Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9](=[O:10])[C:8]2[NH:7][CH:6]=[N:5][C:4]=2[N:3]=[CH:2]1.[CH2:11]([OH:13])[CH3:12]>N.[OH-].[OH-].[Pd+2]>[OH:13][C@@H:11]1[C@@H:8]([CH2:9][OH:10])[CH2:4][N:3]([N:5]2[CH:6]=[N:7][C:8]3[C:9](=[O:10])[NH:1][CH:2]=[N:3][C:4]2=3)[CH2:12]1
Reactant: O=c1[nH]cnc2nc[nH]c12
Reactant: CCO
Agent: [Pd+2]
Agent: N
Agent: [OH-]
Product: O=c1[nH]cnc2c1ncn2N1C[C@H](CO)[C@@H](O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
tert-Butyl nitrite (3.5 mL, 30 mmol, 4 eq.) was added to a solution of the free base of 3 (2.25 g, 7.5 mmol) in dry THF (30 mL) and the reaction mixture was stirred at ambient temperature for 3 days. The solution was concentrated to dryness. Chromatography gave the N-nitroso compound 42 as a colorless syrup (2.05 g, 83%). A solution of 42 (1.0 g, 3.1 mmol) in dry THF (20 mL) was cooled to 0° C. under argon atmosphere and lithium aluminum hydride (1 g, 26.3 mmol) was added slowly. The mixture was stirred at room temperature for 6 h, then quenched carefully with a 15% solution of NaOH (25 mL) followed by water (10 mL). The mixture was extracted twice with chloroform, washed with aq NaHCO3 and dried and concentrated to dryness. Chromatography (chloroform:ethyl acetate:methanol, 5:2:1) afforded hydrazine 43 (0.41 g, 43%) as a syrup. Formimidate 44 (Watson, A. A. J. Org. Chem. 1974, 39, 2911-2916) (0.224 g, 1.44 mmol, 1.2 eq.) was added to a solution of 43 (0.375 g, 1.2 mmol) in ethanol (1.5 mL) and the reaction mixture was heated under reflux for 10 min, then allowed to cool. The solution was concentrated to dryness. Chromatography (chloroform:ethyl acetate:methanol, 5:2:1) gave the imidazole 45 as a light brown gum (0.155 g, 31%). A solution of 45 (77 mg, 0.183 mmol) in dry MeOH (1 mL) was treated with 5 M aq HCl (36.5 μL, 0.183 mmol). The solvent was removed to leave the hydrochloride salt as a brown gum. DMF (1.5 mL) was added followed by triethyl orthoformate (0.304 mL, 1.83 mmol, 10 eq.) and the reaction mixture was heated at 120° C. for 30 min. After cooling the solvent was removed in vacuo. The residue was purified by column chromatography on silica gel (chloroform:ethyl acetate:methanol, 5:2:0.5) to afford the hypoxanthine 46 (49 mg, 62%) as a gum. Palladium hydroxide on carbon (20 mg, 20% Pd) was added to a solution of 46 (41 mg, 0.095 mmol) in ethanol (3 mL) and 25% aqueous ammonia (1 mL). The reaction mixture was stirred under hydrogen at ambient temperature and pressure for 3 h. Then the catalyst was filtered off and washed with ethanol (1.5 mL). The solution was concentrated to dryness and chromatography of the residue (dichloromethane:methanol:aq. ammonia, 7:2:0.5) furnished the title compound 47 (21 mg, 88%) as a white solid. 1H NMR (CD3OD) δ 8.17 (s, 1H), 8.07 (s, 1H), 4.26 (m, 1H), 3.85-3.64 (m, 4H), 3.48-3.43 (m, 2H), 2.49-2.41 (m, 1H); 13C NMR δ 159.3 (C), 149.7 (C), 146.7 (CH), 142.3 (CH), 124.7 (C), 72.7 (CH), 63.7, 63.6, 58.4 (CH2), 50.2 (CH). M/Z calculated for C10H13N5O3 (MH+): 252.109. Found: 252.108.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:39]1[CH2:43][CH2:42][NH:41][CH2:40]1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11](=[O:12])[N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:27])([F:28])[F:26])=[N:20][C:21]([C:22]([N:41]3[CH2:42][CH2:43][S:39][CH2:40]3)=[O:23])=[C:15]2[CH2:14]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CSCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCSC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 89.4 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.15 g, 0.27 mmol), thiazolidine (57 mg, 0.6 mmol), triethylamine (0.275 g, 2.72 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.138 g, 0.544 mmol) were dissolved in 10 mL of dichloromethane under stirring. The reaction mixture was stirred at room temperature for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concen-trated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-oxo-3-[1-(thiazolidine-3-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 20a (0.15 g, yield 89%) as a white solid.
