Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][CH2:6][NH:7][C:8](=O)OC(C)(C)C)C.[H-].[Na+].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)CBr>CN(C=O)C.C(OCC)(=O)C>[O:15]1[CH2:16][CH2:17][O:3][CH:4]1[CH2:5][CH2:6][NH:7][CH2:8][C:28]1[CH:27]=[CH:24][CH:23]=[C:22]([O:21][CH3:20])[CH:29]=1
Reactant: COc1cccc(CBr)c1
Reactant: CCOC(CCNC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cccc(CNCCC2OCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a stirred solution of tert-butyl (3,3-diethoxypropyl)carbamate (1.0 g, 4.05 mmol) in DMF (15 mL) was added sodium hydride (0.25 g, 6.25 mmol). The reaction mixture was stirred at room temperature for 30 minutes and 3-methoxybenzyl bromide (0.875 mL, 6.25 mmol) added. The reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was diluted with ethyl acetate and washed with water and twice with brine. The organic phase was dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was dissolved in ethanol (10 mL) and 4M hydrogen chloride in dioxane (10 mL) added. The reaction mixture was stirred at room temperature for 2 hours and the solvent evaporated at reduced pressure. The residue was loaded onto an SCX-2 cartridge and eluted with ethanol (4 column volumes) and then 10% triethylamine/ethanol (4 column volumes). The product containing fractions were combined and the solvent evaporated at reduced pressure to afford the title compound (0.543 g, 50%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[O:11]1[CH2:16][CH2:15][N:14]([CH:17](O)[CH2:18]C)[CH2:13][CH2:12]1.[C:21](=O)([O-])[O-:22].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C.O>[O:11]1[CH2:12][CH2:13][N:14]([CH:17]([CH3:18])[CH2:21][O:22][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:15][CH2:16]1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CCC(O)N1CCOCC1
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(COc1ccccc1[N+](=O)[O-])N1CCOCC1
Yield: 83.7 %

Procedure:
0.57 g 2-fluoronitrobenzene, 0.65 g morpholino-propanol., 3.0 g caesium carbonate and 30 ml dimethylformamide are stirred for 2 days at room temperature in a closed 50 ml round-bottomed flask. One pours the suspension on to 50 ml water, extracts the aqueous phase 3 times with, in each case, 50 ml ethyl acetate and evaporates the combined organic phases on a rotavapor. For the removal of the dimethylformamide, which would disturb the chromatographic separation, the DMF-containing residue is again evaporated 2 to 3 times, together with some toluene, at 50° C. and 30 mbar vacuum. The oily residue is then purified on silica gel (0.04 to 0.063 mm) at 0.1 bar by flash chromatography. One obtains 0.9 g of oil (82.4%).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].NCP(=O)(O)[OH:9].C(O)(=O)C(C)C.[OH-].[Na+]>>[C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:2]([OH:9])(=[O:3])[C:1]([OH:5])=[O:4]
Reactant: O=C(O)CO
Reactant: NCP(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)C(=O)O
Product: O=C(O)C(=O)O
Product: O=CC(=O)O
Temperature: 5 °C
Reaction time: 15 h

