Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18](Br)=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:22]1([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[CH:17][N:16]=4)[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccc(N2CCCN(c3ccc(Br)cn3)CC2)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(-c2ccc(N3CCCN(c4ccc(-c5ccccc5)cn4)CC3)nc2)cc1

Procedure:
Under nitrogen, to a solution of the 1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (200 mg, 0.585 mmol) synthesized in Reference Example 1 in ethanol-toluene (2.0 mL-2.0 mL) were added phenylboronic acid (130.0 mg, 1.07 mmol), tetrakis(triphenylphosphine)palladium (56.0 mg, 0.050 mmol) and a 2.0 M aqueous potassium carbonate (0.5 mL, 1.0 mmol), and the resulting mixture was stirred at 80° C. for 3 hours. After cooling, the organic layer was collected and the aqueous layer was extracted with chloroform. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield crude crystals. The crude crystals were recrystallized from chloroform-hexane to yield the title compound as slightly yellow needles (melting point: 221.0–222.0° C.) (61.0 mg, yield: 31%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[S:6][CH:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[NH:4][C@H:3]1[C:14]([OH:16])=[O:15]>N1C=CC=CC=1.C(OC(=O)C)(=O)C>[C:8]([O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C@H:5]1[N:4]([C:14](=[O:15])[CH3:3])[C@@H:3]([C:14]([OH:16])=[O:15])[C:2]([CH3:17])([CH3:1])[S:6]1)(=[O:13])[CH3:7]
Reactant: CC1(C)SC(c2ccccc2O)N[C@H]1C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccccc1[C@@H]1SC(C)(C)[C@H](C(=O)O)N1C(C)=O
Reaction time: 20 h

Procedure:
A solution containing 1.0 g of 5,5-dimethyl-2-(2-hydroxyphenyl)-thiazolidine-4(S)-carboxylic acid in 7 ml of pyridine and 3 ml of acetic anhydride is kept for 20 hours, then the mixture is evaporated and three times 20 ml of toluene each are distilled from the residue. The remained crystalline material is recrystallized from the mixture of acetone and petroleum ether to give the title compound in a yield of 0.9 g (67.5 %), m.p.: 214°-216° C. [α]D22 =+34 (c=0.47, chloroform).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:9]=[CH:8][C:7](=[O:10])[CH:6]=[CH:5]1.[Cl:11][C:12]1[CH:31]=[CH:30][C:15]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23](O)=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[C:14]([F:32])[CH:13]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C(Cl)Cl.CCOCC>[ClH:11].[Cl:11][C:12]1[CH:31]=[CH:30][C:15]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:1][CH2:2][CH2:3][N:4]4[CH:9]=[CH:8][C:7](=[O:10])[CH:6]=[CH:5]4)=[C:24]([O:27][CH3:28])[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[C:14]([F:32])[CH:13]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Reactant: O=c1ccn(CCO)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCn1ccc(=O)cc1
Product: Cl
Temperature: 5 °C
Reaction time: 2 h
Yield: 32.3 %

