Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:15])[CH:5]=[N:6][CH:7]=1.[C:16]1([CH2:22][CH2:23][CH2:24][C:25]#[CH:26])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:16]1([CH2:22][CH2:23][CH2:24][C:25]#[C:26][C:2]2[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]3[CH2:14][CH2:13][CH2:12][N:11]3[CH3:15])[CH:5]=[N:6][CH:7]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: C#CCCCc1ccccc1
Reactant: CN1CCC[C@H]1COc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CN1CCC[C@H]1COc1cncc(C#CCCCc2ccccc2)c1
Temperature: 25 °C
Yield: 81.9 %

Procedure:
To a solution of 5-bromo-3-(1-methyl-2-(S)-pyrrolidinylmethoxy)-pyridine (408 mg, 1.50 mmol), bis(triphenylphosphine)palladium(II) chloride (21 mg, 0.029 mmol) and copper (I) iodide (5 mg, 0.029 mmol) in CH2Cl2 (3.0 mL) and NEt3 (1.0 mL) was added 5-phenyl-1-pentyne (324 mg, 2.25 mmol). The mixture was refluxed overnight then cooled to room temperature. Water (2 mL) was added, and solid sodium bicarbonate was added until the aqueous layer was saturated. The mixture was extracted with EtOAc, which was dried over MgSO4, filtered and concentrated. The residue was chromatographed on a silica gel column, eluting with NH4OH/MeOH/EtOAc 0:1:9 and 1:10:90 to afford an oil (411 mg, 80%). MS (CI/NH3) m/z 335 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.65-2.10 (m, 6H), 2.26-2.37 (m, 1H), 2.41-2.47 (m, 2H), 2.48 (s, 3H), 2.61-2.73 (m, 1H), 2.76-2.83 (m, 2H), 3.07-3.16 (m, 1H), 3.89-4.03 (m, 2H), 7.17-7.36 (m, 6H), 8.21-8.26 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])C=O.CO[CH:17]([O:20][CH3:21])[O:18][CH3:19].C[O-].[Na+]>CO.Cl>[CH3:21][O:20][CH:17]([O:18][CH3:19])[C:5]1[CH:8]=[C:9]([O:13][CH3:14])[C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COC(OC)OC
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(OC)OC)cc(OC)c1OC
Yield: 100.3 %

Procedure:
A mixture of 196.2 g of 3,4,5-trimethoxybenzaldehyde, 127.3 g of trimethoxymethane, 200 ml of methanol and 0.1 g of hydrochloric acid is refluxed for 3 hours. After cooling the reaction mixture, 0.2 g of a 24% sodium methoxide solution in methanol is added thereto and the mixture is evaporated under reduced pressure to remove solvent. 150 ml of tetrahydrofuran are added to the residue, and the mixture is evaporated under reduced pressure to remove solvent. 243 g of 3,4,5-trimethoxybenzaldehyde dimethyl acetal are thereby obtained as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[N+:14]([O-])[CH:15]=[CH:16][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)(Br)=O.C(=O)(O)[O-].[Na+].BrC1C=CC(CCCOCC2C=CC=CC=2)=CN=1.BrC1C(CCCOCC2C=CC=CC=2)=CC=CN=1.[CH2:65]([N:67]1[CH2:72][CH2:71][N:70]([C:73]2[C:82]3[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=3)[CH:76]=[C:75](Br)[N:74]=2)[CH2:69][CH2:68]1)[CH3:66]>C(Cl)Cl.O>[CH2:65]([N:67]1[CH2:68][CH2:69][N:70]([C:73]2[C:82]3[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=3)[CH:76]=[C:75]([C:15]3[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:13][N:14]=3)[N:74]=2)[CH2:71][CH2:72]1)[CH3:66]
Reactant: CCN1CCN(c2nc(Br)cc3ccccc23)CC1
Reactant: [O-][n+]1cccc(CCCOCc2ccccc2)c1
Agent: Brc1ccc(CCCOCc2ccccc2)cn1
Agent: Brc1ncccc1CCCOCc1ccccc1
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: CCN1CCN(c2nc(-c3ccc(CCCOCc4ccccc4)cn3)cc3ccccc23)CC1
Reaction time: 2 h
Yield: 33.8 %

