Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][C@H:9]([OH:12])[CH2:10]O)([CH3:4])([CH3:3])[CH3:2].CS(Cl)(=O)=O.[OH-].[Na+]>N1C=CC=CC=1.O.CS(C)=O>[C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][C@@H:9]1[CH2:10][O:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC[C@H](O)CO
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC[C@@H]1CO1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49.9 %

Procedure:
((S)-2,3-Dihydroxypropyl)carbamic acid tert-butyl ester (5.00 g, 26.16 mmol) obtained in Step 1 above was dissolved in pyridine (32 ml), and cooled to 0° C. Methanesulfonyl chloride (2.22 ml, 28.71 mmol) was dropwise added to the solution, and stirred for 10 minutes. This solution was dropwise added to a solution of sodium hydroxide (3.18 g, 79.61 mmol) in water (33 ml) and dimethylsulfoxide (22 ml) at 0° C., and stirred for 10 minutes. This reaction solution was poured into ice water (300 ml), and then extracted with a mixture of n-hexane (80 ml) and ethyl acetate (320 ml). The organic layer was separated and washed with water and a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. After the inorganic salt was removed by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: n-hexane to n-hexane:ethyl acetate=4:1) to yield (R)-1-oxiranylmethylcarbamic acid tert-butyl ester (2.26 g).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:14])[C:7]([CH3:13])([CH3:12])[CH2:8][O:9]2)=[CH:4][CH:3]=1.[BH4-].[K+]>CO>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([OH:14])[C:7]([CH3:12])([CH3:13])[CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)COc2cc(Br)ccc2C1=O
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Product: CC1(C)COc2cc(Br)ccc2C1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) solution of 7-bromo-3,3-dimethyl-chroman-4-one (1.5 g, 5.91 mmol) in methanol (17 mL) was added potassium borohydride (0.351 g, 6.5 mmol). After completion of addition the reaction stirred at room temperature for 2 hours and was then quenched with 2M HCl (aq.). The aqueous layer was extracted with ethyl acetate (3×) The combined organic layers were dried over sodium sulfate, filtered, and concentrated to yield an off-white solid, which was used in the next step without further purification.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1.O.[NH2:31][NH2:32]>CN(C=O)C>[CH3:28][O:27][C:24]1[CH:23]=[CH:22][C:21]([CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:32][N:31]=2)=[CH:26][CH:25]=1
Reactant: COc1ccc(CC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)cc1
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)cc1
Yield: 88.5 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-2-(4-methoxyphenyl)ethyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (50 mg, 0.13 mmol, prepared in Synthetic Example 15) in DMF (1 ml) was added hydrazine monohydrate (80%, 1 ml, 24.96 mmol, 192 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (44 mg, 89%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1([CH:20]=[CH:19][CH:18]=[CH:17][CH2:16]1)[CH2:14][OH:15].O>N1C=CC=CC=1>[C:1]([O:15][CH2:14][C:13]1([C:9]2[S:8][CH:12]=[CH:11][CH:10]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH2:20]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: OCC1(c2cccs2)C=CC=CC1
