Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[NH:8][C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[Na+].[Na+].[CH2:21](I)[CH2:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C>[CH2:21]([N:8]1[C:7]2[N:6]=[CH:5][N:4]([CH2:1][CH:2]=[CH2:3])[C:12]=2[C:11](=[O:13])[NH:10][C:9]1=[O:14])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: C=CCn1cnc2[nH]c(=O)[nH]c(=O)c21
Reactant: CCCCCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CCCCC
Yield: 56 %

Procedure:
7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.61 g, 3.2 mmol), sodium carbonate (0.60 g, 5.7 mmol) and pentyl iodide (0.64 g, 3.2 mmol) were stirred in DMF (5 ml) at 50° C. for 18 h. The solution was cooled, separated between ethyl acetate and brine and the organics isolated, dried (MgSO4) and concentrated. Chromatography over silica (gradient elution dichloromethane to 5:1 dichloromethane/ethyl acetate) provided the title compound as a pale yellow solid (0.47 g, 56%). m/z 263 [MH+]
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:16][CH:17]1[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[CH2:19][O:18]1)(=O)=O.NC1C=CC=CN=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:16][CH:17]2[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[CH2:19][O:18]2)[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(Br)n1
Reactant: CC1(C)COC(COS(C)(=O)=O)CO1
Agent: Nc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)COC(CNc2cccc(Br)n2)CO1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 45.6 %

Procedure:
6-Bromopyridin-2-amine (771 mg, 4.46 mmol) was dissolved in 10 mL of anhydrous DMF and cooled to 0° C. NaH (60% in mineral oil, 214 mg, 5.35 mmol) was added. After 10 min the solution was warmed to ambient temperature and stirred for 15 min until bubbling ceased, to give a dark green solution. (5,5-Dimethyl-1,4-dioxan-2-yl)methyl methanesulfonate (500 mg, 2.23 mmol) in 2 mL of DMF was added. After the addition was completed the solution was stirred at ambient temperature for 20 min, then heated at 60° C. for 1.5 hr. It was diluted with EtOAc and washed four times with water. The aqueous layers were combined and extracted once with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated. The resulting residue was purified on a silica gel column (heptane:EtOAc 1:0 to 1:1) to give the product contaminated with the starting aminopyridine. Another purification on silica gel column (DCM:ether 20:1) gave the pure product (306 mg, 46%). LC-MS (m/z): 301.0/303.0 (M+H), retention time=0.89 min.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([NH:9][C:10](=[O:11])[C:4]2=[CH:3][CH:2]=1)=[O:8].[O:12]1[C@@H:14]([CH2:15][CH3:16])[CH2:13]1>CN(C=O)C.O>[OH:12][C@@H:14]([CH2:15][CH3:16])[CH2:13][N:9]1[C:7](=[O:8])[C:5]2[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=2)[C:10]1=[O:11]
Reactant: CC[C@H]1CO1
Reactant: O=C1NC(=O)c2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@H](O)CN1C(=O)c2ccccc2C1=O
Temperature: 60 °C

Procedure:
To 1,2-Benzenedicarboximide (4.29 g) in DMF (10 ml), (S)-(−)-1,2-epoxybutane (2.1 g) was added followed by K2 CO3 (4.03 g) and heated at 60° C. for 48 h. The reaction was diluted with water, extracted with EtOAc, dried and solvent removed to give the subtitle compound as a white solid, 1.8 g.
Reaction SMILES: [C:1]([C:3]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][CH:9]([C:12]([OH:14])=O)[CH2:8][CH2:7]1)#[N:2].Cl.[CH3:23][NH2:24]>>[C:1]([C:3]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH:6]1[CH2:7][CH2:8][CH:9]([C:12]([NH:24][CH3:23])=[O:14])[CH2:10][CH2:11]1)#[N:2]
Reactant: N#Cc1c(OC2CCC(C(=O)O)CC2)cccc1[N+](=O)[O-]
Reactant: CN
Agent: Cl
Product: CNC(=O)C1CCC(Oc2cccc([N+](=O)[O-])c2C#N)CC1

