Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C:5]([O:7]CC)=[O:6].[OH-].[K+].CO>O>[F:1][C:2]([F:11])([F:10])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CCC(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCC(F)(F)F
Yield: 98 %

Procedure:
To 160 g of ethyl 4,4,4-trifluorobutyrate, a mixed solution of 123 g of potassium hydroxide, 900 ml of methanol and 80 ml of water was added under ice cooling and the mixture was further reacted at room temperature for 12 hours. After the reaction solution was concentrated under reduced pressure, the resulting residue was then partitioned between water and diethyl ether. The ether layer was extracted once with water and the water layer was combined with the aqueous layer which had already been partitioned. After adjusting the pH to about 1 by the addition of an aqueous 10% ice-cooled hydrochloric acid solution, the mixture was extracted three times with diethyl ether. The layers were combined and the Combined ether layer was washed twice with saturated saline and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure to give 131 g of 4,4,4-trifluorobutyric acid (yield: 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.C1C(=O)N([Br:16])C(=O)C1>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[C:3]=1[Br:16]
Reactant: Nc1ccnc(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: Nc1ccnc(Cl)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Amino-2-chloropyridine (50 g, 388 mmol) was dissolved in glacial acetic acid (500 mL). To this solution was added NBS (75 g, 426 mmol) portionwise at RT (water bath cooling was provided to control the exothermicity). The reaction mixture was stirred at RT for 1 h at which point the reaction was found complete (as monitored by TLC). Solvent was removed under reduced pressure followed by azeotropic distillation with ethanol. The crude product was purified by column chromatography on silica gel (230-400 mesh) eluting with ethyl acetate hexane mixture.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CN1CCNCC1
Solvent: CCO
Product: CN1CCN(c2ccnc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4-dichloropyrimidine (447 mg, 3 mmol) in ethanol (10 mL) was added 1-methylpyperazine (360 mg, 3.6 mmol). The resulting mixture was stirred at room temperature overnight. The resulting white solid was collected by filtration and washed with ethanol, Na2CO3 solution and water and ethanol.
Reaction SMILES: [CH2:1]([C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)[CH:2]=[CH2:3].CCC(OO)=[O:16]>C1C=CC=CC=1>[O:16]1[CH2:3][CH:2]1[CH2:1][C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1
Reactant: C=CCc1ccc2c(c1)OCO2
Reactant: CCC(=O)OO
Solvent: c1ccccc1
Product: c1cc2c(cc1CC1CO1)OCO2
Temperature: 40 °C
Reaction time: 5 h

Procedure:
19.90 g (0.11 mol) of 5-(2-propenyl)-1,3-benzodioxole were initially introduced into a double-walled flask having a stirrer and reflux condenser and are warmed to 40° C. 43.58 g (0.10 mol) of a 20.58% strength solution of perpropionic acid in benzene were added dropwise, whilst stirring, and stirring was continued at this temperature for a further 5 hours. Titrimetric analysis then showed a peracid conversion of 98%. Analysis of gas chromatography gave a selectivity for the 5-(oxiranylmethyl)-1,3-benzodioxole formed of 61%.
Reaction SMILES: [C:1]([CH:4]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[O:6][CH2:5]1)(=[O:3])[CH3:2].[H-].[Na+].[C:17](OCC)(=[O:23])[C:18]([O:20]CC)=[O:19]>O1CCCC1>[O:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13](=[O:14])[CH:4]([C:1](=[O:3])[CH2:2][C:17](=[O:23])[C:18]([OH:20])=[O:19])[CH2:5]1
Reactant: CC(=O)C1COc2ccccc2C1=O
Reactant: CCOC(=O)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(O)C(=O)CC(=O)C1COc2ccccc2C1=O