Reaction SMILES: [C:1]1([C:17]([C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=2)=[O:18])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[OH-:29].[K+].[K].Cl>C1C=CC=CC=1.CO>[C:1]1([C:17]([C:19]2[CH:20]=[CH:21][C:22]([C:23]([O:25][O:29][C:1]([CH3:17])([CH3:14])[CH3:2])=[O:24])=[CH:27][CH:28]=2)=[O:18])[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(C(=O)c2ccc3ccc4cccc5ccc2c3c45)cc1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Agent: [K]
Solvent: c1ccccc1
Solvent: CO
Product: CC(C)(C)OOC(=O)c1ccc(C(=O)c2ccc3ccc4cccc5ccc2c3c45)cc1
Yield: 142.9 %

Procedure:
4-[(1-Pyrenyl)carbonyl]benzoic acid, methyl ester (2.55 g; 7 mmol) was dissolved in 25 ml of benzene. A solution of 354 mg (6.4 mmol) of KOH in 5 ml MeOH was added, and the mixture boiled. Preciptation of the potassium salt occurred. The mixture was extracted with water to give a yellow water layer which was acidified with dilute HCl to give a light yellow precipitate. Filtration gave 1.73 g (5 mmol) of the 4-[(pyrenyl)carbonyl]benzoic acid.
Reaction SMILES: [NH2:1][C:2]1[N:12]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:6]2[N:7]=[C:8](Cl)[N:9]=[CH:10][C:5]=2[C:4](=[O:18])[C:3]=1[C:19]([NH2:21])=[O:20].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.O.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[NH2:1][C:2]1[N:12]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:6]2[N:7]=[C:8]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[CH:27][CH:28]=3)[N:9]=[CH:10][C:5]=2[C:4](=[O:18])[C:3]=1[C:19]([NH2:21])=[O:20]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: NC(=O)c1c(N)n(C2CCCC2)c2nc(Cl)ncc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: NC(=O)c1c(N)n(C2CCCC2)c2nc(Nc3ccc(N4CCOCC4)cc3)ncc2c1=O
Temperature: 90 °C
Yield: 24.1 %

Procedure:
A mixture of 184 mg (0.60 mmol) of the product prepared in step 3.3 and 0.266 g (1.49 mmol) of N-(4-aminophenyl)morpholine (Lancaster) in 6 mL of NMP is placed in a 10 mL microwave tube. The sealed tube is placed in the microwave oven (CEM machine, Discover model) and the mixture is heated under pressure at 90°C. for 1 hour at a power of 100 W and then cooled to room temperature. 20 mL of water and then 5 mL of saturated aqueous NaHCO3 are added and the precipitate formed is drained by suction and dried in an oven. The crude solid is purified by chromatography on a column of silica, eluting with a dichloromethane/methanol gradient (98/2 to 95/5). 0.065 g of the expected product is obtained in the form of a beige-coloured powder. Yield=24%. m.p.=265°C. M+H+=450.
