Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][N:9]=[C:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.O>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[N:8]=[N:9][C:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:11]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccccc1NN=C(C(=O)c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cccc2c(-c3ccccc3)c(-c3ccccc3)nnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.3 %

Procedure:
1,2-Diphenylethane-1,2-dione (2-methylphenyl)-hydrazone (0.50 g, 1.59 mmol) was dissolved in 70% of sulfuric acid (10 mL) and the reaction was stirred at room temperature overnight. The reaction was poured into iced water and extracted with ethyl acetate. The combined organics was dried over MgSO4 and concentrated. The material was purified via column chromatography using 5-100% ethyl actetate in hexane as the eluent to yield 0.025 g of the title compound as an orange solid. MS (ESI) m/z 297([M+H]+); HRMS (ESI, [M+H]+) 297.1406.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16]C(=O)C2C=CC([N+]([O-])=O)=CC=2)[CH2:13][CH:12]1[C:28]([C:30]1[C:38]2[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=2)[NH:32][CH:31]=1)=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Na+].CC(O)=O>C1COCC1.CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([OH:16])[CH2:13][CH:12]1[C:28]([C:30]1[C:38]2[C:33](=[CH:34][C:35]([F:39])=[CH:36][CH:37]=2)[NH:32][CH:31]=1)=[O:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC1CC(C(=O)c2c[nH]c3cc(F)ccc23)N(C(=O)OCc2ccccc2)C1)c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: O=C(c1c[nH]c2cc(F)ccc12)C1CC(O)CN1C(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a suspension of 5 (82.9 g) in THF (600 mL), MeOH (200 mL), and water (100 mL) was added 50% aq. NaOH (16.0 g, 200 mmol) [Note: exothermic; temp. increase: 23.7° C. to 25.9° C.]. After 2 h, glacial HOAc (5.3 g) was added to adjust the pH to 7-8 [Note: the orange-colored solution changed to pale yellow] and the reaction mixture was concentrated in vacuo. Water (500 mL) was added and solvent was removed in vacuo until a thick suspension formed. The solid was collected on a vacuum filter and washed with water (400 mL in portions). The solid was dried in a vacuum oven at 55° C. to afford 42.6 g (83%, 2 steps) of 6 as an off-white solid. 1H NMR (300 MHz, d6-DMSO): δ8.38 (d, J=11.1 Hz, 1H), 8.14 (ddd, J=5.7, 8.7, 14.1 Hz, 1H), 7.35-7.29 (m, 2H), 7.25 (app. dd, J=2.1, 9.9 Hz, 1H), 7.10-6.95 (m, 4H), 5.16-4.98 (m, 2H), 4.90 (app. q, J=13.5, 25.8 Hz, 1H), 4.26 (m, 1H), 3.74 (app. ddd, J=6.3, 11.1, 18.3 Hz, 1H), 3.22 (m, 1H), 2.59 (m, 1H), 1.73 (app. ddd, J=6.6, 12.9, 25.2 Hz, 1H) ppm; 13C NMR (75 MHz, d6-DMSO): δ193.8, 193.3, 160.0 (d, JCF=235.2 Hz), 154.4 (d, JCF=14.5 Hz), 137.5 (d, JCF=26.0 Hz), 137.2 (d, JCF=12.3 Hz), 129.0, 128.5, 128.2 (d, JCF=35.4 Hz), 128.1, 127.4, 123.2, 123.1, 114.4 (d, JCF=11.4 Hz), 110.8 (d, JCF=23.7 Hz), 110.8 (d, JCF=23.7 Hz), 99.0 (d, JCF=25.8 Hz), 69.4, 68.6, 66.5, 66.4, 61.5, 61.2, 54.9, 54.6 ppm. Mass spectrum (ESI), m/z 383.8 [(M+H)+; calcd for C21H20FN2O4: 383.3].
Reaction SMILES: C([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C:16]=3[C:17](=[O:37])[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[OH:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C:16]=3[C:17](=[O:37])[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC(=O)C2=C3CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)CCC[C@@H](C)[C@H]1CC(=O)C2=C3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
Then a stirred mixture of the precursor (6) in a protic solvent, preferably methanol, is treated with potassium carbonate and heated at reflux for 3 hours to give the desired product (3β,5α)-3-hydroxycholest-8(14)en-15-one (7). This conversion was based upon the procedures of E. J. Parish and G. J. Schroepfer and J. Org. Chem., 45, 4034-4037 (1980) and R. E. Dolle and L. Kruse, J. Org. Chem., 51, 4047-4053 (1986). Alternatively, the precursor (6) is treated with perchloric acid in n-propanol or ethanol at reflux or treated with potassium hydroxide or sodium hydroxide methanol at room temperature to give the desired product (7).
Reaction SMILES: [OH-].[Na+].[CH3:3][Si:4]([CH3:32])([CH3:31])[C:5]1[CH:6]=[C:7]([C:15]([NH:17][C:18]2[CH:30]=[CH:29][C:21]([CH:22]=[CH:23][C:24]([O:26]CC)=[O:25])=[CH:20][CH:19]=2)=[S:16])[CH:8]=[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1.Cl>C(O)C>[CH3:14][Si:11]([CH3:12])([CH3:13])[C:9]1[CH:8]=[C:7]([C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([CH:22]=[CH:23][C:24]([OH:26])=[O:25])=[CH:29][CH:30]=2)=[S:16])[CH:6]=[C:5]([Si:4]([CH3:3])([CH3:31])[CH3:32])[CH:10]=1
Reactant: CCOC(=O)C=Cc1ccc(NC(=S)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[Si](C)(C)c1cc(C(=S)Nc2ccc(C=CC(=O)O)cc2)cc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
A 2N sodium hydroxide aqueous solution (6.99 ml) was added to an ethanol solution of Compound 17b (319 mg) in a nitrogen atmosphere. The obtained mixture was stirred at room temperature overnight. After the reaction was over, the reaction mixture was ice-cooled, and a 2N hydrochloric acid aqueous solution was added thereto. The precipitated solid was filtered off and recrystallized with a mixed solvent of n-hexane and ethyl acetate to obtain Compound 17 (183 mg, 61%) as a yellow solid.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.[NH:32]1[CH2:37][CH2:36][S:35](=[O:39])(=[O:38])[CH2:34][CH2:33]1>>[O:38]=[S:35]1(=[O:39])[CH2:36][CH2:37][N:32]([C:3]([C:4]2[CH:5]=[N:6][C:7]([N:10]3[CH:14]=[C:13]([C:15]4[C:16]([C:24]5[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=5)=[N:17][O:18][C:19]=4[C:20]([F:22])([F:23])[F:21])[N:12]=[CH:11]3)=[CH:8][CH:9]=2)=[O:2])[CH2:33][CH2:34]1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1
Reactant: O=S1(=O)CCNCC1
Product: O=C(c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1)N1CCS(=O)(=O)CC1
Yield: 97.4 %

