Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=[CH:32][C:31]=1[N:45]1[N:54]=[CH:53][C:52]2[C:47](=[C:48]([F:59])[CH:49]=[C:50]([C:55]([CH3:58])([CH3:57])[CH3:56])[CH:51]=2)[C:46]1=[O:60])(=[O:27])[CH3:26].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:55]([C:50]1[CH:51]=[C:52]2[C:47](=[C:48]([F:59])[CH:49]=1)[C:46](=[O:60])[N:45]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([CH2:17][N:18]5[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]5)=[CH:13][N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=3)[C:30]=1[CH2:29][O:28][C:25](=[O:27])[CH3:26])[N:54]=[CH:53]2)([CH3:56])([CH3:57])[CH3:58]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: CN1CCN(Cc2ccc(Nc3cc(Cl)nn(C)c3=O)nc2)CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(CN4CCN(C)CC4)cn3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 115 °C

Procedure:
6-Chloro-2-methyl-4-(5-((4-methylpiperazin-1-yl)methyl)pyridin-2-ylamino)pyridazin-3(2H)-one (3.1 g, 8.89 mmol, Eq: 1.00), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (7.69 g, 15.6 mmol, Eq: 1.75), X-PHOS (424 mg, 0.89 mmol, Eq: 0.10), bis(dibenzylideneacetone)palladium (255 mg, 0.44 mmol, Eq: 0.05) and tripotassium phosphate (4.72 g, 22.2 mmol, Eq: 2.50) were added to a large microwave vial. The vial was capped and purged. N-butanol (35.5 ml) and water (9 ml) were added and the vial was purged again and backfilled with nitrogen. The reaction was heated in a sand bath at 115° C. for 2.5 hours. Water and DCM were added to the reaction and the layers were separated. The organic layer was filtered through celite, concentrated, and purified by chromatography using a gradient of 0% to 25% methanol in DCM. Fractions with and without the protecting group were combined to give a combined yield of 4.5 g (approximately 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([C@H:7]([CH3:12])[C:8]([O:10]C)=[O:9])[CH:6]=1.Cl>>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([C@H:7]([CH3:12])[C:8]([OH:10])=[O:9])[CH:6]=1
Reactant: COC(=O)[C@@H](C)n1cc(Cl)cn1
Agent: Cl
Product: C[C@H](C(=O)O)n1cc(Cl)cn1
Temperature: 0 °C
Reaction time: 18 h
Yield: 33.5 %

Procedure:
(R)-Methyl 2-(4-chloro-1H-pyrazol-1-yl)propanoate (1.00 g, 5.30 mmol) was suspended in a solution of aqueous hydrochloric acid (6M, 8.8 mL, 53 mmol). The reaction mixture was stirred for 18 h at reflux. The mixture was cooled to 0° C. and quenched with a saturated aqueous solution of sodium phosphate (NaH2PO4). The pH was adjusted to 1-2 using aqueous sodium hydroxide and hydrochloric acid. The mixture was extracted with ethyl acetate (20 mL×3). The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was dried under vacuum, dissolved in a hot solution of heptanes:ethyl acetate (3:1, 9 mL) and allowed to cool to room temperature. A seed crystal was added while cooling. The mixture was stirred for 18 h. The solids were collected by filtration and washed with a solution of heptanes:ethyl acetate (3:1, 2 mL×2) and heptanes (2 mL×2). The resulting solids were air dried to afford (R)-2-(4-chloro-1H-pyrazol-1-yl)propanoic acid (310 mg, 33%). 1H NMR (500 MHz, CDCl3) δ 1.8 (d, 3H), 5.13 (q, 1H), 7.51 (s, 1H), 7.55 (s, 1H), 11.8 (s, 1H); MS (EI+) (M+) 174; Chiral HPLC retention time: 3.81 min (Method: Chiralpak AD-H 0.46×25 cm, Mobile Phase: 90/10 CO2/methanol; Flow: 2.5 mL/min); >99.5% ee.
Reaction SMILES: [N:1]1[N:9]2[C:4]([N:5]=[C:6]3[CH2:15][CH2:14][CH2:13]CC[C:7]3=[C:8]2[OH:10])=[CH:3][CH:2]=1.COC(C1CCCC1=O)=O.N1NC(N)=CC=1>C(O)(=O)C>[N:1]1[N:9]2[C:4]([N:5]=[C:6]3[C:7](=[C:8]2[OH:10])[CH2:13][CH2:14][CH2:15]3)=[CH:3][CH:2]=1
Reactant: Oc1c2c(nc3ccnn13)CCCCC2
Agent: COC(=O)C1CCCC1=O
Agent: Nc1ccn[nH]1
Solvent: CC(=O)O
Product: Oc1c2c(nc3ccnn13)CCC2

