Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[NH:31][C:32](=[O:37])[C:33]([OH:36])([CH3:35])[CH3:34])[NH:27][C:26](=[O:38])[CH2:25]2>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:25]3[C:24]4[C:28](=[CH:29][C:30]([NH:31][C:32](=[O:37])[C:33]([OH:36])([CH3:34])[CH3:35])=[C:22]([F:21])[CH:23]=4)[NH:27][C:26]3=[O:38])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: CC(C)(O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cc(NC(=O)C(C)(C)O)c(F)cc43)c(C)c2C1=O
Yield: 65.7 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-2-methyl-propionamide as starting materials to give N-{3-[5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-2-methyl-propionamide (48 mg, 65.7%) as a yellow solid.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]([F:33])([F:32])[C:6]1[N:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]4[CH:31]=[CH:30][C:24]([O:25][CH2:26][C:27]([O-:29])=[O:28])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[CH:13]=[CH:14][C:9]2=[N:8][N:7]=1.O.CO>C1COCC1>[F:33][C:5]([F:4])([F:32])[C:6]1[N:10]2[N:11]=[C:12]([N:15]3[CH2:20][CH2:19][CH:18]([C:21]4[CH:31]=[CH:30][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[CH:13]=[CH:14][C:9]2=[N:8][N:7]=1
Reactant: O=C([O-])COc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)COc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.8 %

Procedure:
Lithium hydroxide monohydrate (0.622 g, 14.81 mmol) was added to 2-[4-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetate (1.29 g, 2.96 mmol) in a mixture of THF (20 mL), water (10 mL) and MeOH (5 mL). The resulting mixture was stirred at ambient temperature for 16 hours. The solvents were evaporated then the residues were suspended in water and acidified to pH 4 with 1M citric acid. The resulting precipitate was collected by filtration, washed with water and dried to afford 2-[4-[1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetic acid (1.020 g, 82%).
Reaction SMILES: [P:1]([O-:22])([O:16][CH2:17][CH:18]([OH:21])[CH2:19]Cl)([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:2].[Na+:23].[OH-].[Na+]>C(O)C>[P:1]([O-:22])([O:16][CH2:17][CH:18]1[O:21][CH2:19]1)([O:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:2].[Na+:23]
Reactant: CCCCCCCCCCCCOP(=O)([O-])OCC(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCCCOP(=O)([O-])OCC1CO1
Temperature: 70 °C
Reaction time: 3 h
Yield: 102.8 %

Procedure:
50 g (0.13 mol) of sodium dodecyl 2-hydroxy-3chloropropyl phosphate was charged into a reactor, to which 1000 ml of ethanol was added, followed by agitation and heating to 70° C. to give a uniform system. Thereafter, the reaction system was cooled down to room temperature, to which 62.5 g (0.13 mol) of a 0.0021 mol/g sodium hydroxide solution in ethanol was gradually added and agitated for 3 hours while keeping the temperature. The high performance liquid chromatography (hereinafter referred to as HPLC) analysis revealed that the peak for the starting material disappeared and a peak for a new product appeared. The precipitated NaCl was removed by filtration, followed by distillation of the ethanol under reduced pressure to obtain 46 g of sodium dodecyl glycidyl phosphate (yield 100%). 1H NMR (D2O, δ(ppm)): see FIG. 1
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[C:14]([N:21](OC)[CH2:22][C:23]([OH:25])=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:3])[CH3:2].CO.Cl>[OH-].[Na+]>[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[C:7]2=[C:14]([NH:21][CH2:22][C:23]([OH:25])=[O:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:3])[CH3:2]
Reactant: CON(CC(=O)O)C(=C1C(=O)Nc2ccc(C(C)=O)cc21)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)c1ccc2c(c1)C(=C(NCC(=O)O)c1ccccc1)C(=O)N2

