Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:14]2[CH:13]=[C:12]([C:15]3[C:20]4[O:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[C:19]=4[CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C([Li])(CC)C.C1CCCCC1.C(O[B:44]1[O:48][C:47]([CH3:50])([CH3:49])[C:46]([CH3:52])([CH3:51])[O:45]1)(C)C>C1COCC1>[CH3:1][C:2]1([CH3:28])[C:14]2[CH:13]=[C:12]([C:15]3[C:20]4[O:21][C:22]5[C:27]([B:44]6[O:48][C:47]([CH3:50])([CH3:49])[C:46]([CH3:52])([CH3:51])[O:45]6)=[CH:26][CH:25]=[CH:24][C:23]=5[C:19]=4[CH:18]=[CH:17][CH:16]=3)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: CC1(C)c2ccccc2-c2ccc(-c3cccc4c3oc3ccccc34)cc21
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: CC1(C)c2ccccc2-c2ccc(-c3cccc4c3oc3c(B5OC(C)(C)C(C)(C)O5)cccc34)cc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
Into a solution of 4-(9,9-dimethyl-9H-fluoren-2-yl)dibenzo[b,d]furan (11.55 g, 32.0 mmol) and THF (200 ml), a solution of sec-butyllithium 1.4 M in cyclohexane (30.9 ml, 43.3 mmol) at −78° C. was slowly added. The resulting mixture was stirred at −78° C. for 2 hours before adding 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.81 ml, 48.1 mmol) by syringe. The reaction solution was allowed to gradually warm to room temperature and stirred for 14 h. The reaction was quenched with methanol (MeOH) and the solvent was removed in vacuo. The residue was dissolved in DCM and washed with water and brine. The organic layer was dried over sodium sulfate, then filtered, before the solvent was evaporated. The crude product was purified by column chromatography on silica gel with a heptane/DCM/EtOAc (75/20/5 to 40/50/10, v/v/v) eluent and recrystallization from toluene yielded 2-(6-(9,9-dimethyl-9H-fluoren-2-yl)dibenzo[b,d]furan-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.1 g, 84%) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([O:16][CH:17]([CH3:21])[C:18]([OH:20])=O)[N:10]=1.[I-].ClC1C=CC=C[N+]=1C.[C:31]1([S:37]([NH2:40])(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(#N)C>[CH3:15][C:13]1[CH:14]=[C:9]([CH3:8])[N:10]=[C:11]([O:16][CH:17]([CH3:21])[C:18]([NH:40][S:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])=[O:20])[N:12]=1
Reactant: Cc1cc(C)nc(OC(C)C(=O)O)n1
Reactant: NS(=O)(=O)c1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(C)nc(OC(C)C(=O)NS(=O)(=O)c2ccccc2)n1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (2.84 g, 0.028 mol) was added to 2.00 g (0.0102 mol) of the product of (b) in dry acetonitrile (100 ml) and then, at 50° C., 3.00 g, 0.0118 mol, of 2-chloro-N-methyl pyridinium iodide was also added. The mixture was stirred at 50° C. for 30 minutes and then 3.32 g (0.0212 mol) of benzene sulphonamide and 1.42 g (0.014 mol) of triethylamine were added and the stirring continued at 50° C. for a further 30 minutes. The mixture was allowed to cool to ambient temperature (~20° C.) and left overnight, stirring being maintained for the entire period. The acetonitrile was then removed by evaporation, 50 ml of water added, the mixture acidified to a pH of 2, 50 ml of diethyl ether added and the solution vigorously stirred for 1 hour. The desired product, a beige solid, formed and was filtered off and dried.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](O)[C:5]2[C:6](=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:9]([CH3:11])[N:10]=2)[N:7]=1.P(Cl)(Cl)([Cl:23])=O>>[CH3:1][C:2]1[CH:3]=[C:4]([Cl:23])[C:5]2[C:6](=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:9]([CH3:11])[N:10]=2)[N:7]=1
Reactant: Cc1cc(O)c2nn(C)c(-c3ccc(Cl)cc3Cl)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)c2nn(C)c(-c3ccc(Cl)cc3Cl)c2n1

