Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])=[N:10][NH:11][CH:12]=2)=[CH:6][CH:7]=1.[NH2:21][NH2:22].[CH:23](=O)[CH2:24][CH:25]([CH3:27])[CH3:26]>>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C:9]1[C:8]([C:5]2[N:4]=[N:3][C:2]([NH:21][NH2:22])=[CH:7][CH:6]=2)=[CH:12][NH:11][N:10]=1.[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([C:23]([CH2:24][CH:25]([CH3:27])[CH3:26])=[N:21][N:22]=3)[N:4]=2)=[CH:12][NH:11][N:10]=1
Reactant: CC(C)CC=O
Reactant: Fc1ccc(-c2n[nH]cc2-c2ccc(Cl)nn2)c(F)c1
Reactant: NN
Product: CC(C)Cc1nnc2ccc(-c3c[nH]nc3-c3ccc(F)cc3F)nn12
Product: NNc1ccc(-c2c[nH]nc2-c2ccc(F)cc2F)nn1
Yield: 8 %

Procedure:
3-(3-(2,4-Difluorophenyl)-1H-pyrazol-4-yl)-6-hydrazinylpyridazine was prepared from 3-chloro-6-(3-(2,4-difluorophenyl)-1H-pyrazol-4-yl)pyridazine (0.26 g, 0.90 mmol) and hydrazine according to General Procedure D and then immediately cyclized with isovaleraldehyde according to General Procedure E to give the title compound (0.028 g, 8%) after purification by RP-HPLC (Table 1, Method d): LC/MS (Table 1, Method a) Rt=2.03 min; MS m/z: 355.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7](OC)([O:10]C)[CH2:8][F:9])=[CH:5][CH:6]=1.Cl.CCCCCC>CC#N.C(Cl)Cl>[Br:1][C:2]1[S:3][C:4]([C:7](=[O:10])[CH2:8][F:9])=[CH:5][CH:6]=1
Reactant: COC(CF)(OC)c1ccc(Br)s1
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CC#N
Product: O=C(CF)c1ccc(Br)s1
Reaction time: 3 h
Yield: 83.5 %

Procedure:
To a stirred solution of 2-bromo-5-(2-fluoro-1,1-dimethoxy-ethyl)-thiophene (9.4 g, 35 mmol) in MeCN (100 mL) was added 10% aq. HCl (50 mL) at 20° C. and the reaction mixture was stirred at ° C. for 3 h. Solvent was removed in vacuo to afford a residue, which was partitioned between DCM and water, the aqueous layer was extracted with DCM. The combined organic layers were washed with water, sat aq. NaHCO3 and brine, dried over sodium sulfate and evaporated in vacuo to give a white solid. It was dissolved in minimum volume of DCM, and a large volume of hexane was added. After evaporation of most of the solvent, solid precipitated and was then collected with filtration, washed with hexane and dried under high vacuum to afford 1-(5-bromo-thiophen-2-yl)-2-fluoro-ethanone (6.52 g, 84%). 1H-NMR (CDCl3): δ 7.64 (d, 1H), 7.15 (d, 1H), 5.26 (d, 2H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:7][O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][N:14]2[N:18]=[N:17][C:16]([C:19]3[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=3)=[N:15]2)=[CH:11][CH:10]=1.[CH2:28]([O:30][C:31]([C:33]1[C:34]2[S:42][CH:41]=[C:40]([CH2:43]Br)[C:35]=2[C:36]([Cl:39])=[N:37][CH:38]=1)=[O:32])[CH3:29]>O1CCCC1.CN(C)C=O>[CH2:28]([O:30][C:31]([C:33]1[C:34]2[S:42][CH:41]=[C:40]([CH2:43][O:25][C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([C:16]4[N:17]=[N:18][N:14]([CH2:13][C:12]5[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:27][CH:26]=5)[N:15]=4)[CH:20]=3)[C:35]=2[C:36]([Cl:39])=[N:37][CH:38]=1)=[O:32])[CH3:29]
Reactant: CCOC(=O)c1cnc(Cl)c2c(CBr)csc12
Reactant: COc1ccc(Cn2nnc(-c3cccc(O)c3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(Cl)c2c(COc3cccc(-c4nnn(Cc5ccc(OC)cc5)n4)c3)csc12
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A suspension of cesium carbonate (0.60 g, 1.83 mmol), 3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-phenol (0.38 g, 1.35 mmol) (from Example 26 supra) in tetrahydrofuran-N,N-dimethylformamide (5:2, 17.5 mL) was heated at 70° C. for 3 hours. 3-Bromomethyl-4-chloro-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.41 g, 1.22 mmol) (from Example 1 supra) was added. Heating was continued for 18 hours. The reaction mixture was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phase washed with water and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography eluting with 30% ethyl acetate in hexanes to give 4-chloro-3-{3-[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl]-phenoxymethyl}-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester. (Yield 0.17 g, 26%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=[O:19])[CH3:18])[C:3]=1[O:20][CH2:21][CH3:22].[CH:23]([N-]C(C)C)(C)C.[Li+]>C1COCC1>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=[O:19])[CH2:18][CH3:23])[C:3]=1[O:20][CH2:21][CH3:22]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOc1c(C(C)=O)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOc1c(C(=O)CC)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Temperature: -78 °C
Reaction time: 2.5 h

