Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[C:32]2[C:27](=[C:28]([Cl:33])[CH:29]=[CH:30][CH:31]=2)[N:26]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43]OS(C)(=O)=O)=[CH:37][CH:36]=2)[CH:25]=1)(=O)C.[N-:49]=[N+]=[N-].[Na+].O>CN(C)C=O>[NH2:49][CH2:43][CH2:42][O:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][N:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[C:24]([C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[CH:25]2)=[CH:40][CH:39]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cn(Cc3ccc(OCCOS(C)(=O)=O)cc3)c3c(Cl)cccc23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NCCOc1ccc(Cn2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3cccc(Cl)c32)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 21.7 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-7-chloro-1-{4-[2-(methanesulfonyloxy)ethoxy]-benzyl}-1H-indole (85 mg) in N,N-dimethylformamide (2 mL) was added sodium azide (12 mg), and the mixture was stirred at 100° C. for 2 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was dissolved in a mixed solvent of methanol (2 mL) and tetra hydrofuran (3 mL). To the solution was added sodium methoxide (28% methanol solution, 0.30 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethylacetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was dissolved in tetra hydrofuran (3 mL). To the solution were added water (0.3 mL) and triphenylphosphine (36 mg), and the mixture was stirred at room temperature for 3 days. The solvent was removed under reduced pressure, and the residue was purified by preparative reverse phase column chromatography (Shiseido CAPCELL PAK C18 ODS, UG80, 5 μm, 20×50 mm, linear gradient water/methanol=90/10-10/90, flow rate 30 mL/min) to give the title compound (12 mg).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:22]CC2C=CC(OC)=CC=2)[C:5]([NH:8][C:9]([C:11]2[N:12]([CH3:21])[N:13]=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:15]=2[Cl:16])=O)=[N:6][CH:7]=1.[C:32](O)([C:34]([F:37])([F:36])[F:35])=O>>[C:17]([C:14]1[C:15]([Cl:16])=[C:11]([C:9]2[NH:22][C:4]3=[N:3][C:2]([C:18]4[CH:17]=[CH:14][CH:15]=[CH:11][C:32]=4[C:34]([F:37])([F:36])[F:35])=[CH:7][N:6]=[C:5]3[N:8]=2)[N:12]([CH3:21])[N:13]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(CNc2nc(Br)cnc2NC(=O)c2c(Cl)c(C(C)(C)C)nn2C)cc1
Product: Cn1nc(C(C)(C)C)c(Cl)c1-c1nc2ncc(-c3ccccc3C(F)(F)F)nc2[nH]1
Temperature: 65 °C
Reaction time: 3 h

Procedure:
A solution of 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [5-bromo-3-(4-methoxy-benzylamino)-pyrazin-2-yl]-amide (28 mg, 0.04 mmol, prepared as described in the previous step) in TFA (3.5 mL) was stirred at 65° C. for 3 h. The resulting mixture was allowed to cool to room temperature, TFA was removed in vacuo and the resulting residue was dissolved in EtOAc (10 mL) and washed with saturated NaHCO3 (20 mL). EtOAc layer was separated, dried (Na2SO4), and concentrated in vacuo. The resulting residue was dissolved in HOAc (3.5 mL) and stirred at 100° C. overnight. The resulting mixture was allowed to cool to room temperature and the HOAc was removed in vacuo. The resulting residue was dissolved in EtOAc (10 mL) and washed with saturated NaHCO3 (10 mL). EtOAc layer was separated, dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified on silica 0:100-50:50 EtOAc-hexane to yield 2-(5-tert-butyl-4-chloro-2-methyl-2H-pyrazol-3-yl)-6-(2-trifluoromethyl-phenyl)-1H-imidazo[4,5-b]pyrazine. 