Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:9]=2[C:10]([NH:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][C:19](=[O:27])[N:20]3[CH2:23][C:24](O)=[O:25])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:36][NH2:37].C1COCC1.Cl>CO>[CH:1]1([NH:7][C:8]2[CH:31]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:29]=[CH:28][C:9]=2[C:10]([NH:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][C:19](=[O:27])[N:20]3[CH2:23][C:24]([NH:37][CH3:36])=[O:25])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN
Reactant: O=C(O)CN1C(=O)CCc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3NC3CCCCC3)cc21
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CNC(=O)CN1C(=O)CCc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3NC3CCCCC3)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of [7-{[2-(cyclohexylamino)-4-(trifluoromethyl)benzoyl]amino}-2-oxo-3,4-dihydroquinolin-1(2H)-yl]acetic acid (70 mg), N,N′-carbonyldiimidazole (70 mg), methylamine aqueous solution (1 mL) and THF was stirred at room temperature for 3 hours, mixed with methanol and stirred for 20 minutes. A 0.5 M hydrochloric acid was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol, 20:1 to 10:1) to obtain 2-(cyclohexylamino)-N-{1-[2-(methylamino)-2-oxoethyl]-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl}-4-(trifluoromethyl)benzamide (12 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1)=[O:8].Cl[CH2:27][O:28][C:29]([N:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:27][O:28][C:29]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[O:30])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:11]=1)=[O:8]
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1O
Reactant: O=C(OCCl)N1CCCCC1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Cl)ccc1OCOC(=O)N1CCCCC1
Yield: 86.2 %

Procedure:
Using 5-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide 1 sodium salt (compound of Example 43(1)) and 1-[(chloromethoxy)carbonyl]piperidine as the raw materials, the same operation as the Example 98 gave the title compound.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.CI.[Mg].[CH2:14]1[O:16][CH2:15]1>>[OH:16][CH2:15][CH2:14][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH:7]=[CH:8][C:4]=2[CH:3]=1
Reactant: C1CO1
Reactant: Brc1ccc2occc2c1
Agent: [Mg]
Solvent: CI
Product: OCCc1ccc2occc2c1

Procedure:
The subject compound is prepared by a Grignard reaction with the reagant prepared from 5-bromobenzo[b]furan, methyl iodide and magnesium turnings and ethylene oxide.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].C(#N)C.Cl.Cl.[NH:19]1[CH2:24][CH2:23][CH:22]([NH:25][C:26]([C:28]2[S:38][C:37]3[N:39]4[C:30](=[CH:31][N:32]=[C:33]4[CH:34]=[CH:35][CH:36]=3)[CH:29]=2)=[O:27])[CH2:21][CH2:20]1.[I-].[Na+]>C(N(CC)CC)C>[C:9]([C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:19]2[CH2:20][CH2:21][CH:22]([NH:25][C:26]([C:28]3[S:38][C:37]4[N:39]5[C:30](=[CH:31][N:32]=[C:33]5[CH:34]=[CH:35][CH:36]=4)[CH:29]=3)=[O:27])[CH2:23][CH2:24]2)[CH:13]=[CH:12][CH:11]=1)#[N:10]
Reactant: O=C(NC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Reactant: N#Cc1cccc(OCCCCl)c1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1cccc(OCCCN2CCC(NC(=O)C3=Cc4cnc5cccc(n45)S3)CC2)c1
Yield: 57.4 %

Procedure:
3-(3-Chloropropan-1-yl)oxybenzonitrile (503 mg) was added, at room temperature, to an acetonitrile solution (20 ml) of N-(piperidin-4-yl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride (800 mg), 1,8b-diazabicyclo[5.4.0]-7-undecene (662 mg), triethylamine (1.09 g) and sodium iodide (285 mg). The mixture was heated under reflux for 6.5 hours under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. To the concentrate was added water, which was subjected to extraction with chloroform. The extract solution was washed with a saturated aqueous saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate was purified by means of a silica gel chromatography (ethyl acetate/methanol=2/1) to afford the object compound (565 mg, 57%) as reddish purple crystals.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[Li+].[CH3:14][Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:4]([OH:5])[CH3:14])[N:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CON(C)C(=O)c1cccnn1
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)c1cccnn1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 123.1 %