Procedure:
88 mg (0.25 mmol) 5-acetyl-3-[(methoxycarboxymethyl-amino)-phenyl-methylidene]-2-indolinone (Example 1.005) are suspended in 0.5 ml 1 N sodium hydroxide solution and 5 ml of methanol and refluxed for 4 h. Then the mixture is cooled, 0.5 ml 1 N hydrochloric acid are added and the precipitate is removed by suction filtering.
Reaction SMILES: [O:1]=[C:2]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]([O:18]C)=[O:17])[C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][CH3:6].[Li+].[OH-].CO.Cl>O>[O:1]=[C:2]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:16]([OH:18])=[O:17])[C:3](=[O:9])[C:4]([CH3:7])([CH3:8])[CH2:5][CH3:6]
Reactant: CCC(C)(C)C(=O)C(=O)N1CCCCC1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCC(C)(C)C(=O)C(=O)N1CCCCC1C(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylate (3.30 g; 12.25 mmol), 1 N LiOH (15 mL), and methanol (60 mL) was stirred at 0° C. for 30 minutes and at room temperature overnight. The mixture was acidified to pH 1 with 1 N HCl, diluted with water, and extracted into 100 mL of methylene chloride. The organic extract was washed with brine and concentrated to deliver 2.80 g (87%) of snow-white solid which did not require further purification, 1H NMR (CDCl3): δ 0.89 (t, 3H); 1.21, 1.24 (s, 3H each); 1.42-1.85 (m, 7H); 2.35 (m, 1H); 3.22 (d, 1H); 3.42(m, 1H); 5.31 (d, 1H).
Reaction SMILES: O.NN.[Br:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[CH2:15][N:16]1C(=O)C2C(=CC=CC=2)C1=O>C(#N)C>[Br:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:6]=1[CH2:15][NH2:16]
Reactant: Cc1cc([N+](=O)[O-])cc(CN2C(=O)c3ccccc3C2=O)c1Br
Agent: NN
Solvent: O
Solvent: CC#N
Product: Cc1cc([N+](=O)[O-])cc(CN)c1Br
Temperature: 25 °C
Yield: 75 %

Procedure:
4.4 mL of hydrazine hydrate was added to 2-[(2-bromo-3-methyl-5-nitrophenyl)methyl]-2,3-dihydro-1H-isoindole-1,3-dione (4.4 g, 11.7 mmol) in 220 mL of acetonitrile. The mixture was stirred under reflux overnight and then was allowed to cool to room temperature. The phtalhydrazide side product was remove by filtration and washed with 100 mL portions of acetonitrile. The combined acetonitrile filtrates were evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was extracted with two 100 mL portions of aqueous HCl 1 M. The combined acidic aqueous layers were basified to pH=10 with solid potassium hydroxide and then extracted with ethyl acetate. The organic layer was dried over Na2SO4 filtered and evaporated to yield expected compound as an orange solid (2.15 g, 75% yield). m/z (ESI) 245.0 [M+H]+;
Reaction SMILES: Br[CH2:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13].[P:14]([O:19]C)([O:17][CH3:18])[O:15][CH3:16]>C1(C)C(C)=CC=CC=1>[C:7]1(=[O:8])[N:3]([CH2:2][P:14](=[O:19])([O:17][CH3:18])[O:15][CH3:16])[C:4](=[O:13])[C:5]2=[CH:12][CH:11]=[CH:10][CH:9]=[C:6]12
Reactant: O=C1c2ccccc2C(=O)N1CBr
Reactant: COP(OC)OC
Solvent: Cc1ccccc1C
Product: COP(=O)(CN1C(=O)c2ccccc2C1=O)OC
Temperature: 25 °C
Yield: 65 %

Procedure:
A mixture of N-(bromomethyl) phthalimide (i) (10.43 g, 43.46 mmol) and trimethyl phosphite (5.93 g, 47.80 mmol) was heated at reflux in xylene (20 mL) for 6 h. The reaction mixture was then cooled to room temperature and concentrated. Crystallization from CHCl3-hexane gave (ii) (7.60 g, 65%) as a white solid: 1H NMR (300 MHz, CDCl3) δH 3.84 (d, JH,P=10.8 Hz, 6 H), 4.12 (d, J=11.4 Hz, 2 H), 7.76 (m, 2 H), 7.87 (m, 2 H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[CH:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]2[C:18]([O:20][C:21](=[O:22])[C:11]=2[CH:10]=1)=O>O>[O:22]=[C:21]1[C:11]2[C:12](=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:9][CH:10]=2)[C:18](=[O:20])[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: NCCCCCCO
Solvent: O
Product: O=C(O)c1ccc2c(c1)C(=O)N(CCCCCCO)C2=O

