Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH3:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].[F:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([C:34]4[CH:33]=[CH:32][C:31]([F:30])=[CH:36][C:35]=4[F:37])=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH3:29])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(-c3ccc(F)cc3F)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Temperature: 80 °C
Yield: 84.3 %

Procedure:
Argon was bubbled through a mixture of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (30 mg, 0.0606 mmol, example 58), 2.4-difluorophenylboronic acid (11 mg, 0.0727 mmol) and Na2CO3 (17 mg, 0.1635 mmol) in DMF (1.5 ml) and water (81.8 ul) for 15 min. Then [1,1′-bis(diphenyl-phosphino)ferrocene]palladium(II) chloride 1:1 complex with DCM (5 mg, 0.00606 mmol) was added and the orange mixture was heated to 80° C. for 3 h. The mixture was then cooled to room temperature, poured onto a mixture of saturated NaHCO3 solution and ice and extracted 3 times with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and evaporated. The remaining brown solid was purified by silica gel chromatography (DCM/MeOH 98:2) to obtain the title compound (27 mg, 84%) as off-white solid. MS (EI): 529.2 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2([CH:18]3[CH2:20][CH2:19]3)[C:9]3[CH:10]=[C:11](B(O)O)[CH:12]=[CH:13][C:8]=3[NH:7][C:6](=[O:17])[O:5]2)[CH2:3][CH2:2]1.[Br:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[C:24](Br)[CH:23]=1>>[Br:21][C:22]1[CH:23]=[C:24]([C:11]2[CH:12]=[CH:13][C:8]3[NH:7][C:6](=[O:17])[O:5][C:4]([CH:18]4[CH2:20][CH2:19]4)([CH:1]4[CH2:3][CH2:2]4)[C:9]=3[CH:10]=2)[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: O=C1Nc2ccc(B(O)O)cc2C(C2CC2)(C2CC2)O1
Reactant: Fc1cc(Br)cc(Br)c1
Product: O=C1Nc2ccc(-c3cc(F)cc(Br)c3)cc2C(C2CC2)(C2CC2)O1

Procedure:
Prepared according to Procedure B from (4,4-dicyclopropyl-1,4-dihydro-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 1,3-dibromo-5-fluorobenzene. A white solid: mp 228-229° C.; 1H-NMR (DMSO-d6) δ10.3 (s, 1H), 7.76-7.72 (m, 2H), 7.65 (dd, 1H, J=8.32, 1.74 Hz), 7.60 (d, 1H, J=10.36 Hz), 7.51 (d, 1H, J=8.3 Hz), 6.93 (d, 1H, J=8.31 Hz), 1.63-1.54 (m, 2H), 0.58-0.41 (m, 6H), 0.30-0.28 (m, 2H); MS (APCI) m/z 402/404 ([M−H]−, 100%); Anal. Calc. For C20H17BrFNO2: C, 58.48; H, 4.17; N, 3.41. Found: C, 58.77; H, 4.23; N, 3.32.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@H:13]([C:14]([O:16]CC)=[O:15])[C@@H:12]([C:19]3[CH:27]=[CH:26][C:22]4[O:23][CH2:24][O:25][C:21]=4[CH:20]=3)[CH2:11][N:10]2[CH2:28][C:29]([N:31]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:32][CH2:33][CH2:34][CH2:35]Br)=[O:30])=[CH:5][CH:4]=1.[CH3:41][NH:42][CH3:43]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@H:13]([C:14]([OH:16])=[O:15])[C@@H:12]([C:19]3[CH:27]=[CH:26][C:22]4[O:23][CH2:24][O:25][C:21]=4[CH:20]=3)[CH2:11][N:10]2[CH2:28][C:29]([N:31]([CH2:37][CH2:38][CH2:39][CH3:40])[CH2:32][CH2:33][CH2:34][CH2:35][N:42]([CH3:43])[CH3:41])=[O:30])=[CH:5][CH:4]=1
Reactant: CCCCN(CCCCBr)C(=O)CN1C[C@H](c2ccc3c(c2)OCO3)[C@@H](C(=O)OCC)[C@H]1c1ccc(OC)cc1
Reactant: CNC
Solvent: CCO
Product: CCCCN(CCCCN(C)C)C(=O)CN1C[C@H](c2ccc3c(c2)OCO3)[C@@H](C(=O)O)[C@H]1c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of the compound of Example 547D (0.825 g, 1.34 mmol) in 3 mL of ethanol was added 5 mL of 4.07 M dimethylamine in ethanol; the resultant solution was heated at reflux for 75 min. Solvents were removed in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 9:1 dichloromethane/methanol. The resultant material was taken up in 5 mL of 1.4N NaOH in 5:1 ethanol/water and stirred at ambient temperature for 14 hrs. Solvents were removed in vacuo; the residue was taken up in water, then adjusted to pH 6-7 with 1M HCl (˜7 mL required). The mixture was extracted with EtOAc (3×); the aqueous layer was concentrated in vacuo. The residue was washed 3× with acetonitrile; the combined washes were filtered through Celite and concentrated to give 596 mg of a white foam.
Reaction SMILES: COC([N:5]1[C:9]2=[N:10][C:11]([Cl:15])=[CH:12][C:13](Cl)=[C:8]2[C:7]([CH3:16])=[CH:6]1)=O.C(=O)([O-])[O-].[K+].[K+].[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([F:31])[CH:25]=1.C(OCC)(=O)C>CS(C)=O>[Cl:15][C:11]1[N:10]=[C:9]2[NH:5][CH:6]=[C:7]([CH3:16])[C:8]2=[C:13]([O:30][C:27]2[CH:28]=[CH:29][C:24]([NH2:23])=[CH:25][C:26]=2[F:31])[CH:12]=1
Reactant: COC(=O)n1cc(C)c2c(Cl)cc(Cl)nc21
Reactant: Nc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1c[nH]c2nc(Cl)cc(Oc3ccc(N)cc3F)c12
Temperature: 120 °C

