Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[CH:4][N:3]=1.[NH2:11][C:12]1[C:13](=[O:26])[N:14]([CH2:23][CH2:24][CH3:25])[C:15](=[O:22])[N:16]([CH2:19][CH2:20][CH3:21])[C:17]=1[NH2:18].O.Cl>C(Cl)Cl.N1C=CC=CC=1.[OH-].[Na+]>[CH2:23]([N:14]1[C:13](=[O:26])[C:12]2[NH:11][C:6]([C:5]3[CH:4]=[N:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[N:18][C:17]=2[N:16]([CH2:19][CH2:20][CH3:21])[C:15]1=[O:22])[CH2:24][CH3:25]
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: CCCn1c(=O)c2[nH]c(-c3ccc(Cl)nc3)nc2n(CCC)c1=O
Temperature: 5 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
6-Chloronicotinoyl chloride (1.83 g, 10.4 mmol), in CH2Cl2 (20 ml) was added dropwise to a solution of 5,6-diamino-1,3-dipropyluracil (1.808 g, 8 mmol) in dry pyridine (8.2 ml) maintained at 5° C. The reaction was warmed to room temperature and stirred for an additional 3 hours. Water (50 ml) was added to quench the reaction. The solvent was evaporated to afford a dark colored oil. The oil was refluxed for 2 h in 2N NaOH (20 ml). After cooling, the pH was carefully adjusted to 7 with concentrated HCl. A solid formed and was collected and washed with water (20 ml), ether (20 ml) and chloroform(20 ml) to provide an off-white solid (1.9 g). The product was used in the next step without further purification.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C@H:4]([NH:10][C@H:11]([C:13]([N:15]1[C@H:23]([C:24]([OH:26])=[O:25])[CH2:22][C@H:21]2[C@@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:14])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:27](N)([CH3:30])([CH3:29])[CH3:28].[C:32]([C@@H:37](N[C@H](C(O)=O)C)[CH2:38]CC)(OCC)=O.ON1C2C=CC=CC=2N=N1>C(N(CC)CC)C>[CH3:1][CH2:2][CH2:3][C@H:4]([NH:10][C@H:11]([C:13]([N:15]1[C@@H:23]([C:24]([O:26][CH2:28][C:27]2[CH:30]=[CH:38][CH:37]=[CH:32][CH:29]=2)=[O:25])[CH2:22][C@H:21]2[C@@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:14])[CH3:12])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CC(C)(C)N
Reactant: CCC[C@H](N[C@@H](C)C(=O)O)C(=O)OCC
Reactant: CCC[C@H](N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@@H]2CCCC[C@@H]21)C(=O)OCC
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: CCC[C@H](N[C@@H](C)C(=O)N1[C@@H](C(=O)OCc2ccccc2)C[C@@H]2CCCC[C@@H]21)C(=O)OCC

Procedure:
EP 308 341 teaches an improved large-scale synthesis of perindopril in the form of the t-butylamine salt. (2S,3aS,7aS)-octahydroindole-2-carboxylic acid benzyl ester p-toluensulfonic salt and N-((S)-1-carbethoxybutyl)-L-alanine are reacted in the presence of triethyl amine, N,N-dicyclohexylcarbodiimide and 1-hydroxybenztriazole. After completion of the reaction, perindopril benzyl ester is obtained, which is reduced, lyophilized and then converted into a salt with t-butylamine in ethyl acetate.
