Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:14])[O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:13])=[CH:6][CH:5]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl>[Br:15][CH:8]1[C:7]2[C:11](=[CH:12][C:4]([O:3][CH:2]([F:1])[F:14])=[CH:5][CH:6]=2)[C:10](=[O:13])[O:9]1
Reactant: O=C1OCc2ccc(OC(F)F)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C1OC(Br)c2ccc(OC(F)F)cc21
Temperature: 76 °C
Yield: 101.1 %

Procedure:
A suspension of 6-difluoromethoxy-3H-isobenzofuran-1-one (1 g, 5 mmoles), prepared as described in example 94, in CCl4 (10 ml), under N2, was added with N-bromosuccinimide (0.91 g, 5.1 mmoles) and the mixture was heated at 76° C. A solution of α,α′-azaisobutyronitrile (0.01 g) in CHCl3 (1 ml) was slowly added. The mixture was refluxed for 1.5 hours, then cooled, filtered over celite and washed with CCl4. By drying, 1.41 g of the title compound were obtained as an oil (quantitative yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[CH:13]=[CH:14][N:15]=[C:8]1[N:7]=[C:6]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]1[CH:13]=[CH:14][N:15]=[C:8]1[NH:7][CH:6]2[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc2c(c1)c(-c1ccccc1)nc1nccn12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)C(c1ccccc1)Nc1nccn1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.1 %

Procedure:
To a suspension of 1.38 g of 7-methoxy-5-phenylimidazo[1,2-a]quinazoline in 25 ml of tetrahydrofuran was added 0.38 g of lithium aluminum hydride, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added dropwise 1 ml of water with ice-cooling, and the resulting precipitate was filtered off and washed with tetrahydrofuran. The filtrate was evaporated under reduced pressure and the residue was recrystallized from ethylacetate-isopropyl ether to give 1.1 g of 4,5-dihydro-7-methoxy-5-phenylimidazo[1,2-a]quinazoline, m.p. 178°-179° C. (decomp.).
Reaction SMILES: [CH2:1]([N:8]([CH3:24])[C@H:9]([C:21]([OH:23])=O)[CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:67]1([CH2:73][CH2:74][CH2:75][NH2:76])[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1>O1CCCC1.C(OCC)(=O)C>[C:67]1([CH2:73][CH2:74][CH2:75][NH:76][C:21](=[O:23])[C@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH3:24])[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1
Reactant: CN(Cc1ccccc1)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)O
Reactant: NCCCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of Nα-benzyl-Nδ-Boc-Nα-methylornithine (300 mg), diisopropylethylamine (326 μl), and anhydrous tetrahydrofuran (4 ml) was treated with PyBop (585 mg) at 0° C. for 10 min., followed by the addition of a solution of 3-phenylpropylamine (147 μl) in anhydrous tetrahydrofuran (2 ml). The resulting solution was stirred at ambient temperature for 4 hrs. The reaction was diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The product was purified by chromatography over silica gel (hexane/ethyl acetate) to give Nα-benzyl-Nδ-Boc-Nα-methylornithine 3-phenylpropylamide (370 mg): 1H NMR (400 MHz, CDCl3) δ1.43 (s, 9H), 1.6-1.9 (m, 6H), 2.2 (s, 3H), 2.65 (t, J=6.2 Hz, 2H), 3.0-3.4 (m, 5H), 3.64 (s, 2H), 4.8 (s, 1H), and 7.1-7.5 (m, 10H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]#[N:12].S(Cl)(Cl)=O.[NH2:17][C:18]1[C:19]([Cl:26])=[N:20][CH:21]=[N:22][C:23]=1[O:24][CH3:25]>C1C=CC=CC=1.ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:17][C:18]2[C:19]([Cl:26])=[N:20][CH:21]=[N:22][C:23]=2[O:24][CH3:25])=[O:8])=[CH:4][C:3]=1[C:11]#[N:12]
Reactant: N#Cc1cc(C(=O)O)ccc1Cl
Reactant: COc1ncnc(Cl)c1N
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1ncnc(Cl)c1NC(=O)c1ccc(Cl)c(C#N)c1
Temperature: 25 °C
Reaction time: 115 h
Yield: 75.4 %

