Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:11])[CH3:10].[Br:12]N1C(=O)CCC1=O>C(#N)C>[CH:9]([C:4]1[CH:5]=[C:6]([Br:12])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([CH3:11])[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccccc1C(C)C
Solvent: CC#N
Product: COc1ccc(Br)cc1C(C)C
Yield: 82 %

Procedure:
A solution of 2-methoxyisopropyl-benzene (2 g) and N-bromosuccinimide (2.6 g) in acetonitrile (20 mL) was stirred at ambient temperature for 18 h. The reaction was concentrated in vacuo, slurried in carbon tetrachloride and filtered. The filtrate was concentrated in vacuo. The residue was flash chromatographed (5% dichloromethane/hexanes) to afford the title compound as an oil (2.5 g).
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].C([O-])(O)=O.[Na+].[NH:16]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:17]([C:21](ON1C(=O)CCC1=O)=[O:22])[CH:18]([CH3:20])[CH3:19]>O.CC#N>[NH:16]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[C@H:17]([C:21]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])=[O:22])[CH:18]([CH3:20])[CH3:19]
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(N)=O)C(=O)O
Temperature: 5 °C

Procedure:
H-Gln-OH (2 eq.) and NaHCO3 (2 eq.) were dissolved under stirring in water at maximum 45° C. and then cooled to about 5° C. Z-Val-OSu (1 eq.) was dissolved in MeCN and added in the aqueous solution in such way that the temperature did not rise above 10° C. The mixture was stirred for at least 1 h at ±5° C. before being warmed to room temperature for at least two hours. The peptide solution was concentrated under vacuum, diluted with water and washed twice with AcOEt. The aqueous phase was then diluted with i-BuOH and the pH was adjusted to 2.5 with a solution of KHSO4. DCM was then added to extract the peptide into the organic phase which was washed with a 5% weight NaCl solution and finally with water. The organic phase was collected and concentrated under reduced pressure until water content in the evaporates was <1% weight. The concentrate was diluted with hot isopropyl acetate and left to cool to 25° C. under gentle stirring to crystallize the peptide. The solid was recovered by filtration, once washed with AcOiPr at 25° C. and dried under vacuum until AcOiPr content in the peptide was ≦5% weight. After drying under vacuum not less than 70% of Z-Val-Gln-OH was recovered.
Reaction SMILES: O=[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[N:10]2[C:6](=[N:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[S:5][N:4]=1.N1C=CC=CC=1.Cl.[NH2:28][OH:29]>C(O)C>[OH:29][N:28]=[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]1[N:10]2[C:6](=[N:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[S:5][N:4]=1
Reactant: NO
Reactant: O=C(c1ccccc1)c1nsc2nc3ccccc3n12
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=C(c1ccccc1)c1nsc2nc3ccccc3n12
Yield: 89.2 %

Procedure:
To a solution of 0.5 g (1.79 mmol) of 3-(oxophenylmethyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole in 7 mL of ethanol was added 0.5 mL (6.46 mmol) of pyridine and 0.5 g (7.20 mmol) of hydroxylamine hydrochloride. The mixture was refluxed for overnight. The precipitate was collected by filtration, and washed with methanol and dichloromethane to give the crude product, which was recrystallized from methanol to yield 0.47 g (89%) of the title compound as white crystals. mp 247° C.; 1H NMR (DMSO-d6) δ11.89 (s, 1H), 7.81 (d, 1H), 7.73 (dd, 2H), 7.45-7.53 (m, 5H), 7.32 (t, 1H) ppm; 13C NMR (CDCl3) δ168.25, 155.24, 150.52, 147.95, 136.94, 135.67, 134.30(2C), 133.03, 131.52(2C), 130.35, 127.26, 124.28, 116.91 ppm; IR (KBr) δ2731, 1549, 1475, 1450, 1251, 1194, 983, 753, 736 cm-1. HRMS calcd for C15H10N4OS 294.0575, found 294.0583.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:15][CH2:14][C@H:13]([CH2:16][OH:17])[CH2:12]3)=[N:9][N:10]=2)[CH:7]=1.CCN(CC)CC.[CH:25]([Si:28](OS(C(F)(F)F)(=O)=O)([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])([CH3:27])[CH3:26]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:15][CH2:14][C@H:13]([CH2:16][O:17][Si:28]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:25]([CH3:27])[CH3:26])[CH2:12]3)=[N:9][N:10]=2)[CH:7]=1
Reactant: OC[C@H]1CCN(c2nnc3ccc(F)cn23)C1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[Si](OC[C@H]1CCN(c2nnc3ccc(F)cn23)C1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
To a solution of Intermediate 92a (667 mg, 2.83 mmol) and Et3N (630 μL, 4.53 mmol) in DCM (5 mL) was added triisopropylsilyltrifluoromethane sulfonate (950 μL, 3.54 mmol) and the mixture was stirred at RT for 1 h. The mixture was washed with sat. sodium hydrogen carbonate solution then brine, dried and concentrated in vacuo. The residue was purified by FCC, 2-6% MeOH in DCM, to give the title compound as a pale green viscous oil (1.11 g, quant.). LCMS (Method 3): Rt 4.76 min, m/z 393 [MH+].
Reaction SMILES: [N+]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:7][N:6]=1)([O-])=O.N[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26]>N1C=CC=CC=1>[OH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:14]=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=2)=[CH:7][N:6]=1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: NCCCCCO
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCCCCO)[nH]c2=O)cn1

