Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][OH:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[CH:24]([C:26]1[C:34]2[C:30](=[CH:31][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:33]=2)[CH:29]=[C:28]([O:43][CH3:44])[CH:27]=1)[CH3:25].[H-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:21][O:22][CH:24]([C:26]3[C:34]4[C:30](=[CH:31][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])[N:33]=4)[CH:29]=[C:28]([O:43][CH3:44])[CH:27]=3)[CH3:25])[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Reactant: COc1cc(C(C)Br)c2nn(COCC[Si](C)(C)C)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)OCC2(c3ccc(F)cc3)CCN(C(=O)OC(C)(C)C)CC2)c2nn(COCC[Si](C)(C)C)cc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (±)-tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (193 mg, 0.66 mmol) and 7-(1-bromoethyl)-5-methoxy-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (240 mg, 0.623 mmol) in dimethylformamide (2.5 mL) at 0° C. was added sodium hydride (60% in mineral oil, 32.4 mg, 0.81 mmol). The resulting solution was stirred at 0° C. for 30 min. The reaction was quenched by the cautious addition of saturated ammonium chloride and diluted with diethyl ether. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (15%→25% EtOAc/Hex) gave 29 mg (7.6%) as oil. 1H-NMR (CDCl3, 300 MHz) δ 7.88 (s, 1H), 7.25-7.30 (m, 2H), 6.95-7.00 (m, 2H), 6.6606.71 (m, 2H), 5.60 (s, 2H), 4.88 (q, J=6.0 Hz, 1H), 3.77 (s, 3H), 3.66-3.71 (m, 2H), 3.53-3.59 (m, 2H), 3.28-3.41 (m, 2H), 1.40 (m, 12H), 0.85-0.9 (m, 2H), -0.08 (s, 9H), 13C-NMR (CDCl3, 76 MHz) δ 161.2 (d, J=972 Hz), 155.5, 154.9, 143.9, 138.8, 135.3, 128.8, 122.3, 121.5, 116.1, 115.0, 114.7, 94.9, 81.4, 79.2, 73.9, 67.0, 60.3, 55.1, 41.2, 31.8, 28.4, 22.6, 20.9, 17.7, 14.1, −1.6; Mass spec.: 614.63 (MH)+.
Reaction SMILES: B(O)O.Br[C:5]1[N:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([C:5]2[N:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH:7]=[O:8])=[CH:17][CH:16]=1
Reactant: O=Cc1cccnc1Br
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: OBO
Product: O=Cc1cccnc1-c1ccc(C(F)(F)F)cc1

Procedure:
2-(4-(trifluoromethyl)phenyl)nicotinaldehyde was prepared using the general boronic acid coupling procedure for 2-bromonicotinaldehyde and (4-(trifluoromethyl)phenyl)boronic acid (93.8 mg, 135.1 mg theoretical, 69.4%). LC-MS m/z 252.2 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]([F:38])([F:37])[C:27]([F:36])([F:35])[C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.C(N(CC)CC)C.[O:46]1C[CH2:49][CH2:48][CH2:47]1.C(Cl)(=O)C=C>O>[C:47]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][C:26]([F:37])([F:38])[C:27]([F:35])([F:36])[C:28]([F:33])([F:34])[C:29]([F:30])([F:31])[F:32])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)(=[O:46])[CH:48]=[CH2:49]
Reactant: OCCCCCCCCOc1ccc(-c2ccc(OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)cc1
Reactant: C1CCOC1
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)OCCCCCCCCOc1ccc(-c2ccc(OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.4 %

