Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][S:9][C:10]=1I)=[O:5])[CH3:2].C(N(CC)CC)C.[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20].Cl>CN(C=O)C.[Cl-].[Na+].O.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[CH3:22][Si:21]([CH3:24])([CH3:23])[C:19]#[C:20][C:10]1[S:9][CH:8]=[N:7][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1ncsc1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ncsc1C#C[Si](C)(C)C
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
4-Ethoxycarbonyl-5-iodothiazole (71.47 g) was dissolved in 250 ml of DMF. Triethylamine (70 ml), 53.4 ml of ethynyltrimethylsilane, 960 mg of copper(I) iodide, and 3.54 g of bis(triphenylphosphine) palladium(II) dichloride were added in that order, and the mixture was stirred at 60° C. under an argon atmosphere for 1.5 hr. The reaction solution was added to 1000 ml of ethyl acetate and 500 ml of brine. The mixture was adjusted to pH 3 by the addition of 1 N aqueous hydrochloric acid. The organic layer was separated and was washed with 500 ml of sodium bicarbonate water and 500 ml of brine in that order. The organic layer was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1 to 3:1) to give 53.66 g of 5-(2-trimethylsilylethynyl)-4-ethoxycarbonylthiazole. This product was dissolved in 250 ml of methanol, 3.1 of potassium carbonate was added to the solution under ice cooling, and the mixture was stirred at the same temperature for 45 min. The reaction solution was added to 500 ml of ethyl acetate and 250 ml of brine. The organic layer was separated and was washed twice with 500 ml of brine. The organic layer was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1 to 1:1) to give 29.91 g of 5-ethynyl-4-methoxycarbonylthiazole.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[C:14](F)[CH:13]=[CH:12][C:11]=3[N+:17]([O-:19])=[O:18])[CH:5]=2)[CH2:3][CH2:2]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([C@@H:27]([NH2:29])[CH3:28])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[C:14]([NH:29][C@H:27]([C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)[CH3:28])[CH:13]=[CH:12][C:11]=3[N+:17]([O-:19])=[O:18])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1cc(C2CC2)[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ccc([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)c1)c1ccc(F)cc1
Temperature: 230 °C
Yield: 96.7 %

Procedure:
A mixture of 5-cyclopropyl-N-(5-fluoro-2-nitrophenyl)-1H-pyrazol-3-amine (Method 82; 0.27 g, 1.03 mmol), (S)-1-(4-fluoro-phenyl)-ethylamine (0.72 g, 5.15 mmol), and DIEA (0.27 ml, 1.54 mmol) in n-BuOH (5 ml) was heated in a sealed tube at 230° C. for 23 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=1:2) to give the title compound as a yellow solid (0.38 g, 97%). NMR (400 MHz) 12.25 (s, 1H), 10.14 (s, 1H), 7.87 (d, J=9.6 Hz, 1H), 7.76 (d, J=6.4 Hz, 1H), 7.36 (m, 2H), 7.15 (m, 2H), 6.68 (s, 1H), 6.22 (d, J=8.4 Hz, 1H), 5.60 (br, 1H), 4.57 (m, 1H), 1.87 (m, 1H), 1.44 (d, J=6.8 Hz, 3H), 0.98 (m, 2H), 0.70 (m 2H). MS: Calcd.: 381; Found: [M+H]+ 382.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]3[N:15]4[CH2:16][CH2:17][S:18][C:19]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])([CH3:21])[CH2:20][C:14]4=[N:13][N:12]=3)[CH2:10][CH2:9]2)=[C:4]([F:31])[CH:3]=1.[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[Si:24]([O:23][CH2:22][C:19]1([CH3:21])[S:18][CH2:17][CH2:16][N:15]2[C:11]([C:8]3([C:5]4[CH:6]=[CH:7][C:2]([C:36]5[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=5)=[CH:3][C:4]=4[F:31])[CH2:10][CH2:9]3)=[N:12][N:13]=[C:14]2[CH2:20]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Br)cc4F)CC3)n2CCS1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: COCCOC
Solvent: O
Product: Cn1cc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)c(F)c2)cn1
Temperature: 25 °C
Yield: 118.2 %

