Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:35]=[CH:34][C:20]([C:21]([N:23]([CH3:33])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4C(O)=O)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C1(P([N:50]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C.Cl>C1C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]([NH:16][C:17]3[CH:35]=[CH:34][C:20]([C:21]([N:23]([CH3:33])[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[NH2:50])=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3C(=O)O)cc2)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N(C)c3ccccc3N)cc2)cc1
Yield: 55.2 %

Procedure:
A mixture of 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-carboxyphenyl)benzamide (232 mg), diphenylphosphoryl azide (151 mg), and triethylamine (0.084 ml) in benzene (10 ml) was refluxed for 5 hours and 1N hydrochloric acid (4 ml) was added to the solution. The mixture was refluxed for 4 hours and the mixture was washed with aqueous saturated sodium hydrogen carbonate and brine. The organic solution was dried over magnesium sulfate and the solvent was evaporated in vacuo to give crude oil. The oil was purified by silica gel column (10 g, 2% methanol in chloroform) and the product was solidified with diethyl ether to give 4-(4′-methylbiphenyl-2-carboxamido)-N-methyl-N-(2-aminophenyl)benzamide (120 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.F[B-](F)(F)F.[CH2:15]([O:17][CH+:18][O:19][CH2:20][CH3:21])[CH3:16].C(N(CC)C(C)C)(C)C>>[CH2:15]([O:17][CH:18]([O:19][CH2:20][CH3:21])[CH:4]1[CH2:3][C:2]([CH3:9])([CH3:1])[CH2:7][CH2:6][C:5]1=[O:8])[CH3:16]
Reactant: CCO[CH+]OCC
Reactant: CC1(C)CCC(=O)CC1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(OCC)C1CC(C)(C)CCC1=O

Procedure:
reacting 4,4-dimethylcyclohexanone, diethoxycarbenium fluoroborate and N,N-diisopropylethylamine to provide (2-(diethoxymethyl)-4,4-dimethylcyclohexanone and isolating or not isolating the 2-(diethoxymethyl)-4,4-dimethylcyclohexanone;
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[C:13](=[CH2:14])[C:12]([CH3:16])([CH3:15])[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:27])C=1.[OH-].[Ca+2].[OH-]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH:7]2[C:13]3([O:27][CH2:14]3)[C:12]([CH3:15])([CH3:16])[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: C=C1C(Cc2ccc(Cl)cc2)CCCCC1(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC1(C)CCCCC(Cc2ccc(Cl)cc2)C12CO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 5 ml of chloroform was dissolved 340 mg of 7-(4-chlorobenzyl)-2,2-dimethyl-1-methylenecycloheptane [Compound (III-3) in Table III), and then 450 mg of m-chloroperbenzoic acid was added to the mixture over 10 minutes and the mixture was stirred at room temperature for one hour. Next, 385 mg of calcium hydroxide was added and the mixture was stirred at room temperature for 10 minutes.
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:22][C:21]=2[CH:31]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[OH-].[Li+].Cl>O1CCOCC1.O>[C:25]1([C:23]2[O:24][C:20]3[CH:19]=[CH:18][C:17]([CH2:16][O:15][C:13]([NH:12][C@H:4]([CH2:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:3]([OH:32])=[O:2])=[O:14])=[CH:31][C:21]=3[N:22]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccc2oc(-c3ccccc3)nc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccc2oc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
A solution (R)-2-(2-phenylbenzoxazol-5-ylmethoxycarbonylamino)-3-phenylpropionic acid methyl ester 59 (374 mg, 0.8 mmol) in dioxane (8 ml) was treated with a solution of lithium hydroxide hydrate (55 mg, 1.3 mmol) in water (4 mL) under an atmosphere of N2 and stirred for 3 hrs at room temperature. The mixture was acidified with 1N HCl, then extracted with ethyl acetate (25 ml). The ethyl acetate extract was washed, and dried. Evaporation of the solvent afforded the product which was recrystallized to yield 220 mg (60%) of (R)-2-(2-phenylbenzoxazol-5-ylmethoxycarbonylamino)-3-phenyl propionic acid 60, mp. 220.0–221.4° C.
Reaction SMILES: O[N:2]=[C:3]([C:9](=[O:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].O.[C:21](O)(=[O:23])[CH3:22]>C(OC(=O)C)(=O)C.[Zn]>[C:21]([NH:2][CH:3]([C:9](=[O:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[CH:13]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:23])[CH3:22]
Reactant: CC(=O)O
Reactant: CCOC(=O)C(=NO)C(=O)CCc1cccc(C)c1
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CCOC(=O)C(NC(C)=O)C(=O)CCc1cccc(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Zinc dust (10 micron, 150 g) was added portionwise to a stirred solution of the product from step (i) (88 g) in acetic acid (400 ml) and acetic anhydride (125 ml) keeping the internal temperature below 40° C. The solution was stirred at room temperature for a further 1 hour before adding water (500 ml) dropwise at such a rate so as to keep the internal temperature below 40° C. The mixture was stirred at room temperature for a further 16 h then filtered and the mother liquor extracted with chloroform. The organic extracts were further washed with brine and water, collected dried over magnesium sulphate and solvent removed under reduced pressure to give the subtitle product.
Reaction SMILES: [CH3:1][NH2:2].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH:13]=O.[BH4-].[Na+].O>CO>[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[CH2:13][NH:2][CH3:1]
Reactant: CN
Reactant: Cc1c(C=O)[nH]c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1[nH]c2ccccc2c1C
Reaction time: 5 h
Yield: 71.3 %