Procedure:
In a flask whose content had been replaced with Ar, 1.5 g of 4-(8-hydroxyoctyloxy)-4'-[2-(perfluorobutyl)ethyloxy]biphenyl, 0.3 g of triethylamine, and 16 ml of tetrahydrofuran were placed. While this solution was being cooled with ice water, 0.3 g of acryloyl chloride was added dropwise. The reaction solution was allowed to warm up to room temperature, and was stirred for 3 hours. Thereafter, the reaction solution was poured into water and an organic layer was extracted with benzene. After the benzene layer was washed with water and dried over sodium sulfate anhydrous, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: benzene), and recrystallized from acetone to give 0.7 g of 4-[8-(acryloyloxy)octyloxy]-4'-[2-(perfluorobutyl)ethyloxy]biphenyl (Y: 44.4%). The purity of the compound thus obtained was 98.4% by GC; 99.4% by HPLC; and 1 spot by TLC. The phase transition temperature of the resultant compound was as shown in Table 2 below.
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH2:4][C:5]1[N:10]=[C:9]([Cl:11])[C:8]([O:12][CH:13]([F:15])[F:14])=[C:7](F)[N:6]=1>CO>[NH2:4][C:5]1[N:10]=[C:9]([Cl:11])[C:8]([O:12][CH:13]([F:15])[F:14])=[C:7]([O:2][CH3:1])[N:6]=1
Reactant: C[O-]
Reactant: Nc1nc(F)c(OC(F)F)c(Cl)n1
Agent: [Na+]
Solvent: CO
Product: COc1nc(N)nc(Cl)c1OC(F)F
Reaction time: 1 h

Procedure:
26.1 g (0.145 mol) of 30% strength sodium methylate were added to 31.0 g (0.145 mol) of 2-amino-4-chlorodifluoromethoxy-6-fluoropyrimidine in 300 ml of methanol in the course of 15 minutes while stirring at from -10° to 0° C. Stirring was continued for 30 minutes at 0° C. and for 1 hour at 25° C. The reaction mixture was evaporated down under reduced pressure and worked up as above. 31.6 g (96.6% of theory) of the title compound were obtained as a colorless oil of nD2 =1.5039.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]2[CH2:17][CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=3[C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1.[NH2:22][C:23]1[N:28]=[CH:27][CH:26]=[C:25](Cl)[N:24]=1>>[NH2:22][C:23]1[N:28]=[C:27]([NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]2[C:7]3[CH2:17][CH2:16][CH2:15][C:14]4[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=4[C:8]=3[N:9]=[C:10]([NH2:12])[N:11]=2)[CH:26]=[CH:25][N:24]=1
Reactant: Nc1nccc(Cl)n1
Reactant: NCCCNc1nc(N)nc2c1CCCc1ccccc1-2
Product: Nc1nccc(NCCCNc2nc(N)nc3c2CCCc2ccccc2-3)n1

Procedure:
The product of Example 3B (45 mg, 0.126 mmol) and 2-amino-6-chloropyrimidine (21 mg, 0.164 mmol) were treated under the conditions described in Example 1F to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.86 (d, J=5.16 Hz, 1H) 7.64-7.70 (m, 1H) 7.28-7.40 (m, 2H) 7.17-7.23 (m, 1H) 5.77 (d, J=5.95 Hz, 1H) 5.30 (s, 1H) 5.02 (t, J=5.55 Hz, 1H) 4.63 (s, 2H) 3.59 (q, J=6.35 Hz, 2H) 3.32 (d, J=5.16 Hz, 2H) 2.58 (t, J=6.54 Hz, 2H) 2.05-2.24 (m, 4H) 1.83-1.96 (m, 2H); MS (ESI+) m/z 377.0 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]([CH2:35][CH2:36][CH3:37])[C@@H:3]([NH:10][C:11](=[O:34])[CH2:12][C:13]([NH:15][C:16]1[CH:17]=[C:18]([NH:26]C(=O)OC(C)(C)C)[CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)=[O:14])[CH2:4][NH:5][CH2:6][CH:7]([CH3:9])[CH3:8]>C(Cl)Cl>[NH2:26][C:18]1[CH:17]=[C:16]([NH:15][C:13](=[O:14])[CH2:12][C:11]([NH:10][C@H:3]([C@@H:2]([OH:1])[CH2:35][CH2:36][CH3:37])[CH2:4][NH:5][CH2:6][CH:7]([CH3:8])[CH3:9])=[O:34])[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=1
Reactant: CCC[C@H](O)[C@H](CNCC(C)C)NC(=O)CC(=O)Nc1cc(NC(=O)OC(C)(C)C)cc(C(F)(F)F)c1
Solvent: ClCCl
Product: CCC[C@H](O)[C@H](CNCC(C)C)NC(=O)CC(=O)Nc1cc(N)cc(C(F)(F)F)c1

