Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])[CH:2]=1.N#CBr.C([OH:19])C>>[NH:9]1[C:8]2[C:7](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]([CH:4]=[CH:5][CH:6]=[O:19])=[CH:2]1
Reactant: Nc1ccccc1-c1cccnc1
Reactant: CCO
Agent: N#CBr
Product: O=CC=Cc1c[nH]c2ccccc12

Procedure:
To a solution of 10.0 g of 2-(pyridin-3-yl)aniline (58.7 mmol) in 100 mL ethanol is slowly added 6.2 mL of cyanogen bromide (12.4 g, 118 mmol). The reaction is heated to reflux for 1 hour, monitoring by TLC (silica, hexanes:ethyl acetate 1:1) for formation of the Zincke salt. The reaction is then quenched via addition of 50 mL saturated NH4Cl, and extracted with 3×50 mL dichloromethane. The combined organic layers are washed 3×100 mL saturated NH4Cl, followed by drying over anhydrous Na2SO4 and removal of the solvent. The crude residue is further purified via column chromatography over silica, using a hexanes-ethyl acetate gradient.
Reaction SMILES: [O:1]=[C:2]([CH2:14][CH3:15])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O.N1CCCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.O>[C:2]([C:3](=[CH:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([Cl:16])[CH:18]=1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])(=[O:1])[CH2:14][CH3:15]
Reactant: CCC(=O)CC(=O)OCc1ccccc1
Reactant: O=Cc1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: C1CCNCC1
Solvent: O
Product: CCC(=O)C(=Cc1cccc(Cl)c1)C(=O)OCc1ccccc1

Procedure:
1.59 g (7.71 mmol) of benzyl 3-oxovalerate, 1.08 g (7.71 mmol) of 3-chlorobenzaldehyde and 65.7 mg (0.771 mmol) of piperidine were heated under reflux in the presence of a catalytic amount of p-toluenesulfonic acid in 50 ml of benzene for 6 hours while water was removed. Benzene was evaporated under reduced pressure. Ethyl acetate was added to the reaction mixture. After washing with 1 N hydrochloric acid and then with a saturated aqueous sodium hydrogencarbonate solution, the organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1) to obtain the title compound.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:8][C:9]([CH2:11][CH2:12]O)=[CH2:10]>CC1C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH3:8][C:9]1[CH2:10][C:1]2([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:7][CH2:12][CH:11]=1
Reactant: O=C1CCCCC1
Reactant: C=C(C)CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1=CCOC2(CCCCC2)C1
Temperature: 115 °C
Yield: 79.4 %

Procedure:
A mixture of p-TSA (20 g, 0.105 mol) and toluene (2 L) was heated to 115° C. To this mixture were added cyclohexanone (980 g, 10 mols) and isoprenol (946 g, 11 mols) and heated further for 3-6 h. Water was removed from the reaction azeotropically. The reaction mixture was then cooled to room temperature. The organic phase was washed with a 5% Na2CO3 solution, washed with water dried and concentrated and distilled further to provide 4-methyl-1-oxaspiro [5.5] undec-3-ene (1.32 kg) having a purity of 98% (sum of the isomers) for a total yield of 80%.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)=[O:2].[CH3:12][C:13]1[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=1.N1C=CC=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:12][C:13]1[CH:17]=[C:16]([CH3:18])[N:15]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH:1]=[O:2])[N:14]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: O=Cc1ccccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cc(C)n(-c2ccccc2C=O)n1
Reaction time: 96 h
Yield: 15 %

Procedure:
To a solution of 2-formylphenylboronic acid (500 mg, 3.33 mmol) in CH2Cl2 (30 mL) are added 3,5-dimethyl-1H-pyrazole (160 mg, 1.67 mmol), Cu(OAc)2 (909 mg, 5.0 mmol), pyridine (528 mg, 6.67 mmol) and molecular sieves (1.0 g) at room temperature. The mixture is stirred at the same temperature for 4 days with loose cap. The mixture is filtered through a short pad of diatomaceous earth and the solids are washed with CH2Cl2. The combined filtrates are concentrated and purified via flash chromatography (12 g silica gel, CH2Cl2 then 20% EtOAc/heptane) to afford 2-(3,5-dimethyl-pyrazol-1-yl)-benzaldehyde (50 mg, 8%).
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2F)[CH:14]=1)=[O:7].[CH3:30][N:31]([CH3:37])[CH2:32][CH2:33][CH2:34][NH:35][CH3:36]>>[CH3:1][N:2]([CH3:29])[C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][CH:28]=1)[C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:25])=[C:13]([NH:15][C:16](=[O:24])[C:17]2[CH:22]=[CH:21][C:20]([N:35]([CH2:34][CH2:33][CH2:32][N:31]([CH3:37])[CH3:30])[CH3:36])=[CH:19][CH:18]=2)[CH:14]=1)=[O:7]
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccccc1F
Reactant: CNCCCN(C)C
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1ccc(N(C)CCCN(C)C)cc1
Yield: 29 %

Procedure:
Using an analogous procedure to that described in Example 20, N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-2-fluorobenzamide was reacted with N,N,N′-trimethyl-1,3-propanediamine to give the title compound in 29% yield; m.p. 178-179° C.; NMR Spectrum: (DMSOd6) 1.64 (m, 2H), 2.13 (s, 6H), 2.17 (s, 3H), 2.22 (t, 2H), 2.95 (m, 9H), 3.41 (t, 2H), 6.73 (d, 2H), 6.89 (m, 1H), 7.19 (m, 3H), 7.29 (t, 1H), 7.56 (m, 1H), 7.8 (d, 1H), 7.84 (d, 2H), 9.44 (s, 1H), 10.05 (s, 1H); Mass Spectrum: M+H+ 488.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=[CH2:2].[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].[OH-].C([N+](C)(C)C)C1C=CC=CC=1.CO>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:18][C:14](=[O:17])[CH2:15][CH2:16][N:6]1[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:4]([C:1]([CH3:3])=[CH2:2])[C:5]1=[O:13])[CH3:20]
Reactant: C=CC(=O)OCC
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: C=C(C)n1c(=O)n(CCC(=O)OCC)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.9 %

Procedure:
To a solution of 1-Isopropenyl-2-benzimidazolidinone (2.5 g, 14.4 mmol) in DMF (10 mL) were added ethyl acrylate (1.7 mL, 15.8 mmol) and benzyltrimethyl ammonium hydroxide in MeOH (1.4 g, 8.6 mmol). The resulting mixture was stirred at room temperature for 1.5 h. When the reaction was complete, the reaction mixture was diluted with ethyl acetate and washed with water (×4). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 1:1 Hexanes:Ethyl acetate as an eluent to afford 3.0 g (76%) of the desired product along with methyl ester. Since the methyl ester was the major product, this product was used for the next reaction.
Reaction SMILES: C1C=CC=CC=1.[CH3:7][NH:8][CH3:9].Cl[C:11]1[S:12][CH:13]=[C:14]([C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=1.O1CCCC1>O>[CH3:7][N:8]([CH3:9])[C:11]1[S:12][CH:13]=[C:14]([C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:15]=1
Reactant: CCOC(=O)C(=O)c1csc(Cl)n1
Reactant: CNC
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(=O)c1csc(N(C)C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture comprising 10 ml of a 2M benzene solution of dimethylamine, 1.3 g of ethyl 2-chlorothiazol-4-ylglyoxylate, and 5 ml of tetrahydrofuran was stirred for 3 hours at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, using as eluent a 9:1 by volume mixture of benzene and ethyl acetate, giving the title compound as a pale yellow oil.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]1[NH:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:12]=1)=[O:7])C.O.Cl>C1COCC1.CO.O>[C:13]1([C:11]2[CH:12]=[C:8]([C:6]([OH:7])=[O:5])[NH:9][CH:10]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cc(-c2ccccc2)c[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
LiOH (180 mg, 4.3 mmol) was added to a stirred solution of 4-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester (143 mg, 0.66 mmol) in THF:MeOH:H2O (3:1:1, 5 mL), and the resulting mixture was stirred at room temperature for 8 hrs. The reaction mixture was concentrated under reduced pressure to get the residue. Cold water was then added and acidified it with concentrated HCl, filtered the solid precipitated to afford 103 mg (83.06% yield) of 4-Phenyl-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[C:33](=[O:34])[O:32]C(C)(C)[O:30][C:29]=4[CH:37]=3)[CH2:20][CH2:21][CH2:22][CH3:23])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CCO>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([O:24][C:25]3[CH:26]=[CH:27][C:28]([C:33]([OH:34])=[O:32])=[C:29]([OH:30])[CH:37]=3)[CH2:20][CH2:21][CH2:22][CH3:23])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(C(CCCC)Oc3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1ccc(C#Cc2ccc(C(CCCC)Oc3ccc(C(=O)O)c(O)c3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of 7-[(1-{4-[(4-butylphenyl)ethynyl]phenyl}pentyl)oxy]-2,2-dimethyl-4H-1,3-benzodioxin-4-one (370 mg, 0.74 mmol) in EtOH (10 mL) was added an aqueous solution of NaOH (0.75 mL, 3.75 mmol, 5N) and the resulting mixture was stirred overnight at rt. An aqueous solution of HCl (10 mL, 1N) was added and the resulting reaction mixture was extracted with Et2O (3×). The combined organic layers were washed with water and brine, dried over MgSO4 and the solvents were removed under reduced pressure to give 320 mg (94%) of the title compound as a colorless oil. HPLC, Rt: 6.8 min (purity: 99.8%). LC/MS, M−(ESI): 455.3. 1H NMR (CDCl3) δ:10.5 (s, 1H); 9.66 (brs, 1H), 7.72 (d, J=9.0 Hz, 1H), 7.48 (d, J=8.3 Hz, 2H), 7.41 (d, J=8.3 Hz, 2H), 7.28 (d, J=8.3 Hz, 2H), 7.15 (d, J=8.3 Hz, 2H), 6.45 (dd, J=2.3 Hz, J=9.0 Hz, 1H), 6.35 (d, J=2.3 Hz, 1H), 5.14 (t, J=7.8 Hz, 1H), 2.61 (t, J=7.9 Hz, 2H), 2.09-1.93 (m, 1H), 1.90-1.75 (m, 1H), 1.66-1.75 (m, 1H), 1.66-1.19 (m, 8H), 0.96-0.84 (m, 6H).
Reaction SMILES: C(O[CH:5]1[CH2:10][CH2:9][N:8]([C:11]([CH3:19])([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:20])[CH:6]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=O)C.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[CH3:19][C:11]([N:8]1[CH2:9][CH2:10][CH:5]=[C:6]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:7]1=[O:20])([CH3:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)OC1CCN(C(C)(C)c2ccccc2)C(=O)C1c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(c1ccccc1)N1CCC=C(c2ccccc2)C1=O
Temperature: 25 °C
Yield: 85.8 %

Procedure:
4.2 g (0.012 mol) of 4-acetoxy-1-(α,α-dimethylbenzyl)-3-phenyl-2-piperidone prepared by the method of Reference Example 20, was dissolved in 100 ml of toluene, and 2,7 g (0.018 mol) of DBU was added thereto. The mixture was refluxed under heating for 10 minutes. The reaction solution was cooled to room temperature and washed with water. Then, the solvent was distilled off under reduced pressure. The residual solid was recrystallized from ethanol to obtain 3.0 g (yield: 75.0%) of the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].S(Cl)([Cl:19])=O>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1)[C:7]([Cl:19])=[O:8])([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Product: O=C(Cl)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1

Procedure:
A solution of thionyl chloride (30 ml) and 3-nitro-5-(trifluoromethyl)benzoic acid (10 g) was heated to reflux for 2 h. The reaction mixture was concentrated under reduced pressure and treated with toluene (10 ml) which was then removed under reduced pressure to afford 3-nitro-5-(trifluoromethyl)benzoyl chloride.
Reaction SMILES: C(OP([CH2:9]/[C:10](/[CH3:17])=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:18]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([CH:33]([CH3:35])[CH3:34])=[CH:26][C:27]([CH3:32])([CH3:31])[O:28]2)=[CH:23][C:22]=1/[C:36](/[CH3:41])=[C:37](/[F:40])\[CH:38]=O)[CH3:19]>>[CH2:18]([O:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25]([CH:33]([CH3:35])[CH3:34])=[CH:26][C:27]([CH3:32])([CH3:31])[O:28]2)=[CH:23][C:22]=1/[C:36](/[CH3:41])=[C:37](/[F:40])\[CH:38]=[CH:9]\[C:10](\[CH3:17])=[CH:11]\[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:19]
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Reactant: CCOc1cc2c(cc1/C(C)=C(/F)C=O)C(C(C)C)=CC(C)(C)O2
Product: CCOC(=O)/C=C(C)/C=C/C(F)=C(/C)c1cc2c(cc1OCC)OC(C)(C)C=C2C(C)C

Procedure:
Following General Procedure O, ethyl 4-(diethoxyphosphoryl)-3-methyl-but-2E-enoate (230 mg, 0.84 mmol) and (2E)-3-(7-ethoxy-4-isopropyl-2,2-dimethyl-2H-chromen-6-yl)-2-fluoro-but-2-enal (Compound 98, 96 mg, 0.29 mmol) were reacted to give the title compound as a yellow oil after purification by column chromatography (silica gel, 5% ethyl acetate in hexane).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:20][C@H:21]([NH:25]C(OC(C)(C)C)=O)[C:22](O)=O.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[ClH:54]>C(Cl)Cl.O>[ClH:54].[ClH:54].[CH3:1][O:2][C:3]([C:4]1[C:5]2[N:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:20]([C@@H:21]([NH2:25])[CH3:22])=[N:11][C:6]=2[CH:7]=[CH:8][C:9]=1[F:10])=[O:19]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)c1c(F)ccc(N)c1Nc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1c(F)ccc2nc([C@H](C)N)n(-c3ccccc3)c12
Temperature: 0 °C
Reaction time: 2 h
Yield: 182.5 %

Procedure:
To a solution of 3-amino-6-fluoro-2-phenylaminobenzoic acid methyl ester (1 g, 3.8 mmol), Boc-ala-OH (727 mg, 3.8 mmol) and HOAT (522 mg, 3.8 mmol) in DCM (20 mL) at 0° C. was added N-(3-dimethylaminopropyl)-n′-ethylcarbodiimide hydrochloride (810 mg, 4.2 mmol) and the reaction mixture stirred at 0° C. for 2 h. The reaction mixture was diluted with water and extracted with DCM (3×10 mL). The combined organic fractions were washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was dissolved in HCl in dioxane (20 mL, 4 M) and the reaction mixture heated at 75° C. for 45 min. The reaction mixture was concentrated in vacuo to give the title product as a dark purple solid (1.48 g, 100%). LCMS (Method C): RT=1.95 min, [M+H]+=314.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][CH2:9][CH2:10][OH:11].C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH2:18]([N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][CH2:9][CH2:10][OH:11])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: OCCCC1CCCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: OCCCC1CCCCN1Cc1ccccc1

Procedure:
To a stirred solution of compound 21 (3 g, 16.71 mmol) in ethanol (23 mL) was added K2CO3 (11.5 g, 83.55 mmol) portion-wise at ice cold conditions. Benzyl bromide (2 mL, 16.71 mmol) was then added and the reaction mixture was heated at reflux for 2 hours. The reaction mixture was filtered, and washed with EtOAc. The filtrate was concentrated, the residue was dissolved in EtOAc, washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by 230-400 silica gel column chromatography using 1-3% MeOH-DCM as eluent to yield compound 22.
Reaction SMILES: [CH2:1]([OH:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH:11][CH:12]=[CH:13][CH3:14].CCCCCC.[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1>[C:22]([O:15][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[CH3:14])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CC=CC=CCCCCCCCCCO
Solvent: CCCCCC
Solvent: c1ccncc1
Product: C/C=C/C=C/CCCCCCCCCOC(C)=O

Procedure:
The 2.4 g of tetradecadienol was dissolved in 55 ml of pentane containing 30 μl of thiophenol in a 100-ml round bottom flask. The flask was heated with a water bath, and the pentane was distilled off. Then a reflux condenser was connected to the flask, and the mixture was heated at 100° C. for 2 hours. The residue was dissolved in 600 ml of heptane which was removed by a rotary evaporator. The thiophenol was removed simultaneously. The yield of isomerized tetradecadienol was 2.01 g (84%). The isomer content by GC analysis was 62% EE, 19% EZ, 15% ZE, 4% ZZ. The tetradecadienol was recrystallized twice at low temperature from pentane to give 0.83 g of a product of 96.2% EE. 10,12-Tetradecadienol in 75 ml pyridine and 5 ml acetic anhydride was refluxed 1.5 hours. After the solution was cooled, 200 ml hexane was added, and the mixture was extracted successively with water, 6N hydrochloric acid (twice), and water. The pentane phase was dried over sodium sulfate, filtered, and the pentane was removed by rotary evaporation, leaving crude product, which was purified by silica gel liquid chromatography (elution in 10% ether/hexane); the yield was 1.0 g (94% based on the alcohol).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[NH:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]1.C(N(CC)CC)C.CS(C)=O>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:11]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]2)=[N:4][C:3]=1[O:9][CH3:10]
Reactant: OC1CCNC1
Reactant: COc1nc(Cl)ccc1Br
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: COc1nc(N2CCC(O)C2)ccc1Br
Temperature: 150 °C
Yield: 21.2 %

Procedure:
A vial was charged with 3-bromo-6-chloro-2-methoxypyridine (1.00 g, 4.5 mmol), rac-pyrrolidin-3-ol (0.59 g, 6.7 mmol), triethylamine (0.91 g, 8.9 mmol) and dimethylsulfoxide (4 mL). The mixture was heated to 150° C. for 5 hrs. The mixture was cooled to room temperature and diluted with 20 mL of water. The solution was extracted with ethyl acetate (10 mL×3). The extracts were combined, dried (sodium sulfate) and concentrated. The resulting residue was purified through flash column chromatography (petroleum ether/ethyl acetate=5:1˜2:1) to give the title compound (0.26 g, 25.3%) as light brown gum.
Reaction SMILES: [F:1][CH:2]([F:22])[C@H:3]1[CH2:20][C@@:18]2([CH3:19])[C@@H:14]([CH2:15][CH2:16][C:17]2=[O:21])[C@H:13]2[C@H:4]1[C@@H:5]1[C:10]([CH2:11][CH2:12]2)=[CH:9][CH2:8][CH2:7][CH2:6]1.C(OCC)C.[Cl-].[NH4+].[C:30]([Mg]Br)#[C:31][CH3:32]>C1COCC1>[F:1][CH:2]([F:22])[C@H:3]1[CH2:20][C@@:18]2([CH3:19])[C@@H:14]([CH2:15][CH2:16][C@@:17]2([OH:21])[C:30]#[C:31][CH3:32])[C@H:13]2[C@H:4]1[C@@H:5]1[C:10]([CH2:11][CH2:12]2)=[CH:9][CH2:8][CH2:7][CH2:6]1
Reactant: CC#C[Mg]Br
Reactant: C[C@]12C[C@H](C(F)F)[C@H]3[C@@H](CCC4=CCCC[C@@H]43)[C@@H]1CCC2=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC#C[C@]1(O)CC[C@H]2[C@@H]3CCC4=CCCC[C@@H]4[C@H]3[C@@H](C(F)F)C[C@@]21C
Reaction time: 16 h

Procedure:
A mixture of 11β-difluoromethylestr-4-en-17-one (XII, Example 14, 0.9 g) in propynyl magnesium bromide (0.5M, 10 ml) and THF is kept at 20°-25° for 16 hours. Diethyl ether and aqueous ammonium chloride are added and the diethyl ether phase is separated and washed with water and concentrated to a solid. The solid is purified by chromatography through silica gel using ethyl acetate/hexane (20/80) as the irrigant. The appropriate fractions are pooled and concentrated to give the title compound, IR (mull) 3400, 2237 and 1666 cm-1 ; MS (m/e) 348, 330, 315, 266 and 251; NMR (CDCl3) 0.87, 1.86 and 6.0 δ.
Reaction SMILES: C(O[C:6]([N:8](C(OC(C)(C)C)=O)[C:9](=[O:41])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([CH3:37])=[CH:35][C:34]([CH:38]3[CH2:40][CH2:39]3)=[CH:33][N:32]=2)[CH2:27][CH2:26]1)=[O:24])=O)(C)(C)C.N1C[CH2:53][O:52][CH2:51][CH2:50]1>>[CH:38]1([C:34]2[CH:35]=[C:36]([CH3:37])[C:31]([N:28]3[CH2:29][CH2:30][N:25]([C:23]([C:11]4[CH:12]=[CH:13][C:14]([N:16]5[CH2:20][CH2:19][CH2:18][S:17]5(=[O:22])=[O:21])=[CH:15][C:10]=4[C:9]([N:8]4[CH2:50][CH2:51][O:52][CH2:53][CH2:6]4)=[O:41])=[O:24])[CH2:26][CH2:27]3)=[N:32][CH:33]=2)[CH2:40][CH2:39]1
Reactant: C1COCCN1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2C(=O)N2CCOCC2)CC1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzamide (155 mg) described in Example 805 and morpholine (24 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (36 mg) was obtained.
Reaction SMILES: O[CH:2]1O[C:5](=[O:7])[CH2:4][CH:3]1[CH2:8][CH2:9][CH3:10].CCN(C(C)C)C(C)C.Cl.[O:21]1[CH:25]=[C:24]([CH2:26][NH2:27])[CH:23]=[N:22]1>ClCCCl.CC(O)=O>[O:21]1[CH:25]=[C:24]([CH2:26][N:27]2[CH2:2][CH:3]([CH2:8][CH2:9][CH3:10])[CH2:4][C:5]2=[O:7])[CH:23]=[N:22]1
Reactant: NCc1cnoc1
Reactant: CCCC1CC(=O)OC1O
Agent: Cl
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC1CC(=O)N(Cc2cnoc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.3 %

Procedure:
A solution of 5-hydroxy-4-propyldihydrofuran-2(3H)-one x252 (0.44 g, 3.0 mmol) in dry DCE (8 ml), DIEA (0.364 g, 2.8 mmol), and several drops AcOH is added to a suspension of 1-isoxazol-4-ylmethanamine hydrochloride x251 (0.46 g, 3.0 mmol) in dry DCE, and NaHB(OAc)3 (0.976 g, 2.3 mmol) is added in 50 min. The reaction mixture is stirred at room temperature for 72 h and washed with 20% K2CO3 (2×25 ml). The aqueous layer is subjected to extraction with dichloromethane (3×30 ml). The combined organic layers are washed with brine (40 ml), dried over Na2SO4, and evaporated. The residue (0.55 g) is purified by chromatography on silicagel (chloroform/ethyl acetate 1/1) to afford 0.202 g of 1-(isoxazol-4-ylmethyl)-4-propylpyrrolidin-2-one 157 (yield 0.202 g, 32%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][NH:9][C:10]1[N:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[C:19]3[S:24][C:23]([CH2:25][N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[C:22]([CH3:32])[C:20]=3[N:21]=2)=[CH:12][N:11]=1.[C:39](O)(=[O:43])[C@H:40]([CH3:42])[OH:41]>>[OH:41][C@@H:40]([CH3:42])[C:39]([N:29]1[CH2:30][CH2:31][N:26]([CH2:25][C:23]2[S:24][C:19]3[C:18]([N:33]4[CH2:34][CH2:35][O:36][CH2:37][CH2:38]4)=[N:17][C:16]([C:13]4[CH:14]=[N:15][C:10]([NH:9][CH3:8])=[N:11][CH:12]=4)=[N:21][C:20]=3[C:22]=2[CH3:32])[CH2:27][CH2:28]1)=[O:43]
Reactant: C[C@H](O)C(=O)O
Reactant: CNc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)c(C)c3n2)cn1
Solvent: O=C(O)C(F)(F)F
Product: CNc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(C(=O)[C@H](C)O)CC4)c(C)c3n2)cn1

Procedure:
The crude TFA salt of N-methyl-5-(7-methyl-4-morpholino-6-((piperazin-1-yl) methyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine was reacted with L-lactic acid via General Procedure B to give 24.5 mg of 389 after reverse phase HPLC purification. MS (Q1) 513.3 (M)+.