Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C2C=CC(O)=C(C3C4C(=CC=CC=4)C=CC=3O)C2=CC=1.CC(C)[O-].CC(C)[O-].CC(C)[O-].[Al+3].CC(O)C.[CH2:40]([Cl:49])[C:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:42].Cl>C1(C)C=CC=CC=1.O>[Cl:49][CH2:40][C@H:41]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[OH:42]
Reactant: O=C(CCl)c1ccccc1
Agent: CC(C)[O-]
Agent: Cl
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: O
Product: O[C@H](CCl)c1ccccc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a slurry solution of 143 mg (0.5 mmol) of (R)-1,1′-bi-2-naphthol in 10 ml of toluene was added 102 mg (0.5 mmol) of aluminum triisopropoxide at room temperature, and the mixture was stirred at room temperature for 20 minutes and further at 50° C. for 1 hour. Thereto 1.52 ml (20 mmol) of 2-propanol was added and the mixture was stirred further at room temperature for 30 minutes. Thereto 1.55 g (10 mmol) of phenacyl chloride was added and the mixture was further stirred at 50° C. for 4 hours. To the mixture were added 2 ml of 1N hydrochloric acid and 20 ml of water to conduct hydrolysis. The mixture was extracted with ethyl acetate and concentrated to obtain an oily product. The after-treatment and the analysis of the product were then carried out in the same manner as described in Example 2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:15]Br>C1COCC1.CCOCC.C(OCC)(=O)C.[Cl-].[Al+3].[Cl-].[Cl-]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[CH:12]([Br:15])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Reaction time: 24 h
Yield: 42.9 %

Procedure:
N-tert-Butoxycarbonyl-4-piperidone (5.67 g, 28.5 mol) is dissolved in a mixture of dry THF (50 ml) and dry ether (50 ml), and thereto is added anhydrous aluminum chloride (57 mg). To the mixture is gradually added dropwise bromine (1.47 ml, 28.5 mmol) at 0° C., and the mixture is allowed to stand at 5° C. for 24 hours. The resulting reaction solution is diluted with ethyl acetate, and the mixture is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent is evaporated. The resulting residue is crystallized from ether to give N-tert-butoxycarbonyl-3-bromo-4-piperidone (3.40 g, yield; 43%) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][O:12][CH3:13])[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[S:27](Cl)(=[O:29])=[O:28]>N1C=CC=CC=1>[CH3:13][O:12][CH2:11][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:27]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])(=[O:29])=[O:28])[CH:7]=[C:8]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: COc1ccccc1S(=O)(=O)Cl
Reactant: CCOC(=O)c1cc2cccc(N)c2n1COC
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3ccccc3OC)c2n1COC
Temperature: 25 °C
Yield: 82 %

Procedure:
To a mixture of ethyl 7-amino-1-(methoxymethyl)-1H-indole-2-carboxylate (12.0 g) and pyridine (100 mL) was added 2-methoxybenzenesulfonyl chloride (10.0 g) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 20 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate. The solution was washed with aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (16.58 g, yield 89%) as pale-gray crystals. melting point: 106-107° C.
Reaction SMILES: [CH:1]1([N:4]2[C:12]([CH3:13])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([N:14]4[CH:19]=[CH:18][C:17](O)=[CH:16][C:15]4=[O:21])=[CH:10]3)=[N:5]2)[CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:24])=O.C(OCC)(=O)C>CN(C=O)C>[Cl:24][C:17]1[CH:18]=[CH:19][N:14]([C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[C:12]([CH3:13])[N:4]([CH:1]4[CH2:3][CH2:2]4)[N:5]=3)[CH:10]=2)[C:15](=[O:21])[CH:16]=1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C1CC1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c2cc(-n3ccc(Cl)cc3=O)ccc2nn1C1CC1
Temperature: 45 °C
Reaction time: 22 h