Procedure:
To a solution of compound 2 (6.35 g, 21 mmol) in THF (20 mL) was added LiHMDS (1 M in THF, 22 mL, 22 mmol) via a syringe at −78° C. under a nitrogen atmosphere. After 1 h a solution of compound 2A (3.31 g, 20.66 mmol) in THF (32 mL) was added dropwise at −78° C. The mixture was stirred at −78° C. for 1.5 h then quenched by addition of a solution of sat. NH4Cl (50 mL), the resulting mixture was stirred overnight at room temperature, extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (2×50 mL), dried over sodium sulfate, concentrated in vacuo and the residue was purified by column chromatography on silica gel (petroleum ether:THF=40:1) to give compound 3 (3.21 g, 42%) as a light yellow solid.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)([OH:20])[CH3:19])[N:14]3[CH3:17])=[C:10]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[CH:36][C:5]=2[N:4]=1)[CH3:2].CCN(CC)CC.[CH:44]1([C:47](Cl)=[O:48])[CH2:46][CH2:45]1>C(Cl)Cl>[CH:44]1([C:47]([N:24]2[CH2:25][CH2:26][CH:21]([C:18]([C:13]3[N:14]([CH3:17])[C:15]4[C:11]([N:12]=3)=[C:10]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:9]=[C:8]([N:7]3[C:6]5[CH:33]=[CH:34][CH:35]=[CH:36][C:5]=5[N:4]=[C:3]3[CH2:1][CH3:2])[N:16]=4)([OH:20])[CH3:19])[CH2:22][CH2:23]2)=[O:48])[CH2:46][CH2:45]1
Reactant: O=C(Cl)C1CC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(C)(O)C3CCNCC3)n(C)c2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(C)(O)C3CCN(C(=O)C4CC4)CC3)n(C)c2n1
Reaction time: 0.25 h
Yield: 44 %

Procedure:
A solution of 1-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-yl]-1-piperidin-4-ylethanol and NEt3 (74 μL, 0.53 mmol) in DCM (5 mL) was cooled to −78° before the addition of cyclopropane carbonyl chloride (18 μL, 0.20 mmol). The resulting mixture was stirred for 15 min then quenched with H2O and extracted with DCM. The combined organics were dried (phase separator) and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 0.1% NH4OH in water on a gradient acetonitrile 10-70%) affording 865 as a white solid (44 mg, 44%). LCMS (method I): RT 3.51 min, [M+H]+ 559.4. 1H NMR (CDCl3, 400 MHz): δ 8.01-8.00 (1 H, m), 7.80 (1 H, d, J=7.13 Hz), 7.33-7.28 (2 H, m), 4.71 (1 H, brd s), 4.32 (4 H, brd s), 3.98 (3 H, s), 3.87 (4 H, t, J=4.69 Hz), 3.40 (2 H, q, J=7.47 Hz), 3.14-2.98 (1 H, m), 2.60-2.43 (1 H, m), 2.20-2.09 (1 H, m), 1.86-1.65 (6 H, m), 1.62-1.36 (3H, m), 1.47 (3 H, t, J=7.47 Hz), 1.00-0.93 (2 H, m), 0.75-0.74 (2 H, m)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[C:28]1([C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:37]1[CH:38]=[CH:39][C:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:35][CH:36]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1ccc(-c2ccccc2)cc1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 4-phenylphenylboronic acid (109 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-biphenyl-4-yl-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][CH2:18][CH3:19])[NH:5][C:6](=[O:9])[C:7]=1[NH2:8].C([O-])(=O)C.[K+].N[C:26](N)=[S:27]>>[CH2:17]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:4]1[N:3]=[C:2]2[C:7](=[N:8][C:26]([SH:27])=[N:1]2)[C:6](=[O:9])[N:5]=1)[CH2:18][CH3:19]
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [K+]
Product: CCCOc1ccccc1C1=NC(=O)C2=NC(S)=NC2=N1