Procedure:
Ethyl 3-(6-methyl-3-pyridyl)propionate was reacted at 0° with ethyl formate and sodium hydride in 1,2-dimethoxyethane to give ethyl 2-formyl-3-(6-methyl-3-pyridyl)propionate, m.p. 142°-144°, which was heated under reflux with dried nitroguanidine and sodium methoxide in methanol to give 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone, m.p. 215°-6° (decomp). p (ii) Reaction of 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone with 5-aminopentanol in refluxing pyridine gives 2-(5-hydroxypentylamino)-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone which can be converted into 2-[5-(O-isoureido)pentylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone by the procedure of Example 5(iii).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[CH:12](=[N+:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:12]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:3]1
Reactant: Cn1ccc2ccccc21
Reactant: C(c1ccccc1)=[N+]1CCOCC1
Agent: [Cl-]
Product: Cn1cc(C(c2ccccc2)N2CCOCC2)c2ccccc21

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methyl-1H-indole and 4-benzylidene-morpholin-4-ium chloride.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.Br[CH2:11][CH:12]([OH:15])[CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:1]1([CH:13]([OH:14])[CH:12]([OH:15])[CH3:11])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: OCC(O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(O)C(O)n1cnc2ccccc21
Yield: 68.7 %

Procedure:
Benzimidazole (590 mg, 5.0 mmol) and 3-bromo-1,2-propanediol (0.52 mL, 6.0 mmol) were dissolved in anhydrous acetonitrile (50 mL) and dry potassium carbonate (2.07 g, 15 mmol) was added. The solution was then heated to reflux for 3 days. Upon cooling the mixture was filtered and the filtrates were concentrated, giving the desired N-benzimidazolyl-1,2-propanediol (0.66 g, 69%) as a pale yellow solid. 1H NMR (CDCl3) δ 3.60 (m, 2H), 3.78 (m, 2H), 4.17 (m, 1H), 4.27 (m, 2H), 7.25 (m, 2H), 7.42 (d, 1H, J=6 Hz), 7.67 (d, 1H, J=6 Hz), 7.87 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1.Cl([O-])=[O:14].[Na+].P(O)(O)([O-])=O.[Na+].CC(=CC)C>C(O)(C)(C)C.O>[Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]([OH:14])=[O:7])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Br)cc(C)c1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1cc(Br)cc(C)c1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.7 %

Procedure:
To a suspension of 4-bromo-2-methoxy-6-methyl-benzaldehyde (1.25 g, 5.45 mmol) in tert-butanol (21.7 ml) is added a solution of sodium chlorite (0.98 g, 10.9 mmol) and monosodium phosphate (4.25 g, 27.3 mmol) in water (11 ml). To the solution is added 2-methyl-2-butene (4.63 ml, 43.7 mmol). The resulting homogeneous solution is stirred at RT for 30 min. After completion of the reaction, the solvent is evaporated and the residue is diluted with water and acidified with 1 M hydrochloric acid to pH=1 and extracted with methyl tert-butyl ether (3×40 ml). The combined organic layers are extracted with 1 M sodium hydroxide solution which is further acidified with 6 M hydrochloric acid and extracted with ethyl acetate (3×50 ml). The organic layer is washed with brine (40 ml), dried over sodium sulfate and concentrated to yield 4-bromo-2-methoxy-6-methyl-benzoic acid (1.2 g, 4.89 mmol, 90%).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C@@:5]([CH3:18])([NH:11][S@](C(C)(C)C)=O)[CH2:6][C@@H:7]([CH3:10])[CH2:8][CH3:9].Cl>CC(C)=O.O>[NH2:11][C@@:5]([CH3:18])([CH2:6][C@@H:7]([CH3:10])[CH2:8][CH3:9])[CH2:4][C:3]([OH:19])=[O:2]
Reactant: CC[C@H](C)C[C@@](C)(CC(=O)OC)N[S@@](=O)C(C)(C)C
Agent: Cl
Solvent: CC(C)=O
Solvent: O
Product: CC[C@H](C)C[C@](C)(N)CC(=O)O
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 76.7 %

