Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C@@H:14]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:26][C@@H:27]1[CH2:32][C@@H:31]2[CH2:33][C@@H:29]([C:30]2([CH3:35])[CH3:34])[C@H:28]1[CH3:36].FC(F)(F)C(O)=O.C(OCC)(=O)C>ClCCl>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([NH:12][CH2:13][C@H:14]2[CH2:18][CH2:17][NH:16][CH2:15]2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:26][C@@H:27]1[CH2:32][C@@H:31]2[CH2:33][C@@H:29]([C:30]2([CH3:35])[CH3:34])[C@H:28]1[CH3:36]
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NC[C@@H]3CCN(C(=O)OC(C)(C)C)C3)c(=O)c1Br)C2(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)NC[C@H]3CCNC3)c(=O)c1Br)C2(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
t-Butyl (3S)-3-[({[5-bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetyl}amino)methyl]pyrrolidine-1-carboxylate (72.5 mg, 0.13 mmol) in dichloromethane (2 mL) was mixed with trifluoroacetic acid (19.7 μL, 0.26 mmol) at room temperature and stirred at room temperature for 12 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol=20/1) to give the desired product.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:9](=[S:10])[NH:8][N:7]=[N:6]1.CN(C)C=O.C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>CC(C)=O>[NH2:2][CH2:3][CH2:4][N:5]1[C:9]([S:10][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[N:8][N:7]=[N:6]1
Reactant: COc1ccc(CCl)cc1
Reactant: NCCn1nn[nH]c1=S
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CSc2nnnn2CCN)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 22.8 g. (12.5 mmol) of 1-(2-aminoethyl)-1,4-dihydro-5H-tetrazole-5-thione, hydrochloride in 100 ml. of N,N-dimethylformamide and 100 ml. of acetone was added 34.3 ml. (25 mmol) of triethylamine. To the resulting suspension was added slowly a solution of 19.5 g. (12.5 mmol) of p-methoxybenzyl chloride in 30 ml. of acetone. After stirring at room temperature for 15 hours, the mixture was filtered. The filtrate was evaporated to dryness. The residue was taken up in 350 ml. of 5% NaHCO3, and extracted with ethyl acetate. The combined extract was dried (MgSO4) and evaporated to dryness to give an oil which was chromatographed on a silica gel column, eluting with a gradient of 5-10% ethanol in chloroform. Fractions containing product by thin layer chromatography were pooled, and evaporated to dryness to give 1-(2-aminoethyl)-5-(4-methoxybenzylthio)-1H-tetrazole as a brown oil (26 g., 80%). An analytical sample of the crystalline amine hydrochloride (mp 148°-150°) was obtained by treating the product with an ethereal HCl solution.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH:15]([CH3:21])[C:16]([O:18]CC)=[O:17])[CH:12]=[CH:11][C:9]=3[S:10][C:2]=12.[OH-].[Na+]>C(O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][C:8]3[CH:14]=[C:13]([CH:15]([CH3:21])[C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:9]=3[S:10][C:2]=12
Reactant: CCOC(=O)C(C)c1ccc2c(c1)Cc1cccnc1S2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)c1ccc2c(c1)Cc1cccnc1S2
Yield: 88.3 %

Procedure:
A mixture of 3 g of ethyl 2-(5H-[1]benzothiopyrano[2,3-b]pyridin-7-yl)propionate and 0.48 g of sodium hydroxide is dissolved in a mixture of 25 ml of ethanol and 5 ml of water, and the solution is heated under reflux for 1.5 hours. The ethanol is distilled off under reduced pressure, and water is added to the residue. The mixture is made acid with acetic acid, and the crystalline precipitate is filtered off and recrystallized from aqueous dioxane to give 2.4 g of 2-(5H-[1]benzothiopyrano[2,3-b]pyridin-7-yl)propionic acid melting at 203°-204°C.
Reaction SMILES: N1([C:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]=2)CCCC1.[F:12][C:13]([F:25])([F:24])[C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17](=[O:20])[CH2:18]Br.C1(C)C=CC=CC=1.[OH2:33]>>[F:12][C:13]([F:25])([F:24])[C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17](=[O:20])[CH2:18][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][C:6]1=[O:33]
Reactant: C1=C(N2CCCC2)CCCC1
Reactant: O
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: O=C(CC1CCCCC1=O)c1cccc(C(F)(F)F)c1