Procedure:
Solid 3-acetyl-4-chromanone (0.570 g, 3 mmoles, described in Example 5) is added in portions at room temperature to a suspension of 57% sodium hydride (0.379 g, 9 mmoles) in dry tetrahydrofuran (10 ml). The mixture is heated within 15 min to 60° C and diethyl oxalate (0.438 g, 3 mmoles) in tetrahydrofuran (10 ml) is added. After heating at reflux temperature under an atmosphere of nitrogen for 17 hr., the solvent is removed under reduced pressure, the residue is dissolved in ice-water and extracted with ether. The aqueous phase is acidified with 6N hydrochloric acid and extracted with chloroform. The organic phase is dried, evaporated, and the residue crystallized from methanol-chloroform to give 4-(4-chromanone-3-yl)-2,4-dioxobutyric acid (Vl; R1, R2, R3, Rl4 and R5 = H, and X = O), νmaxnujol 1705, 1615 and 1560 cm-1.
Reaction SMILES: Cl.[S:2]1[CH2:6][C@@H:5]([C:7]([NH2:9])=[O:8])[NH:4][CH2:3]1.CCN(CC)CC.[Cl:17][CH2:18][C:19](Cl)=[O:20]>ClCCl>[Cl:17][CH2:18][C:19]([N:4]1[C@H:5]([C:7]([NH2:9])=[O:8])[CH2:6][S:2][CH2:3]1)=[O:20]
Reactant: O=C(Cl)CCl
Reactant: NC(=O)[C@@H]1CSCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)[C@@H]1CSCN1C(=O)CCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a stirred suspension of the hydrochloride salt obtained in step III (16.5 g, 0.1 mol) in dichloromethane (200 mL) cooled to 0° C. were added Et3N (41 mL, 0.3 mol) and chloroacetyl chloride (8.8 mL, 0.11 mol). The reaction mixture was slowly warmed to room temperature and stirred for 1 h. The reaction mass was filtered through a sintered funnel, the salt bed was washed with ether, and the filtrate was evaporated under vacuum to obtain the crude product (4R)-3-(chloroacetyl)-1,3-thiazolidine-4-carboxamide (20.8 g) as viscous liquid, which was used in the next step without further purification. m/z (M+1) 209; IR cm−1 3418, 2925, 1736, 1667, 1416, 1219, 771; 1H NMR (CDCl3) 300 MHz δ 6.60-6.30 (s (br), ½H), 6.0-5.65 (s (br), ½H), 5.02 (dd, J=3.6, 6.9 Hz, 0.8H), 4.88-4.75 (m, 0.4H), 4.70 (d, J=8.8 Hz, 0.8H), 4.62 (d, J=8.8 Hz, 0.8H), 4.51 (d, J=10.0 Hz, 0.2H), 4.16 (s, 1.6H), 4.11 (s, 0.4H), 3.56 (dd, J=3.4, 11.8 Hz, 0.8H), 3.44 (dd, J=4.7, 8.0 Hz, 0.4H), 3.15 (dd, J=7.1, 11.8 Hz, 0.8H), 1.28 (s, 1.6H), 1.25 (s, 7.4H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]#[CH:20]>CC(CC)=O>[CH2:20]([O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10])[C:19]#[CH:18]
Reactant: NS(=O)(=O)c1ccccc1O
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C#CCOc1ccccc1S(N)(=O)=O

Procedure:
A mixture of 35 g of 2-hydroxyphenylsulfonamide, 55.2 g of potassium carbonate, 15.5 ml of propargyl bromide and 1000 ml of ethyl methyl ketone is refluxed for 1.5 hours; it is then cooled, filtered, and concentrated by evaporation. The yield after recrystallisation of the residue from ethyl acetate is 30 g of 2-propargyloxyphenylsulfonamide, m.p. 143°-145° C.
Reaction SMILES: CC(C)=O.[CH3:5][O:6][C:7](=[O:18])[C@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[I-:19].CS[C:22]1[S:26][CH:25]=[CH:24][S+:23]=1>O>[I-:19].[S:23]1[CH:24]=[CH:25][S:26][C:22]1=[N+:9]([CH3:10])[CH:8]([C:7]([O:6][CH3:5])=[O:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CN[C@@H](Cc1ccccc1)C(=O)OC
Reactant: CSc1scc[s+]1
Agent: [I-]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C(Cc1ccccc1)[N+](C)=c1sccs1
Temperature: 25 °C
Yield: 55.7 %