Procedure:
A mixture of 6-aminohexan-1-ol (11.7 g, 10 mmol) and 1,2,4-benzenetricarboxylic anhydride (7.68 g, 4 mmol) was heated to 175°-225° C. for 15 min or until evolution of H2O vapor stops. The melt was poured into water to give a white crystalline solid. The solid was collected by vacuum filtration and dried overnight in vacuo to give 9.1 g (78%) of analytically pure 27.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:26](O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CCOC(C)=O>[CH2:26]([O:12][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)=[O:13])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OCc1ccccc1
Reactant: O=C(O)c1ccc2ncccc2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of quinoline-6-carboxylic acid (2.0 g, 11.6 mmol) in EtOAc (30 mL) was added carbonyldiimidazole (2.15 g, 13.3 mmol). The resulting mixture was stirred at room temperature for 2 h at which time all solids had dissolved. Benzyl alcohol (1.4 mL) was added and the reaction was stirred overnight. The mixture was then extracted successively with aqueous 1 N HCl (25 mL), aqueous NaHCO3 and brine. Evaporation of the solvent gave a solid, which was triturated with cold 1:1 EtOAc/hexane to afford the title compound as a solid (1.9 g, 62%). 1H NMR (selected signals, CD3OD) δ=9.00 (dd, 1H), 8.61 (d, 1H), 8.34 (d, 1H), 8.29 (dd, 1H), 8.25 (d, 1H), 5.43 (s, 2H)
Reaction SMILES: [OH-].[Na+].[C:3]1([C@H:9]([NH2:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>O>[C:3]1([C@H:9]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C[C@@H](NC(=O)C(C)(C)C)c1ccccc1
Reaction time: 1.5 h

Procedure:
In 1,300 ml of water is dissolved 130 g of sodium hydroxide and in the solution is suspended 188 g of (1R)-1-phenylethylamine, after which 287 ml of pivaloyl chloride is dropwise added to the suspension at 20° C. over 40 minutes. The resulting mixture is stirred at the same temperature for 1.5 hours and the crystals deposited are collected by filtration to obtain 289 g of N-[(1R)-1-phenylethyl]-2,2-dimethylpropanamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8](O)=O)[CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[C:17]([NH2:18])=[CH:16][C:15]([N+:19]([O-:21])=[O:20])=[CH:14][N:13]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:11][C:12]3=[N:13][CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[CH:16]=[C:17]3[N:18]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccnc(Cl)c1
Reactant: Nc1cc([N+](=O)[O-])cnc1N
Product: O=[N+]([O-])c1cnc2[nH]c(-c3ccnc(Cl)c3)nc2c1

Procedure:
was prepared as described for example 4-1, starting from 2-chloropyridine-4-carboxylic acid and 2,3-diamino-5-nitropyridine.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=C1)[CH2:3][C:2]2([CH2:10]O)[CH2:8][OH:9].C12CC(CC1)CC2(CO)C[OH:20].C12CC(CC1)CC2CO.[C@@H]1(O)CCC[C@@H]1O.CC(C)(C)C(O)CO.[C@@H]1(O)CCC[C@H]1O.CC(O)(C(C)(O)C)C.CC(CO)CO.CC(O)C(O)C.C(O)C(O)C>>[CH3:10][C:2]1([CH3:1])[CH:3]([OH:20])[C:4]([CH3:5])([CH3:7])[CH:8]1[OH:9]
Reactant: OCC1(CO)CC2CCC1C2
Reactant: OCC1(CO)CC2C=CC1C2
Agent: CC(C)(C)C(O)CO
Agent: CC(C)(O)C(C)(C)O
Agent: CC(CO)CO
Solvent: CC(O)CO
Product: CC1(C)C(O)C(C)(C)C1O