Procedure:
A stirred mixture of 15.9 g. (0.11 mole) of 1-pyrrolidino-1-cyclohexene, 28.0 g. (0.11 mole) of m-trifluoromethylphenacyl bromide, and 100 ml. of toluene was heated under reflux for 2 hours, diluted with water and refluxed for 2 hours. The layers were separated, and the organic phase was dried and concentrated to 25 g. of liquid. Distillation provided 12.0 g. (42%) of liquid, b.p. 137°-138° (0.075 mm.).
Reaction SMILES: [CH2:1]([N:4]([CH3:7])[CH:5]=[O:6])[CH2:2][CH3:3].[CH3:8][N:9]([CH3:18])[C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CN(C)C(=O)C>[CH2:1]([N:4]([CH3:7])[C:5](=[O:6])[CH3:8])[CH2:2][CH3:3].[CH2:8]([N:9]([CH3:18])[C:10](=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:1][CH3:2]
Reactant: CCCN(C)C=O
Reactant: CN(C)C(=O)c1ccccc1
Solvent: CC(=O)N(C)C
Product: CCCN(C)C(=O)c1ccccc1
Product: CCCN(C)C(C)=O

Procedure:
Table 1 lists the addition products of some typical small molecule amides. In the case of N,N-dimethylformamide (DMF), the double bond content nearly completely disappeared, after stirring for 3 days in the presence of DTBP at 125° C. to give a mixture of products 2a and 2b. Abstraction of the carbonyl-bonded hydrogen atom results in the formation of the N,N-dimethyl amide 2b (13C NMR: 171 ppm; IR: 1655 cm−1; >N—CO—CH2—). However, abstraction of the hydrogen atom of the nitrogen-bonded methyl group also yields N-propyl-N-methyl formamide 2a (13C NMR: 161 ppm; IR: 1684 cm−1; >N—CO—H). Solid state 13C NMR shows an approximately 1:1 ratio of a mixture which is consistent with the results reported for the similar small molecules [ ] Friedman and Schecter y1961 ibid]. Similarly, addition of N,N-dimethylacetamide and N,N-dimethylbenzamide to (vinyl)polystyrene gave only N-propyl-N-methylacetamide 3a and N-propyl-N-methylbenzamide 4a, respectively. Cyclic N-methylamide N-methylpyrrolidione (NMP) also gave good yields of the possible addition products 7a-c although the exact proportions could not be determined.20 N-methylacetamide, acetamide and formamide showed none of the addition products 5a and 8a respectively. Substituted ureas such as N,N,N′,N′-tetramethylurea and DMPU were succesful in adding to the residual vinyl groups although in moderately low yeilds of 6a and 9a and 9b. The addition of an N-acetyl α-amino acids was also performed (22).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[CH:24]=[N:23][N:22]([CH:25]([CH3:27])[CH3:26])[C:16]=2[N:17]=[C:18]([CH:20]=[CH2:21])[CH:19]=1)=[O:13].C[N+]1([O-])CC[O:32]CC1.CC(O)(C)C.[OH2:41]>C(Cl)Cl.O=[Os](=O)(=O)=O.CO.C(Cl)Cl>[OH:41][CH:20]([C:18]1[CH:19]=[C:14]([C:12]([NH:11][CH2:10][C:3]2[C:4](=[O:9])[NH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])=[O:13])[C:15]2[CH:24]=[N:23][N:22]([CH:25]([CH3:27])[CH3:26])[C:16]=2[N:17]=1)[CH2:21][OH:32]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Solvent: CO
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(C(O)CO)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-6-vinyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.8 g, 2.19 mmol) in DCM (10 mL), N-Methylmorpholine-N-oxide (0.769 g, 6.57 mmol) was added at 0° C. Then 2.5% OsO4 in t-BuOH (0.139 g, 5.56 mL, 0.547 mmol) was added to it. Resulting solution was stirred at room temperature for 1 h. After completion of reaction, water was added to it and extraction was carried out using 20% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (0.66 g, 75.4%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1.[Cl:21][C:22]1[CH:23]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:26][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>COCCOC.CCCCCC.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>[Cl:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:3]=[C:4]3[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)[C:5]3=[N:6][CH:7]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1ccc(Cn2nc(C)c3cc(Br)cnc32)cc1
Reactant: CC1(C)OB(c2cccc(Cl)c2)OC1(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: [Cs+]
Solvent: COCCOC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nc(C)c3cc(-c4cccc(Cl)c4)cnc32)cc1
Temperature: 100 °C