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCC1(c2cccs2)C=CC=CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic anhydride (5 ml) was added to a solution of 1-(2-thienyl)benzyl alcohol in pyridine. The resultant solution was stirred at 70° C. for 3 h. Water (50 ml) was added and the reaction mixture was stirred at room temperature for 2 h. This was extracted with ethyl acetate (2×50 ml) and the combined organic layers dried over anhydrous MgSO4. Removal of the solvent gave crude product, which was purified by passing through silica gel using 3:1 hexane/ethyl acetate mixture to give 1-(2-thienyl)benzyl acetate.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=[O:3].[CH3:12][S:13]([N:16]([CH2:31][CH2:32][Cl:33])[N:17]([S:27]([CH3:30])(=[O:29])=[O:28])C(OC1C=CC=CC=1)=O)(=[O:15])=[O:14]>>[CH3:12][S:13]([N:16]([CH2:31][CH2:32][Cl:33])[N:17]([S:27]([CH3:30])(=[O:29])=[O:28])[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=[O:3])(=[O:14])=[O:15]
Reactant: CS(=O)(=O)N(CCCl)N(C(=O)Oc1ccccc1)S(C)(=O)=O
Reactant: Cc1ccc(OC(=O)Cl)cc1
Product: Cc1ccc(OC(=O)N(N(CCCl)S(C)(=O)=O)S(C)(=O)=O)cc1

Procedure:
1,2-Bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(4-tolyloxy)carbonyl]hydrazine (compound 10e) was prepared by reacting compound 2 with 4-tolyl chloroformate using a procedure similar to that employed for compound 10d. The product was recrystallized from ethanol, and the yield was about 31.2% by weight. The Mp was approximately 85-86° C. 1H NMR (CDCl3): δ 7.3 and 7.1 (4H, 2d, aromatic H), 3.7-4.2 (4H, m, CH2CH2Cl), 3.5 and 3.2 (6H, 2s, 2 CH3SO2), 2.4 (3H, s, ArCH3).
Reaction SMILES: [I:1][C:2]1[C:11]([CH:12]=[O:13])=[C:10]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[C:9]2[CH:8]=[C:7]3[O:22][CH2:23][CH2:24][O:25][C:6]3=[CH:5][C:4]=2[N:3]=1.[BH4-].[Na+]>CO>[I:1][C:2]1[C:11]([CH2:12][OH:13])=[C:10]([CH2:14][N:15]2[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]2)[C:9]2[CH:8]=[C:7]3[O:22][CH2:23][CH2:24][O:25][C:6]3=[CH:5][C:4]=2[N:3]=1
Reactant: CN1CCN(Cc2c(C=O)c(I)nc3cc4c(cc23)OCCO4)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCN(Cc2c(CO)c(I)nc3cc4c(cc23)OCCO4)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 3-necked 2-L round-bottom flask is equipped with an overhead mechanical stirrer and nitrogen flow is maintained. The flask is charged with 7-iodo-9-(4-methyl-piperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-carbaldehyde (105 g, 232 mmol), prepared as in example 13g, as a suspension in 700 mL of methanol. The mixture is cooled to 0° C., then sodium borohydride (8.76 mmol) is added in three portions over 15 min. The mixture is allowed to warm to ambient temperature and stirred for 2 hr. The solvent is mostly removed in vacuo and the resultant residue is treated with 2.5 L of water and extracted with methylene chloride (4×1.5 L). The combined organic layers are washed with brine (2.5 L), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resultant solid residue is successively treated with 300 mL of methylene chloride and 300 mL of MeOH-EtOAc (1:1). The mixture was swirled at 0° C. for 30 min. The precipitate is filtered by suction, washed with 500 mL of hexane and dried in vacuo at 30° C. yielding [7-iodo-9-(4-methyl-piperazin-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-g]quinolin-8-yl]-methanol as an off-white powder: mp 201°-203° C. (dec.). 1H NMR (CDCl3, 200 MHz): δ2.26 (s, 3H), 2.62 (m, 8H), 4.02 (s, 2H). 4.39(s, 4H), 4.93 (m, 2H), 6.05 (br. s, 1H), 7.49 (s, 1H), 7.51 (s, 1H). HRMS (EI+): Calculated for C18H22 N3O3 : 455.0706. Found: 455.0699.