Procedure:
Prepared as in Example 24a from 4-(2-cyano-3-nitrophenoxy)cyclohexanecarboxylic acid (Example 154d) and methylamine hydrochloride as an orange solid (80%). MS 304 (MH+).
Reaction SMILES: Cl.[O-:2][Si:3]([O-:5])=[O:4].[Na+:6].[Na+].[OH2:8]>>[Si:3]([O-:8])([O-:5])([O-:2])[O-:4].[Na+:6].[Na+:6].[Na+:6].[Na+:6]
Reactant: O=[Si]([O-])[O-]
Reactant: O
Agent: Cl
Agent: [Na+]
Product: [O-][Si]([O-])([O-])[O-]
Yield: 18.5 %

Procedure:
Heimann (U.S. Pat. No. 2,316,241 dated 13 Apr. 1943) uses a gel that contains more water than the gels used in this invention. The patentee uses concentrated hydrochloric acid (the commercial product generally has 36% HCl) diluted with an equal volume of water, yielding approximately 18% acid. He neutralizes this with 40° Baume waterglass solution (37% sodium silicate) which is also diluted with an equal volume of water, resulting in an approximately 18.5% sodium silicate solution. The ingredients for the gel preparation used in a specific embodiment of the present invention are 41.5% sulfuric acid and 29% sodium silicate. The resulting reaction mixture of the present invention has approximately half the amount of water compared with Heimann's mixture. Those skilled in the art know that this difference in concentration causes the solidification of a gel to take approximately ten times longer for the more dilute system. This is the reason Heimann makes his gel by one of three methods: 1. Precipitation with ammonia, or 2. by letting the mixture stand for several days or 3. by heating the mixture to 90 or 100 degrees C. The gel used in the present invention gelatinizes in 30 to 60 minutes. (Date for this difference of gelation time are given in "The chemistry of silica" by Ralph K. Iler, John Wiley & Sons, 1979, page 368). The differences in the character of gels is given by Heimann in his patent. On page one, left side line 53, he mentions that the stabilizing effect of his product "cannot be attained when employing an ordinary silica gel prepared with an acid". The gel of this invention is an ordinary silica gel prepared with acid.
Reaction SMILES: O1CCCC1.[CH:6]([C@H:9]1[CH2:13][O:12][C:11](=[O:14])[NH:10]1)([CH3:8])[CH3:7].[C:15](Cl)(=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19]>O>[CH:6]([C@H:9]1[CH2:13][O:12][C:11](=[O:14])[N:10]1[C:15](=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19])([CH3:8])[CH3:7]
Reactant: CC(C)[C@H]1COC(=O)N1
Reactant: C=CCCC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Tetrahydrofuran (2 L) solution of 108 g of (S)-4-isopropyl-oxazolidin-2-one was cooled in a dry ice bath at −70° C., 345 mL of 2.66 M n-butyllithium-hexane solution was added thereto, and the reaction liquid was stirred at −70° C. for 30 minutes. Next, 102 mL of 4-pentenoyl chloride was added thereto at −70° C., the reaction liquid was stirred for 30 minutes, and water was added thereto to stop the reaction. This was extracted with ethyl acetate, the organic layer was washed with aqueous saturated sodium deuteride solution, and dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure to obtain a crude product of the entitled compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:42])[N:12]([CH:15]([C:17]3[N:18]=[CH:19][N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:21]=3[CH3:22])[CH3:16])[CH2:13][CH2:14][C:3]=12>C(O)(=O)C.O>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:42])[N:12]([CH:15]([C:17]3[N:18]=[CH:19][NH:20][C:21]=3[CH3:22])[CH3:16])[CH2:13][CH2:14][C:3]=12
Reactant: Cc1c2n(c3ccccc13)C(=O)N(C(C)c1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]cnc1C(C)N1CCc2c(C)c3ccccc3n2C1=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 3,4-dihydro-5-methyl-2-[1-(5-methyl-1-trityl-1H-imidazol-4-yl)ethyl]pyrimido[1,6-a]indol-1(2H)-one (60 mg) in 70% acetic acid in water (2.6 ml) was stirred at 60° C. for 2 hours. After evaporation of the solvent, the residue was dissolved in 10% methanol in chloroform. The mixture was washed with aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (10% methanol-chloroforms) to give 3,4-dihydro-5-methyl-2-[1-(5-methyl-1H-imidazol-4-yl)ethyl]pyrimido[1,6-a]-indol-1(2H)-one as a powder. The powder was dissolved in 9N hydrogen chloride in ethanol (1 ml) and evaporated in vacuo. The residue was triturated with ether to give 3,4-dihydro-5-methyl-2-[1-(5-methyl-1H-imidazol-4-yl)-ethyl]pyrimido[1,6-a]indol-1(2H)-one hydrochloride (36.8 mg).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH2:10][C:8](=[O:9])[CH2:7][C:6]([CH3:12])([CH3:11])[CH:5]=1.CC1[CH2:15][CH:16]([OH:22])CC(C)(C)C=1.C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+]>CO>[C:16]([O:9][CH:8]1[CH2:7][C:6]([CH3:12])([CH3:11])[CH:5]=[C:4]([CH3:3])[CH2:10]1)(=[O:22])[CH3:15]
Reactant: CC1=CC(C)(C)CC(O)C1
Reactant: CC1=CC(C)(C)CC(=O)C1
Agent: CC(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC1CC(C)=CC(C)(C)C1

