Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][CH:18]=1)[C:8]([CH:10]([CH3:15])[CH2:11][C:12](O)=[O:13])=O)([O-:4])=[O:3].O.[NH2:20][NH2:21]>C(O)C>[CH3:15][CH:10]1[C:8]([C:7]2[CH:16]=[CH:17][CH:18]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=2)=[N:21][NH:20][C:12](=[O:13])[CH2:11]1
Reactant: NN
Reactant: CC(CC(=O)O)C(=O)c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC1CC(=O)NN=C1c1cccc([N+](=O)[O-])c1

Procedure:
A 28 g. portion of 3-(m-nitrobenzyoly)butyronitrile [prepared as described in J. Org. Chem., Vol. 38, No. 23, 4044-4048 (1973)] is added to one liter of 6N hydrochloric acid and is stirred at reflux for one hour using a magnetic stirrer and a heating mantle. The reaction mixture is cooled and extracted with methylene chloride. The organic layer is separated and extracted with saturated sodium bicarbonate. The bicarbonate layer is added dropwise to a stirred cold hydrochloric acid solution and the resulting solid is kept cold in ice then is filtered and air dried to afford 27.24 g. of 3-m-nitrobenzoyl butyric acid as a white solid. The entire amount of the preceding compound is mixed with 12.8 ml of 99% hydrazine hydrate in 140 ml. of ethyl alcohol and is stirred at reflux for 3 hours. A solid beings to appear after about half an hour. The reaction mixture is cooled in an ice bath and the resulting solid is filtered and air dried to afford the compound 4,5-dihydro-5-methyl-6-(m-nitrophenyl)-3-(2H)-pyridazinone as white to light yellow crystals.
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Cl)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:4]2[C:3](=[O:8])[CH:2]([CH3:1])[NH:6][C:5]2=[O:7])=[CH:13][CH:12]=1
Reactant: CC1NC(=O)NC1=O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)NC(C)C2=O)cc1
Temperature: 90 °C
Reaction time: 9 h

Procedure:
To a mixture of 5-methylimidazolidine-2,4-dione (2.00 g), 4-methoxybenzyl chloride (2.85 mL) and potassium carbonate (3.15 g) were added N,N-dimethylformamide (20 mL) and potassium iodide (0.29 g), and the mixture was stirred at 90° C. for 9 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was recrystallized from ethyl acetate/diisopropyl ether to give the title compound (2.82 g).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([CH:14]=[O:15])[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:16][Mg]Br>>[OH:15][CH:14]([C:10]1[CH:9]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:13]=[CH:12][N:11]=1)[CH3:16]
Reactant: C[Mg]Br
Reactant: O=Cc1cc(CN2CCOCC2)ccn1
Product: CC(O)c1cc(CN2CCOCC2)ccn1
Yield: 94.5 %