Procedure:
To a stirred solution of 5-bromo-1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine (7) (100 mg, 0.301 mmol, 1 eq) and 2-(3-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (95) (71 mg, 0.301 mmol, 1 eq) in 1,2-dimethoxyethane (10 mL) was added Cs2CO3 (244 mg, 0.752 mmol, 25 eq) 2M aqueous solution followed by degassing, purging with N2 for 15 min and addition of Pd(PPh3)4 (13 mg, 0.012 mmol, 0.04 eq). The reaction mixture was heated at 100° C. in a sealed tube overnight. After completion of the reaction the mixture was partitioned between ethyl acetate and water and the organic layer was separated and again extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and the solvent completely distilled off to get the crude. The crude was passed through 100-200 mesh silica gel eluting the pure compound at 50% ethyl acetate in hexane as off-white coloured solid compound 96 (60 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[S:11]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1)(=[O:14])(=[O:13])[NH2:12]>>[S:11]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][N:22]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:19][CH:20]=1)(=[O:14])(=[O:13])[NH2:12]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=Cc2ccc(F)cc2)cc1
Yield: 58 %

Procedure:
A solution of 4-fluorobenzaldehyde (5 mmol) and 4-sulfamyl-phenylhydrazine hydrochloride was subjected to the General Procedure. The title compound, melting point 205–206° C., was obtained in 58% yield.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:25])[C:14]3[CH:19]=[C:18]([CH2:20][CH2:21][CH:22]=O)[CH:17]=[N:16][C:15]=3[Cl:24])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:26][CH2:27][CH2:28]CO.C([BH3-])#N.[Na+].[CH3:35][OH:36]>C(O)(=O)C>[C:1]12([CH2:11][NH:12][C:13](=[O:25])[C:14]3[CH:19]=[C:18]([CH2:20][CH2:21][CH2:22][NH:26][CH2:27][CH2:28][CH2:35][OH:36])[CH:17]=[N:16][C:15]=3[Cl:24])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: NCCCO
Reactant: CO
Reactant: O=CCCc1cnc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCNCCCO)cnc1Cl
Reaction time: 20 h

Procedure:
To a stirred solution of N-(1-adamantylmethyl)-2-chloro-5-(3-oxopropyl)nicotinamide (Example 3(ii)) (0.10 g) in methanol (3 ml) and acetic acid (0.1 ml) was added. 3-aminopropanol (0.042 g) and the resulting solution was stirred for 2 hours and then sodium cyanoborohydride (0.020 g) was added and the reaction mixture stirred for 20 hours. The mixture was concentrated and the residue partitioned between 2M aqueous hydrochloric acid solution and ethyl acetate (2×10 ml). The layers were separated and the organic phase re-extracted with 2M aqueous hydrochloric acid solution (2×10 ml). The combined aqueous extracts were basified with 5M aqueous ammonium hydroxide solution, extracted into ethyl acetate (2×25 ml) and the combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to afford the titled compound (0.075 g) as a white solid.
Reaction SMILES: [I:1]I.C[Si](C)(C)[CH:5]=[CH:6][C:7]1[C:8](=[O:15])[CH2:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH:12]=1.C[Si](C)(C)/C=C/C1C(=O)CCC(C)(C)C=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.ClCCl>[I:1]/[CH:5]=[CH:6]/[C:7]1[C:8](=[O:15])[CH2:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH:12]=1
Reactant: CC1(C)C=C(C=C[Si](C)(C)C)C(=O)CC1
Reactant: II
Agent: CC1(C)C=C(/C=C/[Si](C)(C)C)C(=O)CC1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC1(C)C=C(/C=C/I)C(=O)CC1
Reaction time: 6 h

