Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13]#[N:14])(=[O:3])[CH3:2].[OH2:15].C([O-])([O-])=O.[Na+].[Na+].[NH2:22]O.Cl>C(O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:13](=[N:22][OH:15])[NH2:14])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2CC1C#N
Reactant: O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(=O)N1c2ccccc2CC1C(N)=NO
Temperature: 25 °C

Procedure:
1-acetyl-2,3-dihydro-1H-indole-2-carbonitrile (0.0132 mole) was treated with water (54 ml) and the resulting suspension was treated sequentially with Na2CO3 (0.00726 mole) and NH2OH.HCl 0.0145 mole). The mixture was treated with ethanol (26 ml) and heated to 80–90° C. Upon achieving reaction temperature, the mixture was still a suspension. Added another 26 ml of ethanol which afforded a clear solution. The reaction was heated for 2.5 hours and cooled to room temperature with stirring. A voluminous precipitate formed which was collected by suction filtration, washed with cold distilled water, and air dried, yielding 2.23 g of 1-acetyl-2,3-dihydro-N′-hydroxy-1H-indole-2-carboximidamide (intermediate 14, mp. 204–205° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[S:17](=[O:22])(=[O:21])[N:18]([CH3:20])[CH3:19])[N:6]([CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH:29]([CH2:32][CH2:33][OH:34])[CH2:28][CH2:27]3)[C:5]=2[CH:4]=1.[C:35](Cl)(=[O:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[S:17](=[O:21])(=[O:22])[N:18]([CH3:19])[CH3:20])[N:6]([CH2:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][CH:29]([CH2:32][CH2:33][O:34][C:35](=[O:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:30][CH2:31]3)[C:5]=2[CH:4]=1
Reactant: CCCCCCC(=O)Cl
Reactant: COc1ccc2c(c1)N(CCCN1CCC(CCO)CC1)c1cccc(S(=O)(=O)N(C)C)c1S2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCC(=O)OCCC1CCN(CCCN2c3cc(OC)ccc3Sc3c2cccc3S(=O)(=O)N(C)C)CC1
Reaction time: 6 h
Yield: 103.4 %

Procedure:
Working in the absence of moisture, a mixture of 2-methoxy-6-dimethylsulphamoyl-10-[3-(4-hydroxyethylpiperidino)propyl]phenothiazine (11.4 g.) and heptanoyl chloride (3.8 g.) in toluene (150 cc.) is heated under reflux, with stirring, for 6 hours. After cooling, ethyl acetate (75 cc.) is added and the mixture is then rendered alkaline, without exceeding a temperature of 5°C., by adding a solution of anhydrous sodium carbonate (2.3 g.) in distilled water (75 cc.). After decanting, the aqueous layer is extracted with ethyl acetate (100 cc.). The organic extracts are combined and then washed three times with distilled water (total 240 cc.). The organic extract is dried over sodium sulphate and the solvent evaporated. 2-Methoxy-6-dimethylsulphamoyl-10-[3-(4-heptanoyloxyethylpiperidino)propyl]phenothiazine (14.4 g.), in the crude state, is thus obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:16]([O-])=O)[CH:13]=2)[N:8]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:7]1=[O:28].O.NN.N>CO.[Ni].CO.C(Cl)Cl>[NH2:16][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[C:7](=[O:28])[CH:6]([CH2:5][CH2:4][CH2:3][N:2]([CH3:29])[CH3:1])[CH2:15]2
Reactant: COc1ccc(CN2C(=O)C(CCCN(C)C)Cc3cc([N+](=O)[O-])ccc32)cc1
Agent: [Ni]
Agent: N
Agent: NN
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CN2C(=O)C(CCCN(C)C)Cc3cc(N)ccc32)cc1
Yield: 72.3 %