Procedure:
Particularly preferred compounds of this invention are 5-norbornene-2,2-dimethanol; norbornane-2,2-dimethanol; 2-norbornanemethanol; 1,2-cis-cyclopentanediol; 2,3-cis-exo-norbornanediol, 2-(propyl-1,2-diol)-norbornane and 3,3-dimethyl-1,2-butanediol. Other preferred compounds are 1,2-trans-cyclopentanediol; 2,3-dimethyl-2,3-butanediol; 2-methyl-1,3-propanediol; 2,3-butanediol; and propylene glycol.
Reaction SMILES: [OH-:1].[K+].[Mn]([O-])(=O)(=O)=O.[K+].[F:9][C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][C:12]([C:20]([OH:22])=[O:21])([CH2:13]3)[CH2:11]1)[CH2:17]2>>[F:9][C:10]12[CH2:19][CH:14]3[CH2:15][C:16]([OH:1])([CH2:18][C:12]([C:20]([OH:22])=[O:21])([CH2:13]3)[CH2:11]1)[CH2:17]2
Reactant: [OH-]
Reactant: O=C(O)C12CC3CC(CC(F)(C3)C1)C2
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: O=C(O)C12CC3CC(O)(CC(F)(C3)C1)C2
Temperature: 50 °C
Yield: 42.7 %

