Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[C:5]2[OH:13].BrC1C=C2C(=CC=1)N=C(Cl)C(CC1C=CC(C#N)=CC=1)=C2Cl.[F:36][C:37]([F:47])([F:46])[C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][N:39]=1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>N1C=CC=CC=1.C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[C:6]([CH2:42][C:41]1[CH:40]=[N:39][C:38]([C:37]([F:47])([F:36])[F:46])=[CH:45][CH:44]=1)=[C:5]2[OH:13]
Reactant: O=c1cc(O)c2cc(Br)ccc2[nH]1
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: N#Cc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Solvent: c1ccncc1
Solvent: CC(C)O
Product: Oc1nc2ccc(Br)cc2c(O)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Bromo-4-hydroxyquinolin-2(1H)-one (3.2 g, 18.3 mmol, Intermediate 44: step a), 6-(trifluoromethyl)nicotinaldehyde (4.0 g, 16.7 mmol), and diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (4.2 g, 16.7 mmol), in pyridine (34 mL) were heated to 105° C. for 3 hours. The solution was allowed to cool to ambient temperature, resulting in the formation of solid. Minimal isopropanol was added to the mixture and the slurry was stirred for 1 hour, sonicated, and filtered. The filtered solids were rinsed with isopropanol and dried under continuous air flow to provide the title compound as an off-white solid. Additional product was recrystallized from the filtrate, filtered, and rinsed with isopropanol.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[O:41]=[C:42]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)[CH2:43][NH:44][C:45](=[O:59])[C:46]1[CH:51]=[CH:50][C:49]([O:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:48][CH:47]=1>CN(C=O)C.O>[CH3:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([N:63]1[CH2:64][CH2:65][N:60]([C:42](=[O:41])[CH2:43][NH:44][C:45](=[O:59])[C:46]2[CH:47]=[CH:48][C:49]([O:52][C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)=[CH:50][CH:51]=2)[CH2:61][CH2:62]1)=[O:15]
Reactant: Cc1ccccc1C(=O)O
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)N1CCN(C(=O)CNC(=O)c2ccc(Oc3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
DIPEA (0.091 mL, 0.53 mmol) was added drop wise to 2-Methyl benzoic acid (23 mg, 0.2123 mmol) in DMF (5 mL). EDCI (84 mg, 0.44 mmol) and HOBT (28 mg, 0.21 mmol) were added consecutively and, after 10 mins, N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide (60 mg, 0.18 mmol) was added and the resulting mixture was stirred at room temperature overnight. Water was then added, and the resulting solid was filtered under reduced pressure. The residue was dissolved in methylene chloride and filtered to afford N-{2-[4-(2-Methyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-4-phenoxy-benzamide in 36% yield. LC-MS purity: 98%, 1H NMR (DMSO-D6): δ 8.5 (d, 1H), 7.9 (d, 2H), 7.4 (t, 2H), 7.2 (m, 5H), 7.1 (q, 4H), 4.2 (2d, 2H), 3.6 (m, 4H), 3.4 (m, 2H), 3.2 (m, 2H), 2.2 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[Cl:28])[C@H:12]([CH3:20])[CH2:13][CH2:14][CH2:15][NH:16]C(=O)C)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(S(N)(=O)=O)C=CC=CC=1.Cl[C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[Cl:28])[C@H:12]([CH3:20])[CH2:13][CH2:14][CH2:15][NH:16][C:40]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:41])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(=O)NCCC[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: NS(=O)(=O)c1ccccc1
Product: C[C@H](CCCNC(=O)OCc1ccccc1)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Yield: 81 %

Procedure:
4-chloro-N-(2,5-dichlorophenyl)-N-[4-[[(benzyloxy)carbonyl]amino]-1(R)-methylbutyl]-benzenesulfonamide was prepared analogous to 4-chloro-N-[2,5-dichlorophenyl]-N-[(R)-1-methyl-4-(acetylamino)butyl]benzenesulfonamide by reacting 4-chloro-N-[2,5-dichlorophenyl]-N-[R]-1-methyl-4-aminobutyl]benzenesulfonamide with benzyl chloroformate. Yield=81%; MS (ESI+), 555 (M+H)+.
Reaction SMILES: [CH:1]([NH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[CH2:2].ClCC=CC1C=CC=CC=1.C(N(CC)CC)C.[F:28][C:29]([F:48])([C:33]([F:47])([F:46])[C:34]([F:45])([F:44])[C:35]([F:43])([F:42])[C:36]([F:41])([F:40])[CH:37]([F:39])[F:38])[C:30](Cl)=[O:31]>C(C1C=CC=C(C(C)(C)C)C=1O)(C)(C)C.C(#N)C>[CH:1]([N:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:30](=[O:31])[C:29]([F:28])([F:48])[C:33]([F:46])([F:47])[C:34]([F:44])([F:45])[C:35]([F:42])([F:43])[C:36]([F:40])([F:41])[CH:37]([F:38])[F:39])=[CH2:2]
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: C=CNCc1ccccc1
Agent: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: ClCC=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CN(Cc1ccccc1)C(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 0 °C
Yield: 65.1 %