Procedure:
3-(3-Benzyloxypropyl)pyridine N-oxide (4.546 g) was dissolved in methylene chloride, phosphorus oxybromide (11.47 g) was added thereto under ice-cooling, and the mixture was stirred for 2 hr. Then, it was further stirred at room temperature for 2 hr. The reaction mixture was poured into warm water, and then it was neutralized by adding sodium bicarbonate thereto. The mixture was extracted with ethyl acetate. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give a mixture of 2-bromo-5-(3-benzyloxypropyl)pyridine and 2-bromo-3-(3-benzyloxypropyl)pyridine (1:1) as a brown oil (2.203 g). The resulting mixture (1.111 g) and 1-(1-ethylpiperazin-4-yl)-3-bromoisoquinoline (662 mg) were treated in the same manner as in Example 167-2, to give the title compound as a yellow oil (326 mg, yield; 33%).
Reaction SMILES: C([SiH2]C1C=CC=CC=1)CCC.C([C:20]1(CCCCCCCC)[C:32]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)CCCCCCC.[B].BrC1C=CC2C3C(=CC(Br)=CC=3)C(CCCCCCCC)(CCCCCCCC)C=2C=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.O.C1COCC1>[CH:22]1[C:21]2[CH2:20][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: CCCC[SiH2]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)Cc1ccccc1-2
Temperature: 60 °C
Reaction time: 48 h

Procedure:
Under a nitrogen gas atmosphere, 289 mg (0.235 mmol) of butylphenylsilane (compound 14), 750 mg (1.17 mmol) of 9,9-dioctylfluorene with boron structures introduced onto the 2 and 7 positions, 515 mg (0.935 mmol) of 2,7-dibromo-9,9-dioctylfluorene, 2.22 g (16.1 mmol) of potassium carbonate, 15 ml of THF and 8 ml of distilled water were added to a 100 ml three-necked flask equipped with a reflux condenser, and this mixture was heated to 60° C. After the dissolution of the substrate was confirmed, one full spatula of tetrakis(triphenylphosphine)palladium was added, and the mixture was heated and agitated for approximately 48 hours. When toluene was added following cooling and the solvent was distilled away as far as possible, a high-viscosity substance was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([F:24])[CH:23]=3)[N:16]=[C:15]([C:25]([OH:27])=O)[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([F:24])[CH:23]=3)[N:16]=[C:15]([C:25]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=[O:27])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:10])([F:12])[F:11])[CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cncc(F)c2)n1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: O=C1CN(C(=O)c2cc(-c3cc(Br)cc(OC(F)(F)F)c3)n(-c3cncc(F)c3)n2)CN1

Procedure:
75 mg (0.17 mmol) of the compound of Example 44A is reacted analogously to the synthesis of the compound of Example 1 with 23 mg (0.19 mmol) of 4-imidazolinone-hydrochloride. 71 mg (82% of theory) of the title compound is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1)=[O:10].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=2)=[O:10])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cccc(C(=O)c2cc(Cl)ccc2N)n1
Product: Cc1cccc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(6-methyl-pyridin-2-yl)-methanone and 4-tert-Butyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR: δ 1.29 (s, 9H), 2.94 (s, 3 H), 7.42-7.46 (m, 3H), 7.51 (d, J=8.8 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.62 (d, J=7.2 Hz, 1 H), 7.66 (d, J=6.8 Hz, 1H), 7.74 (d, J=8.0 Hz, 1 H), 8.1 (bs, 1H). MS: M/z 443.1 (M++1).
Reaction SMILES: CO[C:3]([C:5]1[NH:6][S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[NH2:22][C:23]1[S:24][C:25]([CH3:29])=[C:26]([CH3:28])[N:27]=1>C1(C)C(C)=CC=CC=1>[CH3:28][C:26]1[N:27]=[C:23]([NH:22][C:3]([C:5]2[NH:6][S:7](=[O:20])(=[O:21])[C:8]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][C:9]=3[C:10]=2[OH:11])=[O:4])[S:24][C:25]=1[CH3:29]
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Reactant: Cc1nc(N)sc1C
Solvent: Cc1ccccc1C
Product: Cc1nc(NC(=O)C2=C(O)c3ccc4ccccc4c3S(=O)(=O)N2)sc1C
Yield: 35 %