Procedure:
Grignard reaction between 4-(4-morpholinyl)methyl-2-pyridine carboxaldehyde (1.03 g, 5.00 mmol) and methylmagnesium bromide (2.50 ml, 7.50 mmol, 1.5 equiv., 3.0 M in ether) yielded 1.05 g (94%) of 2-(1-hydroxyethyl)-4-(4-morpholinyl)methylpyridine.
Reaction SMILES: [F:1][C:2]1[C:18]([N:19]2[C:28](=[O:29])[C:23]3[CH2:24][CH2:25][CH2:26][CH2:27][C:22]=3[C:20]2=[O:21])=[CH:17][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15]C)[N:7]=[N:8][C:4]=2[CH:3]=1.B(Br)(Br)Br.C(OCC)(=O)C>C(Cl)Cl>[F:1][C:2]1[C:18]([N:19]2[C:20](=[O:21])[C:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C:23]=3[C:28]2=[O:29])=[CH:17][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[OH:15])[N:7]=[N:8][C:4]=2[CH:3]=1
Reactant: COc1ccccc1-n1nnc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc21
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc2c(cc1F)nnn2-c1ccccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of N-[5-fluoro-1-(o-methoxyphenyl)-1H -benzotriazol-6-yl]-1-cyclohexene-1,2-dicarboximide (1.00 g, 0.003 mol) in methylene chloride is slowly added to a one molar boron tribromide in methylene chloride solution (5 mL, 0.005 mol) at -20° C. The reaction mixture is stirred at room temperature overnight, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a tan solid. Flash column chromatography of the solid using silica gel and 2.5% to 10% ethyl acetate in methylene chloride solutions gives the title product as a white solid, mp 274°-275° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[C:20]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.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>[C:20]([C:24]1[CH:25]=[C:26]([C:2]2[CH:3]=[C:4]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=3)[CH:5]=[CH:6][C:7]=2[OH:8])[CH:27]=[CH:28][C:29]=1[N:30]([CH2:33][CH3:34])[CH2:31][CH3:32])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)c1ccc(-c2ccc(O)c(Br)c2)cc1
Reactant: CCN(CC)c1ccc(B(O)O)cc1C(C)(C)C
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccc(O)c(-c3ccc(N(CC)CC)c(C(C)(C)C)c3)c2)cc1
Temperature: 40 °C
Yield: 15.8 %

Procedure:
To 5.6 g of ethyl 3′-bromo-4′-hydroxy-biphenyl-4-carboxylate (17 mmol) are added 6.5 g of 3-tert-butyl-4-diethylaminophenylboronic acid (26 mmol) dissolved in 112 mL of toluene and 30.5 mL of 2M potassium carbonate (61 mmol). The reaction medium is stirred and heated to 40° C.; 2 g of tetrakis(triphenylphosphine)palladium (Pd(PPh3)4) (1.74 mmol) are added and the medium is heated to 110° C. and stirred for 3 hours. The reaction is stopped by adding 200 mL of water and the medium is then extracted with 200 mL of ethyl acetate. The organic phases are washed with 400 mL of water and neutralized with 200 mL of saturated NH4Cl and then dried over magnesium sulfate. The solvents are evaporated off and the residue is then purified by chromatography on silica gel (eluent: 9/1 heptane/ethyl acetate). 1.2 g of ethyl 3″-tert-butyl-4″-diethylamino-4′-hydroxy[1,1′;3′,1″]terphenyl-4-carboxylate are obtained (yield=16%) in the form of an orange solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[C:14]([CH3:22])[CH:13]=1.C([O-])([O-])=O.[K+].[K+].CN1CCCC1=O>O>[CH3:22][C:14]1[CH:13]=[C:12]([NH:11][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: Cc1cc(N)c2ccccc2n1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(Nc2ccc([N+](=O)[O-])cc2)c2ccccc2n1
Temperature: 60 °C
Yield: 7.6 %

Procedure:
0.6 g of 4-fluoronitrobenzene, 0.807 g of 4-aminoquinaldine, and 0.705 g of K2CO3 were added to a solution of 2.5 ml of N-methylpyrrolidinone. The reaction medium was heated at 60° C. for 6 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The yellow precipitate formed was filtered off, reslurried in water and then dried over P2O5. 0.09 g of 2-methyl-N-(4-nitrophenyl)quinol-4-amine (13) was obtained after purification by chromatography on a column of silica (eluent: 50/50 dichloromethane/heptane).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:6]([NH2:19])[CH:5]=1.C([C:23]1[C:24]([N:30]=[CH:31][N:32]([CH3:34])C)=[N:25][C:26]([CH3:29])=[CH:27][CH:28]=1)#N>>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:6]([NH:19][C:34]2[C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[N:25][C:24]=3[N:30]=[CH:31][N:32]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(Sc2ccc(OC)cc2)c(N)c1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Product: COC(=O)c1ccc(Sc2ccc(OC)cc2)c(Nc2ncnc3nc(C)ccc23)c1
Yield: 44.8 %