Procedure:
A sample of tert-butyl 3-(3-((2S,3S)-3-hydroxy-1-(isobutylamino)hexan-2-ylamino)-3-oxopropanamido)-5-(trifluoromethyl)phenylcarbamate (86 mg, title compound from Example 24) was dissolved in methylene chloride (2 mL). The resultant solution was cooled to 0° C. and charged with trifluoroacetic acid (1 mL). The mixture was allowed to warm to RT and stirred for 45 min before being concentrated in vacuo. The residue was purified by RP-HPLC to afford the TFA salt of the title compound as a white powder after lypholization. MS found: (M+H)+=433.3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[OH:17][C:18]([CH3:23])([CH3:22])[C:19](O)=O>O>[CH3:22][C:18]([CH3:23])([C:19]1[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[OH:17]
Reactant: CC(C)(O)C(=O)O
Reactant: CC(C)CNc1c(N)cnc2ccccc12
Solvent: O
Product: CC(C)Cn1c(C(C)(C)O)nc2cnc3ccccc3c21
Temperature: 160 °C
Yield: 22.8 %

Procedure:
3-Amino-4-(2-methylpropyl amino) quinoline (28.7 g; 0.133 mol) and 2-hydroxyisobutyric acid (27.8 g; 0.267 mol) were mixed and the mixture was heated at 160° C. for 5 hrs. Water was added to the dark mixture and a green oil formed. The oil was extracted with ether to yield 8.6 g of an oil which contained two products. The mixture was purified by silica gel column chromatography to yield 3.2 g of the intended product. A small amount was recrystallized from ethyl acetate for analysis and characterization. m.p. 156-164° C. Analysis: Calculated: C, 72.1; H, 7.5; N, 14.8. Found: C, 71.9; H, 7.4; N, 14.6.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[N:27]([CH2:30][CH2:31][C:32]([OH:34])=O)[N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1.[CH2:35]([NH2:38])[CH2:36][CH3:37]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[N:27]([CH2:30][CH2:31][C:32]([NH:38][CH2:35][CH2:36][CH3:37])=[O:34])[N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1
Reactant: O=C(O)CCn1ncc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc21
Reactant: CCCN
Product: CCCNC(=O)CCn1ncc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc21
Yield: 76 %

Procedure:
Following a similar procedure to that described in example 48, but using 3-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-1-yl]propionic acid (obtained in example 47) instead of 2-[4,6-bis(4-fluorophenyl)-5-(4-pyridyl)pyrazolo[3,4-b]pyridin-2-yl]acetic acid, and propylamine instead of morpholine, the title compound was obtained (yield: 76%).
Reaction SMILES: [N+:1]([O-:16])([O:3][C@@H:4]([C@H:6]([O:12][N+:13]([O-:15])=[O:14])[CH:7]([CH3:11])[CH2:8][CH2:9][OH:10])[CH3:5])=[O:2].[CH2:17]([O:19][C:20]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[N:42]([C:43]([C:56]4[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=4)([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[N:41]=[N:40][N:39]=3)=[CH:28][CH:27]=2)[C:23]2[C:62]([C:66]([O:68][C:69]([CH3:84])([O:71][C:72](OC3C=CC([N+]([O-])=O)=CC=3)=[O:73])[CH3:70])=[O:67])=[CH:63][CH:64]=[CH:65][C:22]=2[N:21]=1)[CH3:18]>C(Cl)Cl>[CH2:17]([O:19][C:20]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[N:42]([C:43]([C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[N:41]=[N:40][N:39]=3)=[CH:28][CH:27]=2)[C:23]2[C:62]([C:66]([O:68][C:69]([O:71][C:72]([O:10][CH2:9][CH2:8][CH:7]([CH3:11])[C@@H:6]([O:12][N+:13]([O-:15])=[O:14])[C@H:4]([O:3][N+:1]([O-:16])=[O:2])[CH3:5])=[O:73])([CH3:84])[CH3:70])=[O:67])=[CH:63][CH:64]=[CH:65][C:22]=2[N:21]=1)[CH3:18]
Reactant: CC(CCO)[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-]
Reactant: CCOc1nc2cccc(C(=O)OC(C)(C)OC(=O)Oc3ccc([N+](=O)[O-])cc3)c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOc1nc2cccc(C(=O)OC(C)(C)OC(=O)OCCC(C)[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-])c2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2R,3R)-6-hydroxy-4-methylhexane-2,3-diyl dinitrate (Intermediate 2, 0.78 g, 3.26 mmol) was added to a stirred solution of 1-methyl-1-{[(4-nitrophenoxy)carbonyl]oxy}ethyl 2-ethoxy-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate (Intermediate 4, 1.96 g, 2.17 mmol) in CH2Cl2 (20 mL). The solution was stirred at room temperature overnight. The solution was diluted with CH2Cl2 (20 mL) washed with a solution of NaH2PO4 5% (2×20 mL) and brine. The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage SP1, SNAP 100 g column, TLC method, n-Hexane/EtOAc 6:4, Rf:0.45) affording the title compound that was used without any further purification.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]=[CH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].C(OO)(=[O:18])C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C.O1CCCC1>[C:8]1([S:5]([CH:4]2[CH:3]([C:2]([F:1])([F:14])[F:15])[O:18]2)(=[O:6])=[O:7])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)OO
Reactant: O=S(=O)(C=CC(F)(F)F)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=S(=O)(c1ccccc1)C1OC1C(F)(F)F
Temperature: 60 °C
Yield: 90 %