Procedure:
N-(4,5-Dimethyl-2-thiazolyl)-4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was prepared analogous to Example 37 from 4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide and 2-amino-4,5-dimethyl-thiazole. Yield: 35% of theory;m.p. 253° C (decomp.; from xylene).
Reaction SMILES: [CH2:1]([C:4]1[C:8](=[O:9])[CH2:7][CH:6]([OH:10])[CH:5]=1)[CH:2]=[CH2:3].N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[Si:16]([O:10][CH:6]1[CH2:7][C:8](=[O:9])[C:4]([CH2:1][CH:2]=[CH2:3])=[CH:5]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: C=CCC1=CC(O)CC1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=CCC1=CC(O[Si](C)(C)C(C)(C)C)CC1=O
Yield: 81 %

Procedure:
To a solution mixture of 8.8 g of (RS)-3-allyl-4-oxo-2-cyclopenten-1-ol, 100 ml of N,N-dimethylformamide and 4.75 g of imidazole was added t-butyldimethylsilyl chloride under ice-cooling, and the resulting mixture was stirred under ice-cooling for 8 hours. Then the reaction liquid was poured into ice-cooled 5% aqueous solution of citric acid and extracted two times with diethyl ether. The combined ether layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography to obtain 13.1 g of (RS)-3-allyl-4-oxo-2-cyclopenten-1-yl (t-butyldimethylsilyl) ether. Yield 81%
Reaction SMILES: [O:1]([C:8]1[C:17]([NH2:18])=[C:16]([NH:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=[CH:34][CH:33]=1.C(Cl)(=O)C>C(OCC)(=O)C>[CH3:33][C:34]1[N:19]([CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[C:16]2[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[N:9]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:17]=2[N:18]=1
Reactant: c1ccncc1
Reactant: Nc1c(Oc2ccccc2)nc2c(c1NCCOCCCc1cccnc1)CCCC2
Solvent: CCOC(C)=O
Solvent: CC(=O)Cl
Product: Cc1nc2c(Oc3ccccc3)nc3c(c2n1CCOCCCc1cccnc1)CCCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A 200 ml round bottom flask was charged with 2-phenoxy-N4-[2-(3-pyridin-3-ylpropoxy)ethyl]-5,6,7,8-tetrahydroquinoline-3,4-diamine (4.1 g, 0.0098 mol.) and pyridine (40 mL) at room temperature. To this solution was slowly added acetyl chloride (0.8 g, 0.011 mol., 1.1 equivalents). The reaction was maintained with stirring at room temperature. After two hours the reaction was monitored and found to only contain the amide intermediate. The reaction mixture was then heated to reflux and maintained overnight. The reaction mixture was concentrated to provide a dark amber syrup. The syrup was taken up in ethyl acetate (300 mL) and washed with water (2×100 mL). The ethyl acetate layer was concentrated to provide 2-methyl-4-phenoxy-1-[2-(3-pyridin-3-ylpropoxy)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline as an orange syrup (3.8 g, 88%). TLC (10%MeOH/CH2Cl2, Rf=0.34). Mass-spec M+1=443.2
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12](OCC)=[O:13])=[C:10]([CH2:17][N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:27])=[C:7]([O:25][CH3:26])[CH:8]=2)[N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(Cl)Cl>[Cl:1][C:2]1[C:11]([CH2:12][OH:13])=[C:10]([CH2:17][N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[C:9]2[C:4](=[CH:5][C:6]([Cl:27])=[C:7]([O:25][CH3:26])[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)c1c(Cl)nc2cc(Cl)c(OC)cc2c1CN1CCN(C)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Product: COc1cc2c(CN3CCN(C)CC3)c(CO)c(Cl)nc2cc1Cl
Reaction time: 1 h
Yield: 80.1 %