Procedure:
To 100 ml of acetone, 2.2 g of N-methylphenylalanine methyl ester was dissolved, and 2.0 g of 2-methylthio-1,3-dithiolium iodide was gradually added thereto under stirring at room temperature. The mixture was stirred at room temperature for 1 hour, and then concentrated under reduced pressure. The residue was dissolved in water. The aqueous layer was washed with ethyl acetate, and then water was distilled off under reduced pressure, whereby 1.7 g (yield: 52%) of N-(1,3-dithiol-2-ylidene)-N-methyl-N-(2-phenyl-1-methoxycarbonylethyl)ammonium iodide (Compound No. 5) was obtained as oily substance.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br:10][C:11]1[CH:20]=[C:19]2[C:14]([NH:15][C@@H:16]([CH3:30])[CH2:17][N:18]2[C:21]2[O:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)=[CH:13][CH:12]=1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>ClCCCl>[O:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[N:18]1[C:19]2[C:14](=[CH:13][CH:12]=[C:11]([Br:10])[CH:20]=2)[N:15]([C:34]([CH:31]2[CH2:33][CH2:32]2)=[O:35])[C@@H:16]([CH3:30])[CH2:17]1
Reactant: C[C@H]1CN(c2nc3ccccc3o2)c2cc(Br)ccc2N1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C[C@H]1CN(c2nc3ccccc3o2)c2cc(Br)ccc2N1C(=O)C1CC1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 100.2 %

Procedure:
N,N-Diisopropylethylamine (0.041 mL, 0.232 mmol) was added to a solution of (S)-2-(7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-yl)benzo[d]oxazole (0.016 g, 0.046 mmol) and cyclopropanecarbonyl chloride (0.021 mL, 0.232 mmol) in 1,2-dichloroethane (1.0 mL), and the mixture stirred at 50° C. for 2.5 h. The reaction mixture was partitioned between water and dichloromethane. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford (S)-(4-(benzo[d]oxazol-2-yl)-6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)(cyclopropyl)methanone (0.019 g, 99%) as a brown oil. MS (ESI, pos. ion) m/z 412, 414 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17]([OH:19])=O)=[N:9]2)=[CH:4][CH:3]=1.COC1N=NC(N2C3[C@@H]4C[C@@H]4CC=3C(C(O)=O)=N2)=CC=1.[NH2:40][C:41]([CH3:45])([CH3:44])[CH2:42][OH:43].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:43][CH2:42][C:41]([NH:40][C:17]([C:10]1[C:11]2[CH2:12][C@H:13]3[CH2:16][C@H:14]3[C:15]=2[N:8]([C:5]2[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)=[O:19])([CH3:45])[CH3:44]
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1nn(-c2ccc(Cl)nn2)c2c1C[C@H]1C[C@@H]21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1ccc(-n2nc(C(=O)O)c3c2[C@@H]2C[C@@H]2C3)nn1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(CO)NC(=O)c1nn(-c2ccc(Cl)nn2)c2c1C[C@H]1C[C@@H]21
Temperature: 23 °C
Reaction time: 3 h

Procedure:
To a solution of a 4:1 mixture of (1aR,5aR)-2-(6-chloropyridazin-3-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid and (1aR,5aR)-2-(6-methoxypyridazin-3-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (100 mg, 0.361 mmol), 2-amino-2-methylpropan-1-ol (32.2 mg, 0.361 mmol), and triethylamine (0.101 mL, 0.723 mmol) in DMF (2 mL) was added HATU (151 mg, 0.398 mmol). The reaction was stirred at 23° C. for 3 h then concentrated. The residue was purified by HPLC to provide the title compound (73 mg) as a white solid. LCMS m/z=348.4 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.47 (td, J=4.6, 3.3 Hz, 1H), 1.29 (td, J=7.9, 4.9 Hz, 1H), 1.41 (s, 3H), 1.42 (s, 3H), 2.30-2.36 (m, 1H), 2.88-2.94 (m, 2H), 3.01 (dd, J=16.4, 6.2 Hz, 1H), 3.72 (s, 2H), 3.84 (bs, 1H), 6.88 (s, 1H), 7.61 (d, J=9.1 Hz, 1H), 8.12 (d, J=9.2 Hz, 1H).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Br[CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C(OCC)C>[C:1]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(C)Br
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCOCC
Product: CCOC(=O)C(C)C(=O)C(C)(C)C
Yield: 56.4 %