Procedure:
To a solution of 25.4 mmol 3,3,3-trifluoro-1-(phenylsulphonyl)prop-1-ene in 80 ml acetonitrile were added 30.5 mmol peracetic acid (39% solution in acetic acid) and 101 mmol potassium carbonate. The mixture was heated at 60° C. for 4 h. The reaction mixture was then diluted with ethyl acetate/tetrahydrofuran (1:1) and was washed with brine. The organic phase was dried over sodium sulfate and concentrated in vacuo to afford the title compound as a light yellow crystalline solid (yield 90%). EI-MS (m/e): 252.0 (M+, 15%), 125.1 (PhSO+, 100%), 77.2 (Ph+, 37%).
Reaction SMILES: Br[CH:2]1[C:7](=[O:8])[C:6]([Br:9])=[CH:5][N:4]=[CH:3]1.C1([Mg]Br)C=CC=CC=1.[Li]CCCC.[CH:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[Br:9][CH:6]1[C:7](=[O:8])[C:2]([CH:23]([OH:30])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:3][N:4]=[CH:5]1
Reactant: O=C1C(Br)=CN=CC1Br
Reactant: O=Cc1ccccc1
Agent: Br[Mg]c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1C(C(O)c2ccccc2)=CN=CC1Br
Reaction time: 0.25 h