Procedure:
A solution of the compound (300 mg, 0.59 mmol) obtained in Example 14-5), 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (130 mg, 0.65 mmol), tetrakis(triphenylphosphine)palladium(0) (66 mg, 0.06 mmol), and potassium carbonate (157 mg, 1.18 mmol) in 1,2-dimethoxyethane (3 mL) and water (1.5 mL) was stirred at 120° C. for 1 h under microwave irradiation. The reaction mixture was cooled to room temperature, water (3 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate:methanol=70:30) to obtain the title compound (368 mg, quant.) in an orange oily form.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13](=[O:15])[C:12]3[CH:11]=[C:10]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[N:23]4C(=O)C5C(=CC=CC=5)C4=O)[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH:4]=[N:3]1.O.NN>C(O)C>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][C:10]1[CH:9]=[CH:8][C:7]2[NH:6][C:5]3[CH:4]=[N:3][N:2]([CH3:1])[C:14]=3[C:13](=[O:15])[C:12]=2[CH:11]=1
Reactant: Cn1ncc2[nH]c3ccc(Cc4ccccc4N4C(=O)c5ccccc5C4=O)cc3c(=O)c21
Agent: NN
Solvent: O
Solvent: CCO
Product: Cn1ncc2[nH]c3ccc(Cc4ccccc4N)cc3c(=O)c21
Temperature: 25 °C
Yield: 81.8 %

Procedure:
A mixture of 2-{2-[(1-methyl-9-oxo-4,9-dihydro-1H-pyrazolo[4,3-b]quinolin-7-yl)methyl]phenyl}-1H-isoindole-1,3(2H)-dione (EXAMPLE 25, step 2, 242 mg, 0.558 mmol) and hydrazine hydrate (0.14 ml, 2.8 mmol) in ethanol (10 ml) was refluxed for 18 h. After cooling to room temperature, the mixture was evaporated in vacuo. The obtained residue was chromatographed on a column of silica gel eluting with methanol/dichloromethane (1:20) to give 139 mg (82%) of 7-(2-aminobenzyl)-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one. 80 mg of this compound was treated with methanolic hydrochloric acid and the mixture was evaporated to give a yellow solid. This was washed with diisopropyl ether to give 78 mg of the title compound as a yellow solid.
Reaction SMILES: Br[CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH3:24])=[CH:19][N:18]=2)=[CH:10][CH:9]=1)[C:3](OC)=[O:4].[NH2:25][C:26]([NH2:28])=[S:27].C([O-])(=O)C.[Na+]>C(O)C>[CH2:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:8]([CH2:7][CH:2]3[S:27][C:26](=[NH:25])[NH:28][C:3]3=[O:4])=[CH:9][CH:10]=2)=[N:18][CH:19]=1)[CH3:24]
Reactant: NC(N)=S
Reactant: CCc1ccc(CCOc2ccc(CC(Br)C(=O)OC)cc2)nc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1ccc(CCOc2ccc(CC3SC(=N)NC3=O)cc2)nc1

Procedure:
A mixture of methyl 2-bromo-3-(4-(2-(5-ethyl-2-pyridyl)ethoxy)phenyl)propionate (28.4 g), thiourea (5.5 g), sodium acetate (6 g) and ethanol (200 ml) is heated to reflux under heating for three hours. The mixture is concentrated and the concentrate is neutralized with saturated solution of sodium hydrogencarbonate. Adding water (80 ml) and ether (40 ml) precipitates a solid from the mixture. Filtering off gives beige-coloured crystalline
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[CH2:17](Br)[CH:18]=[CH2:19].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:19]([N:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1=[O:1])[CH:18]=[CH2:17]
Reactant: CCOC(=O)c1nc2ccccc2[nH]c1=O
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCn1c(=O)c(C(=O)OCC)nc2ccccc21

