Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH:4]=1.[Br:12][C:13]1[C:14](Cl)=[N:15][C:16]([Cl:19])=[N:17][CH:18]=1.C(OCC)(=O)C>CN(C=O)C.O>[Br:12][C:13]1[C:14]([N:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=[CH:4]2)=[N:15][C:16]([Cl:19])=[N:17][CH:18]=1
Reactant: c1ccc2[nH]cnc2c1
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ncc(Br)c(-n2cnc3ccccc32)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
Sodium hydride (60% dispersion in oil; 110 mg, 2.75 mmol) was added to a solution of benzimidazole (295 mg, 2.5 mmol) in DMF (6 ml) at 0° C. The mixture was stirred at 0° C. for 10 minutes and then added dropwise to a cold (0° C.) solution of 5-bromo-2,4-dichloropyrimidine (712 mg, 3.14 mmol) in DMF (6 ml). The mixture was stirred for at 0° C. for 2 hours and then ethyl acetate (20 ml) and water (20 ml) were added. The organic phase was separated and dried and volatile material was removed by evaporation. The residue was purified by column chromatography, eluting with 20% ethyl acetate/DCM, to give the product as a white solid (500 mg, 52%). NMR: 7.4 (m, 2H), 7.8 (m, 2H), 8.8 (s, 1H), 9.3 (s, 1H); MS (MH+): 309, 311.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7][CH2:6]2.[C:13](OC(=O)C)(=[O:15])[CH3:14]>CO>[C:13]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:2][OH:1])=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH2:8]1)(=[O:15])[CH3:14]
Reactant: OCc1ccc2c(c1)CCCN2
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: CC(=O)N1CCCc2cc(CO)ccc21
Reaction time: 1 h
Yield: 57.5 %

Procedure:
To a solution of 6-hydroxymethyl-1,2,3,4-tetrahydroquinoline (314 mg) in methanol (4 ml) was dropwise added acetic anhydride (589 mg) under ice-cooling, and the mixture was stirred for 1 hour at the same temperature. The solvent was removed in vacuo, and ethyl acetate and saturated sodium bicarbonate solution were added to the residue. The organic layer was washed with water and brine, dried and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (n-hexane:ethyl acetate =1:2, v/v) to give 1-acetyl-6-hydroxymethyl-1,2,3,4-tetrahydroquinoline (227 mg).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1([OH:59])[CH2:56][S:57][CH3:58])[CH3:2].C[OH:61]>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1([OH:59])[CH2:56][S:57]([CH3:58])=[O:61])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1(O)CSC)C(C)CC2OC
Reactant: CO
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1(O)CS(C)=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
A solution of 0.050 g (0.059 mmole) of 17-ethyl-1,14,16-trihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-16-(methylthiomethyl)-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10-trione in 5 mL of methanol was cooled to 0° C. in an ice bath. Then 2 mL of a 0.5M solution of NaIO4 was added and the mixture was stirred at room temperature for 1 h. The solution was partitioned between ether and water and the ether layer was washed with KHCO3 and brine, then dried over MgSO4 and concentrated. The residue was purified by flash chromatography (2×20 cm silica gel) using 20% acetone-hexane to afford 0.022 g (44%) of the title compound as a white solid; MASS SPECTRUM (FAB) m/e 876 (M+Li).
Reaction SMILES: ClC(Cl)C.[CH3:5][O:6][C:7]1[CH:44]=[CH:43][C:10]([CH2:11][N:12]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:13]2[N:18]=[CH:17][C:16]([C:19]3[C:20]4[CH2:33][CH2:32][NH:31][C:21]=4[N:22]=[C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[N:24]=3)=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH2:45]([O:47][C:48](=[O:53])[CH2:49][N:50]=[C:51]=[O:52])[CH3:46].[Cl-].[NH4+]>C(N(CC)CC)C>[CH2:45]([O:47][C:48](=[O:53])[CH2:49][NH:50][C:51]([N:31]1[C:21]2[N:22]=[C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:24]=[C:19]([C:16]3[CH:15]=[N:14][C:13]([N:12]([CH2:11][C:10]4[CH:9]=[CH:8][C:7]([O:6][CH3:5])=[CH:44][CH:43]=4)[CH2:34][C:35]4[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=4)=[N:18][CH:17]=3)[C:20]=2[CH2:33][CH2:32]1)=[O:52])[CH3:46]
Reactant: CCOC(=O)CN=C=O
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)N1CCc2c(-c3cnc(N(Cc4ccc(OC)cc4)Cc4ccc(OC)cc4)nc3)nc(N3CCOCC3)nc21
Temperature: 25 °C