Procedure:
A 300-mL EZE-Seal stirred autoclave reactor (Autoclave Engineers) was charged with 100 mL of a solution containing glycolic acid (0.500M), aminomethylphosphonic acid (0.375M), isobutyric acid (0.100M, HPLC internal standard), and flavin mononucleotide (0.01 mM) at pH 8.3 (adjusted with 50% NaOH), and the solution cooled to 5° C. Freshly-harvested Aspergillus nidulans FT17SYCSL/OL (37 g, 44 IU glycolate oxidase and 57,800 IU catalase) were washed with 4×100 mL of KH2PO4 (50 mM, pH 7.0)/FMN (0.01 mM) buffer at 5° C. and the washed cells added to the reactor with 1.4×106 units of Aspergillus niger soluble catalase (Sigma). The pH of the resulting mixture was re-adjusted to 8.3 with 50% NaOH, then stirred at 400 rpm and 5° C. under 120 psig of oxygen while bubbling oxygen through the mixture at 50 mL/min. After 15 hours, the yields of glyoxylic acid, oxalic acid, and formic acid were 84%, 0%, and 9.4%, respectively, with 6.4% recovery of glycolic acid.
Reaction SMILES: [N:1]1([CH2:6][C:7]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[N+:8]([O-:10])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:21]([O:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[CH:22]=[CH2:23].C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[N:1]1([CH2:6][C:7]2([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=3)[CH2:23][CH:22]([CH2:21][O:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[O:10][N:8]2[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C[N+]([O-])=C(Cn1ccnc1)c1ccc2ccccc2c1
Reactant: C=CCOc1ccc(OC)cc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(OCC2CC(Cn3ccnc3)(c3ccc4ccccc4c3)N(C)O2)cc1

Procedure:
A mixture of compound 2 (13.0 g, 0.049 mol) and p-methoxyphenyl allyl ether (12.07 g, 0.073 mol) in 400 ml of toluene is refluxed for 48 hours, cooled, and the solvent removed in vacuo leaving a dark oil. Chloroform is added to the oil and carbon is added to decolorize the solution which is filtered through a bed of celite. The chloroform is evaporated and the oil that remained is purified by flash chromatography on silica gel (eluent comprised of 98% CHCl3 and 2% MeOH). The resulting tan solid (5.56 g, 26%) is recrystallized from ethyl acetate, m.p. 143°-145° C. (Found: C, 72.58; H, 6.46; N, 9.66. C26H27N3O3 requires: C, 72.71; H, 6.34; N, 9.78).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([OH:30])=O)=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[NH:32]1[CH2:37][CH2:36][S:35](=[O:39])(=[O:38])[CH2:34][CH2:33]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([N:32]5[CH2:37][CH2:36][S:35](=[O:39])(=[O:38])[CH2:34][CH2:33]5)=[O:30])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: O=S1(=O)CCNCC1
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)N5CCS(=O)(=O)CC5)nc4CCC3C2C2CCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.2 %

Procedure:
In a dried reaction flask, 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (0.421 g, 1.0 mmol), thiomorpholine-1,1-dioxide hydrochloride (0.223 g, 1.3 mmol), DIEA (0.26 mL, 1.49 mmol), and HATU (0.418 g, 1.1 mmol) were added to a mixed solvent of DMF (4 mL) and dichloromethane (8 mL). The mixture was stirred at room temperature for 1.5 hr and was concentrated under reduced pressure. Water was added to the residue. The mixture was filtered to produce a crude yellow solid, which was washed with methanol to obtain a purified product (0.410 g) in 76.2% yield.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]([F:19])([F:18])[O:7][C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]>>[CH3:13][O:12][C:10](=[O:11])[C:9]1[CH:14]=[C:15]([N+:1]([O-:4])=[O:2])[CH:16]=[CH:17][C:8]=1[O:7][C:6]([F:5])([F:19])[F:18]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccccc1OC(F)(F)F
Product: COC(=O)c1cc([N+](=O)[O-])ccc1OC(F)(F)F
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Fuming nitric acid (5 mL) was cooled on an ice bath. Methyl 2-(trifluoromethoxy)benzoate (5 g, 22.7 mmol) was slowly added within 30 min keeping the temperature below 15° C. The reaction was then stirred at 60° C. for 1 hour and 2 hours at room temperature. The mixture was poured on ice water whereupon an oil separated. The aqueous supernatant was decanted and additional water (50 mL) was added to the oil. After neutralisation with sodium hydrogen carbonate, the mixture was extracted with ethyl acetate (25 mL). The aqueous phase was extracted with ethyl acetate (15 mL) once more. The combined organic phases were washed with saturated sodium chloride (2×15 mL), dried (magnesium sulphate), and concentrated in vacuo to give 5.69 g of 5-nitro-2-trifluoromethoxybenzoic acid methyl ester. 1H NMR (DMSO-d6): δ 3.93 (3H, s), 7.82 (1H, d), 8.58 (1H, d), 8.67 (1H, s); HPLC-MS (method B): m/z: 266; Rt=6.0 min.
Reaction SMILES: [CH3:1][C:2]1[S:11][C:10]2[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]=[C:5]([N:16]3[CH2:21][CH2:20][NH:19][C@@H:18]([CH2:22][CH2:23][OH:24])[CH2:17]3)[C:4]=2[N:3]=1.C=O.[C:27](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:41]C(Cl)C>C(=O)(O)[O-].[Na+]>[ClH:41].[ClH:41].[CH3:27][N:19]1[CH2:20][CH2:21][N:16]([C:5]2[C:4]3[N:3]=[C:2]([CH3:1])[S:11][C:10]=3[NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]=2)[CH2:17][C@@H:18]1[CH2:22][CH2:23][OH:24]
Reactant: CC(Cl)Cl
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Cc1nc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCO)C1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1nc2c(s1)Nc1ccccc1N=C2N1CCN(C)[C@@H](CCO)C1
Product: Cl
Yield: 46 %