Procedure:
The product from Example 136B (2.67 g, 9.23 mmol) and the product from Example 9B (1.72 g, 9.23 mmol) were reacted according to the procedure from Example 136C substituting the product from Example 9B for the product from Example 8E to give a residue which was purified by silica gel chromatography using 4% methanol in dichloromethane as eluent to provide the title compound as a white solid (1.79 g, 45%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[N:3]=1.[CH2:11]([O:13][C:14](=[O:18])[C@H:15](O)[CH3:16])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1>[CH2:11]([O:13][C:14](=[O:18])[C@H:15]([O:9][C:5]1[C:4]([Cl:10])=[N:3][C:2]([Cl:1])=[N:7][C:6]=1[Cl:8])[CH3:16])[CH3:12]
Reactant: Oc1c(Cl)nc(Cl)nc1Cl
Reactant: CCOC(=O)[C@@H](C)O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](C)Oc1c(Cl)nc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.9 %

Procedure:
A mixture of 2,4,6-trichloro-pyrimidin-5-ol (600 mg, 3.01 mmol), (R)-2-hydroxy-propionic acid ethyl ester (411 μL, 3.60 mmol), triphenylphosphine (906 mg, 3.45 mmol) and DIAD (678 μL, 3.45 mmol) in dioxane (5 mL) was stirred at RT for 18 hours before being concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0-25% ethyl acetate in cyclohexane) affording (R)-2-(2,4,6-Trichloro-pyrimidin-5-yloxy)-propionic acid ethyl ester (522 mg, 52%). 1H NMR (400 MHz, CDCl3): δ 4.30-4.16 (2H, m), 4.12 (1H, q, J=7.14 Hz), 1.70 (3H, d, J=6.78 Hz), 1.29 (3H, t, J=7.19 Hz).
Reaction SMILES: C[N:2](/[CH:4]=[CH:5]/[C:6]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=O)C.O.[NH2:18]N>C(O)C>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][NH:2][N:18]=2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: NN
Reactant: CN(C)/C=C/C(=O)c1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-c2cc[nH]n2)cc1
Yield: 78.9 %

Procedure:
A solution of 1-(4-nitrophenyl)-3-N,N-dimethylamino-2-propen-1-one (27.3 g) and 85% hydrazine hydrate (23.6 g) in ethanol was heated at 60° C. for one hour. The crystallized solid was filtered to give 18.5 g of 3-(4-nitrophenyl)-pyrazole; M.p. 196°-197° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[C:19]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[O:10])[S:6][CH:7]=1.[CH3:26][S:27]([CH2:30][C:31](O)=[O:32])(=[O:29])=[O:28]>>[CH:21]1([C:19]([C:13]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=2[NH:11][C:9](=[O:10])[NH:8][C:5]2[S:6][CH:7]=[C:3]([CH2:2][NH:1][C:31](=[O:32])[CH2:30][S:27]([CH3:26])(=[O:29])=[O:28])[N:4]=2)=[O:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Cc1ccc(NC(=O)Nc2nc(CN)cs2)c(C(=O)C2CCCC2)c1
Reactant: CS(=O)(=O)CC(=O)O
Product: Cc1ccc(NC(=O)Nc2nc(CNC(=O)CS(C)(=O)=O)cs2)c(C(=O)C2CCCC2)c1
Yield: 86.1 %

Procedure:
N-{2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl}-2-methanesulfonyl-acetamide (103 mg, 84%) was prepared from 1-(4-aminomethyl-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (90 mg, 0.25 mmol) and methanesulfonyl acetic acid (55 mg, 0.4 mmol) following the general procedure T.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:15]=[C:14]([Cl:16])[C:11]([C:12]#[N:13])=[C:10]([Cl:17])[CH:9]=2)[N:3]=1.[CH:18]([C:20]1[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:22][CH:21]=1)=O.C(O)(=O)C.Cl>CO>[Cl:16][C:14]1[CH:15]=[C:8]([NH:7][C:4]2[N:3]=[C:2]([NH:1][CH2:18][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])=[CH:22][CH:21]=3)[NH:6][N:5]=2)[CH:9]=[C:10]([Cl:17])[C:11]=1[C:12]#[N:13]
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)cc1
Reactant: N#Cc1c(Cl)cc(Nc2n[nH]c(N)n2)cc1Cl
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1ccc(CNc2nc(Nc3cc(Cl)c(C#N)c(Cl)c3)n[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.2 %