Reaction SMILES: OO.[CH3:3][O:4][CH:5]1[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[N:14]=[N+:15]([O-:26])[C:16]3[CH:25]=[C:24]4[C:20]([CH2:21][CH2:22][CH2:23]4)=[CH:19][C:17]=3[N:18]=2)[CH2:6]1.C(O)(C(F)(F)F)=[O:28]>C(Cl)Cl.N>[CH3:3][O:4][CH:5]1[CH2:8][N:7]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[N:14]=[N+:15]([O-:26])[C:16]3[CH:25]=[C:24]4[C:20]([CH2:21][CH2:22][CH2:23]4)=[CH:19][C:17]=3[N+:18]=2[O-:28])[CH2:6]1
Reactant: COC1CN(CCCNc2nc3cc4c(cc3[n+]([O-])n2)CCC4)C1
Reactant: O=C(O)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Product: COC1CN(CCCNc2n[n+]([O-])c3cc4c(cc3[n+]2[O-])CCC4)C1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 29 %

Procedure:
H2O2 (70%, 2.0 mL, ca. 40 mmol) was added dropwise to a stirred solution of TFM (5.6 mL, 40 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 54 (1.3 g, 4.0 mmol) and TFA (1.5 mL, 20 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 20° C. for 26 h, diluted with dilute aqueous NH3 solution (80 mL) and extracted with DCM (4×125 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-15%) of MeOH/DCM, to give 1,4-dioxide 55 (400 mg, 30%) as a red solid: mp 150-152° C.; 1H NMR δ 8.12 (s, 1H, H-9), 8.10 (s, 1H, H-5), 8.06 (br s, 1H, NH), 4.18 (p, J=5.9 Hz, 1H, CHO), 3.91 (br s, 2H, CH2N), 3.64 (t, J=6.4 Hz, 2H, CH2N), 3.28 (s, 3H, OCH3), 2.98-3.13 (m, 6H, H-6, H-8, CH2N), 2.80 (t, J=6.3 Hz, 2H, CH2N), 2.20 (p, J=7.5 Hz, 2H, H-7), 1.82 (p, J=6.4 Hz, 2H, CH2); 13C NMR δ 155.7, 149.4, 145.7, 138.0, 129.7, 115.8, 111.6, 69.3, 61.4 (2), 57.3, 56.2, 40.4, 33.4, 32.4, 26.0, 25.6; MS (APCI) m/z 346 (MH+, 100%); HRMS (FAB+) calcd for C17H24N5O3 (MH+) m/z 346.1879, found 346.1878.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([C@@H:10]3[CH2:12][C@H:11]3[NH:13][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=4)[CH2:17][CH2:16]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C@@H:10]3[CH2:12][C@H:11]3[NH:13][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=4)[CH2:17][CH2:16]3)=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccc(C4CC4)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccc(C4CC4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 40.3 %

Procedure:
To a solution of methyl 4-((4-(((trans-2-(4-cyclopropylphenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoate (118 mg, 0.282 mmol) in methanol (3 mL) was added sodium hydroxide (1M, 2 mL, 2 mmol), and the mixture was stirred at room temperature for 6 h. The mixture was purified using reverse-phase HPLC. The fractions containing the product were combined, treated with 1N HCl and concentrated. The residue was dried under vacuum to give 46 mg of product (HCl salt) as white solid. MS: (M+H)+=405.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.54-0.72 (m, 2H), 0.84-1.01 (m, 2H), 1.15-1.29 (m, 1H), 1.51-1.71 (m, 3H), 1.82-2.12 (m, 4H), 2.96 (br. s., 4H), 3.12 (br. s., 1H), 4.33 (br. s., 2H), 6.94-7.14 (m, 4H), 7.74 (d, J=8.08 Hz, 2H), 8.01 (d, J=8.34 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([CH3:21])[CH3:20])[CH:13]=2)[C:10](=[O:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[H-].[Na+].[Br:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>CN(C=O)C>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([NH:1][C:2]2[N:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([CH3:20])[CH3:21])[CH:13]=3)[C:10](=[O:22])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[O:34])=[CH:28][CH:27]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: CC(C)Oc1cccc(-n2c(N)nc3ccccc3c2=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc(-n2c(NC(=O)Nc3ccc(Br)cc3)nc3ccccc3c2=O)c1