Procedure:
To an aqueous solution (400 ml) containing potassium hydroxide (13.0 g; 0.20 mol) was added 34.76 g (0.22 mol) of potassium permanganate and the solution was warmed on a steam bath (about 50° C). To this solution was added portion-wise 39.8 g (0.20 mol) of 3-fluoroadamantane-l-carboxylic acid. After the addition was complete, the reaction mixture was allowed to warm to a gentle reflux and stirred until all the potassium permanganate was consumed (about 1.5 hours). The reaction mixture was then cooled and acidified with 6N HCl. Sodium bisulfite was added to remove MnO2 and the white suspension was filtered and washed with water to yield recovered starting material (19.0 g). The aqueous filtrate was saturated with NaCl and extracted with 95:5 EtOAc:MeOH (4×350 ml). The organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to afford 18.3 g (43%; 81% based on recovered 3-fluoroadamantan-1-carboxylic acid) of 3-fluoro-5-hydroxyadamantane-1-carboxylic acid. To an aqueous solution (250 ml) containing tetrabutylammonium hydrogen sulfate (42g, 0.124 mol) was added portion-wise sodium bicarbonate (41.0 g, 0.496 mol). This solution was allowed to stir for 20 minutes at which point 26.5 g (0.124 mol) of 3-fluoro-5-hydroxyadamantane-1-carboxylic acid was added portion-wise. The reaction mixture was allowed to stir for 30 minutes, was concentrated in vacuo to afford a viscous oil which was dissolved in acetone (300 ml) and mixed with methyl iodide (40 ml) and allowed to stir for 48 hours. The crude reaction mixture was filtered, concentrated in vacuo and triturated with Et2O to remove tetrabutylammonium iodide and the crude filtrate was concentrated in vacuo to afford 31 g of crude ester which was chromatographed on 800 g of silica gel using 2:1 hexane:ethyl acetate to afford 23.5 g (83%) of the title compound: mp 51.5-52.6°C.; 1H NMR (CDCl3) 1.60-1.70 (4H, m), 1.75-1.82 (4H, m), 1.88-1.92 (3H, M), 1.94-1.98 (2H, m), 2.42-2.50 (1H, m) 3.67 (3H, s). 13C NMR (CDCl3) 30.52 (10.33), 36.36, 40.35, 42.60 (20.38), 45.16, 45.42 (10.18), 49.44 (17.36), 51.94, 70.62 (12.53), 92.71 (186.33), 175.04; Anal. Calc'd for C12H17O3F: C, 63.14; H, 7.51; N, F, 8.32; Found: C, 63.25; H, 7.38; F, 8.52.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH3:10])[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:23](O)(=[O:26])[CH2:24][OH:25].N1C=CN=C1>O1CCCC1.C(N(CC)CC)C>[C:1]([S:4][CH2:5][CH:6]([CH3:10])[C:7]([O:9][C:24](=[O:25])[CH2:23][OH:26])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCC(C)C(=O)O
Reactant: O=C(O)CO
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)SCC(C)C(=O)OC(=O)CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Acetylthio-2-methylpropanoic acid (6.48 g.) is taken into 40 ml. of dry tetrahydrofuran. To this 1,1'-carbonyldiimidazole (0.48 g.) is added and stirred for 30 minutes at room temperature. Glycolic acid (6.08 g.) and 11.2 ml. of triethylamine in 60 ml. of dry tetrahydrofuran are added. After several minutes, the imidazole salt of glycolic acid begins to come out of solution. The reaction is permitted to run overnight at room temperature. The crystalline salt is filtered and the filtrate concentrated to dryness in vacuo. The residue is taken up into ethyl acetate, washed with 1 N hydrochloric acid and three times with water, dried over magnesium sulfate and concentrated to dryness in vacuo. This product is converted to its dicyclohexylamine salt by dissolving in ether/hexane and precipitating by the addition of dicyclohexylamine. The salt is recrystallized from ether, m.p. 120°-122°. This salt is then converted to the free acid, O-[3-(acetylthio)-2-methylpropanoyl]glycolic acid, by adding to ethyl acetate, adding 10% potassium bisulfate solution, then crystallizing from ethyl/hexane, yield 2.96 g., m.p. 50°-51°.
Reaction SMILES: CS[C:3]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)=[CH:4][N+:5]([O-:7])=[O:6].O.[NH2:21][NH2:22]>C(O)C>[NH:21]([C:3]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)=[CH:4][N+:5]([O-:7])=[O:6])[NH2:22]
Reactant: CSC(=C[N+](=O)[O-])Nc1ccc(OC(F)(F)F)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=C[N+](=O)[O-])Nc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
3.00 g of 1,1-bis(methylthio)-2-nitroethene, 3.38 g of 4-trifluoromethoxyaniline and 30 ml of ethanol were reacted for 5 hours under heating and refluxing and then cooled to room temperature, whereupon precipitated crystals were collected by filtration and washed with a small amount of ethanol and dried to obtain 3.40 g of crystals, to which 1.81 g of 4-trifluoromethoxyaniline and 30 ml of ethanol were added and reacted for 6.5 hours under heating and refluxing. After completion of the reaction, the solution was cooled to room temperature, and precipitated crystals were collected by filtration, washed with a small amount of ethanol and dried to obtain 2.51 g of N-(1-methylthio-2-nitroethenyl)-4′trifluoromethoxyaniline (Intermediate No. 30) having a melting point of from 114 to 115° C. (2) To 2.00 g of N-(1-methylthio-2-nitroethenyl)-4-trifluoromethoxyaniline (Intermediate No. 30) obtained in the above step (1), 40 ml of ethanol was added at room temperature, and then 0.36 g of hydrazine monohydrate was dropwise added thereto. Thereafter, the reaction was carried out for 1 hour under heating and refluxing. After completion of the reaction, the solution was cooled to room temperature, and precipitated crystals were collected by filtration, washed with a small amount of ethanol and dried to obtain 1.36 g of the desired product (Compound No. 61) having a melting point of 161° C. (decomposition point).
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:29])[N:5]([CH3:28])[C:6]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])=[C:7]2[C:12]=1[C:11](=[O:13])[N:10](CC1C=CC(OC)=CC=1)[CH2:9][CH2:8]2.Br>CC(O)=O>[OH:2][C:3]1[C:4](=[O:29])[N:5]([CH3:28])[C:6]([C:23]([N:25]([CH3:26])[CH3:27])=[O:24])=[C:7]2[C:12]=1[C:11](=[O:13])[NH:10][CH2:9][CH2:8]2
Reactant: COc1ccc(CN2CCc3c(c(OC)c(=O)n(C)c3C(=O)N(C)C)C2=O)cc1
Agent: Br
Solvent: CC(=O)O
Product: CN(C)C(=O)c1c2c(c(O)c(=O)n1C)C(=O)NCC2
Temperature: 75 °C
Reaction time: 8 h

Procedure:
In a 50 mL heavy walled glass pressure flask 4-methoxy-6-(4-methoxybenzyl)-N,N,2-trimethyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide (3.9 g) and 15 ml of (commercial) 33% HBr in HOAc were mixed. The flask was sealed, heated to 75° C. and allowed to stir overnight. The solvent was removed in vacuo. The remaining oil was dissolved in CH3CN and purified by reverse phase on a Biotage KPCM 250 compression module containing a 10 cm×60 cm Kiloprep cartridge. The product elutes at 13% CH3CN in water containing 0.1% TFA.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[N:12]1[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=[CH:13]1.[OH-].[Na+]>Cl>[NH2:8][C:6]1[CH:5]=[C:4]([Cl:11])[C:3]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[N:14]=[CH:13]2)=[C:2]([Cl:1])[CH:7]=1
Reactant: O=c1cc(C(F)(F)F)ncn1-c1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(Cl)c(-n2cnc(C(F)(F)F)cc2=O)c(Cl)c1
Temperature: 0 °C