Procedure:
1-(2-Hydroxyethyl)-1,4-dihydro-4-pyridone (221 mg, 1.6 mmol) was added to a stirred solution of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (230 mg, 0.7 mmol), (prepared as described for the starting material in Example 15), and tributylphosphine (0.53 ml, 2.1 mmol) in methylene chloride (20 ml) under nitrogen at 5° C. 1,1′-(Azodicarbonyl)dipiperidine (552 mg, 2.2 mmol) was added in portions over 10 minutes and the mixture was stirred at 5° C. for 2 hours, allowed to warm to ambient temperature and stirred for a further 18 hours. The mixture was diluted with ether, the insolubles removed by filtration and the solvent was removed from the filtrate by evaporation. The residue was partitioned between ethyl acetate and water, the organic phase was separated and dried (MgSO4), and solvent was removed by evaporation. The residue was dissolved in acetone and ethereal hydrogen chloride (1.2 ml of a 3M solution) was added. The mixture was left to stand for 15 minutes and the precipitated product was collected by filtration, washed with ether and dried to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-[2-(4-oxo-1,4-dihydro-1-pyridyl)ethoxy]quinazoline hydrochloride (54 mg, 16%). 1H NMR Spectrum: (DMSOd6) 3.98(s, 3H); 4.63(dd, 2H); 4.83(dd, 2H); 7.42(d, 1H); 7.50(s, 1H); 7.56(d, 1H); 7.6-7.65(m, 3H); 8.39(s, 1H); 8.77(s, 1H); 8.80(s, 2H) MS-ESI: 441 [MH]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=C([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:14][CH2:13][CH:12]([N:15]([CH3:17])[CH3:16])[CH2:11]1)C#N.[OH-:18].[Na+].[CH2:20]([OH:22])[CH3:21]>>[Cl:1][C:2]1[CH:3]=[C:21]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:14][CH2:13][CH:12]([N:15]([CH3:17])[CH3:16])[CH2:11]1)[C:20]([OH:18])=[O:22]
Reactant: [OH-]
Reactant: CCO
Reactant: CN(C)C1CCN(c2ccc(C#N)cc2Cl)C1
Agent: [Na+]
Product: CN(C)C1CCN(c2ccc(C(=O)O)cc2Cl)C1

Procedure:
Prepared analogously to Example 13b from 3-chloro-4-(3-dimethylamino-pyrrolidin-1-yl)-benzonitrile with 10-molar sodium hydroxide solution and ethanol.
Reaction SMILES: [CH2:1]=[C:2]=[CH:3][CH3:4].C=CC=C.C#CCC.CC#CC.[CH:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O1CCCC1>[CH3:1][CH2:2][C:3]#[C:4][CH:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: C=C=CC
Reactant: CCCCCC=O
Agent: C#CCC
Agent: C=CC=C
Agent: CC#CC
Solvent: C1CCOC1
Product: CCC#CC(O)CCCCC

Procedure:
Following the procedure of Example 1, but with a pressure equalizing dropping funnel in place of the gas addition tube, 5.2 g. of lithium metal powder and 125 ml. of tetrahydrofuran are added to the flask. 65 g. of ammonia gas is condensed into the slurry with stirring forming a liquid-copper-gold colored lithium ammonia adduct. 190 g. of a mixture containing about 18% 1,2-butadiene, 21% 1,3-butadiene, 4% 1-butyne, 3.3% 2-butyne and about 25% isomeric butenes dissolved in 800 ml. tetrahydrofuran was added over a 70 minute period with stirring while maintaining the temperature at about 50°C. to 60°C. The mixture was refluxed to drive off excess gases and cooled. An aliquot of the product was reacted with 1-hexanal producing 3-decyn-5-ol which by gas chromotograph analysis, establishes a yield of butynyllithium in excess of 90%, based on lithium.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[CH:26]=[N:27][CH:28]=[N:29][CH:30]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([C:25]5[CH:30]=[N:29][CH:28]=[N:27][CH:26]=5)[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cc(-c3cncnc3)ccc21
Product: CC1c2ccc(-c3cncnc3)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-pyrimidin-5-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([S:7](Cl)(=[O:9])=[O:8])[C:4]([CH3:11])=[N:3]1.[OH-].[NH4+:13]>C1COCC1>[CH3:1][N:2]1[CH:6]=[C:5]([S:7]([NH2:13])(=[O:9])=[O:8])[C:4]([CH3:11])=[N:3]1
Reactant: Cc1nn(C)cc1S(=O)(=O)Cl
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nn(C)cc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 64 h
Yield: 111.6 %

Procedure:
A solution of 1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (232 mg, 1.192 mmol) in THF (10.0 mL) was cooled to 0° C. and to it was added dropwise ammonium hydroxide (0.650 mL, 16.69 mmol). The reaction mixture was allowed to warm to RT and left to stir over the weekend (ca. 64 hours). The reaction mixture was concentrated in vacuo. The residues were taken up in water, then neutralized with 1M aqueous HCl (dropwise addition) to pH 5-6 and extracted with ethyl acetate (3×50 mL). The combined organics were dried over MgSO4, filtered and evaporated to dryness, producing the title compound (233 mg). LCMS (A): m/z (M+H)+ 176, C5H9N3O2S requires 175 (acidic).
Reaction SMILES: ClC[CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[CH2:12]([NH:20][CH3:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH3:22][O-].[Na+]>CO>[CH2:13]([CH:12]([NH:20][CH3:21])[CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:22]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: CCCCCCCCNC
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCC(CC[Si](OC)(OC)OC)NC