Procedure:
3,4-Dihydro-3-oxo-2-quinoxalinecarboxylic acid, ethyl ester (5 g), allyl bromide (2.8 g) and anhydrous potassium carbonate (15 g) in butanone (100 ml) were stirred and heated under reflux for 3 hours and cooled. The solid was filtered off and the filtrate was evaporated. The residue was crystallised from cyclohexane to give a yellow solid, which had m.p. 77°-79° (56%).
Reaction SMILES: Cl[CH:2]([CH3:23])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:22])[CH2:13][C:14]([NH:16][C:17]1[S:18][CH:19]=[CH:20][N:21]=1)=[O:15])=O>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:23][CH:2]1[C:3]2=[N:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:12]([OH:22])=[C:13]2[C:14](=[N:16][C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[O:15]1
Reactant: CC(Cl)C(=O)Nc1ccccc1C(=O)CC(=O)Nc1nccs1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC1OC(=Nc2nccs2)c2c1nc1ccccc1c2O
Temperature: 25 °C
Yield: 59.2 %

Procedure:
A mixture of 7 g of the product of Step B, 50 ml of tetrahydrofuran and 2.92 g of 4-dimethylamino-pyridine was refluxed for 24 hours and was cooled to room temperature and iced and vacuum filtered. The product was washed with tetrahydrofuran and dried under reduced pressure at 90° C. The product was stirred with 100 ml of water at room temperature and was vacuum filtered. The product was washed with water and dried under reduced pressure at 90° C. to obtain 3.5 g of 1,3-dihydro-3-methyl-1-(2-thiazolylimino)-furo[3,4-b]quinoline-9-ol melting at >270° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].Br[C:11]1[S:12][CH:13]=[C:14]([Br:16])[N:15]=1.C(N(CC)CC)C.O>CN(C)C=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:11]2[S:12][CH:13]=[C:14]([Br:16])[N:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Brc1csc(Br)n1
Reactant: CC(=O)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1CCN(c2nc(Br)cs2)CC1
Temperature: 65 °C
Reaction time: 6 h
Yield: 54.8 %

Procedure:
To a solution of 1-acetylpiperazine (316 mg, 4.78 mmol) and 2,4-dibromo-1,3-thiazole (900 mg, 3.71 mmol) in N,N-dimethylformamide (8 ml) was added triethylamine (0.78 ml, 5.56 mmol). The reaction mixture was stirred at 50° C. for 14 hrs and at 65° C. for 6 hrs. After cooling to room temperature, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=100:0→98:2) to give 1-acetyl-4-(4-bromo-1,3-thiazol-2-yl)piperazine (590 mg, yield 55%) as a pale-white brown solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:34])[C:18]=1[NH:19][C:20]1[C:29]2[C:24](=[C:25]([OH:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[O:23][C:22](=[O:33])[CH:21]=1>>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:34])[C:18]=1[NH:19][C:20]1[C:29]2[C:24](=[C:25]([O:32][CH2:2][C:3]3[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=3)[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[O:23][C:22](=[O:33])[CH:21]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCc1ccc([N+](=O)[O-])cc1

Procedure:
The title compound was prepared from 1-(bromomethyl)-4-nitrobenzene and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 8.81 (s, 2H), 8.25 (d, 2H), 7.99 (d, 1H), 7.80 (d, 2H), 7.25 (d, 1H), 5.20 (s, 2H), 4.66 (s, 1H), 3.93 (s, 3H); MS (ESI): 487.8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]=3[C:29]([O:31]C)=[O:30])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C1COCC1.O[Li].O>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH2:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]=3[C:29]([OH:31])=[O:30])(=[O:15])=[O:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1c(CCS(=O)(=O)c2ccc(-c3ccc(Cl)cc3)cc2)ccc2ccccc12
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1c(CCS(=O)(=O)c2ccc(-c3ccc(Cl)cc3)cc2)ccc2ccccc12
Temperature: 80 °C
Reaction time: 16 h
Yield: 17.2 %

