetate/methanol (=8/2) to give the desired ethyl 4-(2-(4-(2-methylsulfinylethyl)phenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (0.20 g, 77%).
Reaction SMILES: Cl[C:2]1[C:3]([C:20]([NH2:22])=[O:21])=[N:4][C:5]([CH2:18][CH3:19])=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[N:7]=1.[CH3:23][C:24]1[CH:30]=[C:29]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH:28]=[CH:27][C:25]=1[NH2:26].C(N(C(C)C)CC)(C)C.CN1CCCC1=O>O>[CH2:18]([C:5]1[N:4]=[C:3]([C:20]([NH2:22])=[O:21])[C:2]([NH:26][C:25]2[CH:27]=[CH:28][C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:30][C:24]=2[CH3:23])=[N:7][C:6]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=1)[CH3:19]
Reactant: Cc1cc(N2CCOCC2)ccc1N
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Oc1cccc([N+](=O)[O-])c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCOCC3)cc2C)nc1Oc1cccc([N+](=O)[O-])c1
Yield: 36 %

Procedure:
A mixture of 3-chloro-6-ethyl-5-(3-nitrophenoxy)pyrazine-2-carboxamide (300 mg), 2-methyl-4-(morpholin-4-yl)aniline (200 mg), diisopropylethylamine (330 μL), and N-methylpyrrolidone (2 mL) was reacted in a microwave reaction device at 180° C. for 2 hours. The reaction mixture was left to be cooled, and then 5 mL of water was added thereto. The precipitated solid was collected by filtration and purified by silica gel column chromatography (eluent; ethyl acetate:hexane=1:9-7:3) to obtain 6-ethyl-3-{[2-methyl-4-(morpholin-4-yl)phenyl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (160 mg) as a brown solid.