Procedure:
To a solution of 4-(5-Amino-1H-[1,2,4]triazol-3-ylamino)-2,6-dichloro-benzonitrile (60 mg, 223 μmol) in MeOH (3.5 ml) was added tert-butyl 4-formylbenzoate (55.2 mg, 268 μmol) followed by acetic acid (21.0 mg, 20 μl, 349 μmol). The reaction was stirred at room temperature for 15 minutes, 2-picoline borane complex (32.2 mg, 349 μmol) was added and the stirring was continued for 4 days. The reaction mixture was poured into 0.1N HCl solution (20 ml) and let stand. The resulting suspension was filtered to collect the solid. Purification by super fluid chromatography and trituration from acetonitrile afforded a white solid as desired product (54.5 mg, 53% yield). MS +m/z: 459 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:35]=[CH:34][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:5][CH:4]=1)#[N:2].[ClH:36].CCOC(C)=O>CCOC(C)=O>[ClH:36].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:35]=[CH:34][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][NH:25][CH3:26])=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[CH:7][CH:8]=1)#[N:2]
Reactant: CN(CCCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3)c2O)nc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CNCCCNC(=O)c1ccc(-n2ncc(-c3ccc(C#N)cc3)c2O)nc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Combined tert-butyl (3-(6-(4-(4-cyanophenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinamido)propyl)(methyl)carbamate and EtOAc (5 mL) and added HCl-EtOAc (5 mL) and stir at room temperature for 5 h. The reaction mixture was evaporated in vacuo to give the title compound as a yellow green solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.09-9.04 (m, 1H), 9.00 (s, 1H), 8.89 (br. s., 2H), 8.67 (s, 1H), 8.48 (br. s., 2H), 8.15 (d, J=8.2 Hz, 2H), 7.79 (d, J=8.4 Hz, 2H), 3.38 (d, J=6.0 Hz, 2H), 2.95 (br. s., 2H), 2.54 (t, J=5.3 Hz, 3H), 1.96-1.85 (m, 2H). MS m/Z [M+H]+ 377.1.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C@H:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[N:10][CH:9]=1.[CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[C:18]=1[N:26]=[C:27]=[O:28])([CH3:16])[CH3:15].C([N-]C(C)C)(C)C.[Li+]>>[CH3:16][CH:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:24])[CH3:25])[C:18]=1[NH:26][C:27]([CH:5]1[CH2:4][CH:3]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:2]([CH3:1])[C:6]1=[O:7])=[O:28])[CH3:15]
Reactant: CN1C(=O)CC[C@H]1c1cccnc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C1CC(c2cccnc2)N(C)C1=O

Procedure:
The title compound was prepared from (-)-cotinine (5.0 g, 0.028 mol), 2,6-diisopropylphenyl isocyanate (5.69 g, 0.028 mol) and lithium diisopropylamide (0.028 mol) using the procedure described in Example 1.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH2:3][C:4]#[CH:5].[O:7](C(OC(C)(C)C)=O)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=O>C(Cl)Cl>[C:11]([O:10][C:8](=[O:7])[NH:6][CH2:1][CH2:2][CH2:3][C:4]#[CH:5])([CH3:14])([CH3:13])[CH3:12]
Reactant: C#CCCCN
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: C#CCCCNC(=O)OC(C)(C)C