Procedure:
To a suspension of 1-(2-cyclopropyl-3-methyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (118 g) in DMF (2 L) was added phosphorus oxychloride (46.9 ml) at room temperature, and the mixture was stirred under an argon atmosphere at an inside temperature of 45° C. for 22 hr. The reaction mixture was poured into ethyl acetate (3 L), and washed with saturated aqueous sodium hydrogen carbonate (1.5 L). The obtained aqueous layer was extracted twice with ethyl acetate (2 L and 1 L). The organic layer was washed with aqueous sodium sulfite solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in a 1:1 mixed solvent (1.1 L) of ethyl acetate and tetrahydrofuran with heating, and the mixture was filtered through NH silica gel (750 g). The eluate was concentrated under reduced pressure, and the obtained residue was solidified with diisopropyl ether to give the title compound (73.2 g).
Reaction SMILES: C(OC([N:8]([CH2:44][C:45]([OH:47])=[O:46])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:43])[CH2:17][N:18]2[N:24]=[C:23]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:22]3[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=3[N:20]([CH2:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[C:19]2=[O:42])[CH:10]=1)=O)(C)(C)C>FC(F)(F)C(O)=O>[CH:25]1([C:23]2[C:22]3[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=3[N:20]([CH2:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[C:19](=[O:42])[N:18]([CH2:17][C:16]([NH:15][C:11]3[CH:10]=[C:9]([NH:8][CH2:44][C:45]([OH:47])=[O:46])[CH:14]=[CH:13][CH:12]=3)=[O:43])[N:24]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)Nc2cccc(NCC(=O)O)c2)N=C(C2CCCCC2)c2ccccc21
Yield: 73.9 %

Procedure:
[tert-Butoxycarbonyl-(3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-amino]-acetic acid (Example 51)(137 mg, 0.21 mmol) was stirred in trifluoroacetic acid for 2 h at room temperature. After concentration, the resulting gum was dissolved in DCM, washed with saturated NaHCO3 and then with 1N HCl. The organic phase was dried over MgSO4, filtered and the solvent was evaporated to afford the title compound as a yellow solid (85 mg, 73%). 1H NMR (DMSO-d6) 9.47 (1H, s), 7.55-7.27 (2H, m), 7.23-7.15 (2H, m), 6.97 (1H, t), 6.92-6.68 (2H, m), 6.25 (1H, m), 5.80 (2H, br s), 4.78 (2H, m), 4.25 (1H, d), 3.95 (1H, d), 3.72 (2H, s), 2.80 (1H, m), 1.86-1.51 (6H, m), 1.26-1.09 (13H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 57.66; H, 7.45; N, 9.07%; C30H36N4O6.C7H17NO5.1.5H2O requires: C, 57.65; H, 7.32; N, 9.09%.
Reaction SMILES: [CH3:1][CH:2]([C:4]([C:24]1[CH:25]=[CH:26][C:27]([O:32][CH3:33])=[C:28]([O:30][CH3:31])[CH:29]=1)([C:22]#[N:23])[CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=1)[CH3:9])[CH3:3].[ClH:34]>>[CH3:3][CH:2]([C@:4]([C:24]1[CH:25]=[CH:26][C:27]([O:32][CH3:33])=[C:28]([O:30][CH3:31])[CH:29]=1)([C:22]#[N:23])[CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=1)[CH3:9])[CH3:1].[ClH:34]
Reactant: COc1ccc(CCN(C)CCCC(C#N)(c2ccc(OC)c(OC)c2)C(C)C)cc1OC
Agent: Cl
Product: COc1ccc(CCN(C)CCC[C@](C#N)(c2ccc(OC)c(OC)c2)C(C)C)cc1OC

Procedure:
The verapamil base was released from the salt using an inorganic base and converted directly into the corresponding hydrochloride. 9.9 g of (R)-verapamil hydrochloride were obtained with an enantiomeric purity=99.66%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15](O)=[O:16])=[C:10]3[C@@H:9]3[CH2:18][CH2:19][N:8]3[C:7](=[O:20])[C:6]=2[CH:21]=1.C(N1C=CN=C1)([N:24]1C=CN=C1)=O.N.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([NH2:24])=[O:16])=[C:10]3[C@@H:9]3[CH2:18][CH2:19][N:8]3[C:7](=[O:20])[C:6]=2[CH:21]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(F)ccc1-2
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1cc(F)ccc1-2
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
100 g (348 mmol) of (S)-7-fluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid were suspended in 600 ml of N,N-dimethylformamide and treated with 64.1 g (395 mmol) of 1,1'-carbonyldiimidazole. After stirring at 50° for 30 minutes 80 ml of 25% ammonia were added dropwise at 13° to 20° and the mixture was stirred for 30 minutes and poured into 21 of water. By suction filtration of the resulting suspension and drying the crystals there were obtained 52.7 g (76%) of (S)-7-fluoro-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamide of m.p. 223°-224°.
Reaction SMILES: [C:1]([C:3]1[C:7](I)=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2].[C:21](#[N:24])[CH:22]=[CH2:23].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[C:1]([C:3]1[C:7](/[CH:23]=[CH:22]/[C:21]#[N:24])=[CH:6][N:5]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:4]=1)#[N:2]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)cc1I
Reactant: C=CC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#C/C=C/c1cn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C#N
Temperature: 70 °C
Reaction time: 24 h