Procedure:
Intermediate (4) (400 mg) was suspended in phosphorous oxychloride (2 ml) and refluxed for 2 hours. The reaction mixture was concentrated, yielding 5-methyl-7-chloro-2-methyl-3-(2,4-dichlorophenyl)pyrazolo[4,3-b]pyridine (intermediate 5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[C:25](#N)C.O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][O:10][C:11]2[N:15]([C:16]3[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][N:17]=3)[N:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(COc2ccnn2-c2cc(C(=O)O)ccn2)cc1Cl
Reactant: CC#N
Solvent: O
Product: COC(=O)c1ccnc(-n2nccc2OCc2ccc(C)c(Cl)c2)c1

Procedure:
The title compound was prepared from 2-[5-[(3-chloro-4-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid (EXAMPLE 92) according to the procedure for the preparation of Example 62. 1H NMR (400 MHz, CDCl3): δ 2.38 (3H, s), 3.96 (3H, s), 5.18 (2H, s), 5.74 (1H, d, J=1.6 Hz), 7.21-7.26 (2H, m), 7.45 (1H, s), 7.58 (1H, d, J=2.0 Hz), 7.77-7.78 (1H, m), 8.33 (1H, s), 8.71 (1H, d, J=5.2 Hz). LCMS (mobile phase: 30%-95% Acetonitrile-Water-0.02% NH4Ac): purity is >95%, Rt=3.628 min. [M+H] Calc'd for C18H16ClN3O3, 358; Found, 358.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=1)[CH2:9][CH3:10].S(=O)(=O)(O)O.[CH2:27](O)[CH3:28]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([CH2:17][O:19][CH2:27][CH3:28])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: CCO
Reactant: CCN(Cc1cc(Br)ccc1O)c1ccc(C(=O)O)nn1
Agent: O=S(=O)(O)O
Product: CCOCc1ccc(N(CC)Cc2cc(Br)ccc2O)nn1

Procedure:
The 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridazine-3-carboxylic acid (example 8) (6.5 g) was suspended in ethanol (30 ml) and treated cautiously with concentrated sulphuric acid (1.5 ml). The reaction was heated to reflux overnight, then the organic solvent was evaporated. The residue was partitioned between ethyl acetate/water and the organic phase was dried over (MgSO4) and evaporated to give the title compound as a brown solid (5.86 g).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:17][CH:18]([F:22])[C:19](O)=[O:20].C(N(CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([CH:10]2[CH2:11][CH2:12][CH:13]([O:16][C:19](=[O:20])[CH:18]([F:22])[F:17])[CH2:14][CH2:15]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: O=C(O)C(F)F
Reactant: CCCC1CCC(C2CCC(O)CC2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC1CCC(C2CCC(OC(=O)C(F)F)CC2)CC1
Temperature: 0 °C
Reaction time: 17 h
Yield: 50.8 %

Procedure:
In 40 ml of dichloromethane were dissolved 3.0 g (13 mmol) of 4-(4-propylcyclohexyl)cyclohexanol, 2.3 g (24 mmol) of difluoroacetic acid, and 0.9 g (9 mmol) of triethylamine, and this solution was cooled down to 0° C. To this solution was added dropwise 20 ml of solution of 3.1 g (15 mmol) of DCC in dichloromethane, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 17 hours. After the crystals in the suspension thus obtained were filtered off, the solvent was distilled off under a reduced pressure. After the residue was purified by column chromatography on silica gel (eluent: heptane/toluene=1/1), the solvent was distilled off, and the residue was subjected twice to recrystallization by using heptane to give 2.0 g (6.6 mmol) of difluoroacetic acid 4-(4-propylcyclohexyl)cyclohexyl ester. Yield of this compound based on 4-(4-propylcyclohexyl)-cyclohexanol was 51%.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([S:11][CH2:12][CH2:13][CH3:14])[N:3]=1.[F:15][C@@H:16]1[C@@H:20]([CH2:21][OH:22])[O:19][C@@H:18](N2C=CC(=O)NC2=O)[CH2:17]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:18]2[O:19][C@H:20]([CH2:21][OH:22])[C@@H:16]([F:15])[CH2:17]2)=[C:4]([S:11][CH2:12][CH2:13][CH3:14])[N:3]=1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CCCSc1nc(N)nc2[nH]cnc12
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: CCCSc1nc(N)nc2c1ncn2[C@H]1C[C@H](F)[C@@H](CO)O1
Temperature: 45 °C
Reaction time: 48 h
Yield: 30.5 %

