Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22](Br)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2].CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.[NH:70]1[CH2:74][CH2:73][CH2:72][CH2:71]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOCC>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([N:70]3[CH2:74][CH2:73][CH2:72][CH2:71]3)=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:41][CH3:42])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(Br)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reactant: C1CCNC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(N3CCCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
(2R*,4S*)-4-{[3,5-Bis(trifluoromethyl)benzyl]-(5-bromopyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (250 mg) is dissolved in toluene (2 ml), and thereto are added tris(dibenzylideneacetone)dipalladium (6.9 mg), sodium tert-butoxide (54.8 mg), 2-(di-tert-butylphosphino)biphenyl (9.0 mg) and pyrrolidine (47 μl). The mixture is stirred at room temperature for 45 minutes under nitrogen flow, then heated to 80° C, and stirred for 18 hours. After cooling to room temperature, ether is added to the reaction solution. The mixture is filtered, and the filtrate is concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=9:1→7:3) to give (2R*,4S*)-4-{[3,5-bis(trifluoromethyl)benzyl]-[5-(pyrrolidin-1-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (158.5 mg). MS (m/z): 653 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:25][C:26]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:27]=1[CH2:28][C:29]1([NH2:32])[CH2:31][CH2:30]1.FC(F)(F)C([O-])=O>>[CH3:25][C:26]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][C:27]=1[CH2:28][C:29]1([NH:32][CH2:21][CH:20]([C:12]2[C:13]3[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=3[C:9]([OH:8])=[CH:10][CH:11]=2)[OH:24])[CH2:30][CH2:31]1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Reactant: Cc1ccc(CC2(N)CC2)c(C)c1
Agent: O=C([O-])C(F)(F)F
Product: Cc1ccc(CC2(NCC(O)c3ccc(O)c4c3OCC(=O)N4)CC2)c(C)c1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 175 mg (1 mmol) 1-(2,4-dimethyl-benzyl)-cyclopropylamine. Yield: 176 mg (36%, trifluoroacetate); mass spectroscopy: [M+H]=383.
Reaction SMILES: [CH2:1]([S:3][C:4]1(SCC)[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:20]([C@@H:21]([OH:23])[CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C:13](=[CH:14][C:15](=[O:24])[CH:16]=[CH:17]1)[CH2:12][CH2:11]3)[CH3:2]>C(C1C=CC=CC=1CC)C>[CH2:1]([S:3][C:4]1[C@:5]2([CH2:22][C@H:21]([OH:23])[C@H:20]3[C@@H:10]([CH2:11][CH2:12][C:13]4[C@:18]3([CH3:19])[CH:17]=[CH:16][C:15](=[O:24])[CH:14]=4)[C@@H:7]2[CH2:8][CH:9]=1)[CH3:6])[CH3:2]
Reactant: CCSC1(SCC)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Agent: CCc1ccccc1CC
Product: CCSC1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]12C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 80.5 %

Procedure:
A suspension of 4.4 g of 17,17-bis(ethylthio)-11β-hydroxyandrosta-1,4-dien-3-one (see example 2) in 100 ml of dry diethyl benzene is stirred at 190°-195° C. (oil bath temperature) for 1.5 hours. The suspension becomes a solution during the heating; the resulting solution is cooled to 0° C. The solid that precipitates is filtered and dried in vacuo to give 3.0 g of the title compound, melting point 216°-218° C., with consistent spectral data.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:39])[F:38])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH:29]3C)=[O:27])[N:9]=2)[CH:7]=1.[CH3:40]C1NCCN(C(OC(C)(C)C)=O)C1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:36][CH:37]([F:38])[F:39])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:28]3[CH2:29][CH2:30][N:31]([CH3:34])[CH:32]([CH3:40])[CH2:33]3)=[O:27])[N:9]=2)[CH:7]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: CC1CN(C)CCN1C(=O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Product: CC1CN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CCN1C

Procedure:
Using synthetic method analoguous that of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-(2,4-dimethylpiperazin-1-yl)-2-oxoethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide, the title compound was prepared from tert-butyl 3-methylpiperazine-1-carboxylate. LCMS (Method 20) [M+H]+=559.2, RT=2.23 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.34 (dd, 1H, J=1.5 Hz, 7.2 Hz), 8.69-8.67 (m, 2H), 8.31 (s, 1H), 7.62 (dd, 1H, J=2.7, 8.7 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=8.7 Hz), 7.28 (dd, 1H, J=4.2, 6.9 Hz), 7.02 (t, 1H, J=73.2 Hz), 5.35-5.13 (m, 2H), 4.18-4.02 (m, 1H), 3.86-3.78 (m, 1H), 3.26-3.10 (m, 1H), 2.84-2.73 (m, 2H), 2.26-1.91 (m, 5H), 1.01 (d, 3H, J=6.0 Hz).
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[C:8]=2[N:9]=1)[CH3:2].[H-].[Na+].I[CH3:31].O>CN(C)C=O>[CH2:1]([S:3][C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][N:11]([CH3:31])[C:10](=[O:14])[C:8]=2[N:9]=1)[CH3:2]
Reactant: CCSc1nc2c(=O)[nH]ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCSc1nc2c(=O)n(C)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 2-(ethylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]-3,7-dihydropyrido[3,4-d]pyrimidine-4,8-dione (40 mg) in N,N-dimethylformamide (5 ml) was added sodium hydride (60% in oil, 193 mg) at room temperature, and the mixture was stirred for 10 min. To the reaction mixture was added iodomethane (0.009 ml), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added water, and the precipitate was collected by filtration. The obtained solid was suspended in toluene, and the suspension was concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of hexane/ethyl acetate/methanol to give the title compound (33 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[CH:7]([CH2:14][C:15]([OH:17])=O)[CH2:6][CH2:5]2.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH3:12])[C:8](=[O:13])[CH:7]([CH2:14][C:15]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17])[CH2:6][CH2:5]2
Reactant: Cc1cc2c(cc1C)C(=O)C(CC(=O)O)CC2
Reactant: C1CCNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc2c(cc1C)C(=O)C(CC(=O)N1CCCC1)CC2
Reaction time: 3 h
Yield: 96.7 %

Procedure:
To a solution of 1,2,3,4-tetrahydro-6,7-dimethyl-1-oxo-2-naphthalene-acetic acid (8.0 g), pyrrolidine (3.8 g) and benzotriazol-1-yloxy-tris(dimethyl-amino) phosphonium hexafluorophosphate (BOP Reagent,16.7 g) in dichloro-methane (80 ml) was added dropwise triethylamine (3.8 g) at 25° C., and the mixture was stirred for three hours. The mixture was concentrated under reduced pressure to remove the solvent, and to the residue were added water and toluene, and the insoluble materials were removed by filtration. The toluene layer was collected, washed successively with 1N aqueous sodium hydroxide solution, water and a saturated aqueous sodium chloride solution, an dried over anhydrous sodium sulfate. The resultant was concentrated under reduced pressure to remove the solvent, and the residue was purified by silica gel column chromatography (eluent; toluene-ethyl acetate=10:1), and the fractions containing the desired compound were combined, and concentrated under reduced pressure to give the desired compound (9.5 g) as an oily product.
Reaction SMILES: [C:1]([N:6]1[C:14]2[C:9](=[C:10]([CH3:17])[C:11]([OH:16])=[C:12]([CH3:15])[CH:13]=2)[CH:8]([CH3:18])[CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].N1C=CC=CC=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(Cl)Cl>[C:1]([N:6]1[C:14]2[C:9](=[C:10]([CH3:17])[C:11]([O:16][C:25](=[O:27])[CH3:26])=[C:12]([CH3:15])[CH:13]=2)[CH:8]([CH3:18])[CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2c(c(C)c1O)C(C)CN2C(=O)C(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1c(C)cc2c(c1C)C(C)CN2C(=O)C(C)C
Temperature: 0 °C
Reaction time: 17 h
Yield: 77.8 %

Procedure:
To an ice-cold solution of N-isobutyryl-5-hydroxy-3,4,6-trimethylindoline (11b, 49 mg, 0.2 mmol) dissolved in methylene chloride (2 mL) were added sequentially pyridine (0.16 mL, 2 mmol) and acetic anhydride (0.1 mL, 1 mmol). The mixture was stirred over the range of 0° C. to room temperature for 17 h. The mixture was diluted with methylene chloride, transferred to a separatory funnel and washed sequentially with 10% hydrochloric acid, saturated aq. sodium bicarbonate and brine. Removal of solvents after drying (MgSO4) gave a viscous liquid, which was purified by flash column chromatography, using 1:4 ethyl acetate:hexanes as eluent, to afford the N-isobutyryl-5-acetoxy-3,4,6-trimethylindoline (12b, 45 mg, 77% yield) as a colorless solid, mp 118°-120° C. Spectral data: 1H NMR: δ 2.0 (s, 3H), 2.06 (s, 3H), 2.26 (s, 3H), 2.7 (quintet, 1H, J=6.7 Hz), 3.3 (t, 1H, J=6.7 Hz), 3.7 (dd, 1H, J=10.2, 1.2 Hz), 4.1 (t, 1H, J=9.3 Hz), 8.0 (s, 1H); CI-HRMS: calcd. for C17H24NO3 (M+H+) 290.1756, fnd. 290.1756.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=1)=O.[C:12](=[S:15])([NH2:14])[CH3:13]>C(O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:14]=[C:12]([CH3:13])[S:15][CH:2]=2)=[N:6][CH:7]=1
Reactant: CC(N)=S
Reactant: O=C(CBr)c1ccc(Br)cn1
Solvent: CCO
Product: Cc1nc(-c2ccc(Br)cn2)cs1
Temperature: 75 °C
Reaction time: 18 h
Yield: 56.3 %

Procedure:
2-bromo-1-(5-bromopyridin-2-yl)ethanone (3.77 g, 13.5 mmol) was dissolved in ethanol (32 mL) and ethanethioamide (1.12 g, 14.8 mmol) was added and the reaction stirred for 18 h at 75° C. The mixture was concentrated; the residual solid was dispersed in ethyl acetate (100 mL), and treated with saturated sodium bicarbonate solution (100 mL) until no further gas evolution was noted. The combined organics were washed with water (50 mL) and brine (50 mL). The aqueous washes were back-extracted with ethyl acetate (100 mL) and the combined organic layers were dried over magnesium sulfate, treated with Darco, filtered through a paper filter, and concentrated to give a yellow solid. The crude product was purified by flash chromatography (90 g silica gel, 1-5% methanol in ethyl acetate). The major product was further purified by flash chromatography (40 g silica gel, 10% ethyl acetate in hexane) to give the title compound (1.94 g) as a colorless crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C@@H:17]([CH2:20][O:21][CH3:22])[CH2:18][CH3:19])[C:11]=1[NH2:23].[C:24](OCC)(=[O:28])[C:25]([CH3:27])=O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[C:11]2[N:23]=[C:25]([CH3:27])[C:24](=[O:28])[N:16]([C@@H:17]([CH2:20][O:21][CH3:22])[CH2:18][CH3:19])[C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: CC[C@H](COC)Nc1ncnc(-c2ccc(OC)cc2Cl)c1N
Reactant: CCOC(=O)C(C)=O
Solvent: CCO
Product: CC[C@H](COC)n1c(=O)c(C)nc2c(-c3ccc(OC)cc3Cl)ncnc21
Temperature: 100 °C
Reaction time: 18 h

Procedure:
(R)-6-(2-Chloro-4-methoxy-phenyl)-N4-(1-methoxymethyl-propyl)-pyrimidine-4,5-diamine (0.20 g, 0.60 mmol) was diluted in ethanol (6 ml) and ethyl pyruvate was added (0.68 ml, 6.0 mmol). The mixture was stirred for 18 hours at which time the solution was concentrated. The residue was diluted in glacial acetic acid (10 ml) and warmed to 100° C. for 1 hour. After concentrating the solution the product was purified by reverse phase HPLC to yield 5.0 mg of (R)-4-(2-chloro-4-methoxy-phenyl)-8-(1-methoxymethyl-propyl)-6-methyl-8H-pteridin-7-one (Example 571a). 1H NMR (300 MHz, CDCl3) δ ppm 9.02 (s, 1 H), 7.41 (d, J=8.79 Hz, 1 H), 7.05 (d, J=2.56 Hz, 1 H), 6.93 (dd, J=8.79, 2.56 Hz, 1 H), 3.87 (s, 3 H), 3.73 (m, 2 H), 3.29 (s, 3 H), 2.63 (m, 2H), 2.49 (s, 3 H), 2.10 (m, 2 H), 0.87 (t, J=7.51 Hz, 3 H). MS (AP) 389.3 [(M+H)+, 100].
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])(C)(C)C.[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCCCCC.C(OCC)(=O)C>O1CCCC1.CCCCC.O>[CH2:14]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27]([OH:30])([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[O:7][CH3:8])[CH2:26][CH2:25]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: COc1ccccc1
Agent: [Li]C(C)(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccccc1C1(O)CCN(C(=O)OCc2ccccc2)CC1
Temperature: -15 °C
Reaction time: 0.75 h

Procedure:
A solution of anisole (2.19 g) in tetrahydrofuran (50 mL) was cooled to -78° C. and treated with tert-butyl lithium (12 mL of a 1.7M solution in pentane). The resulting reaction mixture was warmed to -15° C. and stirred for 45 minutes. The reaction mixture was cooled back to -78° C. and treated with a solution of 1-benzyloxycarbonyl-4-piperidone (4.67 g) in tetrahydrofuran (5 mL). The reaction mixture was warmed to -15° C. and stirred for 1 hour before it was allowed to reach ambient temperature and stirred for 72 hours. The reaction mixture was diluted with water, and extracted several times with ethyl acetate. The combined organic layers were dried and evaporated to afford the crude product. Chromatography, with hexane:ethyl acetate (2:1) as the eluent, gave a mixture of the alcohol and starting material (2.98 g); NMR (CDCl3): 1.95-2.04 (m, 4), 2.9 (broad, 2), 3.90 (s, 3), 5.15 (s, 2), 6.93-6.99 (m, 2), 7.21-7.36 (m, 7); MS: m/z=342(M+1). This material was used in the next step without further purification.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:13]=[CH:12][C:7]2[C:8](=[O:11])[O:9][CH2:10][C:6]=2[CH:5]=1.[C:14]([N:21]1[CH2:26][CH2:25][NH:24][C@H:23]([CH2:27][OH:28])[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>C(O)C>[OH:28][CH2:27][C@H:23]1[N:24]([CH2:3][CH:2]([OH:1])[C:4]2[CH:13]=[CH:12][C:7]3[C:8](=[O:11])[O:9][CH2:10][C:6]=3[CH:5]=2)[CH2:25][CH2:26][N:21]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:22]1
Reactant: O=C1OCc2cc(C3CO3)ccc21
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(CC(O)c2ccc3c(c2)COC3=O)[C@H](CO)C1
Temperature: 150 °C

Procedure:
5-(Oxiran-2-yl)-2-benzofuran-1(3H)-one (1.5 g, 8.5 mmol) and commercially available (S)-4-N—BOC-2-hydroxymethyl piperazine (2.394 g, 11.07 mmol) were combined in ethanol (10 mL) in a microwave tube. The mixture was degassed then heated for 60 min at 150° C. LC-MS showed the product peak. The reaction was worked up by adding ethyl acetate and washing once with brine. The organic layer was separated, dried, and concentrated to dryness. The crude product was purified by MPLC using an 80 g Redi-sep column and eluted with 50%-100% EtOAc/hexane yielding the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:10]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]=[O:9])#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=Cc1ccncc1Br
Reactant: C#CCCCCCCCCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC#Cc1cnccc1C=O
Temperature: 105 °C
Reaction time: 19 h
Yield: 73 %

Procedure:
Palladium acetate (10.8 mg) was added to a stirred, deaerated solution of 3-bromopyridine-4-carboxaldehyde (0.80 g, 4.5 mmole; prepared as described by E. J. Corey, S. G. Pyne and A. I. Schafer, Tet. Letters, 3291, 1983), 1-tridecyne (1.4 g) and triphenylphosphine (36 mg) in anhydrous triethylamine (18 ml) maintained under an atmosphere of nitrogen. The mixture was stirred at 105° C. for 19 hours after which time it was cooled and the precipitated triethylamine hydrobromide filtered off. Chromatography of the evaporated filtrate on silica using dichloromethane as eluant afforded 0.93 g (73%) of the title compound as a white crystalline solid of mp (petroleum ether [bp. 40°-60° C.]) 38°-39° C., νmax (mull) 2230, 1710 cm-1 ; δ(CDCl3) 0.87 (3H, distorted t, terminal CH3), 1.12-1.76 (18H, m, alkylene chain), 2.48 (2H, t, J 6 Hz, CH2 --C≡C), 7.62 (1H, d, J 5 Hz, C-5H), 8.63 (1H, d, J 5 Hz, C-6H), 8.82 (1H, s, C-2H), 10.52 (1H, s, aldehyde C-H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([OH:19])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:23]2)=[CH:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N([CH2:43][CH3:44])CC)C.Cl>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1>[Si:1]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:17](=[O:19])[C@:16]([CH2:43][CH3:44])([CH3:11])[CH2:15][CH2:14][CH3:13])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:37])[C@@H:15]2[CH2:20][CH2:21][C@H:22]2[O:27][C:26](=[O:28])[CH2:25][C@H:24]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:31])[CH3:32])[CH2:23]2)=[CH:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CCC[C@](C)(CC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Temperature: 25 °C
Yield: 31 %

Procedure:
121 μl (1.66 mmol) of thionyl chloride were added to 60 mg (0.42 mmol) of (-)-(2S)-2-ethyl-2-methylpentanoic acid [prepared as described in Preparation 16], and the resulting mixture was heated at 100° C. for one hour. At the end of this time, the mixture was concentrated by evaporation under reduced pressure. The whole of the (-)-(2S)-2-ethyl-2-methylvaleryl chloride obtained in this manner was added, directly and without purification, to a solution of 458 mg (0.83 mmol) of (4R,6R)-6-{2-[(1S,2S,6S,8S,8aR)-1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], 203 mg (1.66 mmol) of 4-(N,N-dimethylamino)pyridine, a catalytic amount (20 mg) of 4-dimethylaminopyridine and 232 μl of triethylamine in 2.5 ml of toluene, and the resulting mixture was heated under reflux for 24 hours. At the end of this time, the reaction mixture was cooled to room temperature and then mixed with 10 ml of a 10% w/v aqueous solution of hydrogen chloride. The aqueous mixture was extracted three times, each time with 20 ml of ethyl acetate. The combined extracts were then washed with a saturated aqueous solution of sodium chloride, after which the washed solution was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting pale-yellow oily residue was purified by flash column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 88 mg (31% yield) of the title compound as a foam-like substance.
Reaction SMILES: C(OC1(O)C=CC(C(=O)CBr)=CC1C(N)=O)C1C=CC=CC=1.NCCC[N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[N:28]1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[N:28]1
Reactant: NCCCn1nnc2ccccc21
Agent: NC(=O)C1C=C(C(=O)CBr)C=CC1(O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: c1ccc2[nH]nnc2c1

Procedure:
A mixture of 17.5 gm of 2-benzyloxy-5-bromoacetyl salicylamide, 17.6 gm of 1-(3-aminopropyl)-1H-benzotriazole, 6 gm of sodium carbonate and 150 ml of ethyl acetate was refluxed for 1.5 hours. After separation of the inorganic constituents, the mother liquor was evaporated, the residue was dissolved in a 100 ml of acetonitrile, and the solution was acidified with 5 gm of oxalic acid. The precipitated 1-[3-(3-carbamoyl-4-benzyloxy-β-oxophenethylamino)-propyl]-1-H-benzotriazole oxalate was collected by suction of filtration converted with aqueous ammonia into the base (m.p. 186°-188° C.) and reduced in 100 ml of ethanol with sodium borohydride to form 1-(3-carbamoyl-4-benzyloxy-β-hydroxyphenethylamino)propyl]-1-H-benzotriazole.
Reaction SMILES: [C:1]([C:4]1[O:8][N:7]=[C:6]([C:9]([OH:11])=O)[CH:5]=1)(=[O:3])[CH3:2].[NH2:12][C@@H:13]([CH3:30])[CH2:14][N:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:27]=[C:26]([F:28])[C:23]([C:24]#[N:25])=[C:22]([Cl:29])[CH:21]=2)=[N:16]1>>[C:1]([C:4]1[O:8][N:7]=[C:6]([C:9]([NH:12][C@@H:13]([CH3:30])[CH2:14][N:15]2[CH:19]=[CH:18][C:17]([C:20]3[CH:27]=[C:26]([F:28])[C:23]([C:24]#[N:25])=[C:22]([Cl:29])[CH:21]=3)=[N:16]2)=[O:11])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)no1
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)no1
Yield: 16.09 %

Procedure:
(S)-5-acetyl-N-(1-(3-(3-chloro-4-cyano-5-fluorophenyl)-1H-pyrazol-1-yl)-propan-2-yl)isoxazole-3-carboxamide was prepared using the method of Example 34(d) starting from 5-acetylisoxazole-3-carboxylic acid (0.200 g, 1.292 mmol) and (s)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (0.3 g, 1.076 mmol). The product was purified by Flash-chromatography. Yield 16.09%. 1H-NMR (400 MHz; CDCl3): δ 1.26 (d, 3H), 2.65 (s, 3H), 4.26 (dd, 1H), 4.46 (dd, 1H), 4.61 (m, 1H), 6.64 (d, 1H), 7.29 (s, 1H), 7.51 (d, 1H), 7.63 (dd, 1H), 7.85 (s, 1H), 8.04 (d, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C1(=O)[NH:21]C(=O)C2=CC=CC=C12.[K]>CN(C=O)C.O>[NH2:21][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(CCBr)CC1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
The compound (0.77 g) obtained in the above (4) is dissolved in DMF (5 ml), and thereto is added potassium phthalimide (0.537 g), and the mixture is stirred at 100° C. for 1.5 hour. The reaction mixture is diluted with water, and extracted three times with ethyl acetate. The extract is washed successively with 1N hydrochloric acid (twice), a saturated brine (once), a saturated aqueous sodium hydrogen carbonate solution (twice) and a saturated brine (twice), and dried over anhydrous magnesium sulfate. The desiccant is removed by the filtration, and the filtrate is concentrated under reduced pressure. The residue is dissolved in ethanol (20 ml) and thereto is added hydrazine monohydrate (2.3 g) and the mixture is stirred at room temperature for 48 hours. The mixture is diluted with ether, and the insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure to give the title compound (0.63 g) as an oily product.