Reaction SMILES: [F: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][CH:12]1[CH2:27][N:16]2[CH2:17][CH2:18][N:19]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:20][CH:15]2[CH2:14][CH2:13]1.[H-].[Na+].[CH3:30]I>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:30])[CH:6]=[C:5]2[CH2:11][CH:12]1[CH2:27][N:16]2[CH2:17][CH2:18][N:19]([C:21]3[N:22]=[CH:23][CH:24]=[CH:25][N:26]=3)[CH2:20][CH:15]2[CH2:14][CH2:13]1
Reactant: Fc1ccc2[nH]cc(CC3CCC4CN(c5ncccn5)CCN4C3)c2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(CC2CCC3CN(c4ncccn4)CCN3C2)c2cc(F)ccc21
Temperature: 50 °C
Yield: 47.1 %

Procedure:
A flame-dried flask was charged with 0.103 g (0.28 mmol) of (7RS,9aSR)-7-(5-fluoro-1H-indol-3-yl)methyl-2-(pyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Example 50), anhydrous DMF (1 mL) and 12 mg (0.30 mmol) of sodium hydride (60% oil dispersion). The suspension was treated with 0.019 mL (0.31 mmol) of methyl iodide and the mixture was heated at 50° C. for 16 h. The mixture was cooled to room temperature, concentrated in vacuo, and diluted with methylene chloride (25 mL) and water (25 mL), and the layers were separated. The organic phase was dried (sodium sulfate), filtered and evaporated to a solid residue. The solid was washed with ethyl acetate (2×), the ethyl acetate was evaporated to give 50 mg of the title compound. 1H NMR (CDCl3): δ 1.00–1.31 (m, 3H), 1.64–2.23 (m, 6H), 2.54–3.1 (m, 5H), 3.69 (s, 3H), 4.51–4.56 (m, 2H), 6.43 (dd, J=1 Hz, 1H), 6.83 (s, 1H), 6.93 (m, 1H), 7.15 (m, 2H), 8.27 (d, J=1 Hz, 2H). TLC Rf: 0.81 (90:10:1 methylene chloride:methanol:ammonium hydroxide).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:29][CH2:30][CH3:31])[CH:26]1[O:28][CH2:27]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:27][CH:26]([OH:28])[CH2:25][O:29][CH2:30][CH3:31])[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: CCOCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOCC(O)Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O
Temperature: 85 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (300 mg, 0.84 mmol), prepared as described in Example 1, in 8 mL of DMF was added ethyl glycidyl ether (86 mg, 0.84 mmol), followed by K2CO3 (232 mg, 1.68 mmol). The mixture was heated at 85° C. After stirring overnight, the reaction was allowed to cool to RT The reaction mixture was diluted with EtOAc (200 mL). The resultant solution was washed with saturated aqueous NaCl (3×40 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified using silica gel column chromatography using an automated system, eluting with a gradient of 0% to 60% EtOAc/hexanes for 30 min followed by 100% EtOAc for 40 min. The title compound, 7,8-bis(4-chlorophenyl)-2-(3-ethoxy-2-hydroxypropyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (0.3 gm, 78% yield) as a yellow solid. MS [M+H]+: found 459; 1H NMR (CDCl3, 400 MHz) δ 8.20 (s, 1H), 7.34-7.25 (m, 6H), 7.09 (d, 2H), 4.29-4.24 (m, 2H), 4.18-4.13 (m, 1H), 3.57-3.49 (m, 4H), 1.17 (t, 3H).