Procedure:
Combine material from Example 300 (0.080 g, 0.233 mmol), formaldehyde (25 μL, 0.303 mmol, 37% aqueous solution), and sodium triacetoxyborohydride (74 mg, 0.349 mmol) in dichloroethane (8 mL) and stir at room temperature overnight. Dilute the mixture with saturated aqueous sodium bicarbonate and extract three times with dichloromethane. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure. Purify by flash chromatography, eluting with a step gradient starting with dichloromethane going to 6% 2N ammonia-methanol in dichloromethane, to obtain the free base of the title compound (0.038 g, 0.106 mmol, 46%). Isolate as the dihydrochloride salt by dissolving the free base in ethanol and adding a solution of 5 equivalents of hydrochloric acid in ethanol. Evaporating the solution and drying the salt provides the title compound as a brown solid: mass spectrum (APCI): m/z=358.3 (M+1 of free base).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[ClH:9].[NH2:10][N:11]1[CH2:15][CH:14]([CH3:16])[N:13]([CH3:17])[C:12]1=[O:18]>CO>[ClH:9].[CH3:17][N:13]1[CH:14]([CH3:16])[CH2:15][N:11]([N:10]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:12]1=[O:18]
Reactant: CC1CN(N)C(=O)N1C
Reactant: O=Cc1cccnc1
Agent: Cl
Solvent: CO
Product: CC1CN(N=Cc2cccnc2)C(=O)N1C
Yield: 84.1 %

Procedure:
2.3 g of pyridine-3-carbaldehyde are added at room temperature to a solution of 3.6 g of 1-amino-3,4-dimethylimidazolidin-2-one hydrochloride in 25 ml of methanol. The solution is concentrated by evaporation and the residue is stirred with tetrahydrofuran. 4.6 g of 3,4-dimethyl-1-(pyridin-3-ylmethyleneamino)-imidazolidin-2-one hydrochloride having a melting point of 232°-236° are obtained. 2.3 g of triethylamine are added to a suspension of 4.4 g of 3,4-dimethyl-1-(pyridin-3-ylmethyleneamino)-imidazolidin-2-one hydrochloride in 100 ml of tetrahydrofuran and after 20 minutes under reflux the reaction mixture is filtered while hot. 300 ml of hexane are added to the filtrate. The crystals that have precipitated are filtered off with suction and dried. 2.5 g of the title compound having a melting point of 126°-129° are obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[CH:19]4[O:23][CH:22]([C:11]=3[C:10]3[CH:24]=[CH:25][CH:26]=[CH:27][C:9]2=3)C=C4)[CH2:4][CH2:3]1.C1(C2C(=O)C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C=2C2C=CC=CC=2)C=CC=CC=1.Cl>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3=[CH:19][O:23][CH:22]=[C:11]3[C:10]3[CH:24]=[CH:25][CH:26]=[CH:27][C:9]2=3)[CH2:4][CH2:3]1
Reactant: CN1CCC(=C2c3ccccc3C3=C(c4ccccc42)C2C=CC3O2)CC1
Agent: Cl
Agent: O=C1C(c2ccccc2)=C(c2ccccc2)C(c2ccccc2)=C1c1ccccc1
Solvent: Cc1ccccc1C
Product: CN1CCC(=C2c3ccccc3-c3cocc3-c3ccccc32)CC1