Procedure:
To a dichloroethane solution (2 ml) of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg), triethylamine (260 μl) and isocyanato-acetic acid ethyl ester (208 μl) were added, followed by refluxing for 3 hours. After this was cooled to room temperature, saturated aqueous ammonium chloride solution was added, and passed through Whatman tube. The resulting organic layer was concentrated under reduced pressure, followed by purification by silica gel column chromatography (dichloromethane/methanol=/) column chromatography (dichloromethane/methanol=1/0 to 100/1), to obtain a crude product of the desired compound (127 mg, quant.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[F:11][C:12]([F:22])([F:21])[C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.CC[O:25][C:26]([C:28]([CH2:30][C:31]([CH3:33])=[O:32])=[O:29])=O>>[C:31]([CH:30]1[CH:16]([C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([C:12]([F:22])([F:21])[F:11])[CH:14]=2)[N:1]([C:2]2[CH:3]=[C:4]([CH3:10])[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=2)[C:26](=[O:25])[C:28]1=[O:29])(=[O:32])[CH3:33]
Reactant: Cc1cc(N)cn(C)c1=O
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)C(=O)CC(C)=O
Product: CC(=O)C1C(=O)C(=O)N(c2cc(C)c(=O)n(C)c2)C1c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 57.1 using 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2), 3-trifluormethylbenzaldehyde and ethyl acetopyruvate. tR: 0.76 min (LC-MS 2); ESI-MS: 407 [M+H]+ (LC-MS 2); ESI-MS: 405 [M−H]− (LC-MS 2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(N(CC)CC)C.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1.Cl>[CH2:22]([O:21][C:19]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH2:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)=[O:20])[CH3:23]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc2[nH]ccc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)n1ccc2cc(N)ccc21
Temperature: 0 °C
Yield: 112.2 %

Procedure:
To a solution of 4.27 gm (32.3 mMol) 5-amino-1H-indole in 50 mL tetrahydrofuran were added 5.4 mL (38.8 mMol) triethylamine and the reaction mixture was then cooled to 0° C. To this solution were then added dropwise 3.4 mL (35.5 mMol) ethyl chloroformate. After 4 hours the reaction mixture was diluted with 1N HCl and was then extracted with ethyl acetate. The organic phase was washed sequentially with 1N HCl, water and saturated aqueous sodium chloride. The remaining organics were dried over sodium sulfate and concentrated under reduced pressure to give 7.4 gm of a dark oil. This oil was purified by flash chromatography, eluting with a gradient of dichloromethane containing 0-2.5% methanol, to give 4.95 gm (75%) of the title compound as a tan solid.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]1[C:15]2([CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16]2)[CH2:14][CH2:13][CH2:12]1.[Cl-].[NH4+]>C(N(CC)CC)C.C(Cl)Cl>[CH2:11]1[C:15]2([CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]2)[CH2:14][CH2:13][CH2:12]1
Reactant: OC1CCCC2(CCCC2)C1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1CCCC2(CCCC2)C1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 95.5 %

Procedure:
With stirring under nitrogen atmosphere at −70° C., 12.0 g of dimethyl sulfoxide was added to a mixture of 14.4 g of oxalyl chloride and 100 ml of methylene chloride. Stirring was continued for 10 minutes. Below −55° C., a mixture of 8.72 g of 7-spiro[4.5]decanol and 20 ml of methylene chloride was added dropwise thereto, followed by stirring for 30 minutes at −70° C. After 50 g of triethylamine was added, the mixture was warmed up to −5° C. while stirring. The reaction mixture was poured into a saturated ammonium chloride aqueous solution, followed by ordinary work-up of extraction, washing and drying, and purification by silica gel chromatography. There was obtained 8.22 g (yield 96%) of 7-spiro[4.5]decanone. This compound was found to have identical spectroscopic characteristics with the former compound.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[NH:8][C:9]1[C:14]([C:15](O)=[O:16])=[CH:13][N:12]=[C:11]([S:18][CH3:19])[N:10]=1.C[N:21](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[NH4+].CCN(C(C)C)C(C)C>CN(C=O)C.O>[OH:1][CH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@H:4]1[NH:8][C:9]1[C:14]([C:15]([NH2:21])=[O:16])=[CH:13][N:12]=[C:11]([S:18][CH3:19])[N:10]=1
Reactant: CSc1ncc(C(=O)O)c(N[C@@H]2CCC[C@@H]2CO)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CSc1ncc(C(N)=O)c(N[C@@H]2CCC[C@@H]2CO)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.7 %