Procedure:
2-Amino-6-propylthio-9H-purine (0.29 g 1.4 mmoles) and 2',3'-dideoxy-3'-fluorouridine (0.39 g, 1.7 mmoles) were suspended in potassium phosphate buffer (10 mM) 90 ml), pH 6.8, containing 0.04% potassium azide. Purified purine nucleoside phosphorylase (370 I.U., PNP) and thymidine phosphorylase (TPase) (Krenitsky et al., Biochemistry, 20, 3615 (1981) and U.S. Pat. No. 4,381,444) adsorbed on to DEAE-cellulose were added to The reaction mixture and the suspension stirred at 45° C. After 2 days, additional PNP (370 I.U.) and TPase adsorbed onto DEAE-cellulose was added. The next day the reaction was filtered to remove the immobilized protein and fresh PNP (2700 I.U.) and TPase (1000 I.U.) was added. After 4 days, additional free PNP (2700 I.U.) and TPase (1000 I.U.) was added to the reaction mixture. After 3 days, PNP (5400 I.U.) and TPase (2000 I.U.) were added. After a total of 14 days, solvent was removed in vacuo and the residue was flash chromatographed on silica gel (2.5×23 cm) using CH2Cl2 :MeOH (97:3). Product-containing fractions were pooled and rechromatographed on a second silica gel column (2.5×20 cm) using CHCl3 :MeOH (199:1). Solvent was removed and lyophilization yielded 2-amino-6-propylthio-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-9H-purine (0.14 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25](=[N:27][OH:28])[NH2:26])[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[S:35](Cl)(Cl)=[O:36].O>O1CCCC1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:18][C:19]3[N:24]=[C:23]([C:25]4[NH:26][S:35](=[O:36])[O:28][N:27]=4)[CH:22]=[CH:21][CH:20]=3)=[C:8]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(Cc3cccc(C(N)=NO)n3)c(-c3ccccc3)[nH]c2c1
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc2c(Cc3cccc(C4=NOS(=O)N4)n3)c(-c3ccccc3)[nH]c2c1
Reaction time: 2 h

Procedure:
Under an argon atmosphere, a solution of 6-(6-methoxy-2-phenyl-1H-indol-3-ylmethyl)pyridine-2-carboxamidoxime (277 mg) and pyridine (0.121 mL) in tetrahydrofuran (3.1 mL) was ice-cooled. A solution of thionyl chloride (0.055 mL) in methylene chloride (0.62 mL) was added dropwise thereto, and this mixture was stirred at the same temperature for 2 hours. To the reaction mixture was added water, followed by extraction with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: methanol-dichloromethane) to obtain the title compound (60.9 mg). 1H-NMR (DMSO-d6) δ ppm: 3.78 (3H, s), 4.44 (2H, s), 6.64 (1H, dd, J=2.3, 8.5 Hz), 6.89 (1H, d, J=2.3 Hz), 7.18 (1H, dd, J=1.8, 7.3 Hz), 7.26-7.38 (2H, m), 7.41-7.54 (2H, m), 7.59-7.66 (2H, m), 7.79-7.90 (2H, m), 11.23 (1H, s), 11.80-12.20 (1H, br). ESI-MS (m/z): 419 (M+H)+
Reaction SMILES: [C:1]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:6]=[C:5]([C:7]([O-:9])=O)[CH:4]=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=1.ON1C2C=CC=CC=2N=N1.Cl.[CH3:31][N:32](C)[CH2:33][CH2:34][CH2:35]N=C=NCC.CNCCC>ClCCl>[CH2:13]([O:12][C:10](=[O:11])[C:3]1[CH:4]=[C:5]([C:7](=[O:9])[N:32]([CH3:31])[CH2:33][CH2:34][CH3:35])[CH:6]=[C:1]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:2]=1)[CH3:14]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCOC(=O)c1cc(C(=O)[O-])cc(C(=O)OCC)c1
Agent: CCCNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(=O)OCC)c1
Yield: 67.7 %