Reaction SMILES: Cl.[OH:2][C@@H:3]1[CH2:7][NH:6][C@@H:5]([C:8]([OH:10])=[O:9])[CH2:4]1.S(Cl)([Cl:13])=O.[CH3:15]O>>[ClH:13].[OH:2][C@@H:3]1[CH2:7][NH:6][C@@H:5]([C:8]([O:10][CH3:15])=[O:9])[CH2:4]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)[C@H]1C[C@H](O)CN1
Reactant: CO
Agent: Cl
Product: COC(=O)[C@H]1C[C@H](O)CN1
Temperature: 22.5 °C
Reaction time: 4 h

Procedure:
To a suspension of trans-4-hydroxy-D-proline hydrochloride (150 g, 0.89 mol, 1 equivalent) in methanol (1.25 L), thionyl chloride (130 mL, 1.79 mol, 2 equivalents) was added drop-wise at 0-5° C. Then the reaction mixture was stirred for 4 hours at 20-25° C. The reaction mixture was concentrated under reduced pressure. This crude material was stirred in a mixture of ethanol-methyl tert-butyl ether (1:4, 750 mL) for 30 minutes and the solid was collected by filtration. The wet cake was dried in a vacuum tray dryer for 8 hours at about 50° C. to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.03-2.23 (m, 2H), 3.06 (d, 1H, J=12.0 Hz), 3.37 (dd, 2H, J=4.5 Hz, J=12.0 Hz), 3.75 (s, 3H), 4.41-4.48 (m, 2H), 5.64 (bs, 1H), 9.43 (bs, 1H), 10.48 (bs, 1H).
Reaction SMILES: [ClH:1].Cl.N1(CCOC2C=CC(N(C3C=CC(OCCN4CCCCC4)=CC=3)C(=O)C3C=CC([F:26])=CC=3)=CC=2)CCCCC1.Cl.Cl.N1(CCOC2C=CC(N(C3C=CC(OCCN4CCCCC4)=CC=3)C(=O)C3C=CC=CC=3)=CC=2)CCCCC1.Cl.Cl.[N:86]1([CH2:92][CH2:93][O:94][C:95]2[CH:100]=[CH:99][C:98]([N:101]([C:119]3[CH:124]=[CH:123][CH:122]=[CH:121][CH:120]=3)[C:102](=[O:118])[C:103]3[CH:108]=[CH:107][C:106]([O:109][CH2:110][CH2:111][N:112]4[CH2:117][CH2:116][CH2:115][CH2:114][CH2:113]4)=[CH:105][CH:104]=3)=[CH:97][CH:96]=2)[CH2:91][CH2:90][CH2:89][CH2:88][CH2:87]1>>[ClH:1].[ClH:1].[F:26][C:122]1[CH:121]=[CH:120][C:119]([N:101]([C:98]2[CH:97]=[CH:96][C:95]([O:94][CH2:93][CH2:92][N:86]3[CH2:91][CH2:90][CH2:89][CH2:88][CH2:87]3)=[CH:100][CH:99]=2)[C:102](=[O:118])[C:103]2[CH:108]=[CH:107][C:106]([O:109][CH2:110][CH2:111][N:112]3[CH2:113][CH2:114][CH2:115][CH2:116][CH2:117]3)=[CH:105][CH:104]=2)=[CH:124][CH:123]=1
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)N(c1ccccc1)c1ccc(OCCN2CCCCC2)cc1
Reactant: O=C(c1ccc(F)cc1)N(c1ccc(OCCN2CCCCC2)cc1)c1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Agent: O=C(c1ccccc1)N(c1ccc(OCCN2CCCCC2)cc1)c1ccc(OCCN2CCCCC2)cc1
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)N(c1ccc(F)cc1)c1ccc(OCCN2CCCCC2)cc1

Procedure:
N,N-Bis[4-(2-piperidin-1-ylethoxy)-phenyl]-4-fluoro-benzamide dihydrochloride (4s); N,N-Bis[4-(2-piperidin-1-ylethoxy)-phenyl]-benzamide dihydrochloride (4t); and N-[4-(2-piperidin-1-ylethoxy)-phenyl]-N-phenyl-[4-(2-piperidin-1-ylethoxy)]-benzamide dihydrochloride (4u).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:5][NH:6][C:7]([C:9]1([C:12]([F:15])([F:14])[F:13])[CH2:11][CH2:10]1)=[O:8].[Cl:20][C:21]1[C:22]([N:33]2[CH2:37][CH2:36][CH2:35][C@H:34]2[CH2:38][O:39][CH3:40])=[CH:23][C:24]([N:30]=[C:31]=[S:32])=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1.CN(C=O)C>[Cl-].[Na+].O>[Cl:19][C:18]1[CH:17]=[CH:16][C:4]([CH2:5][NH:6][C:7]([C:9]2([C:12]([F:13])([F:14])[F:15])[CH2:10][CH2:11]2)=[O:8])=[CH:3][C:2]=1[NH:1][C:31]([NH:30][C:24]1[CH:23]=[C:22]([N:33]2[CH2:37][CH2:36][CH2:35][C@H:34]2[CH2:38][O:39][CH3:40])[C:21]([Cl:20])=[CH:26][C:25]=1[N+:27]([O-:29])=[O:28])=[S:32]