Procedure:
300 mg (1.16 mmol) of methyl-4,6-dichloro-3-methyl-1H-pyrrolo[2,3-b]pyridine-1-carboxylate and 320 mg (2.32 mmol) of powdered potassium carbonate are suspended in 9 ml of DMSO. The mixture is degassed, and 442 mg (3.48 mmol) of 4-amino-2-fluorophenol are added. The mixture is heated at 120° C. for 4 hours. After addition of ethyl acetate, the mixture is filtered off with suction through Celite®, and the celite is washed with ethyl acetate. The filtrate is shaken three times with saturated sodium bicarbonate solution and with saturated sodium chloride solution. The filtrate is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by column chromatography (silica gel 60, mobile phase: dichloromethane/methanol=50:1).
Reaction SMILES: [CH3:1]/[CH:2]=[C:3]1\[C@H:4]([CH2:25][C:26]([O:28][CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([OH:38])=[C:35]([OH:37])[CH:36]=2)=[O:27])[C:5]([C:21]([O:23][CH3:24])=[O:22])=[CH:6][O:7][C@H:8]\1[O:9][C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O.[C:39]([O-])(=[O:41])C.[Na+]>>[CH:32]1[C:31]([CH2:30][CH2:29][CH2:39][OH:41])=[CH:36][C:35]([OH:37])=[C:34]([OH:38])[CH:33]=1.[CH3:1]/[CH:2]=[C:3]1\[C@H:4]([CH2:25][C:26]([O:28][CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([OH:38])=[C:35]([OH:37])[CH:36]=2)=[O:27])[C:5]([C:21]([O:23][CH3:24])=[O:22])=[CH:6][O:7][C@H:8]\1[OH:9]
Reactant: CC(=O)[O-]
Reactant: C/C=C1/[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)OC=C(C(=O)OC)[C@H]1CC(=O)OCCc1ccc(O)c(O)c1
Agent: [Na+]
Product: C/C=C1/[C@H](O)OC=C(C(=O)OC)[C@H]1CC(=O)OCCc1ccc(O)c(O)c1
Product: OCCCc1ccc(O)c(O)c1