Procedure:
Stir a solution of diethyl 1,3,5-benzene tricarboxylate (2.47 g, 9.28 mmol), 1-hydroxybenzotriazole (1.38 g, 10.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (1.96 g, 10.2 mmol), N-methylpropylamine (1.04 mL, 10.2 mmol) in dichloromethane (50 mL) at room temperature overnight. Dilute with dichloromethane (300 mL) and extract the solution with 0.1 N citric acid (2×50 mL), saturated aqueous sodium bicarbonate (50 mL), and saturated aqueous sodium chloride (50 mL). Dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes) to give the title compound (2.02 g, 68%).
Reaction SMILES: CO[C@H](C1C=CC=CC=1)C([O:6][C@@H:7]1[CH2:16][CH2:15][C:14]2[C:9](=[C:10]([NH2:17])[CH:11]=[CH:12][CH:13]=2)[CH2:8]1)=O.[OH-].[Li+]>O1CCCC1>[NH2:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH2:8][C@H:7]([OH:6])[CH2:16][CH2:15]2
Reactant: CO[C@@H](C(=O)O[C@@H]1CCc2cccc(N)c2C1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1cccc2c1C[C@H](O)CC2
Yield: 81.9 %

Procedure:
A mixture of Example 24D (3.05 g, 9.80 mmol) in tetrahydrofuran (40 mL) and lithium hydroxide (1 M aq, 30 mL, 30.0 mmol) was stirred vigorously at ambient temperature. After 1.5 hours the reaction mixture was partitioned between 100 mL ethyl acetate:H2O (1:1). The separated organic phase was washed with aq saturated NaHCO3 and brine, dried over Na2SO4, and filtered. The solvent was removed at the rotary evaporator to yield 1.31 g (82% yield) of the title compound as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 6.76 (t, 1H), 6.41 (d, 1H), 6.28 (d, 1H), 4.74, (d, 1H), 4.65 (bs, 2H), 3.90 (m, 1H), 2.52-2.79 (m, 3H), 2.16 (m, 1H), 1.83 (m, 1H), 1.55 (m, 1H). MS (DCI+) m/z 164 (M+H)+, 181 (M+NH4)+.
Reaction SMILES: [F:1]/[C:2](=[C:5](/[C:8]1[C:17]([O:18][CH2:19][O:20][CH3:21])=[CH:16][C:15]2[C:14]([CH3:23])([CH3:22])[CH2:13][CH2:12][C:11]([CH3:25])([CH3:24])[C:10]=2[CH:9]=1)\[CH2:6][CH3:7])/[CH2:3][OH:4].C[N+]1([O-])CCOCC1>CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O.C(Cl)Cl>[F:1]/[C:2](=[C:5](/[C:8]1[C:17]([O:18][CH2:19][O:20][CH3:21])=[CH:16][C:15]2[C:14]([CH3:23])([CH3:22])[CH2:13][CH2:12][C:11]([CH3:24])([CH3:25])[C:10]=2[CH:9]=1)\[CH2:6][CH3:7])/[CH:3]=[O:4]
Reactant: CC/C(=C(\F)CO)c1cc2c(cc1OCOC)C(C)(C)CCC2(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC/C(=C(\F)C=O)c1cc2c(cc1OCOC)C(C)(C)CCC2(C)C