Procedure:
A 500 mL 3-neck round-bottom flask was equipped with a reflux condensor and thermometer and purged with nitrogen. To it was charged 100 mL dry, deoxygenated diethyl ether and 4.4 g of zinc strips. This mixture was agitated in a water-filled sonicating bath for 5 minutes. To this was slowly added a mixture of 12.06 g pivaloyl chloride (0.10 mole), 18.1 g of ethyl 2-bromopropionate (0.10 mole, synthesized by the method of Strunk, R. J.; DiGiacomo, P. M.; Aso, K.; Kuivila, H. G. J Am. Chem. Soc., 1970, 92, 2849-2856.) and 100 mL of ethyl ether. The resulting mixture was refluxed 6 hours and stirred at room temperature overnight. The mixture was then successively extracted with cold 20% aqueous sulfuric acid, water and brine before drying over sodium sulfate. The solution was stripped to obtain 12.8 g of crude oil. This was distilled under vacuum to yield 10.5 g of ethyl 2-pivaloylpropionate. 1H NMR (CDCl3): δ4.103 (q, J=7.1 Hz, 2H), 3.959 (q, J=6.9, 1 Hz), 1.287 (d, J=7.0 Hz, 3H), 1.196 (t, J=7.1 Hz, 3H), 1.157 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH:13]=[CH:12][CH2:11][C@@H:10]1[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:23].[Na+].OO>O1CCCC1>[C:19]([O:18][C:16]([NH:15][C@@H:10]1[CH2:11][CH2:12][CH:13]([OH:23])[CH2:14][C@@H:9]1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC=CC[C@H]1NC(=O)OC(C)(C)C
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC(O)CC[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
cis-N1,N2-Bis(tert-butoxycarbonyl)-4-cyclohexene-1,2-diamine (6.1 g) was dissolved in absolute tetrahydrofuran (40 ml), and borane-dimethyl sulfide complex (2.22 ml) was added by a syringe under ice cooling. The mixture was stirred for 16 hours while gradually heating the mixture to room temperature as it is. Ice was added to the reaction mixture, and a 1N aqueous solution of sodium hydroxide and 30% aqueous hydrogen peroxide (50 ml) were added to stir the mixture at room temperature for 2 hours as it is. The reaction mixture was extracted with ethyl acetate, and the resultant organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:2→2:1) to obtain the title compound (6.1 g) as a colorless oil.
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4]1([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18](OC)=[O:19])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1>C(O)C>[CH:4]1([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:22])[C:18]([NH:2][NH2:3])=[O:19])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: NN
Reactant: COC(=O)C(=O)Nc1ccc(C2CCCCC2)cc1
Solvent: CCO
Solvent: O
Product: NNC(=O)C(=O)Nc1ccc(C2CCCCC2)cc1
Temperature: 85 °C
Reaction time: 3 h