Procedure:
A mixture of 19.9 grams of gamma-chloropropyltrimethoxysilane (commercially available) and 14.3 gm. of octylmethylamine is heated to 100°-120° C. for 16 hours. NMR indicated complete quaternization of the amine. To this mixture is added 0.1 mole of sodium methoxide in 50 ml. of methanol. After stirring for 6 hours the methanol is removed under vacuum and the residue is dissolved in cold hexane and filtered to yield gamma-octylmethylaminopropyltrimethoxysilane. To this product is added 0.1 mole of sodium beta-bromopropionate in 300 ml. of methanol. The mixture is warmed gently for 6 hours, then refluxed for an additional 6 hours to yield the desired quaternary ammonium salt.
Reaction SMILES: [NH4+:1].[Cl-].[C-:3]#[N:4].[Na+].[F:6][C:7]1[N:8]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=[C:10]([CH:12]=O)[N:11]=1>C1COCC1.CCO>[NH2:1][CH:12]([C:3]#[N:4])[C:10]1[N:11]=[C:7]([F:6])[N:8]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: [C-]#N
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: N#CC(N)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reaction time: 0.08 h

Procedure:
An aqueous solution of NH4Cl and NaCN was added to a solution of 2-fluoro-4-formyl-1-triphenylmethylimidazole in THF and EtOH. After stirring 2 hours at 20° and 5 minutes at 60°, the solution was evaporated and triturated with ether, to give 4-(1-aminocyanomethyl)-2-fluoro-1-triphenylmethylimidazole having the following n.m.r. in CDCl3 : 5.37 (s, 1H); 6.73 (s, 1H); 7.04-7.45 (m, 15H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[C:12]1[C:17]([F:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=1.CN(C)C=O.O1CCOCC1>C(N(CC)CC)C>[F:18][C:17]1[C:12]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[N:13][CH:14]=[C:15]([C:19]([F:21])([F:20])[F:22])[CH:16]=1
Reactant: Fc1cc(C(F)(F)F)cnc1Br
Reactant: C1CC2(CCN1)OCCO2
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Fc1cc(C(F)(F)F)cnc1N1CCC2(CC1)OCCO2
Reaction time: 1 h

Procedure:
1,4-Dioxa-8-azaspiro[4.5]decane (1.76 g), 2-bromo-3-fluoro-5-(trifluoromethyl)-pyridine (2.95 g), N,N-dimethylformamide (50 mL), 1,4-dioxane (75 mL) and triethylamine (5.07 ml) are heated in a sealed vessel at 120° C. with stirring for 1 h. After cooling the mixture is concentrated and partitioned between ethyl acetate (100 mL) and water (100 mL). The water layer is extracted with ethyl acetate (100 mL) and the combined ethyl acetate layers are dried over Na2SO4, filtered and concentrated to give the title compound. LC (method 21): tR=7.59 min; Mass spectrum (APCI): m/z=307 [M+H]+.
Reaction SMILES: [CH:1]([NH:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.[C:32](Cl)(=[O:34])[CH3:33].CS(C)=O>C1C=CC=CC=1>[C:32]([N:14]([CH:1]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)CCCNC(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Solvent: CS(C)=O
Product: CCOC(=O)CCCN(C(C)=O)C(c1ccccc1)c1ccccc1
Yield: 92.5 %

