Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]([CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1)[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCOC1CCCCO1
Reactant: CC(C)(C)OC(=O)NOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCOC1CCCCO1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a stirred solution of N-tert-butyloxycarbonyl-O-benzylhydroxylamine 28 (5.79 g, 25.96 mmol) in dry DMF (50 ml) was added NaH (60%, 1.2 g, 30 mmol) slowly during 15 min period under argon atmosphere at 0° C. The reaction was allowed to stir at 0° C. for 30 min and at room temperature for 1 h. 1-Chloro-2-(tetrahydropyranyl)oxy-ethane 29 (4.95 g, 30 mmol) was added and the reaction mixture was heated at 80° C. for 12 h. The reaction was cooled and evaporated to dryness. The residue was suspended in water (50 ml), pH of the solution adjusted to 7 and extracted in EtOAc (150 ml). The EtOAc extract was washed with water and brine, dried and evaporated to dryness. The residue was purified by flash chromatography over silica gel using hexane→CH2Cl2 as the eluent. The required fractions were collected and evaporated to give 6.0 g (66%) of an oily product. 1HNMR (CDCl3): δ1.48 (s, 9H, Boc), 1.49-1.84 (m, 6H, 3.CH2), 3.48-3.70 (m, 4H, 2.CH2), 3.86 (m, 2H, CH2), 4.60 (t, 1H, CH), 4.84 (s, 2H, CH2Ph) and 7.32-7.42 (m, 5H, Ph).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[N:12]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[N:11]=[CH:10][CH:9]=2)=[CH:6][N:5]2[C:21](=[O:24])[NH:22][N:23]=[C:4]2[C:3]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:42][C:43]([N:45]([CH3:47])[CH3:46])=[O:44].O>CN(C=O)C>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([N:12]2[C:8]([C:7]3[C:2]([CH3:1])=[C:3]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)[C:4]4[N:5]([C:21](=[O:24])[N:22]([CH2:42][C:43]([N:45]([CH3:47])[CH3:46])=[O:44])[N:23]=4)[CH:6]=3)=[CH:9][CH:10]=[N:11]2)=[CH:14][CH:15]=1)#[N:18]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2c(=O)[nH]nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2c(=O)n(CC(=O)N(C)C)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.6 %

Procedure:
To a solution of 4-{5-[7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 9, 55 mg. 0.12 mmol) in DMF (3 mL) was added cesium carbonate (58 mg, 0.18 mmol) followed by 2-chloro-N,N-dimethylacetamide (19 μL, 0.18 mmol). The reaction mixture was stirred at RT for 18 hrs then water was added and the reaction mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by preparative HPLC, eluting with a gradient of 20-70% MeCN in water (+0.1% formic acid) to give the title compound as a yellow solid (22 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH:17][C:18]1[CH:19]=[C:20]([CH2:26][C:27](O)=[O:28])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>CN(C=O)C.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)[C:27](=[O:28])[CH2:26][C:20]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([OH:17])[CH:19]=2)=[CH:15][CH:16]=1
Reactant: Cc1ccc(CNC2CCN(C)CC2)cc1
Reactant: COc1ccc(CC(=O)O)cc1O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CC(=O)N(Cc2ccc(C)cc2)C2CCN(C)CC2)cc1O
Reaction time: 1 h
Yield: 280 %

Procedure:
N-((4-methylphenyl)methyl)-4-amino-1-methylpiperidine (50ELH25) (105 mg, 0.48 mmol) and 3-hydroxy-4-methoxyphenylacetic acid (88 mg, 0.48 mmol) were dissolved in DMF (10 ml). Diisopropylethylamine (DIEA, 250 μL, 1.44 mmol) was added followed by bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP, 336 mg, 0.72 mmol), and the mixture was stirred at r.t for 1 h. Water (50 mL) was added, and the reaction mixture was extracted with EtOAc (2×50 mL). Drying by Na2SO4 and concentration yielded 514 mg crude material, which was purified by flash chromatography (0-30% MeOH in CH2Cl2). This gave 105 mg (57%) of the title compound as a white solid. Rf=0.20 (10% MeOH in CH2Cl2). HPLC-MS (method A) showed MH+=383. UV/MS (%)=100/92. 1H-NMR (400 MHz, CD3OD, Rotamers 52:48): δ 7.18-6.58 (m, 7H), 4.53 (s, 2H), 4.31 and 3.97 (2m, 1H), 3.82 and 3.81 (2s, 3H), 3.80 and 3.55 (2s, 2H), 3.04 and 2.85 (2m, 2H), 2.41 and 2.32 (2s, 3H), 2.35 and 2.12 (2m, 2H), 2.29 and 2.27 (2s, 3H), 1.83 and 1.74 (2m, 2H), 1.72 and 1.33 (2m, 2H)
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Cl:8][C:9]1[CH:16]=[C:15]([N:17]2[C:21](=[O:22])[CH2:20][C@@H:19]([OH:23])[C@@H:18]2[CH2:24][CH3:25])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12].IC.O>O1CCCC1>[Cl:8][C:9]1[CH:16]=[C:15]([N:17]2[C:21](=[O:22])[C@H:20]([CH3:1])[C@@H:19]([OH:23])[C@@H:18]2[CH2:24][CH3:25])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: CC[C@H]1[C@H](O)CC(=O)N1c1ccc(C#N)c(Cl)c1
Reactant: CC(C)NC(C)C
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: CC[C@H]1[C@H](O)[C@@H](C)C(=O)N1c1ccc(C#N)c(Cl)c1
Reaction time: 1 h
Yield: 37 %