Procedure:
To a solution of Example 8A (0.12 g, 0.26 mmoL) in MeOH (3 mL), H2O (3 mL), and THF (15 mL) was added LiOH.H2O (0.17 g, 3.84 mmoL). The mixture was stirred at 80° C. for 16 hours, poured into H2O, and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered, and concentrated. Purification on silica gel with 2% MeOH/CH2Cl2 provided 0.02 g (20%) of the desired compound.
Reaction SMILES: FC(F)(F)C(O)=O.O.[CH2:9]([O:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:26]=[N:27][CH:28]=[C:29]([O:31][CH2:32][C@H:33]3[CH2:36][CH2:35][N:34]3C(OC(C)(C)C)=O)[CH:30]=2)[CH2:21][CH2:20]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[NH:34]1[CH2:35][CH2:36][C@@H:33]1[CH2:32][O:31][C:29]1[CH:28]=[N:27][CH:26]=[C:25]([N:22]2[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17][O:16][CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:24][CH2:23]2)[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]1COc1cncc(N2CCC(CCOCc3ccccc3)CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: c1ccc(COCCC2CCN(c3cncc(OC[C@H]4CCN4)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
Trifluoroacetic acid (1.5 mL) and water (0.15 mL) were added to CH2Cl2 (7.5 mL). This mixture was added to 3-[4-[2-(benzyloxy)ethyl]-1-piperidinyl]-5-[[1-(tert-butoxycarbonyl)-2(R)-azetidinyl]methoxy]pyridine (260 mg, 0.54 mmol) in a 25 mL round-bottom flask with a magnetic stirrer under N2. After stirring overnight at room temperature, TLC analysis of the crude reaction mixture indicated that the starting material had disappeared. The mixture was concentrated, and the residue was purified by preparative HPLC (column: SunFire Prep C18, 150×19 mm, 5 μm particle size; UV detection at 270 nm; mobile phase: A, water with 0.05% CF3COOH; B, methanol; 40-50% B in A in 6 min, up to 100% in 1 min, back to 40% in 1 min). The eluate was partially evaporated under reduced pressure (bath 30° C.) to remove CH3OH. The residue was basified with saturated aqueous NaHCO3 solution and extracted with EtOAc. The combined organic layers were washed with brine and dried. After concentrated in vacuo, the free base (130 mg, 63%) was obtained as a yellow oil. 1H NMR (CDCl3, 300 MHz) δ 7.97 (s, 1H), 7.79 (s, 1H), 7.38-7.28 (m, 5H), 6.78 (s, 1H), 4.53 (s, 2H), 4.43-4.41 (m, 1H), 4.15-4.09 (m, 2H), 3.85-3.82 (m, 1H), 3.70-3.66 (m, 2H), 3.58-3.50 (m, 2H), 2.79-2.71 (dd, 2H, J=7.2 Hz, 2.1 Hz), 2.47-2.39 (m, 2H), 1.82-1.78 (d, 2H, J=1.2 Hz), 1.64-1.58 (m, 3H), 1.40-1.27 (m, 3H). LC-MS (ESI) m/z 382 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:15]([OH:21])([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:7]([CH2:9][CH2:10][O:11]C(=O)C)[CH:8]=1.[OH-].[Na+]>O>[F:17][C:16]([F:18])([F:19])[C:15]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=1[CH2:9][CH2:10][OH:11])([OH:21])[CH3:20]
Reactant: COc1ccc(C(C)(O)C(F)(F)F)c(CCOC(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C(C)(O)C(F)(F)F)c(CCO)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52 %