Procedure:
A mixture of 3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (0.864 g), acrylonitrile (0.264 g), triethylamine (0.4 ml), palladium acetate (0.04 g) and dimethylformamide (10 ml) were stirred under an atmosphere of nitogen at 70° C. for 24 hours. The reaction mixture was evaporated and the residue partitioned between water and dichloromethane. The organic layer was separated, washed with water, brine, then dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (40 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a white solid m.p. 144-145° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][C:20]([OH:22])=O)[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH3:1][O:2][C:3]1[C:4](=[O:24])[C:5]([CH3:23])=[C:6]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:19][C:20]([NH:28][CH:25]([CH3:27])[CH3:26])=[O:22])[CH:16]=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: CC(C)N
Reactant: COC1=C(OC)C(=O)C(Cc2cccc(CC(=O)O)c2)=C(C)C1=O
Product: COC1=C(OC)C(=O)C(Cc2cccc(CC(=O)NC(C)C)c2)=C(C)C1=O
Yield: 44.4 %

Procedure:
3-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenylacetic acid (90 mg, 0.27 mmol) obtained in Example 57 and isopropylamine (0.035 ml, 0.41 mmol) were used, and a method similar to that described in Example 46 was employed to obtain the title compound (43 mg, 0.12 mmol, yield 44%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1.[N+:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])([O-:22])=[O:21].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O.O>[N+:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:8]([OH:15])=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: CC(C)(C)c1cc(CCCBr)cc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(CCCOc2ccccc2[N+](=O)[O-])cc(C(C)(C)C)c1O
Yield: 74.3 %

Procedure:
A mixture of 4-(3-bromopropyl)-2,6-di-t-butylphenol (1.20 g), 2-nitrophenol (0.51 g), potassium carbonate (1.01 g) and a catalytic amount of sodium iodide was stirred in dimethylformamide (10 ml) at 60°-70° C. for 1.5 hrs. The reaction solution was poured into water, extracted with ethyl acetate, washed with water and then saturated saline, and dried over anhydrous MgSO4. After distilling off the solvent, the residue was purified by a silica gel column chromatography (hexane:ethyl acetate=10:1) to give 4-[3-(2-nitrophenoxy)propyl]-2,6-di-t-butylphenol (1.05 g, 74%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([O:13][C:14]1[CH:15]=[C:16]([CH:33]=[C:34]([CH3:36])[CH:35]=1)[O:17][CH2:18][CH2:19][CH2:20][O:21][N:22]1C(=O)C2=CC=CC=C2C1=O)(=[O:12])=[O:11])([O-:3])=[O:2].C(O)C.[BH4-].[Na+]>O1CCCC1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([O:13][C:14]1[CH:15]=[C:16]([CH:33]=[C:34]([CH3:36])[CH:35]=1)[O:17][CH2:18][CH2:19][CH2:20][O:21][NH2:22])(=[O:12])=[O:11])([O-:3])=[O:2]
Reactant: Cc1cc(OCCCON2C(=O)c3ccccc3C2=O)cc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(OCCCON)cc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.4 %

Procedure:
A solution of N-[3-[3-(2-nitrophenylsulfonyloxy)-5-methylphenoxy]propoxy]-phthalimide (2.33 g, 4.55 mmol), as prepared in the preceding step, in tetrahydrofuran (30 mL) and ethanol (30 mL) was treated with sodium borohydride (524 mg, 13.9 mmol). The reaction mixture was stirred at room temperature overnight, quenched carefully with 2N HCl (14 mL) and heated at 50° C. for 90 min. The reaction mixture was then concentrated to ¼ volume, basified with 2N NaOH, diluted with water, and extracted into ethyl acetate. The organic phase was dried (K2CO3) and purified by flash chromatography (1:4 to 1:2 diethyl ether/dichloromethane to give 1.12 g (64%) of the title compound as a pale yellow oil. 1H-NMR (300 MHz, CDCl3) δ7.98-8.01 (m, 1H), 7.79-7.87 (m, 2H), 7.66-7.74 (m, 1H), 6.64 (m, 1H), 6.60 (s, 1H), 6.57 (t, 1H, J=2 Hz), 3.96 (t, 2H, J=6 Hz), 3.80 (t, 2H, J=6 Hz), 2.27 (s, 3H), 2.02 (penet, 2H, J=6 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid) calcd. for C16H18N2O7S: 405.1 (M+Na). Found 405.2.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[CH2:18][C:19]([O:21]CC)=[O:20])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>CO.O1CCOCC1>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[CH2:18][C:19]([OH:21])=[O:20])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)CC1CCCCN1S(=O)(=O)c1cccc(C(F)(F)F)c1
Reaction time: 8 h