Procedure:
Methylamine (0.34 mL, 8.4 mmol, 33% in ethanol) was added to a solution of 3-methylindole-2-carboxaldehyde (447 mg, 2.8 mmol) in methanol (10 mL) and stirred for 5 hours. Sodium borohydride (104 mg, 2.8 mmol) was slowly added at 0° C. The resultant mixture was warmed to room temperature and stirred overnight. Water (2 mL) was added slowly at 0° C. and the mixture was evaporated to a paste. The paste was partitioned between water (2 mL) and dichloromethane (15 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×15 mL). The combined organic phases were dried and evaporated to afford title compound (348 mg, 71%). NMR (400 MHz, DMSO-d6): 10.63 (s, 1H), 7.38 (d, J=7.7 Hz, 1H), 7.25 (d, J=8.0 Hz, 1H), 6.99 (t, J=8.0 Hz, 1H), 6.92 (t, J=6.6 Hz, 1H), 3.73 (s, 2H), 2.25 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3][CH2:2]1.Cl[C:35]([CH2:37][O:38]C(=O)C)=[O:36]>>[OH:38][CH2:37][C:35]([N:1]1[CH2:2][CH2:3][CH:4]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:5][CH2:6]1)=[O:36]
Reactant: CC(=O)OCC(=O)Cl
Reactant: O=C(NCC1CCNCC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: O=C(NCC1CCN(C(=O)CO)CC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (piperidin-4-ylmethyl)-amide (example A144) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:13][O:14][CH2:15][CH2:16][O:17]C=C)=[O:12])[C:3]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[F:28].Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:13][O:14][CH2:15][CH2:16][OH:17])=[O:12])[C:3]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[F:28]
Reactant: C=COCCONC(=O)c1cc2snnc2c(F)c1Nc1ccc(I)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NOCCO)c1cc2snnc2c(F)c1Nc1ccc(I)cc1F
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d][1,2,3]thiadiazole-6-carboxamide (190 mg, 0.37 mmol) in CH2Cl2 (10 mL) was added 1.0 N HCl (aq., 1.5 mL, 1.5 mmol). After stirring for 1 h, the reaction mixture was neutralized with saturated NaHCO3 (aq.). The aqueous layer was washed with CH2Cl2 (10 mL×2). The combined organic layer was washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 20:1, v/v) and gave the desired product as a yellow solid (154 mg, 84.6% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.88 (s, 1H), 8.65 (s, 1H), 8.52 (s, 1H), 7.36 (d, 1H), 7.25 (d, 1H), 6.42 (d, 1H), 4.69 (m, 1H), 4.05 (m, 2H), 3.80 (m, 2H). MS APCI (+) m/z: m/z 493.2, [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:5].Cl.[N:20]([O-])=O.[Na+].[OH-].[Na+]>C(Cl)(Cl)Cl.O>[Br:18][C:15]1[CH:16]=[CH:17][C:2]2[N:1]=[N:20][N:6]([CH2:7][C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[C:4](=[O:5])[C:3]=2[CH:14]=1
Reactant: Nc1ccc(Br)cc1C(=O)NCc1cccnc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=c1c2cc(Br)ccc2nnn1Cc1cccnc1
Yield: 84.1 %