Procedure:
To the crude reaction mixture described in example 3 containing acetic acid 2-[5-methoxy-2-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-phenyl]-ethyl ester was added 1N aqueous sodium hydroxide (75.0 mL, 75 mmol). The reaction mixture was allowed to warm to room temperature and was stirred 12 hours. The reaction mixture was poured into water (75 mL) and extracted with methyl tert-butyl ether (150 mL). The organic layer was washed with water (75 mL) and brine (75 mL), dried over magnesium sulfate, and concentrated to an oil. To the crude oil was added hexanes (20 mL) and methyl tert-butyl ether (4 mL) and a solid precipitated. The mixture was stirred for 30 minutes and filtered to provide 1,1,1-trifluoro-2-[2-(2-hydroxy-ethyl)-4-methoxy-phenyl]-propan-2-ol (7.3 g, 52% overall yield from acetic acid 2-(2-acetyl-5-methoxy-phenyl)-ethyl ester). M.p. 110-111° C. 1H NMR (300 MHz, CDCl3) δ1.83 (s, 3), 2.91 (dt, 1, J=13.7, 3.9), 3.76 (ddd, 1, J=13.7, 9.3, 4.4), 3.85 (s, 3), 3.85-3.93 (m, 1), 4.08 (dt, 1, J 9.3, 3.7), 6.80-6.83 (m, 2), 7.38 (d, 1, J=8.4). 13C NMR (100 MHz, CDCl3) δ26.01, 36.12, 55.19, 64.13, 76.52 (q, J=28.9), 111.47, 117.43, 125.99 (q, J=287), 129.69, 129.94, 140.86, 159.55. IR 3395, 3162, 1610, 1513, 1467, 1248, 1157, 1087, 1046 cm−1. Analysis calculated for C12H15F3O3: C, 54.54; H, 5.72. Found: C, 54.65; H, 5.70.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].Cl[C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[N:17][CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[N:17][CH:16]=2)[CH:6]=1)=[O:4]
Reactant: Clc1cnnc2ccccc12
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(-c2cnnc3ccccc23)c2ccccc12
Temperature: 80 °C
Reaction time: 60 h

Procedure:
1 mmol (175 mg) of 1H-indole-3-carboxylic acid methyl ester, 1.1 mmol (181 mg) of 4-chloro-cinnoline and 1.2 mmol (390 mg) of Cs2CO3 are suspended in 3 ml of dry DMF. The mixture is stirred for 60 h at 80° C. under argon, allowed to cool to room temperature, and diluted with water (20 ml). Part of the product precipitates and is filtered off, the filtrate is extracted twice with ethyl acetate (20 ml portions). The combined extracts are dried over anhydrous Na2SO4 and evaporated. The residue is combined with the precipitate and purified by prep. HPLC to yield 1-(cinnolin-4-yl)-1H-indole-3-carboxylic acid methyl ester (MS molpeak 304 (M+H, electrospray ionization)) as an off-white foam after freeze-drying.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:28][CH2:29][N:30]([CH:33]([CH3:35])[CH3:34])[C:31](=[O:32])[C:10]=12)C1C=CC=CC=1.[H][H].CO>C(O)C.ClCCl.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)[N:11]2[CH2:28][CH2:29][N:30]([CH:33]([CH3:35])[CH3:34])[C:31](=[O:32])[C:10]=12
Reactant: [H][H]
Reactant: CC(C)N1CCn2c(CC3(c4ccccn4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CCO
Product: CC(C)N1CCn2c(CC3(c4ccccn4)CCCC3)nc(=O)c(O)c2C1=O
Yield: 64.1 %

Procedure:
To a stirred solution of 9-benzyloxy-2-isopropyl-6-(1-pyridin-2-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (440) (50 mg, 0.106 mmol) in ethanol (5 mL), Pd—C (10% w/w, 10 mg) was added and the reaction mixture was allowed to stir for 1 h in a hydrogen atmosphere at balloon pressure while silica thin layer chromatography was performed (10% methanol in dichloromethane; Rf=0.3). After completion of the reaction, the reaction mixture was filtered through a celite bed and concentrated to obtain a crude product which was purified by normal silica gel (100-200 mesh) column chromatography using 2-5% methanol in dichloromethane as a gradient polarity mobile phase to get 9-hydroxy-2-isopropyl-6-(1-pyridin-2-yl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (441) (26 mg, 64%) as an off-white solid.
Reaction SMILES: [OH:1][C:2]([CH:4]([C:6]1[CH:15]=[CH:14][C:9]([CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:8][CH:7]=1)[CH3:5])=[O:3].[CH2:16]([NH:24][CH2:25][C@@H:26]([C@H:28]([C@@H:30]([C@@H:32]([CH2:34][OH:35])[OH:33])[OH:31])[OH:29])[OH:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(O)(C)C>[CH2:16]([NH:24][CH2:25][C@@H:26]([C@H:28]([C@@H:30]([C@@H:32]([CH2:34][OH:35])[OH:33])[OH:31])[OH:29])[OH:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[OH:3][C:2]([C@H:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][CH:11]([CH3:12])[CH3:13])=[CH:14][CH:15]=1)[CH3:5])=[O:1]
Reactant: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Agent: CCCCCCCCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CC(C)O
Product: CC(C)Cc1ccc([C@H](C)C(=O)O)cc1
Temperature: 33 °C