Reactant: COC[C@@H]1CCCN1c1cc(N=C=S)c([N+](=O)[O-])cc1Cl
Reactant: Nc1cc(CNC(=O)C2(C(F)(F)F)CC2)ccc1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@@H]1CCCN1c1cc(NC(=S)Nc2cc(CNC(=O)C3(C(F)(F)F)CC3)ccc2Cl)c([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(3-amino-4-chlorobenzyl)-1-(trifluoromethyl)cyclopropanecarboxamide (150 mg; 0.51 mmol), (S)-5-chloro-2-isothiocyanato-4-(2-(methoxymethyl)pyrrolidin-1-yl)-nitrobenzene (169 mg; 0.51 mmol) and DMF (3 mL) was stirred at rt overnight. The mixture was poured into brine and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was washed with Et2O to give the sub-title compound.
Reaction SMILES: C([Al](C[CH:11]([CH3:13])[CH3:12])CC(C)C)C(C)C.[CH2:14]=[CH2:15].C[CH:17]([CH3:21])[CH2:18][CH:19]=[CH2:20]>C1C=CC=CC=1>[CH3:14][CH2:15][CH2:20][CH2:19][CH2:18][CH2:17][CH2:21][CH2:13][CH2:11][CH3:12]
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Reactant: C=C
Reactant: C=CCC(C)C
Solvent: c1ccccc1
Product: CCCCCCCCCC

Procedure:
The polymerization of Example 18 was repeated except that in place of the benzene-soluble organoaluminum oxy-compound, there were used 0.3 mg atom in terms of the aluminum atom of the benzene-insoluble organoaluminum oxy-compound as prepared above, 1 mmole of triisobutylaluminum and 1×10-3 mg atom in terms of titanium atom of the solid catalyst component, whereby 30.2 g of an ethylene/4-methyl-1-pentene copolymer having MFR of 0.81 g/10 min, a density of 0.917 g/cm3, an amount of decane soluble portion of 1.4% by weight and Mw/Mn of 6.1 was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7](Cl)=[N:8][OH:9].[OH:11][C:12]1[CH:13]=[C:14]([C:18]#[CH:19])[CH:15]=[CH:16][CH:17]=1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[OH:11][C:12]1[CH:13]=[C:14]([C:18]2[O:9][N:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH:19]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: ON=C(Cl)c1ccccn1
Reactant: C#Cc1cccc(O)c1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Oc1cccc(-c2cc(-c3ccccn3)no2)c1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
A stirred solution of pyridine-2-carbohydroximoyl chloride (300 mg, 1.9 mmol) and 3-hydroxyphenylacetylene (760 mg, 6.4 mmol) in a 1:1 mixture of THF/CH2Cl2 (10 mL) at 0° C. was treated with triethylamine (2 mL, 1.45 g, 15 mmol). The mixture was allowed to warm to room temperature overnight. The solvent was removed in vacuo. The residue was dissolved in dichloromethane, washed with brine and dried over anhydrous sodium sulphate. Removal of the solvent in vacuo followed by trituation with 10% ethylacetate in hexane afforded 200 mg (44%) of 5-[3-hydroxyphenyl]-3-[pyridin-2-yl]-1,2-oxazole as a beige solid.