Procedure:
A mixture of (3S,5S)-3,5-dimethyl-3-((S)-2-methyl-propane-2-sulfinylamino)-heptanoic acid methyl ester (0.4 g, 1.37 mmol) and concentrated hydrochloric acid (7.6 mL) in acetone (10 mL) was refluxed for 3 hours. The solvents were stripped under reduced pressure. The residue was dissolved in water (10 mL) and extracted by EtOAc (2×15 mL). The aqueous phase was evaporated to dryness. The residue was dissolved in a mixture of water (10 mL) and triethylamine (0.5 mL). The mixture was stirred at 40° C. for 20 minutes and then was evaporated to dryness. The residue was washed thoroughly with acetonitrile, filtered, and dried under vacuum to give the final product, (3S,5S)-3-amino-3,5-dimethyl-heptanoic acid (0.182 g, 77% yield) as a white solid. m.p. 215–217° C.: 1H NMR (CDCl3) δ 4.85 (s, 3H), 2.38 (m, 2H), 1.75 (m, 1H), 1.39 (m, 4H), 1.35(s, 3H), 0.98 (d, J=6.6 Hz, 3H), 0.90 (t, J=7.5 Hz, 3H); MS (APCl) (M+1)+ 174.1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[NH:4][C:5](=[O:14])[C:6](=[O:13])[NH:7]2.[NH2:15]OS(O)(=O)=O>[OH-].[K+].O>[NH2:15][N:7]1[C:8]2[C:3](=[C:2]([Cl:1])[CH:11]=[C:10]([Cl:12])[CH:9]=2)[NH:4][C:5](=[O:14])[C:6]1=[O:13]
Reactant: O=c1[nH]c2cc(Cl)cc(Cl)c2[nH]c1=O
Reactant: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nn1c(=O)c(=O)[nH]c2c(Cl)cc(Cl)cc21
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
The procedure of Wallace, R. G., Org. Prep. Proc. Int. 14: 269 (1982) was adapted. 5,7-Dichloro-1,4-dihydroquinoxaline-2,3-dione (52 mg, 0.225 mmole) was dissolved in 3N KOH (1 mL) at 60° C. for 0.5 h, and NH2OSO3H (30 mg, 0.265 mmole, Aldrich) in distilled water (0.5 mL) was dropwise added into above solution with stirring at 60° C. Some precipitate came out after 15 mins. The mixture was stirred at room temperature overnight. The white precipitate was collected by filtration, washed with cold distilled water (0.5 mL) and dried on rotavapor at 60° C. for 2 h affording crude 1-amino-5,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (38 mg, 69%), which included a little of the isomer (4-amino-5,7-dichloro-2,3-quinoxalinedione) by 1H NMR (it is not known which isomer is present in a greater amount).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][NH:8][C:7]2=O)([O-:3])=[O:2].P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=[CH:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2ccc([N+](=O)[O-])cc12
Product: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Temperature: 105 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
In a 100 mL flask equipped with a reflux condenser, 6-nitro-quinazolin-4-one 2.85 g (15 mmol), phosphoryl chloride 25 mL were added. The mixture was stirred at 105° C. for 3 h, and then was dropped into 150 mL of ice water carefully, the squama solid deposited was filtered out, dried, and identified as the title compound. Yield: 78%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:3]=1[CH3:21].[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:29]=2[NH2:40])[CH2:24][CH2:23]1.Cl.O1CCOCC1>CO>[N:25]1([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][C:29]=2[NH:40][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[C:9]([F:12])[CH:10]=3)[N:5]=[C:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:3]=2[CH3:21])[CH2:26][CH2:27][O:22][CH2:23][CH2:24]1
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Reactant: Cc1c(-c2ccccc2F)nc2cc(F)c(F)cc2c1Cl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2F)nc2cc(F)c(F)cc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure K, Method 1 using 4-chloro-6,7-difluoro-2-(2-fluorophenyl)-3-methylquinoline (100 mg, 325 μmol), 2,5-dimorpholinobenzenamine (86 mg, 325 μmol) and 4N hydrochloric acid solution in dioxane (0.081 mL, 325 μmol) in MeOH (3.00 mL) to afford product as a colorless solid after purification by chromatography on silica gel eluting with MeOH gradient in DCM. 1H NMR (400 MHz, chloroform-d) δ ppm 7.91 (1H, dd, J=11.0, 7.8 Hz), 7.55-7.71 (2H, m), 7.43-7.54 (1H, m, J=7.9, 7.9, 5.4, 2.0 Hz), 7.31-7.40 (1H, m), 7.09-7.25 (3H, m), 6.46 (1H, dd, J=8.6, 2.7 Hz), 6.01 (1H, br. s.), 3.87-4.05 (4H, m), 3.73-3.83 (4H, m), 3.06 (4H, dd, J=2.5, 1.8 Hz), 2.90-3.01 (4H, m), 2.21 (3H, d, J=2.0 Hz). Mass Spectrum (ESI) m/e=535.3 (M+1).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH3:22][O:23][C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)=[O:25].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH3:22][O:23][C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C@@H:27]1[N:32]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)[C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)=[O:25]
Reactant: COC(=O)[C@@H]1CCCC[C@@H]1NCc1ccc(F)cc1
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H]1CCCC[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
(7-Methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.1 g, 0.3 mmol) was dissolved in anhydrous N,N-dimethylformamide (4 mL). (1R,2S)-2-(4-Fluoro-benzylamino)-cyclohexanecarboxylic acid methyl ester (0.79 g, 0.3 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.06 g, 0.315 mmol). Then N-methylmorpholine (0.07 mL, 0.63 mmol) was added into the above reaction mixture. The mixture was stirred at 25° C. for 2 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (50 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude product, (1R,2S)-2-{(4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclohexanecarboxylic acid methyl ester (0.3 mmol), as a yellow oil. LC-MS (ESI) calcd for C25H29FN4O7S2 580.15, found 581.3 [M+H+].
Reaction SMILES: C([O:8][C:9]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[C:31]([CH3:32])=[CH:30][C:29]([N+:33]([O-])=O)=[C:28]3[C:24]=2[CH2:25][CH2:26][CH2:27]3)=[CH:18][C:10]=1[CH:11]=[C:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)C1C=CC=CC=1.[H][H]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:33][C:29]1[CH:30]=[C:31]([CH3:32])[C:23]([O:22][C:19]2[CH:20]=[CH:21][C:9]([OH:8])=[C:10]([CH2:11][CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:18]=2)=[C:24]2[C:28]=1[CH2:27][CH2:26][CH2:25]2
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(OCc3ccccc3)c(C=C3CCOCC3)c1)CCC2
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(N)c2c(c1Oc1ccc(O)c(CC3CCOCC3)c1)CCC2
Yield: 80 %