Procedure:
Using the method described for the preparation of 6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]inden-10-ol, the reaction of 2-oxo-cyclopentanecarboxylic acid methyl ester and 2H-pyrazol-3-ylamine in acetic acid provided the title compound.
Reaction SMILES: [CH:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[C:9]([Cl:19])[C:10]([Cl:18])=[C:11]([O:16]C)[CH:12]=3)[C:7]2=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.N1C=CC=CC=1>O>[CH:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[C:9]([Cl:19])[C:10]([Cl:18])=[C:11]([OH:16])[CH:12]=3)[C:7]2=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)CC2
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C1c2c(cc(O)c(Cl)c2Cl)CCC1C1CCCC1
Temperature: 180 °C

Procedure:
2-Cyclopentyl-6-methoxy-7,8-dichloro-1-tetralone (6.58 g., 0.02 mole) is mixed with pyridine hydrochloride (60 g.) and the mixture is heated at 180° C. for one hour. The mixture is poured into water (ca. 400 ml.). The solid that separates is collected, washed with water and air dried to obtain 2-cyclopentyl-6-hydroxy-7,8-dichloro-1-tetralone.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1>[Pd].CO>[CH2:10]([NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:9]([C:10]([NH2:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1)[C:9]1[CH:13]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NCCOc1ccc(O)c(C(N)=O)c1
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cc(OCCNCc2ccccc2)ccc1O

Procedure:
The 5-(2-aminoethoxy)-salicylamide required as starting material is obtained by catalytic debenzylation of 5-(2-benzylamino-ethoxy)-salicylamide by means of a 5% palladium-charcoal catalyst in methanol under normal conditions. After the hydrogen absorption is completed, the catalyst is filtered off, and the filtrate is concentrated under reduced pressure to thus obtain 5-(2-aminoethoxy)-salicylamide, m.p. 140°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH3:19])=[C:6]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[O:10])[CH:7]=1.[C:20]1(=[O:26])[O:25][C:23](=[O:24])[CH2:22][CH2:21]1>N1C=CC=CC=1>[CH3:19][O:18][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:20](=[O:26])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:7][C:6]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[N:16][CH:15]=[CH:14][N:13]=1)=[O:10]
Reactant: O=C1CCC(=O)O1
Reactant: COc1ccc(N)cc1NC(=O)Nc1cnccn1
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)CCC(=O)O)cc1NC(=O)Nc1cnccn1
Yield: 48.7 %

Procedure:
A solution of 1-(5-amino-2-methoxyphenyl)-3-pyrazin-2-yl-urea (Compound 14, Example 4) (260 mg, 1 mmol) and succinic anhydride (131 mg, 1.3 mmol) in dry pyridine (10 mL) was stirred 16 h at room temperature. The resulting solid was collected by filtration and triturated with chloroform, and dried in vacuo to afford the off-white product (175 mg, 50%). 1H NMR (300 Mhz, d6-DMSO) δ: 10.15 (s, 1H), 10.05 (s, 1H), 9.87 (s, 1H), 8.90 (s, 1H), 8.33 (s, 2H), 8.24 (s, 1H), 7.42 (dd, J=8.8, 2.2 Hz, 1H), 6.96 (d, J=8.8 Hz, 1H), 3.87 (s, 3H), 2.54 (br s, 4H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]3[N:16]=[C:15]([CH3:17])[C:14]([N:18]4[C:22]([CH3:23])=[N:21][C:20]([CH3:24])=[N:19]4)=[C:10]3[O:11][C:12]=2[CH3:13])=[C:4]([CH3:25])[CH:3]=1.COC1C2[C:32](=[C:33]3C(=CC=2)C(OC)=C[CH:35]=[N:34]3)[N:31]=CC=1.N1C=CN=C1.C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1>[N:31]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]4[N:16]=[C:15]([CH3:17])[C:14]([N:18]5[C:22]([CH3:23])=[N:21][C:20]([CH3:24])=[N:19]5)=[C:10]4[O:11][C:12]=3[CH3:13])=[C:4]([CH3:25])[CH:3]=2)[CH:32]=[CH:33][N:34]=[CH:35]1
Reactant: COc1ccnc2c1ccc1c(OC)ccnc12
Reactant: Cc1nc(C)n(-c2c(C)nn3c(-c4ccc(Br)cc4C)c(C)oc23)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1c[nH]cn1
Solvent: CN1CCCC1=O
Product: Cc1nc(C)n(-c2c(C)nn3c(-c4ccc(-n5ccnc5)cc4C)c(C)oc23)n1
Temperature: 110 °C
Reaction time: 120 h