Procedure:
A mixture of 4,5-diamino-2-(2-propoxyphenyl)pyrimidin-6-one (13 g), anhydrous potassium acetate (0.34 g) and thiourea (0.96 g) was heated at 170°-180° C. for 2 hours. After digestion with water the mixture was filtered and the solid was dissolved in I Normal sodium hydroxide solution then re-precipitated by the addition of acetic acid. The dried solid was digested with chloroform and with ethanol to leave l.12 g of a crude product. Repeated recrystallisations from dimethylformamide, 2-methoxyethanol, and acetic acid yielded the title compound, 0.32 g, m.p. 305°-307° C.
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]([NH:11][NH:12][C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[O:18][C:17]3[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:16]2=3)=[O:14])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:36].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[C:1]1([S:7]([CH2:8][C:9]([NH:11][NH:12][C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[O:18][C:17]3[CH:26]=[CH:27][C:28]([Cl:30])=[CH:29][C:16]2=3)=[O:14])=[O:10])=[O:36])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CSc1ccccc1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CS(=O)c1ccccc1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
To a stirred solution of 1.0 g (2.19 mmole) of the title product of Example 2 in 30 ml of cold (ca.0° ) dichloromethane was added 0.463 g (2.19 mmole) of 81% m-chloroperoxybenzoic acid. After about ninety minutes, 5 ml of saturated aqueous sodium thiosulfate was added. The mixture was washed sequentially with three portions of saturated aqueous sodium bicarbonate and three portions of water. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuo to give tht title compound.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].[CH3:25][O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)=[O:28].C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:32]3[CH:33]=[CH:34][C:29]([C:27]([O:26][CH3:25])=[O:28])=[CH:30][CH:31]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccc(C#N)cn2)C[C@H](C)N3C(C)=O)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a flask charged with 6-(((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (for a preparation see Intermediate 2) (1000 mg, 2.60 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (561 mg, 3.11 mmol), tetrakis(triphenylphosphine)palladium(0) (300 mg, 0.260 mmol) and potassium carbonate (1076 mg, 7.79 mmol) was added DME (20 mL) and water (4.0 mL). The resulting mixture was stirred at 100° C. under nitrogen for 1 h, then cooled to room temperature and concentrated in vacuo. The residue was partitioned between EtOAc and water and the layers were separated. The organic phase was dried (MgSO4), concentrated in vacuo and the residue was purified by chromatography (10 g column, MeOH/DCM gradient) to give methyl 4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (1002 mg, 2.275 mmol, 88% yield) as an orange foam. LCMS (HpH, 2 min), Rt=1.09 min, MH+=441.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([N+:11]([O-:13])=[O:12])=[CH:4][N:3]=1.Cl.[NH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(N(CC)CC)C>O1CCOCC1>[N+:8]([C:7]1[C:2]([NH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:3][CH:4]=[C:5]([N+:11]([O-:13])=[O:12])[CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)CCCN
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCCNc1ncc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A suspension of 3 g (14.74 mmol) of 2-chloro-3,5-dinitropyridine in dioxane is admixed with 3.46 g (17.69 mmol) of tert-butyl 4-aminobutanoate hydrochloride and then with 4.21 ml (22.11 mmol) of triethylamine. The reaction mixture is stirred at 60° C. for 3 hours.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]3)O1.[OH:26]OS([O-])=O.[K+]>CC(C)=O.O>[OH:26][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][C@H:13]([NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])[CH2:12]2
Reactant: O=S([O-])OO
Reactant: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2C1
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)S(=O)(=O)N[C@H]1Cc2ccc(O)cc2C1

Procedure:
To a stirred solution of (S)-N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (6.95 mmol, 2.54 g) in Acetone (20.00 mL), a solution of Oxone(R), monopersulfate compound (7.65 mmol, 4.70 g) in Water (20 mL) was added dropwise over 2 min. The resultant solution was stirred for a further 10 min before being quenched with NaHSO3 (aq). The solution was extracted with DCM (×3), dried (MgSO4), filtered and concentrated in vacuo to give the crude product as a pale yellow oil (2.42 g). On standing the reaction mixture solidified to a pale yellow solid in an oily residue. The solid was triturated with heptane then ether to give the title compound as an off white solid (1.66 g, 94%). MS (ESI): m/z [M−H]− 254.0
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.[CH3:20][C:21]1[C:22](=[O:27])[O:23][C:24](=O)[CH:25]=1.C(O)(=O)C>O>[CH3:20][C:21]1[C:22](=[O:27])[N:1]([C:2]2[CH:19]=[CH:18][CH:17]=[C:4]([CH2:5][C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9](=[O:16])[NH:8][N:7]=3)[CH:3]=2)[C:24](=[O:23])[CH:25]=1
Reactant: CC1=CC(=O)OC1=O
Reactant: Nc1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Solvent: O
Solvent: CC(=O)O
Product: CC1=CC(=O)N(c2cccc(Cc3n[nH]c(=O)c4ccccc34)c2)C1=O
Reaction time: 65 h