Procedure:
To a suspension of the above-mentioned 4-chloro-3-cyanobenzoic acid (1.20 g, 6.61 mmol) in dry benzene (10 mL) was added thionyl chloride (0.58 mL, 7.95 mmol). The mixture was heated under refluxing for 4 hours, and then placed under reduced pressure to distill the solvent off. To the residue was added dry dichloromethane (5 mL), and the mixture was placed under reduced pressure to distill the dry benzene and the remaining thionyl chloride off. The residue was dissolved in dry dichloromethane (45 mL). The resulting solution was dropwise added under ice-cooling to a solution of 5-amino-4-chloro-6-methoxypyrimidine (2.11 g, 13.2 mmol) in dry dichloromethane (45 mL) for 5 minutes. The mixture was stirred at room temperature for 115 hours. The precipitated crystalline product was collected by filtration, washed with dichloromethane (5 mL×2), and placed under reduced pressure to distill the solvent off. The residue was repeatedly purified by silica gel column chromatography (methanol/chloroform), to obtain 1.61 g (yield 75%) of the titled compound as a pale brown crystalline product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]([NH2:45])=[O:44])[CH2:39][CH2:38]1.[C:46]1([C:52]2([C:58]([OH:60])=[O:59])[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(OCC)(=O)C.CCCCCC>CO.ClCCl>[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]([NH2:45])=[O:44])[CH2:39][CH2:38]1.[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:55]3[CH2:54][CH2:53][C:52]([C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)([C:58]([OH:60])=[O:59])[CH2:57][CH2:56]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: CN1CCN(C(N)=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 27.3.1 using 2-[3-(3,4-dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (2.8 g, 5.24 mmol) and 4-phenyl-piperidine-4-carboxylic acid 4-methylpiperazine-amide hydrochloride (2.8 g, 3.9 mmol). Chromatograph on silica gel eluting sequentially with 50% ethyl acetate/hexane, 3% methanol/dichloromethane, and then 6% methanol/dichloromethane to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].[CH2:35]([O:37][CH2:38][CH2:39][N:40]1[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2[N:42]=[C:41]1[NH:49][CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)[CH3:36].C(N(CC)C(C)C)(C)C.C(N(CC)CC)C>C(#N)C>[CH3:34][O:33][C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:30]=1[O:31][CH3:32])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:53]2[CH2:54][CH2:55][CH:50]([NH:49][C:41]3[N:40]([CH2:39][CH2:38][O:37][CH2:35][CH3:36])[C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=4[N:42]=3)[CH2:51][CH2:52]2)([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)[CH2:9]1)=[O:7]
Reactant: CCOCCn1c(NC2CCNCC2)nc2ccccc21
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCn1c(NC2CCN(CCC3(c4ccc(F)c(F)c4)CCN(C(=O)c4cc(OC)c(OC)c(OC)c4)C3)CC2)nc2ccccc21
Reaction time: 48 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-difluorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (0.48 g, 1.66 mmol) and (1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.83 g, 1.66 mmol), and N,N-diisopropylethylamine (0.32 g, 2.49 mmol) in acetonitrile (10 mL). Heat to reflux. After 48 hours, cool and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 2% triethylamine/10% methanol/ethyl acetate to give the title compound: Rf=0.36 (silica gel, 2% triethylamine/10% methanol/ethyl acetate).
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C[Si](N[Si](C)(C)C)(C)C.Cl[Sn](Cl)(Cl)Cl.C(O[CH:28]1[CH2:32][CH2:31][CH2:30][O:29]1)(=O)C.COC1CCCO1>C(Cl)CCl>[O:29]1[CH2:30][CH2:31][CH2:32][CH:28]1[N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: CC(=O)OC1CCCO1
Agent: COC1CCCO1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: O=c1[nH]c(=O)n(C2CCCO2)cc1F
Reaction time: 4 h
Yield: 87 %

Procedure:
0.65 g. (5 mmol) of 5-fluorouracil was agitated in 50 ml. of absolute ethylene chloride for one hour with 0.65 g. (4 mmol) of HMDS, 0.43 g. (4 mmol) of TCS, and 1.56 g. (6 mmol) of SnCl4 ; then 0.65 g. (5 mmol) of 2-acetoxytetrahydrofuran or 0.51 g. (5 mmol) of 2-methoxytetrahydrofuran was added to the mixture, and the latter was agitated for 2 hours and 4 hours, respectively, at 24° C. The mixture was worked up as described in Example 1, giving in an 87% yield N1 -(2-tetrahydrofuryl)-5-fluorouracil, m.p. 165°-167° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Li]C(C)(C)C.CCCCC.[CH3:21][Si:22]([CH3:25])([CH3:24])Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([Cl:1])[C:7]=1[Si:22]([CH3:25])([CH3:24])[CH3:21]
Reactant: C[Si](C)(C)Cl
Reactant: COc1ccc(F)cc1Cl
Agent: O=C([O-])O
Agent: [Li]C(C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc(F)c([Si](C)(C)C)c1Cl
Reaction time: 0.25 h