Procedure:
The ethyl 2-(1-(3-(trifluoromethyl)phenylsulfonyl)piperidin-2-yl)acetate (10.45 g, 27.5 mmol) was dissolved in a mixture of methanol (150 ml), dioxane (40 ml) and aqueous NaOH solution (4 M, 41.3 ml, 165.2 mmol, 6 eq.) and the solution was stirred overnight When the reaction had ended (TLC control, MC/methanol 95:5), the solution was concentrated. The crude product was taken up in ethyl acetate (600 ml) and the mixture was . . . with KHSO4 solution (0.5 M, 600 ml). The aqueous phase was extracted once more with ethyl acetate (100 ml) and the combined organic phases were washed with sat. NaCl solution (500 ml), dried over Na2SO4 and concentrated. Yield: 9.4 g, 97%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[N:18]=1>>[N:22]1[CH:21]=[CH:20][C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:15]=3[N:16]=2)=[CH:24][CH:23]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Cc1sc2nc(-c3ccncc3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3ccncc3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-4-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3-nitrobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH3:14])[CH:9]=2)=[N:6][CH:7]=1.[Cl-].[C:16]([O:20][C:21](=[O:24])[CH2:22][Zn+])([CH3:19])([CH3:18])[CH3:17].CCOCC>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2].C1COCC1>[CH3:14][C:10]1[CH:9]=[C:8]([C:5]2[N:4]=[CH:3][C:2]([CH2:22][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:24])=[CH:7][N:6]=2)[CH:13]=[CH:12][N:11]=1
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: Cc1cc(-c2ncc(Br)cn2)ccn1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(-c2ncc(CC(=O)OC(C)(C)C)cn2)ccn1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a sealed tube were added 5-bromo-2-(2-methylpyridin-4-yl)pyrimidine 183-3 (50 mg, 0.20 mmol), 0.5 M (2-tert-butoxy-2-oxoethyl) zinc(II) chloride in ether (0.60 mL, 0.30 mmol), Pd(dba)2 (6 mg, 0.01 mmol), Q-phos (14 mg, 0.02 mmol) and THF (1.5 mL). The reaction mixture was bubbled with nitrogen for 1 minute and stirred at 100° C. for 1 hour. After cooling to room temperature, all the solvents were evaporated and the residue was redissolved in ethyl acetate, washed with water and brine, dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography and eluted with 25% ethyl acetate in hexane to give tert-butyl 2-(2-(2-methylpyridin-4-yl)pyrimidin-5-yl)acetate 183-4. MS m/z 286.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([C:16](=[N:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[C:17](=[N:20][C:21]([O:23]C)=O)SC)[C:9]=1[F:34].[N:36]1[CH:41]=[CH:40][CH:39]=[N:38][C:37]=1[NH:42][NH2:43].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:35])[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([C:16](=[N:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]#[N:33])=[CH:30][CH:31]=2)[C:17]2[NH:20][C:21](=[O:23])[N:42]([C:37]3[N:38]=[CH:39][CH:40]=[CH:41][N:36]=3)[N:43]=2)[C:9]=1[F:34]
Reactant: NNc1ncccn1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(C#N)cc1)c1cc(OC)cc(OCCOC(=O)OC)c1F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)OCCOc1cc(OC)cc(C(=Nc2ccc(C#N)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1F
Temperature: 50 °C
Yield: 61 %