Procedure:
A stirred mixture of 4-(3-aminobenzyl)-2H-phthalazin-1-one (0.1 g, 0.4 mmol; prepared in a manner similar to that described in Example 1), 3-methylfuran-2,5-dione (0.045 g, 0.4 mmol) and acetic acid (4 ml) was heated under reflux for 8.25 hours and allowed to stand at ambient temperature for 65 hours, then it was diluted with water (10 ml). The resulting solid was collected by filtration, washed with water (10 ml) and dried in vacuo to give 3-methyl-1-[3-(4oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]pyrrole-2,5-dione (0.068 g) as an off-white solid, 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 1.95 (s, 3H) (CH3), 4.3 (s, 2H) (ArCH2—), 6.7 (s, 1H) (—COCH═CMeCO—), 7.15 (d, 1H) (ArH), 7.2 (s, 1H) (ArH), 7.25–7.35 (m, 2H) (2×ArH), 7.7–7.9 (m, 3H) (3×ArH), 8.2 (d, 1H) (ArH), 12.55 (s, 1H) (CONH); m/z (M+H)+. 346, 100% purity.
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:8]=1.Cl.[CH:22]1([C:25]2[CH:26]=[C:27]([CH3:37])[C:28]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)=[N:29][CH:30]=2)[CH2:24][CH2:23]1>>[CH:22]1([C:25]2[CH:26]=[C:27]([CH3:37])[C:28]([N:31]3[CH2:32][CH2:33][N:34]([C:11]([C:10]4[CH:14]=[CH:15][C:7]([N:3]5[CH2:4][CH2:5][CH2:6][S:2]5(=[O:1])=[O:20])=[CH:8][C:9]=4[S:16]([CH3:19])(=[O:18])=[O:17])=[O:13])[CH2:35][CH2:36]3)=[N:29][CH:30]=2)[CH2:24][CH2:23]1
Reactant: Cc1cc(C2CC2)cnc1N1CCNCC1
Reactant: CS(=O)(=O)c1cc(N2CCCS2(=O)=O)ccc1C(=O)O
Agent: Cl
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2S(C)(=O)=O)CC1
Yield: 81.8 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-methanesulfonylbenzoic acid (319 mg) described in Preparation Example 22 and 1-(5-cyclopropyl-3-methylpyridin-2-yl)piperazine hydrochloride (254 mg) described in Preparation Example 82 and by the reaction and treatment in the same manner as in Example 86, the title compound (424 mg) was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([OH:19])=O)=[N:15][CH:16]=2)[CH2:4][C:3]1([CH3:21])[CH3:20].ClC(OCC)=O.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:31][CH:30]=1>C(Cl)Cl.C1COCC1>[CH3:1][N:2]1[C:3]([CH3:20])([CH3:21])[CH2:4][CH:5]([O:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:33][CH:34]=3)=[O:19])=[N:15][CH:16]=2)[CH2:6][C:7]1([CH3:8])[CH3:9]
Reactant: CN1C(C)(C)CC(Oc2ccc(C(=O)O)nc2)CC1(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1C(C)(C)CC(Oc2ccc(C(=O)Nc3ccc(NC(=O)OC(C)(C)C)cc3)nc2)CC1(C)C
Temperature: 50 °C
Yield: 120.5 %