Procedure:
A solution of pent-4-ynylamine (480 mg; Li, Y. et al. J. Am. Chem. Soc. 1996, 118, 9295) in DCM (5 mL) was treated with (BOC)2O at rt for 15 min. Evaporation gave the title compound as a colorless oil. 1H NMR (CDCl3) δ 4.68 (s, 1H), 3.24 (q, 2H), 2.25 (td, 2H), 1.97 (t, 1H), 1.70 (quint., 2H), 1.45 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C1COCC1.[NH4+].[Cl-]>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CN2CCCC2)cc1
Reaction time: 18 h

Procedure:
4-nitrobenzyl chloride Compound 1n1 (4.0 g, 23.3 mmol) and pyrrolidine Compound 1n2 (4.8 mL, 58.3 mmol) were combined in THF (50 mL) at ambient temperature. After 18 hr, the reaction was diluted with 10% NH4Cl and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and evaporated in vacuo to provide 1-(4-nitrobenzyl)-pyrrolidine Compound 1n3 (4.7 g) as a pale yellow oil without further purification (prepared as described in Mitsuru Shiraishi, et al., J. Med. Chem., 2000, 43, 2049-2063). 1H NMR (CDCl3) δ 8.17 (d, J=8.6 Hz, 2H); 7.51 (d, J=8.6 Hz, 2H); 3.72 (s, 2H); 2.58-2.48 (m, 4H); 1.89-1.72 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.Br[C:24]1[C:25]([F:35])=[CH:26][C:27]([F:34])=[C:28]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:29]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:24]4[C:25]([F:35])=[CH:26][C:27]([F:34])=[C:28]([S:30]([NH2:33])(=[O:31])=[O:32])[CH:29]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: NS(=O)(=O)c1cc(Br)c(F)cc1F
Product: NS(=O)(=O)c1cc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)c(F)cc1F

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-3-ethynyl-7-trifluoromethyl pyrazolo[1,5-a]pyrimidine (example C.4) (161 mg, 0.5 mmol) and 5-bromo-2,4-difluoro-benzenesulfonamide (136 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (146 mg, 57%). MS (ISP) 513.3 [(M+H)+]; mp 292–293° C.
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C@H:7]([C:23]2[S:24][CH:25]=[C:26]([CH2:28]OS(C)(=O)=O)[N:27]=2)[CH2:6]1)(=[O:3])[CH3:2].[N-:34]=[N+:35]=[N-:36].[Na+]>CN(C)C=O>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)=[O:11])[C@H:7]([C:23]2[S:24][CH:25]=[C:26]([CH2:28][N:34]=[N+:35]=[N-:36])[N:27]=2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)S[C@H]1C[C@@H](c2nc(COS(C)(=O)=O)cs2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1C[C@@H](c2nc(CN=[N+]=[N-])cs2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 70 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-2-[4-(methanesulfonyloxymethyl) thiazol-2-yl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.5 g) in dimethylformamide (20 ml) was added sodium azide (0.15 g) at ambient temperature. After stirring at 70° C. for 2 hours, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine successively, dried over magnesium sulfate and concentrated to give a syrup. The syrup was subjected to a column chromatography on silica gel and eluted with a mixture of acetone and dichloromethane (1:9, V/V) to give (2S, 4S)-4-acetylthio-2-(4-azidomethylthiazol-2-yl) -1-(4-nitrobenzyloxycarbonyl)pyrrolidine (500 mg).
Reaction SMILES: [F-].[K+].Br[CH2:4][C:5](OCC)=[O:6].[NH2:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[OH:20]>CN(C)C=O>[N+:17]([C:15]1[CH:14]=[CH:13][C:12]2[O:20][CH2:4][C:5](=[O:6])[NH:10][C:11]=2[CH:16]=1)([O-:19])=[O:18]
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CCOC(=O)CBr
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1COc2ccc([N+](=O)[O-])cc2N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 26.5 %