Procedure:
To a solution of 1-(4-bromo-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-109, 1.75 g, 4.81 mmol) in THF (33 mL) at −78° C. was added lithium diisopropylamide (1.5 M in cyclohexane, 3.85 mL, 5.78 mmol). The bath was removed and the mixture was stirred for 2.5 h. The mixture was cooled to −78° C. again and methyl iodide was added. The mixture was stirred at room temperature for 16 h, quenched with saturated ammonium chloride, and extracted with diethyl ether. The combined ethereal layers were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 2% ethyl acetate in hexanes) followed by HPLC (normal phase, 2% ethyl acetate in hexanes) to give the title compound as clear oil.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH:14]1([CH2:17][NH2:18])[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][NH:18][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[C:10]([F:13])([F:12])[F:11])[CH2:16][CH2:15]1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Reactant: NCC1CC1
Product: N#Cc1ccc(NCC2CC2)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 1A from 4-fluoro-3-(trifluoromethyl)benzonitrile and (cyclopropylmethyl)amine: MS (APCI) m/z 241 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH2:18]([C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1)[CH3:19]>CN1CCCC1=O.O>[CH2:18]([C:20]1[N:21]=[CH:22][C:23]([CH2:26][CH2:27][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:24][CH:25]=1)[CH3:19]
Reactant: C=Cc1ccc(CC)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1ccc(CCn2c3c(c4cc(C)ccc42)CN(C)CC3)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 18 %

Procedure:
To a solution of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.15 g. 0.749 mmol) in N-methyl 2-pyrolidone (1.2 mL) was added powdered potassium hydroxide (0.42 g, 7.49 mmol) and allowed to stir for 10 min at RT. 2-Ethyl-5-vinyl-pyridine (0.299 g, 2.24 mmol) was added and stirred for further 18 h. at 100 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (7% McOH:DCM in silica 100-200 mesh, Diameter of column 2.5 cm, Height of silica—approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.045 g, 18% yield). 5-[2-(6-Ethyl-pyridin-3-yl)-ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.040 g, 0.12 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.012 g, 0.096 mol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.030 g, 60% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][CH2:7][CH2:8][N:9]([CH2:10][CH2:11][N:12]([CH3:20])[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:4]=2[CH:3]=1.I.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29](SC)=[NH:30]>>[CH3:20][N:12]([CH2:11][CH2:10][N:9]1[CH2:8][CH2:7][O:6][C:5]2[CH:21]=[CH:22][C:2]([NH:1][C:29]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)=[NH:30])=[CH:3][C:4]1=2)[C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:18])[CH3:16]
Reactant: CSC(=N)c1cccs1
Reactant: CN(CCN1CCOc2ccc(N)cc21)C(=O)OC(C)(C)C
Agent: I
Product: CN(CCN1CCOc2ccc(NC(=N)c3cccs3)cc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 44 h
Yield: 50 %