Procedure:
3-(4-Bromo-2-methylphenyl)-7-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-2,6-dimethyl pyrazolo[5,1-b]oxazole (Ex. 6.41) (40 mg, 0.100 mmol), 4,7-dimethoxy-1,10-phenanthroline (24.01 mg, 0.100 mmol), 1H-imidazole (8.16 mg, 0.120 mmol), Cu2O (0.715 mg, 5.00 μmol) and Cs2CO3 (45.6 mg, 0.140 mmol) are added to NMP (2 ml) and stirred at 110° C. for 5 days.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](=O)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[CH3:32][N:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)N>>[CH3:1][CH:2]([CH3:31])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:33]([CH3:32])[C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CN(N)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCC(=O)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCc3c(-c4ccccc4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(6-oxo-6-phenylhexyl)-4-piperidinyl]phenyl}propanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 508.3 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([O:14][C@H:15]([CH3:28])[C@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:17](O)=[O:18])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>C(OCC)C.O>[C:24]([O:23][C:21](=[O:22])[NH:20][C@@H:16]([C@H:15]([O:14][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH3:28])[CH2:17][OH:18])([CH3:25])([CH3:26])[CH3:27]
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: C[C@@H](OCc1ccccc1)[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a suspension of lithium aluminum hydride (2.94 g, 78 mmol) in 50 mL diethyl ether at 0° C. was slowly added a solution of (2S,3R)-3-(benzyloxy)-2-((tert-butoxycarbonyl)amino)butanoic acid (8.0 g, 25.9 mmol) in 25 mL diethyl ether. The reaction was allowed to warm to rt and stirred 1 hr. Water (3 ml) was added with caution, to the reaction mixture. This addition was followed by an addition of 15% NaOH (3 ml) and water (9 ml). These additions were made with extreme caution to control the rate of gas evolution. After stirring 1 hr at rt, MgSO4 was added and the mixture was filtered. The filtrate was concentrated to afford an oil, which was chromatographed on a 120 gm Isco cartridge using an 0-75% EtOAc/Hex gradient. The pure fractions were concentrated to afford tert-butyl((2R,3R)-3-(benzyloxy)-1-hydroxybutan-2-yl)carbamate (5.44 g, 18.42 mmol, 71.2% yield) as a colorless oil. 1H NMR (400 MHz, CCl3D) δ 7.32 (s, 5H), 5.07 (br. s., 1H), 4.64 (d, J=11.4 Hz, 1H), 4.38 (d, J=11.7 Hz, 1H), 3.83 (d, J=6.2 Hz, 1H), 3.79-3.71 (m, 1H), 3.70-3.59 (m, 2H), 2.60-2.38 (m, 1H), 1.48-1.42 (m, 9H), 1.27-1.25 (m, 3H).
Reaction SMILES: C[N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[C:3]1[CH2:13]O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[Cl:42]CCCl>>[Cl:42][CH2:13][C:3]1[NH:2][CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=1
Reactant: Cn1cc(-c2ccccc2)nc1CO
Reactant: ClCCCl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Product: ClCc1nc(-c2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of (1-Methyl-4-phenyl-1H-imidazol-2-yl)-methanol 5 (50.0 mg, 0.266 mmol) in 1,2-dichloroethane (4.0 mL) under Ar was added Dess-Martin periodinane (124 mg, 0.292 mmol), and the mixture was stirred at room temperature for 2 hours. Saturated NaHCO3 solution was added, the organic layer was separated and the aqueous layer was extracted with 1,2-dichloroethane. The combined organic layers were dried over Na2SO4, volatiles were evaporated and the residue was purified by silica gel chromatography on a FlashMaster system (gradient elution; 0-100% ethylacetate in heptane) to afford the title compound as a white solid (39.1 mg, 79%). 1H NMR (500 MHz, DMSO-d6): δ9.76 (s, 1H), 8.11 (s, 1H), 7.84 (d, J=7.7 Hz, 2H), 7.42 (t, J=7.6 Hz, 2H), 7.30 (t, J=7.4 Hz, 1H), 3.99 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[OH-].[K+]>>[Br:1][C:2]1[CH:10]=[C:6]2[C:7](=[O:9])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=3)[O:11][C:5]2=[N:4][CH:3]=1
Reactant: COc1ccc(Oc2ncc(Br)cc2C(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc2oc3ncc(Br)cc3c(=O)c2c1
Temperature: 25 °C