Reaction SMILES: [CH2:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:6][C:7]([F:14])([F:13])[C:8]([F:12])=[C:9]([F:11])[F:10]>>[F:10][C:9]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)([F:11])[CH:8]([F:12])[C:7]([F:14])([F:13])[F:6]
Reactant: FC(F)=C(F)C(F)(F)F
Reactant: C1CCCC1
Product: FC(C(F)(F)F)C(F)(F)C1CCCC1
Yield: 71 %

Procedure:
Cyclopentane (65 mmole) and hexafluoropropene (22 mmole) heated at 290° for 2 days gave a 71% yield (based on hexafluoropropene consumed) of analytically and spectroscopically pure 1,1,2,3,3,3-hexafluoropropylcyclopentane: ##STR15## identical with material prepared by an alternative route.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[CH2:7][N:8]([CH2:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=1)[C:9](=[O:32])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:31])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[C:27]([F:30])([F:29])[F:28])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[CH:70][C:69]([C:72]([NH:74][NH2:75])=[O:73])=[CH:68][CH:67]=2)=[CH:62][CH:61]=1>C1COCC1.CN(C=O)C.C(Cl)Cl>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C:17]([NH:16][C:13]2[CH:14]=[CH:15][C:10]([C:9]([N:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:43])[CH2:33][C:34]3[CH:35]=[CH:36][C:37]([C:38]([NH:75][NH:74][C:72]([C:69]4[CH:68]=[CH:67][C:66]([C:63]5[CH:64]=[CH:65][C:60]([CH3:59])=[CH:61][CH:62]=5)=[CH:71][CH:70]=4)=[O:73])=[O:39])=[CH:41][CH:42]=3)=[O:32])=[CH:11][CH:12]=2)=[O:31])=[C:20]([C:27]([F:29])([F:28])[F:30])[CH:21]=1
Reactant: Cc1ccc(-c2ccc(C(=O)NN)cc2)cc1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(C(=O)O)cc3)cc2)c(C(F)(F)F)c1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(C(=O)NNC(=O)c4ccc(-c5ccc(C)cc5)cc4)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a stirring solution of 4-((N-(2-(tert-butoxy)-2-oxoethyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)methyl)benzoic acid INT-37 (157 mg, 0.26 mmol) and 4-methylmorpholine (63.0 μL, 0.58 mmol) in THF (3 mL) was added isobutyl chloroformate (34.0 μL, 0.26 mmol). After 1 h, the reaction mixture was added to a stirring solution of 4′-methyl-[1,1′-biphenyl]-4-carbohydrazide INT-50 (65.0 mg, 0.29 mmol) in DMF (2 mL). After 2 h, additional 4′-methyl-[1,1′-biphenyl]-4-carbohydrazide INT-50 (12 mg, 0.05 mmol) was added. After stirring at room temperature for 18 h, the reaction mixture was diluted with DCM (4 mL), washed with NaHCO3 (10 mL) and split though a hydrophobic frit. The crude product was purified by column chromatography (EA/isohexanes) to yield 138 mg (65%) of tert-butyl 2-(4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)-N-(4-(2-(4′-methyl-[1,1′-biphenyl]-4-carbonyl)hydrazine carbonyl)benzyl)benzamido)acetate INT-51. LCMS-ESI (m/z) calculated for C45H43F3N4O7: 808; found 809 [M+H]+, tR=2.75 min (Method 5).
Reaction SMILES: O[C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:22])[C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[F:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N+:18]([C:16]1[CH:17]=[C:12]([C:11]2[O:22][C:2]3[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=3[N:10]=2)[C:13]([F:21])=[CH:14][CH:15]=1)([O-:20])=[O:19]
Reactant: O=C(Nc1ccc(F)c(F)c1O)c1cc([N+](=O)[O-])ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c(-c2nc3ccc(F)c(F)c3o2)c1

Procedure:
Prepared by the method of Example 15b), from N-(2-hydroxy-3,4-difluorophenyl)-2-fluoro-5-nitrobenzamide (718 mg, 2.3 mmol) and p-toluenesulfonic acid monohydrate (961 g, 5.1 mmol) the subtitle compound was obtained (303 mg, 45%). 1H NMR (DMSO) δ 8.92(m, 1H), 8.57(m, 1H), 7.85(d, 1H), 7.81(m, 1H), 7.61(m, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:31][C@H:30]([CH2:32][O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C@@H:21]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@@H:12]3[O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:41][NH2:42]>>[NH:41]([C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:31][C@H:30]([CH2:32][O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C@@H:21]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@@H:12]3[O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:4]=2[N:5]=[CH:6][N:7]=1)[NH2:42]
Reactant: Clc1ncnc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: NN
Product: NNc1ncnc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 1 h

Procedure:
A mixture of 10 g of 4-chloro-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine and 100 ml of anhydrous hydrazine is heated under reflux and a nitrogen atmosphere for one hour, evaporated in vacuo, and coevaporated with xylenes. The residue is distributed between a mixture of ethyl acetate and water. The aqueous layer is reextracted with ethyl acetate and the dried ethyl acetate solution is evaporated in vacuo to provide 9.0 g of crude product. Purification of this material by silica gel chromatography (ethyl acetate) provides pure 4-hydrazino-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine as a yellow syrup.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:13][CH3:14])[C:8]([NH2:12])=[CH:9]2)=[CH:4][CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].N1C=CC=CC=1>O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([O:13][CH3:14])[C:8]([NH:12][C:15](=[O:17])[CH3:16])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: COc1cc2ccc(Br)cc2cc1N
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2ccc(Br)cc2cc1NC(C)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
A mixture of 7-bromo-3-methoxy-naphthalen-2-ylamine (2.2 g, 8.76 mmol), acetic anhydride (1.4 g, 13.14 mmol) and pyridine (20 mL) was stirred at room temperature for 3 hours. Water (300 mL) was added and the solid precipitate was collected by filtration and copiously washed with water. The solid residue was dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 2.569 g of N-(7-bromo-3-methoxy-naphthalen-2-yl)-acetamide as a light pink solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[N:12]=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[N:12]=[N:13][CH:14]=2)=[CH:3][C:2]=1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[F:23]
Reactant: Fc1ccc(-c2nncc(-c3ccc(F)c(Br)c3)n2)c(F)c1
Reactant: OB(O)c1ccccc1F
Product: Fc1ccc(-c2nncc(-c3ccc(F)c(-c4ccccc4F)c3)n2)c(F)c1

Procedure:
5-(3-Bromo-4-fluorophenyl)-3-(2,4-difluorophenyl)-[1,2,4]triazine was coupled to 2-fluorophenylboronic acid by the method of Example 12 to give 5-(2,2′-difluorobiphenyl-5-yl)-3-(2,4-difluorophenyl)-[1,2,4]triazine as a fluffy yellow solid: δH (400 MHz, CDCl3) 6.99-7.10 (2H, m), 7.21-7.23 (1H, m), 7.27-7.31 (1H, m), 7.37-7.48 (3H, m), 8.29-8.35 (3H, m), 9.64 (1H, s); m/z (ES+) 382.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[CH2:24]([O:26][C:27](=[O:35])[CH2:28][C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1)[CH3:25].C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O>[CH2:24]([O:26][C:27](=[O:35])[CH2:28][C:29]1[N:30]=[C:31]([NH:34][C:9](=[O:11])[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[S:32][CH:33]=1)[CH3:25]
Reactant: O=C(O)C(CC1CCCC1)c1cccc(Cl)c1
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1csc(NC(=O)C(CC2CCCC2)c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
A solution of 2-(3-chloro-phenyl)-3-cyclopentyl-propionic acid (252 mg, 1.0 mmol) in methylene chloride (10 mL) was cooled to 0° C. and then treated with a 2.0 M solution oxalyl chloride in methylene chloride (0.6 mL, 1.2 mmol) and a few drops of N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 15 min and at 25° C. for 2 h. The reaction mixture was then treated with (2-amino-thiazol-4-yl)-acetic acid ethyl ester (409 mg, 2.2 mmol) and N,N-diisopropylethylamine (0.5 mL, 2.4 mmol). This solution was stirred at 25° C. for 48 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded {2-[2-(3-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazol-4-yl}-acetic acid ethyl ester (254 mg, 60.3%) as a white solid: mp 121-125° C.; EI-HRMS m/e calcd for C21H25ClN2O3S (M+) 420.1274, found 420.1268.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[NH:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:16][C:17]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>O.C(Cl)Cl>[CH3:16][C:17]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:9])=[O:20]
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cc1cccc(C(=O)Cl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1cccc(C(=O)NNC(=O)OC(C)(C)C)c1C
Reaction time: 0.25 h
Yield: 101.7 %

Procedure:
T-butylcarbazate (35.15 g, 266 mmol) and 200 mL of CH2Cl2 were added to a round bottom flask. Potassium carbonate (55.2 g, 0.4 moles) dissolved in 350 mL of water was added to the flask, and the mixture was stirred for 15 minutes with ice chilling. 2,3 dimethylbenzoyl chloride (44.9 g, 266 mmol) in ca. 200 mL of CH2Cl2 was added drop-wise from a 500 mL separatory funnel over 30 minutes. The reaction was allowed to stir overnight and then the reaction mixture was poured into a 1 L separatory funnel and the CH2Cl2 phase was separated. Then ca. 150 mL of water was added, and the mixture was extracted twice with 150 mL of CHCl3. The combined organic phase was back-extracted with 100 mL of water, then with 1N HCl (250 mL), to remove the hydrazide. The organic phase was dried, stirred with charcoal, and the solvent removed in vacuo to yield a light tan solid (71.5 g) of N′-(2,3-dimethyl-benzoyl)-hydrazinecarboxylic acid, tert-butyl ester. 1H NMR (300 MHz, CHCl3) δ (ppm): 7.7 (br, 1H), 7.22 (m, 2H), 7.1 (t, 1H), 7.85 (br, 1H), 2.35 (s, 3H), 2.3 (s, 3H), 1.5 (s, 9H).
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BrH:14].CS(C)=O>C(O)(=O)C.O>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([OH:13])=[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH:12]=1
Reactant: Br
Reactant: Oc1ccccc1C1CCCCC1
Solvent: O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: Oc1ccc(Br)cc1C1CCCCC1
Yield: 93 %

Procedure:
To a stirring solution of 2-cyclohexylphenol (26.0 g, 146.8 mmol) in glacial acetic acid (100 mL) was added HBr in acetic acid (150 mL of 33% w/w,) and H2O (52 mL), followed by the dropwise addition of DMSO (100 mL) over 10 min. The reaction was then carefully quenched with saturated NaHCO3 and concentrated in vacuo. The residue was brought up in ether (400 mL), washed with water (2×100 mL) and brine (1×100 mL), and dried over anhydrous Na2SO4, filtered and concentration to yield a crude oil that was purified by silica gel column chromatography, using 15-30% EtOAc/hexane gradient to yield 4-bromo-2-cyclohexyl-phenol (35.0 g, 93%)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:15][O:16][CH3:17])([CH2:12][O:13][CH3:14])[CH:9]3[O:18][CH:8]3[C:7]=2[CH:19]=1)#[N:2].[C:20]([C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)#[N:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:15][O:16][CH3:17])([CH2:12][O:13][CH3:14])[C@@H:9]([OH:18])[C@H:8]([N:24]3[C:25]4[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:22]([C:20]#[N:21])=[CH:23]3)[C:7]=2[CH:19]=1)#[N:2]
Reactant: COCC1(COC)Oc2ccc(C#N)cc2C2OC21
Reactant: N#Cc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCC1(COC)Oc2ccc(C#N)cc2[C@@H](n2cc(C#N)c3ccccc32)[C@@H]1O
Yield: 64.3 %

Procedure:
A reaction mixture containing 6-cyano-3,4-epoxy-3,4-dihydro-2,2-bis(methoxymethyl)-2H-1-benzopyran (300 mg), 3-cyanoindole (210 mg) and potassium carbonate (480 mg), in dimethylformamide (3 ml), was stirred at 80° C. for 2.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water, 1N-hydrochloric acid, an aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2) to give 298 mg of the title compound.