Procedure:
To a solution of 3.20 g. (0.0093 mole) of 1-methyl-4-(1,4-dihydro-1,4-epoxy-9H-tribenzo[a,c,e]cyclohepten-9-ylidene)-piperidine in 105 ml. of xylene (b.p. 139°-140°) is added 3.60 g. (0.00936 mole) of tetraphenylcyclopentadienone ("tetracyclone"). The solution is stirred and refluxed for 22 hours. To the cooled solution is added 100 ml. of 3N hydrochloric acid. The crystalline solid that forms is removed by filtration and is washed thoroughly with benzene and ether. The white crystalline solid is dissolved in warm water and is treated with a solution of sodium carbonate. The resulting precipitate is extracted into benzene, washed with water, dried over magnesium sulfate, filtered, and the benzene is removed on a rotary evaporator. The crystalline residue, weighing 2.62 gm., is recrystallized from absolute methanol to give 1-methyl-4-(8H-dibenzo[a,e]furo[3,4-c]cyclohepten-8-ylidene)-piperidine, m.p. 147°-148°.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(N[C@H]2C3C(=CC=CC=3)C[C@H]2O)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Agent: CCc1cnc(CC)c(N[C@H]2c3ccccc3C[C@H]2O)n1
Product: CCc1nc(N[C@H]2c3ccccc3C[C@H]2O)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting (1S,2R)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a pale yellow solid. MS (ESI+) for C17H20BrN3O m/z 361.9 (M+H)+.
Reaction SMILES: Cl[CH2:2][NH:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].[CH3:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[NH:13][C:12]=1[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1>>[C:20]([C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:2][NH:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])[C:12]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[C:11]2[CH3:10])#[N:21]
Reactant: CC(C)(C)C(=O)NCCl
Reactant: Cc1c(-c2cccnc2)[nH]c2ccc(C#N)cc12
Product: Cc1c(-c2cccnc2)n(CNC(=O)C(C)(C)C)c2ccc(C#N)cc12

Procedure:
N-Chloromethyl-2,2-dimethyl-propionamide and 3-methyl-2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 6) are processed according to the method described in Example 68 to give N-(5-cyano-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-2,2-dimethyl-propionamide. 1H NMR (400 MHz, MeOD) δ ppm 1.06 (s, 9H), 2.27 (s, 3H), 5.54 (s, 2H), 7.55 (dd, J=8.6, 1.8 Hz, 1H), 7.66 (ddd, J=7.9, 5.0, 1.0 Hz, 1H), 7.81 (d, J=8.6 Hz, 1H), 8.01-8.09 (m, 2H), 8.65-8.73 (m, 2H). HRMS (ESI) m/z 347.1863 [(M+H)+ Calcd for C21H23N4O: 347.1872].
Reaction SMILES: [O:1]1[C:14]2[C:13]3[N:12]=[CH:11][CH:10]=[CH:9][C:8]=3[CH:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[CH2:15]([I:18])[CH:16]=[CH2:17]>C1(C)C=CC=CC=1>[I-:18].[CH2:17]([N+:12]1[C:13]2[C:14]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:6]=[CH:7][C:8]=2[CH:9]=[CH:10][CH:11]=1)[CH:16]=[CH2:15]
Reactant: C=CCI
Reactant: c1cnc2c3c(ccc2c1)OCCO3
Solvent: Cc1ccccc1
Product: C=CC[n+]1cccc2ccc3c(c21)OCCO3
Product: [I-]
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
2,3-Dihydro[1,4]dioxino[2,3-h]quinoline (3.65 g; 19.52 mmol) and allyl iodide (6.52 ml; 39.04 mmol) were refluxed in toluene (50 ml) at 100° C. After 2.5 h more allyl iodide (0.65 ml; 3.9 mmol) was added to the mixture and the reaction continued under the same conditions for a further 0.5 h. The solvent was removed and the tar like product washed with toluene. This was dried under high vacuum overnight to afford the desired product (5.91 g; 85%).
Reaction SMILES: [N:1]1[C:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]=2O[CH:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[S:14]1C2C=CSC=2C=N1>>[N:1]1[C:5]2[C:6]3[C:11]([CH:12]=[CH:13][C:4]=2[S:14][CH:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: c1ccc2c(c1)ccc1ocnc12
Reactant: c1cc2sncc2s1
Product: c1ccc2c(c1)ccc1scnc12