Procedure:
300 ml of acetonitrile, 33.9 g (0.3 mol) of vinylbenzylamine (synthesized by the method described in "Kobunshi Gakkai Yokoshu", vol. 26, page 834 (G3 C-07) (1977) from chloromethylstyrene (meta:para=about 6:4); p.b.: 82° C./1.5 mm Hg), 30.3 g (0.3 mol) of triethylamine, and 0.5 g of 2,6-di-t-butylphenol were charged into a 500-ml three-necked flask equipped with a stirrer, and a calcium chloride tube, and the mixture was then cooled with ice water. 109.5 g (0.3 mol) of the 2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoro-n-heptanoic acid chloride synthesized in Synthesis Example 1 was added dropwise, with stirring and ice-cooling. Next, the mixture was stirred for 1 hour at room temperature, and the deposited triethylamine hydrochloride was filtered off. The filtrate was distilled under reduced pressure to remove the acetonitrile, 200 ml of ethyl acetate was added to the remainder to be dissolved, and white insolubles were filtered off. The filtrate was distilled under reduced pressure to be condensed, and 300 ml of n-hexane was added to the remainder, followed by cooling. The deposited white crystals were filtered and dried in vacuo at room temperature, thus producing 90.1 g (yield: 65.2%; m.p.: 53° to 57° C.) of 2,2,3,3,4,4,5,5,6,6,7,7-dodecafluoro-n-heptanoic acid vinylbenzylamide.
Reaction SMILES: [CH:1](=[C:8]1[C:12]2[N:13]=[C:14]3[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][N:15]3[C:16](=[O:17])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.C(Cl)(=O)OCC.[NH3:36]>O1CCOCC1.C(N(CC)CC)C>[CH:1](=[C:8]1[C:12]2[N:13]=[C:14]3[CH:21]=[CH:20][C:19]([C:22]([NH2:36])=[O:23])=[CH:18][N:15]3[C:16](=[O:17])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: O=C(O)c1ccc2nc3c(c(=O)n2c1)CCC3=Cc1ccccc1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: NC(=O)c1ccc2nc3c(c(=O)n2c1)CCC3=Cc1ccccc1
Temperature: 15 °C
Reaction time: 2 h

Procedure:
3-benzylidene-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d]pyrido[1,2-a]pyrimidine-7-carboxylic acid (3.2 g) suspended in dioxane (70 ml) and tetrahydrofurane (30 ml) was reacted with ethyl chlorocarbonate (4.55 g) in the presence of triethylamine (4.05 g) under stirring at 15° C. for 2 hours. Then the reaction mixture was treated with dioxane (200 ml) saturated with gaseous ammonia for 30 minutes under stirring. After dilution with ice water and neutralization with HCl, the precipitate was filtered and purified by washing with dimethylformamide to give 2.52 g of 3-benzylidene-1,2,3,10-tetrahydro-10-oxo-cyclopenta[d]pyrido[1,2-a]pyrimidine-7-carboxamide, m.p. 350°-357° C., NMR (CF3COOD) δ ppm: 3.40 (bs) (4H, C-1 and C-2 protons), 7.60 (m) (6H, =CH-- and phenyl protons), 8.42 (d) (1H, C-5 proton), 9.03 (d d) (1H, C-6 proton), 10.09 (d) (1H, C-8 proton).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=3[F:51])[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:52]C(C(C)(C)C)(C)O[SiH3])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=[O:63])C>CO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[C:43]([F:50])[C:42]=3[F:51])[CH:34]=2)([O:31][CH3:32])[O:11][C@@H:10]1[CH2:52][OH:63])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CC(C)(O[SiH3])C(C)(C)C)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Reactant: CC(=O)Cl
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 409.1 %