Procedure:
Prepared by reduction by means of sodium borohydride in methanol of β-isophorone [obtained according to J. Am. Chem. Soc., 63, 2308 (1941)]and subsequent acetylation of the obtained 3,5,5-trimethyl-cyclohex-3-en-1-ol by means of acetic anhydride in the presence of sodium acetate at 50°C during 20 hours.
Reaction SMILES: [CH2:1]1COCC1.C[O:7][C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][CH:15]=2)[CH:11]=[CH:10][N:9]=1.C(=O)([O-])[O-].[K+].[K+].CI>C(Cl)Cl>[CH3:1][N:9]1[CH:10]=[CH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:18][CH:19]=2)=[CH:13][C:8]1=[O:7]
Reactant: C1CCOC1
Reactant: COc1cc(-c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccn(C)c(=O)c3)cc2)C(=O)O1
Temperature: 85 °C
Yield: 69 %

Procedure:
To a stirred anhydrous THF (10 mL) mixture of N-({(5S)-3-[4-(2-methoxypyridin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (0.667 g, 1.95 mmol) in a sealed tube, is added potassium carbonate (0.807 g, 6.0 mmol) and methyl iodide (1 mL, 17 mmol). The mixture is heated to 85° C. for 16 hours. The reaction is cooled to RT and diluted to 300 mL with CH2Cl2. The K2CO3 is filtered. The solution is concentrated to dryness, dissolved in MeOH (20 mL) and treated with saturated Na2S2O3. The solution is concentrated to dryness on silica. The residue is loaded onto a SIM and purified on a Biotage 12M column with 2–4% MeOH in CH2Cl2 to yield the desired compound (0.460 g, 69%). 1H-NMR (DMSO) δ: 8.26, 7.77, 7.64, 6.68, 6.60, 4.74, 4.17, 3.78, 3.43, 1.83
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[NH:17][C:16]([CH:18]=[C:19]4[N:46]=[C:22]([C:23]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH2:42][CH2:43][CH2:44]O)[CH:36]=5)=[C:24]5[NH:34][C:27](=[CH:28][C:29]6[CH:30]=[CH:31][C:32]=2[N:33]=6)[CH:26]=[CH:25]5)[CH:21]=[CH:20]4)=[CH:15][CH:14]=3)[CH:9]=[CH:10][CH:11]=1.C(N(CC)CC)C.[CH3:54][S:55](Cl)(=[O:57])=[O:56]>C(Cl)Cl>[CH3:54][S:55]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[NH:17][C:16]([CH:18]=[C:19]4[N:46]=[C:22]([C:23]([C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH2:42][CH2:43][CH2:44][S:55]([CH3:54])(=[O:57])=[O:56])[CH:36]=5)=[C:24]5[NH:34][C:27](=[CH:28][C:29]6[CH:30]=[CH:31][C:32]=2[N:33]=6)[CH:26]=[CH:25]5)[CH:21]=[CH:20]4)=[CH:15][CH:14]=3)[CH:9]=[CH:10][CH:11]=1)(=[O:57])=[O:56]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCOc1cccc(-c2c3nc(cc4ccc([nH]4)c(-c4cccc(OCCCO)c4)c4nc(cc5ccc2[nH]5)C=C4)C=C3)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCCOc1cccc(-c2c3nc(cc4ccc([nH]4)c(-c4cccc(OCCCS(C)(=O)=O)c4)c4nc(cc5ccc2[nH]5)C=C4)C=C3)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 47.2 %