Procedure:
naphthoxazole; or thienoisothiazole.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14]C=C[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:16]#[C:17][NH2:18].C(O)(C(F)(F)F)=O.BrC#N>>[CH2:1]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:18]([C:17]#[N:16])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CN
Reactant: c1ccc(COCc2ccccc2)cc1
Agent: N#CBr
Solvent: O=C(O)C(F)(F)F
Product: N#CN1CCC(COCc2ccccc2)C1

Procedure:
Following general procedure 12, to a cold (0° C.), stirred solution of the alcohol (26) (188 mg, 1 equiv.) in DMF (9 mL) was added NaH (60% in oil, 56 mg, 1.5 equiv.). The suspension was stirred at 0° C. for 40 minutes followed by the addition of the benzyl chloride (215 uL, 2 equiv.). The suspension was warmed to rt and stirred for 16 h. MeOH was added followed by sat. aq. NH4Cl. The aqueous phase was extracted with EtOAc (3×) and the combined organic extracts were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (20% EtOAc in hexane) to afford the desired benzyl ether (27). The N-Boc group of the benzyl ether (27) was then converted to the cyanamide (N—CN) following general procedure 3 (i.e. successive treatment with TFA and BrCN). The crude material was purified by flash chromatography (gradient elution: 30% EtOAc in hexane to 50% EtOAc in hexane) to afford the desired product 3-[(benzyloxy)methyl]-1-cyanopyrrolidine (28).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([O:9]C)=O.[NH2:11][CH2:12][CH2:13][OH:14]>>[OH:14][CH2:13][CH2:12][NH:11][C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)=[O:9]
Reactant: NCCO
Reactant: COC(=O)c1cccn1C
Product: Cn1cccc1C(=O)NCCO