Procedure:
[[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]tert-butyl-dimethyl-methoxy]silane 3h (4.7 g, 5.46 mmol) was dissolved in 50 mL methanol, followed by addition of acetyl chloride (80 mg, 0.82 mmol). The reaction mixture was stirred for 1 hour at room temperature. Thereafter, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound [(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydro-pyran-2-yl]methanol 31 (2.5 g, yellow grease), yield: 61.4%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH2:15])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[N:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:24]=[CH:23][C:22]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][N:16]=4)=[CH:30][CH:29]=3)=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(-c2cnccn2)cc1
Reactant: NCc1ccc(-c2ccnc(F)c2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(-c2ccnc(F)c2)nc1)c1ccc(-c2cnccn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2′-fluoro-[2,4′-bipyridin]-5-yl)methanamine 24-2 (15 mg, 0.074 mmol), 4-(pyrazin-2-yl)benzoic acid 18-3 (18 mg, 0.09 mmol), and HATU (36 mg, 0.095 mmol) were added N,N-diisopropylethylamine (DIEA, 26 μL, 0.15 mmol) and DMF (0.6 mL). The solution was stirred overnight at room temperature and was subjected directly to reverse phase preparative HPLC to yield N-((2′-fluoro-[2,4′-bipyridin]-5-yl)methyl)-4-(pyrazin-2-yl)benzamide 24 as a solid. MS m/z 386.2 (M+1).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:10]>[O-2].[O-2].[Zr+4]>[C:9](=[O:10])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Zr+4]
Agent: [O-2]
Product: O=C(Oc1ccccc1)Oc1ccccc1

Procedure:
Example 1 was repeated at 140° C. with 14.1 g of a powdered zirconium dioxide from the Aldrich company. After 2 h reaction time, the phenol conversion was 6.3%, whereby 3.2 g phenyl chloroformate and 7.8 g diphenyl carbonate were formed. The selectivity to carbonate esters was greater than 99%.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.[C:32]1([CH:38]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:39](O)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:9][CH2:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:39](=[O:40])[CH:38]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:2][CH2:3]1
Reactant: OCCC1CCNCC1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C(c1ccccc1)c1ccccc1)N1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.8 %

Procedure:
2-Piperidin-4-ylethanol (1.12 g; 8.65 mmol) was introduced into dimethylformamide (DMF, 10 ml). Then hydroxybenzotriazole (HOBT, 1.46 g, 9.51 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl, 1.83 g; 9.51 mmol) and diphenylacetic acid (2.02 g; 9.51 mmol) were added in this sequence. N,N-diisopropyl-ethylamine (DIEA; 1.67 ml; 9.51 mmol) was then added to the reaction mixture, which was stirred at RT for 16 h. The reaction solution was concentrated under reduced pressure. The residue was taken up in EA, and the organic solution was washed successively with saturated NaHCO3 solution, 2N HCl and saturated NaCl solution. The organic phase was separated off, dried over Na2SO4, filtered and concentrated. The 1-[4-(2-hydroxyethyl)piperidin-1-yl]-2,2-diphenylethanone (2.39 g; 8.11 mmol) obtained in this way was reacted further without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[OH-].[K+].[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Cl.O>CC(N(C)C)=O>[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:20][C:21]3[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=3[CH3:23])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: Cc1ccccc1CCl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccccc1COc1ccc(C(C)(C)c2ccc(OCc3ccccc3C)cc2)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
Under an inert atmosphere, 5.23 g Bisphenol A (BPA) (22.9 mmol) and 2.83 g potassium hydroxide (50.4 mmol) were dissolved in 50 mL dimethylacetamide. Stirring was started at 500 rpm and the contents were warmed to 70° C. After 30 minutes, 7.09 g 2-methylbenzyl chloride (50.4 mmol) dissolved in 50 mL dimethylacetamide was added to the reaction mixture. The mixture was then heated at 100° C. for 4 h until no 2-methylbenzyl chloride was noted in the GPC trace. During the course of the reaction, a white precipitate had formed. The reaction mixture was cooled to room temperature and then poured into a 1 L separatory funnel containing 200 mL deionized water. The aqueous layer immediately became opaque. The reaction flask was washed with 50 mL deionized water and this wash was added along with 150 mL toluene to the separatory funnel. The separatory funnel was shaken and the bilayer allowed to settle. The lower, aqueous layer appeared opaque while the upper, organic layer was clear and colorless. The organic layer was separated and the aqueous layer was washed 3 additional times with 100 mL toluene. The combined organic fractions were dried over 20 g magnesium sulfate and filtered into a 1 L round bottom flask. The solvent was removed from the filtered toluene solution on a rotary evaporator initially at room temperature then at 70° C. Following solvent removal, a viscous oil remained in the round bottom flask. This crude product was recrystallized at 0° C. from an acetone solution. The crystalline white solid that had formed was filtered on a 7.0 cm Büchner funnel using Whatman 540 filter paper. The crystals were pulverized into a powder and washed with cold acetone. The white powder was transferred to a 75° C. vacuum oven and dried for 24 h. For Bisphenol A bis(2-methylbenzyl) ether: 52% yield (5.2 g, 12 mmol); white powder; mp 117° C. 1H NMR (500.1 MHz, CD2Cl2, ppm, J=Hz): 7.40 (d, 7.2, 2H, Ph), 7.23 (m, 6H, Ph), 7.17 (m, 4H, Ph), 6.90 (m, 4H, Ph), 5.02 (s, 4H, -PhCH2O—), 2.37 (s, 6H, -PhCH3), 1.65 (s, 6H, —C(CH3)2).
Reaction SMILES: [C:1]([N:3]=[C:4](OC)[CH2:5][CH2:6][CH3:7])#[N:2].Cl.[CH3:11][O:12][C:13](=[O:16])[CH2:14][NH2:15].C(N(CC)CC)C>CO>[C:1]([N:3]=[C:4]([NH:15][CH2:14][C:13]([O:12][CH3:11])=[O:16])[CH2:5][CH2:6][CH3:7])#[N:2]
Reactant: CCCC(=NC#N)OC
Reactant: COC(=O)CN
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCC(=NC#N)NCC(=O)OC
Temperature: -5 °C
Reaction time: 17 h