Procedure:
ethyl 2,7-dichloro-6-methoxy-4-[(4-methyl-1-piperazinyl)methyl]-3-quinolinecarboxylate (6 g, 14.5 mmol) is dissolved in methylene chloride (120 ml). A molar solution of diisobutylaluminium hydride in methylene chloride (60 ml, 60 mmol) is added slowly. Agitation is carried out for one hour at ambient temperature. The reaction mass is slowly poured into 300 ml of a 20% solution of Rochelle salt. Agitation is carried out for one hour, followed by filtering on celite and decanting; the organic phase is washed with a saturated solution of sodium chloride, dried over magnesium sulphate, filtered and evaporated under reduced pressure. The solid is taken up in isopropyl ether, filtered and dried under vacuum. 4.3 g of sought product (80%) is obtained, in the form of a yellow solid.
Reaction SMILES: O=[CH:2][C@@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4].[Cl-].[NH4+:12].N>CO>[CH:9]1([NH2:12])[O:10][CH2:2][C@@H:3]([OH:4])[C@@H:5]([OH:6])[C@H:7]1[OH:8]
Reactant: [NH4+]
Reactant: O=C[C@H](O)[C@H](O)[C@H](O)CO
Agent: N
Agent: [Cl-]
Solvent: CO
Product: NC1OC[C@@H](O)[C@@H](O)[C@H]1O
Reaction time: 312 h
Yield: 932.5 %

Procedure:
To 100 ml of methanol was added 20 g of D-ribose and 0.5 g of ammonium chloride. This mixture was treated with anhydrous ammonia at 0° C. until a solution was obtained. This solution was stored at 0° C. for 13 days, then the solid was collected, giving 13 g of D-ribopyranosylamine.
Reaction SMILES: C[O:2][C:3](=O)[C:4](=[O:29])[N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10](=[O:28])[CH:11]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:31][C:32]([Mg]Cl)([CH3:35])[CH2:33][CH3:34].[Cl-].[NH4+]>C1COCC1>[CH3:31][C:32]([CH3:35])([CH2:33][CH3:34])[C:3](=[O:2])[C:4]([N:5]1[CH2:9][CH2:8][CH2:7][CH:6]1[C:10](=[O:28])[CH:11]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:29]
Reactant: COC(=O)C(=O)N1CCCC1C(=O)C(CCc1ccccc1)CCc1ccccc1
Reactant: CCC(C)(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(C)(C)C(=O)C(=O)N1CCCC1C(=O)C(CCc1ccccc1)CCc1ccccc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 69.5 %

Procedure:
To a solution of 0.18 g (0.45 mmol) of 12a in anhydrous THF (2 mL) was added dropwise at −78° C. a 1.0M solution of 2.2 mL (2.20 mmol) of 1,1-dimethylpropyl magnesium chloride in THF, and the mixture was stirred for 3 hours at −78° C. The solution was poured over saturated ammonium chloride (50 mL) and extracted with EtOAc (3×100 mL). The organic phase was dried (MgSO4) and evaporated to a clear oil which was subject to column chromatography (EtOAc/Hexanes, 1:3) to yield 0.14 g (76.5%) of 13a as a clear oil. TLC Rf=0.5 (EtOAc/Hexanes, 1:3) 1H NMR (CDCl3, 400 MHz): δ 0.82–0.90 (m, 3H); 1.12–1.33 (m, 6H); 1.59–1.79 (m, 7H); 2.00–2.20 (m, 3H); 2.40–2.70 (t, 5H); 3.41–3.52 (m, 2H); 4.63–4.64 (m, 1H); 7.12–7.29 (m, 10H); Anal. (C29H37NO3) C, H, N.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][CH2:22][CH2:23][OH:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:21][CH2:22][CH2:23][OH:24])[CH:12]=2)[S:6]1(=[O:18])=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCCCBr
Reactant: CC(C)(C)N1C(=O)C=C(c2cccc(O)c2)S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C=C(c2cccc(OCCCO)c2)S1(=O)=O
Yield: 88.4 %