Procedure:
To a solution of 2-chloro-4-fluoroanisole (16.5 g, 100 mmol) in THF (500 mL) cooled at −75° C. was added dropwise a solution of t-BuLi in pentane (1.7 M, 61.8 mL, 105 mmol). The reaction was kept at −75° C. for 15 min, quenched at −75° C. with trimethylchlorosilane (19.0 mL, 150 mmol) and finally poured into a saturated solution of sodium bicarbonate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel eluting with 20:1 hexane:diethyl ether to give the title product.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][NH2:30])=[CH:28][C:23]=2[O:22][CH2:21]1.CCN(C(C)C)C(C)C>>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][NH:30][C:3]3[S:4]/[C:5](=[CH:9]\[C:10]4[CH:11]=[C:12]5[C:17](=[CH:18][CH:19]=4)[N:16]=[CH:15][CH:14]=[CH:13]5)/[C:6](=[O:8])[N:7]=3)=[CH:28][C:23]=2[O:22][CH2:21]1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: NCc1ccc2c(c1)OCO2
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCc2ccc3c(c2)OCO3)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, benzo[1,3]dioxol-5-ylmethyl amine and DIEA to give 2-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 390 (MH+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@@H:5]([CH3:7])[NH2:6].[Cl:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:33]=3[NH:32][CH:31]=[C:30]4[CH:34]=O)[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18].[OH-].[Na+]>CO>[Cl:9][C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:33]=3[NH:32][CH:31]=[C:30]4[CH2:34][NH:6][C@@H:5]([C:4]([O:3][CH3:2])=[O:8])[CH3:7])[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:18])[CH3:19]
Reactant: COC(=O)[C@@H](C)N
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)c[nH]c34)no2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@@H](C)NCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
D-alanine methyl ester hydrochloride (420 mg) and 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole-3-carbaldehyde (D71) (382 mg) was added to a solution of NaOH (120 mg) in methanol (20 mL). After stirring for 0.5 hour, methanol was evaporated off. A solution of AcOH (0.5 mL) in dichloromethane (40 mL) was added to the residue. NaBH(OAc)3 (847 mg) was added to the above mixture. The reaction mixture was stirred at room temperature overnight, and quenched by saturated NaHCO3 solution. The organic layer was separated and washed with water and brine. After the solvent was evaporated off the residue was purified by Mass Directed AutoPrep to afford methyl N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}-D-alaninate (D75) (262 mg) as a white solid. MS (ES): C24H25ClN4O4 requires 468; found 491.1 (M+Na+).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][CH2:19][C:18]2[N:21]=[C:22]([NH:24][C:25]([NH:27][CH2:28][CH:29]=[CH2:30])=[O:26])[S:23][C:17]=2[CH2:16]1)=O)(C)(C)C>C(Cl)(Cl)Cl>[CH2:28]([NH:27][C:25]([NH:24][C:22]1[S:23][C:17]2[CH2:16][NH:15][CH2:20][CH2:19][C:18]=2[N:21]=1)=[O:26])[CH:29]=[CH2:30]
Reactant: C=CCNC(=O)Nc1nc2c(s1)CN(C(=O)OC(C)(C)C)CC2
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: C=CCNC(=O)Nc1nc2c(s1)CNCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
10% TFA in 60 ml chloroform was added to 2.5 g 2-(3-allyl-ureido)-6,7-dihydro-4H-thiazolo (5,4-c) pyridine-5-carboxylic acid tert-butyl ester in 28 ml chloroform and stirred for 2 h at RT. The mixture was concentrated, the residue was diluted with chloroform and basified with 2.5 M aqueous potassium carbonate solution and extracted with chloroform. The organic layer was concentrated. The residue was washed with a mixture 50% ethyl acetate and 50% hexane to yield 1.7 g of the desired product. (M+H)+: 239
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=O)[CH2:10][N:9]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].C(=O)(O)[O-].[Na+].COCCOCCOC>O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:22])[CH2:10][N:9]=1
Reactant: O=C1CN=C(c2ccccc2F)c2cc(I)ccc2N1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: Fc1ccccc1C1=NCC(=S)Nc2ccc(I)cc21
Yield: 82 %