Procedure:
Hydrazine monohydrate (7.40 mL) was added to a stirred suspension of methyl [(4-cyclohexylphenyl)amino](oxo)acetate (3990 mg) in ethanol (50 mL) at ambient temperature. The reaction was heated to 85° C. and allowed to stir for a further 3 hours. Allowed to cool to ambient temperature overnight. The precipitate was filtered off, washed with Et2O and dried under vacuum, to give the title compound (Intermediate 47, 3750 mg) as a solid; 1H NMR δ10.42 (1H, s), 10.17 (1H, s), 7.68 (2H, d), 7.16 (2H, d), 4.58 (1H, s), 2.48 (1H+DMSO, m), 1.89-1.65 (5H, m), 1.46-1.13 (5H, m); MS m/e M−H− 260.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].C([O:9][CH:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C:12](=[CH:13][C:14](=[O:37])[C@@H:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)(=O)C>C1COCC1>[CH2:3]([C:14]1([OH:37])[CH:13]=[C:12]2[C@:32]([CH3:35])([CH2:33][CH2:34][CH:10]([OH:9])[CH2:11]2)[C@@H:31]2[C@@H:15]1[C@H:16]1[C@:28]([CH3:36])([CH2:29][CH2:30]2)[C@@H:19]([C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:25])[CH3:26])[CH2:18][CH2:17]1)[CH:2]=[CH2:1]
Reactant: C=CC[Mg]Br
Reactant: CC(=O)OC1CC[C@@]2(C)C(=CC(=O)[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Solvent: C1CCOC1
Product: C=CCC1(O)C=C2CC(O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]21

Procedure:
Following the analogous general Grignard procedure of Example 2, allyl magnesium bromide was reacted with Compound 1 in dry THF to yield the titled product 11. Proton NMR confirmed the assigned structure.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([C:13]#[N:14])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:30]4[CH:35]=[CH:34][C:33]([C:36]5[NH:37][C:38]([CH:41]6[CH2:47][C:44]7([CH2:46][CH2:45]7)[CH2:43][N:42]6[C:48](=[O:58])[CH:49]([NH:53][C:54]([O:56][CH3:57])=[O:55])[CH:50]([CH3:52])[CH3:51])=[N:39][CH:40]=5)=[CH:32][CH:31]=4)[CH:26]=3)[CH:21]=2)=[CH:18][N:19]=1)=O)(C)(C)C.[ClH:59].O1CCOCC1>C(Cl)Cl>[ClH:59].[ClH:59].[ClH:59].[CH3:57][O:56][C:54](=[O:55])[NH:53][CH:49]([C:48]([N:42]1[CH:41]([C:38]2[NH:37][C:36]([C:33]3[CH:32]=[CH:31][C:30]([C:25]4[CH:24]=[CH:23][C:22]5[C:27](=[CH:28][CH:29]=[C:20]([C:17]6[NH:16][C:15]([CH:9]7[CH2:10][CH:11]([C:13]#[N:14])[CH2:12][NH:8]7)=[N:19][CH:18]=6)[CH:21]=5)[CH:26]=4)=[CH:35][CH:34]=3)=[CH:40][N:39]=2)[CH2:47][C:44]2([CH2:45][CH2:46]2)[CH2:43]1)=[O:58])[CH:50]([CH3:52])[CH3:51]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CC(C#N)CN6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CC(C#N)CN6)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Reaction time: 0.62 h
Yield: 92 %

Procedure:
4-Cyano-2-{5-[6-(4-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (639 mg, 0.816 mmol) was dissolved in DCM (8 mL) and 4.0 M HCl in dioxane (2 mL, 8 mmol) was added. After stirring for 37 min, the solid was filtered off and rinsed with EtOAc, affording the title compound (597 mg, 92%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:11]=[CH:10][C:8](=[O:9])[NH:7][C:5]1=[O:6].Br[CH:13]([CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18].O>CS(C)=O>[CH3:3][N:4]1[CH:11]=[CH:10][C:8](=[O:9])[N:7]([CH2:21][CH2:20][CH2:19][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])[C:5]1=[O:6]
Reactant: Cn1ccc(=O)[nH]c1=O
Reactant: C=CCCCC(Br)CCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCCCCn1c(=O)ccn(C)c1=O
Reaction time: 0.25 h
Yield: 92.9 %

