Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N1CCC(O)(C2C=CC(C)=CC=2)CC1)C1C=CC=CC=1.II.[Mg].Br[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1.C([N:40]1[CH2:45][CH2:44][CH2:43][CH2:42][C:41]1=[O:46])C1C=CC=CC=1.[Cl-].[NH4+]>BrC1C=CC(C)=CC=1.C(OCC)C>[CH3:32][C:29]1[CH:30]=[CH:31][C:26]([N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][C:41]2=[O:46])=[CH:27][CH:28]=1
Reactant: O=C1CCCCN1Cc1ccccc1
Reactant: Cc1ccc(Br)cc1
Agent: Cc1ccc(C2(O)CCN(Cc3ccccc3)CC2)cc1
Agent: II
Agent: [Cl-]
Solvent: CCOCC
Product: Cc1ccc(N2CCCCC2=O)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
1-Benzyl-4-hydroxy-4-(4-methylphenyl)piperidine may be prepared in the following manner: several drops of p-bromotoluene and a crystal of iodine are added to magnesium turnings (1.7 g) in diethyl ether (25 cc), under a current of argon. The mixture in heated to boiling, then a solution of p-bromotoluene (12.1 g) in diethyl ether (70 cc) is poured in in such a manner as to maintain the reflux. The reaction medium is stirred for 30 minutes at the boiling point of the solvent, then cooled to a temperature of about 20° C. A solution of 1-benzylpiperidone (6.7 g) in diethyl ether (60 cc) is added, and stirring is maintained for 15 hours at the same temperature. A saturated solution of ammonium chloride (150 cc) is added to the mixture; the aqueous phase is decanted and the organic phase is extracted with diethyl ether (2×150 cc), dried over anhydrous magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The residue obtained is purified by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and methanol (95-5 vol) as eluant. 1-Benzyl-4-hydroxy-4- ((4-methylphenyl)piperidone (5 g) is obtained in the form of an oil, which is used in the crude state in the subsequent syntheses.
Reaction SMILES: CO[C:3]([O:20]C)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:35][C:36](=[NH:38])[CH3:37]>CN(C=O)C.O>[CH3:37][C:36]1[N:38]=[C:9]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:20])=[CH:13][CH:12]=2)[O:11][N:35]=1
Reactant: CC(=N)NO
Reactant: COC(Cc1ccc(C(=O)O)cc1)(OC)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccc(CC(=O)c3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.9 %

Procedure:
To 4-(2,2-dimethoxy-2-phenylethyl)benzoic acid (1.1 g, 3.84 mmole) in DMF (15 mL) was added carbonyldiimidazole (0.68 g, 4.2 mmole). After 20 min, N-hydroxy ethanimidamide (0.33 g, 4.5 mmole) was added and the mixture stirred for 45 min. at r.t. followed by 100° C. overnight. The reaction was cooled, poured in H2O (30 mL) and extracted with hexane/ethylacetate 1:1. The organic phase was dried over Na2SO4 and concentrated. The residue was dissolved in 100 mL acetone and treated with p-toluene sulfonic acid (100 mg) for 2 h. Et3N (0.5 mL) was added, and the mixture was concentrated to dryness. The residue was dissolved in 2:1 hexane/ethyl acetate (10 mL) and passed through a pad of silica gel, eluting with 1: 1 hexane:EtOAc. The fractions were concentrated, and the residue was stirred with 4:1 hexane:EtOAc 10 mL to give 0.49 g of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[CH:12][NH:13][C:6]=12>CC(O)=O.[Fe]>[NH:13]1[C:6]2[C:7](=[N:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]2[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:2]=2[F:1])[CH:11]=[CH:12]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccc(Oc2ccnc3cc[nH]c23)c(F)c1
Reaction time: 0.17 h
Yield: 98 %

Procedure:
To a solution of 267 (35 mg, 0.13 mmol) in AcOH (1 mL) at 90° C., was added iron powder (36 mg, 0.65 mmol). The reaction mixture was stirred vigorously for 10 min, cooled, filtered through a Celite pad and concentrated. The residue was partitioned between DCM and NaHCO3 saturated solution. Phases were separated; the aqueous phase was neutralized with AcOH and extracted with DCM. Primary organic phase and the extract were combined and concentrated to give the title compound 268 (31 mg, 99%) as an off-white solid. MS (m/z): 244. 1 (M+H) (found).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]2[C:23]3[CH:22]=[CH:21][C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[C:14]=3[NH:13][S:12](=[O:25])(=[O:24])[N:11]2[CH3:26])=[CH:6][C:3]=1[CH:4]=O.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]2[C:23]3[CH:22]=[CH:21][C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[C:14]=3[NH:13][S:12](=[O:25])(=[O:24])[N:11]2[CH3:26])=[CH:6][C:3]=1[CH2:4][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1
Reactant: C1CNCCN1
Reactant: CN1C(c2ccc(F)c(C=O)c2)c2ccc3cccnc3c2NS1(=O)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1C(c2ccc(F)c(CN3CCNCC3)c2)c2ccc3cccnc3c2NS1(=O)=O
Yield: 10.5 %

Procedure:
In a similar fashion using route 37 general procedure 90, 2-fluoro-5-(2-methyl-3,3-dioxo-1,2,3,4-tetrahydro-3λ*6*-thia-2,4,5-triaza-phenanthren-1-yl)-benzaldehyde 422 (50 mg, 0.13 mmol), piperazine (12 mg, 0.13 mmol) and sodium triacetoxyborohydride (40 mg, 0.19 mmol) in DCE (2 ml) gave the title compound (6 mg, 10%) after purification by preparative HPLC (acidic conditions 1).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][C:9]2[O:10][C:11]([CH2:14][CH2:15][CH3:16])=[N:12][N:13]=2)=[CH:6][CH:5]=1)([O-])=O>[C].[Pd].O1CCCC1>[CH2:14]([C:11]1[O:10][C:9]([CH2:8][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:18][CH:17]=2)=[N:13][N:12]=1)[CH2:15][CH3:16]
Reactant: CCCc1nnc(Cc2ccc([N+](=O)[O-])cc2)o1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCc1nnc(Cc2ccc(N)cc2)o1
Yield: 55.3 %

Procedure:
2-(4-Nitrobenzyl)-5-propyl-1,3,4-oxadiazole (7.70 g), 5% palladium carbon (7.0 g) and tetrahydrofuran (200 mL) were subjected to catalytic reduction under a hydrogen atmosphere at atmospheric pressure. The catalyst was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 4-[(5-propyl-1,3,4-oxadiazol-2-yl)methyl]aniline as pale-yellow crystals (3.74 g, yield 55%) from a fraction eluted with hexane-ethyl acetate (1:1-1:2, v/v). Recrystallization thereof from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 60-61° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[C:4]([O:14][CH3:15])[CH:3]=1.C(Cl)CCl.[CH:20]([C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1)([CH3:22])[CH3:21].CCOC(C)=O>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([O:14][CH3:15])[C:5]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[C:6]([NH:8][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([CH:20]([CH3:21])[CH3:22])=[CH:24][CH:25]=2)[CH:7]=1
Reactant: COCCNc1c(N)cc(Br)cc1OC
Reactant: CC(C)c1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COCCNc1c(NC(=O)c2ccc(C(C)C)cc2)cc(Br)cc1OC
Yield: 98.6 %

Procedure:
A solution of 4.95 g (18 mmol) 5-bromo-3-methoxy-N*2*-(2-methoxy-ethyl)-benzene-1,2-diamine, 5.15 g (27 mmol) EDC, 3.3 g (27 mmol) 4-dimethylamino-pyridine and 2.94 g (18 mmol) 4-isopropyl benzoic acid in 150 ml dichloromethane is stirred at room temperature for 14 h. After that 400 ml EtOAc are added and the organic phase washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=3:1) to afford 7.48 g of the title compound as a reddish oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:6]1[N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:8]=[C:9]([C:11]([O:13]C)=[O:12])[N:10]=1)[CH3:5])[CH3:2].C(OC(C1N(COCC[Si](C)(C)C)C=C(C(OCC)=O)N=1)C)C>>[CH2:1]([O:3][CH:4]([C:6]1[N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:21])[CH3:22])[CH:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=1)[CH3:5])[CH3:2]
Reactant: CCOC(C)c1nc(C(=O)OC)cn1COCC[Si](C)(C)C
Agent: CCOC(=O)c1cn(COCC[Si](C)(C)C)c(C(C)OCC)n1
Product: CCOC(C)c1nc(C(=O)O)cn1COCC[Si](C)(C)C

Procedure:
The title compound was prepared using the procedure described in Example 58(e) starting from the mixture of methyl 2-(1-ethoxyethyl)-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-imidazole-4-carboxylate and ethyl 2-(1-ethoxyethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (600 mg). Yield 370 mg. 1H-NMR (400 MHz; DMSO-d6): δ −0.01 (s, 9H), 0.86 (t, 2H), 1.08 (d, 3H), 1.45 (t, 3H), 3.41 (q, 2H), 3.50 (t, 2H), 4.71 (q, 1H), 5.42 (s, 2H), 7.92 (s, 1H), 12.13 (bs, 1H). LC-MS: [M+1]=315.12.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[N:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([C:11]3=[O:18])[CH2:9]1)[CH2:15]2.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O.[CH3:41][C:42]1[CH:47]=[CH:46][C:45]([S:48]([OH:51])(=[O:50])=[O:49])=[CH:44][CH:43]=1>C(O)(=O)C.CCO.C(OCC)(=O)C>[OH2:18].[CH3:41][C:42]1[CH:43]=[CH:44][C:45]([S:48]([OH:51])(=[O:50])=[O:49])=[CH:46][CH:47]=1.[CH3:41][C:42]1[CH:43]=[CH:44][C:45]([S:48]([OH:51])(=[O:50])=[O:49])=[CH:46][CH:47]=1.[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C@@H:11]2[CH:12]3[CH2:17][N:8]4[CH2:15][CH:14]([CH2:16][CH:10]2[CH2:9]4)[CH2:13]3)[CH:2]=1.[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C@@H:11]2[CH:12]3[CH2:17][N:8]4[CH2:15][CH:14]([CH2:16][CH:10]2[CH2:9]4)[CH2:13]3)[CH:2]=1.[CH3:41][C:42]1[CH:43]=[CH:44][C:45]([S:48]([OH:51])(=[O:50])=[O:49])=[CH:46][CH:47]=1.[CH3:41][C:42]1[CH:43]=[CH:44][C:45]([S:48]([OH:51])(=[O:50])=[O:49])=[CH:46][CH:47]=1
Reactant: Nc1cccnc1
Reactant: O=C1C2CC3CC1CN(C3)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: c1cncc(NC2C3CC4CC2CN(C4)C3)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Pyridine-3-amine (143 mg, 1.52 mmol) was added to a solution of 1-azatricyclo[3.3.1.13,7]decan-4-one (151 mg, 1.00 mmol) in acetic acid (5 mL). Anhydrous sodium sulfate (1.82 g, 12.8 mmol) was added, and the mixture was stirred at room temperature. After 10 minutes, sodium triacetoxyborohydride (412 mg, 1.94 mmol) was added and the mixture was stirred at room temperature for 10 hours. The reaction mixture was filtered through diatomaceous earth with a chloroform (5 mL) rinse. The filtrate was concentrated under vacuum, and the residue was purified by flash chromatography on silica (eluted with chloroform-methanol-concentrated ammonium hydroxide, 90:10:1) to provide a colorless gum. This was combined with 4-methylbenzenesulfonic acid monohydrate (29 mg) in a boiling mixture of ethyl acetate (5 mL) and EtOH (0.5 mL) and cooled to room temperature. After 30 hours, the product was collected by filtration, washed with ethyl acetate (2 mL) and dried under vacuum-n to provide the titled compound: 1H NMR (300 MHz, methanol-D4) δ 1.91-2.00 (m, 3H), 2.14-2.33 (m, 5H), 2.36 (s, 6H), 3.57 (s, 2H), 3.69 (s, 4H), 4.03 (s, 1H), 7.23 (d, J=7.9 Hz, 4H), 7.70 (d, J=8.3 Hz, 4H), 7.72-7.77 (m, 1H), 7.81-7.87 (m, 1H), 8.01 (d, J=5.6 Hz, 1H), 8.18 ppm (d, J=2.8 Hz, 1H): MS (DCI/NH3) m/z 230 (M+H)+; Anal. Calcd. for C14H19N3.2C7H8O3S.0.5H2O: C, 57.71; H, 6.23; N, 7.21. Found C, 57.78; H, 6.03; N, 7.19.