Procedure:
As described for Example 38b, 6-{4-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-imidazol-1-yl}-nicotinic acid methyl ester (100 mg, 0.23 mmol), was converted, using thiomorpholine 1,1-dioxide (124.9 mL, 0.9 mmol) instead of cyclopropanemethylamine, to the title compound (120 mg, 97%) which was obtained as a colourless oil. MS: m/e=535.8 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:7]=[CH:6][NH:5][C:4]=1[C:8]([OH:10])=O.[CH3:13][CH:14]([CH3:32])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[N:21]=[N:22][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:24][CH:25]=1)=[O:19]>>[CH3:13][CH:14]([CH3:32])[CH2:15][CH2:16][NH:17][C:18]([C:20]1[N:21]=[N:22][C:23]([N:26]2[CH2:31][CH2:30][N:29]([C:8]([C:4]3[NH:5][CH:6]=[N:7][C:3]=3[C:2]([F:1])([F:12])[F:11])=[O:10])[CH2:28][CH2:27]2)=[CH:24][CH:25]=1)=[O:19]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: O=C(O)c1[nH]cnc1C(F)(F)F
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3[nH]cnc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 5-trifluoromethyl-3H-imidazole-4-carboxylic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-ylpyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white powder (48% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.03, 7.86, 7.70, 6.99, 3.80, 3.46, 1.75-1.62, 1.48, 0.92. MS (ES+) m/z 440.2 (M+1).
Reaction SMILES: FC(F)(F)COC1C(C(N)=O)=NC=CC=1.[Cl:16][C:17]1[C:18]([C:25]([O:27]C)=[O:26])=[N:19][CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1>>[Cl:16][C:17]1[C:18]([C:25]([OH:27])=[O:26])=[N:19][CH:20]=[C:21]([O:23][CH3:24])[CH:22]=1
Reactant: COC(=O)c1ncc(OC)cc1Cl
Agent: NC(=O)c1ncccc1OCC(F)(F)F
Product: COc1cnc(C(=O)O)c(Cl)c1