Procedure:
1-(2,6-Dichloro-4-nitrophenyl)-4-trifluoromethylpyrimidin-6-one (2.0 g) was added in one portion to a stirred suspension of stannous chloride (4.46 g) in concentrated aqueous hydrochloric acid (50 ml) at ambient temperature. After a period of 61/2 hours, the reaction mixture was poured into ice/water, made basic with aqueous sodium hydroxide solution, and extracted into ethyl acetate. The organic extracts were dried (magnesium sulphate), filtered, and evaporation of the solvent, under reduced pressure, gave 1-(4-amino-2,6-dichlorophenyl)-4-trifluoromethylpyrimidin-6-one as a yellow oil which solidified on standing (1.41 g). The compound showed:
Reaction SMILES: O.[CH3:2][N:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5]([CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])=[CH:4]1.C(=O)([O-])O.[Na+].[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]=[CH:32][C:33](ON1C(=O)CCC1=O)=[O:34])#[N:24]>O1CCOCC1>[C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]=[CH:32][C:33]([NH:8][C@H:7]([C:9]([OH:11])=[O:10])[CH2:6][C:5]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]([CH3:2])[CH:4]=1)=[O:34])#[N:24]
Reactant: N#Cc1ccccc1C=CC(=O)ON1C(=O)CCC1=O
Reactant: Cn1cc(C[C@H](N)C(=O)O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(C[C@H](NC(=O)C=Cc2ccccc2C#N)C(=O)O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.9 %

Procedure:
To water (60 mL)-dioxane (60 mL) suspension of 1-methyl-L-tryptophan (2.1 g) was added sodium hydrogencarbonate (0.8 g) at 0° C., and the mixture was stirred for 30 minutes at room temperature. Dioxane (80 mL) solution of 2,5-dioxopyrrolidin-1-yl 3-(2-cyanophenyl)acrylate (2.5 g, 9.2 mmol) was added dropwise to the reaction mixture at 0° C., and the mixture was stirred for 15 hours at room temperature. The reaction mixture was concentrated to a ⅓ volume under a reduced pressure, water was added thereto, and the mixture was washed with diethyl ether. The aqueous layer was made acidic with a 10% aqueous citric acid solution, and thereafter extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, and thereafter dried over anhydrous sodium sulfate. The solvent was distilled off under a reduced pressure, to give the captioned compound (0.96 g, 27%) as an amorphous solid product.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[C:4]([CH3:12])([CH2:9][CH2:10][NH2:11])[CH:3]1[CH3:13].Br[CH2:15][CH2:16][CH2:17][CH2:18]Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOCC>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([CH3:8])[C:4]([CH3:12])([CH2:9][CH2:10][N:11]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:3]1[CH3:13]
Reactant: CC1CCN(C)C(C)C1(C)CCN
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: CC1CCN(C)C(C)C1(C)CCN1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.9 %

Procedure:
A solution of 1,2,3,4-tetramethyl-3-piperidineethanamine (9.8 g, 53 mmol) in acetonitrile (50 mL) was added dropwise over about 2 hours to a suspension of 1,4-dibromobutane (6.6 mL, 55.7 mmol) and potassium carbonate (26 g, 200 mmol) in acetonitrile (250 mL). The reaction mixture was stirred at room temperature for 24 hours, diluted with ether and the inorganic salts were removed by filtration. The solvent was removed in vacuo and the oily residue was purified by column chromatography on silica gel eluting with 2% isopropylamine/hexanes to afford 5.8 g (46%) of 1,2,3,4-tetramethyl-3-[2-(1-pyrrolidinyl)ethyl]piperidine. The product was dissolved in ether (25 mL) and treated with 6.5N ethereal HCl (10 mL) at 0° C. The mixture was warmed to room temperature, diluted with ether (10 mL) and cooled back to 0° C. to precipitate the dihydrochloride salt. The salt (4.3 g) was isolated as a white solid and had a melting point of 225°-227° C. (dec.) when recrystallized from ether (35 mL).