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[CH2:16]([O:23][CH2:24][C@H:25]([NH:28][C@@H:29]([CH3:43])[CH:30]([O:37][CH2:38]C(C)(C)C)[O:31][CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])CO)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:16]([O:23][CH2:24][C@@H:25]1[NH:28][C@@H:29]([CH3:43])[C@@H:30]([O:31][CH2:32][C:33]([CH3:34])([CH3:35])[CH3:36])[O:37][CH2:38]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1.[CH2:16]([O:23][CH2:24][C@@H:25]1[NH:28][C@@H:29]([CH3:43])[C@H:30]([O:31][CH2:32][C:33]([CH3:34])([CH3:35])[CH3:36])[O:37][CH2:38]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: C[C@H](N[C@H](CO)COCc1ccccc1)C(OCC(C)(C)C)OCC(C)(C)C
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C[C@@H]1N[C@@H](COCc2ccccc2)CO[C@@H]1OCC(C)(C)C
Product: C[C@@H]1N[C@@H](COCc2ccccc2)CO[C@H]1OCC(C)(C)C
Temperature: 100 °C
Yield: 40 %
Yield: 39 %

Procedure:
Add camphorsulfonic acid (1.69 g, 7.28 mmol) to (R)-3-benzyloxy-2-[(S)-2,2-bis-(2,2-dimethylpropoxy)-1-methylethylamino]-propan-1-ol (1.60 g, 4.04 mmol) in toluene (65 mL) and heat to 100° C. for 1 hour. Cool to room temperature, dilute with ethyl acetate, wash with 2 N sodium hydroxide and saturated aqueous sodium chloride. Dry (magnesium sulfate), filter and concentrate. Purify (silica gel chromatography using deactivated silica gel prepared as previously described, eluting with 10:90 to 70:30 ethyl acetate:hexanes) to give the desired compounds (2S,3S,5S)-5-benzyloxymethyl-2-(2,2-dimethylpropoxy)-3-methylmorpholine (490 mg, 39% top spot,) and (2R,3S,5S)-5-benzyloxymethyl-2-(2,2-dimethylpropoxy)-3-methylmorpholine (495 mg, 40% bottom spot).
Reaction SMILES: [C-]#N.[K+].[C:4]([O:12]C)(=O)[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[NH2:14][OH:15].O>O1CCCC1.CO>[OH:15][NH:14][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1
Reactant: NO
Reactant: COC(=O)c1ccncc1
Agent: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(NO)c1ccncc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Positively charged bi-functional precursor molecules for self-assembly. Potassium cyanide (50 mg) was added to a solution of methyl isonicotinate (1.17 g, 0.01 mole) and 50% hydroxylamine in water (1.3 g, 0.02 mole) in 10 mL tetrahydrofuran and 5 mL methanol. After stirring the mixture at room temperature for 18 hours, the precipitate was filtered and washed with diethyl ether and dried to give analytically pure N-hydroxy isonicotinamide. The latter was added to 5% methyl iodide in methanol and stirred at room temperature for two days. Methanol was evaporated under reduced pressure and the solid residue was crystallized from ethanol resulting in pure 4-hydroxamido-N-methylpyridinium iodide.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Hg](C#N)C#N.[C:15]([O:18][C@@H:19]1[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:22][S:21][C@@H:20]1Br)(=[O:17])[CH3:16]>>[C:15]([O:18][C@@H:19]1[C@@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:23]([O:29][C:30](=[O:32])[CH3:31])[CH2:22][S:21][C@H:20]1[S:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5])(=[O:17])[CH3:16]
Reactant: N#Cc1ccccc1S
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Agent: N#C[Hg]C#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2ccccc2C#N)SC[C@H]1OC(C)=O
Yield: 50 %

Procedure:
If the procedure described in Preparation I is followed starting from 9.70 g (72.10-3 mol) of 2-mercaptobenzonitrile, 19.45 g (77.10-3 mol) of mercuric cyanide, Hg(CN)2, and 27.4 g (77.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 14.7 g (yield: 50%) of the expected product are obtained.