Procedure:
A white suspension of the 4-(cis-2-(hydroxymethyl)-cyclopentylamino)-2-(methylthio)pyrimidine-5-carboxylic acid (5.6 g, 19.76 mmol) and HATU (11.27 g, 29.60 mmol) were dissolved in DMF (79 mL) and stirred for 5 min at room temperature before adding ammonium chloride (5.29 g, 99 mmol) and DIEA (17.26 mL, 99 mmol). The reaction mixture was stirred at room temperature for 1 h and then diluted with water (200 mL) and extracted with ethyl acetate (2×200 mL). The combined organic layers were washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated. The residual DMF was removed by suspending the white suspension in 200 mL water and 200 mL hexanes. The biphasic mixture was stirred vigorously for 30 min, filtered and washed with hexanes to afford 4-(cis-2-(hydroxyl-methyl)cyclopentylamino)-2-(methylthio)pyrimidine-5-carboxamide (4.50 g, 81% yield) as a white solid. MS (ESI) m/z 283.4 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:22](Cl)=[O:23]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][C:10]=2[C:22](=[O:23])[C:21]2[CH:25]=[C:26]([CH3:28])[CH:27]=[C:19]([CH3:18])[CH:20]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2coc3ccccc23)cc1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Product: COc1ccc(-c2c(C(=O)c3cc(C)cc(C)c3)oc3ccccc23)cc1

Procedure:
When 3-p-methoxyphenylbenzofuran is acylated with 3,5-dimethylbenzoyl chloride as described in the procedure of Example 1, 3-p-methoxyphenyl-2-(3',5'-dimethylbenzoyl)benzofuran is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=1[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1.[Si](Cl)(Cl)(Cl)Cl.Cl>O.N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:10]=1[C:11]([NH:19][C:20]1[NH:24][N:23]=[N:22][N:21]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(Cl)ccc1OCc1ccccc1
Reactant: Nc1nnn[nH]1
Agent: Cl
Agent: Cl[Si](Cl)(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1nnn[nH]1)c1cc(Cl)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 20.1 %

Procedure:
Dry 2-benzyloxy-5-chlorobenzoic acid (1.15 g) was treated, with stirring, with dry pyridine (20 ml) and anhydrous 5-aminotetrazole (3.72 g). The mixture was stirred at 25° C. and treated dropwise with silicon tetrachloride (0.45 g), and the mixture was then stirred at 25° C. for 20 hours. The resulting clear yellow solution was cautiously poured into a mixture of ice and water (50 ml) and the mixture was acidified to pH 1 by treatment with concentrated hydrochloric acid. The white precipitated solid was filtered off, washed with water, with ethanol and with diethyl ether, and recrystallized from a mixture of dimethylformamide and water to give 2-benzyloxy-5-chloro-N-(tetrazol-5-yl)benzamide, (0.29 g), m.p. 256°-257° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][C:12]([OH:14])=O)[CH:10]=1)[N:7]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:6]=[CH:5]2.Cl.Cl.[NH2:21][CH2:22][C:23]1[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][N:24]=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][C:12]([NH:21][CH2:22][C:23]3[CH:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][N:24]=3)=[O:14])[CH:10]=1)[N:7]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:6]=[CH:5]2
Reactant: CC(C)Cn1ncc2cc(Cl)cc(CC(=O)O)c21
Reactant: COC(=O)c1ccnc(CN)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1ccnc(CNC(=O)Cc2cc(Cl)cc3cnn(CC(C)C)c23)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.5 %

Procedure:
A mixture of compound 58 (0.155 g, 0.58 mmoles) and methyl 2-(aminomethyl)pyridine-4-carboxylate dihydrochloride (0.139 g, 0.58 mmoles) (see WO2003070732, example 6, step 2 for preparation, which is incorporated by reference in its entirety) in dichloromethane (20 ml) was treated with N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uranium hexafluorophosphate (0.264 g, 0.69 mmoles) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.133 g, 0.69 mmoles) and N-methylmorpholine (0.255 ml, 2.32 mmoles) then stirred at ambient temperature under a nitrogen atmosphere for 18 h. The mixture was washed with water (2×20 ml) and saturated brine (20 ml) then separated and dried over sodium sulphate, filtered and evaporated to dryness. The residue was chromatographed on silica gel eluting with an ethyl acetate/isohexane gradient. This gave the title compound as a colorless oil (0.184 g 76%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13]CC)=[O:12])=[CH:9][N:10]=2)[CH:7]=1.O.[OH-].[Li+].O.C1COCC1>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([OH:13])=[O:12])=[CH:9][N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1cnc2ccc(F)cn12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cnc2ccc(F)cn12
Temperature: 65 °C
Yield: 100.6 %