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1.Cl.[NH2:27][C:28]([NH2:30])=[NH:29].C(=O)([O-])[O-].[K+].[K+].C(O)C>C(OCC)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:29]=[C:28]([NH2:30])[N:27]=[CH:13][C:10]=3[CH2:9][N:8]=[C:7]([C:17]3[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=3[F:23])[C:6]=2[CH:25]=1
Reactant: CN(C)C=C1CN=C(c2c(F)cccc2F)c2cc(Cl)ccc2C1=O
Reactant: N=C(N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: Nc1ncc2c(n1)-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2
Yield: 88.6 %

Procedure:
8-Chloro-4-dimethylaminomethylene-1-(2,6-difluorophenyl)-3,4-dihydrobenzo[c]azepin-5-one (5aa) (3.6 g, 10 mmol), guanidine hydrochloride (1.06 g, 11 mmol), potassium carbonate (4.6 g, 33 mmol), and ethanol (100 mL) were combined in a 100-mL round-bottomed flask and stirred at reflux for 3 hours. The reaction mixture was poured into 500 mL water with stirring. The mixture was extracted with ethyl acetate (4×200 mL). The organic extracts were combined, washed with saline, dried (Na2SO4), filtered, and evaporated to leave a brown solid. The solid was stirred with diethyl ether, filtered, washed with ether, then dried in vacuo to provide 9-chloro-7-(2,6-difluoro-phenyl)-5H-benzo[c]pyrimido[4,5-e]azepin-2-yl amine (3.16 g, 89%) as a light brown solid MS m/z=357 (M+H). The amine (2.0 g, 5.6 mmol), diiodomethane (7.7 g, 28.6 mmol), copper (I) iodide (1.1 g, 5.6 mmol), dry tetrahydrofuran (40 mL), and isoamyl nitrite (2.0 g, 16.8 mmol) were combined in a round-bottomed flask and stirred at reflux for 1 hour. The dark purple solution was cooled to room temperature and then transferred to a separatory funnel containing 1N HCl (250 mL) and ethyl acetate (150 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The organic extracts were combined, washed with ammonium hydroxide (3%), saturated ammonium chloride, and saturated saline, and then dried (Na2SO4), filtered, and concentrated to leave a dark oil. Purification by column chromatography (silica gel, CH2Cl2 to 10% ethyl acetate in CH2Cl2) afforded 9-Chloro-7-(2,6-difluoro-phenyl)-2-iodo-5H-benzo[c]pyrimido[4,5-e]azepine as a pale yellow solid (1.3 g, 50%) MS m/z=468 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([F:10])[N:3]=1.ClC(Cl)C.[NH:15]1[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>>[Cl:1][C:2]1[N:3]=[C:4]([F:10])[C:5]([CH2:6][N:15]2[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]2)=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(Cl)nc1F
Reactant: O=S1(=O)CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: O=S1(=O)CCN(Cc2ccc(Cl)nc2F)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
6-Chloro-2-fluoronicotinaldehyde (116 mg, 0.73 mmol) was added to a 200 mL round bottom under argon. Dichloroethane (2.9 ml) was added followed by thiomorpholine 1,1-dioxide (98 mg, 0.73 mmol). The mixture was stirred for 45 min at room temperature, at which time sodium triacetoxyborohydride (216 mg, 1.02 mmol) was added. The resulting slurry was stirred for 72 hours at room temperature. Saturated aqueous sodium bicarbonate was added and the resulting mixture was extracted twice with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (silica, 0-100% ethyl acetate/hexanes) to afford the title compound.