1H-NMR (CD3OD) δ: 8.53-8.57 (br s, 1H), 7.82-7.86 (m, 1H), 7.68-7.74 (m, 1H), 7.61-7.67 (m, 1H), 7.57-7.60 (m, 1H), 4.19 (s, 3H), 1.43 (s, 9H). Mass Spectrum (LCMS, ESI pos.): Calculated for C20H18ClF3N6: 435.1 (M+H); Measured: 435.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=O)[O:6]/[C:5]/2=[CH:13]\[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])[CH:15]=1.O.[NH2:32][NH2:33]>O.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[C:7](=[O:6])[NH:33][N:32]=[C:5]2[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])[CH:15]=1
Reactant: NN
Reactant: COC1CCN(C(=O)c2cc(/C=C3\OC(=O)c4cc(Cl)c(Cl)cc43)ccc2F)CC1
Solvent: CN(C)C=O
Solvent: O
Product: COC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4cc(Cl)c(Cl)cc34)ccc2F)CC1
Temperature: 105 °C
Reaction time: 1.5 h
Yield: 35.4 %

Procedure:
(Z)-5,6-dichloro-3-(4-fluoro-3-(4-methoxypiperidine-1-carbonyl)benzylidene)isobenzofuran-1(3H)-one (64) (127 mg, 0.28 mmol) was taken up in water (2 mL) and N,N-dimethylformamide (0.500 mL). The resulting mixture was treated with hydrazine hydrate (0.080 mL, 1.65 mmol) and the reaction was heated to 105° C. with stirring for 90 minutes. The reaction mixture was cooled, diluted with water (˜10 mL) and solid collected by suction filtration to afford the crude product, which was purified by flash silica chromatography, eluting with neat ethyl acetate. Pure fractions were evaporated to dryness and the residue triturated under diethyl ether and dried under vacuum to afford the desired material as a white solid (46.0 mg, 35% yield); 1H NMR (400.132 MHz, DMSO) δ 1.30-1.40 (1H, m), 1.44-1.53 (1H, m), 1.72-1.79 (1H, m), 1.87-1.94 (1H, m), 3.04-3.11 (1H, m), 3.29 (3H, s), 3.30-3.40 (2H, m), 3.44-3.49 (1H, m), 3.92-4.00 (1H, m), 4.37 (2H, s), 7.26 (1H, t), 7.38-7.45 (2H, m), 8.29 (1H, s), 8.40 (1H, s), 12.83 (1H, s); m/z (LC-MS, ESI+), RT=2.13 (M+H 464 & 465.9).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)O)=[C:4]([CH3:16])[CH:3]=1.CC(C)=[O:19].P(=O)(O)(O)O>O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:12])[CH:14]=[CH:15][CH:11]2[OH:19])=[C:4]([CH3:16])[CH:3]=1
Reactant: CC(C)=O
Reactant: Cc1cc(F)cc(C)c1C(O)c1ccco1
Agent: O=P(O)(O)O
Solvent: O
Product: Cc1cc(F)cc(C)c1C1C(=O)C=CC1O
Temperature: 120 °C

Procedure:
A mixture of (4-fluoro-2,6-dimethylphenyl)furan-2-ylmethanol (6 g, 27 mmol), acetone (150 ml), water (24 ml) and orthophosphoric acid (0.6 ml) is heated under microwave conditions at 120° C. for 50 minutes. The organic solvent is evaporated under vacuo, diluted with water (150 ml) and extracted with ethylacetate (3×100 ml). The combined organic extracts are combined, washed with water and brine, dried over anhydrous sodium sulphate, filtered and the filtrate is concentrated in vacuo. The residue is purified by column chromatography on silica gel to give 5-(4-fluoro-2,6-dimethylphenyl)-4-hydroxy cyclopent-2-enone (3 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([NH:21]C(OC(C)(C)C)=O)=[CH:18][CH:19]=2)[C:14]([CH3:29])=[CH:13][C:12]1([CH3:31])[CH3:30])(=[O:10])[CH3:9].[Al+3].[Cl-].[Cl-].[Cl-]>>[C:8]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([NH2:21])=[CH:18][CH:19]=2)[C:14]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)([CH3:29])[CH2:13][C:12]1([CH3:30])[CH3:31])(=[O:10])[CH3:9]