Procedure:
This example illustrates a synthesis of 1-Methyl-3-(8,9-oxidononyl)uracil (inventive compound no. 1804). Sodium hydride (365 mg, 16 mmol) was added to a stirring solution of 1-methyluracil (2.00 g, 16 mmol) in dimethyl sulfoxide (40 mL). After 15 minutes, 6-bromo-1-nonene (3.26 g, 16 mmol) was added and the mixture stirred for 3 days. The reaction was then poured into water (50 mL) and extracted with dichloromethane (3×60 mL). The combined organic layers were washed with water (50 mL), and aqueous saturated salt solution (30 mL) was then dried over sodium sulfate. The solvent was evaporated under vacuum to yield 3.72 g (94%) 1-methyl-3-(8-nonenyl)uracil (inventive compound no. 1817) as a colorless oil which solidified upon standing.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][NH:4][C:5]1[N:10]([CH3:11])[C:9](=[O:12])[C:8]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:7]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:6]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>CO>[C:33]([NH:1][C@@H:2]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][NH:4][C:5]1[N:10]([CH3:11])[C:9](=[O:12])[C:8]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[C:7]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:6]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(NC[C@@H](N)Cc2ccccc2)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Solvent: CO
Product: CC(=O)N[C@H](CNc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c(=O)n1C)Cc1ccccc1

Procedure:
A solution of 2-(((S)-2-amino-3-phenylpropyl)-amino)-5-(4-fluorophenyl)-3-methyl-6-(4-pyridyl)-4(3H)-pyrimidinone (25 mg, 0.058 mmol) and acetic anhydride (200 ml) in methanol (2 ml) was kept at room temperature for 1 h. Evaporation followed by chromatography of the resultant product on a column of silica gel (10% methanol/dichloromethane) provided the title compound.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][CH:3]1[NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].[H-].[Na+].[CH2:32]([O:34][CH:35]([O:38][CH2:39][CH3:40])[CH2:36]Br)[CH3:33]>CN(C)C=O>[CH2:32]([O:34][CH:35]([O:38][CH2:39][CH3:40])[CH2:36][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][CH:3]([NH:19][C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[C:2]1=[O:1])[CH3:33]
Reactant: CCOC(CBr)OCC
Reactant: O=C(NC1CN(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(CN1C(=O)C(NC(=O)OCc2ccccc2)CN(c2ccccc2)c2ccccc21)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.7 %

Procedure:
Under argon atmosphere, 2-oxo-3-benzyloxycarbonylamino-5-phenyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (930 mg) in anhydrous N,N-dimethylformamide (20 ml) was added to a suspension of 60% sodium hydride (192 mg) in anhydrous N,N-dimethylformamide (20 ml), then stirred at room temperature for one hour. After bromoacetaldehyde diethylacetal (946 mg) in anhydrous N,N-dimethylformamide (10 ml) was added to the mixture, the resultant mixture was stirred overnight internal temperature at 70-75° C. Ice-water was added to the reaction mixture, extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1), to thereby obtain 468 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][CH:2]([C:19]([NH:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])=[O:20])[C:3]([NH:5][C@@H:6]1[C:12](=[O:13])[N:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[NH:8][CH2:7]1)=[O:4].ClCCl.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl>C(N(CC)CC)C>[C:33]([N:8]1[CH2:7][C@H:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:1])[C:19]([NH:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:26])([F:25])[F:27])=[O:20])[C:12](=[O:13])[N:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]1=2)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@H]1CNc2ccccc2N(C)C1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@H]1CN(C(=O)c2ccccc2)c2ccccc2N(C)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.6 %

Procedure:
To a solution of 0.2 g (0.47 mmol) of 2-methyl-N-((3S)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide in 3 ml of dichloromethane 0.096 g (0.95 mmol) of triethylamine and 0.08 mg (0.57 mmol) of benzoylchloride were added. The mixture was stirred for 20 min at room temperature. Hydrochloric acid (10 ml of a 1 N solution) was added and the mixture was extracted two times with dichloromethane. The combined organic layers were extracted with 1N sodiumbicarbonate solution, dried (MgSO4) and concentrated in vacuo. The remaining oil was purified by column chromatography to yield 0.15 g (60%) of a white foam.