Procedure:
To a heterogeneous mixture of 3,5-dibromo-pyridin-4-one 10 (0.313 g, 1.24 mmol) in anhydrous THF (4 mL) at −78° C. under nitrogen atmosphere was added phenylmagnesium bromide solution (1.36 mL of 1 M solution in THF, 1.36 mmol) [Borzilleri, et al., U.S. Pat. 20050245530]. After stirring for 15 min, n-BuLi solution (0.68 mL of 2 M solution in cyclohexane, 1.36 mmol) was added and the reaction mixture stirred for 15 min at −78° C. under nitrogen atmosphere. To this mixture was added benzaldehyde (0.26 mL, 2.6 mmol) and the mixture was stirred for 2 h at −78° C. The reaction mixture was quenched by adding HOAc (0.38 mL) and TFA (0.38 mL), concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (dichloromethane:methanol, 95:5). Yield 0.125 g (36%), white solid, 123-124° C. 1H NMR (MeOH— d4, 500 MHz): δ 8.09 (s, 1H), 7.81 (s, 1H), 7.38-7.17 (m, 5H), 5.92 (s, 1H), 3.83 (s, 2H). 13C NMR (MeOH— d4, 125 MHz): δ 174.3, 144.4, 139.7, 135.8, 133.6, 129.4, 129.3, 128.6, 128.0, 128.0, 114.8, 70.8.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO>C1COCC1>[C:1]1([O:7][C:8]2[CH:16]=[CH:15][C:11]([CH2:12][OH:13])=[C:10]([C:17]([F:18])([F:19])[F:20])[CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1C(F)(F)F
Solvent: CO
Solvent: C1CCOC1
Product: OCc1ccc(Oc2ccccc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of 4-(phenyloxy)-2-(trifluoromethyl)benzoic acid (for a preparation see Intermediate 35)(0.507 g, 1.80 mmol), in THF (40 ml), under nitrogen, was added borane-tetrahydrofuran complex (0.463 g, 5.39 mmol, Aldrich) carefully over about 2 min. The solution was stirred for 40 min at ambient temperature and then heated at gentle reflux for 20 h. To the mixture at ambient temperature was added methanol (10 ml) dropwise and then the solution was heated to reflux for 30 min. The solvent was evaporated in vacuo and the residue acidified with dilute aqueous HCl. The mixture was extracted with chloroform and the phases separated using a hydrophobic frit. The solvent was evaporated in vacuo to leave [4-(phenyloxy)-2-(trifluoromethyl)phenyl]methanol as a colourless oil (0.491 g). [4-(phenyloxy)-2-(trifluoromethyl)phenyl]methanol (0.491 g, 1.83 mmol) in dichloromethane (10 ml) under nitrogen was stirred and cooled to −5° C. A solution of phosphorus tribromide (0.173 ml, 1.831 mmol) in DCM (3.5 ml) was then added dropwise over about 10 min. The solution was then allowed to warm to room temperature and stirred for 4 h. A saturated solution of aqueous sodium bicarbonate (10 ml) was then added and the mixture stirred vigorously. The emulsion was further diluted with water and chloroform. The phases were separated using a hydrophobic frit. The aqueous phase was further extracted with chloroform. The combined organic extracts were dried (Na2SO4) and filtered. The filtrate was re-dried with (MgSO4), filtered and the solvent removed in vacuo to give 4-(bromomethyl)-3-(trifluoromethyl)phenyl ether as a colourless oil (0.518 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)=[CH:11][C:10]([C:23]([O:25]CC)=[O:24])=[N:9]2)=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)=[CH:11][C:10]([C:23]([OH:25])=[O:24])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(-c2cccc(C(F)(F)F)c2)n(-c2ccc(Cl)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2cccc(C(F)(F)F)c2)n(-c2ccc(Cl)cc2)n1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
4.75 g (12.0 mmol) of the compound of Example 55A are provided in 108 ml of 1,4-dioxane, 108 ml (216 mmol) of a 2N solution of lithium hydroxide in water are added, and the mixture is stirred at 70° C. for 2 h. The mixture is concentrated, a conc. aqueous hydrogen chloride solution is subsequently added to the residue until the pH is acidic, the mixture is extracted with dichloromethane, and the organic phase is dried over magnesium sulfate, filtered and concentrated. 4.40 g (100% of theory) of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([CH2:18][OH:19])[O:12]2)=[C:4]([NH:20][CH3:21])[N:3]=1.O.[NH2:23][NH2:24]>>[NH:23]([C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([CH2:18][OH:19])[O:12]2)=[C:4]([NH:20][CH3:21])[N:3]=1)[NH2:24]
Reactant: NN
Reactant: CNc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Solvent: O
Product: CNc1nc(NN)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(4S,2R,3R,5R)-2-[2-chloro-6-(methylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol, a compound of formula (2) (0.5 mmol), was suspended in hydrazine hydrate (5 mL), and the mixture was allowed to stir at room temperature for 24 hours. The hydrazine was removed under reduced pressure and the residue triturated with ether and filtered, to afford (4S,2R,3R,5R)-2-[2-hydrazino-6-(methylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol, a compound of formula (3), as a white solid.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][N:14]1[CH:19]([CH3:20])[C:18]2([CH3:24])[CH:21]([CH3:23])[CH2:22][CH:15]1[CH:16]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17]2.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C1COCC1.[Cl-].[Na+]>[CH3:13][N:14]1[CH:19]([CH3:20])[C:18]2([CH3:24])[CH:21]([CH3:23])[CH2:22][CH:15]1[C:16]([C:31]([O:33][CH2:34][CH3:35])=[O:32])([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:17]2
Reactant: CCOC(=O)C1CC2(C)C(C)CC1N(C)C2C
Reactant: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)OCC)CC2(C)C(C)CC1N(C)C2C
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a solution of diisopropylamine (3.0 mL, 22 mmol) in THF (34 mL) at 0° C. under nitrogen was added n-BuLi (8.8 mL, 22 mmol, 2.5M in hexanes). A solution of ethyl 2,3,4,8-tetra-methyl-2-azabicyclo[2.2.2]octane-6-carboxylate (4.8 g, 20 mmol) in THF (46 mL) was added to the mixture and the reaction was stirred at 0° C. for 1 hour. Ethyl chloroformate (2.3 mL, 24 mmol) in THF (3 mL) was then added and the mixture was stirred for 15 minutes. The reaction mixture was diluted with saturated sodium chloride and partitioned between water and ether. The aqueous layer was extracted with ether (2X) and the combined organic layers were dried over anhydrous MgSO4. The solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with ether/hexanes (15/85) to afford 3.9 g (63%) of diethyl 2,3,4,8-tetramethyl-2-azabicyclo[2.2.2]octane-6,6-dicarboxylate as a yellow oil.
Reaction SMILES: CC(C)([O-])C.[Na+].[C:7]([O:14][CH2:15][CH3:16])(=[O:13])[C:8]([O:10]CC)=O.[C:17]1(=[O:32])[N:21]([CH2:22][CH2:23][C:24](=[O:26])[CH3:25])[C:20](=[O:27])[C:19]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:18]12.[Na]>C(O)C>[O:10]=[C:8]([CH2:25][C:24](=[O:26])[CH2:23][CH2:22][N:21]1[C:17](=[O:32])[C:18]2=[CH:31][CH:30]=[CH:29][CH:28]=[C:19]2[C:20]1=[O:27])[C:7]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 54.6 %