Procedure:
Using an analogous reaction to that described for Intermediate 5, step 2 methyl 3-chloro-5-methoxypicolinate was converted to the title compound. MS m/z=188 (M+H).
Reaction SMILES: [N+:1]([C:4]([CH3:11])=[CH:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:11][CH:4]([NH2:1])[CH2:5][C:6]1[S:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(=Cc1cccs1)[N+](=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(N)Cc1cccs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 3.7 g (21.9 mmol) 2-(2-nitro-propenyl)-thiophene in 50 ml THF is added dropwise to a suspension of 4.1 g (109.3 mmol) lithium aluminium hydride in 150 ml THF. After the addition has ended the mixture is refluxed. After 1.5 hours it is cooled to RT and stirred for another 16 hours. Then the mixture is slowly combined with 10 ml sat. sodium sulphate solution and filtered through Celite. The filtrate thus obtained is evaporated down i. vac.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([N+:13]([O-])=O)=[CH:8][CH:9]=2)[CH:4]1[CH2:16][CH2:17][CH3:18]>C(O)C>[ClH:1].[CH3:2][N:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([NH2:13])=[CH:8][CH:9]=2)[CH:4]1[CH2:16][CH2:17][CH3:18]
Reactant: CCCC1c2cc([N+](=O)[O-])ccc2CCN1C
Agent: Cl
Solvent: CCO
Product: CCCC1c2cc(N)ccc2CCN1C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a suspension of 2-methyl-7-nitro-1-propyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.30 g, 4.80 mmol) in ethanol (100 ml) was added 10% Pd--C (0.2 g) and the reaction mixture was hydrogenated at 50 psi for 3 h. The solution was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in isopropanol (30 ml) and allowed to stand overnight to give the title compound (1.04 g, 90%) as a tan solid, m.p. 217-9° C. (dec.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:20][C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:8][C:9]1[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=1[NH:11][C:25](=[O:26])[CH2:24][NH:23][C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1ccccc1OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 39.3 %

Procedure:
2-Benzyloxyaniline (S1) (16.4 g), 4-dimethylamino-pyridine (11.0 g), and N-tertiarybutoxycarbonylglycine (14.4 g) were dissolved in dichloromethane. To the resulting solution, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (16.3 g) was added and stirred for 12 hours at room temperature. The reaction mixture was washed -successively with 1N HCl, saturated aqueous sodium hydrogencarbonate solution and brine, then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, obtaining 11.5 g of the compound S2 as white powder.
Reaction SMILES: C(NC(C)C)(C)C.[OH:8][C@@H:9]1[CH2:14][O:13][C:11](=[O:12])[CH2:10]1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN1CCN(C)C1=O.[Cl-].[NH4+]>C1COCC1>[CH2:15]([C@H:10]1[C@H:9]([OH:8])[CH2:14][O:13][C:11]1=[O:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1C[C@H](O)CO1
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN1CCN(C)C1=O
Solvent: CC(C)NC(C)C
Product: O=C1OC[C@@H](O)[C@@H]1Cc1ccccc1
Temperature: -45 °C
Reaction time: 0.25 h
Yield: 30.7 %