Procedure:
Iodine (657 mg, 2.59 mmol) was dissolved in 5 mL of THF and the solution was added to a solution of 2-(2-(trimethylsilyl)ethenyl)-4,4-dimethyl-2-cyclohexen-1-one (Compound 18, 575 mg, 2.59 mmol) and dichloromethane (15 mL) at room temperature. The solution was stirred for 6 hours, and then treated with 10% aqueous Na2S2O3 to remove the excess iodine. The layers were separated and the aqueous layer was extracted 3× with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and filtered, and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel (9:1, hexane:ethyl acetate) to give the product as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:18]3C(=O)C4C(=CC=CC=4)C3=O)[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].NN>C(O)C.ClCCl>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:29])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN1C(=O)c3ccccc3C1=O)OC2
Agent: NN
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN)OC2
Temperature: 80 °C
Reaction time: 14 h
Yield: 87.9 %

Procedure:
In a 50-ml round-bottom flask, a suspension of 2-amino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (2.00 g, 4.8 mmol) in absolute ethanol (20 ml) was flushed with nitrogen and sealed with a rubber septum. Hydrazine (0.5 ml, 15.9 mmol) was added, followed by an additional portion of absolute ethanol (20 ml) at room temperature. The reaction mixture was heated to 80° C. for 3.5 hours and then allowed to stir at room temperature for 14 hours. The precipitate was filtered off and washed with absolute ethanol. The filtrate was concentrated in vacuo leaving an oil, which was dissolved in dichloromethane (30 ml) and refiltered. The solvent was evaporated in vacuo affording 1.2 g (86%) of 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@@H:21](/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C@@:22]([OH:33])(CCO)[C:23]([O:25]C(C)(C)C)=[O:24])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].F[C:52](F)(F)[C:53]([O:55][C:56](=[O:61])[C:57](F)(F)F)=O.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[C:56]([O:55][CH2:53][CH2:52][C@:22]([OH:33])([C@@H:21]([C:19](=[O:20])[NH:18][C@H:13]([C:14]([O:16][CH3:17])=[O:15])[CH2:12][C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:11][CH:10]=1)/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42](=[O:50])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:23]([OH:25])=[O:24])(=[O:61])[CH3:57]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCOC(C)=O)C(=O)O)C(=O)OC)cc1
Temperature: 25 °C
Yield: 45.6 %