Procedure:
To a stirred ethanolic solution of tert-butyl 2-(6-amino-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethyl(methyl)carbamate (0.118 g, 0.384 mmol) under an argon atmosphere was charged methyl thiophene-2-carbimidothioate hydroiodide (0.219 g, 0.768 mmol), and the resulting yellow solution stirred at room temperature. After 44 hours, argon was bubbled through the mixture, which was then concentrated to residue and partitioned between EtOAc (100 mL) and saturated NaHCO3 solution (10 mL). The aqueous layer (pH˜9) was further extracted with EtOAc, and the combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated to yield an orange residue. The residue was purified on silica gel twice, with the first purification using 100% EtOAc as the eluent and the second purification using 5% (2M NH3 in MeOH)/CH2Cl2 to yield the title compound as a yellow solid (80 mg, 50.0%). 1H NMR (DMSO-d6) δ 7.68 (d, 1H, J=2.9 Hz), 7.57 (d, 1H, J=5.0 Hz), 7.10-7.03 (m, 1H), 6.60 (d, 1H, J=8.1 Hz), 6.30 (m, 3H), 6.00 (dd, 1H, J=8.1, 1.6 Hz), 4.18-4.02 (m, 2H), 3.40-3.21 (m, 6H, merged with H2O peak), 2.81 (s, 3H), 1.34, 1.29 (2×s, 9H); ESI-MS (m/z, %): 417 (MH+, 100).
Reaction SMILES: [H-].[Na+].C[C:4](P(OC)(O)=O)([C:6]([O-:8])=[O:7])C.[C:14]([O:18][C:19]([NH:21][CH:22]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[CH:40]=O)=[CH:29][CH:28]=1)[C:23]([OH:25])=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].[CH3:42]CCCCC>C1COCC1>[CH3:42][O:8][C:6](=[O:7])[CH:4]=[CH:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[O:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH:22]([NH:21][C:19]([O:18][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:20])[C:23]([OH:25])=[O:24])=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccccc2C=O)cc1)C(=O)O
Reactant: COP(=O)(O)C(C)(C)C(=O)[O-]
Reactant: CCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C=Cc1ccccc1Oc1ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 2.5 °C
Reaction time: 0.08 h
Yield: 98 %

Procedure:
Sodium hydride (60% in mineral oil, 0.57 g, 14.278 mmol) was washed with anhydrous hexane (3×30 mL) under an atmosphere of argon. Dry THF (50 mL) was added and cooled to 0-5° C. A solution of trimethylphosphonoacetate (1.30 mL, 7.139 mmol) in dry THF (8.0 mL) was added dropwise to the above mixture with stirring. After about 5 min, a solution of the aldehyde 58 (2.5 g, 6.486 mmol) in dry THF (20 mL) was added and the reaction mixture was then brought up to room temperature and stirred. After 30 min, the clear reaction mixture was quenched with 10% citric acid (50 mL) and further acidified to pH ˜2.0 with 2.0 M HCl. The THF was evaporated under reduced pressure and the resulting oily material was extracted with EtOAc (2×200 mL). The organic layer was extracted with water (3×200 mL), and brine (1×200 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to yield the unsaturated ester 59 (2.7 g, 98.0%). 1H NMR (400 MHz, DMSO-d6): 12.62 (s, 1H), 7.91 (dd, J=7.6 and 1.6 Hz, 1H) 7.85 (d, J=16.4 Hz, 1H), 7.42 (dt, J=8.4 and 1.2 Hz, 1H), 7.28 (d, J=13.6, 2H), 7.17 (t, 8.0 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H) 6.93 (d, J=2.8 Hz, 2H), 6.84 (d, J=8.4 Hz, 1H), 6.65 (d, J=16.4 Hz, 1H), 4.08 (m, 1H), 3.68 (s, 3H), 3.03 (dd, J=13.6 and 4.4 Hz, 1H), 2.80 (dd, J=13.6 and 10.0 Hz, 1H), 1.32 (s, 9H).
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][C:43]([CH:46]5[CH2:51][CH2:50][C:49]([F:53])([F:52])[CH2:48][CH2:47]5)=[CH:42][CH:41]=4)[C:38]([CH3:54])=[C:37]([OH:55])[C:36]3=[O:56])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:41]=[CH:42][C:43]([CH:46]5[CH2:51][CH2:50][C:49]([F:53])([F:52])[CH2:48][CH2:47]5)=[CH:44][CH:45]=4)[C:38]([CH3:54])=[C:37]([O:55][CH3:3])[C:36]3=[O:56])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: CC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1c1ccc(C2CCC(F)(F)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: CO
Solvent: CCOCC
Product: COC1=C(C)C(c2ccc(C3CCC(F)(F)CC3)cc2)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (8 eq), ethylene glycol/Et2O (1/2.5 v/v, 28 ml), 1-(1H-Benzo[d]imidazol-6-yl)-5-(4-(4,4-difluorocyclohexyl)-phenyl)-3-hydroxy-4-methyl-1H-pyrrol-2(5H)-one (0.800 g, 1.88 mmol, 1 eq) and MeOH (10 ml); yield: 0.060 g (7.3%); MS m/z: 438.3 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 12.39 (s, 1H), 8.14 (d, 1H), 7.69 (d, 1H), 7.49 (d, 1H), 7.26-7.15 (m, 4H), 5.79 (s, 1H), 3.93 (s, 3H), 2.67-2.54 (m, 1H), 2.03-1.88 (m, 3H), 1.83-1.76 (m, 3H), 1.69 (s, 3H), 1.59-1.50 (m, 2H); HPLC (METHOD [A]): rt 14.64 min (95.14%)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[Cl:19][CH2:20][CH2:21][CH2:22][N:23]1[C:28](=[O:29])[C:27]([CH3:30])=[CH:26][N:25]([CH2:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:24]1=[O:38]>>[ClH:19].[CH:32]1([CH2:31][N:25]2[CH:26]=[C:27]([CH3:30])[C:28](=[O:29])[N:23]([CH2:22][CH2:21][CH2:20][N:14]3[CH2:15][CH2:16][N:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3][C:2]([F:1])([F:17])[F:18])[CH2:12][CH2:13]3)[C:24]2=[O:38])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: Cc1cn(CC2CCCCC2)c(=O)n(CCCCl)c1=O
Reactant: FC(F)(F)COc1ccccc1N1CCNCC1
Product: Cc1cn(CC2CCCCC2)c(=O)n(CCCN2CCN(c3ccccc3OCC(F)(F)F)CC2)c1=O
Product: Cl