Procedure:
To a mixture of 29.4 g of 2-amino-5-bromo-N-(3-pyridylmethyl)benzamide, 32 ml of conc. hydrochloric acid and 400 ml of water was dropwise added a solution of 6.83 g and 400 ml of water was dropwise added a solution of 6.83 g of sodium nitrite and 48 ml of water at 0° to 2° C. The resultant mixture was stirred at 0° to 2° C. for 45 minutes, neutralized with 1N aqueous sodium hydroxide and shaken with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 25.6 g of the titled compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[N:7]([CH:9]([C:11](=[O:38])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[NH:25][CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:49][S:50](Cl)(=[O:52])=[O:51]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:39])[N:7]([CH:9]([C:11](=[O:38])[NH:12][CH:13]([C:18]([N:20]1[CH2:24][CH2:23][CH:22]2[N:25]([S:50]([CH3:49])(=[O:52])=[O:51])[CH2:26][CH:27]([CH2:28][O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=3)[CH:21]12)=[O:19])[C:14]([CH3:16])([CH3:17])[CH3:15])[CH3:10])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C(=O)NC(C(=O)N1CCC2NCC(COc3ccc(F)c(F)c3)C21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(COc1ccc(F)c(F)c1)CN2S(C)(=O)=O)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reaction time: 2.5 h
Yield: 107.4 %

Procedure:
A solution of amine 84 (220 mg, 0.4 mmol) in DCM (10 mL) was cooled to 0° C. and treated with DIPEA (0.21 mL, 1.2 mmol) followed by methanesulfonyl chloride (0.03 mL, 0.42 mmol) and DMAP (5 mg, 0.04 mmol). After 2.5 h, the reaction mixture was diluted with DCM, washed successively with 1M HCl, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 85 (271 mg, 100%) as a yellow-colored foam that was used without further purification. 1H NMR (CDCl3, 300 MHz): δ7.08 (q, J=9.3, 18.9 Hz, 1H), 6.86 (br, 1H), 6.76-6.69 (m, 1H), 6.63-6.58 (m, 1H), 4.73-4.65 (m, 1H), 4.60 (d, J=9.6 Hz, 1H), 4.47 (d, J=6.3 Hz, 1H), 4.33-4.29 (m, 1H), 4.16-4.07 (m, 2H), 4.01-3.96 (m, 1H), 3.68-3.53 (m, 3H), 2.93-2.79 (m, 6H), 2.57-2.50 (m, 1H), 2.12-2.06 (m, 1H), 1.61 (s, 1.5H), 1.49 (s, 7.5H), 1.31 (d, J=6.9 Hz, 3H), 0.99 (s, 9H) ppm.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH:5]([O:34][CH2:35][CH3:36])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:22][CH2:21]3)[N:17]=[C:16]([NH2:33])[N:15]=2)=[CH:9][CH:8]=1)C>O1CCCC1.O.[K]>[NH2:33][C:16]1[N:15]=[C:14]([O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:34][CH2:35][CH3:36])[C:4]([OH:37])=[O:3])=[CH:8][CH:9]=2)[CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:22][CH2:21]2)[N:17]=1
Reactant: CCOC(=O)C(Cc1ccc(Oc2cc(N3CCN(Cc4ccccc4)CC3)nc(N)n2)cc1)OCC
Agent: [K]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(Oc2cc(N3CCN(Cc4ccccc4)CC3)nc(N)n2)cc1)C(=O)O
Reaction time: 20 h