Procedure:
To a mixture of No. 5217614, tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-(2-hydroxy-ethyl)-12-oxo-nonadec-4-enoate (150 mg, 0.214 mmol) and dichloromethane (15 mL) were added trifluoroacetic acid anhydride (TFAA, 36 μL, 0.258 mmol), triethylamine (89 μL, 0.642 mmol), and DMAP (1.3 mg, 0.0107 mmol), and the mixture was stirred at room temperature. After being stirred for 3 hours, trifluoroacetic acid anhydride (72 μL, 0.516 mmol) was added again. After confirming the consumption of No. 5217614 tert-butyl (E)-(2S,3S)-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-2-hydroxy-2-(2-hydroxy-ethyl)-12-oxo-nonadec-4-enoate by LCMS, formic acid (5 mL) was added and the mixture was stirred overnight. The solvent was distilled off under reduced pressure. THF (5 mL) and a saturated aqueous solution (0.5 mL) of NaHCO3 were then added and the mixture was stirred at room temperature for 10 minutes. The solvent was distilled off under reduced pressure. The residue was then purified by preparative HPLC. The purified fraction was freeze-dried to obtain the title compound (67 mg, 48% yield, yellow oil).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:22])=[CH:19][CH:20]=3)[N:15]([C:23](=[O:33])[C:24]3[CH:29]=[CH:28][C:27]([N:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=3)[C@@H:14]([CH3:34])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[CH2:35]([O:37][C:38](=[O:74])[CH2:39]CCOC1C=CC(C(N2C3C(=CC=CC=3)[C@H](N(C3C=CC(Cl)=CC=3)C(=O)CC)C[C@@H]2C)=O)=CC=1)[CH3:36].BrCCCC(OCC)=O>>[CH2:35]([O:37][C:38](=[O:74])[CH2:39][O:22][C:18]1[CH:17]=[C:16]2[C:21]([C@H:12]([N:8]([C:9](=[O:11])[CH3:10])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH2:13][C@H:14]([CH3:34])[N:15]2[C:23](=[O:33])[C:24]2[CH:25]=[CH:26][C:27]([N:30]([CH3:32])[CH3:31])=[CH:28][CH:29]=2)=[CH:20][CH:19]=1)[CH3:36]
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N(C)C)cc2)c2cc(O)ccc21
Reactant: CCOC(=O)CCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(=O)CC)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: CCOC(=O)CCCBr
Product: CCOC(=O)COc1ccc2c(c1)N(C(=O)c1ccc(N(C)C)cc1)[C@@H](C)C[C@H]2N(C(C)=O)c1ccc(Cl)cc1

Procedure:
(±)-Cis-[4-[acetyl-(4-chloro-phenyl)-amino]-1-(4-dimethylamino-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-7-yloxy]-acetic acid ethyl ester was prepared from (±)-cis-N-(4-chloro-phenyl)-N-[1-(4-dimethylamino-benzoyl)-7-hydroxy-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide, following the alkylation conditions described for the synthesis of (±)-cis-4-(4-{4-[(4-chloro-phenyl)-propionyl-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-butyric acid ethyl ester, substituting ethyl bromoacetate for ethyl 4-bromobutyrate.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[Br:9][C:10]1[C:15]2[N:16]=[C:17](Cl)[N:18]=[N+:19]([O-:20])[C:14]=2[CH:13]=[C:12]([CH3:22])[CH:11]=1.C(OCC)(=O)C>O1CCCC1.O>[Br:9][C:10]1[C:15]2[N:16]=[C:17]([O:6][CH2:5][C:4]([F:8])([F:7])[F:3])[N:18]=[N+:19]([O-:20])[C:14]=2[CH:13]=[C:12]([CH3:22])[CH:11]=1
Reactant: Cc1cc(Br)c2nc(Cl)n[n+]([O-])c2c1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Br)c2nc(OCC(F)(F)F)n[n+]([O-])c2c1
Reaction time: 2 h