Procedure:
4-[2-Benzyloxy-5-(5-methyl-7-nitroindan-4-yloxy) benzylidene]tetrahydropyran (230 mg) was dissolved in ethanol (10 mL) and ethyl acetate (2 mL). After adding 10% Pd/C (50 mg) under ice-cooling, the mixture was stirred at room temperature under an atmospheric pressure of hydrogen for 24 hours. The insoluble material was removed by filtration. The filtrate was evaporated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel (eluent: exane/ethyl acetate) to give the title compound (138 mg).
Reaction SMILES: [C:1]([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.Cl[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24]>C(Cl)Cl>[CH:26]([O:25][C:23]([N:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:10][CH2:11]1)=[O:24])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)N1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.6 %

Procedure:
To a solution of 4-(N-Boc amino)piperidine (2.61 g, 13 mmol) and triethylamine (3 mL, 21.5 mmol) in 25 mL of DCM, was added isopropyl chloroformate (1 M in toluene, 13.1 mL, 13.1 mmol). The mixture was stirred at room temperature for 20 h. It was then washed with a saturated solution of NaHCO3 (50 mL), followed by brine (50 mL). The solution was dried, filtered and evaporated to afford 3.26 g (87%) of 18a.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:49]1[CH:54]=[CH:53][CH:52]=[C:51]([C:55]2[CH:56]=[C:57]([CH:59]=[CH:60][CH:61]=2)[NH2:58])[CH:50]=1>CN(C=O)C>[N:49]1[CH:54]=[CH:53][CH:52]=[C:51]([C:55]2[CH:56]=[C:57]([NH:58][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:59]=[CH:60][CH:61]=2)[CH:50]=1
Reactant: Nc1cccc(-c2cccnc2)c1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
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(Nc1cccc(-c2cccnc2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 32.5 %