Procedure:
A solution of diisopropylamine (0.208 mL) in tetrahydrofuran (8 mL) was cooled to −78° C., n-butyllithium-hexane solution (0.885 mL, 1.6 mol/L) was added dropwise, and the mixture was stirred for 1 hr. A solution of 2-chloro-4-[(2S,3R)-2-ethyl-3-hydroxy-5-oxopyrrolidin-1-yl]benzonitrile (145.5 mg) in tetrahydrofuran (2 mL) was added dropwise and the mixture was stirred at −78° C. for 1 hr. A solution of iodomethane (0.176 mL) in tetrahydrofuran (2 mL) was added dropwise at −78° C., and the mixture was stirred at −78° C. for 30 min and at 0° C. for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→1/3) to give the title compound as a colorless solid (yield: 57.0 mg, 37%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].Cl.Cl.[CH3:20][C@H:21]1[CH2:26][NH:25][CH2:24][C@H:23]([CH3:27])[NH:22]1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.C(Cl)CCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([C:15]([N:25]3[CH2:24][C@H:23]([CH3:27])[NH:22][C@@H:21]([CH3:20])[CH2:26]3)=[O:17])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1ccc(N2CCC(C(=O)O)CC2)cc1
Reactant: C[C@H]1CNC[C@H](C)N1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@H]1CN(C(=O)C2CCN(c3ccc(C#N)cc3)CC2)C[C@H](C)N1

Procedure:
The title compound (D18) was prepared using a similar procedure to Description 4 step 1from 1-(4-cyanophenyl)-piperidine4-carboxylic acid (D3), (2S, 6S)-2,6-dimethylpiperazine dihydrochloride (J. W. Mickleson, K. L. Belonga and E. J. Jacobsen, J. Org. Chem., 1995, 60(13), 4177-4183), EDC, HOBT and N-methyl morpholine in DMF.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7](Cl)[N:6]=[C:5]([Cl:10])[N:4]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1)[NH2:16].C(Cl)Cl.[K+].[Br-]>>[CH3:21][O:20][C:18]1[CH:17]=[C:15]([NH:16][C:7]2[N:8]=[C:3]([NH:2][CH3:1])[N:4]=[C:5]([Cl:10])[N:6]=2)[CH:14]=[C:13]([O:12][CH3:11])[CH:19]=1
Reactant: COc1cc(N)cc(OC)c1
Reactant: CNc1nc(Cl)nc(Cl)n1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CNc1nc(Cl)nc(Nc2cc(OC)cc(OC)c2)n1
Yield: 73 %

Procedure:
The title compound was synthesized from 2-methylamino-4,6-dichloro-1,3,5-triazine and 3,5-dimethoxyaniline using a similar procedure to the one used in 2. Yield: 73%; Tm 240° C.; FTIR (CH2Cl2/KBr) 3338, 3254, 3136, 3118, 3001, 2955, 2939, 2907, 2838, 1638, 1614, 1583, 1560, 1536, 1484, 1468, 1455, 1431, 1422, 1397, 1384, 1273, 1251, 1228, 1206, 1191, 1176, 1151, 1127, 1072, 1064, 986, 923, 874, 846, 836, 805, 795, 739, 717, 683 cm1; 1H NMR (300 MHz, DMSO-d6, 298K) δ 10.02, 9.84 (s, s, 1H), 8.12, 8.00 (s, s, 1H), 7.08, 7.00 (s, s, 2H), 6.19 (s, 1H), 3.71 (s, 6H), 2.85, 2.80 (s, d, 3J=4.7 Hz, 3H) ppm; 13C NMR (75 MHz, DMSO-d6): δ 168.3, 167.5, 165.8, 165.7, 163.6, 163.0, 160.2, 140.6, 140.5, 98.5, 98.1, 94.9, 94.5, 54.9, 27.4, 27.2 ppm; HRMS (EI) calcd. for C12H14ClN5O2 (m/e): 295.0836. found: 295.0843.
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:19])[CH2:16][CH2:17][SH:18])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:20].[K+]>C(O)C>[NH:1]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:19])[CH2:16][CH2:17][S:18][CH2:17][CH2:16][C:15]([NH:14][C:11]2[CH:12]=[CH:13][C:8]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:9][CH:10]=2)=[O:20])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCS)Nc1ccc(Nc2ccccc2)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: O=C(CCSCCC(=O)Nc1ccc(Nc2ccccc2)cc1)Nc1ccc(Nc2ccccc2)cc1
Reaction time: 2 h