Procedure:
Following General Procedure D and using (E)-2-fluoro-3-(3-methoxymethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-pent-2-en-1-ol (Intermediate 16, 1.69 g, 4.83 mmol), NMO (1.4 g, 12.1 mmol), TPAP (catalytic amount), and CH2Cl2 (5 mL) followed by flash column chromatography on silica gel (5% EtOAc-hexane) the title compound was obtained as a off-white solid (1.48 g, 88%).
Reaction SMILES: [CH3:1][N+:2]([CH2:5][CH:6]([OH:11])[CH2:7][C:8]([OH:10])=[O:9])([CH3:4])[CH3:3].[Cl-]>O>[CH3:1][N+:2]([CH2:5][CH:6]([OH:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:3])[CH3:4]
Reactant: C[N+](C)(C)CC(O)CC(=O)O
Agent: [Cl-]
Solvent: O
Product: C[N+](C)(C)CC(O)CC(=O)[O-]
Yield: 97.7 %

Procedure:
A solution of 35.0 g (0.177 mole) of DL-carnitine hydrochloride in 300 ml of water is passed through OH type strongly basic resin (Dowex-1X8) and the solution is concentrated to give 28.0 g (0.173 mole) of DL-carnitine. To DL-carnitine are added 61.9 g (0.173 mole) of dibenzoyl-L(+)tartaric acid and 90 ml of methanol. The mixture is dissolved under heat to form dibenzoyl-L(+)tartarates of D-carnitine and L-carnitine. The tartarates are cooled from 60° C. to 5° C. over a period of 24 hours to fractionally crystallize L-carnitine dibenzoyl-L(+)tartarate. The tartarate is filtered and washed to give L-carnitine dibenzoyl-L(+)tartarate (yield 39.0 g, purity 92.7%). The tartarate obtained is dissolved under heat in 190 ml of ethanol, and cooled from 60° C. to 25° C. over a period of 24 hours. This recrystallization gives 21.5 g of crystals of L-carnitine dibenzoyl-L(+)tartarate. [α]D25 =-96.2° (c= 1, MeOH), m.p. 154° C. (dec.), purity 99.7%.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([CH:9]([CH2:13][CH2:14][CH2:15][C@H:16]1[C@@H:24]2[C@@H:19]([NH:20][C:21]([NH:23]2)=[O:22])[CH2:18][S:17]1)[C:10](=[O:12])[OH:11])=[O:8])C(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][CH2:2][C:7]([CH:9]([CH2:13][CH2:14][CH2:15][C@H:16]1[C@@H:24]2[C@@H:19]([NH:20][C:21]([NH:23]2)=[O:22])[CH2:18][S:17]1)[C:10](=[O:11])[OH:12])=[O:8]
Reactant: CC(C)(C)[C@H](N)C(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCC(=O)C(CCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.6 %

Procedure:
To a solution of tert-butylglycylbiotin (0.271 g, 0.758 mmol) in CH2Cl2 (0.5 mL) was added 0.5 mL trifluoroacetic acid. The reaction mixture was stirred at room temperature for 2 h, concentrated, and triturated with anhydrous diethyl ether. The off-white precipitate was collected to yield 0.209 g (0.694 mmol, 92%) of glycylbiotin. Mass. spec [M+H]+ at m/z 302.
Reaction SMILES: [OH-].[Na+].[NH2:3][C@H:4]([C:12]([OH:14])=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:15](Cl)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>>[C:15]([NH:3][C@H:4]([C:12]([OH:14])=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1