Reaction time: 0.5 h
Yield: 14.2 %

Procedure:
To a solution of 2-amino-3-(3-isopropoxy-phenyl)-3H-quinazolin-4-one (295 mg, 1.0 mmol) in anhydrous DMF (10 mL) was added 50% NaH (48 mg, 1 mmol) at room temperature and stirred for 30 minutes. To this mixture was added, 4-bromo phenyl isocyanate and stirred for 2 hours at room temperature. The reaction mixture was quenched with water and concentrated. It was then diluted with ethyl acetate and filtered. The filtrate was concentrated and chromatographed using 100% CH3Cl to isolate pure product as a white solid (70 mg, 14.2%), mp 230°-233° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([SH:10])=[CH:5][C:3]=1[NH2:4].[C:11](=O)([O-])[O-].[K+].[K+].IC>O>[F:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10][CH3:11])=[CH:5][C:3]=1[NH2:4]
Reactant: Cc1cc(F)c(N)cc1S
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: CSc1cc(N)c(F)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
9.2 g of 2-fluoro-4-methyl-5-mercaptoaniline disclosed in WO2006/043635 was dissolved in 70 mL of water, and 9.7 g of potassium carbonate and 8.3 g of iodomethane were added under cooling with ice, followed by stirring at room temperature for 2 hours. The formed crystals were collected by filtration and washed with water to obtain 10.0 g of 2-fluoro-4-methyl-5-methylthioaniline.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=1.[CH:17]1[C:22]([OH:23])=[CH:21][CH:20]=[C:19]([Br:24])[CH:18]=1>>[CH2:11]([O:10][C:8](=[O:9])[CH2:7][N:6]1[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[N:3]=[C:2]1[O:23][C:22]1[CH:21]=[CH:20][C:19]([Br:24])=[CH:18][CH:17]=1)[CH3:12]
Reactant: Oc1ccc(Br)cc1
Reactant: CCOC(=O)Cn1c(Cl)nc2ccccc21
Product: CCOC(=O)Cn1c(Oc2ccc(Br)cc2)nc2ccccc21
Temperature: 120 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
To a mixture of ethyl 2-(2-chloro-1H-benzo[d]imidazol-1-yl)acetate (11.0 g) and p-bromophenol (23.9 g) was added TEA (19.2 mL) at room temperature. After stirring overnight at 120° C., the reaction mixture was quenched with water and extracted with AcOEt. The organic layer was separated, washed with 1 M NaOH aqueous solution and brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane) and recrystallized from AcOEt/hexane to give the title compound (11.0 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:16]#[N:17].[Na+].O>CS(C)=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:16]#[N:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: BrCC1CCCCN1Cc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCC1CCCCN1Cc1ccccc1
Temperature: 85 °C
Reaction time: 18 h

Procedure:
(RS)-1-Benzyl-2-bromomethylpiperidine, D31 (4.2 g) was dissolved in dry dimethylsulphoxide (15 ml) and treated with sodium cyanide (5.0 g). The solution was then stirred at 85° C. under argon for 18 h. The reaction solution was then poured into water (300 ml) and extracted with dichloromethane (2×200 ml). The organic solution was dried (MgSO4) and the solvent removed in vacuo. Chromatography (silica gel, diethyl ether/petroleum ether mixtures) afforded the title compound (3.3 