Procedure:
To a suspension of 20.4 grams of N-4(anilinophenyl)acrylamide in 200 milliliters of ethanol was added 23.3 grams of N-(4-anilinophenyl)-3-mercaptopropionamide. A solution of one gram of potassium hydroxide in 10 milliliters of ethanol was added at 17.5°C. Within a few minutes the temperature began to rise, reaching a maximum of 28°C. Simultaneous with the increase in temperature, product began to precipitate. The reaction mixture was stirred for 2 hours. The solid product was filtered off and allowed to dry. There was obtained 41 grams (94 percent of theory) of product which melted at 199°-203°C.
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.O>ClCCl>[F:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:3]2[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C1CCN(Cc2ccc(F)cc2)CC1

Procedure:
To 10 mmol of piperidin-4-one hydrochloride monohydrate and 20 mmol of triethylamine, dissolved in dichloromethane, there are slowly added 10 mmol of 4-fluorobenzyl chloride; the reaction mixture is then heated at reflux of the solvent for 48 hours, with vigorous stirring. After returning to ambient temperature, water is added and then, after separation of the phases, the organic phase is dried, filtered and concentrated in vacuo to yield the expected product in the form of an orange oil.
Reaction SMILES: [CH:1]([C:3]([CH3:5])=[O:4])=[CH2:2].O.[CH:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[CH2:11][CH2:10]1)=O.[OH-].[K+]>C(O)C>[O:4]=[C:3]1[CH2:5][CH2:7][C:9]2([CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:11][CH2:10]2)[CH:2]=[CH:1]1
Reactant: C=CC(C)=O
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2

Procedure:
Methyl vinyl ketone (1.64 ml), ethanol (5 ml) and water (5 ml) were added to benzyl 4-formylpiperidine-1-carboxylate (5 g). The mixture was then added to a boiling solution of potassium hydroxide (0.22 g) in ethanol (10 ml) and the resulting reaction mixture was refluxed for 1 h (TLC control). When the reaction was complete, the mixture was added to water (25 ml) and extracted with ethyl acetate (2×50 ml). The combined organic phases were dried (Na2SO4) and concentrated in vacuo. The crude product obtained in this way was purified by column chromatography (silica gel, 25% ethyl acetate/hexane). Yield: 2.8 g (46%)
Reaction SMILES: [C:1]([N:14]([CH3:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(=O)(=O)(O)O.[CH:26](O)([CH3:28])[CH3:27]>>[CH:26]([O:18][C:17](=[O:19])[CH2:16][CH2:15][N:14]([C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH3:20])([CH3:28])[CH3:27]
Reactant: CCCCCCCCCCCC(=O)N(C)CCC(=O)O
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Product: CCCCCCCCCCCC(=O)N(C)CCC(=O)OC(C)C

Procedure:
One hundred grams(100) of N-lauroyl-N-methyl-β-alanine and 750 ml of isopropanol were charged into a 1,000-milliliter flask. Further, 2 ml of conc. sulfuric acid were added as the catalyst. The mixture was heated under ref lux for reaction for 8 hours.
Reaction SMILES: NC1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(O)CO.[OH-].[K+].C1(C)C=CC=CC=1>C(O)(=O)C>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([SH:3])[CH:10]=1
Reactant: COc1ccc2nc(N)sc2c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: OCCO
Solvent: CC(=O)O
Product: COc1ccc(N)c(S)c1
Temperature: 25 °C
Yield: 86 %