Procedure:
A solution of 3-(3-(dimethylamino)propyl)-1-(4-methoxybenzyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (115 mg, 0.29 mmol) in 10 mL methanol was added to Raney Nickel (slurry in H2O, 50 mg) in a round bottom flask. The suspension was treated with hydrazine hydrate (90 μL, 2.90 mmol) and heated at reflux for 10 minutes then filtered through a pad of celite. The celite pad was rinsed with 10 mL methanol. The filtrate was concentrated to give a yellow residue which was subjected to flash silica gel chromatography using 5% 2M NH3 in MeOH/CH2Cl2 to give a yellow semi-solid (77 mg, 72.3%). 1H-NMR (CDCl3) δ: 7.13-7.10 (m, 2H), 6.83-6.80 (m, 2H), 6.69 (d, J=8.4 Hz, 1H), 6.50 (d, J=2.4 Hz, 1H), 6.42 (dd, J=2.4, 8.4 Hz, 1H), 5.05 (dd, J=15.6, 29.1 Hz, 2H), 3.76 (s, 3H), 3.48 (br s, 2H), 3.01-2.91 (m, 1H), 2.70-2.58 (m, 2H), 2.28 (t, J=7.2 Hz, 2H), 2.21 (s, 6H), 1.88-1.42 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-])=O)=[C:8]([CH:13]([CH3:15])[CH3:14])[NH:7][N:6]=1)=[O:4]>C(O)CC.O.Cl.O=[Pt]=O>[NH2:10][C:9]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6][NH:7][C:8]=1[CH:13]([CH3:15])[CH3:14]
Reactant: COC(=O)c1n[nH]c(C(C)C)c1[N+](=O)[O-]
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCCO
Solvent: O
Product: COC(=O)c1n[nH]c(C(C)C)c1N
Reaction time: 9 h
Yield: 95 %

Procedure:
To a solution of methyl-5-isopropyl-4-nitropyrazol-3-carboxylate (7.34 g, 34.4 mmol) in 36 mL n-propanol, 6 mL water and 5.6 mL 10 M HCl was added 0.55 g PtO2. The mixture was stirred under hydrogen atmosphere (760 torr) for 9 hours. The reaction mixture was filtered and the filtrate was concentrated t dryness in vacuo. The desired amine was liberated by treatment of aq. ammonia during extraction into chloroform. The product crystallized after evaporation; yield 95%; mp=122-123. MS (EI, 70 eV, direct inlet): 183 (88; C8H13N3O2+; −1.0), 168(59), 152(3), 136(100), 108(8), 80(16), 68(20). 1H NMR (400 MHz, CDCl3): 1.31 d (6H; J=6.9 Hz), 2.93 sept (1H), 3.9 s (3H). IR (KBr, cm−1): 3399, 3296, 1710, 1626, 1584, 1302.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[C:10](=[O:11])[CH:9]=[C:8]([CH3:12])[O:7][C:6]1=[O:13])[CH3:3].Cl.[C:15]([C:17]1[CH:24]=[CH:23][C:20](CN)=[CH:19][CH:18]=1)#[N:16].CC(C)([O-])C.[Na+].Cl>C(O)C>[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH2:3][N:2]2[C:8]([CH3:12])=[CH:9][C:10](=[O:11])[C:5]([C:6]([OH:7])=[O:13])=[CH:4]2)=[CH:19][CH:18]=1)#[N:16]
Reactant: CC1=CC(=O)C(=CN(C)C)C(=O)O1
Reactant: N#Cc1ccc(CN)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(=O)c(C(=O)O)cn1Cc1ccc(C#N)cc1

Procedure:
A solution of 3-dimethylaminomethylene-6-methyl-pyran-2,4-dione (preparation 1a, 2.00 g, 9.38 mmol based on 85% purity), 4-cyanobenzylamine hydrochloride (4.00 mL, 23.7 mmol) and sodium tert-butoxide (2.74 g, 28.5 mmol) in ethanol (11 mL) is heated for 48 h at 90° C. The reaction mixture is acidified with 4N aqueous HCl and extracted several times with dichloromethane. The combined organic layer is dried over Na2SO4, evaporated under reduced pressure and purified by preparative reversed-phase HPLC (Sunfire, gradient of methanol in water, 0.1% TFA, 60° C.). Yield: 0.94 g (37% of theory); ESI mass spectrum: [M+H]+=269; Retention time HPLC: 0.86 min (Z002—005).
Reaction SMILES: PP.C(O)C.[C:6]([NH:9][C:10](=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])(=[O:8])[CH3:7].[H][H]>C(N(CC)CC)C>[C:6]([NH:9][C@H:10]([C:11]([OH:13])=[O:12])[CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:8])[CH3:7]
Reactant: CC(=O)NC(=Cc1ccccc1)C(=O)O
Reactant: [H][H]
Agent: PP
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 1 h
Yield: 82 %

Procedure:
3.1 mg of the complex of the formula [RhCl-1,5-cyclooctadiene]2, 57 mg of the diphosphine of Example 1 and 400 cm3 of ethyl alcohol are introduced under an argon atmosphere into a reactor. The mixture is stirred for 1 hour. 66.62 g of α-acetamidocinnamic acid and 25 microlitres of triethylamine are then added and hydrogen is introduced under a pressure of 1 bar at 25° C. After 4 hours 30 minutes the hydrogenation is complete. After treatment to remove the catalyst similar to that of Example 5, N-acetylphenylalanine is obtained, after extraction, in 97% chemical yield and with an optical rotation [α]D22 of 42.5° (optical yield 82%).
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1.[CH3:12][O-:13].[Na+].Cl>>[CH3:12][O:13][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1Cl
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Product: COc1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C

Procedure:
4-fluoro-2-chloro-benzoic acid (10 g) was combined with sodium methoxide (393 mL, 4.37 M in methanol) and heated at 75 C for 46 h. The reaction was cooled to room temp and acidified with 1 N HCl. The mixture was extracted with EtOAc (3×). The combined extracts were then dried (MgSO4) and concentrated to give 8.5 g of 4-methoxy-2-chloro-benzoic acid as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].CN1CCOCC1.Cl[C:28]([O:30][CH:31]([Cl:35])[CH:32]([CH3:34])[CH3:33])=[O:29]>ClCCl>[Cl:35][CH:31]([O:30][C:28]([NH:2][CH2:3][CH:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:5][C:6]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:7])=[O:29])[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)CC(CN)CC(=O)OCc1ccccc1
Reactant: CC(C)C(Cl)OC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)CC(CNC(=O)OC(Cl)C(C)C)CC(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
To a stirred solution of (39) (594 mg, 2.38 mmol) in dichloromethane at 0° C. was added N-methylmorpholine (0.523 mL, 4.77 mmol) and 1-chloro-2-methylpropyl chloroformate (0.347 mL, 2.38 mmol). The resulting solution was stirred at 0° C. until the reaction was complete (˜30 min, as monitored by TLC) and then was diluted with dichloromethane, washed successively with cold 1N HCl solution, water and brine, then dried over anhydrous Na2SO4. Filtration and removal of the solvent in vacuo afforded the title compound (42) as a mixture of two diastereomers (840 mg, 92%), which was used without further purification in the following example. 1H-NMR (CDCl3, 400 MHz): δ 0.86 (2 d, 6H), 1.02 (2 d, 6H), 1.15 (m, 2H), 1.63 (m, 1H), 2.14 (m, 2H), 2.34 (m, 2H), 3.10 (m, 1H), 3.28 (m, 1H), 5.11 (br.s, 3H), 6.29 (d, 1H), 7.31 (m, 5H).
Reaction SMILES: I.[CH3:2]C1C(C)NC(SC)=N1.I.CSC1NCCN=1.[NH2:19][C:20]1[N:21]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[C:22]2[N:23]([CH:29]([CH3:33])[CH:30]([CH3:32])[N:31]=2)[C:24](=[O:28])[C:25]=1[N:26]=O>>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][N:21]2[C:20]3[NH:19][CH:2]=[N:26][C:25]=3[C:24](=[O:28])[N:23]3[CH:29]([CH3:33])[CH:30]([CH3:32])[N:31]=[C:22]23)=[CH:36][CH:37]=1
Reactant: CSC1=NC(C)C(C)N1
Reactant: CC1N=C2N(Cc3ccc(Cl)cc3)C(N)=C(N=O)C(=O)N2C1C
Agent: CSC1=NCCN1
Agent: I
Product: CC1N=C2N(Cc3ccc(Cl)cc3)c3[nH]cnc3C(=O)N2C1C

Procedure:
Procedure 1 is repeated with substitution of 4,5-dimethyl-2-(methylthio)-2-imidazoline hydroiodide for the 2-(methylthio)-2-imidazoline hydroiodide specified. The resulting 7-amino-2,3-dihydro-2,3-dimethyl-8-[(4-chlorphenyl)methyl]-6-nitrosoimidazo[1,2-a]pyrimidin-5(8H)-one is converted to the corresponding 6-formylamino compound by the method of Procedure 2 and the latter is converted to the desired product by the method of Procedure 4.
Reaction SMILES: C(O[K])(C)(C)C.[CH2:7]([O:9][C:10]([CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH:16]([C:20]([O:22]CC)=O)[CH2:15]1)=[O:11])[CH3:8].CCO>C1(C)C=CC=CC=1>[CH2:7]([O:9][C:10]([C:12]1[CH2:13][N:14]2[CH2:15][CH:16]([C:20]=1[OH:22])[CH2:17][CH2:18][CH2:19]2)=[O:11])[CH3:8]
Reactant: CCOC(=O)CCN1CCCC(C(=O)OCC)C1
Agent: CC(C)(C)O[K]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=C(O)C2CCCN(C1)C2
Yield: 40.1 %

Procedure:
A suspension of tert-BuOK (505 mg, 4.5 mmol) in anhydrous toluene (4.5 mL) was refluxed (1 h) and then an anhydrous toluene solution (1.5 mL) of 15a (386 mg, 1.5 mmol) was added (20 min) and the reaction mixture was refluxed for an additional 3 h, and then cooled. EtOH (2 mL) was added, and the reaction was filtered (Celite pad) and concentrated in vacuo. The residue was purified by PTLC (5% MeOH—CHCl3) to give 4 (127 mg, 40%) as a yellow oil: Rf 0.21 (5% MeOH—CHCl3); IR (neat) 2932, 2857, 1656, 1292, 1207 cm−1; 1H NMR (CDCl3, 500 MHz) δ 1.25 (t, J=7.1 Hz, 3H, CH2CH3), 1.55-1.64 (m, 2H, C(7)H2), 1.65-1.73 (m, 1H), C(6)HH′), 1.84-1.86 (m, 1H, C(6)HH′), 2.19 (br s, 1H, C(5)H), 2.89 (d, J=13.0 Hz, 1H), C(9)HH′), 2.90-2.96 (m, 2H, C(8)H2), 2.96 (d, J=13.0 Hz, 1H, C(9)HH′), 3.24 (d, J=16.8 Hz, 1H, C(2)HH′), 3.73 (d, J=16.8 Hz, 1H, C(2)HH′), 4.17 (q, J=7.1 Hz, 2H, CH2CH3), 11.83 (br s, 1H, C(4)OH), the 1H NMR assignments were consistent with the COSY spectrum; 13C NMR (CDCl3, 150 MHz) 14.2 (CH2CH3), 19.1 (C(7)), 26.6 (C(6)), 32.2 (C(5)), 49.5 (C(2)), 51.4 (C(9)), 55.2 (C(8)), 60.2 (CH2CH3), 99.3 (C(3)), 170.6 (C(O)), 172.1 (C(4) ppm, the assignments were consistent with the DEPT, HMQC and HMBC spectra; MS (+CI) 212 [M+1]+; Mr (+CI) 212.128 08 [M+1]+ (calcd for C11H18NO3 212.128 67). Anal. (C11H17NO3): C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[C:11]([O:14][CH:15](OC(=O)C)[C:16]([CH3:18])=[CH2:17])(=[O:13])[CH3:12]>>[C:11]([O:14][CH:15]=[C:16]([CH3:18])[CH2:17][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([O:9][CH3:10])[CH:5]=1)(=[O:13])[CH3:12]
Reactant: C=C(C)C(OC(C)=O)OC(C)=O
Reactant: COc1ccccc1OC
Product: COc1ccc(CC(C)=COC(C)=O)cc1OC
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
In an argon gas atmosphere, a three necked flask having a capacity of 25 ml was charged with 13.82 g (100 m moles) of 1,2-dimethoxybenzene and 1.87 g (10 m moles) of 3,3-diacetoxy-2-methylpropene having a purity degree of 92.0% by mass. Then, the resultant mixture was mixed with 0.142 g (1 m mole) of boron trifluoride-ether complex at an internal temperature of 18 to 19° C. The mixture was stirred at an internal temperature of 22 to 23° C. for 2 hours. After the reaction was completed, the resultant reaction liquid was subjected to a quantitative analysis using a high performance liquid chromatography. In the result, the target 1-acetoxy-2-methyl-3-(3,4-dimethoxyphenyl)propene was obtained in a yield of 94.4% (amount: 2.36 g).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[O:12][C@@H:11]([N:23]2[C:41]3[N:40]=[CH:39][N:38]=[C:27]([O:28][C:29]4[CH:34]=[CH:33][C:32]([N+]([O-])=O)=[CH:31][CH:30]=4)[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1(OC2C3N=CN(C=3N=CN=2)[C@@H]2O[C@H](CO[Si](C(C)(C)C)(C)C)[C@@H](O[Si](C(C)(C)C)(C)C)C2)C2C=CC=CC=2N=N1.C([O-])([O-])=O.[Cs+].[Cs+].O[C:90]1[CH:102]=[CH:101][C:100]2C3C(=CC=CC=3)[CH2:93][C:92]=2[CH:91]=1>COCCOC>[Si:16]([O:15][C@@H:14]1[C@@H:13]([CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[O:12][C@@H:11]([N:23]2[C:41]3[N:40]=[CH:39][N:38]=[C:27]([O:28][C:29]4[CH:34]=[CH:33][C:32]5[C:100]6[C:92](=[CH:91][CH:90]=[CH:102][CH:101]=6)[CH2:93][C:31]=5[CH:30]=4)[C:26]=3[N:25]=[CH:24]2)[CH2:10]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: Oc1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(Oc4ccc([N+](=O)[O-])cc4)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(On4nnc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(Oc4ccc5c(c4)Cc4ccccc4-5)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 87 %

Procedure:
As described for the synthesis of 3′,5′-bis-O-(tert-butyldimethylsilyl)-O6-(4-nitrophenyl)-2′-deoxyinosine, this fluorenyl derivative was prepared by a reaction between O6-(benzotriazol-1-yl)-3′,5′-bis-O-(tert-butyldimethylsilyl)-2′-deoxyinosine (26) (59.8 mg, 0.100 mmol), Cs2CO3 (65.2 mg, 0.200 mmol) and 2-hydroxyfluorene (20.0 mg, 0.110 mmol) in dry DME (1.0 mL) at 85° C. for 1 h. Chromatographic purification (SiO2, elution with 20% EtOAc in hexanes) afforded 56.0 mg (87% yield) of the title compound as a clear, yellowish gum. Rf (20% EtOAc in hexanes)=0.31. 1H NMR (500 MHz, CDCl1): δ 8.52 (s, 1H, Ar—H), 8.41 (s, 1H, Ar—H), 7.83 (d, 1H, Ar—H, J=8.3), 7.77 (d, 1H, Ar—H, J=7.3), 7.53 (d, 1H, Ar—H, J=7.3), 7.45 (s, 1H, Ar—H), 7.37 (t, 1H, Ar—H, J=7.6), 7.29 (t, 1H, Ar—H, J=7.8), 6.55 (t, 1H, H-1′, J=6.4), 4.66 (m, 1H, H-3′), 4.05 (q, 1H, H-4′, J=3.4), 3.94 (s, 2H, CH2), 3.92 (dd, 1H, H-2′, J=11.2, 4.1), 3.81 (dd, 1H, H-2′, J=11.2, 2.9), 2.67 (app quint, 1H, H-2′, Japp˜6.3), 2.50 (ddd, 1H, H-2′, J=13.2, 6.0, 4.3), 0.94, 0.93 (2 s, 18H, tert-Bu), 0.12 (s, 12H, SiCH3). 13C NMR (126 MHz, CDCl1): δ 160.5, 152.5, 152.1, 151.6, 144.7, 143.3, 141.6, 141.1, 139.5, 126.8, 126.5, 124.9, 122.2, 120.5, 120.47, 119.7, 118.7, 88.1, 84.7, 71.9, 62.8, 41.5, 37.0, 25.9, 25.7, 18.4, 18.0, −4.7, −4.8, −5.4, −5.5. FAB HRMS calcd for C35H49N4O4Si2 (M++H) 645.3292. found 645.3303.
Reaction SMILES: CC(C)([O-])C.[K+].[N+]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)([O-])=O.[CH2:19]([OH:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[C:21]1([CH2:20][CH2:19][O:27][C:10]2[CH:11]=[C:12]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:14][CH:15]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Reactant: OCCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=[N+]([O-])c1cccc(OCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 168 h
Yield: 219.9 %

Procedure:
Potassium t-butoxide (11.2 g; 0.1 mol) is added under a nitrogen atmosphere to a stirred mixture of m-dinitrobenzene (16.8 g; 0.1 mol), phenethyl alcohol (12.2 g; 0.1 mol) and hexamethylphosphoramide (HMPA; 200 ml). Almost instantly a dark red color develops and then slowly fades in the course of the reaction and turns black. The reaction mixture is stirred for 7 days at room temperature. It is then drowned in water, and extracted twice with methylene chloride (500 ml). The methylene chloride solution is washed with water (3X), saturated brine (1X), dried over magnesium sulfate and evaporated to yield 53.5 g of a dark oil. Additional solvent (HMPA) and some m-dinitrobenzene is removed from the oil by heating same at about 90° C. under 0.5 mm vacuum. The residual oil (~25 g) is chromatographed on 1 kg silica gel with 3:1 hexane:methylene chloride. Collected fractions, containing the same material by thin layer chromatography, are combined and evaporated to afford 7.4 g (30%) of product, a light yellow oil. On standing, the oil crystallizes, mp. 46.5°-49° C.
Reaction SMILES: [F:1][C:2]1[C:3](=O)[C:4]2[C:12](=[CH:13][CH:14]=1)[C:11]1[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH:5]=2.[C:16]1([Li])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1C[O:26]CC1>C1CCCCC1.CCOCC>[F:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([OH:26])[C:4]=2[CH:3]=1
Reactant: O=C1C(F)=CC=C2C1=Cc1ccccc12
Reactant: C1CCOC1
Reactant: [Li]c1ccccc1
Solvent: C1CCCCC1
Solvent: CCOCC
Product: OC1(c2ccccc2)c2ccccc2-c2ccc(F)cc21
Yield: 90 %

Procedure:
To a stirred, ice-cooled solution of 2-fluorofluorenone (2.0 g, 10 mmol) in 15 mL of dry THF under N2 was added 10 mL of 2.4 M phenyllithium solution in cyclohexane-Et2O (7:3), keeping T<20° C. The mixture was quenched with water and the product isolated with EtOAc and purified by flash chromatography (7% EtOAc-hexanes) to give 2.52 g (90%) of 2-fluoro-9-phenylfluoren-9-ol.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([N:6]1[C:10]2=[N:11][C:12]([C:15]#[C:16][Si](C)(C)C)=[CH:13][N:14]=[C:9]2[N:8]=[C:7]1[OH:21])[CH2:4][CH3:5].[F-].[K+]>CO.C1COCC1.O>[C:15]([C:12]1[N:11]=[C:10]2[N:6]([CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1])[C:7]([OH:21])=[N:8][C:9]2=[N:14][CH:13]=1)#[CH:16]
Reactant: CCC(CC)n1c(O)nc2ncc(C#C[Si](C)(C)C)nc21
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1cnc2nc(O)n(C(CC)CC)c2n1
Temperature: 25 °C
Yield: 36.9 %