Procedure:
rac-3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-ethoxy-propionic acid ethyl ester was dissolved in tetrahydrofuran (THF)/alcohol solvent in the presence of an excess of aqueous potassium hydrate, the reaction is allowed to proceed for about 20 h. After most of the solve was removed in vacuo, the aqueous solution was acidified to pH 6, the white product was precipitated, then filtered through celite, rac-3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-ethoxy-propionic acid (95%) was collected.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:36])[NH:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)=[O:24])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:77]1([O:83][C:84]([N:86]2[CH2:91][CH2:90][NH:89][CH2:88][CH2:87]2)=[O:85])[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1>CN(C=O)C>[C:77]1([O:83][C:84]([N:86]2[CH2:91][CH2:90][N:89]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]3[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]4[CH2:29][CH2:28][CH2:27][C@H:26]4[C:30](=[O:36])[NH:31][CH:32]4[CH2:33][CH2:34][CH2:35]4)=[O:24])[N:18]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[N:17]=3)=[O:15])[CH2:8][CH2:7][C:6]([OH:43])=[O:5])[CH2:88][CH2:87]2)=[O:85])[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Reactant: O=C(Oc1ccccc1)N1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)N1CCN(C(=O)Oc2ccccc2)CC1
Reaction time: 36 h

Procedure:
To a solution of 100 mg (S)-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 5 ml DMF were added 55 μl DIPEA, 64 mg HATU and 54 mg piperazine-1-carboxylic acid phenyl ester hydrotrifluoroacetate. After stirring for 36 h the solution was concentrated, the residue dissolved in 1.5 ml dichloromethane and treated with 190 μl TFA. After stirring for 4 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 40 mg MS (ES+): m/e=730.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][O:16]1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.O>CN(C)C=O>[OH:16][CH:15]([CH2:17][N:38]1[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC1CO1
Reactant: CN1CCNCC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCC(O)CN1CCN(C)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
(2-{[6-Methoxy-7-(2-oxiranylmethoxy)-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (39 mg) and 4-methylpiperazine (27 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (40 mg, yield 84%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH:18]([CH3:20])[CH3:19])[C:9]=2[S:8][CH:7]=1)=[O:5])[CH3:2].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13](=[O:15])[N:12]([CH3:16])[C:11](=[O:17])[N:10]([CH:18]([CH3:19])[CH3:20])[C:9]=2[S:8][C:7]=1[CH:26]([C:25]1[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=1)[OH:27])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc2c1c(=O)n(C)c(=O)n2C(C)C
Reactant: O=Cc1ccc(F)cc1
Product: CCOC(=O)c1c(C(O)c2ccc(F)cc2)sc2c1c(=O)n(C)c(=O)n2C(C)C

Procedure:
Prepared by the method of example 15 part a) using 1,2,3,4-tetrahydro-3-methyl-1-(1-methylethyl)-2,4-dioxothieno[2,3-d]pyrimidine-5-carboxylic acid ethyl ester and 4-fluorobenzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.O.[NH2:23][NH2:24]>CCO>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([NH:23][NH2:24])=[O:15])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CNC(=O)c2ccc(Cl)cc2)cc1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1ccc(CNC(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 70 %

Procedure:
To a suspension of methyl 4-{[(4-chlorobenzoyl)amino]methyl}benzoate (303 mg, 1.0 mmol) in EtOH (6 mL) was added hydrazine hydrate (1.0 mL). After stirring for 15 h at reflux, the reaction mixture was cooled to rt and a white solid precipitated out. Filtration, washing with water (3×2 mL) and drying under vacuo at 60° C. for 2 hrs gave 213 mg of the title compound (70%) as a white solid in 96.5% purity by HPLC (MaxPlot detection between 230 and 400 nm).
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.[NH2:26][N:27]1[CH2:32][CH2:31][O: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]([NH:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: NN1CCOCC1
Reactant: CP(C)(=O)c1ccc(Nc2ncnc(Cl)n2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CP(C)(=O)c1ccc(Nc2ncnc(NN3CCOCC3)n2)cc1