Procedure:
To a solution of 5,15-bis-[3-(3-hydroxypropoxy)phenyl]porphyrin (30 mg, 0.049 mmol) in anhydrous CH2Cl2, under nitrogen atmosphere, at 0° C., triethylamine (29 mg mg, 0.29 mmol) and methansulphonylchloride (17 mg, 0.15 mmol) were added. The mixture was kept under magnetic stirring at 0° C. for 3 hours, then washed with NaHCO3 saturated solution and with water. The organic phase was dried under Na2SO4 and the solvent removed by evaporation. The crude product was purified by chromatography on silica gel (CHCl3), to obtain 17 mg of the pure title product (yield 45%).
Reaction SMILES: C(O)=O.C(O[C:8](=[O:10])[CH3:9])(=O)C.[O:11]=[C:12]1C[NH:16][CH2:15][CH2:14][NH:13]1>C(Cl)Cl>[CH:12]([N:13]1[CH2:14][CH2:15][NH:16][C:8](=[O:10])[CH2:9]1)=[O:11]
Reactant: O=C1CNCCN1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: ClCCl
Product: O=CN1CCNC(=O)C1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 56 %

Procedure:
To 80 ml of formic acid was added 28 ml of acetic anhydride at room temperature, and the mixture was stirred at 60° C. for 20 minutes. After stirring at room temperature for further 15 minutes, the reaction mixture was added dropwise to a solution of 4.2 g of 2-oxopiperazine in 400 ml of methylene chloride at 0° C. over a period of 1.25 hours, and the resulting mixture was stirred at 0° C. for further 30 minutes. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was recrystallized from acetone/hexane to give 3.0 g (56%) of 1-formyl-3-oxopiperazine.
Reaction SMILES: [C:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-])=O)[C:14]=2[C:15]#[N:16])=[C:6]([CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])[C:5]=1[OH:32])(=[O:3])[CH3:2].C1CCCCC=1>C(O)C>[NH2:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:24]=[CH:25][C:4]([C:1](=[O:3])[CH3:2])=[C:5]([OH:32])[C:6]=2[CH2:26][CH2:27][C:28]([F:29])([F:30])[F:31])[C:14]=1[C:15]#[N:16]
Reactant: CC(=O)c1ccc(OCCCOc2cccc([N+](=O)[O-])c2C#N)c(CCC(F)(F)F)c1O
Solvent: CCO
Solvent: C1=CCCCC1
Product: CC(=O)c1ccc(OCCCOc2cccc(N)c2C#N)c(CCC(F)(F)F)c1O
Temperature: 25 °C

Procedure:
2.5 g of 10% Pd-on-charcoal are added to a solution of 10 g of 2-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-6-nitro-benzonitrile and 10 g of cyclohexene in 500 ml of ethanol and the mixture is refluxed for 30 minutes. After cooling to room temperature, it is filtered and freed from the solvent. Ether is added to the residue and the crystals which have separated out are filtered off. 2-Amino-6-{-3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-benzonitrile is obtained.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[CH:7]1[C:15]2[C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[O:12][C:11]=2[CH:10]=[CH:9][C:8]=1[NH2:21].N1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH:7]1[C:15]2[C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:13]=3[O:12][C:11]=2[CH:10]=[CH:9][C:8]=1[NH:21][C:2](=[O:3])[O:4][CH2:5][CH3:6]
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: CCOC(=O)Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
Ethyl chloroformate (0.16 mL, 1.6 mmol) was added to a solution of 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.30 g, 1.5 mmol) and pyridine (0.36 mL, 4.5 mmol) in acetonitrile (20 mL). The reaction mixture was stirred overnight at room temperature. The crude material was diluted in ethyl acetate and washed with water, dried (MgSO4) and concentrated. The solid was washed with hexane to provide ethyl 7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylcarbamate (0.40 g). MS (ESI) m/z 274; Profiled 100% purity, m/z 274.1 ([M+H]+), 2.5 min, Anal. Calcd. for C16H,9NO3: C, 70.31; H, 7.01; N, 5.12. Found: C, 70.18; H, 6.95; N, 5.01.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][NH:20][CH2:21][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl.[CH3:23][N:24]([CH:31]([CH3:33])[CH3:32])[CH2:25]/[CH:26]=[CH:27]/[C:28](O)=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][N:20]([C:28](=[O:29])/[CH:27]=[CH:26]/[CH2:25][N:24]([CH:31]([CH3:33])[CH3:32])[CH3:23])[CH2:21][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(Nc2ncnc3sc4c(c23)CNC4)cc1Cl
Reactant: CC(C)N(C)C/C=C/C(=O)O
Agent: Cl
Product: CC(C)N(C)C/C=C/C(=O)N1Cc2sc3ncnc(Nc4ccc(F)c(Cl)c4)c3c2C1