Procedure:
Methyl N-cyanobutyrimidate (240 g, 1.90 mol) from Example 2 was dissolved in absolute methanol (1.5 L) and glycine methyl ester HCl (250 g, 1.99 mol) added to the reaction mixture. The suspension was cooled to -5° C. and triethylamine (211 g, 2.09 mol) added over a period of 15 minutes. The resulting solution was stirred at 20° C. for 17 hours, then concentrated under reduced pressure to an oily-solid residue (690 g). The residue was taken up in ethyl acetate and the insoluble salts removed by filtration. The filtrate was washed with water followed by 10% aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. This product (370 g) was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[C:9]([C:16]([NH2:18])=[O:17])=[CH:10][N:11]([CH3:15])[C:12](=[O:14])[CH:13]=2)=[C:5]([F:21])[CH:4]=1)#[CH:2]>CO.C1COCC1.[Pd]>[CH2:1]([C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[C:9]([C:16]([NH2:18])=[O:17])=[CH:10][N:11]([CH3:15])[C:12](=[O:14])[CH:13]=2)=[C:5]([F:21])[CH:4]=1)[CH3:2]
Reactant: C#Cc1ccc(Nc2cc(=O)n(C)cc2C(N)=O)c(F)c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Nc2cc(=O)n(C)cc2C(N)=O)c(F)c1
Yield: 82 %

Procedure:
4-(4-Ethynyl-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide was hydrogenated in MeOH/THF in the presence of 5% Pd/C as for example 3. Purification of the crude oil was carried out by column chromatography on silica gel (50% acetone/CH2Cl2 as eluant) to give 4-(4-ethyl-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a cream solid (82%), m.p. (EtOAc) 268-272° C. 1H NMR [(CD3)2SO, 400 MHz] δ 10.14 (s, 1H), 8.32 (s, 1H), 7.84 (br s, 1H), 7.43 (br s, 1H), 7.33 (t, J=8.4 Hz, 1H), 7.19 (dd, J=11.1, 1.7 Hz, 1H), 7.08 (dd, J=8.2, 1.5 Hz, 1H), 5.39 (d, J=1.1 Hz, 1H), 3.36 (s, 3H), 2.62 (q, J=7.6 Hz, 2H), 1.19 (t, J=7.6 Hz, 3H). Anal. Calcd for C15H16FN3O2: C, 62.3; H, 5.6; N, 14.5. Found: C, 62.5; H, 5.4; N, 14.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[NH2:18]C1(CC#C)CCN(C)C1=O>CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O-:16])=[O:15])[CH:7]=[CH:6]2.[NH4+:18]
Reactant: C#CCC1(N)CCN(C)C1=O
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Solvent: CC(C)O
Product: COc1ccc2cc([C@H](C)C(=O)[O-])ccc2c1
Product: [NH4+]
Temperature: 75 °C