Procedure:
A mixture of the crude product containing carbonic acid {3-[1-(4-cyanophenylimino)-2-methoxycarbonylimino-2-methylsulfanylethyl]-2-fluoro-5-methoxyphenoxy}ethyl ester methyl ester (37 g, 73.4 mmol), toluene (740 mL), pyrimidin-2-yl-hydrazine (8.08 g, 73.4 mmol), and triethylamine (12.3 mL, 88.2 mmol) was heated at 50° C. for 10 minutes under stirring, gradually heated to 110° C., and heated at 110° C. for 4 hours under stirring. The mixture was gradually cooled to room temperature, and then the precipitate was filtered and dried to obtain the captioned compound (23.89 g) as a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:4][C:3]=1[NH:19][NH2:20].O.[C:22]1([CH3:28])[CH:27]=[CH:26]C=[CH:24][CH:23]=1>>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])=[CH:4][C:3]=1[N:19]1[C:27]([CH3:26])=[C:22]([CH3:28])[C:23]([CH3:24])=[N:20]1
Reactant: NNc1cc(OS(=O)(=O)c2ccccc2)c(Cl)cc1F
Reactant: Cc1ccccc1
Solvent: O
Product: Cc1nn(-c2cc(OS(=O)(=O)c3ccccc3)c(Cl)cc2F)c(C)c1C
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of (2-fluoro-4-chloro-5-phenylsulfonyloxyphenyl)-hydrazine (31.7 g), 3-methylpenta-2,4-dione (11.4 g) and water (150 ml) was stirred at 70° C. for one hour. After the reaction mixture was cooled, toluene was added thereto whereby to form two layers. The toluene layer thus separated was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent by distillation in vacuo gave the titled compound (37.5 g) as a pale brown crystalline solid. Recrystallization of this solid from carbon tetrachloride afforded a white crystalline solid. nD23 =1.5492.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([CH3:23])[C:17]=1[CH3:24].[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37](=[O:38])[C:36]([C:39](O)=[O:40])=[CH:35][N:34]([CH:42]([CH3:44])[CH3:43])[C:33]2=[O:45])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:39]([C:36]2[C:37](=[O:38])[N:32]([C:29]3[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=3)[C:33](=[O:45])[N:34]([CH:42]([CH3:44])[CH3:43])[CH:35]=2)=[O:40])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: CC(C)n1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4cn(C(C)C)c(=O)n(-c5ccc(F)cc5)c4=O)c(C)c3C)c2cc1OC

Procedure:
This compound was synthesized using 4-(6,7-Dimethoxy-quinolin-4-yloxy)-2,3-dimethyl-phenylamine and 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. mp=238-240° C.; LCMS m/z=599 (M+1); 1H NMR (DMSO-d6) δ: 10.82 (s, 1H), 8.68 (s, 1H), 8.43 (d, 1H, J=5.5 Hz), 8.06 (d, 1H, J=9 Hz), 7.56 (s, 1H), 7.47-7.42 (m, 2H), 7.39-7.34 (m, 2H), 7.09 (d, 1H, J=9 Hz), 6.27 (d, 1H, J=5.5 Hz), 4.78 (p, 1H, J=8 Hz), 3.95 (s, 6H), 2.21 (s, 3H), 2.07 (s, 3H), 1.43 (d, 6H, J=6 Hz).
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][P:7]([CH2:27][NH2:28])([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])=[O:8].[C:29]1(=O)[O:34][C:32](=[O:33])[CH2:31][CH2:30]1.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.C(N(CC)CC)C>[CH3:5][O:6][P:7]([CH2:9][CH:10]([C:15](=[O:26])[NH:16][C@H:17]([C:22](=[O:25])[NH:23][CH3:24])[CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:11][CH:12]([CH3:14])[CH3:13])([CH2:27][N:28]1[C:32](=[O:33])[CH2:31][CH2:30][C:29]1=[O:34])=[O:8]
Reactant: O=C1CCC(=O)O1
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(CN1C(=O)CCC1=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
0.36 g of (aminomethyl)[(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid methyl ester acetate, prepared as described in Example 2(A)(i), was dissolved in 10 ml of dichloromethane and 0.17 g of succinic anhydride and 0.17 g of triethylamine were added. After stirring at room temperature for 2 hours, 0.2 g of hydroxybenzotriazole and 0.2 g of N,N'-dicyclohexylcarbodiimide were added. The mixture was stirred at room temperature for 18 hours and then filtered in order to remove dicyclohexylurea. The filtrate was washed twice with 15 ml of saturated sodium hydrogen carbonate solution each time. After drying over anhydrous sodium sulfate the solvent was removed by evaporation to give a colorless gum. This gum was purified by flash chromatography on silica gel using ethyl acetate/methanol (8:1) for the elution. There was obtained 0.23 g of [(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl](succinimidomethyl)phosphinic acid methyl ester in the form of a white foam.