Procedure:
In analogy to Example 89, the title compound was prepared from N-(3-chloro-4-fluorophenyl)-6,7-dihydro-5H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidin-4-amine from Example 23A (60 mg, 0.19 mmol) and (2E)-4-[methyl(1-methylethyl)amino]but-2-enoic acid hydrochloride from Example 2A (51 mg, 0.26 mmol) to yield 30 mg (35%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C(OC([N:34]1[CH2:39][CH2:38][N:37]([C:40](=[O:43])[CH2:41]Cl)[CH2:36][CH2:35]1)=O)(C)(C)C>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:41][C:40](=[O:43])[N:37]2[CH2:38][CH2:39][NH:34][CH2:35][CH2:36]2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Product: O=C(Cn1cc(C(=O)N2CCC3(CC2)OCc2ccccc23)c2ccc(Cl)cc21)N1CCNCC1

Procedure:
Following the general procedure V as described hereinabove, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (the preparation of which have been described in example 69) with commercially available 4-(2-chloro-acetyl)-piperazine-1-carboxylic acid tert-butyl ester as electrophile, the title compound was obtained as a white solid after removal of the Boc protecting group under standard conditions (TFA/dichloromethane, room temperature).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([N:13]3[CH2:20][CH:19]4[CH:15]([CH2:16][NH:17][CH2:18]4)[CH2:14]3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[C:30]([C:31](O)=[O:32])[C:25]=2[O:24][CH2:23][CH2:22]1>>[O:21]1[C:26]2[CH:27]=[CH:28][CH:29]=[C:30]([C:31]([N:17]3[CH2:16][CH:15]4[CH:19]([CH2:20][N:13]([C:9]5[N:8]=[C:7]([C:1]6[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=6)[CH:12]=[CH:11][N:10]=5)[CH2:14]4)[CH2:18]3)=[O:32])[C:25]=2[O:24][CH2:23][CH2:22]1
Reactant: c1ccc(-c2ccnc(N3CC4CNCC4C3)n2)cc1
Reactant: O=C(O)c1cccc2c1OCCO2
Product: O=C(c1cccc2c1OCCO2)N1CC2CN(c3nccc(-c4ccccc4)n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 26 and 2,3-dihydro-benzo[1,4]dioxine-5-carboxylic acid. MS (ESI) mass calcd. for C25H24N4O3, 428.50; m/z found, 429.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][N:18]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:19]3[CH:31]=[CH:30][C:22]4[O:23][C:24](C)(C)[O:25][C:26](=[O:27])[C:21]=4[CH:20]=3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:39]=[CH:38][C:16]([CH2:17][N:18]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:19]3[CH:31]=[CH:30][C:22]([OH:23])=[C:21]([CH:20]=3)[C:26]([O:25][CH3:24])=[O:27])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc2c(c1)C(=O)OC(C)(C)O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(O)c(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-[{4-[(4-butylphenyl)ethynyl]benzyl}(hexyl)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one (4.41 g, 8.4 mmol) in MeOH (500 mL) and water (30 mL) was added an aqueous solution of NaOH (7.0 mL, 5N). The reaction mixture was stirred at rt for 2 hrs and a yellow powder precipitated out progressively. Filtration and washing with water (2×) gave the title compound as a yellow powder. HPLC, Rt: 5.3 min (purity: 98.7%). LC/MS, M+(ESI): 498.3. 1H NMR (CDCl3) δ: 10.16 (s, 1H), 7.45 (m, 4H), 7.19 (m, 5H), 6.94 (dd, J=9.0, 3.0 Hz, 1H), 6.86 (d, J=9.0 Hz, 1H), 4.43 (s, 2H), 3.92 (s, 3H), 3.28 (t, J=7.5 Hz, 2H), 2.63 (t, J=7.5 Hz, 2H), 1.60 (m, 4H), 1.30 (m, 8H), 0.92 (m, 6H).
Reaction SMILES: [CH:1]1([NH:7][C:8](=[N:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[O:9][N:10]=[C:11]([CH2:13][CH3:14])[CH3:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>CN(C)C1C=CN=CC=1.ClCCl.CCCCCC>[C:29]([N:15]([CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[C:8](=[N:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[O:9][N:10]=[C:11]([CH2:13][CH3:14])[CH3:12])(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCC(C)=NOC(=NC1CCCCC1)NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCC(C)=NOC(=NC1CCCCC1)N(C(=O)C(C)(C)C)C1CCCCC1
Temperature: 25 °C
Reaction time: 43 h
Yield: 72.7 %