Procedure:
A mixture of 1-(pentan-3-yl)-6-((trimethylsilyl)ethynyl)-1H-imidazo[4,5-b]pyrazin-2-ol (3.2 g, 10.6 mmol), KF (1.6 g, 27.5 mmol) in MeOH/THF/H2O (50 mL, 2/2/1) was stirred at room temperature. Upon complete conversion by LCMS, the solution was concentrated in vacuo, diluted with EtOAc, washed with NH4CI solution, dried over Na2SO4, and concentrated in vacuo. Purification over silica gel (Biotage MPLC 10-80% EtOAc/Heaxanes) gave a brown solid, which was washed with 15% EtOAc/hexanes to give product the title compound as a white solid (0.9 g, 37%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[OH:16])[C:7]1=[O:17].Cl[CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:16][CH2:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:7]1=[O:17]
Reactant: ClCCCN1CCOCC1
Reactant: COc1ccc(CN2C(=O)c3cccc(O)c3C2=O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)c3cccc(OCCCN4CCOCC4)c3C2=O)c(OC)c1
Temperature: 60 °C
Yield: 67.7 %

Procedure:
A mixture of 2-(2,4-dimethoxy-benzyl)-4-hydroxy-isoindole-1,3-dione (313 mg, 1.00 mmol), 4-(3-chloropropyl)morpholine (160 mg, 1.11 mmol) and potassium carbonate (350 mg, 2.5 mmol) in DMF (5 mL) was heated at 60° C. for 18 hours. The mixture was diluted with ethyl acetate and extracted twice with 1N hydrochloric acid. The aqueous extracts were made basic with solid potassium carbonate and extracted with ethyl acetate. The organic extract was washed with brine, dried (MgSO4) and concentrated to give a yellow solid which was recrystallised from methanol/petrol then ethyl acetate/chloroform/petrol to give the title compound (298 mg, 68%) as an off-white solid. 1H NMR (methanol-d4) 7.72 (1H, t), 7.41 (1H, d), 7.39 (1H, d), 7.02 (1H, d), 6.51 (1H, d), 6.43 (1H, dd), 4.72 (2H, s), 4.27 (2H, t), 3.81 (3H, s), 3.76 (3H, s), 3.68 (4H, t), 2.61 (2H, t), 2.50 (4H, m), 2.05 (2H, qn). MS: [M+H]+ 441.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][CH2:11][C@H:12]([OH:24])[CH2:13][N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:9])[CH:3]=1.[O:25]1[CH2:28][CH:27]([NH2:29])[CH2:26]1.CCN(C(C)C)C(C)C>CC(O)C>[CH2:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][CH2:23][N:14]1[CH2:13][C@@H:12]([OH:24])[CH2:11][NH:10][C:8]([C:4]1[CH:3]=[C:2]([NH:29][CH:27]2[CH2:28][O:25][CH2:26]2)[N:7]=[CH:6][N:5]=1)=[O:9]
Reactant: NC1COC1
Reactant: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1cc(Cl)ncn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=C(NC[C@H](O)CN1CCc2ccccc2C1)c1cc(NC2COC2)ncn1
Temperature: 110 °C
Reaction time: 16 h
Yield: 16.3 %

Procedure:
To a solution of (S)-6-chloro-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxy propyl)pyrimidine-4-carboxamide (347 mg, 1 mmol) in i-PrOH (5 mL) was added oxetan-3-amine (73.1 mg, 1 mmol) and DIPEA (129 mg, 1 mmol). The resulting mixture was stirred at 110° C. for 16 hours, at which time LCMS showed the completion of the reaction. After evaporation of the solvent, the residue was purified by preparative HPLC to give the target compound (S)—N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-6-(oxetan-3-ylamino)pyrimidine-4-carboxamide (62.5 mg, yield: 16.3%). 1H NMR (400 MHz, MeOD-d4) δ 8.24 (s, 1H), 7.15-7.05 (m, 4H), 7.02-6.98 (m, 1H), 5.09 (s, 1H), 4.95 (t, J=6.8 Hz, 2H), 4.59 (t, J=6.3 Hz, 2H), 4.10-4.03 (m, 1H), 3.72 (s, 2H), 3.56-3.46 (m, 2H), 2.96-2.91 (m, 2H), 2.87-2.80 (m, 2H), 2.65 (d, J=6.3 Hz, 2H). LCMS (m/z): 384.1 [M+H]+.