Procedure:
A mixture of 2-amino-6-methoxybenzothiazole (15 g, 83.2 mmol), ethylene glycol (20.23 g, 0.33 mol) and 50% w/v KOH (100 ml) was heated under reflux for 24 h. On cooling to room temperature, toluene (60 ml) was added and the reaction mixture was cooled in an ice-bath and acidified with acetic acid (final pH 5-6). The reaction mixture was extracted with toluene (5×300 ml) and the combined organic extracts were washed with brine (2×200 ml), dried (MgSO4) and the solvent removed under reduced pressure to give the title compound (11.1 g, 86%) as a yellow solid which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][NH2:20])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C@H:25]1[O:27][CH2:26]1>[N+](C)([O-])=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][NH:20][CH2:26][C@@H:25]([C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([Cl:21])[CH:23]=3)[OH:27])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: Clc1cccc([C@@H]2CO2)c1
Reactant: COC(=O)c1cccc(-c2cccc(OCCN)c2)c1
Solvent: C[N+](=O)[O-]
Product: COC(=O)c1cccc(-c2cccc(OCCNC[C@H](O)c3cccc(Cl)c3)c2)c1
Yield: 55.8 %

Procedure:
A solution of methyl-3′-[(2-amino)ethoxy]-[1,1′-biphenyl]-3-carboxylate (284.5 mg) and (R)-(-)-3-chlorostyrene oxide (124 mg) in nitromethane (4.0 mL) was heated at 70-75° C. for 20 h. The mixture was concentrated with a rotary evaporator to afford the crude product. Purification by silica gel chromatography (eluting with ethyl acetate followed by 10:1 ethyl acetate: methanol followed by 3:1 ethyl acetate: methanol) afforded the title compound (190.6 mg) as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].C([Li])CCC.CCCCCC.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:23]#[N:24])[CH3:18]>C1COCC1.O>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([C:23]([NH2:24])=[CH:1][S:2]([CH3:5])(=[O:4])=[O:3])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH3:18]
Reactant: CS(C)(=O)=O
Reactant: CCOc1cc(C#N)ccc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCOc1cc(C(N)=CS(C)(=O)=O)ccc1OC
Temperature: 27.5 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
A slurry of dimethylsulfone (85 g, 903 mmol) in THF (480 ml) was treated with a 1.6M solution of n-butyllithium in hexane (505 ml, 808 mmol) at 0-5° C. The resulting mixture was agitated for 1 hour then a solution of 3-ethoxy-4-methoxybenzonitrile (80 g, 451 mmol) in THF (240 ml) was added at 0-5° C. The mixture was agitated at 0-5° C. for 0.5 hour, warmed to 25-30° C. over 0.5 hour and then agitated for 1 hour. Water (1.4 L) was added at 25-30° C. and the reaction mass was agitated overnight at room temperature (20-30° C.). The solid was filtered and subsequently washed with a 2:1 mixture of water:THF (200 ml), water (200 ml) and heptane (2×200 ml). The solid was dried under reduced pressure at 40-45° C. to provide the product as a white solid (102 g, 83% yield); 1H NMR (DMSO-d) δ 1.34 (t, J=7.0 Hz, 3H), 2.99 (s, 3H), 3.80 (s, 3H), 4.08 (q, J=7.0 Hz, 2H), 5.03 (s, 1H), 6.82 (s, 2H), 7.01 (d, J=8.5 Hz, 1H), 7.09-7.22 (m, 2H).
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[NH:10][NH:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(Cl)(Cl)Cl>[CH3:15][C:14]([N:10]1[C:11](=[O:12])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:13])[NH:9]1)=[O:16]
Reactant: O=c1[nH][nH]c(=O)n1-c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)n1[nH]c(=O)n(-c2ccccc2)c1=O
Yield: 54 %