Procedure:
substituting 1-[2-(2,2,2-trifluoroethoxy)phenyl]piperazine and 3-(3-chloropropyl)-1-cyclohexylmethyl-5-methyl-2,4(1H,3H)-pyrimidinedione gave 1-cyclohexylmethyl-3-(3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}propyl)-5-methyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 130°-132° C.; Anal.: Calcd. for C27H37F3N4O3.HCl: C, 57.99; H, 6.88; N, 10.02%; Found: C, 58.01; H, 6.80; N, 9.87%;
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][CH2:5][CH2:4]1.C(O)[C:9]1[O:13][CH:12]=[CH:11][CH:10]=1.C(Br)C#C>O.CN(C)C=O>[CH2:12]([O:13][CH2:9][C:4]1[O:3][CH:7]=[CH:6][CH:5]=1)[C:11]#[CH:10]
Reactant: C1CCOC1
Reactant: OCc1ccco1
Agent: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOCc1ccco1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a mixture of sodium hydride (7.7 g, 190 mmol, 60% in oil) and tetrahydrofuran (100 mL) was added dropwise furfuryl alcohol (15 mL, 170 mmol) at 0° C. The reaction mixture was warmed to room temperature, N,N-dimethylformamide (30 mL) was added at that temperature, and the mixture was stirred at that temperature for 30 minutes. The reaction mixture was returned to 0° C., propargyl bromide (23 g, 190 mmol) was added at that temperature, and the mixture was stirred for 1 hour at room temperature. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with brine, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:30) to give the title compound (7.6 g, 32% yield).
Reaction SMILES: [C:1]([OH:15])(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[C:20]([Cl:24])=[CH:19][C:18]=1O>C(Cl)Cl>[C:1]([O:15][C:18]1[CH:19]=[C:20]([Cl:24])[C:21]([Cl:23])=[CH:22][C:17]=1[Cl:16])(=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: CCCCCCCCCCCCC(=O)O
Solvent: ClCCl
Product: CCCCCCCCCCCCC(=O)Oc1cc(Cl)c(Cl)cc1Cl
Yield: 95.9 %