Reaction SMILES: [OH-].[Na+].[S:3]=[C:4]1[NH:9][C:8](=[O:10])[N:7]2[N:11]=[CH:12][CH:13]=[C:6]2[NH:5]1.[CH3:14]I>CCO>[CH3:14][S:3][C:4]1[NH:9][C:8](=[O:10])[N:7]2[N:11]=[CH:12][CH:13]=[C:6]2[N:5]=1
Reactant: CI
Reactant: O=c1[nH]c(=S)[nH]c2ccnn12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nc2ccnn2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A 1.75N NaOH solution (39.52 mmol, 22.58 ml) was added to a suspension of 2-thioxo-2,3-dihydropyrazolo[1,5-a][1,3,5]triazin-4(1H)-one (3.32 g, 19.76 mmol) from 1b in absolute EtOH (80 mL). Methyl iodide (2.80 g, 19.76 mmol) was then added and the reaction mixture was allowed to stir for 2 hours at room temperature. The resulting precipitate was collected by vacuum filtration, suspended in water (110 mL) and acidified with 2NH2SO4. The solution was stirred at 0° C. for 5 minutes and the new precipitate was collected by vacuum filtration, washed with cold water, and then air dried to give 1.88 g (52%) of 2-(methylthio)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([N:13]2[CH2:17][C@H:16]([OH:18])[C@H:15]([NH:19][C:20](=[O:29])[O:21]CC3C=CC=CC=3)[CH2:14]2)[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.I[Si](C)(C)C.Cl.[NH2:36][NH2:37]>C(#N)C.C(O)C(C)C>[OH:18][C@H:16]1[CH2:17][N:13]([C@H:8]([C:5]2[CH:6]=[N:7][C:2]([NH:36][NH2:37])=[CH:3][CH:4]=2)[C:9]([F:12])([F:10])[F:11])[CH2:14][C@H:15]1[NH:19][C:20](=[O:29])[O:21][C:5]([CH3:8])([CH3:6])[CH3:4]
Reactant: O=C(N[C@@H]1CN([C@H](c2ccc(Cl)nc2)C(F)(F)F)C[C@@H]1O)OCc1ccccc1
Reactant: NN
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: CC(C)CO
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1CN([C@H](c2ccc(NN)nc2)C(F)(F)F)C[C@@H]1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.3 %

Procedure:
To a solution of benzyl (3R,4S)-1-((R)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl)-4-hydroxypyrrolidin-3-ylcarbamate (1.16 g, 2.7 mmol) in acetonitrile (2 mL) cooled to 0° C. in an ice bath was added iodotrimethylsilane (1.22 mL, 8.10 mmol) and the mixture allowed to warm to ambient temperature for 1 hour. The reaction mixture was poured into aqueous 1N HCl (15 mL) and stirred for 10 minutes and extracted with diethyl ether. The aqueous layer was pH adjusted to 10 with a 5N sodium hydroxide solution and extracted with ethyl acetate. The organic extract was dried (MgSO4), filtered and concentrated under reduced pressure. The residue (0.512 g, 1.29 mmol) was combined with anhydrous hydrazine (0.81 mL, 25.87 mmol) in i-BuOH (3 mL) in a sealed tube and heated with stirring at 100° C. for 18 hours. After cooling, the mixture was partitioned between water (15 mL) and ethyl acetate (50 mL). The layers were separated and the organic layer was washed with saturated sodium bicarbonate and brine, dried (MgSO4), filtered and concentrated under reduced pressure to afford tert-butyl (3R,4S)-4-hydroxy-1-((R)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (0.44 g, 86%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.Cl.[F:27][C:28]([F:40])([F:39])[C:29]1[CH:30]=[C:31]([C:35]2([NH2:38])[CH2:37][CH2:36]2)[CH:32]=[CH:33][CH:34]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl.CN(C)C=O>[F:27][C:28]([F:39])([F:40])[C:29]1[CH:30]=[C:31]([C:35]2([NH:38][C:17]([C:16]3[C:11]4[CH:10]=[N:9][N:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[C:12]=4[CH:13]=[N:14][CH:15]=3)=[O:19])[CH2:36][CH2:37]2)[CH:32]=[CH:33][CH:34]=1