Procedure:
To 30 ml of a 1 N sodium hydroxide solution is added 4.95 g of L-phenylalanine. The solution is cooled and stirred in an ice bath and 5.4 ml of a 6.1 M solution of carbobenzoxychloride is added dropwise along with additional 1 N sodium hydroxide solution so that the pH remains at 11.0-11.5. The reaction mixture is washed with ether. The aqueous layer is acidified to pH 1.0 with 12 N hydrochloric acid, then the solution is extracted with ethyl acetate. The ethyl acetate extract is separated and is washed three times with water then dried over magnesium sulfate. The solvent is removed under vacuum. The residue crystallizes on rubbing with water to give N-carbobenzoxy-L-phenylalanine. 3.99 Grams of methyl 3-amino-1-adamantanecarboxylate hydrochloride and 4.78 g of carbobenzoxy-L-phenylalanine are dissolved in 40 ml methylene chloride. To this solution is added 1.8 ml of N-methylmorpholine followed immediately by 2.19 g of dicyclohexylcarbodiimide. The reaction mixture is allowed to stand for 24 hours at room temperature, then the treatment with carbobenzoxy-L-phenylalanine and dicyclohexylcarbodiimide is repeated. The reaction mixture is again allowed to stand for 24 hours at room temperature. The dicyclohexylurea is removed by filtration and washed with methylene chloride. The combined filtrates are washed twice with 0.5 M potassium bisulfate, water and 1 M solution of potassium bicarbonate and dried over magnesium sulfate. The dicloromethane is removed under vacuum and the residue is purified by low pressure chromatography on silica gel using mixtures of hexane and chloroform as eluting solvent to give methyl carbobenzoxy-L-phenylalanyl-3-amino-1-adamantanecarboxylate which has the following structural formula ##STR13## wherein Cbz represents carbobenzoxy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:4]=1[CH2:5][NH:6][C:7](=[O:10])[CH2:8]Cl.[I-:17].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:4]=1[CH2:5][NH:6][C:7](=[O:10])[CH2:8][I:17]
Reactant: COc1ccc(CNC(=O)CCl)c(OC)c1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(CNC(=O)CI)c(OC)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 132.1 %

Procedure:
To a solution of N-(2,4-Dimethoxy-benzyl)-2-chloro-acetamide (2.2074 g, 9.0584 mmol) in acetone (20 mL) was added sodium iodide (4.121 g, 27.49 mmol). The reaction mixture was stirred at 50° C. for two hours, and then filtered to remove inorganic salts. The filtrate was evaporated in vacuo, re-suspended in ethyl acetate, and filtered again. The filtrate was evaporated in vacuo to provide 4.01 g of N-(2,4-Dimethoxy-benzyl)-2-iodo-acetamide, which was carried forward without purification. LCMS (Method E, ESI): RT=1.46 min, m+H=336.2; 1H NMR (400 MHz, CDCl3) δ: 7.17 (d, J=8.2, 1H), 6.55 (s, 1H), 6.47 (d, J=2.2, 1H), 6.44 (dd, J=8.2, 2.3, 1H), 4.36 (d, J=5.8, 2H), 3.85 (s, 3H), 3.80 (s, 3H), 3.68 (s, 2H).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12](S(C)(=O)=O)[N:11]=2)=[CH:8][C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:25]1([OH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:11]=2)=[CH:8][C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccnc(S(C)(=O)=O)n2)n(C(C)(C)C)n1
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccnc(Oc3ccccc3)n2)n(C(C)(C)C)n1
Yield: 77 %

Procedure:
50 mg (0.142 mmol) of ethyl 1-tert-butyl-5-[2-(methylsulfonyl)pyrimidin-4-yl]-1H-pyrazole-3-carboxylate were dissolved in 1.5 mL of dry DMF, 14.7 mg (0.156 mmol) of phenol and 59 mg (0.426 mmol) of potassium carbonate were added. The final suspension was stirred at 70° C. for 3 h then partitioned between H2O and AcOEt. The organic layer was washed with brine dried over Na2SO4, filtered and concentrated under reduced pressure to provide the title compound (77%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:32][C@H:33]1[NH:38][CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34]1>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH2:29][N:38]3[CH2:37][CH2:36][NH:35][CH2:34][C@H:33]3[CH3:32])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(CN3CCNC[C@H]3C)c2c1

Procedure:
The title compound was prepared as a solid according to the method of Example 81 using the product of Example 75 step i) and (R)-3-methylpiperazine-1-carboxylic acid, tert-butyl ester and the product purified by HPLC.