Procedure:
A mixture of 5.5 parts of methyl 1-methyl-1H-pyrrole-2-carboxylate and 2.4 parts of 2-aminoethanol is stirred and refluxed for 2 hours. The reaction mixture is evaporated till dry. Benzene is added twice to the residue and evaporation is continued each time till dry. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is taken up in petroleumether and upon scratching, the product solidifies. It is filtered off and dried, yielding 1.9 parts of N-(2-hydroxyethyl)-1-methyl-1H-pyrrole-2-carboxamide; mp. 78.1° C.
Reaction SMILES: [CH2:1]([O:3][P:4]([O:23][CH2:24][CH3:25])([CH:6]1[CH2:10][CH2:9][CH:8]([CH2:11]OS(C2C=CC(C)=CC=2)(=O)=O)[O:7]1)=[O:5])[CH3:2].[Br-:26].[Li+]>CN(C=O)C>[Br:26][CH2:11][C@@H:8]1[O:7][C@@H:6]([P:4]([O:23][CH2:24][CH3:25])([O:3][CH2:1][CH3:2])=[O:5])[CH2:10][CH2:9]1
Reactant: CCOP(=O)(OCC)C1CCC(COS(=O)(=O)c2ccc(C)cc2)O1
Reactant: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOP(=O)(OCC)[C@H]1CC[C@H](CBr)O1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a stirring solution of (±)-2-diethoxyphosphinoyl-5-(p-toluenesulfonyloxymethyl)-tetrahydrofuran (example 60) (12.0 g, 30.61 mmol) in dry DMF (60 mL) was added anhydrous lithium bromide (13.3 g, 153.05, mmol). The solution was then stirred at 80° C. for 4 h. The mixture was cooled and concentrated to dryness under reduced pressure. The residue was then dissolved in methylene chloride and the solution was washed with water (2×50 mL), brine (50 mL), dried (MgSO4) and concentrated. The cis-trans mixture was separated by flash chromatography eluting with 10→20% acetone in hexanes.
Reaction SMILES: COC1C=CC(C[N:8]2[C:16](=[O:17])[C:15]3[N:14]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=4)[C:13]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]([F:37])([F:36])[F:35])[CH:28]=4)=[N:12][C:11]=3[N:10]([CH3:38])[C:9]2=[O:39])=CC=1.OS(C(F)(F)F)(=O)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:38][N:10]1[C:11]2[N:12]=[C:13]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][C:34]([F:37])([F:36])[F:35])[CH:28]=3)[N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)[C:15]=2[C:16](=[O:17])[NH:8][C:9]1=[O:39]
Reactant: COc1ccc(Cn2c(=O)c3c(nc(Cc4cccc(OC(F)(F)F)c4)n3Cc3ccc(C)cn3)n(C)c2=O)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(Cn2c(Cc3cccc(OC(F)(F)F)c3)nc3c2c(=O)[nH]c(=O)n3C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
To a solution of 1-(4-methoxybenzyl)-3-methyl-7-((5-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione (120 mg, 0.212 mmol) in DCM (1.4 mL) was added triflic acid (0.7 mL) and TFA (0.7 mL). The reaction was stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with saturated NaHCO3 and brine, dried over sodium sulfate, filtered and concentrated to give crude product, which was purified by silica gel chromatography eluting with petroleum/ethyl acetate (10:1 to 1:1) to give 3-methyl-7-((5-methylpyridin-2-yl)methyl)-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)-dione (60 mg, 63.5% yield) as white solid. LCMS MH+ 446.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:6]=[C:7]([C:17]([NH:19][CH2:20][C:21]2[C:22](=[O:29])[NH:23][C:24]([CH3:28])=[CH:25][C:26]=2[CH3:27])=[O:18])[C:8]2[CH:13]=[N:12][N:11]([CH:14]([CH3:16])[CH3:15])[C:9]=2[N:10]=1)CO>C1COCC1.O>[CH3:27][C:26]1[CH:25]=[C:24]([CH3:28])[NH:23][C:22](=[O:29])[C:21]=1[CH2:20][NH:19][C:17]([C:7]1[C:8]2[CH:13]=[N:12][N:11]([CH:14]([CH3:16])[CH3:15])[C:9]=2[N:10]=[C:5]([CH:2]=[O:1])[CH:6]=1)=[O:18]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(C(O)CO)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(C=O)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a stirred solution of 6-(1,2-dihydroxyethyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide 0.66 g, 1.65 mmol) in 50% THF/Water (12 mL), NaIO4 (1.06 g, 4.95 mmol) was added at 0° C. and stirred at room temperature for 1 h. After completion of reaction, solid was filtered and washed with water. Azeotrope with toluene to obtain the desired compound (0.515 g, 84.8%). LCMS: 368.05 (M+1)+; HPLC: 99.53% (@ 254 nm), (Rt; 5.901); 1H NMR (DMSO-d6, 400 MHz) δ 11.54 (s, 1H), 10.09 (s, 1H), 9.10 (bs, 1H), 8.53 (s, 1H), 8.11 (s, 1H), 5.89 (s, 1H), 5.37-5.31 (m, 1H), 4.37 (d, 2H, J=4.4 Hz), 2.21 (s, 3H), 2.12 (s, 3H), 1.55 (d, 6H, J=6.4 Hz).