Procedure:
To a suspension of 5.3 g (30 mmol) of 4-phenyl-1,2,4-triazolidine-3,5-dione in 175 ml of chloroform was added dropwise over a 15 minute period 45.9 g (450 mmol) of acetic anhydride with stirring. The reaction mixture was stirred at room temperature for five days. The reaction mixture was filtered to remove a white precipitate which was washed with 30 ml of chloroform to give 3.55 g (54.0 %) of 1-methylcarbonyl-4-phenyl-1,2,4-triazolidine-3,5-dione as white solid, m.p. 215°-218.5° C. The filtrate Was washed with three 100 ml portions of water and three 80 ml portions of 10% sodium carbonate. The carbonate washings were acidified with concentrated hydrochloric acid. No precipitate was formed. The chloroform solution was dried (Na2SO4) and evaporated under reduced pressure to give a liquid residue containing acetic anhydride. The filtered solid was recrystallized from 95% ethanol to yield pure 1-methylcarbonyl-4-phenyl-1,2,4-triazolidine-3,5-dione: m.p. 216.5° -218.5° C.; IR (Nujol) 1726, 1710, 1688 cm-1 (CO); 1H NMR (60 MHz, CDCl3) δ 7.90 (s, 5H) 2.55(s, 3H). Found: C, 54.5; H, 4.2: N, 19.4. C10H9N3O3 requires C, 54.8; H, 4.2; N, 19.4.
Reaction SMILES: [C:1]12([C:12]([O:14]C)=[O:13])[CH2:7][C:4]([C:8]([O:10][CH3:11])=[O:9])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[OH-].[K+].O>CO>[CH3:11][O:10][C:8]([C:4]12[CH2:7][C:1]([C:12]([OH:14])=[O:13])([CH2:6][CH2:5]1)[CH2:2][CH2:3]2)=[O:9]
Reactant: COC(=O)C12CCC(C(=O)OC)(CC1)C2
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)C12CCC(C(=O)O)(CC1)C2
Temperature: 25 °C
Yield: 63.6 %

Procedure:
To a solution of dimethyl bicyclo[2.2.1]heptane-1,4-dicarboxylate (2.00 g, 9.44 mmol, as prepared in Aust. J. Chem., 1985, 38, 1705-18) in MeOH (47 mL) was added KOH (0.475 g, 8.46 mmol) and water (2.5 mL). The reaction was stirred at reflux for about 16 h and then cooled to room temperature and concentrated to dryness under reduced pressure. Water (25 mL) was added to the remaining residue and the mixture was extracted with Et2O (2×25 mL). The aqueous layer was acidified to about pH 4 using aqueous 6 N HCl and was extracted with DCM (3×20 mL). The combined DCM extracts were dried over anhydrous MgSO4, filtered, and concentrated to provide 4-(methoxycarbonyl)bicyclo[2.2.1]heptane-1-carboxylic acid as an off-white solid (1.19 g, 71%): 1H NMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 3.61 (s, 3H), 1.92 (d, J=6.6 Hz, 4H), 1.76 (s, 2H), 1.65-1.54 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([F:21])[CH:15]=2)[C@H:10]2[CH2:22][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2].[CH3:23][S:24]([NH:27][C:28]1[CH:43]=[CH:42][C:31]2[NH:32][C:33]([CH2:38][C:39](O)=[O:40])=[N:34][S:35](=[O:37])(=[O:36])[C:30]=2[CH:29]=1)(=[O:26])=[O:25].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:1]([O:3][C:4]([C@H:6]1[C@@H:11]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([F:21])[CH:15]=2)[C:39](=[O:40])[CH2:38][C:33]2[NH:32][C:31]3[CH:42]=[CH:43][C:28]([NH:27][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:29][C:30]=3[S:35](=[O:36])(=[O:37])[N:34]=2)[C@H:10]2[CH2:22][C@@H:7]1[CH2:8][CH2:9]2)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccc(C)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(Cc1ccc(C)c(F)c1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1S,2R,3S,4R)-3-(3-fluoro-4-methyl-benzylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (92 mg, 0.30 mmol), (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1g, 100 mg, 0.30 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (60 mg, 0.315 mmol) in N,N-dimethylformamide (4.0 mL) was added N-methylmorpholine (0.07 mL, 0.63 mmol). After stirring at 25° C. for 3 h, the mixture was poured into a 1.0 M aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with saturated aqueous brine solution, dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, (1S,2R,3S,4R)-3-{(3-fluoro-4-methyl-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester, as an orange oil. The crude product was used in the next step without further purification. LC-MS (ESI) calcd for C28H33FN4O7S2 620.18, found 621.4 [M+H+].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])[CH2:15][NH:16][C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:20][O:19][C:17](=[O:18])[NH:16][CH2:15][CH:14]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])[N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: COC(=O)NCC(c1ccc(F)cc1F)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)NCC(c1ccc(F)cc1F)N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
To 4-[1-(2,4-Difluoro-phenyl)-2-methoxycarbonylamino-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (420) (0.225 g, 0.564 mmol) in MeCl2 (2.0 mL) was added TFA (2.0 mL). The reaction was allowed to stir at room temperature for 1 h. The reaction mixture was concentrated to dryness. The resulting residue was taken up in 1N HCl (30 mL) and washed with EtOAc (30 mL). The aqueous layer was made alkaline with 5N NaOH (10 mL) and the desired product was extracted into EtOAc. The organic phase was concentrated to dryness yielding 0.14 g (83%) pure product.