Procedure:
To a mixture of 10.6 g (182 mmol) of potassium fluoride and 55 ml of anhydrous dimethylformamide was added 7.76 ml (72 mmol) of ethyl bromoacetate and the reaction mixture was stirred at room temperature for 15 minutes. Then 10.79 g (70.0 mmol) of 2-amino-4-nitrophenol was added and the reaction mixture was heated to 55° C. for 6 hours. The reaction mixture was cooled slowly to room temperature, stirred for 12 hours and poured onto 300 ml ice. The solid which formed was filtered off, washed with water and dried (20-50 Torr, 50° C., 16 hrs). The resulting orange solid was taken up in 100 ml EtOAc and 100 ml H2O. The aqueous layer was extracted with EtOAc (2×100 ml). The organic layers were then combined and washed with water (3×150 ml) and 10% HCl and dried (MgSO4). The solvent was removed in vacuo and the resulting solid was recrystallized from ethylene dichloride to yield 3.6 g (27% yield) of 6-nitro-2H-1,4-benzoxazin-3(4H)-one as an orange solid, m.p. 221°-223° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH2:15])[C:7]=12.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:23][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[CH2:15])[C:7]=12)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCc1ccccc1
Reactant: C=CCn1c(C)c(C)c2cnnc(Cl)c21
Product: C=CCn1c(C)c(C)c2cnnc(OCc3ccccc3)c21
Yield: 63.2 %

Procedure:
The title compound was prepared as a white powder in 63.2% yield in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazine and benzyl alcohol.
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]([N:24]1[C@H:29]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[C@@H:28]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH2:27][C@@:26]([C:45]2([C:48]([O:50][CH3:51])=[O:49])[CH2:47][CH2:46]2)([CH3:44])[C:25]1=[O:52])[CH:21]1[CH2:23][CH2:22]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:43][C:39]1[CH:38]=[C:37]([C@@H:28]2[C@@H:29]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[N:24]([C@@H:20]([CH:21]3[CH2:22][CH2:23]3)[CH2:19][OH:18])[C:25](=[O:52])[C@:26]([C:45]3([C:48]([O:50][CH3:51])=[O:49])[CH2:46][CH2:47]3)([CH3:44])[CH2:27]2)[CH:42]=[CH:41][CH:40]=1
Reactant: COC(=O)C1([C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)cc3)N([C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C3CC3)C2=O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)C1([C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)cc3)N([C@H](CO)C3CC3)C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 1-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylate (53 mg, 0.070 mmol; Example 270, Step C) in THF (0.70 mL) was added 1 M TBAF in THF (0.21 mL, 0.21 mmol) and the reaction was stirred at rt overnight. The reaction was quenched (sat. NH4Cl), extracted (2×EtOAc), and washed (brine). The combined organic layers were dried (Na2SO4) and concentrated under the reduced pressure. Purification of the residue by chromatography on silica gel (4 g SiO2, 10%, 45%, and 55% EtOAc/Hex) provided the title compound as a white foam
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]C.[CH2:21]([C:23]1([CH3:43])[CH:28]([CH3:29])[CH:27]([NH-:30])[CH2:26][C:25]([CH2:32][CH3:33])([CH3:31])[N:24]1[O:34][CH:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:36])[CH3:22]>>[CH2:21]([C:23]1([CH3:43])[CH:28]([CH3:29])[CH:27]([NH:30][C:1](=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:26][C:25]([CH2:32][CH3:33])([CH3:31])[N:24]1[O:34][CH:35]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[CH3:36])[CH3:22]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCC1(C)CC([NH-])C(C)C(C)(CC)N1OC(C)c1ccccc1
Product: CCCCCCCCCCCCCCCCC(=O)NC1CC(C)(CC)N(OC(C)c2ccccc2)C(C)(CC)C1C

Procedure:
Octadecanoic acid[2,6-diethyl-2,3,6-trimethyl-1-(1-phenyl-ethoxy)-piperidin-4-yl-amide;