Procedure:
A mixture of 31 g (0.08 mol) of 1,3-dihydro-5-(2-fluoro phenyl)-7-iodo-1,4-benzodiazepin-2(2H)-one [ref. G. F. Field and L. H. Sternbaoh, Swiss patents Nos. 561,706; May 1975; and 562,222; April 1975], 20 g (0.09 mol) of phosphorus pentasulfide, 20 g of sodium bicarbonate and 300 ml of diglyme was stirred and heated to 80°-85° C. for 3 hours. The reaction mixture was then poured onto ice and diluted with water. After stirring for 30 minutes, the solid yellow product was filtered off, washed with water, 2-propanol and little ether. It was sucked dry in the funnel and further dried in vacuum to leave 26 g (80%) of 1,3-dihydro-5-(2-fluorophenyl)-7-iodo-1,4-benzodiazepine-2(2H)-thione which was further transformed as described below. Pure material was obtained by recrystallization from tetrahydrofuran/ethanol and had m.p. 242°-244° C.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C.CCCCCC>CN(C)C=O.C(=O)(O)[O-].[Na+]>[C:18]([CH2:17][CH2:16][CH2:15][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CCCCl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Combine t-butyl 1-piperazinecarboxylate (10.7 g, 57.5 mmol), ethyl 4-chlorobutyrate (10.4 mL), and potassium carbonate (8 g) in dimethylformamide (60 mL). Heat at reflux. After 4.5, hours, cool the reaction, dilute with an aqueous solution of sodium bicarbonate, and extract twice with diethyl ether (200 mL). Combine the organic layers and extract with a 1M aqueous solution of hydrochloric acid. Adjust the pH of the aqueous layer to basic using sodium bicarbonate and then extract twice with diethyl ether. Dry the combined organic layers over MgSO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting sequentially with 10% ethyl acetate/hexane, 20% ethyl acetate/hexane, 25% ethyl acetate/hexane to give t-butyl 4-carboethoxypropyl-1-piperazinecarboxylate. Rf =0.5 (silica gel, ethyl acetate).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15]C)=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][C@@H:19]([CH3:22])[CH2:20][CH3:21])=[N:10][C:11]=2[NH2:17].[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH2:17][C:11]1[N:10]=[C:9]([O:18][C@@H:19]([CH3:22])[CH2:20][CH3:21])[N:8]=[C:7]2[C:12]=1[NH:13][C:14](=[O:15])[N:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C1CCNCC1
Reactant: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Product: CC[C@H](C)Oc1nc(N)c2[nH]c(=O)n(CCCCN3CCCCC3)c2n1

Procedure:
Prepared similarly to Example 29 from 9-(4-chlorobutyl)-8-(methyloxy)-2-{[(1S)-1-methylpropyl]oxy}-9H-purin-6-amine and piperidine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11](CCC2C=CC=CC=2)[C:10](=[O:22])[C@H:9]1[CH2:23][C:24]1[CH:33]=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1)=O)(C)(C)C.C(=O)([O-])O.[Na+].C(OC(NC(C)(C)C/C=C/C(O)=O)=O)(C)(C)C.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:23][C@H:9]1[NH:8][CH2:13][CH2:12][NH:11][C:10]1=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2ccccc2)C(=O)[C@H]1Cc1ccc2ccccc2c1
Agent: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCCN[C@@H]1Cc1ccc2ccccc2c1
Reaction time: 0.25 h
Yield: 47.8 %