Procedure:
DIEA (0.028 mL, 0.160 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.030 g, 0.146 mmol) and HATU (0.061 g, 0.160 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-pyridin-3-ylaniline (0.025 g, 0.146 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.017 g of product in 32% yield: LCMS (ESI) m/z 359 (MH+).
Reaction SMILES: [C:1]1([C:7]2(O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C.O.C1(C)C(S(O)(=O)=O)=CC=CC=1>[C:1]1([C:7]2([C:17]3[CH:18]=[CH:19][C:14]([OH:20])=[CH:15][CH:16]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: OC1(c2ccccc2)CCCCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1ccc(C2(c3ccccc3)CCCCC2)cc1
Temperature: 85 °C
Reaction time: 4 h
Yield: 78.9 %

Procedure:
A mixture of 5 g (28.4 mmol) of 1-phenyl-1-cyclohexanol, 5.35 g (56.8 mmol) of phenol and 250 mg (1.32 mmol) of toluenesulfonic acid monohydrate was stirred at 85° C. under nitrogen atmosphere for 4 hours. The material was allowed to cool to room temperature, diluted with ethyl acetate, washed with saturated sodium bicarbonate, water and brine. The resulting solution was dried (Na2SO4), filtered and concentrated to a white solid which was heated under high vacuum to remove residual phenol. The resulting residue was purified by flash chromatography on silica gel, eluting with methanol/dichloromethane to provide 5.64 g (22.4 mmol) of 4-(1′-(phenyl)cyclohexyl)phenol.
Reaction SMILES: Cl.[C:2](=[NH:8])([O:6][CH3:7])[CH2:3][CH2:4][CH3:5].[N:9]#[C:10]N.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>>[C:10]([N:8]=[C:2]([O:6][CH3:7])[CH2:3][CH2:4][CH3:5])#[N:9]
Reactant: CCCC(=N)OC
Reactant: N#CN
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CCCC(=NC#N)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
The methyl butyrimidate salt from Example 1 (322 g, 2.34 mol) was dissolved in a 50% aqueous solution of cyanamide (236 g, 2.81 mol) and cooled in an ice-bath. Dibasic sodium phosphate (164 g, 1.15 mol) was added to the reaction mixture in portions over a period of 1 hour. The resulting suspension was stirred at room temperature for 2 hours and the liquid decanted from the reaction mixture. The remaining solid was diluted with water (2 L) and extracted with ether (3×600 mL). The combined organic layers were washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue distilled under high vacuum to afford 258 g of methyl N-cyanobutyrimidate. MS (DEI) 127 (M+1).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[N:7]([CH:8]([CH3:10])[CH3:9])[CH2:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:4]=2[N:3]1[CH2:20][CH:21]=C.[O:24]=[O+][O-].CSC>ClCCl>[O:1]=[S:2]1(=[O:23])[N:7]([CH:8]([CH3:9])[CH3:10])[CH2:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:4]=2[N:3]1[CH2:20][CH:21]=[O:24]
Reactant: C=CCN1c2c(cccc2C(=O)OCC)CN(C(C)C)S1(=O)=O
Reactant: O=[O+][O-]
Solvent: ClCCl
Solvent: CSC
Product: CCOC(=O)c1cccc2c1N(CC=O)S(=O)(=O)N(C(C)C)C2
Temperature: -75 °C
Reaction time: 1 h

Procedure:
Ethyl 3,4-dihydro-2,2-dioxo-3-(1-methylethyl)-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-8-carboxylate (1.1 g)(prepared from ethyl 3,4-dihydro-2,2-dioxo-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-8-carboxylate and (prop-2-en-1-yl) bromide) was dissolved in dichloromethane (80 ml) and cooled to -75° C. Ozone was passed through the solution until the solution became blue. At which time, dimethyl sulfide (5 ml) was added and the solution allowed to come to room temperature over 1 hour. The solution was washed with water to remove the DMSO present, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give a solid, ethyl 3,4-dihydro-2,2-dioxo-3-(1-methylethyl)-1-(2-oxoethyl)-1H-2,1,3-benzothiadiazine-8-carboxylate. This was dissolved in dichloroethane (50 ml) containing glacial acetic acid(5 drops) together with 4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydropyridine (0.8 g, 1.1 equiv.). Sodium triacetoxy borohydride (0.8 g, 1.1 equiv.) was added and the solution stirred overnight at room temperature. After washing with 2N sodium hydroxide (30 ml) and brine, the solution was dried, filtered and evacuated in vacuo to yield an off-white solid. Column chromatography eluting with ethyl acetate/hexane to ethyl acetate gave the required product, ethyl 3,4-dihydro-2,2-dioxo-1-{2-[4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydro-1-pyridyl]-1-ethyl}-3-(1-methylethyl)-1H-2,1,3-benzothiadiazine-8-carboxylate, m.p. 95-97° C.