Procedure:
Diisopropylamine (2.7 ml, 19.59 mmol) and 1.6 M of n-butyllithium-hexane solution (12.2 ml, 19.59 mmol) were added to THF (30 ml) under argon gas at 0° C. After stirring for 15 minutes, the solution was cooled to −45° C. Then, (S)-3-hydroxy-γ-butyrolactone (1 g, 9.794 mmol) in THF (20 ml) was added thereto. After stirring for 30 minutes at −45° C., benzyl bromide (1.4 ml, 11.75 mmol) and 1,3-dimethyl2-imidazolidinone (2.9 ml) in THF (20 ml) were added thereto. After stirring for 3 hours at the same temperature, an aqueous saturated ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and condensed in vacuo. The residue was purified by silica gel chromatography to give (2S,3S)-2-benzyl-3-hydroxy-γ-butyrolactone (0.577 g, yield 31%).
Reaction SMILES: [Na].[C:2](#[N:4])[CH3:3].[F:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1>O>[NH2:11][C:10]([C:9]1[CH:12]=[CH:13][C:6]([F:5])=[CH:7][CH:8]=1)=[CH:3][C:2]#[N:4]
Reactant: CC#N
Reactant: N#Cc1ccc(F)cc1
Agent: [Na]
Solvent: O
Product: N#CC=C(N)c1ccc(F)cc1

Procedure:
The procedure of Example 1 was used to react 2.7 grams (0.117 mole) of sodium and 5.2 grams (0.126 mole) of acetonitrile with 10.0 grams (0.083 mole) of p-fluorobenzonitrile. After the addition of water, the reaction mixture was extracted three times with chloroform. The combined chloroform extracts were concentrated to obtain a dark-colored crystalline mass which was recrystallized four times from a mixture of chloroform and hexane to obtain yellow plates of β-amino-β-(p-fluorophenyl)acrylonitrile, mleting point 110°-112°C. Analysis: -- Calculated for C9H7N2F (percent): C, 66.66; H, 4.35; N, 17.27; F, 11.72. Found (percent): C, 66.48; H, 4.34; N, 17.21; F, 11.19.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4](Cl)=[O:5])[CH3:2].CN(C1C=CC=CN=1)C.[O:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH2:24][S:25][C:26]1[N:30]=[CH:29][NH:28][N:27]=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:3]([CH2:7][CH3:8])[C:4]([N:28]1[CH:29]=[N:30][C:26]([S:25][CH2:24][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][O:18]2)=[N:27]1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)Cl
Reactant: c1nc(SCC2CCCCO2)n[nH]1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)n1cnc(SCC2CCCCO2)n1

