Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[CH3:10][C:11]1([CH3:20])[CH2:16][CH2:15][C:14](B(O)O)=[CH:13][CH2:12]1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:14]2[CH2:15][CH2:16][C:11]([CH3:20])([CH3:10])[CH2:12][CH:13]=2)[CH:3]=1
Reactant: Nc1ccc(Br)cc1I
Reactant: CC1(C)CC=C(B(O)O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC1(C)CC=C(c2cc(Br)ccc2N)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 93.8 %

Procedure:
A mixture of 4-bromo-2-iodo-phenylamine (873 mg, 2.93 mmol), 4,4-dimethylcyclohexen-1-ylboronic acid (496 mg, 3.22 mmol), Pd(PPh3)4 (169 mg, 0.147 mmol) and 2.0 M aq Na2CO3 (11.7 mL, 23.4 mmol) in 20 mL of 1,4-dioxane was stirred at 80° C. for 12 h under Ar. After cooling to RT, the reaction was treated with EtOAc (50 mL) and washed with H2O (25 mL) and brine (20 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (5% EtOAc/hexane) to afford 770 mg (91%) of the title compound as a colorless oil. Mass spectrum (ESI, m/z): Calcd. for C14H18BrN, 280.1 (M+H), found 280.1.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7]CC)=[O:6])=[C:2]=[O:3].[CH:10]1([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>ClCCl>[CH:10]1([O:16][C:2]([NH:1][CH2:4][C:5]([OH:7])=[O:6])=[O:3])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: OC1CCCCC1
Reactant: CCOC(=O)CN=C=O
Solvent: ClCCl
Product: O=C(O)CNC(=O)OC1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
620 mg (4.80 mmol) of ethyl isocyanatoacetate was dissolved in 5 ml of dichloromethane. 10 ml of a solution of 0.56 ml (5.28 mmol) of cyclohexanol in dichloromethane was added to the obtained solution under cooling with ice, and they were stirred at room temperature for 15 minutes. The reaction mixture was concentrated under reduced pressure. 5.8 ml of 1 N aqueous lithium hydroxide solution was added to the concentrate, and the obtained mixture was stirred in a solvent mixture of methanol: water=2:1 at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. Water was added to the concentrate and the resultant aqueous layer was washed with ethyl acetate. 0.1 N aqueous hydrochloric acid solution was added to the aqueous layer to control pH at 2 to 3. After extracting with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: C[Al](C)C.CO[C:7](=[O:25])[CH2:8][C:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:13][CH:14]=1.[NH2:26][C:27]1[C:32]([Br:33])=[CH:31][CH:30]=[CH:29][N:28]=1>ClCCCl>[Br:33][C:32]1[C:27]([NH:26][C:7](=[O:25])[CH2:8][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:13][CH:14]=2)=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)CC1=CCN(C(=O)OCc2ccccc2)CC1
Reactant: Nc1ncccc1Br
Agent: C[Al](C)C
Solvent: ClCCCl
Product: O=C(CC1=CCN(C(=O)OCc2ccccc2)CC1)Nc1ncccc1Br
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 189 %

Procedure:
Trimethylaluminum (2.0 M, 2.05 mL, 4.10 mol) was added slowly to a 0° C. solution of benzyl 4-(2-methoxy-2-oxoethyl)-3,6-dihydropyridine-1(2H)-carboxylate (0.79 g, 2.73 mol) and 2-amino-3-bromopyridine (0.520 g, 3.00 mmol) in 1,2-dichloroethane (15 mL). After 30 min, the reaction was heated to 55° C. for 48 h. The reaction was quenched by the careful addition of saturated aqueous sodium bicarbonate and the mixture extracted with dichlormethane (4×). The combined organic layers were washed with 1N sodium potassium tartrate, brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography, eluting with a gradient of 50 to 100% ethyl acetate:hexanes to give the title compound (2.44 g). MS: m/z=430.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]([O:11][CH2:12][CH3:13])[CH3:10])[C:6](=[S:14])[NH:5][C:4](=[O:15])[CH:3]=1.[N:16]([O-])=[O:17].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[N:7]([CH2:8][CH:9]([O:11][CH2:12][CH3:13])[CH3:10])[C:6](=[S:14])[NH:5][C:4](=[O:15])[C:3]=1[N:16]=[O:17]
Reactant: O=N[O-]
Reactant: CCOC(C)Cn1c(N)cc(=O)[nH]c1=S
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(C)Cn1c(N)c(N=O)c(=O)[nH]c1=S
Temperature: 75 °C
Reaction time: 0.25 h
Yield: 84.7 %

Procedure:
6-Amino-1-(2-ethoxy-propyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (1.1 g, 4.8 mmol) obtained from Example 5b was suspended in 10% acetic acid (20 mL) and the mixture was stirred for 15 minutes. Sodium nitrite (0.36 g, 5.3 mmol) was added and the resulting mixture was heated at 75° C. for 1 h. The reaction mixture turned pink and then purple. The mixture was cooled to room temperature, and the purple solid was collected by filtration and washed with water to give the title compound (1.05 g, 70% yield). This solid was used in Example 5(d) without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.[C:20](O)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=3)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1
Reactant: Nc1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Reactant: O=C(O)c1cccnc1
Product: O=C(Nc1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1)c1cccnc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-cyclopropylmethoxy-pyridin-3-ylamine and nicotinic acid as starting materials, MS (LC/MS): 380.2 (M+H).
Reaction SMILES: Cl.Cl.C([S:6][CH2:7][C:8]1[S:9][C:10]([CH2:14][N:15]([CH3:17])[CH3:16])=[C:11]([CH3:13])[CH:12]=1)(=N)N.[OH-].[Na+]>O>[CH3:17][N:15]([CH2:14][C:10]1[S:9][C:8]([CH2:7][SH:6])=[CH:12][C:11]=1[CH3:13])[CH3:16]
Reactant: Cc1cc(CSC(=N)N)sc1CN(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(CS)sc1CN(C)C
Temperature: 25 °C
Yield: 83.3 %

Procedure:
In 5 ml of water was dissolved 10 g of 2-amidinothiomethyl-5-(dimethylamino)methyl-4-methylthiophene dihydrochloride, and 2.52 g of sodium hydroxide was added thereto, and the resulting mixture was subjected to reaction under reflux for 2.5 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and then extracted with 100 ml of methylene chloride, and the extract was dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation under reduced pressure. The oily substance thus obtained was distilled under reduced pressure in a nitrogen atmosphere to obtain 5.3 g (yield 83%) of 5-(dimethylamino)methyl-2-mercaptomethyl-4-methylthiophene having a boiling point of 102°-105° C./3 mmHg.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10](O)[CH3:11].[Cl:13]C(Cl)C.S(Cl)(Cl)=O>>[Cl:13][CH:10]([C:2]1[NH:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=1)[CH3:11]
Reactant: CC(Cl)Cl
Reactant: CC(O)c1nc2ccccc2[nH]1
Solvent: O=S(Cl)Cl
Product: CC(Cl)c1nc2ccccc2[nH]1
Temperature: 25 °C

Procedure:
1-(1H-Benzimidazol-2-yl)-ethanol (146) (1.00 g, 6.16 mmol) was suspended in dichloro ethane (50 mL, 800 mmol). Thionyl chloride (4.00 mL, 54.8 mmol) was added dropwise and the reaction was stirred at room temperature and then heated to 60° C. for 6 hours. After cooling to room temperature the reaction was evaporated to dryness under reduced pressure. The obtained solid was washed with ethyl acetate. The powder was suspended in ethyl acetate and washed with saturated sodium bicarbonate solution and brine. The organic portion was dried over anhydrous sodium sulfate and concentrated. The obtained off-white solid was used without further purification (147, 0.864 g, 76%). MS (ESI) [M+H+]+=181.2.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([OH:13])[CH:9]=2)=[CH:4][CH:3]=1.Cl[CH2:15][O:16][CH3:17]>CCN(CC)CC.CS(C)=O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([O:13][CH2:15][O:16][CH3:17])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: Oc1cc(-c2ccc(I)cc2)on1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COCOc1cc(-c2ccc(I)cc2)on1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.6 %

Procedure:
To a solution of 5-(4-iodophenyl)isoxazol-3-ol (128 mg, 0.43 mmol) in Et3N/DMSO (10:1 v/v, 5.5 mL) at 0° C., chloro(methoxy)methane (45 mg, 0.64 mmol) was added dropwise. After stirring at 0° C. for 0.5 h, the reaction mixture was poured into ice-water (50 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified on a silica gel column using EtOAc in petroleum ether (1:20) to afford the title compound as white solid (55 mg, 40%). 1H NMR (DMSO-d6, 400 MHz): δ 7.79 (d, 2H), 7.46 (d, 2H), 6.23 (s, 1H), 5.36 (s, 2H), 3.57 (s, 3H). LCMS: 332 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:68]=[CH:67][N:66]([CH2:69][C:70]([CH3:73])([OH:72])[CH3:71])[N:65]=1>>[OH:72][C:70]([CH3:73])([CH3:71])[CH2:69][N:66]1[CH:67]=[CH:68][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:37])[CH3:35])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:32])=[N:65]1.[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)O)n2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.25 g, 0.44 mmol), was reacted with diisopropylethylamine (0.23 g, 1.8 mmol), diphenylphosphinic chloride (0.32 g, 1.3 mmol), then reacted with 1-(3-amino-1H-pyrazol-1-yl)-2-methylpropan-2-ol (WO2009127544) (0.11 g, 0.67 mmol) at room temperature and purified by Prep-HPLC to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide as a trifluoroacetic acid salt: white solid (Yield 62 mg, 20%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:10])=[N:4][C:5](O)=[N:6][C:7]=1[CH3:8].O=P(Cl)(Cl)[Cl:13].N(C1C=CC=CC=1)(CC)CC>>[Cl:13][C:5]1[N:4]=[C:3]([CH3:10])[C:2]([Cl:1])=[C:7]([CH3:8])[N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(O)nc(C)c1Cl
Solvent: CCN(CC)c1ccccc1
Product: Cc1nc(Cl)nc(C)c1Cl
Temperature: 125 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To 5-chloro-4,6-dimethylpyrimidin-2-ol (992 mg, 6.26 mmol) was added POCl3 (2.22 mL, 23.77 mmol) followed by Et2NPh (0.75 mL, 4.69 mmol) dropwise. The mixture was heated at 125° C. for 2 h. At approximately 2 h the reaction became homogeneous and was checked by HPLC and it showed all starting material had been consumed. The mixture was allowed to cool to room temperature and was then added dropwise to ice. After the ice had melted there was a white solid in a pink liquid. The aqueous layer was extracted with DCM and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Chromatography (Hex to 10% EtOAc/Hex) afforded the desired product as a white solid (915 mg, 83%). 1H NMR (500 MHz, CDCl3): 2.57 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[S:12][CH:13]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:15]=1.[C:19]1(=[O:30])[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]2[CH2:20]1.C1(C)C=CC=CC=1>CCCCCC>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:19](=[O:30])[CH2:20][C:21]2[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=2[C:23]([OH:25])=[O:24])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[S:12][CH:13]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:15]=1
Reactant: Cc1ccc(N)cc1/C=C/c1nc(C(C)C)cs1
Reactant: O=C1Cc2ccccc2C(=O)O1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1ccc(NC(=O)Cc2ccccc2C(=O)O)cc1/C=C/c1nc(C(C)C)cs1
Yield: 61.4 %

Procedure:
A mixture of 0.5 g of (E)-4-methyl-3-[2-[4-(1-methylethyl)-2-thiazolyl]ethenyl]benzenamine, 0.5 g of homophthalic anhydride and 35 ml of toluene was heated to reflux for 1 hr. After cooling and dilution with hexane, 0.5 g of (E)-2-[2-[4-methyl-3-[2-[4-(1-methylethyl)-2-thiazolyl]ethenyl]phenylamino]-2-oxoethyl]benzoic acid was isolated by filtration; m.p. 181°-183° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[F:25][C:26]([F:35])([F:34])[C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:33][C:30]3[CH:31]=[CH:32][C:27]([C:26]([F:25])([F:34])[F:35])=[CH:28][CH:29]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(NC(=O)c1coc(Oc2ccc(C(F)(F)F)cc2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 68.5 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 4-trifluoromethyl phenol (43 mg, 0.26 mmol) to give the title compound (45 mg, 67%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH:13]([OH:14])[CH2:12][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:27](Br)[CH:28]=[CH2:29].O>C1COCC1>[CH2:29]([O:14][C@@H:13]1[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10][N:11]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:12]1)[CH:28]=[CH2:27]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CC1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.5 %

Procedure:
To a solution of 26 g (77 mmol) of benzyl 3-[(tert-butoxycarbonyl)amino]-4-hydroxypyrrolidine-1-carboxylate in 120 mL of THF was added 5 g (211 mmol) of sodium hydride at 0° C. The reaction mixture was stirred at 0° C. for 1 h, then 10 mL (115 mmol) of allyl bromide was added. The reaction mixture was warmed up to room temperature and continuously stirred at room temperature overnight. Water (50 mL) was added to quench the reaction. The organic phase was separated, and the aqueous layer was extracted with ethyl acetate twice (100 mL×2). The combined extracts were washed with brine, dried over Na2SO4, evaporated under reduced pressure. Chromatography on silica gel column with 25% EtOAc-hexane provided the title compound (21.3 g, 73%). MS (M+H)+ 377.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C:33]1[CH:37]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:35][N:34]=1.[C:44]([O:48][C:49]([NH:51][CH2:52][CH2:53]O)=[O:50])([CH3:47])([CH3:46])[CH3:45]>O1CCCC1>[C:44]([O:48][C:49]([NH:51][CH2:52][CH2:53][O:32][C:33]1[CH:37]=[C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:35][N:34]=1)=[O:50])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Oc1cc(-c2ccccc2)on1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccccc2)on1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
Triphenylphosphine (0.87 g) was dissolved in tetrahydrofuran (10 ml), and diethyl azodicarboxylate (0.57 g) was added dropwise to the solution under ice-cooling with stirring, and the mixture was stirred at the same temperature for 10 minutes. 3-Hydroxy-5-phenylisoxazole (0.48 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.48 g) were added to the reaction mixture, and the resulting mixture was stirred under ice-cooling for 10 minutes and at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: cyclohexane/ethyl acetate=4/1) and was crystallized from isopropyl ether to obtain the title compound (0.63 g, 69%) as colorless crystals.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1.[CH3:11][O:12][C:13](=[O:22])[C@:14]([N:19]=[C:20]=[O:21])([CH:16]([CH3:18])[CH3:17])N>CN(C)C1C=CN=CC=1.ClCCl>[CH3:11][O:12][C:13](=[O:22])[C@H:14]([CH:16]([CH3:17])[CH3:18])[NH:19][C:20]([O:1][CH2:2][C:3]1[N:4]=[C:5]([CH:8]([CH3:10])[CH3:9])[S:6][CH:7]=1)=[O:21]
Reactant: CC(C)c1nc(CO)cs1
Reactant: COC(=O)[C@](N)(N=C=O)C(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)OCc1csc(C(C)C)n1)C(C)C
Yield: 56.6 %

Procedure:
A solution of 2.18 g (15 mmol) of 4-(hydroxymethyl)-2-isopropylthiazole, 15.8 mmol of a-isocyanato-valine methyl ester and 1.5 mmol of 4-dimethylaminopyridine in 75 ml of dichloromethane was heated at reflux for 5 h. The resulting solution was washed successively with 10% citric acid, aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. Silica gel chromatography of the residue using 5% ethyl acetate in chloroform provided 2.67 g (57%) of the pure desired compound, Rf 0.46 (4% methanol in chloroform). NMR 1H NMR (DMSO-d6) δ 1.26(d, J=8 Hz, 3 H), 1.32(d, J=7 Hz, 6H), 3.27 (heptet, J=7 Hz, 1 H), 3.63 (s, 3 H), 4.10 (pentet, J=8 Hz, 1 H), 5.02 (s, 2 H), 7.47 (s, 1 H), 7.81 J=8 Hz, 1 H). Mass spectrum: (M+H)+ =287.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=[N:27][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccccc1OCCCN1CCCCC1
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Product: C(=NCCc1ccccc1)c1ccccc1OCCCN1CCCCC1

Procedure:
2-[3-(1-Piperidinyl)propoxy]benzaldehyde (47.6g) is reacted with 24g of phenethylamine in 190ml of toluene following the procedure described in Example 1A to yield 61.9g of product as an oil, boiling point 214°-218° C. at 0.2-0.3mm of Hg.
Reaction SMILES: C(O[C@@H:5]1[C@H:10]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:8]2([CH3:9])[C:7](=[O:27])[CH2:6]1)[C@:19]1([CH3:20])[C:14]([C:15]([CH3:26])=[C:16]([O:24]C)[CH2:17][CH2:18]1)=[CH:13][CH2:12]3)(=O)C.[CH:28]#[CH:29].Cl>CO.O>[C:28]([C@:7]1([OH:27])[CH:6]=[CH:5][C@H:10]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:8]12[CH3:9])[C@:19]1([CH3:20])[C:14](=[C:15]([CH3:26])[C:16](=[O:24])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)#[CH:29]
Reactant: COC1=C(C)C2=CC[C@H]3[C@@H]4[C@@H](OC(C)=O)CC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Reactant: C#C
Agent: Cl
Solvent: CO
Solvent: O
Product: C#C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=C(C)C(=O)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
3.5 g of 15α-acetoxy-3-methoxy-4-methylandrosta-3,5-dien-17-one is reacted with acetylene analogously to Example 5. The resultant 17α-ethynyl-3-methoxy-4-methylandrosta-3,5,15-trien-17β-ol is allowed to react, as described in Example 5, with concentrated hydrochloric acid in a mixture of methanol/water. After the crude product has been chromatographed on silica gel with a hexane-ethyl acetate gradient, 1.3 g of 17α-ethynyl-17β-hydroxy-4-methylandrosta-4,15-dien-3-one is obtained as a foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][Si](C)(C)C)[N:4]=1.C1C=CC(O[C:22](Cl)=[S:23])=CC=1>C1(C)C=CC=CC=1>[N:10]([C:5]1[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([CH3:9])[N:6]=1)=[C:22]=[S:23]
Reactant: COc1cc(C)nc(N[Si](C)(C)C)n1
Reactant: S=C(Cl)Oc1ccccc1
Solvent: Cc1ccccc1
Product: COc1cc(C)nc(N=C=S)n1
Temperature: 80 °C
Yield: 63.9 %

Procedure:
A mixture of 4.2 g of 4-methoxy-6-methyl-2-trimethylsilylaminopyrimidine and 3.5 g of phenyl chlorothionocarbonate in 30 ml of toluene is stirred with heating at ca. 80° C. for 5.5 hours. The reaction solution is cooled to room temperature and filtered to remove the precipitate. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel chromatography (eluent: ethyl acetate: toluene =1:3) to give the title compound (2.3 g). mp 54°~55° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:27]([CH3:34])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29]>>[CH3:33][C:27]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][NH:10][C:8](=[O:9])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:14][CH:15]=2)=[CH:20][CH:21]=1)([CH3:34])[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=C(Cc1ccccc1)NCCc1ccc(-c2ccc(O)cc2)cc1
Product: CCOC(=O)C(C)(C)Oc1ccc(-c2ccc(CCNC(=O)Cc3ccccc3)cc2)cc1
Yield: 26 %

Procedure:
Ethyl 2-Methyl-2-{4-[2-(phenyl-acetamido)-ethyl]-biphenyl-4'-oxy}-propionate was prepared from 4-[2-(phenyl-acetamido)-ethyl]-4' -hydroxy-biphenyl and ethyl 2-bromo-2methyl-propionate analogous to Example 1. Yield: 26% of theory; m.p. <20° C.
Reaction SMILES: Cl.[O:2]([CH2:9][CH2:10][NH2:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O:20][C@@H:21]1[C@H:25]([O:26]C(=O)C2C=CC=CC=2)[C@@H:24]([CH2:35][O:36]C(=O)C2C=CC=CC=2)[O:23][C@H:22]1[N:45]1[CH:53]=[N:52][C:51]2[C:46]1=[N:47][C:48]([Cl:55])=[N:49][C:50]=2Cl)(=O)C1C=CC=CC=1.C(N(CC)CC)C.N>O1CCOCC1>[Cl:55][C:48]1[N:49]=[C:50]([NH:11][CH2:10][CH2:9][O:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:51]2[N:52]=[CH:53][N:45]([C:46]=2[N:47]=1)[C@@H:22]1[O:23][C@H:24]([CH2:35][OH:36])[C@@H:25]([OH:26])[C@H:21]1[OH:20]
Reactant: NCCOc1ccccc1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: Cl
Agent: N
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: OC[C@H]1O[C@@H](n2cnc3c(NCCOc4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound was prepared by reacting 2-phenoxyethylamine hydrochloride (0.80 g, 4.6 mmol) with 9-(2,3,5-tri- O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.0 g, 3.2 mmol) in dioxan (25 ml) in the presence of triethylamine (1.0 g, 9.6 mmol) followed by deprotection of the purified product using methanolic ammonia to provide the title nucleoside (0.75 g, 60%)(following flash chromatography) as an amorphous foam, 1H NMR (DMSO-d6)δ 3.52-3.59 (1H, m, H-5'a), 3.64-3.71 (1H, m, H-5'b), 3.82 (2H, q, --OH2 --), 3.96 (1H, q, H-4'), 4.14 (1H, m, H-3'), 4.52 (1H, q, H-2'), 5.12 (1H, t, 5'-0H), 5.25, 5.54 (2H, 2d, 2'- and 3'-OH), 5.85 (1H, d, H-1'), 6.92-7.02 (3H, m, Ar--H), 7.26-7.34 (2H, t, Ar--H), 8.46 (1H, m, H-8), 8.56 (1H, br, t, N--H).