Reaction SMILES: [CH2:1]([CH2:11][C:12](=O)[CH3:13])[C:2]1[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1.O>C1(C)C=CC=CC=1>[F:15][C:16]([F:25])([F:26])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH:22][CH:12]([CH3:13])[CH2:11][CH2:1][C:2]2[CH:10]=[CH:9][C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=2)=[CH:19][CH:18]=1
Reactant: COc1cc(CCC(C)=O)ccc1O
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(CCC(C)NCc2ccc(C(F)(F)F)cc2)ccc1O
Temperature: 0 °C
Yield: 74 %

Procedure:
Vanillylacetone (5.00 g, 25.7 mmol) was dissolved in toluene (250 mL) and 4-trifluoromethylbenzylamine (4.73 g, 27.0 mmol) was added. The mixture was maintained under an atmosphere of nitrogen and heated at reflux with removal of water by Dean-Stark distillation for 16 hours. At this time the Dean-Stark trap was removed and the reaction mixture was cooled to 0° C. on an ice bath. A solution of sodium borohydride (5 g) in methanol (100 mL) was added portion-wise over 30 minutes with vigorous stirring. When the addition was complete the mixture was heated at reflux for 16 hours. At this time the reaction mixture was cooled to room temperature and poured into saturated aqueous sodium bicarbonate solution (300 mL). The resulting mixture was concentrated by rotary evaporation and the aqueous residue was partitioned between water and chloroform. The chloroform layer was dried over anhydrous sodium sulfate and then filtered and concentrated. The product was then purified using silica gel column chromatography employing a mobile phase of 5% ammonia-methanol in chloroform. Product-containing fractions were combined and concentrated then dried under high vacuum overnight to provide a light brown oil (6.72 g, 74%). 1H NMR, 13C NMR, and Mass Spectrum of the product were substantially the same as those in Example 2, A (made by the Conditioned Extraction method).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH:10]=[CH2:11])[CH:3]=1.[BH4-].[Na+]>CO.O>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([CH:10]=[CH2:11])[CH:3]=1
Reactant: C=Cc1cc(F)ccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=Cc1cc(F)ccc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a mixture of 1-bromo-4-fluoro-2-vinylbenzene (0.32 g, 1.592 mmol) in tetrahydrofuran (5 mL) at −78° C. was added BuLi (0.764 mL, 1.910 mmol) dropwise. It was then stirred at this temperature for 1 h, then N,N-dimethylformamide (0.185 mL, 2.388 mmol) was added. The reaction mixture was stirred at −78° C. for 30 min, then warmed to rt and stirred at rt for 3 h. It was then quenched with NH4Cl, extracted with ether. The organic layer was dried over MgSO4, filtered and concentrated to obtain 4-fluoro-2-vinylbenzaldehyde (0.2 g) as an oil, which was used in the next step without purification. A mixture of 4-fluoro-2-vinylbenzaldehyde (200 mg, 1.332 mmol) and NaBH4 (50.4 mg, 1.332 mmol) in MeOH (2 mL) was stirred at rt for 1 h. It was then diluted with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 20% EtOac/hexane to obtain (4-fluoro-2-vinylphenyl)methanol (150 mg, 0.986 mmol, 74.0% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.35 (dd, J=8.3, 5.9 Hz, 1H), 7.25 (dd, J=10.0, 2.7 Hz, 1H), 7.09-7.02 (m, 1H), 7.02-6.95 (m, 1H), 5.73 (d, J=17.4 Hz, 1H), 5.44 (d, J=11.0 Hz, 1H), 4.75 (d, J=4.9 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl.O>CN(C=O)C>[Cl:1][C:2]1[N:6]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-1H-benzimidazole (3.8 g) in DMF (25 ml) was added sodium hydride (60% in oil, 1.1 g) at 0° C. in several portions. The reaction mixture was stirred at 0° C. for 30 min, 2-(trimethylsilyl)ethoxymethyl chloride (4.7 ml) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) to give the title compound (6.3 g).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH:5]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:6][CH:7]=[CH:8][CH:9]=[CH:10][C:11](O)=[O:12].C(Cl)(=O)C([Cl:25])=O>C1C=CC=CC=1>[CH3:3][O:4][CH:5]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:6][CH:7]=[CH:8][CH:9]=[CH:10][C:11]([Cl:25])=[O:12]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(C(CC=CC=CC(=O)O)OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1ccc(C(CC=CC=CC(=O)Cl)OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
To a suspension of 60% NaH (0.059 g, 1.47 mmol) washed previously with dry pentane (2×5 mL) in dry benzene (5 mL) at 5° C. was added dropwise a solution of carboxylic acid 4 (0.30 g, 1.14 mmol) in dry benzene (5 mL) via cannula. After 20 min, oxalyl chloride (117 μL, 1.34 mmol) was added via microsyringe, and then the reaction mixture was allowed to warm to rt over 30 min. After stirring for an additional 1.5 h at rt, the mixture was filtered and the filtrate was concentrated under reduced pressure to give the desired acid chloride 5 in 93% yield as a red-orange oil. Without further purification, this crude product was used in the next step: 1H NMR (300 MHz, CDCl3) δ 7.40 (dd, J=15.3, 10.5 Hz, 1H), 7.20 (d, J=8.4 Hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 6.30 (m, 2H), 5.98 (d, J=15.3 Hz, 1H), 4.18 (dd, J=7.5, 4.8 Hz, 1H), 3.82 (s, 3H ), 3.20 (s, 3H ), 2.61 (m, 1H), 2.48 (m, 1H).