Procedure:
To 0.5 g of 60% sodium hydride stirring in 30 ml of tetrahydrofuran, 3.0 mlof 2,2,2-trifluoroethanol was added dropwise at ambient temperature. A solution resulted and 2.0 g (7.29 mmol) of the above 5-bromo-3-chloro-7-methyl-1,2,4-benzotriazine-1-oxide was added and at ambient temperature and the mixture stirred 2 h. Ethyl acetate (200 ml) and excess water were added and the separated organic extract washed with water, brine, and dried over magnesium sulfate. The solvent was removed invacuo, hexane added to the residue, and the suspended yellow s 61id filtered and dried to afford 1.7 g of 5-bromo-7-methyl-3-(2,2,2-trifluoroethoxy) -1,2,4-benzotriazine-1-oxide, m.p. 127°-128° C.
Reaction SMILES: [F:1][C:2]1[C:3]([Cl:12])=[C:4](Br)[C:5](Cl)=[C:6]([F:9])[C:7]=1[Cl:8].[Mg].[C:14]([Cl:17])(=O)[CH3:15].S(=O)(=O)(O)[OH:19]>C1COCC1.C1(C)C=CC=CC=1>[F:9][C:6]1[CH:5]=[C:4]([C:15](=[O:19])[CH2:14][Cl:17])[C:3]([Cl:12])=[C:2]([F:1])[C:7]=1[Cl:8]
Reactant: O=S(=O)(O)O
Reactant: CC(=O)Cl
Reactant: Fc1c(Cl)c(F)c(Cl)c(Br)c1Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(CCl)c1cc(F)c(Cl)c(F)c1Cl
Temperature: -30 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
0.1 mol of 3,5-difluoro-2,4,6-trichlorobromobenzene, powder of magnesium (0.11 mol), cuprous chloride (0.12 mol) in 120 ml of THF were stirred at room temperature until the reaction mixture appeared black, which showed the reaction had been initiated. The reaction then was quickly cooled to −30±10° C. GLC was used to monitored the reaction to the completion. Then, to the reaction mixture was added dropwise 11.78 g of acetyl chloride (0.27 mol) in 25 ml of toluene. The reaction was carried out at −30±10° C. for 8 hours. The reaction was then heated to room temperature and stirred for 3 hours. The reactant was poured into 150 g of crushed ice containing 75 ml of 25% sulfuric acid solution and stirred for 5 minutes. The organic layer was separated. The aqueous layer was extracted with toluene. The combined organic layers were washed with aqueous solution (45 ml) of NaCl, aqueous solution (44 ml) of NaHCO3, water (45 ml) and saturated aquoues solution (25 ml) of NaCl, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized form ethanol to give 0.0819 mol of 3,5-difluoro-2,4,6-trichloroacteylbenzene in 81.9% yield, mp. 73-76° C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH:19][C:20](=[O:33])[C:21]2C=CC=CC=2C2ON=C(C)N=2)=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:8]=1)[CH3:2].Cl.C(C1C(N[C@H]2CCC[C@@H]2N)=NC=C(C(F)(F)F)N=1)C.[N:54]1[CH:59]=[CH:58][CH:57]=[N:56][C:55]=1[C:60]1C(C(O)=O)=[N:62][CH:63]=[CH:64][CH:65]=1>>[CH2:1]([C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH:19][C:20]([C:21]2[C:60]([C:55]3[N:54]=[CH:59][CH:58]=[CH:57][N:56]=3)=[CH:65][CH:64]=[CH:63][N:62]=2)=[O:33])=[N:5][CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[N:8]=1)[CH3:2]
Reactant: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-c1nc(C)no1
Reactant: O=C(O)c1ncccc1-c1ncccn1
Agent: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1N
Agent: Cl
Product: CCc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ncccc1-c1ncccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-{[3-ethyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzamide (Example 149) from (1S,2S)-1-N-[3-ethyl-5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 41; 450 mg, 1.64 mmol) and 3-(pyrimidin-2-yl)pyridine-2-carboxylic acid (CAS number 1228431-21-7; 330 mg, 1.64 mmol) to afford the title compound.
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9][C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=2[O:18][CH3:19])C(=O)C2=CC=CC=C12.Cl>C1COCC1.CC(OC)(C)C>[NH2:8][CH2:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][C:11]=1[O:18][CH3:19]
Reactant: COc1cc(C#N)ccc1CN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: NN
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COc1cc(C#N)ccc1CN
Temperature: 25 °C
Reaction time: 20 h
Yield: 67.6 %

Procedure:
10.6 ml of hydrazine hydrate were added to 21.2 g (73 mmol) of 4-phthalimidomethyl-3-methoxybenzonitrile dissolved in 290 ml of THF, and the mixture was stirred at room temperature for 20 h. Then 180 ml of 2H [sic] HCl were added dropwise and, after 1.5 h, the solvent was completely stripped off. The residue was taken up in MTBE, extracted with 1N HCl, adjusted to pH 9-10 with 2N NaOH and extracted with methylene chloride. 8.0 g (68%) of product were obtained. 1H-NMR (DMSO-d6 ; δ in ppm): 7.55 (dd, 1H); 7.40 (dd, 1H; 7.37 (d, 1); 3.85 (s, 3H); 3.70 (s, 2H); 2.5-1.6 (NH2).