Reactant: Fc1ccccc1
Reactant: CC(=O)N1c2ccc(NC(=O)OC(C)(C)C)cc2C(C)=CC1(C)C
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)N1c2ccc(N)cc2C(C)(c2ccc(F)cc2)CC1(C)C

Procedure:
Friedel-Crafts alkylation of fluorobenzene (2 ml) with 1-acetyl-6-(tert-butoxycarbonyl)amino-1,2-dihydro-2,2,4-trimethylquinoline (25 mg) in the presence of AlCl3 (35 mg) was performed according to the method described in example 3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[Cl:18][C:19]1[C:20]([C:29](O)=[O:30])=[N:21][CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:20]3[C:19]([Cl:18])=[CH:24][C:23]([C:25]([F:27])([F:26])[F:28])=[CH:22][N:21]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@H]1F
Reactant: O=C(O)c1ncc(C(F)(F)F)cc1Cl
Product: C[C@]1(c2cc(NC(=O)c3ncc(C(F)(F)F)cc3Cl)ccc2F)N=C(N)OC[C@H]1F

Procedure:
The condensation of (4R,5S)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.1) and 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=449.2 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].C1(C)C(S(O[CH2:31][CH2:32][CH:33]2[CH2:37][CH:36]=[CH:35][CH2:34]2)(=O)=O)=CC=CC=1>>[CH:33]1([CH2:32][CH2:31][N:8]2[C:9]([S:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])[CH2:37][CH:36]=[CH:35][CH2:34]1
Reactant: Cc1ccccc1S(=O)(=O)OCCC1CC=CC1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2CCC2CC=CC2)c1
Yield: 34.8 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenylthio)-2,4-pyrimidinedione and 2-(cyclopent 3-en-1-yl)ethyl toluenesulfonate were reacted by the same method with example 35 to obtain the titled compound (134 mg).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:30])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:51][C:52]1[O:53][C:54](=[O:58])[O:55][C:56]=1[CH3:57].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([O:30][CH2:51][C:52]2[O:53][C:54](=[O:58])[O:55][C:56]=2[CH3:57])[C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26][C:27](=[O:29])[CH3:28])[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]3[O:14][C:15](=[O:17])[CH3:16])[C:6]=2[N:7]=1
Reactant: Cc1oc(=O)oc1CO
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3c(OCc4oc(=O)oc4C)nc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 71.1 %

Procedure:
To a solution of triacetate 25 (1.55 g, 3.50 mmol) in THF (50 mL) at 0° C. was added polymer supported-triphenylphosphine (4.95 g, 10.50 mmol, Argonaut). To this mixture was added 4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one (0.91 g, 7.00 mmol), prepared according to the procedure of Alepegiani, Syn. Comm., 22(9), 1277-82 (1992) Diethyl azodicarboxylate (0.73 ml, 4.60 mmol) was then added dropwise. The resulting mixture was stirred at room temperature for 48 h, filtered and washed with MeOH and CHCl3. The filtrate was concentrated and purified by flash column chromatography (silica, acetone/CHCl3=10-20%) to afford dioxolone derivative 66 (1.38 g, 71%) as white solid: 1H (400 MHz, d6-DMSO) 66; δ 7.06 (s, 2H), 6.00 (d, J=4.0 Hz, 1H), 5.92 (dd, J=6.6, 4.4 Hz, 1H), 5.56 (t, J=6.4 Hz, 1H), 5.30 (s, 2H), 4.38 (dd, J=11.6, 3.6 Hz, 1H), 4.25 (t, J=3.6 Hz, 1H), 4.10 (q, J=6.0 Hz, 1H), 2.23 (s, 3H), 2.08 (s, 3H), 2.07 (s, 3H), 2.00 (s, 3H); MS (+)-ES [M+H]+ m/z 555.3. Elemental Analysis calc'd for C21H22N4O12S.Me2CO: C, 47.06; H, 4.61; N, 9.15; S, 5.23. Found: C, 47.25; H, 4.37; N, 9.53; S, 5.52.