Procedure:
Hydroxytyrosol was prepared from homogeneous oleuropein isolated from OLE. The procedure involves treatment of oleuropein with β-glycosidase (including but not limited to Sigma G4511) in 80 mM sodium acetate pH 5.0 using 1 Unit of enzyme/μ mole of substrate at 37° C. for 1 hr to remove the glucose moiety and to yield oleuropein aglycone. The oleuropein aglycone was then be treated with esterase (including but not limited to Sigma E0887) in sodium phosphate buffer at pH 7.5 using 1 Unit of enzyme/μ mole of substrate at 25° C. for 1 hr to yield hydroxytyrosol and elonelic acid. The final products were resolved and quantitated by LC-MS as described above. Detection and quantification were performed at 280 and 320 nm for hydroxytyrosol at 0.698 min (m/z 153) and oleuropein aglycone at 2.087 min (m/z 377). while 240 nm was used for the detection of elenolic acid at 1.846 min (m/z 241).
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[C:14]2[CH:15]=[C:16]([C:19](Cl)=[O:20])[CH:17]=[CH:18][C:13]=2[N:12]=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:10]1.[CH:28]1[N:29]=[CH:30][N:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=12.[CH3:37][OH:38]>C(#N)C.CN(C)C1C=CN=CC=1.CN(C)C=O>[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:30]2[N:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]3=[CH:28][N:29]=2)=[O:20])=[CH:15][C:14]=1[C:9]([O:38][CH3:37])=[O:8])(=[O:10])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CO
Reactant: O=C(Cl)c1ccc2nc(-c3ccccc3)oc(=O)c2c1
Reactant: c1ccn2cncc2c1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C(=O)c2ncc3ccccn23)ccc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
5.2 ml (0.037 mol) of triethylamine and then, under nitrogen atmosphere at 0° C., 10 g (0.035 mol) of 4-oxo-2-phenyl-4H-3,1-benzoxazine-6-carbonyl chloride are added to 1.97 g (0.017 mol) of imidazo[1,5-a]pyridine [described in J. Chem. Soc., (1955), 2834-2836] in 100 ml of acetonitrile. After stirring at ambient temperature for 22 hours, the reaction medium is filtered. The residue obtained is washed with ethyl acetate, with water and with acetone and then dried. 0.32 g (2.65 mmol) of N,N-dimethylpyridine-4-amine is added to 9.75 g (0.026 mol) of the yellow solid obtained above in 50 ml of methanol and 50 ml of N,N-dimethylformamide. After heating at reflux for 22 hours, the reaction medium is filtered. The residue is washed with water and then dried. The product is purified by column chromatography on silica gel, elution being carried out with a mixture of dichloromethane and methanol (99.9/0.1). 3.67 g of a yellow solid are obtained. Melting point: 218° C.; 1H NMR (CDCl3): 4.05 (3H, s), 7.08-7.09 (1H, m), 7.27-7.29 (1H, m), 7.57-7.60 (3H, m), 7.76-7.81 (2H, m), 8.12 (2H, d), 8.78 (1H, d), 9.15 (1H, d), 9.28 (1H, s), 9.88 (1H, d)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:11]([N+:16]([O-:18])=[O:17])=[CH:12][C:13]=1[O:14][CH3:15])[CH:9]=[O:10].[OH-:19].[Na+].OO>CO>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:11]([N+:16]([O-:18])=[O:17])=[CH:12][C:13]=1[O:14][CH3:15])[C:9]([OH:19])=[O:10]
Reactant: COc1cc([N+](=O)[O-])c(C=O)cc1OCCCCl
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: COc1cc([N+](=O)[O-])c(C(=O)O)cc1OCCCCl
Yield: 86 %

Procedure:
Methanol (4 lt), 3-(3-chloropropoxy)-4-methoxy-6-nitro benzaldehyde (560 gm) and 30% methanolic NaOH solution (5 ml) were heated to 45° C. To this reaction mass 35% of H2O2 solution (1200 ml) was added drop wise in 3-4 hours maintaining a pH of 10.5-11.5 with 30% methanolic NaOH solution. The reaction mass was quenched into ice water (10 kg) and the pH adjusted to 2.0-3.0 using hydrochloric acid. The solid obtained was filtered, washed with 50% aqueous methanol (500 ml) and dried at 45-50° C. to yield the title compound (510 gm, 86% yield).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([OH:7])=[O:6].[CH2:12](O)[CH3:13]>Cl>[CH2:12]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([I:11])=[C:2]([OH:1])[CH:3]=1)[CH3:13]
Reactant: O=C(O)c1ccc(I)c(O)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc(I)c(O)c1
Yield: 97 %

Procedure:
Dissolve 3-hydroxy-4-iodobenzoic acid (2.02 g, 7.65 mmol) in ethanol saturated with HCl gas (50 ml). Heat the solution under reflux overnight. Evaporate ethanol to yield 3-Hydroxy-4-iodo-benzoic acid ethyl ester compound (97% yield).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][C:8]=2[O:18][CH3:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C.O1CCOCC1>[CH:1]1([O:6][C:7]2[CH:17]=[CH:16][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[O:18][CH3:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)c1ccc(OC2CCCC2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1OC1CCCC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
A mixture of ethyl 4-cyclopentyloxy-3-methoxybenzoate (1.06 g) and 4N aqueous sodium hydroxide (4 ml) in ethanol (8 ml) and 1,4-dioxane (8 ml) was stirred at 80° C. for 3 hours. Then the mixture was poured into dilute hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with dilute hydrochloric acid and brine, dried over magnesium sulfate and concentrated. The resultant solid was collected and washed with isopropyl ether to give 4-cyclopentyloxy-3-methoxybenzoic acid (730 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[CH:8]([CH3:12])[C:9]([OH:11])=[O:10].[F:18]C(C)(C(OCC)=O)C(OCC)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([F:17])[CH:16]=1)[CH2:5][NH:6][C:7](=[O:13])[C:8]([F:18])([CH3:12])[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C(C)(F)C(=O)OCC
Reactant: CC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1
Product: CC(F)(C(=O)O)C(=O)NCc1cc(F)cc(F)c1