Procedure:
Ethyl 6-fluoroimidazo[1,2-a]pyridine-3-carboxylate (0.10 g, 0.48 mmol) and lithium hydroxide monohydrate (0.020 g, 0.48 mmol) were added to a mixture of water, THF and ethanol (1:2:1) and heated in a sealed vial at 65° C. for 6 hours. The solvent was removed by rotary evaporation to yield 87 mg of the desired product. MS (ES+APCI) m/z=181.1 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>CN(C)C=O.O>[CH2:14]([O:13][P:12]([CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)(=[O:19])[O:16][CH2:17][CH3:18])[CH3:15]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOP(OCC)OCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Reaction time: 1.5 h

Procedure:
10 g (46.3 mmol) of 4-nitrobenzylbromide and 10.03 g (60.3 mmol) of triethyl phosphite are dissolved in 25 ml dimethylformamide. The reaction mixture is held at 155° C. for 1.5 h, diluted with 20 ml water and extracted 3 times with ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[N:15]3[C:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=[CH:18][C:17]=4[N:26]=[C:14]3[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=O.[NH4+:38].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>ClCCCl.C(Cl)(Cl)Cl.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[N:15]3[C:16]4[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=[C:18]([NH2:38])[C:17]=4[N:26]=[C:14]3[CH:13]=[CH:12]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc4cnc5ccccc5c4n32)cc1
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: O
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)n2ccc3nc4c(N)nc5ccccc5c4n32)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A solution of 10-[(4-methylphenyl)sulfonyl]-10H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]quinoline (0.55 g, 1.5 mmol) in 1,2-dichloroethane (15 mL) was placed in a 48 mL heavy wall glass pressure flask and treated with 3-chloroperoxybenzoic acid (0.56 g, 2.3 mmol). After 1.5 h the reaction was treated with concentrated NH4OH (5 mL, 30%); the flask was sealed and heated to 70° C. Once at temperature, p-toluenesulfonyl chloride (0.31 g, 1.7 mmol) was quickly added, the flask was resealed and heated to 75° C. After 1 h additional NH4OH (1 mL) and p-toluenesulfonyl chloride (50 mg) were added and the flask heated for another hour. After 2 h total, the flask was cooled to ambient temperature, and the reaction mixture was diluted with chloroform (15 mL) and water (10 mL). The phases were separated and the organic portion was washed with 10% Na2CO3 aqueous solution (10 mL) and water (10 mL). The combined aqueous washes were back-extracted with chloroform (20 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield an orange solid. The solid was recrystallized twice from acetonitrile to yield 0.14 g of 10-[(4-methylphenyl)sulfonyl]-10H-pyrazolo[1′,5′:1,2]imidazo[4,5-c]quinolin-6-amine as tan crystals, mp 204-206° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.55-8.53 (m, 1H), 8.13 (d, J=2.3 Hz, 1H), 7.68-7.67 (m, 2H), 7.66-7.64 (m, 2H), 7.41-7.389 (m, 1H), 7.35 (d, J=8.2 Hz, 2H), 7.24 (s, 2H), 6.64 (d, J=2.0 Hz, 1H), 3.29 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 148.1, 147.6, 147.4, 142.8, 131.7, 131.3, 131.0, 130.9, 128.4, 127.2, 125.9, 125.5, 123.4, 122.7, 111.3, 90.8, 21.5; MS (APCI) m/z 378.06 (M+H)+; Anal. Calcd for C19H15N5O2S: C, 60.47; H, 4.01; N, 18.56. Found: C, 60.21; H, 3.84; N, 18.52.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]([C:18]1[CH:19]=[N:20][CH:21]=[N:22][CH:23]=1)[CH2:10][C:11]([O:13][C:14](C)(C)[CH3:15])=[O:12].[ClH:24]>C(O)C.O1CCOCC1>[ClH:24].[NH2:8][CH:9]([C:18]1[CH:23]=[N:22][CH:21]=[N:20][CH:19]=1)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CC(C)(C)OC(=O)CC(N)c1cncnc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)CC(N)c1cncnc1