Procedure:
11.6 g (85 mmol) of diethylcarbamoyl chloride and a spatula-tipful of dimethylaminopyridine were added to a solution of 200 ml of absolute tetrahydrofuran and 17.0 g (85 mmol) of 3-(tetrahydropyran-2-yl)methylthio-1,2,4-triazole (step b). 9.5 g (94 mmol) of triethylamine were then added dropwise and the mixture was heated under reflux for 2 hours. The solvent was distilled off and the residue was purified by chromatography over silica gel. 11.2 g (44% of theory) of a viscous clear oil were obtained. (1H-NMR (CDCl3; δ in ppm): 8.75 (s,1H); 4.00 (d,1H); 3.70-3.50 (bm,5H); 3.40 (dt,1H); 3.25 (d,2H); 1.85 (d,1H); 1.80 (d,1H); 1.65-1.45 (m,4H); 1.30 (t,6H))
Reaction SMILES: C([O:4][C:5]1[CH:19]=[CH:18][C:8]([C:9]([N:11]([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])=[O:10])=[CH:7][C:6]=1[O:20][CH3:21])(=O)C.NCCO>>[OH:4][C:5]1[CH:19]=[CH:18][C:8]([C:9]([N:11]([CH:12]([CH3:13])[CH3:14])[CH:15]([CH3:17])[CH3:16])=[O:10])=[CH:7][C:6]=1[O:20][CH3:21]
Reactant: COc1cc(C(=O)N(C(C)C)C(C)C)ccc1OC(C)=O
Solvent: NCCO
Product: COc1cc(C(=O)N(C(C)C)C(C)C)ccc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The combined filtrate (about 1260 mL), containing 4-acetoxy-3-methoxy-N,N-bis(1-methylethyl)-benzamide, is treated at room temperature under nitrogen while stirring with 2-aminoethanol (43.1 g, 42.6 mL) added dropwise over a 5 minute period. The reaction mixture is then heated at 78°-85° for 5 hours. The heat source is removed and water (400 mL) is added slowly over a period of 30 minutes. The stirred slurry is cooled to room temperature and stirring at room temperature is continued for 16 hours. The suspension is cooled to 5° C. and filtered. The resulting solid is washed with xylenes and dried in a vacuum oven at 40°-45° C. for 48 hours to obtain 4-hydroxy-3-methoxy-N,N-bis(1-methylethyl)benzamide; 1H-NMR (CDCl3): δ1.10-1.50 (m, 12H), 3.62-3.80 (m, 2H), 3.82 (s, 3H), 6.42-6.70 (m, 1H), 6.72-6.88 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9]CC)=O.Cl.Cl[C:14]([NH2:16])=[NH:15].CS(C)(=O)=O.[OH-].[NH4+]>O>[NH2:15][C:14]1[NH:16][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][S:3][C:2]=2[N:1]=1
Reactant: N=C(N)Cl
Reactant: CCOC(=O)c1ccsc1N
Agent: CS(C)(=O)=O
Agent: Cl
Agent: [NH4+]
Solvent: O
Product: Nc1nc2sccc2c(=O)[nH]1
Temperature: 125 °C
Yield: 45.1 %

Procedure:
A mixture of ethyl 2-aminothiophene-3-carboxylate (0.5 g, 3.18 mmol), chloroformamidine hydrochloride (0.91 g, 7.95 mmol) and dimethylsulfone (1.50 g, 15.9 mmol) was heated at 120-130° C. for 30 minutes. After cooling down to room temperature, water (10 ml) was added and ammonium hydroxide was used to neutralize the suspension. The solid was filtered off, washed with water and dried. The crude residue was purified by flash chromatography on silica gel (CH2Cl2/MeOH 10:1) to yield the title compound as a white solid (0.24 g, 45%).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[OH:27][C@H:28]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:29][C:30](O)=O>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:30]([CH2:29][C@H:28]([OH:27])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: O=C(O)C[C@H](O)c1ccccc1
Product: CON=C1C[C@@H](c2noc(C[C@H](O)c3ccccc3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and (3S)-3-hydroxy-3-phenylpropanoic acid, the title compound was obtained in 89% purity by HPLC. MS(ESI+): m/z=483.3.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[F:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[CH:18][CH:17]=[CH:16]2>O>[N+:1]([C:14]1[CH:13]=[CH:12][C:11]([F:10])=[C:20]2[C:15]=1[CH:16]=[CH:17][CH:18]=[N:19]2)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Fc1cccc2cccnc12
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(F)c2ncccc12
Reaction time: 0.5 h

Procedure:
15 ml of nitric acid were added with stirring at -5° C. to 30 ml of concentrated sulfuric acid and then 16 g of 8-fluoroquinoline were added thereto with stirring over 30 minutes at -5° to 0° C. The mixture was stirred at 0° C. for three hours and was then allowed to return to room temperature. The mixture was stirred at room temperature for two hours and was then poured into a mixture of water and ice. The mixture was vacuum filtered and the product was suspended in water. The mixture was made alkaline by addition of 10% sodium carbonate solution and was extracted with methylene chloride. The organic phase was dried and evaporated to dryness under reduced pressure to obtain 12 g of 5-nitro-8-fluoro-quinoline melting at 132°-133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C:6](=[O:10])[CH2:7][C:8]#[N:9].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][NH:5][C:6](=[O:10])[C:7]([C:8]#[N:9])=[CH:17][N:18]([CH3:19])[CH3:20]
Reactant: N#CCC(=O)NCc1ccccc1Cl
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C#N)C(=O)NCc1ccccc1Cl