Procedure:
N-(3,5-Difluoro-benzyl)-2-fluoro-2-methyl-malonamic acid was prepared in analogy to N-(3,5-difluoro-benzyl)-2-methyl-malonamic acid (example 1) from diethyl 2-fluoro-2-methyl-malonate.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[H-].[Na+].C([O:14][C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1)C.Cl>C1COCC1.C(OCC)(=O)C.O>[N:18]1[CH:19]=[CH:20][CH:21]=[C:16]([C:15]([CH:7]2[CH2:8][C:2]3[S:1][CH:5]=[CH:4][C:3]=3[C:6]2=[O:9])=[O:14])[CH:17]=1
Reactant: CCOC(=O)c1cccnc1
Reactant: O=C1CCc2sccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(c1cccnc1)C1Cc2sccc2C1=O
Temperature: 100 °C
Yield: 35 %

Procedure:
5,6-Dihydro-cyclopenta[b]thiophen-4-one (3.34 g, 24.2 mmol) in 40 mL of THF was treated with NaH (60 percent, 1.45 g, 36.25 mmol). After the addition of Nicotinic acid ethyl ester, the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was added with ethyl acetate (80 mL). The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(Pyridine-3-carbonyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.23 g, 5 mmol) as red solid in 35% yield.
Reaction SMILES: [C:1]([C:4]1[NH:8][C:7]2[C:9]([Cl:13])=[C:10]([Cl:12])[S:11][C:6]=2[CH:5]=1)([OH:3])=O.[NH2:14][C@@H:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@H:16]1[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:12][C:10]1[S:11][C:6]2[CH:5]=[C:4]([C:1](=[O:3])[NH:14][C@@H:15]3[CH2:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C@H:16]3[NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[NH:8][C:7]=2[C:9]=1[Cl:13]
Reactant: O=C(O)c1cc2sc(Cl)c(Cl)c2[nH]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@H]1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 79.3 %

Procedure:
5-Carboxy-2,3-dichloro-4H-thieno[3,2-b]pyrrole (Method 4; 2.36 g, 10.0 mmol), trans-2-amino-1-{N-[(1,1-dimethylethoxy)]carbonylamino}indan (Method 6; 2.5 g, 10.0 mmol), DIPEA (1.7 ml, 10.0 mmol) and HOBT (1.35 g, 10.0 mmol) was stirred in DCM (75 ml) at room temperature for 2 minutes. EDCI (2.4 g, 12.5 mmol) was added and the mixture stirred at room temperature for 20 hours during which time the product precipitated. The reaction was filtered, washed with DCM (2×25 ml) and dried to give the title compound (3.7 g, 80%) as a pale green powder.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[F:23][C:24]([F:41])([F:40])[C:25]1[CH:39]=[CH:38][C:28]([CH2:29][O:30][C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1>>[CH3:11][N:8]1[C:9]2[CH:10]=[C:2]([N:34]3[CH:35]=[CH:36][C:31]([O:30][CH2:29][C:28]4[CH:38]=[CH:39][C:25]([C:24]([F:40])([F:41])[F:23])=[CH:26][CH:27]=4)=[CH:32][C:33]3=[O:37])[CH:3]=[CH:4][C:5]=2[C:6]2[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13][CH2:12][C:7]1=2
Reactant: O=c1cc(OCc2ccc(C(F)(F)F)cc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(C(F)(F)F)cc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Yield: 25.1 %