Procedure:
(2R)-2-(2-naphthyl)methyl-3-oxo-4-phenethylpiperazine-1-carboxylic acid tert-butyl ester (1.2 g; 2.7 mmol) was dissolved in a mixture of TFA (5 ml) and methylene chloride (5 ml) and stirred for 15 min. Methylene chloride (30 ml) and aqueous sodium hydrogencarbonate (saturated) was added to pH 8. The mixture was extracted with methylene chloride (3×10 ml) and the combined aqueous phases were dried (magnesium sulphate) and the solvent was removed in vacuo. Part of the residue (400 mg 1.2 mmol) were added to a mixture of (2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoic acid (282 mg; 1.2 mmol); HOAt (158 mg; 1.2 mmol), EDAC (245 mg; 1.3 mmol) and DIEA (150 mg; 1.2 mmol) and stirred overnight. Methylene chloride (50 ml) was added and the mixture was washed with aqueous sodium hydrogensulphate (10%; 50 ml); aqueous sodium hydrogencarbonate (saturated; 50 ml) and water (50 ml). The organic phase was dried (magnesium sulphate) and the solvent removed in vacuo. The residue was chromatographed on silica (2×20 cm) and the residue was dissolved in a mixture of TFA (2 ml) and methylene chloride (2 ml) and stirred for 5 min. Methylene chloride and an aqueous solution of sodium hydrogenarbonate (sat.) was added to pH 8. The mixture was extracted with methylene chloride (2×10 ml). The organic phase was dried (magnesium sulphate) and the solvent was removed in vacuo to afford 310 mg of the title compound.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][C:12]1[NH:13][C:14](=[O:53])[C:15]2[N:16]=[CH:17][N:18]([C:51]=2[N:52]=1)[C@@H:19]1[O:50][C@H:24]([CH2:25][O:26][C:27]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C@@H:22]([OH:23])[C@H:20]1[OH:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.ClCC(C#N)[CH2:66][O:67][CH2:68][CH:69]([C:72]#[N:73])CCl.C(=O)(O)[O-].[Na+]>ClCCCl>[O:1]([CH2:8][C:9]([NH:11][C:12]1[NH:13][C:14](=[O:53])[C:15]2[N:16]=[CH:17][N:18]([C:51]=2[N:52]=1)[C@@H:19]1[O:50][C@H:24]([CH2:25][O:26][C:27]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[C@@H:22]([OH:23])[C@H:20]1[O:21][CH2:66][O:67][CH2:68][CH2:69][C:72]#[N:73])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC(CCl)COCC(C#N)CCl
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)COc5ccccc5)nc43)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(=O)[nH]c(NC(=O)COc5ccccc5)nc43)[C@H](OCOCCC#N)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 1 h
Yield: 47.8 %

Procedure:
N2-Phenoxyacetyl-5′-O-(4,4′-dimethoxytrityl)guanosine (720 mg, 1 mmol) was dissolved in 4 mL of 1,2-dichloroethane, and 452 mg of diisopropylethylamine (3.5 mmol) was added, and 365 mg of dibutylstannyl dichloride (1.2 mmol) was added subsequently. Then, the reaction was performed at room temperature for 1 hour. Then, the reaction was performed at 80° C., and 155.4 mg of chloromethyl 2-cyanoethylether (1.3 mmol) was added dropwise, and the solution was stirred for 60 minutes. After the reaction completed, the reaction solution was mixed with an aqueous saturated sodium bicarbonate solution, and was subjected to extraction with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The obtained mixture was purified by 30 g of silica gel column chromatography to obtain N2-phenoxyacetyl-5′-O-(4,4′-dimethoxytrityl)-2′-O-(2-cyanoethoxymethyl)guanosine (384 mg; yield 48%).
Reaction SMILES: [C:1]([O:7][CH2:8][C:9]([CH3:24])([CH3:23])[CH2:10][N:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Br:21])[CH:17]=2)[C:12]1=[O:22])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].O=P(Cl)(Cl)Cl.CN([CH:33]=[O:34])C>>[C:1]([O:7][CH2:8][C:9]([CH3:24])([CH3:23])[CH2:10][N:11]1[CH:20]=[C:19]([CH:33]=[O:34])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Br:21])[CH:17]=2)[C:12]1=[O:22])(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: CN(C)C=O
Reactant: CC(C)(COC(=O)C(C)(C)C)Cn1ccc2cc(Br)ccc2c1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(COC(=O)C(C)(C)C)Cn1cc(C=O)c2cc(Br)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of 3-(6-bromo-1-oxoisoquinolin-2(1H)-yl)-2,2-dimethylpropyl pivalate (51.3 g) in DMF (150 mL) at 75° C. (flask fitted with a CaCl2 drying tube) was treated dropwise over ˜20 min with a freshly prepared solution of Vilsmeyer Haak reagent [freshly prepared by dropwise addition of POCl3 (182 mL) over ˜40 min to DMF (302 mL) at 0° C. and then stirred for 1 h at room temperature]. Heating was continued for 8 h, and then the reaction mixture was cooled to room temperature and stirred overnight. The mixture was poured onto ice water (6 L) [CAUTION: exotherm] and extracted with tert-butyl methyl ether (2×2.5 L). The combined organics were washed with 20% w/v aqueous brine (2.5 L), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified (SiO2 chromatography, eluting with 10% to 20% ethyl acetate/isohexane) to give the subtitle product (41.5 g).