Reaction SMILES: [S-2:1].[Na+].[Na+].[S].Cl[CH2:6][CH2:7][CH2:8][Si:9]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>C(O)C>[CH2:11]([O:10][Si:9]([CH2:8][CH2:7][CH2:6][S:1][S:1][CH2:6][CH2:7][CH2:8][Si:9]([O:16][CH2:17][CH3:18])([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:12]
Reactant: CCO[Si](CCCCl)(OCC)OCC
Reactant: [S-2]
Agent: [Na+]
Agent: [S]
Solvent: CCO
Product: CCO[Si](CCCSSCCC[Si](OCC)(OCC)OCC)(OCC)OCC
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
17.8 kg of virtually anhydrous sodium sulfide are mixed with 190 l of ethanol and added to an enameled 500 l capacity reactor. This is followed by the addition through a fine nozzle of 13.85 kg of sulfur in molten form. The mixture is heated to 50° C. and 190 l of 3-chloropropyltriethoxysilane are metered in within 10 minutes. On account of the exothermic reaction the temperature of the reactor contents rises to 74° C. A further 4.45 kg of virtually anhydrous sodium sulfide are added at this temperature. Three further portions of sodium sulfide are added at 5 minute intervals (i.e. each 5 minutes), the temperature of the reactor contents rising to 82° C. After completion of the sodium sulfide addition the reaction mixture is kept for 1.5 hours at 82-83° C. and the sodium chloride that has precipitated is separated after cooling the mixture. A yellow product is obtained after evaporating the reaction mixture in vacuo and renewed fine filtration. HPLC analysis confirms the presence of a product with a mean polysulfane chain length of 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[CH:12]1([CH:18]=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([CH:18]([OH:19])[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:10]#[N:11])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: COc1ccc(CC#N)cc1
Reactant: O=CC1CCCCC1
Product: COc1ccc(C(C#N)C(O)C2CCCCC2)cc1
Yield: 68 %

Procedure:
Reaction of p-methoxyphenylacetonitrile and cyclohexane-carboxaldehyde on a 20 mmol scale according to the procedure in Example 1, and two successive recrystallizations from chloroform/hexane gave 3.51 g of the desired anti-aldol product (68%), mp: 112.0-113.2° C. NMR (1H, 13C), IR, and Mass spectra were consistent with the assigned structure. Analysis: Calcd for C16H21NO2 : C, 74.10; H, 8.16; N, 5.40. Found: C, 74.25; H, 8.15; N, 5.39.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.Cl.[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[C:24]([C:26]3[CH:35]=[C:34]4[C:29]([CH2:30][CH2:31][NH:32][CH2:33]4)=[CH:28][CH:27]=3)[N:23]=[C:22]([NH2:36])[N:21]=2)[CH2:16][CH2:15]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:32]2[CH2:31][CH2:30][C:29]3[C:34](=[CH:35][C:26]([C:24]4[CH:25]=[C:20]([N:17]5[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]5)[N:21]=[C:22]([NH2:36])[N:23]=4)=[CH:27][CH:28]=3)[CH2:33]2)=[O:10])=[CH:4][CH:3]=1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Cc3ccc(F)cc3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 2 starting from (4-fluorophenyl)acetyl chloride (Aldrich, Cat. #466956) and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=461.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH2:15])=[N:10][C:9]=2[CH3:16])=[CH:4][CH:3]=1.Cl>C(O)C.[Pd]>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]([CH3:16])[N:10]=[C:11]([NH:14][NH2:15])[NH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1nc(NN)nnc1-c1ccc(Cl)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC1N=C(NN)NN=C1c1ccc(Cl)cc1
Yield: 80.4 %

Procedure:
6-(4-Chlorophenyl)-3-hydrazino-5-methyl-1,2,4-triazine (4.36 g) was dissolved in ethanol (70 ml) containing anhydrous hydrogen chloride, and then hydrogenated over 5% palladium on carbon (0.73 g) under atmospheric pressure at room temperature. After the theoretical amount of hydrogen gas was absorbed, the catalyst was filtered off. The filtrate was evaporated under reduced pressure to give a residual solid, which was recrystallized from diluted hydrochloric acid to give colorless crystals of 6-(4-chlorophenyl)-3-hydrazino-5-methyl-2,5-dihydro-1,2,4-triazine hydrochloride (2.04 g), m.p. 207°~208° C.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]2[CH2:24][CH2:23][C@H:22]([CH2:25][OH:26])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1>ClCCl.C(OCC)C>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C@H:19]2[CH2:20][CH2:21][C@H:22]([CH:25]=[O:26])[CH2:23][CH2:24]2)=[CH:17][CH:18]=1
Reactant: OC[C@H]1CC[C@H](c2ccc(F)cc2)CC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C[C@H]1CC[C@H](c2ccc(F)cc2)CC1
Reaction time: 4 h

Procedure:
A suspension of 11.35 g of pyridinium chlorochromate in 80 ml of dichloromethane was treated dropwise with a solution of 6.06 g of (trans-4-(4-fluorophenyl)cyclohexyl]methanol in 18 ml of diethyl ether. The reaction mixture was stirred for 4 hours, then diluted with 50 ml of diethyl ether, decanted off from the dark residue and filtered. Concentration of the filtrate gave 4.86 g of trans-4-(4-fluorophenyl)cyclohexanecarboxaldehyde as a yellowish oil which solidified at room temperature; m.p. <30° C.
Reaction SMILES: [OH-].[Na+].[NH:3]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[C@H:4]([C:17]([O:19]C)=[O:18])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][CH:7]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O>[NH:3]([C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])[C@H:4]([C:17]([OH:19])=[O:18])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Aqueous sodium hydroxide (1 N, 15 ml, 15 mmoles) was added to an ice-cold solution of Z-Tyr(But)-OMe (3.85 g, 10 mmoles) in methanol (20 ml) and the mixture was stirred at 0° to 50° C. for one hr. After completion of the reaction, the solution was acidified with 10% aqueous citric acid, diluted with water (100 ml) and extracted with ethyl acetate. The organic layer was washed several times with water and dried over anhydrous sodium sulfate. Evaporation of the solvent gives Z-Tyr(But)-OH in quantitative yield, which was used as such in the next step. The latter acid and 1-hydroxybenzotriazole (1.62 g, 12 mmoles) were dissolved in dry, distilled dimethylformamide (30 ml), the solution was cooled to 0° C. and dicyclohexylcarbodiimide (2.48 g, 12 mmoles) was added. The mixture was stirred 1 hr at 0° C. and 1 hr at room temperature and a solution of H-Phe-OMe.HCl (2.58 g, 12 mmoles) in dimethylformamide (35 ml) containing N-ethylmorpholine (1.6 ml, 13 mmoles) was added at 0° C. The mixture was stirred at room temperature overnight. After filtering, the filtrate was evaporated and the residue was dissolved in ethyl acetate. The solution was washed with 5% aqueous citric acid, water, saturated NaHCO3 solution and water, dried over sodium sulfate and evaporated. The residue was crystallized twice from methanol-isopropyl ether giving 4.3 g of the title compound: mp 106°-107° C., [α]D -36.40 (1% in dimethylformamide), nmr (CDCl3)δ 1.25(s), 3.60(s) and 5.10(s), and Anal. Calc'd. for C31H36N2O6 : C, 69.91%; H, 6.81%; N, 5.26% and Found: C, 69.63%; H, 6.85%; N, 5.41%.