Procedure:
A solution of n-tridecanoic acid (Sigma Chemical Co.) (12.5 g.), 2,4,5-trichlorophenol (11.5 g.), and N,N-dicyclohexylcarbodiimide (12.0 g.) in methylene chloride (650 ml.) is stirred at room temperature for 16 hours. The reaction mixture is then filtered and dried in vacuo to give 2,4,5-trichlorophenyl n-tridecanoate (22 g.). The material is purified by column chromatography over silica gel (Woelm) using toluene as the eluent. Fractions are monitored by TLC using a shortwave UV light for detection. Fractions containing the purified product are pooled and concentrated in vacuo to dryness.
Reaction SMILES: [OH:1][C:2]1([C:15]#[C:16][CH2:17][OH:18])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.C(O)(=O)C.O>[Pd].C(O)C>[OH:1][C:2]1([CH2:15][CH2:16][CH2:17][OH:18])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(C#CCO)CC1
Agent: [Pd]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(O)(CCCO)CC1
Yield: 57 %

Procedure:
Palladium on carbon (5%, 800 mg) was added to a solution of 1,1-dimethylethyl 4-hydroxy-4-(3-hydroxypropynyl)-1-piperidinecarboxylate (from step (ii) above; 8.37 g, 32.8 mmol) in ethanol (400 ml), acetic acid (40 ml) and water (5 ml) and the mixture was shaken under an atmosphere of hydrogen (40 psi) for 20 hours. The mixture was filtered through Hyflo™ and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (50:50 increasing to 0:100), to give the title compound (4.84 g, 57%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[CH2:21]1[O:23][CH2:22]1.[C:24](O)(=[O:26])[CH3:25]>O>[OH:26][CH2:24][CH2:25][N:1]([CH2:22][CH2:21][OH:23])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CC(=O)O
Reactant: C1CO1
Reactant: CCCCCCCCOc1cc(C(=O)OC)ccc1N
Solvent: O
Product: CCCCCCCCOc1cc(C(=O)OC)ccc1N(CCO)CCO
Temperature: 25 °C
Reaction time: 12 h
Yield: 42 %

Procedure:
Methyl 4-amino-3-octoxybenzoate (3.47 g, 12.4 mmol) and ethylene oxide (4.5 g, 198 mol) were dissolved in 100 mL acetic acid to form a reaction mixture. The mixture was stirred at room temperature for 12 hours. It was then diluted with H2O (500 mL), extracted with chloroform/methanol (95/5, 4×100 mL). The organic extract was concentrated to brown oil. Flash chromatographic purification (silica gel, 5% to 10% methanol in chloroform) afforded the intermediate methyl 4-bis(2'-hydroxyethyl)amino-3-octoxybenzoate as an off-white oil (2.25 g, 42%). 1H NMR (300 MHz, CDCl3): 7.62 (dd, J=8.1, 2.1 Hz, 1H), 7.55 (d, J=2.1 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 4.06 (t, J=6.9 Hz, 2H), 3.90 (s, 3H), 3.64 (t, J=5.1 Hz, 4H), 3.38 (t, J=5.1 Hz, 4H), 1.86 (J=5.1 Hz, 2H), 1.30 (m, 10H), 0.89 (t, J=6.9 Hz, 3H). ESMS calcd (C20H33NO5): 367.2; found: 390.3 (N+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15].[O-:17][C:18]#[N:19].[Na+]>C(O)(=O)C.O>[NH:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:16])[CH3:15])[C:18]([NH2:19])=[O:17]
Reactant: N#C[O-]
Reactant: CC(=O)NCCc1c[nH]c2ccc(N)cc12
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)NCCc1c[nH]c2ccc(NC(N)=O)cc12