Procedure:
As for Example 1, N-o-chlorobenzyl-2-cyanoacetamide, colorless needles, m.p. 108°-109° C., (prepared as described in U.S. Pat. No. 3,116,312) is heated with N,N-dimethylformamide dimethylacetal to give N-o-chlorobenzyl-2-cyano-3-dimethylaminoacrylamide as colorless needles, m.p. 144°-146.5° C.
Reaction SMILES: [NH:1]1[CH2:3][CH2:2]1.C(=O)([O-])O.[Na+].[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[C:12]([N+:19]([O-:21])=[O:20])[CH:11]=1.[OH-].[Na+]>ClC(Cl)Cl>[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:1]2[CH2:3][CH2:2]2)=[O:15])=[C:12]([N+:19]([O-:21])=[O:20])[CH:11]=1
Reactant: C1CN1
Reactant: O=C(Cl)c1ccc(F)cc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(F)cc1[N+](=O)[O-])N1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 21.6 parts of aziridine and 37.8 parts of sodium hydrogen carbonate is added dropwise a solution of 85 parts of 4-fluoro-2-nitro benzoyl chloride in 75 parts of trichloromethane while stirring vigorously at 0° C. Upon completion, stirring vigorously is continued for 30 minutes without cooling. After warming to 25° C, the reaction mixture is adjusted to pH 8 with a diluted sodium hydroxide solution. The product is extracted three times with trichloromethane. The combined extracts are washed with water, dried filtered and evaporated, yielding 75 parts of 1-(4-fluoro-2-nitrobenzoyl)aziridine as a residue.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]3)[N:12]=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:24][CH:23]=3)[N:10]=1)[CH2:2]2.C(O)(C(F)(F)F)=O.Cl.[CH3:46][O:47][C:48](=[O:51])[CH2:49][NH2:50]>C(N(CC)CC)C>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:10]=[C:11]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)=[O:30])=[CH:26][CH:27]=3)[N:12]=[C:13]([N:15]3[CH2:16][CH2:17][CH:18]([NH:50][CH2:49][C:48]([O:47][CH3:46])=[O:51])[CH2:19][CH2:20]3)[N:14]=1)[CH2:2]2
Reactant: O=C1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1
Reactant: COC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CNC1CCN(c2nc(-c3ccc(NC(=O)Nc4ccncc4)cc3)nc(N3CC4CCC(C3)O4)n2)CC1

Procedure:
Starting from 1-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-oxopiperidin-1-yl)-1,3,5-triazin-2-yl)phenyl)-3-(pyridin-4-yl)urea.TFA (50 mg) and glycine methyl ester hydrochloride (20 mg) and triethylamine (10 drops) and following the procedure as outlined in example 118 the title compound was isolated as its di-TFA salt after HPLC purification; MS (ES+) 574.8 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:33]=[CH:32][C:6]([CH2:7][CH:8]([C:16]([NH:18][S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)(=[O:21])=[O:20])=[O:17])[C:9]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2].[N+:34]([C:37]1[CH:42]=[CH:41][C:40]([N:43]2CCNCC2)=[CH:39][CH:38]=1)([O-:36])=[O:35]>>[C:1]([C:3]1[CH:33]=[CH:32][C:6]([CH2:7][CH:8]([C:9]([N:11]2[CH2:12][CH2:13][N:43]([C:40]3[CH:41]=[CH:42][C:37]([N+:34]([O-:36])=[O:35])=[CH:38][CH:39]=3)[CH2:15][CH2:14]2)=[O:10])[C:16]([NH:18][S:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)(=[O:20])=[O:21])=[O:17])=[CH:5][CH:4]=1)#[N:2]
Reactant: CCN(CC)C(=O)C(Cc1ccc(C#N)cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Product: N#Cc1ccc(CC(C(=O)NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Yield: 92.6 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (300 mg) obtained in Example 111 (4) and 1-(4-nitrophenyl)piperazine (183 mg). This was purified by silica gel column chromatography to give the title compound (358 mg) as a white powder.