Reaction SMILES: [CH2:1]([N:5]([CH3:19])[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([OH:18])=O)[CH:14]=2)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][C@@H:54]([CH2:68][C:69]1[CH:74]=[C:73]([F:75])[CH:72]=[C:71]([F:76])[CH:70]=1)[C@H:55]([OH:67])[CH2:56][NH:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[C:61]([CH2:65][CH3:66])[CH:60]=1>C(Cl)Cl>[CH2:1]([N:5]([CH3:19])[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([NH:53][C@@H:54]([CH2:68][C:69]3[CH:70]=[C:71]([F:76])[CH:72]=[C:73]([F:75])[CH:74]=3)[C@H:55]([OH:67])[CH2:56][NH:57][CH2:58][C:59]3[CH:64]=[CH:63][CH:62]=[C:61]([CH2:65][CH3:66])[CH:60]=3)=[O:18])[CH:14]=2)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C)c1nccc2ccc(C(=O)O)cc12
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(C)c1nccc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1-[butyl(methyl)amino]isoquinoline-7-carboxylic acid (130 mg, 0.5 mmol) and N,N-diisopropylethylamine (525 μL, 3.0 mmol) in methylene chloride (6.25 mL) was added HBTU (190 mg, 0.5 mmol) and the reaction mixture was stirred for 0.5 h. (2R,3S)-3-Amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (174 mg, 0.42 mmol) was added in one portion and the reaction mixture was stirred at room temperature 18 h. The reaction mixture was diluted with methylene chloride and washed with saturated sodium bicarbonate, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, 1–5% methanol in chloroform) gave 1-[butyl(methyl)amino]-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}isoquinoline-7-carboxamide
Reaction SMILES: [C:1]1([C@H:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B1OC(C)(C)C(C)(C)O1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:20]1[CH:21]=[CH:22][C:17]([C:16]2[O:15][N:14]=[C:13]([CH3:24])[C:12]=2[NH:11][C:10]([O:9][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])=[O:25])=[CH:18][CH:19]=1)[CH3:27]
Reactant: CCOC(=O)Cc1ccccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Product: CCOC(=O)Cc1ccccc1-c1ccc(-c2onc(C)c2NC(=O)O[C@H](C)c2ccccc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-phenyl-ethyl ester and [2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide {4′-[3-Methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-2-yl}-acetic ac id ethyl ester, which was hydrolyzed to the acid as described in Example 34, Step 2.
Reaction SMILES: [P:1]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([O:3][CH2:4][C@@H:5]1[C@@H:12]2[C@@H:8]([O:9]C(C)(C)[O:11]2)[C@H:7]([N:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]([NH2:23])=[O:22])[C:16]2=[O:24])[O:6]1)=[O:2].Cl>O1CCCC1.O>[P:1]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([O:3][CH2:4][C@@H:5]1[C@@H:12]([OH:11])[C@@H:8]([OH:9])[C@H:7]([N:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]([NH2:23])=[O:22])[C:16]2=[O:24])[O:6]1)=[O:2]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](COP(=O)(OCc1ccccc1)OCc1ccccc1)O[C@H]2n1ccnc(C(N)=O)c1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1nccn([C@@H]2O[C@H](COP(=O)(OCc3ccccc3)OCc3ccccc3)[C@@H](O)[C@H]2O)c1=O
Reaction time: 48 h
Yield: 43 %

Procedure:
In a mixture of 2 mL of tetrahydrofuran and 1 mL of water was dissolved 100 mg of {(3aR,4R,6R,6aR)-6-[3-(aminocarbonyl)-2-oxo-1(2H)-pyrazinyl]-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl dibenzyl phosphate. After adjusting the pH value to 0.5 with 6 mol/L hydrochloric acid, the mixture was left to stand at room temperature for 2 days. The deposited solid matter was collected by filtration and washed with ethanol to obtain 40 mg of {(2R,3S,4R,5R)-5-[3-(aminocarbonyl)-2-oxo-1(2H)-pyrazinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl dibenzyl phosphate as a solid product.