Procedure:
A controlled lab reactor with heater/cooler jacket and an overhead paddle-stirrer was charged with IPA (2250 mL) and (2S)-2-(6-methoxy-2-naphthyl)propanoic acid (84.72 g, 367.92 mmol) was added. The suspension was stirred and warmed to 75° C. giving a solution. A solution of 3-amino-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (which may be prepared as described in Description 3, Method 2) (55.99 g, 367.92 mmol) in IPA (1100 mL) was then added dropwise over 1.5 hours. In a cooling process, the reaction mixture was stirred at 75° C. for 1 hr then cooled to 55° C. over 1 hr. The reaction was seeded with pure (S) isomer salt at every 1 degree drop in temperature until the seed remained out of solution (ca. 71° C.). The reaction mixture crystallised and was stirred at 55° C. for 1 hr. The mixture was then cooled to 40° C. over approximately 20 minutes and filtered under suction into a pre-warmed filter funnel over a fast filter paper. The vessel was rinsed out with IPA (600 mL) pre-warmed to 40° C. and this was used to wash the collected solids. The solids were dried under suction until no more solvent came out and then were dried in a vacuum oven at 50° C. to give a white solid, 59.37 g (3S)-1-methyl-2-oxo-3-prop-2-ynyl-pyrrolidin-3-yl]ammonium (2S)-2-(6-methoxy-2-naphthyl)propanoate. A portion of this material was removed and dissolved in methanol, passed down an SCX column, washed with methanol and then eluted with 0.5M ammonia in methanol. The ammonia eluent was evaporated to a pale yellow gum, which was analysed by chiral HPLC (20:80 EtOH:heptane, IA column) showing S-isomer 99.5% and R-isomer 0.5%. Ambersep 900-OH (500 g) was stirred in methanol (1000 mL) for 5 minutes, then filtered and dried under suction until no more liquid came out. The washed resin was added to a stirred suspension of S-isomer salt (59.37 g, 155.24 mmol) in methanol (1000 mL). The mixture was stirred for 1 hr, then filtered. The resin was resuspended in methanol (1000 mL) and stirred for an hour and then filtered. The combined filtrates were evaporated to give a slightly cloudy yellow oil. The oil was dissolved in dichloromethane (ca. 200 mL) and dried over magnesium sulphate, filtered and evaporated to give a clear yellow oil (3S)-3-amino-1-methyl-3-prop-2-ynyl-pyrrolidin-2-one (D3S) (22.729 g). This material was characterised as identical to that prepared by chiral chromatography in Method 2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1F)#[N:2].[CH3:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:13][C:14]1[N:15]=[CH:16][N:17]([C:8]2[CH:7]=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=2[C:1]#[N:2])[CH:18]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cn(-c2ccc([N+](=O)[O-])cc2C#N)cn1

Procedure:
A suspension of 831 mg (5 mmol) of 3-cyano-4-fluoronitrobenzene, of 0.82 g (10 mmol) 4-methylimidazol and of 1.38 g (10 mmol) potassium carbonate in acetonitrile (10 mL) was stirred for 60 h at 20° C. The solvent was evaporated and the residue was partitioned between ethyl acetate and 1N aqueous sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, and the solvent was evaporated under reduced pressure. The crude product was crystallized from ethanol/water yielding the title compound (0.65 g, 57%) as an off-white solid. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=8.95 (s, 1H), 8.62 (d, 1H), 8.16 (s, 1H), 7.93 (d, 1H), 7.49 (s, 1H), 2.21 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:21](=[O:24])(=[O:23])[NH2:22])[C:12]=1[S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[C:7]([OH:9])=[O:8])([O-])=O.C(SC1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1[N+]([O-])=O)CCC>>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:21](=[O:23])(=[O:24])[NH2:22])[C:12]=1[S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])[C:7]([OH:9])=[O:8]
Reactant: Cc1ccccc1Sc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Agent: CCCCSc1c([N+](=O)[O-])cc(C(=O)O)cc1S(N)(=O)=O
Product: Cc1ccccc1Sc1c(N)cc(C(=O)O)cc1S(N)(=O)=O

Procedure:
By substituting 3-nitro-5-sulphamyl-4-(o-tolylthio)-benzoic acid (7.7 g) for the 4-butylthio-3-nitro-5-sulphamyl-benzoic acid of Example 32 B, 3-amino-5-sulphamyl-4-(o-tolylthio)-benzoic acid was obtained with a melting point of 277°C.