Procedure:
The t-butyl 3-amino-3-(5-pyrimidinyl)propanoate trifluoroacetate salt (1 g), prepared as in example 22, Step 2 was dissolved in 100 mL dry ethanol and 10 mL 4N HCl in dioxane and stirred at room temperature until transesterification was complete. The solvents were removed in vacuo and the residue taken up in ethyl acetate and diethyl ether. The resulting precipitate was filtered, washed with ether and dried (0.8 g) 1H NMR (300 MHz) (d6-DMSO) d 1.05 (t, J=7 Hz, 3H), 3.25 (m, 2H), 4.05 (q, J=7 Hz, 2H), 4.7 (m, 1H), 9.05 (s, 1H), 9.25 (s, 1H)
Reaction SMILES: [Cl-].[CH3:2][C:3]1[S:32][C:6]2=[N:7][C:8]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)=[CH:9][C:10](=[O:11])[N:5]2[C:4]=1[CH3:33].[H-].[Na+].[CH:36]1([CH2:39][O:40][C:41]2[C:48]([O:49][CH3:50])=[CH:47][CH:46]=[CH:45][C:42]=2[CH:43]=O)[CH2:38][CH2:37]1>CS(C)=O>[CH:36]1([CH2:39][O:40][C:41]2[C:48]([O:49][CH3:50])=[CH:47][CH:46]=[CH:45][C:42]=2/[CH:43]=[CH:12]/[C:8]2[N:7]=[C:6]3[S:32][C:3]([CH3:2])=[C:4]([CH3:33])[N:5]3[C:10](=[O:11])[CH:9]=2)[CH2:37][CH2:38]1
Reactant: Cc1sc2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cc(=O)n2c1C
Reactant: COc1cccc(C=O)c1OCC1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1cccc(/C=C/c2cc(=O)n3c(C)c(C)sc3n2)c1OCC1CC1

Procedure:
A stirred suspension of Step 2 intermediate (1.0 g, 2.00 mmol) in dry DMSO (12 ml) was treated with NaH (89 mg, 2.240 mmol) and 2-(cyclopropylmethoxy)-3-methoxybenzaldehyde (462 mg, 2.240 mmol) according to the procedure described in Step 3, Intermediate 2 to yield a crude solid which was purified by column chromatography using 2% ethyl acetate in DCM to afford 600 mg of the desired compound as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ 0.32-0.35 (m, 2H), 0.54-0.58 (m, 2H), 1.15-1.21 (m, 1H), 2.26 (s, 3H), 2.59 (s, 3H), 3.73-3.75 (m, 2H), 3.79 (s, 3H), 6.13 (s, 1H), 6.99-7.00 (m, 3H), 7.29-7.31 (m, 1H), 8.03 (d, J=16.2 Hz, 1H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][C:26]=4[N+:34]([O-:36])=[O:35])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:38][C:39]1[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[N:43][CH:44]=1.C(N(C(C)C)CC)(C)C>O1CCCC1.C(OCC)(=O)C>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:37])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:32])[NH:38][C:39]5[CH:44]=[N:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=5)=[CH:27][C:26]=4[N+:34]([O-:36])=[O:35])=[CH:20][CH:19]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(N)cn1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Cl)cc2[N+](=O)[O-])cc1)OCC1c2ccccc2-c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)c2ccc(Sc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc3)c([N+](=O)[O-])c2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.8 %

Procedure:
A solution of the product of Example 19C (290 mg, 0.546 mmol) in anhydrous tetrahydrofuran (5 mL) was treated with 5-amino-2-methoxypyridine (78.5 mg, 0.601 mmol) and diisopropylethylamine (0.143 mL, 0.819 mmol), and stirred at room temperature under a nitrogen atmosphere for 18 hours. The reaction was diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (25 mL), water (2×25 mL), and brine (25 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Trituration with 3% methanol/methylene chloride provided the title compound as a dark yellow solid (202 mg, 60%).
Reaction SMILES: N#N.C([NH:6][C:7]1[NH:8][C:9](=[O:23])[C:10]2[N:11]=[CH:12][N:13]([CH2:16][O:17][CH:18]([CH2:21][OH:22])[CH2:19][OH:20])[C:14]=2[N:15]=1)(=O)C>N>[OH:20][CH2:19][CH:18]([O:17][CH2:16][N:13]1[CH:12]=[N:11][C:10]2[C:9](=[O:23])[NH:8][C:7]([NH2:6])=[N:15][C:14]1=2)[CH2:21][OH:22]
Reactant: CC(=O)Nc1nc2c(ncn2COC(CO)CO)c(=O)[nH]1
Agent: N
Agent: N#N
Product: Nc1nc2c(ncn2COC(CO)CO)c(=O)[nH]1
Yield: 95.1 %

Procedure:
N2 -Acetyl-9-(1,3-dihydroxy-2-propoxymethyl)guanine (721.9 mg, 2.4 mmol) was stirred with 50 ml of methanolic ammonia solution (methanol saturated with ammonia at 0° C.) for 17 hours at 21° C. The solution was concentrated to a white solid and the residue recrystallized from methanol to give 582.3 mg of 9-(1,3-dihydroxy-2-propoxymethyl)guanine, mp 250° C. d.