Procedure:
Racemic ibuprofen (27.03, 131.03 mmol), N-octyl-D-glucamine (16.35 g, 55.73 mmol), and isopropanol (150 mL) were heated to 80° C., forming a clear solution, and the solution then cooled to 33° C. over 4 hours. The resulting precipitate was recovered by filtration, washed with isopropanol, and dried to give (S)-ibuprofen N-octyl-D-glucamine salt (23.95 g, 47.93 mmol, 73.2% yield, 99.0% ee).
Reaction SMILES: [CH:1]([C@H:4]1[N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:7][N:6]2[C:17]3[CH:23]=[C:22]([S:24]([CH3:27])(=[O:26])=[O:25])[C:21]([C:28](OC)=[O:29])=[CH:20][C:18]=3[N:19]=[C:5]12)([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.CCOC(C)=O>C(Cl)Cl>[OH:29][CH2:28][C:21]1[C:22]([S:24]([CH3:27])(=[O:25])=[O:26])=[CH:23][C:17]2[N:6]3[CH2:7][CH2:8][N:9]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[C@H:4]([CH:1]([CH3:2])[CH3:3])[C:5]3=[N:19][C:18]=2[CH:20]=1
Reactant: COC(=O)c1cc2nc3n(c2cc1S(C)(=O)=O)CCN(C(=O)OC(C)(C)C)[C@@H]3C(C)C
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)[C@@H]1c2nc3cc(CO)c(S(C)(=O)=O)cc3n2CCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 3 h
Yield: 74.6 %

Procedure:
To a 50 mL three-necked flask containing (R)-2-tert-butyl 8-methyl 1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2,8(1H)-dicarboxylate (250 mg, 0.554 mmol, from preparation 2) in DCM (5 mL) was added DIBAL-H (1.70 mL, 1.67 mmol, 1.0 M in toluene) dropwise at −78° C. under N2. The mixture was stirred at −78° C. for 3 h. The reaction was quenched with sat. aq. ammonium chloride (10 mL) at −78° C. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with water (15 mL) and brine, and then dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE: EtOAc 8:1˜2:1 to give (R)-tert-butyl 8-(hydroxymethyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazine-2(1H)-carboxylate (175 mg, 74.1% yield) as a white solid.
Reaction SMILES: CN.[CH2:3]([N:5](CC)CC)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>O1CCCC1.C(Cl)Cl>[CH3:3][NH:5][S:17]([C:14]1[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: CCN(CC)CC
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
A mixture of 125 ml of methylamine (0.25 molar) in tetrahydrofuran and 13.9 ml (0.10 mol) of triethylamine was chilled in an ice bath. To this chilled solution was added dropwise 19.4 g (0.10 mol) of 4-fluorobenzenesulfonyl chloride in 150 ml of CH2Cl2 was added and the mixture refluxed for 2 hours and then stirred overnight at room temperature. The mixture was with CH2Cl2, washed with H2O, 2N citric acid, brine and dried (Na2SO4). The solution was filtered through a pad of hydrous magnesium silicate and the filtrate concentrated to dryness under vacuum to give 18.0 g of white solid, mp 67-70° C.