Procedure:
The product from Example 3 is dissolved in acetic acid-water (1:2, 3 mL) and sodium cyanate (2 mmol) added. This is stirred until a brownish gum is precipitated. The mixture is extracted with chloroform (3×30 mL), and the organic extracts washed with saturated sodium bicarbonate, dried with magnesium sulfate and the solvent evaporated in vacuo. The resulting product is purified by reverse-phase HPLC as above.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C@@H:10]1[C@H:17]2[C@@H:13]([O:14]C(C)(C)[O:16]2)[C@H:12]([N:20]2[CH:28]=[N:27][C:26]3[C:21]2=[N:22][CH:23]=[N:24][C:25]=3[NH:29][CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[O:11]1>C(O)(=O)C.O>[CH:30]1([NH:29][C:25]2[N:24]=[CH:23][N:22]=[C:21]3[C:26]=2[N:27]=[CH:28][N:20]3[CH:12]2[C@H:13]([OH:14])[C@H:17]([OH:16])[C@@H:10]([CH2:9][S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[O:11]2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC1(C)O[C@@H]2[C@@H](O1)[C@@H](CSc1ccccc1F)O[C@H]2n1cnc2c(NC3CCCC3)ncnc21
Solvent: O
Solvent: CC(=O)O
Product: O[C@@H]1[C@@H](CSc2ccccc2F)OC(n2cnc3c(NC4CCCC4)ncnc32)[C@@H]1O

Procedure:
(9-{(4S,1R,2R,5R)-4-[(2-fluorophenylthio)methyl]-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl}purin-6-yl)cyclopentylamine, a compound of formula (4) (50 mg) was dissolved in a mixture of acetic acid (8 mL) and water (2 mL) and heated at 90 C for 16 hours. Solvents were removed under reduced pressure, and the residue was purified by preparative TLC [methanol-dichloromethane(1:9)] to afford (4S,5S,3R)-2-[6-(cyclopentylamino)purin-9-yl]-5-[(2-fluorophenylthio)methyl]oxolane-3,4-diol, a compound of Formula I.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:44])[NH:24][C@@H:25]([CH2:38][CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:26][N:27](C)[C:28](OCC[Si](C)(C)C)=O)[CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.C(O)=O>CC#N>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([C@@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:44])[NH:24][C@@H:25]([CH2:38][CH2:39][C:40]([CH3:42])([CH3:41])[CH3:43])[CH2:26][NH:27][CH3:28])[CH2:18]2)[O:9][CH2:10][CH2:11][NH:12][C:13](=[O:16])[O:14][CH3:15])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)NCCO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)N[C@@H](CCC(C)(C)C)CN(C)C(=O)OCC[Si](C)(C)C)C1
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: CC#N
Product: CNC[C@H](CCC(C)(C)C)NC(=O)N1CCC[C@@H]([C@@H](OCCNC(=O)OC)c2cccc(Cl)c2)C1
Temperature: 55 °C

Procedure:
Methyl 2-((R)-(3-chlorophenyl)((R)-1-((S)-5,5-dimethyl-1-(N-methyl-N-(2-trimethylsilylethoxycarbonyl)amino)hexan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate was dissolved in CH3CN and treated with 75 mg (0.504 mmol, 4.5 equiv) of TEAF and the mixture heated to 55° C. for 3 h. The solution was evaporated and purified by prep HPLC to afford methyl 2-((R)-(3-chlorophenyl)((R)-1-((S)-5,5-dimethyl-1-(methylamino)hexan-2-ylcarbamoyl)piperidin-3-yl)methoxy)ethylcarbamate.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[C:8](=[O:14])[CH2:7][C:6]([CH3:16])([CH3:15])[CH2:5][C:4]=2[N:3]=1.[CH:17]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C.O>C(O)C>[CH:17]1([NH:22][C:2]2[C:11]([C:12]#[N:13])=[CH:10][C:9]3[C:8](=[O:14])[CH2:7][C:6]([CH3:16])([CH3:15])[CH2:5][C:4]=3[N:3]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NC1CCCC1
Reactant: CC1(C)CC(=O)c2cc(C#N)c(Cl)nc2C1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCO
Product: CC1(C)CC(=O)c2cc(C#N)c(NC3CCCC3)nc2C1
Yield: 48.3 %

Procedure:
A solution of 2-chloro-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-quinoline-3-carbonitrile (0.25 g, 1.06 mmol), cyclopentylamine (0.136 g, 1.6 mmol) and triethylamine (0.154 ml, 0.11 g, 1.1 mmol) in ethyl alcohol (3 ml) was heated at reflux for 3 h. Then water (10 ml) was added and the mixture was extracted by dichloromethane. The extract was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (CH2Cl2-hexane, 1:1) to give the title compound (0.145 g, 48%).