Procedure:
A solution of 4.08-B (0.2 g, 0.7 mmol), 3-bromo-1-propanol (0.1 mL, 1.1 mmol), and potassium carbonate (147 mg, 1.1 mmol) in N,N-dimethylformamide (3 mL) was heated at 80° C. for 1 h. The reaction mixture was diluted with ethyl acetate (75 mL) and washed with 0.5 N HCl (50 mL) and brine (50 mL), dried with Na2SO4, filtered, and concentrated to give a crude residue which was purified using flash column chromatography (100% hexane to 50% ethyl acetate/hexane) to yield 4.08-C as a white solid (0.21 g, 88%). 1H NMR (500 MHz, CDCl3): δ 7.42 (dd, J=7.8, 7.8 Hz, 1H), 7.36–7.34 (m, 1H), 7.30 (dd, J=2.0, 2.0 Hz, 1H), 7.11–7.09 (m, 1H), 6.63 (s, 1H), 4.18–4.12 (m, 2H), 3.90–3.86 (m, 2H), 2.10–2.05 (m, 2H), 1.73 (s, 9H); LCMS found for C16H22NO5S (M+H)+: m/z=340.
Reaction SMILES: FC(F)(F)C(O)=O.N[C@H]1C[C@@H](N2C=NC3C2=NC(Cl)=NC=3NCC(C2C=CC=CC=2)C2C=CC=CC=2)[C@H](O)[C@@H]1O.ClC1N=C2C(N=CN2C2CC(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)C(O)C2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1.[Cl:88][C:89]1[N:97]=[C:96]2[C:92]([N:93]=[CH:94][N:95]2[C@@H:98]2[CH2:102][C@H:101]([N:103](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C@@H:100]([OH:118])[C@H:99]2[OH:119])=[C:91]([NH:120][C@H:121]([CH2:129][OH:130])[CH2:122][C:123]2[CH:128]=[CH:127][CH:126]=[CH:125][CH:124]=2)[N:90]=1>>[NH2:103][C@H:101]1[CH2:102][C@@H:98]([N:95]2[CH:94]=[N:93][C:92]3[C:96]2=[N:97][C:89]([Cl:88])=[N:90][C:91]=3[NH:120][C@H:121]([CH2:129][OH:130])[CH2:122][C:123]2[CH:128]=[CH:127][CH:126]=[CH:125][CH:124]=2)[C@H:99]([OH:119])[C@@H:100]1[OH:118]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Agent: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1CC(n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)C(O)C1O
Agent: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
(1S,2R,3S,5R)-3-Amino-5-[2-chloro-6-((S)-1-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-cyclopentane-1,2-diol is prepared analogously to (1S,2R,3S,5R)-3-amino-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopentane-1,2-diol trifluoroacetate (Step AAI3) by replacing 1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(di-Boc-amino)-cyclopentane-1,2-diol (Step AAI2) with (1R,2S,3R,5S)-3-[2-chloro-6-((S)-1-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(di-Boc-amino)-cyclopentane-1,2-diol (Step TA2).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]([CH3:13])[C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.Cl.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1>C(O)CCC>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[C:8](=[O:10])[C:7]3=[CH:6][NH:5][C:4]([CH3:13])=[C:3]([C:14]4[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=4)[C:2]3=[N:32]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(NN)cc1
Reactant: CCOC(=O)c1cnc(C)c(-c2ccc(OC)cc2)c1Cl
Agent: Cl
Solvent: CCCCO
Product: COc1ccc(-c2c3nn(-c4ccc(OC)cc4)c(=O)c-3c[nH]c2C)cc1
Yield: 20.9 %