Procedure:
4-Phthalimido-2-butanone was obtained from the literature procedure, Eriks et al, J. Med. Chem., 1992, 35, 3239-3246. Sodium tert-butoxide (20.75 g, 0.216 mol) was added over a period of 12 minutes to ethanol (160 mL) under a nitrogen atmosphere. When all solids had dissolved, diethyl oxalate (31.55 g, 0.216 mol) and a suspension of 4-phthalimido-2-butanone (46.9 g, 0.216 mol) were sequentially added. The reaction was stirred at ambient temperature for 2.5 hours. A precipitate was present and was isolated by filtration to provide 37.4 g of ethyl 2,4-dioxo-6-phthalimidohexanoate, sodium salt as a light orange solid.
Reaction SMILES: [CH3:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([OH:12])=[O:11])([CH2:6][CH2:7]1)[CH:4]=[CH:3]2.[H][H]>[Pd].C(O)C>[CH3:1][C:2]12[CH2:9][CH2:8][C:5]([C:10]([OH:12])=[O:11])([CH2:4][CH2:3]1)[CH2:6][CH2:7]2
Reactant: CC12C=CC(C(=O)O)(CC1)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC12CCC(C(=O)O)(CC1)CC2

Procedure:
In this preparation a mixture containing 0.1 mole of 4-methylbicyclo[2.2.2]oct-2-ene-1-yl carboxylic acid and 1 g. of 5% palladium on carbon catalyst in 300 ml. of ethanol is stirred under hydrogen, at room temperature, until no more hydrogen is absorbed (about 2.4 liters are absorbed). The catalyst is then filtered off and the solvent removed from the filtrate by evaporation, under vacuum, affording 4-methylbicyclo[2.2.2]oct-1-yl carboxylic acid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].CS[C:15]1C2C(=CC(Br)=CC=2Br)N[C:16]=1SC>Cl.CCO>[CH2:15]([O:9][C:8](=[O:10])[C:7]1[CH:11]=[C:3]([CH2:2][NH2:1])[CH:4]=[CH:5][C:6]=1[Cl:12])[CH3:16]
Reactant: CSc1[nH]c2cc(Br)cc(Br)c2c1SC
Reactant: NCc1ccc(Cl)c(C(=O)O)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cc(CN)ccc1Cl

Procedure:
Prepared analogously to example 42d with 5-aminomethyl-2-chlorobenzoic acid (2 g; 9.01 mmol) in 20 mL HCl in EtOH. Yield: 2.38 g (90%); MS: [M+H]+=214 (Cl isotope pattern); HPLC: Rt=1.20 min (Method MC-6)