Procedure:
Analogously to Example 19, 10.8 g of ethyl 4-benzhydrylaminobutyrate and 5.2 g of ethyl diisopropylamine are dissolved in 100 ml of benzene and reacted with 3.1 g of acetyl chloride. As reaction product one obtains 11.4 g (92.5% of theory) of ethyl N-acetyl-4-benzhydrylaminobutyrate as a viscous non-distillable oil. The saponification of this ester yields 9.2 g (88% of theory) of N-acetyl-4-benzhydrylaminobutyric acid (M.P. 173° to 174°).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23]C(=O)OC(C)(C)C)[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH:11]2C[O:12]2)[CH2:9][CH3:10])=[CH:4][CH:3]=1.[CH3:31][O:32][Na].[CH3:34]O>>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:17]=1[CH:16]=[CH:15][N:14]2[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH2:9][CH3:10])[CH:11]([OH:12])[CH2:34][O:32][CH3:31]
Reactant: CO[Na]
Reactant: CO
Reactant: CCC(c1ccc(Cl)cc1)(C1CO1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Product: CCC(c1ccc(Cl)cc1)(C(O)COC)n1ccc2c(N)cccc21
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product from Step A (60 mg, 0.140 mmol) in MeOH (3 mL) was added MeONa (15 mg, 0.281 mmol). The mixture was stirred at 120° C. under microwave for 0.5 h. The solution was removed and the residue was purified by PREP-TLC eluting with PE/EA (1/1, v/v) to give the title compound as a colorless amorphous solid. LC/MS m/z=359.1[M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[CH3:18][O:19][C:20](=[O:27])[C@H:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[NH2:22]>>[CH3:18][O:19][C:20](=[O:27])[C@@H:21]([NH:22][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([N:5]2[CH2:4][CH2:3][C:2](=[O:1])[CH2:7][CH2:6]2)=[CH:16][CH:15]=1)[CH2:23][CH:24]([CH3:26])[CH3:25]
Reactant: O=C1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1ccc(N2CCC(=O)CC2)cc1

Procedure:
The title compound was prepared from 4-(4-oxo-piperidine-1-yl)-benzoic acid (which was obtained in Example 151) and L-leucine methyl ester hydrochloride according to the procedure of Example 154 as a gum; 1H NMR (300 MHz, CDCl3) δ 0.96 (t, J=6.2 Hz, 6H), 1.60-1.80 (m, 3H), 2.57 (t, J=6.1 Hz, 4H), 3.71 (t, J=6.1 Hz, 4H), 3.77 (s, 3H), 4.80-4.90 (m, 1H), 6.40 (d, J=8.2 Hz, 1H), 6.94 (d, J=7.0 Hz, 2H), 7.75 (d, J=7.0 Hz, 1H); MS (ES) m/z: 347.4 (MH+); HRMS Calcd. for C19H26N2O4 (M+): 346.1892. Found: 346.1881.
Reaction SMILES: Cl[CH2:2]C=CC=C.[CH3:7][C:8]([CH:10]([CH3:12])[CH3:11])=[O:9].[OH-].[K+].[C:15]1([CH3:21])[CH:20]=CC=[CH:17][CH:16]=1>>[CH3:11][C:10]([CH3:2])([CH2:12][CH:20]=[C:15]([CH3:21])[CH:16]=[CH2:17])[C:8](=[O:9])[CH3:7]
Reactant: Cc1ccccc1
Reactant: C=CC=CCCl
Reactant: CC(=O)C(C)C
Agent: [K+]
Agent: [OH-]
Product: C=CC(C)=CCC(C)(C)C(C)=O

Procedure:
According to the procedure described in Example 1, from 58.1 g of 1-chloro-2,4-pentadiene and 45.2 g of isopropyl methyl ketone in the presence of 100 g of powdered potassium hydroxide in 300 ml of toluene there are obtained 49.9 g of crude 3,3,6-trimethyl-5,7-octadien-2-one which are subjected to a fraction distillation.
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][CH:7]=[C:6]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([NH2:23])=[O:22])[CH:15]=1)[CH2:2][CH2:3][CH3:4]>C(O)(=O)C>[CH2:1]([N:5]1[C@H:9]([CH2:10][CH2:11][CH3:12])[CH2:8][CH2:7][C@@H:6]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([NH2:23])=[O:22])[CH:15]=1)[CH2:2][CH2:3][CH3:4].[CH2:1]([N:5]1[C@@H:9]([CH2:10][CH2:11][CH3:12])[CH2:8][CH2:7][C@@H:6]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]([NH2:23])=[O:22])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(CCC)ccc1Cc1cccc(NC(N)=O)c1
Solvent: CC(=O)O
Product: CCCCN1[C@@H](CCC)CC[C@@H]1Cc1cccc(NC(N)=O)c1
Product: CCCCN1[C@H](CCC)CC[C@@H]1Cc1cccc(NC(N)=O)c1
Temperature: 0 °C
Yield: 5 %
Yield: 37 %

Procedure:
A solution of 3 g (90 mmol) of 1-butyl-2-(3'-ureidobenzyl)-5-propylpyrrole in 150 ml of glacial acetic acid was hydrogenated at 45 p.s.i. in the presence of 2 g of 5% rodium on activated alumina as catalyst, for 41/2 hours. The catalyst was then separated by filtration and the filtrate evaporated in vacuo. The residue was suspended in 100 ml of ethyl acetate, cooled to 0° C. and 30 ml of concentrated ammonium hydroxide was added thereto. The organic phase was separated, dried and evaporated in vacuo. The residue was purified by t.l.c. using a (50:50) mixture of chloroform-[chloroform:methanol:ammonium hydroxide (60:10:1)] as the eluant, to produce 1.1 g (37%) of the less polar cis-1-butyl-2-(3'-ureidobenzyl)-5-propylpyrrolidine isomer, and 150 mg (5%) of the more polar trans-1-butyl-2-(3'-ureidobenzyl)-5-propylpyrrolidine isomer, which was recrystallized from ether hexane.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH2:9])=[C:4]([Cl:10])[CH:3]=1.[H][H]>O1CCCC1.C([O-])(=O)C.[Fe+2].C([O-])(=O)C.[Rh]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([Cl:10])[CH:3]=1
Reactant: C=Cc1ccc(Br)cc1Cl
Reactant: [H][H]
Agent: [Fe+2]
Agent: [Rh]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: CCc1ccc(Br)cc1Cl
Yield: 46.5 %

Procedure:
A solution of 4-bromo-2-chloro-1-ethenylbenzene (883 mg), iron(II) acetate (7 mg) and 5% rhodium-activated carbon (167 mg) in tetrahydrofuran (17 mL) was stirred at room temperature for three hours in a hydrogen atmosphere. The reaction solution was filtered through celite and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane only) to give the title compound as a colorless oil (414 mg, 46%).
Reaction SMILES: C(N(C(C)C)[CH:4]([CH3:6])[CH3:5])C.[CH2:10](Br)[CH2:11][CH3:12].[NH2:14][CH2:15][C:16]1[O:20][C:19]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][S:33][C:29]=4[C:28](=[O:34])[N:27]([CH3:35])[CH2:26][C:25]=23)=[N:18][N:17]=1>CN(C)C=O>[CH2:10]([N:14]([CH2:15][C:16]1[O:20][C:19]([C:21]2[N:22]=[CH:23][N:24]3[C:30]4[CH:31]=[CH:32][S:33][C:29]=4[C:28](=[O:34])[N:27]([CH3:35])[CH2:26][C:25]=23)=[N:18][N:17]=1)[CH2:5][CH2:4][CH3:6])[CH2:11][CH3:12]
Reactant: CCCBr
Reactant: CN1Cc2c(-c3nnc(CN)o3)ncn2-c2ccsc2C1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN(CCC)Cc1nnc(-c2ncn3c2CN(C)C(=O)c2sccc2-3)o1
Reaction time: 12 h
Yield: 49.3 %