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[CH2:16]([O:23][C:24](=[O:56])[NH:25][C:26]1[N:55]=[C:29]2[N:30]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=3)[C:31]([CH3:44])=[C:32]([C:42]#[N:43])[C@@H:33]([C:34]3[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=3)[N:28]2[N:27]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([O:23][C:24]([N:25]([C:26]1[N:55]=[C:29]2[N:30]([C:45]3[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:52])[F:53])[CH:46]=3)[C:31]([CH3:44])=[C:32]([C:42]#[N:43])[C@@H:33]([C:34]3[CH:35]=[CH:36][C:37]([C:40]#[N:41])=[CH:38][CH:39]=3)[N:28]2[N:27]=1)[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:56])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N(CC(=O)OC(C)(C)C)C(=O)OCc3ccccc3)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Potassium carbonate (8.0 mg, 58 μmol, 1.6 eq.) and tert-butyl bromoacetate (11.2 mg, 58 μmol, 1.6 eq.) were added to a solution of benzyl{(7R)-6-cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}carbamate (20 mg, 36 μmol) in dry DMF (5 ml). The reaction mixture was stirred at RT for 12 h and then concentrated under reduced pressure, and the residue purified by preparative HPLC (Kromasil C18 column, 5 μm, 50×20 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (25 mg, 76% of theory).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][O:12][C:11](=[O:15])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.O.[NH2:19][NH2:20]>C(O)C>[OH:12][CH2:13][CH2:14][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:4]=1)[CH2:10][C:11]([NH:19][NH2:20])=[O:15]
Reactant: NN
Reactant: O=C1CC(c2cccc(C(F)(F)F)c2)CCO1
Solvent: CCO
Solvent: O
Product: NNC(=O)CC(CCO)c1cccc(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
4-(3-Trifluoromethylphenyl)tetrahydropyran-2-one (2.5 g) was dissolved in ethanol (10 mL), and hydrazine monohydrate (4.96 mL) was added at room temperature. The mixture was stirred at 80° C. for 4.5 hours and then concentrated under reduced pressure. The resulting oil was partitioned with methylene chloride and water. The aqueous layer was extracted with methylene chloride five times. After drying over magnesium sulfate, concentration under reduced pressure and purification by silica gel column chromatography (amino silica gel, mobile phase:ethyl acetate/heptane=0 to 50%→methanol/ethyl acetate=10%) gave the title compound (1.55 g).
Reaction SMILES: C[N:2]([CH3:19])/[CH:3]=[C:4](/[C:10](=[O:18])[C:11]1[C:16](Cl)=[CH:15][CH:14]=[CH:13][N:12]=1)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1CN.O>CC(N(C)C)=O>[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:19][N:2]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[C:10](=[O:18])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:3]1
Reactant: NCc1ccccc1Br
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1ncccc1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)c1cn(Cc2ccccc2Br)c2cccnc2c1=O
Temperature: 74 °C
Reaction time: 15 h
Yield: 49.2 %

Procedure:
To a brown solution of (Z)-ethyl 2-(3-chloropicolinoyl)-3-(dimethylamino)acrylate (35) (850 mg, 3.01 mmol) in DMA (dimethylacetamide) (50 mL) were added a solid powder of tribasic potassium phosphate (1.4 g, 6.61 mmol) and then (2-bromophenyl)methanamine (615 mg, 3.31 mmol) at room temperature under a nitrogen atmosphere. The resulting brown suspension was heated to 74° C. and stirred for 15 h at which time LCMS analysis indicated the absence of starting material. Then, it was cooled to room temperature and poured slowly into water (100 mL). Then, the organic compound was extracted into dichloromethane (2×200 mL). The combined extracts were washed with water, brine solution, and dried over anhydrous MgSO4. Filtration and concentration gave a crude brown oil which was purified using an ISCO (120 g) column, eluting with ethyl acetate in hexanes (0 to 100%) and then 5 to 10% methanol in dichloromethane. The pure fractions were combined and the solvent was removed under vacuum to obtain ethyl 1-(2-bromobenzyl)-4-oxo-1,4-dihydro-1,5-naphthyridine-3-carboxylate (36) (574 mg, 46.8% yield) as a light brown solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.I[C:12]1[CH:13]=[C:14]([CH3:19])[CH:15]=[C:16]([CH3:18])[CH:17]=1>>[CH3:19][C:14]1[CH:13]=[C:12]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[CH:17]=[C:16]([CH3:18])[CH:15]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: Cc1cc2ccccc2[nH]1