Reactant: NC1(c2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(O)c1cncc2c1cnn2-c1ccc(F)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1(c2cccc(C(F)(F)F)c2)CC1)c1cncc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 1-(4-fluoro-phenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (40.0 mg, 0.156 mmol) in methylene chloride (1 mL) is added oxalyl chloride (14 μL, 0.16 mmol) dropwise. After 10 minutes, a drop of N,N-dimethylformamide is added and the suspension is stirred at room temperature. After 60 minutes, an additional portion of oxalyl chloride (14 μL, 0.16 mmol) and a drop of N,N-dimethylformamide are added. After stirring for 30 minutes, the solvent is removed in vacuo; the residue is suspended in methylene chloride (1 mL) and concentrated in vacuo. The residue is dried under vacuum for 30 minutes, suspended in methylene chloride (1 mL) and added to a solution of 1-(3-trifluoromethyl-phenyl)-cyclopropylamine hydrochloride (74.1 mg, 0.312 mmol) and N,N-diisopropylethylamine (0.080 mL, 0.46 mmol) in methylene chloride (500 μL). After shaking at room temperature for 15 hours, the reaction is quenched with methanol (500 μL) and concentrated. The residue is purified by reverse phase HPLC using a Water BEH column (2.1×50 mm C18 1.7 μM) and a gradient of 10-95% acetonitrile in water containing 0.05% formic acid to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:13]1[CH:14]=[CH:15][C:16]2[NH:22][C:21](=[O:23])[CH2:20][O:19][C:18]([CH3:30])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]=2[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClS([N:36]=[C:37]=O)(=O)=O>>[C:1]([O:5][C:6]([N:8]1[C:9]([C:13]2[CH:14]=[CH:15][C:16]3[NH:22][C:21](=[O:23])[CH2:20][O:19][C:18]([CH3:30])([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:17]=3[CH:31]=2)=[CH:10][CH:11]=[C:12]1[C:37]#[N:36])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1cccc1-c1ccc2c(c1)C(C)(c1ccccc1)OCC(=O)N2
Reactant: O=C=NS(=O)(=O)Cl
Product: CC(C)(C)OC(=O)n1c(C#N)ccc1-c1ccc2c(c1)C(C)(c1ccccc1)OCC(=O)N2

Procedure:
tert-Butyl-2-cyano-5-(5-methyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl)-1H-pyrrole-1-carboxylate was prepared from tert-butyl-2-(5-methyl-2-oxo-5-phenyl-1,2,3,5-tetrahydro-4,1-benzoxazepin-7-yl)-1H-pyrrole-1-carboxylate and chlorosulfonyl isocyanate according to the cyanation procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.02 (s, 1H), 7.42-7.38 (m, 2H), 7.32-7.10 (m, 7H), 6.49 (d, J=3.80 Hz, 1H), 4.20 (d, J=14.63 Hz, 1H), 3.99, (d, J=14.41 Hz, 1H), 1.87 (s, 3H), 1.39 (s, 9H); MS (ES) n?z 442 ([M−H]−, 100%).
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].[Cl:17][CH2:18][CH2:19][CH2:20]I.O>CN(C=O)C>[Cl:17][CH2:18][CH2:19][CH2:20][NH:2][C:3]([CH3:10])([CH3:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C)(C)N
Reactant: ClCCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)NCCCCl
Reaction time: 8 h
Yield: 102.5 %

Procedure:
A solution of ethyl aminoisobutyrate hydrochloride (10 g) in DMF (50 mL) was cooled to 0° C. To the solution were added potassium carbonate (18 g) and 1-chloro-3-iodopropane (12 g), and the mixture was stirred overnight at 0° C. to room temperature. Water was added to the reaction solution and the mixture was extracted with ethyl acetate toluene organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 12.5 g of crude ethyl 2-(3-chloropropylamino)isobutyrate.