Procedure:
The compound was prepared from tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (250 mg, 0.701 mmol) and 4-(4-(trifluoromethyl)benzyloxy)pyridin-2(1H)-one (142 mg, 0.526 mmol) according to the procedure in Example 1 (step c). Purification by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 80:20 to 50:50 to 25:75 then 0:100) provided the title compound (73 mg, 19%) as a solid, that contained an impurity: ESI MS m/z 554 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:16]3[CH:17]=[C:18]([C:21]([NH2:23])=O)[S:19][CH:20]=3)=[CH:9][N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:6]=2[CH:5]=[CH:4][NH:3]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>CC(N(C)C)=O.O>[O:1]=[C:2]1[C:7]2[C:8]([C:16]3[CH:17]=[C:18]([C:21]#[N:23])[S:19][CH:20]=3)=[CH:9][N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:6]=2[CH:5]=[CH:4][NH:3]1
Reactant: CCC(CC)n1cc(-c2csc(C(N)=O)c2)c2c(=O)[nH]ccc21
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCC(CC)n1cc(-c2csc(C#N)c2)c2c(=O)[nH]ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a solution of 4-(4-oxo-1-(pentan-3-yl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)thiophene-2-carboxamide (13.0 mg) obtained in Example 8 in DMA (2 mL) was slowly added dropwise trifluoroacetic anhydride (8.36 μL) under nitrogen atmosphere at 0° C., and the mixture was allowed to be warmed to room temperature, and stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate) to give the title compound (9.2 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39].C[N:41]([CH:49]1CCNC[CH2:50]1)[C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45].C([N:58]([CH2:62][CH3:63])[CH:59]([CH3:61])C)(C)C>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:58]3[CH2:59][CH2:61][CH:50]([CH2:49][NH:41][C:42](=[O:48])[O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:63][CH2:62]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[O:23])[CH:32]=[CH:33][C:34]=3[CH3:35])[C:13]=2[CH2:12][NH:11][C:10]1=[O:39]
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(N2CCC(CNC(=O)OC(C)(C)C)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 23.4 %

Procedure:
To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (40 mg, 0.073 mmol) in THF (3 mL) and DMF (0.5 mL) were added 1,1-dimethylethyl methyl(4-piperidinyl)carbamate (49 mg, 0.229 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.574 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. Flash chromatography (mobile phase DCM/DCM [90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (12 mg, 25%). LC-MS m/z 702 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:21])[NH:12][C:13]1[S:14][CH:15]=[C:16]([S:18]([CH3:20])=[O:19])[N:17]=1)(=O)C.Cl>C1COCC1>[OH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:12][C:13]1[S:14][CH:15]=[C:16]([S:18]([CH3:20])=[O:19])[N:17]=1)=[O:21]
Reactant: CC(=O)Oc1ccccc1C(=O)Nc1nc(S(C)=O)cs1
Agent: Cl
Solvent: C1CCOC1
Product: CS(=O)c1csc(NC(=O)c2ccccc2O)n1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
Into a solution of 1 (0.150 g, 0.425 mmol) and THF (11 mL) was added 2M HCl (16 mL). The reaction was warmed to reflux. After refluxing 2 h, the reaction was allowed to cool to room temperature. A solid formed on standing. The reaction was cooled in an ice bath. The cold suspension was filtered. The filter pad was washed with water. The filtrate was concentrated in vacuo. The residue was suspended in water and filtered and combined with the original filter pad. The combined solids were stirred with a mixture of warm methanol and THF, adding more THF until the mixture became homogeneous. The homogeneous solution was concentrated in vacuo. The white residue was suspended in methanol and concentrated in vacuo four more times. The white residue was stirred with ether, filtered and the filter pad dried under a stream of nitrogen to give to give 2 (0.095 g, 79%) as a white solid: mp=240° C. (dec., begins turning dark then melts 260-261° C.). HPLC tR=5.33 min (100%, Condition C). 1H NMR (400 MHz, DMSO-d6) δ 12.18 (br. s., 1H), 11.69 (br. s., 1H), 7.98 (dd, J=2, 8 Hz, 1H), 7.81 (s, 1H), 7.46-7.54 (m, 1H), 6.97-7.10 (m, 2H), 2.86 (s, 3H). MS (ESI+) m/z 305.1 (M+Na)+, 283.1 (M+H)+, MS (ESI−)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[F:34])=[C:20]([C:35]([F:38])([F:37])[F:36])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:40]>C(O)C>[ClH:40].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])=[C:20]([C:35]([F:38])([F:36])[F:37])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3ccccc3F)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2ccccc2F)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
Compound 22-3 (740 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (540 mg) as a white powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:6]([C:16]([F:19])([F:18])[F:17])[CH:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][C:6]=1[C:16]([F:17])([F:18])[F:19])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: [H][H]
Reactant: CCCCCOc1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: CCCCCOc1ccc(N)cc1C(F)(F)F
Yield: 101.1 %

Procedure:
A solution of 4-Nitro-1-pentyloxy-2-trifluoromethyl-benzene (1.2 g, 4.8 mmole) and 0.1 g of 10% Palladium on activated carbon in 40 mL of ethanol is hydrogenated with hydrogen balloon at room temperature overnight. Filtration and concentration gave a pink oil 1.2 g (100%) of 4-Pentyloxy-3-trifluoromethyl-phenylamine MS: 248 (M+1).