Procedure:
To a solution of 1,3-dicyclohexyl-O—(N-2-butylideneamino)-isourea (Cmpd. 2) (5.87 g, 20 mmol) and 4-dimethylaminopyridine (60 mg) in dichloromethane (25 ml) and triethylamine (3.1 ml, 22 mmol) is added pivaloyl chloride (2.46 g, 21 mmol). The mixture is stirred 43 h at room temperature, diluted with hexane (200 ml), washed with water (4×20 ml), dried over MgSO4 and evaporated. The residue is chromatographed on silica gel (hexanes-ethyl acetate 4:1) to afford 5.49 g of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:15]([CH:18]=[O:19])=[CH:14][C:11]=1[C:12]#[N:13]>>[CH:18]([C:15]1[CH:16]=[CH:17][C:10]([O:8][C:5]2[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[C:11]([CH:14]=1)[C:12]#[N:13])=[O:19]
Reactant: Cc1ccc(O)cn1
Reactant: N#Cc1cc(C=O)ccc1F
Product: Cc1ccc(Oc2ccc(C=O)cc2C#N)cn1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 6-methyl-3-pyridinol and 2-fluoro-5-formylbenzonitrile.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=[O:7].O.C([O-])([O-])=O.[Na+].[Na+].[CH:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:23][C:24](Cl)=[O:25])=[CH:18][CH:17]=1>C1COCC1>[CH2:22]([O:23][C:24]([N:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=[O:7])=[O:25])[C:19]1[CH:20]=[CH:21][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
To a stirred solution of (S)-pyrrolidine-2-carboxylic acid (7) (2.0 g, 17.39 mmol) in THF:H2O (20 mL, 1:1) were added Na2CO3 (2.76 g, 26.08 mmol) and Cbz-Cl (3.54 g, 20.80 mmol) and stirred at RT for 18 h. The reaction mixture was washed with EtOAc (10 mL) and the aqueous layer was acidified with 3N HCl and extracted with EtOAc (2×20 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to yield compound 8 (3.0 g, 69.7%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]1[OH:13].[C:20]1([CH:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:27][CH2:28][NH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[C:30]1([CH:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:27][CH2:28][NH:29][C:2]2[C:3]3[N:4]=[CH:5][N:6]([C:7]=3[N:8]=[CH:9][N:10]=2)[C@@H:11]2[O:17][C@H:16]([CH2:18][OH:19])[C@@H:14]([OH:15])[C@H:12]2[OH:13])[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCO
Product: OC[C@H]1O[C@@H](n2cnc3c(NCCC(c4ccccc4)c4ccccc4)ncnc32)[C@H](O)[C@@H]1O
Temperature: 5 °C

Procedure:
A solution of 6-chloro-9-β-D-ribofuranosylpurine (2.87 g, 0.010 mol) and 3,3-diphenylpropylamine (5.28 g, 0.025 mol, 250 mol%) in absolute ethanol (75 ml) is heated at reflux for six days, during which time the starting material is mostly consumed according to TLC analysis (5/1 CHCl3 /MeOH). The solution is cooled to 5° C. and the resulting first and second crops of white crystals are combined to give N6 -(3,3-diphenylpropyl)adenosine, mp 103°-118° C. (from absolute ethanol).