Procedure:
3.48 ml (20 mmol) of N-ethyldiisopropylamine and 1.1 ml (12 mmol) of propyl bromide were added to a solution of 0.632 g (2 mmol) of 3-(5-aminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-one in 20 ml of dimethylformamide, whereupon the mixture was stirred at 70° for 12 hours. The dimethylformamide was evaporated and the residue was partitioned between methylene chloride and 2N sodium carbonate solution. The aqueous phase was washed twice with methylene chloride and the organic phases were dried with sodium sulfate, filtered and evaporated. Chromatography (silica gel, ethyl acetate/methanol 20:1) yielded 0.395 g (49%) of 3-(5-dipropylaminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a]thieno[2,3-f][1,4]diazepin-6-one as a colourless foam, Rf=0.33 (silica gel, ethyl acetate/methanol 20:1).
Reaction SMILES: [N+](C1C=C(C=CC=1)CNC(N)=O)([O-])=[O:2].[NH2:15][C:16]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N+:29]([O-])=O)[CH:24]=2)[C:20](=[O:32])[N:19]([CH3:33])[C:18](=[O:34])[CH:17]=1>C(O)C.[Pd]>[C:18]([OH:34])(=[O:2])[CH3:17].[NH2:15][C:16]1[N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH2:29])[CH:24]=2)[C:20](=[O:32])[N:19]([CH3:33])[C:18](=[O:34])[CH:17]=1
Reactant: Cn1c(=O)cc(N)n(Cc2cccc([N+](=O)[O-])c2)c1=O
Reactant: NC(=O)NCc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)O
Product: Cn1c(=O)cc(N)n(Cc2cccc(N)c2)c1=O
Reaction time: 1.5 h

Procedure:
Using the general procedure for Intermediate 1, (3-nitrobenzyl)-urea [J. Med. Chem. 1996, 39, 1924] is converted into 6-amino-3-methyl-1-(3-nitro-benzyl)-1H-pyrmidine-2,4-dione, [M-H]− 275. A suspension of this compound (4.88 g, 17.7 mmol) and 10% Pd/C (0.484 g) in ethanol (200 ml) is hydrogenated at 1 atmosphere for 1.5 hours. The reaction mixture is filtered through a celite plug and evaporated to give 6-amino-1-(3-amino-benzyl)-3-methyl-1H-pyrimidine-2,4-dione acetic acid salt [M-H]− 245. Acetic anhydride (1.85 ml, 19.57 mmol) is added to a cooled (0° C.) suspension of 6-amino-1-(3-amino-benzyl)-3-methyl-1H-pyrimidine-2,4-dione acetic acid salt (5.01 g, 16.35 mmol) in pyridine (50 ml). The reaction mixture is warmed to room temperature, stirred for 6 hours and the solvent evaporated. The residue is triturated with water and the solid collected by filtration and dried to afford N-[3-(6-amino-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-phenyl]-acetamide, 1H NMR (400 MHz, DMSO): δ: 2.00 (s 3H), 3.09 (s 3H), 4.72 (s 1H), 5.02 (s 2H), 6.75 (s 2H), 6.88 (d J 6 1H), 7.25 (t J 6 1H), 7.30 (s 1H), 7.55 (d f 6 1H), Using the general procedure for Intermediate 1, this compound is converted into N-[3-(5,6-diamino-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-phenyl]-acetamide [MH]+ 304.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[N:11]1([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[C:25](=O)[CH2:24][CH2:23][CH2:22]3)[CH:15]=[CH:14][N:13]=[CH:12]1.[OH-:30].[K+]>CCO>[N:11]1([CH2:16][CH2:17][O:18][CH:19]2[CH2:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27](=[O:30])[C:28]2=[CH:7][C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: [OH-]
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Reactant: CSc1ccc(C=O)cc1
Agent: [K+]
Solvent: CCO
Product: CSc1ccc(C=C2C(=O)c3ccccc3CC2OCCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(Methylthio)benzaldehyde (0.114 g, 0.75 mmol) was added to a stirring solution of (1) (0.25 g, 0.98 mmol) in 2 mL 4% KOH in EtOH (wt/vol). The reaction stirred at room temperature for 2 hours and the resulting precipitate was collected and washed well with water and then cold iPrOH. The solid was dried in vacuo at 40° C. for 3 hours affording the title compound, 0.277 g (95%) as an off-white solid, mp 161-161.5° C.; CI-MS m/e 390 (M+), 391 M++1);