Procedure:
A mixture of ethyl 4-chloro-3-(4-methoxyphenyl)-2-methyl-5-pyridinecarboxylate (0.1842 g, 0.602 mmol) and 4-methoxyphenylhydrazine hydrochloride (0.1000 g, 0.724 mmol) in anhydrous 1-butanol (7 ml) was degassed by evaporating the flask under vacuum and refilling with nitrogen several times. The mixture was then stirred at reflux under nitrogen for 32 h, during which time more 4-methoxyphenylhydrazine hydrochloride (0.1001 g, 0.724 mmol) was added. The solvent was removed in vacuo and the residue was purified by flash chromatography (silica gel, 3-7% MeOH/CH2Cl2) to give 45.5 mg (21%) of the title compound as a yellow solid; mp 274-282° C. (CH2Cl2-MeOH-EtOAc); 1H NMR (360 MHz, DMSO-d6) δ2.40 (3H, s), 3.88 (3H, s), 3.96 (3H, s), 7.08 (2H, d, J 9.2 Hz), 7.19 (2H, d, J 8.7 Hz), 7.59 (2H, d, J 8.7 Hz), 8.11 (2H, d, J 9.1 Hz), 8.61 (1H, s), 12.43 (1H, br s); MS (ES+) m/z 362 MH]+. Anal. found: C, 69.95; H, 5.02; N, 11.60. C21H19N3O3 requires: C, 69.79; H, 5.30; N, 11.63%.
Reaction SMILES: CO[C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([F:18])[CH:12]=2)[CH:7]=[N:6][CH:5]=1.[CH3:20][NH2:21]>CO>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][C:8]2[CH:7]=[N:6][CH:5]=[C:4]([CH:9]=2)[C:3]([NH:21][CH3:20])=[O:19])=[CH:12][C:13]=1[F:18]
Reactant: CN
Reactant: COC(=O)c1cncc(Oc2ccc(N)c(F)c2)c1
Solvent: CO
Product: CNC(=O)c1cncc(Oc2ccc(N)c(F)c2)c1
Temperature: 40 °C
Yield: 80.2 %

Procedure:
To a solution of 5-(4-amino-3-fluorophenoxy)nicotinic acid methyl ester (0.50 g, 1.91 mmol) in MeOH (2 mL) was added methylamine (0.63 g, 19.1 mmol, 2.0 M in MeOH). The reaction flask was sealed and heated at 40° C. for 4 h. Solvent was removed under reduced pressure, and the crude product was purified by column chromatography eluted with 5% MeOH/CH2Cl2 to give the 0.4 g (80%) of the title compound. 1H-NMR (DMSO-d6) δ 8.65 (d, J=1.8 Hz, 1H), 8.62 to 8.60 (m, 1H), 7.54 to 7.52 (m, 1H), 6.94 (dd, J=2.7, 12.0 Hz, 1H), 6.81 to 6.67 (m, 3H), 5.10 (s, 2H), 2.72 (d, J=2.4 Hz, 3H); MS LC-MS [M+H]+=262.2, RT=0.27 min.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH2:13]([OH:18])[C:14]([CH3:17])([CH3:16])[CH3:15].[H-].[Na+].Cl>CN(C)C=O>[CH2:13]([O:18][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11])[C:14]([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)CO
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)COc1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 90.3 %

Procedure:
1.83 g of 4-Chloro-3-nitrobenzonitrile and 1.06 g of neopentyl alcohol were dissolved in 10 ml of N,N-dimethylformamide. The solution was cooled to 0° C., and 480 mg of sodium hydride (60% in oil) was gradually added thereto. Then, 30 min after the addition, 13 ml of 1N hydrochloric acid was added to the mixture, and the precipitated crystal was collected by filtration to give 2.12 g of 4-neopentyloxy-3-nitrobenzonitrile. 1.2 g of thioacetamide was added thereto, and the mixture was heated at 80° C. for an hour in N,N-dimethylformamide saturated with hydrochloric acid. After the completion of the reaction, the reaction mixture was neutralized with 30 ml of water and 18 ml of 2N sodium hydroxide, and the lower layer was separated and dried. The lower layer was dissolved in 30 ml of ethanol, 2.11 g of ethyl 2-chloroacetoacetate was added thereto, and the mixture was heated under reflux for 5 hours. After the reaction mixture was cooled, the precipitated crystal was collected by filtration and recrystallized from ethanol to give 2.38 g of ethyl 4-methyl-2-(4-neopentyloxy-3-nitrophenyl)-5-thiazolecarboxylate (yield: 63%). This product was hydrolyzed by a conventional process, and the resulting crystal was recrystallized from a 80% aqueous ethanol solution to give 1.98 g of 2-(4-neopentyloxy-3-nitrophenyl)-4-methyl-5-thiazolecarboxylic acid (yield: