Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[CH3:6][O:7][C:8](=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[OH:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:6][O:7][C:8]([C:9]1[C:10]2[O:16][CH2:2][C:3](=[O:4])[NH:15][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)c1cccc(N)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1OCC(=O)N2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
At RT chloro-acetyl chloride (29.0 mmol) is added dropwise to a solution of 3-amino-2-hydroxy-benzoic acid methyl ester (26.4 mmol) in DMF (100 mL). After 20 min K2CO3 (126 mmol) is added portionwise, the mixture is stirred for 16 h at RT and the solvents are removed in vacuo. Water and DCM are added, the layers are separated and the organic layer is washed with brine and dried over Na2SO4. The solvents are removed in vacuo to give a crude product which is used without further purification. LC-MS: tR=0.68 min; [M+H]+=208.0.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11](OC(=O)C)[C:2]=12.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C>[N:16]([CH:11]1[C:2]2=[N:1][CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10]1)=[N+:17]=[N-:18]
Reactant: CC(=O)OC1CCCCc2cccnc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCCCc2cccnc21
Temperature: 60 °C
Yield: 42 %

Procedure:
This ester was dissolved in DMF (420 mL), treated with sodium azide (33.40 g, 0.514 mol), and heated at 60° C. overnight. The mixture was cooled to room temperature and concentrated. The resultant slurry was poured into brine (500 mL) and extracted with ether (4×500 mL). The combined organic extracts were washed with brine (2×100 mL), dried (Na2SO4), and concentrated. The crude material was filtered (eluant CH2Cl2) through a short plug of silica gel to provide 23.18 g (42% from 2,3-cycloheptenopyridine) of 9-azido-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine as a red oil. 1H NMR (CDCl3) δ 1.53-1.66 (m, 1H), 1.73-2.14 (m, 5H), 2.63-2.72 (m, 1H), 2.99-3.09 (m, 1H), 4.93 (dd, 1H, J=7.8, 1.7 Hz), 7.13 (dd, 1H, J=7.9, 4.8 Hz), 7.44 (d, 1H, J=5.7 Hz), 8.39 (dd, 1H, J=4.8, 1.9 Hz).
Reaction SMILES: [C:1]1([CH2:7]/[CH:8]=[CH:9]/[CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C(Cl)Cl.CCOC(C)=O>[C:19]([Si:22]([CH3:24])([CH3:23])[O:12][CH2:11][CH2:10]/[CH:9]=[CH:8]/[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:21])([CH3:20])[CH3:18]
Reactant: OCC/C=C/Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCC/C=C/Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a stirred solution of (E)-5-phenylpent-3-en-1-ol (Preparation example 236, 6.3 g, 38.83 mmol) in CH2Cl2 was added imidazole (3.4 g, 50.48 mmol) and TBDMS-Cl (7.6 g, 50.48 mmol) at 0° C. then stirred for 1 h at room temperature. The resulting mixture was diluted with EtOAc, washed with water, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude compound was purified by a silica gel column to produce the title compound (10.6 g, 80˜98%)
Reaction SMILES: [C:1]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([C:27]1[CH:32]=[CH:31][C:30]([O:33]C)=[CH:29][CH:28]=1)[C:8]1[C:13]2[O:14][C:15]3[C:20]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:19][CH:18]=[CH:17][C:16]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1.Cl.N1C=CC=CC=1>>[C:1]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([C:8]1[C:13]2[O:14][C:15]3[C:20]([CH:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)=[CH:19][CH:18]=[CH:17][C:16]=3[C:12]=2[CH:11]=[CH:10][CH:9]=1)[C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1
Reactant: COc1ccc(N(c2ccccc2-c2ccccc2)c2cccc3c2oc2c(C4CCCCC4)cccc23)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc(N(c2ccccc2-c2ccccc2)c2cccc3c2oc2c(C4CCCCC4)cccc23)cc1
Yield: 75 %

Procedure:
A mixture of N-([1,1′-biphenyl]-2-yl)-6-cyclohexyl-N-(4-methoxyphenyl)dibenzo[b,d]furan-4-amine (8.9 g, 17.0 mmol) and pyridine hydrochloride (19.6 g, 170.0 mmol) was purged with nitrogen overnight. The mixture was then refluxed for 2 h. After cooling, the precipitate was filtered and washed by excess water. The residue was purified by flash chromatography using 90% DCM/hexane (containing 1% triethylamine) to yield 4-([1,1′-biphenyl]-2-yl(6-cyclohexyldibenzo[b,d]furan-4-yl)amino)phenol (6.5 g, 75% yield) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([NH2:11])[CH:7]=[CH:8]2)=[N:3]1.C[Al](C)C.C[O:17][C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[NH:25][CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[C:29]([Cl:33])[CH:28]=1>ClCCCl>[Cl:33][C:29]1[CH:28]=[C:27]([CH2:26][NH:25][C:20]2[N:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:18]([NH:11][C:6]2[CH:7]=[CH:8][C:9]3[C:4]([CH:5]=2)=[N:3][N:2]([CH3:1])[CH:10]=3)=[O:17])[CH:32]=[CH:31][N:30]=1
Reactant: Cn1cc2ccc(N)cc2n1
Reactant: COC(=O)c1cccnc1NCc1ccnc(Cl)c1
Agent: C[Al](C)C
Solvent: ClCCCl
Product: Cn1cc2ccc(NC(=O)c3cccnc3NCc3ccnc(Cl)c3)cc2n1
Temperature: 100 °C
Yield: 77.2 %

Procedure:
To a stirred and chilled (0° C.) suspension of 2-methyl-2H-indazol-6-ylamine (1.52 g) in DCE (6 mL), under nitrogen, was added trimethylaluminium (2M solution in toluene, 5 mL, 9.37 mmol). This mixture was added dropwise to a stirred and chilled (0° C.) solution of 2-[(2-chloro-pyridin-4-ylmethyl)-amino]-nicotinic acid methyl ester (1.45 g, 5.21 mmol) in DCE (14.7 mL). The mixture was heated at 100° C. for 2 hours before cooling to room temperature and quenching by pouring into aqueous sodium-potassium tartrate solution. The mixture was extracted with EtOAc and the combined organic layers washed successively with dilute aqueous citric acid solution, dilute aqueous sodium hydrogen carbonate solution and brine, dried and concentrated in vacuo to give 2-[(2-chloro-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-nicotinamide (1.58 g); 1H-NMR (300 MHz, d6-DMSO) 10.26 (1H, s), 8.40 (1H, t), 8.28 (1H, d), 8.25 (1H, s), 8.06-8.12 (3H, m), 7.62 (1H, d), 7.35 (1H, s), 7.30 (1H, unresolved dd), 7.27 (1H, unresolved dd), 6.68 (1H, dd), 4.67 (2H, d), 4.10 (3H, s).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C1(C(C2C=CC=CC=2)=[N:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])C=CC=CC=1.[N+:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br)([O-:31])=[O:30]>C1COCC1>[CH2:21]([O:20][C:18](=[O:19])[CH:17]([CH2:35][C:34]1[CH:37]=[CH:38][CH:39]=[C:32]([N+:29]([O-:31])=[O:30])[CH:33]=1)[NH2:16])[CH3:22]
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(N)Cc1cccc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 90.7 %

Procedure:
LDA (2M in heptane/THF/ethyl benzene, 25.45 ml, 50.9 mmol) was added dropwise to a solution of ethyl N-(diphenylmethylene)glycinate (13 g, 48.5 mmol) in THF (200 ml) at −78°. After 40 min a solution of 3-nitrobenzyl bromide (10 g, 46.3 mmol) in THF (40 ml) was added dropwise. The mixture was stirred for 2 h and then partitioned between EtOAc (100 ml) and water (100 ml). The aqueous layer was separated and extracted with EtOAc (2×50 ml) and the combined organics dried (Na2SO4) and evaporated in vacuo. The residue was then dissolved in ethanol (200 ml) and hydrochloric acid (1M, 50 ml) was added and the mixture stirred for 0.25 h. The volatiles were then removed in vacuo and the residue purified by chromatography (SiO2, Et2O) to give the title compound as an orange oil (10.0 g, 96%). δH (CDCl3) 8.09-8.06 (2H, m, Ar), 7.56-7.53 (1H, m, ArH), 7.48-7.43 (1H, m, ArH), 4.15 (2H, q, J 7.2, OCH2CH3), 3.71 (1H, dd, J 7.8, 5.5 Hz, CHCH2), 3.14 (1H, dd, J 13.7, 5.5 Hz, CHCHAHB)2.95 (1H, dd, J 13.7, 7.8 Hz, CHCHAHB), 1.51 (2H, br s, NH2) and 1.23 (3H, t, J 7.2, OCH2CH3); m/z (ESI, 60V) 239 (M++1).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].C(N(CC)CC)C.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.O>C(OCC)(=O)C>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH:18][C:1](=[O:3])[CH3:2])=[CH:15][CH:14]=1
Reactant: CC(=O)Cl
Reactant: NCc1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)NCc1ccc(F)cc1
Reaction time: 12 h
Yield: 102.5 %

Procedure:
Step b) Add acetyl chloride (9.28 g, 118 mmol) to a mixture of triethylamine (16.0 g, 158 mmol) and 4-fluorobenzylamine (9.90 g, 78.8 mmol) in 200 mL of ethyl acetate at 0° C. and stir for 12 hours. Add 100 mL of water to the mixture. Extract aqueous layer with ethyl acetate (3×100 mL). Combine organic layers and wash with brine then dry over anhydrous Na2SO4 Remove solvent under reduced pressure to give N-(4-fluorobenzyl)acetamide (13.5 gm) in 100% yield as a yellow oil. Add NaH (6.5 g, 162 mmol) to N-(4-fluorobenzyl)-acetamide (13.5 g, 80.8 mmol) in 200 mL of tetrahydrofuran at 0° C. and stir for 4 hours. Then add methyl iodide (22.9 g, 161.6 mmol) to the above mixture and stir for 12 hours. Pour mixture into 200 mL of water. Extract aqueous layer with methylene chloride (3×200 mL). Combine organic layers and wash with brine then dry over anhydrous Na2SO4. Remove solvent under reduced pressure. Purify the residue by column chromatography (silica gel, 5% acetone in hexanes, 50% acetone in hexanes) to give N-(4-fluorobenzyl)-N-methylacetamide (9.1 gm) in 64% yield as a yellow oil. Add Lawesson reagent (20.3 g, 50.3 mmol) to N-(4-fluorobenzyl)-N-methylacetamide (9.1 g, 50.3 mmol) in 200 mL of toluene and heat to 100° C. for three hours. Remove solvent under reduced pressure. Purify the residue with a column chromatography (silica gel, 2% methylene chloride in hexanes, 100% methylene chloride) to give N-(4-fluorobenzyl)-N-methylthioacetamide (5.6 g) 56.5% as a yellow solid: MS 198 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH:15]=[C:14]([CH:16]=[O:17])[C:13]([CH3:18])=[N:12]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH:19]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1>[CH:19]1([CH:16]([C:14]2[C:13]([CH3:18])=[N:12][N:11]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=3)[CH:15]=2)[OH:17])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Br[Mg]C1CCCCC1
Reactant: COc1cc(OC)cc(-n2cc(C=O)c(C)n2)c1
Solvent: C1CCOC1
Product: COc1cc(OC)cc(-n2cc(C(O)C3CCCCC3)c(C)n2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
To a solution (10 mL) of 1-(3,5-dimethoxyphenyl)-3-methyl-1H-pyrazole-4-carbaldehyde (2.0 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise cyclohexylmagnesium bromide (15.0 mL, 1M tetrahydrofuran solution) under ice-cooling. After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (2.6 g, 40%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([NH2:8])[CH:7]=1.[CH3:19]OC(OC)OC.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(O)(=O)C>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][C:5]2[N:9]=[CH:19][NH:8][C:6]=2[CH:7]=1
Reactant: Nc1cc(Cl)c(Oc2ccccc2)cc1[N+](=O)[O-]
Reactant: COC(OC)OC
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Clc1cc2[nH]cnc2cc1Oc1ccccc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of 5-chloro-2-nitro-4-phenoxyphenylamine (0.810 g, 3.06 mmol) in DMF (12 mL) was added trimethylorthoformate (12 mL) followed by sodium dithionite (2.66 g, 15.3 mmol), and glacial acetic acid (1.5 mL). The reaction mixture was heated in a sealed tube at 100° C. for 14 h. Additional sodium dithionite (0.5 g) and acetic acid (1 mL) were added and heating was continued at 120° C. for an additional 3 h. The reaction flask was cooled in ice, added cautiously to half-saturated sodium bicarbonate solution (300 mL) and extracted with EtOAc. Combined organic layers were washed with 5% NaHCO3, brine, dried, filtered, and concentrated under reduced pressure. The residue was purified (FCC) (hexanes:EtOAc, 0% to 5% over 20 minutes) to yield the titled compound as a yellow amorphous solid (0.57 g, 76%) as a mixture of tautomers. MS (ESI/CI): mass calcd. for C13H9ClN2O, 244; m/z found, 245 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.55 (s, 1H), 8.06 (s, 1H), 8.0-7.2 (m, 2H), 7.32 (t, J=7.9 Hz, 2H), 7.09 (t, J=7.3 Hz, 1H), 6.96 (d, J=8.3 Hz, 2H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[CH:14]([C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21])[C:15]([CH3:19])([CH2:17]Cl)[S:16][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>N1C=CC=CC=1>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[C:14]([C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:25])[Cl:26])=[O:21])=[C:15]([CH3:19])[CH2:17][S:16][C@H:12]23)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(CCl)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2SC1
Yield: 25.9 %

Procedure:
A mixture of 2,2,2-trichloroethyl 6-(2-phenylacetamido)-2-methyl-2-chloromethylpenam-3-carboxylate (0.50 g.) in 1,1,2-trichloroethane(7 cc) and pyridine (0.16 g.) was heated under reflux for 3.5 hours. After cooling the reaction mixture was washed with water, dried and then concentrated under reduced pressure. The residue was subjected to chromatography on silica gel and eluated with chloroform. The eluate was concentrated and the residue was crystalized with ether to yield crystals (0.12 g.) of 2,2,2-trichloroethyl 7-(2-phenylacetamido)-3-methyl-3-cephem-4-carboxylate, m.p. 161°-162° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([N+:12]([O-:14])=[O:13])=[C:8]([CH:11]=1)[CH:9]=O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:34](Br)(Br)([Br:36])[Br:35].CCCCCC>ClCCl>[Br:35][C:34]([Br:36])=[CH:9][C:8]1[CH:11]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: BrC(Br)(Br)Br
Reactant: CCOc1ccc([N+](=O)[O-])c(C=O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCOc1ccc([N+](=O)[O-])c(C=C(Br)Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a solution of 5-ethoxy-2-nitrobenzaldehyde (519 mg) and triphenylphosphine (2.09 g) in dichloromethane (13 mL) was added a solution of carbon tetrabromide (1.32 g) in dichloromethane in three minutes under cooling with ice, and the mixture was stirred overnight at room temperature. Hexane (20 mL) was added to the reaction mixture, and this resulting mixture was stirred for 10 minutes and then filtered through silica gel. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (712 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([CH3:7])[NH2:6].[C:9](O)(=[O:31])[CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH3:30].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[C:9]([NH:6][C@@H:5]([CH3:7])[C:4]([O:3][CH3:2])=[O:8])(=[O:31])[CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29][CH3:30]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)O
Reactant: COC(=O)[C@H](C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)N[C@@H](C)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.3 %

Procedure:
L-Alanine methyl ester hydrochloride (0.85 g, 6.1 mmol) was taken up in CH3CN (20 mL) along with (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (2.0 g, 6.1 mmol), EDCI (1.3 g, 6.72 mmol) and DIEA (1.3 mL). The resulting reaction mixture was stirred at room temperature for 2 h. It was then diluted with EtOAc and washed with dilute aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to afford (S)-methyl 2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)propanoate (2.0 g, 79%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][NH:12][CH3:13].O>CN1C(=O)CCC1>[CH3:11][N:12]([CH3:13])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CN1CCCC1=O
Solvent: O
Product: CN(C)c1ccc([N+](=O)[O-])cn1

Procedure:
2-Chloro-5-nitropyridine (1.0 eq) and dimethylamine (2 M in EtOH, 4.6 eq) in NMP were heated for 2 h at 100° C. The solution was then poured slowly into H2O. The filtrate that formed was filtered and dried to give 2-(dimethylamino)-5-nitropyridine.
Reaction SMILES: [NH2:1][C:2]1[C:23](I)=[CH:22][C:5]([CH2:6][NH:7][C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[O:9])=[CH:4][C:3]=1[F:25].[CH2:26]([Sn](CCCC)(CCCC)C=C)[CH2:27]CC>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.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:23]([CH:26]=[CH2:27])=[CH:22][C:5]([CH2:6][NH:7][C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[O:9])=[CH:4][C:3]=1[F:25]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)c1ccc(CNC(=O)NCc2cc(F)c(N)c(I)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cc(CNC(=O)NCc2ccc(C(C)(C)C)cc2)cc(F)c1N

Procedure:
To the 50 ml round bottom flask were put 1-(4-amino-3-fluoro-5-iodo-benzyl)-3-(4-t-butyl-benzyl)-urea (0.17 g, 0.37 mmol) and Pd(PPh3)4 (0.05 eq, 21.3 mg). And to this reaction mixture was added 20 ml toluene and tributyl(vinyl)tin (1.1 eq, 0.13 g) by syringe and refluxed for 2 hours. After confirming the completion of the reaction with TLC, the reaction mixture was extracted with ethylacetate, washed with 1M KF solution. And the combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The obtained liquid was column-chromatographed (n-hexane/ethyl acetate=2/1).
Reaction SMILES: [SH:1][CH:2]([CH3:6])[C:3](=O)[CH3:4].[C:7](#[N:11])[CH2:8][C:9]#[N:10].C(N(CC)CC)C>C(O)C>[NH2:10][C:9]1[S:1][C:2]([CH3:6])=[C:3]([CH3:4])[C:8]=1[C:7]#[N:11]
Reactant: CC(=O)C(C)S
Reactant: N#CCC#N
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1sc(N)c(C#N)c1C
Temperature: -2 °C
Yield: 64.2 %

Procedure:
A solution of 3-mercapto-2-butanone (1.00 kg, 9.0 mole, 93.6% assay) in 2.0 L SDA 3C 200 Proof, absolute Ethanol (Ethanol) is prepared in a 5 L 1N RBF fitted with torian and transfer tubing. Malononitrile (588.8 g, 8.9 mole) is dissolved in 5.0 L Ethanol and cooled to 4° C. at which point triethylamine (250 mL, 1.8 mole, 0.2 equivalent) is added with a 560 mL ethanol rinse. The anionic malononitrile solution is cooled to −2° C. and the 3-mercaptobutanone solution is added over 1.3 hrs at −1 to −5° C. After an hour, the reaction shows less than 0.1% malononitrile. The reaction is concentrated on the rotovap (40° C. bath) to a slurry of approximately 2.5 L and 3.0 L of heptanes are added. The slurry is cooled to 5° C. for 30 minutes and the solids collected by filtration. The solids are rinsed with 2.5 L of 20% Ethanol in heptanes in 7 portions. The excess solvent is removed on the filter, and the wet cake dried in a vacuum oven overnight at 40° C. and full vacuum to give an off white solid as 2-amino-4,5-dimethylthiophene-3-carbonitrile (870 g, 64.1% yield, 99.7% purity shown by HPLC). The filtrates are re-concentrated to an oily slurry which is filtered and rinsed with 0.5 L of 20% Ethanol in heptanes. The second crop of solids is dried separately (47 g, 3.5% yield, 98.6% purity shown by HPLC). 1H NMR (400 MHz, DMSO-d6) δ 1.93 (d, J=1.2 Hz, 3H), 2.07 (d, J=1.2 Hz, 3H), 3.33 (s, 2H). MS 153 (MH+). HPLC Retention Time: approximately 10.9 minute (Phenomenex Luna C18 (2) column, acetonitrile/water with 0.1% AcOH).
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][C:14]1=[O:26]>Cl.O1CCOCC1>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][C:14]1=[O:26]
Reactant: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2=O)nnn1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(N2CCNCC2=O)nnn1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4N hydrochloric acid/dioxane solution (10 ml) was added to tert-butyl 4-(5-methyl-1-phenyl-1H-[1,2,3]triazol-4-yl)-3-oxopiperazine-1-carboxylate prepared in Example 29 followed by stirring at room temperature for 3 hours and the solvent was evaporated in vacuo to give 60 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([OH:11])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:20][CH2:21][CH2:22][O:23][CH3:24]>C(#N)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([O:11][CH2:20][CH2:21][CH2:22][O:23][CH3:24])[CH:5]=1
Reactant: COCCCI
Reactant: COC(=O)c1ccc(C)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCCOc1cc(C(=O)OC)ccc1C

Procedure:
A solution of 3-hydroxy-4-methyl-benzoic acid methyl ester (7.7 g, 32.43 mmol), potassium carbonate (6.72 g, 48.65 mmol) and 1-iodo-3-methoxy propane (7.14 g, 35.68 mmol) in acetonitrile (125 mL) is stirred at reflux for 26 h. The solvent is concentrated under reduced pressure, H2O (100 mL) is added, and the aqueous layer is extracted with ether (50 mL×4). The combined organic extracts are washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the title which is used without further purification in the next step. TLC, Rf (hexane/AcOEt 2:1)=0.65. 1H-NMR (CDCl3, 300 MHz): δ=2.10 (p, 2H), 2.3 (s, 3H), 3.38 (s, 3H), 3.62 (t, 2H), 3.9 (s, 3H), 4.15 (t, 2H), 7.15 (d, 1H), 7.45 (s, 1H), 7.55 (d, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([OH:10])=[CH:4][CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH2:11]([O:10][C:5]1[C:6]([C:8]#[N:9])=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1nc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: N#Cc1nc(Br)ccc1OCc1ccccc1

Procedure:
6-Bromo-3-hydroxypyridine-2-carbonitrile (53.8 g) obtained in Reference Example 72(1) is dissolved in acetone (550 ml), and thereto are added benzyl bromide (35.6 ml) and potassium carbonate (43.1 g). The mixture is then heated under reflux for 4 hours. After allowing to cool, water (600 ml) is added to the reaction solution, and the mixture is extracted with ethyl acetate. The aqueous layer is extracted with ethyl acetate once, and combined with the previous organic layer. The solution is washed with saturated brine and dried over sodium sulfate. The solvent is removed by evaporation under reduced pressure and the residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1, followed by 3/1). The resulting residue is suspended in diethyl ether/n-hexane and the solid is collected by filtration to give the title compound (24.1 g).