Reaction SMILES: [CH3:1][C:2]12[C:15](=[O:16])[CH:6]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=31)[NH:5][CH2:4][CH2:3]2.[CH:17]1([CH2:20]Br)[CH2:19][CH2:18]1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH:17]1([CH2:20][N:5]2[CH2:4][CH2:3][C:2]3([CH3:1])[C:15](=[O:16])[CH:6]2[CH2:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=23)[CH2:19][CH2:18]1
Reactant: CC12CCNC(Cc3ccc(O)cc31)C2=O
Reactant: BrCC1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC12CCN(CC3CC3)C(Cc3ccc(O)cc31)C2=O

Procedure:
A mixture of 1,2,3,4,5,6-hexahydro-6-methyl-8-hydroxy-11-oxo-2,6-methano-3-benzazocine (part A, 0.220 g.), cyclopropylmethyl bromide (0.200 g.), sodium bicarbonate (0.084 g.) and N,N-dimethylformamide (5 ml.) was stirred in a nitrogen atmosphere under reflux (for 2 hr.), then stripped of N,N-dimethylformamide. A solution of the residue in dilute hydrochloric acid (5%) was extracted with ether, neutralized and extracted with ether again. Desiccation and concentration of the latter ether extracts afforded 1,2,3,4,5,6-hexahydro-3-cyclopropylmethyl-6-methyl-8-hydroxy-11-oxo-2,6-methano-3-benzazocine (I: Q = CH2CHCH2CH2, R = CH3, X = HO, Y + Z = O) as a yellow oil, from which with methanesulfonic acid was obtained the methanesulfonate salt as another oil, from which with 1,5-naphthalenedisulfonic acid was obtained the crystalline 1,5-naphthalenedisulfonate tetrahydrate salt (220 mg., m.p. 287°-288° C.).
Reaction SMILES: [O:1]1[C:7]2[C:2]1=C(C)C(O)=CC=2.[CH2:10]([O:12][C:13](=[O:15])[CH3:14])[CH3:11]>>[CH3:11][CH:10]([O:12][C:13]([CH3:14])=[O:15])[CH2:2][O:1][CH3:7]
Reactant: Cc1c(O)ccc2c1O2
Reactant: CCOC(C)=O
Product: COCC(C)OC(C)=O

Procedure:
An epoxy cresol novolac resin (ECN 1299) was dissolved in a 75:25 solvent solution of ethylacetate:PGMEA to obtain a reaction mixture having a solids content of approximately 20% by weight. Equimolar amounts of 4-hydroxybenzoic acid were added to the reaction mixture. BTEAC was added to the mixture (2% by weight, based upon the weight of epoxy cresol novolac resin), and the reaction mixture was heated to 120° C. in an oil bath under a nitrogen atmosphere for twenty-four hours. The reaction mixture was cooled and formulated into an anti-reflective coating (at a solids content of approximately 5% by weight) by the addition of trimethylolpropane trivinylether (crosslinking agent, obtained from Aldrich Chemical Company) and p-TSA as the catalyst for crosslinking at a temperature of 205° C. Tables 5 and 6 set forth the respective formulations of the mother liquor and anti-reflective coating compositions.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[CH3:12][S:13]([NH:16][C:17]1[N:21]([C:22]2[C:27]([F:28])=[C:26]([F:29])[C:25]([C:30]([F:33])([F:32])[F:31])=[C:24]([F:34])[C:23]=2[F:35])[N:20]=[CH:19][CH:18]=1)(=[O:15])=[O:14].O>C(O)(=O)C>[CH3:12][S:13]([NH:16][C:17]1[N:21]([C:22]2[C:23]([F:35])=[C:24]([F:34])[C:25]([C:30]([F:33])([F:32])[F:31])=[C:26]([F:29])[C:27]=2[F:28])[N:20]=[CH:19][C:18]=1[N+:8]([O-:11])=[O:9])(=[O:14])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: CS(=O)(=O)Nc1ccnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CS(=O)(=O)Nc1c([N+](=O)[O-])cnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 80 %

Procedure:
1.07 ml (0.011 mol) of acetic anhydride and 0.45 ml (0.0106 mol) of 98 percent strength nitric acid are added in succession to a solution of 3.8 g (0.01 mol) of 5-methanesulphonamido-1-(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-pyrazole in 20 ml of glacial acetic acid at about 15° C. The mixture is stirred at room temperature for 16 hours and the reaction solution is poured onto 100 ml of water. The precipitate is filtered off with suction, washed neutral and dried in vacuo. 3.4 g (80% of theory) of 5-methanesulphonamido-4-nitro-1-(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-pyrazole of melting point 163° C.-168° C. are obtained.