Reaction SMILES: [CH2:1]=[C:2]([CH2:12][CH3:13])[CH2:3][CH2:4][C:5]1([OH:11])[CH2:10][CH2:9][CH2:8][O:7][CH2:6]1.C(OO)(=[O:16])C.C([O-])(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:12]([C:2]1([CH2:1][OH:16])[CH2:3][CH2:4][C:5]2([CH2:10][CH2:9][CH2:8][O:7][CH2:6]2)[O:11]1)[CH3:13]
Reactant: C=C(CC)CCC1(O)CCCOC1
Reactant: CC(=O)OO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCC1(CO)CCC2(CCCOC2)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.2 %

Procedure:
To a solution of 5.75 g of tetrahydro-3-(3-methylenepentyl)-2H-pyran-3-ol in 40 ml methylene chloride was added in four portions, 6.5 g of 40% peracetic acid in acetic acid containing 145 mg of anhydrous sodium acetate. A temperature increase from 20° C. to 37° C. resulted. The resulting solution was refluxed for 1 hour and stirred at ambient temperature for 4 hours. The resulting mixture was diluted with 60 ml of methylene chloride and washed with 100 ml of water. The organic phase was washed successively with two 100 ml portions of 25% potassium carbonate, and 100 ml of saturated sodium chloride, dried with MgSO4 and vacuum concentrated to leave 5.7 g of the desired product as an oil.
Reaction SMILES: [C@@H:1]1([NH:10][C:11]2[C:20]3[CH:19]=[N:18][CH2:17][N:16]([NH2:21])[C:15]=3[N:14]=[CH:13][N:12]=2)[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@H:2]1[OH:3].P(Cl)(Cl)(Cl)=O.C[O:28][P:29](OC)([O:31]C)=[O:30]>>[P:29]([O:9][CH2:8][C@H:6]1[O:7][C@@H:1]([NH:10][C:11]2[C:20]3[CH:19]=[N:18][CH2:17][N:16]([NH2:21])[C:15]=3[N:14]=[CH:13][N:12]=2)[C@H:2]([OH:3])[C@@H:4]1[OH:5])([OH:31])([OH:30])=[O:28]
Reactant: COP(=O)(OC)OC
Reactant: NN1CN=Cc2c(N[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)ncnc21
Solvent: O=P(Cl)(Cl)Cl
Product: NN1CN=Cc2c(N[C@@H]3O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]3O)ncnc21

Procedure:
reacting said N4 -(β-D-ribofuranosyl)pyrimido[4,5-d]pyrimidine-4,8-diamine with acetic anhydride in the presence of an acid scavenger to produce N4 -(2,3,5-tri-O-acetyl β-D-ribofuranosyl)pyrimido[4,5-d]pyrimidine-4,8-diamine or, alternatively reacting said N4 -(β-D-ribofuranosyl)pyrimido[4,5-d]pyrimidine-4,8-diamine with phosphoryl chloride in trimethylphosphate at a temperature below about 10° C. to produce N4 -(5-O-phosphono-β-D-ribofuranosyl)pyrimido[4,5-d]pyrimidine-4,8-diamine.