Procedure:
To a stirred solution of 5-(1,2,2,6,6-pentamethylpiperidin-4-yloxy)picolinic acid (250 mg, 0.86 mmol) in DCM/THF (6 mL, 2:1, v/v) at rt was added TEA (144 μL, 1.03 mmol) and ethyl chloroformate (82 μL, 0.86 mmol). The resulting mixture was stirred at rt for 20 min before tert-butyl 4-aminophenylcarbamate (178 mg, 0.86 mmol) was added. The resulting mixture was heated at 50° C. for 1 h. LC-MS indicated the reaction was complete. Solvents were then removed under reduced pressure and the residue was partitioned between EtOAc (30 mL) and brine (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to give crude tert-butyl 4-(5-(1,2,2,6,6-pentamethylpiperidin-4-yloxy)picolinamido)phenylcarbamate (500 mg) as an off-white foam. LC-MS (ESI) m/z 483 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:16]4=[O:23])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:24]=1.CI.[C:27](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:12]=[C:13]([N:15]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[N:17]([CH3:27])[C:16]4=[O:23])[S:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:24]=1
Reactant: CC1(C)C(=O)NC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2nc3c(s2)CCOc2cc(Br)ccc2-3)C(C)(C)C1=O
Temperature: 80 °C

Procedure:
A mixture of 204 mg (0.50 mmol) of 1-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2,4-dione, 0.0411 ml (0.66 mmol) of methyl iodide and 244 mg (0.750 mmol) of Cesium Carbonate in 5.0 ml of N,N-Dimethylformamide was heated at 80° C. for 2 hours. The mixture was filtered, the filtrate concentrated in high vacuum, the residue partitioned between ethyl acetate and water. The organic extracts were washed with water, brine, dried over MgSO4 and concentrated to give 1-(8-Bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-3,5,5-trimethylimidazolidin-2,4-dione. Weight 0.205 (97%). MS (ESI+): 421.9
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][CH3:8])[N:6]=1.[C:9]1([CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16](Cl)=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:7]([N:5]1[N:4]=[N:3][C:2]([NH:1][C:16](=[O:17])[CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:6]1)[CH3:8]
Reactant: CCn1nnc(N)n1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CCn1nnc(NC(=O)C(c2ccccc2)c2ccccc2)n1

Procedure:
The title compound, white solid, m.p. 169-170° and MS: (neg. ions): m/e=306.2 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-ethyl-2H-tetrazole and diphenylacetyl chloride.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[N:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][C:19]=2[CH3:26])=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH:29][C@@H:30]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31]1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[N:13][N:12]([CH2:15][C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:32]3[CH2:33][CH2:34][CH2:35][C@@H:30]([OH:29])[CH2:31]3)=[CH:20][C:19]=2[CH3:26])=[O:17])[C:11](=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@@H]1CCCNC1
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ncc(OCc2ccccc2)cc1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(CN2CCC[C@@H](O)C2)ccc1C(=O)Cn1ncc(OCc2ccccc2)cc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-benzyloxy-2-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-2H-pyridazin-3-one (preparation 5b, 100 mg, 0.23 mmol) in DMF (2 mL) is added (R)-3-hydroxypiperidine hydrochloride (96 mg, 0.70 mmol) and N-ethyldiisopropylamine (362 μL, 2.1 mmol). The reaction mixture is stirred overnight at room temperature. The mixture is purified via reverse phase HPLC chromatography (Waters Xbridge C18 5 μm, gradient 5%→90% acetonitrile in water+0.3% NH4OH, 120 mL/min).
Reaction SMILES: [C:1]([N:4]1[C:9]2[CH:10]=[CH:11][C:12]([NH:14][C:15](=[O:17])[CH3:16])=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N+:18]([O-])([OH:20])=[O:19]>C(OC(=O)C)(=O)C>[C:1]([N:4]1[C:9]2[CH:10]=[C:11]([N+:18]([O-:20])=[O:19])[C:12]([NH:14][C:15](=[O:17])[CH3:16])=[CH:13][C:8]=2[O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)OCCN2C(C)=O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])N(C(C)=O)CCO2
Reaction time: 0.5 h
Yield: 82 %

Procedure:
To a stirred solution of 5 (5.0 g) in acetic anhydrid (50 ml) in an ice bath was added slowly fuming nitric acid (5 ml). The mixture was stirred for 0.5 h and the yellow precipitate was filtered, washed with water three times and dried under reduced pressure to give 4.9 g (82%) of 6: mp 199°-202° C.; MS m/e 279 (M+).