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-1,3,5-triazin-2-amine (prepared as in Example 92: 0.12 mmol) in 2 mL of ethanol is added 50 μL of triethylamine and 4-Aminomorpholine (12 mg, 0.12 mmol). The mixture is microwave 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: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23][CH2:24][CH2:25][CH2:26][C:27](O)=[O:28])[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[N:4]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:3]1=[O:34].C([N:37](CC)CC)C.ClC(OCC)=O>O1CCCC1>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2=[C:9]([S:23][CH2:24][CH2:25][CH2:26][C:27]([NH2:37])=[O:28])[N:10]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)[CH:11]=[C:5]2[N:4]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:3]1=[O:34]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCC(=O)O)n(Cc3cccc4ccccc34)cc21
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(SCCCC(N)=O)n(Cc3cccc4ccccc34)cc21
Reaction time: 0.25 h

Procedure:
The compound of Example 5, 4-[(2,3,4,6-tetrahydro-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-2,4-dioxo-1H-pyrrolo[3,4-d]pyrimidin-5-yl)thio]butanoic acid (100 mg), was dissolved in tetrahydrofuran (3 ml) and the solution was cooled in ice. Triethylamine (30 μl) was added followed by ethyl chloroformate (21 μl); the ice bath was removed and the solution was allowed to stir for 15 minutes and was then cooled in ice again. Aqueous ammonia (0.88 specific gravity, 1 ml) was added and the mixture was stirred for 3 days. The mixture was poured onto water and extracted thrice with dichloromethane. The organic extracts were combined, washed with brine, dried, filtered and evaporated to give an oil which was purified by chromatography, eluting first with ethyl acetate:isohexane:acetic acid (75:25:1) and then with ethyl acetate:acetic acid (199:1) to give the title compound (70 mg).
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]([C:16]1[CH:21]=[C:20]([NH2:22])[CH:19]=[C:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[OH:27])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[C:23]([C:18]1[CH:19]=[C:20]([NH:22][C:1](=[O:10])[CH:2]=[CH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:21]=[C:16]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:17]=1[OH:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(NC(=O)C=Cc2ccccc2)cc(C(C)(C)C)c1O
Reaction time: 0.5 h

Procedure:
N-(3,5-di tert.butyl-4-hydroxyphenyl)cinnamamide was prepared by adding a solution of 18.2 grams of cinnamoyl chloride in 50 milliliters of benzene to a solution of 2,6-di tert.butyl-4 -aminophenol prepared as described in Example 2 to which had been added 6 grams of sodium carbonate. The addition was accomplished in 30 minutes at 24° C. to 37° C. The mixture was stirred for 1 hour. The solid product was filtered, washed thoroughly with 2% hydrochloric acid, and dried. The yield was 17 grams of product which melted at 211° C. to 214° C.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26][NH:27][C:28](=[O:30])[CH3:29])[O:23][C:22]3=[O:31])=[CH:17][C:16]=2[F:32])[CH2:11][CH2:10]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].CO>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26][NH:27][C:28](=[O:30])[CH3:29])[O:23][C:22]3=[O:31])=[CH:17][C:16]=2[F:32])[CH2:13][CH2:14]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(N(Cc4ccccc4)Cc4ccccc4)CC3)c(F)c2)C(=O)O1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(N)CC3)c(F)c2)C(=O)O1
Yield: 100 %

Procedure:
Using the amino compound, (S)-N-{3-[4-(4-dibenzylamino-piperidin-1-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (Compound No. 5) was synthesized by the same method as in Example 1. To a methanol solution (200 ml) of this compound (5.28 g), palladium hydroxide on carbon (20%, 3.3 g) was added and the mixture was stirred at room temperature under 3 atm hydrogen atmosphere. Palladium hydroxide on carbon was filtered off and the filtrate was concentrated under vacuum to afford the title compound (3.48 g) in a yield of 100%.