Product: Cc1cc(C)cc(-n2c(C)cc3ccccc32)c1
Yield: 94.8 %

Procedure:
Using general procedure A, 2-methylindole (165 mg, 1.26 mmol)) was coupled with 5-iodo-m-xylene (150 μL, 1.04 mmol). The crude product was purified by flash chromatography on silica gel (2×15 cm; hexane-ether 40:1; 15 mL fractions). Fractions 4-9 provided 232 mg (95% yield) of the product as a colorless oil. 1H NMR (300 MHz, CDCl3): δ 7.62−7.53 (m, 1H), 7.15−7.05 (m, 4H), 6.98 (s, 2H), 6.39 (s, 1H), 2.41 (s, 6H), 2.31 (d, J=1.0 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][N:12]1[C:21]2[C:16](=[CH:17][C:18]([Cl:23])=[C:19]([Cl:22])[CH:20]=2)[N:15]=[CH:14][C:13]1=[O:24])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:25]O.O>C(O)(=O)C>[C:2]1([CH2:1][O:8][C:9]([CH2:11][N:12]2[C:21]3[C:16](=[CH:17][C:18]([Cl:23])=[C:19]([Cl:22])[CH:20]=3)[NH:15][C:14](=[O:25])[C:13]2=[O:24])=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OO
Reactant: O=C(Cn1c(=O)cnc2cc(Cl)c(Cl)cc21)OCc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: O=C(Cn1c(=O)c(=O)[nH]c2cc(Cl)c(Cl)cc21)OCc1ccccc1

Procedure:
The above ester (12.0 g, 33 mmol) was reacted with 30% H2O2 (50 ml) in glacial acetic acid (350 ml) at 55° C. for 24 h. The mixture was cooled and 600 ml of icecold water was added. The precipitate was filtered off and recrystallized from DMF-water to afford 7.16 g of the title compound. M.p. 286°-289° C. 1H-NMR(DMSO-d6):δ5.08(s, 2H), 5.22(s, 2H), 7.28-7.45(m, 6H), 7.75(s, 1H), 12.35(s, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][NH2+:19][CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.C1COCC1.C([O-])(O)=O.[Na+].[CH:33]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1>O>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:38]([CH:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[O:39])[CH2:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCC[NH2+]C3)c21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCN(C(=O)C4CCCC4)C3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.1 %

Procedure:
To a solution of (S)-3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidinium hydrochloride (Example 2a, 528 mg, 1.52 mmol) in H2O:THF (20 mL, 2:1), was added NaHCO3 (640 mg, 7.60 mmol). Upon complete dissolution of the NaHCO3, cyclopentanecarbonyl chloride (945 uL, 7.60 mmol) was added dropwise. The reaction was stirred at room temperature overnight. The precipitate was collected by vacuum filtration and purified by preparative HPLC (10-90% acetonitrile in water). The pure fractions were combined, concentrated then dissolved in a solution of NaHCO3 (250 mg in 10 mL water). After complete dissolution, the mixture was cooled in an ice bath and neutralized with 1N HCl. The resulting white solid was collected by vacuum filtration to provide the desired product (322 mg, 52%) as a white solid. 1H NMR (DMSO-d6, 400 MHz, 80° C.): 1.43 (m, 2H), 1.51-1.80 (m, 10H), 1.90 (m, 1H), 2.09 (m, 1H), 2.96 (m, 2H), 4.01 (br m, 2H), 4.12 (d, J=6.4 Hz, 2H), 6.67 (d, J=7.8 Hz, 1H), 6.77 (d, J=8.3 Hz, 1H), 7.46 (t, J=8.3 Hz, 1H), 7.92 (br s, 2H), 10.70 (br s, 1H). MS=407 (MH+).