Procedure:
A slurry of 5-bromo-2-(4-methoxyphenoxy)nicotinic acid (12.20 g, 37.6 mmol) and polyphosphoric acid (200 g) was heated at 135° C. for 1.5 hours. The reaction was cooled to rt and poured onto 300 g of ice before being basified to pH 12 with 50% aq. KOH (1.5 L). The resulting yellow slurry was filtered and washed with 100 mL of ether. The wet solid was then partitioned between water and DCM (1:1; 2000 mL). The layers were separated and the aqueous layer was extracted with DCM 5×500 mL. The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to provide 3-bromo-7-methoxy-5H-chromeno[2,3-b]pyridin-5-one as a yellow solid. MS m/z=306.2 [M+H]+. Calc'd for C13H9BrNO3: 306.0.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:9][C@@H:8]([P:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[CH2:7][C@H:6]1[CH2:24][OH:25])(=[O:4])=[O:3].[H][H]>CO>[CH3:1][S:2]([N:5]1[CH2:9][C@@H:8]([P:10]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:7][C@H:6]1[CH2:24][OH:25])(=[O:3])=[O:4]
Reactant: [H][H]
Reactant: CS(=O)(=O)N1C[C@@H](P(=O)(c2ccccc2)c2ccccc2)C[C@H]1CO
Solvent: CO
Product: CS(=O)(=O)N1C[C@@H](P(=O)(C2CCCCC2)C2CCCCC2)C[C@H]1CO
Yield: 59856.5 %

Procedure:
An autoclave was charged with 1.70 g (4.5 m-xol) of (2S,4S)-N-methanesulfonyl-4-diphenylphosphinyl-2-hydroxymethylpyrrolidine [VII], 850 mg of 5% Ph/Al2O3 and 20 ml of methanol, and the mixture was stirred for 2 days at 150° C. under 150 atm. pressure of hydrogen. The reaction mixture was subjected to microfiltration and the filtrate was concentrated and subjected to column chromatography on silica gel (solvent: ethanol) to be separated from a fraction insoluble in the organic solvent. The eluent was concentrated until dryness under reduced pressure whereby 1050 g (yield: 84%) of crystals were obtained.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.S(=O)(=O)(O)O.II.[I:19](O)(=O)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C.C(Cl)(Cl)(Cl)Cl>[CH2:10]([O:9][C:7]([C:5]1[N:6]=[C:2]([CH3:1])[S:3][C:4]=1[I:19])=[O:8])[CH3:11]
Reactant: CCOC(=O)c1csc(C)n1
Reactant: [O-][I+2]([O-])O
Agent: II
Agent: O=S(=O)(O)O
Agent: O=S([O-])([O-])=S
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(C)sc1I
Temperature: 80 °C
Reaction time: 19 h
Yield: 46.3 %

Procedure:
To a solution of ethyl 2-methylthiazole-4-carboxylate (11.2 g, 65.4 mmol) in acetic acid (200 mL) were added sulfuric acid (30%, 20 mL), carbontetrachloride (30 mL), iodine (33.2 g, 131 mmol) and iodic acid (11.5 g, 65.4 mmol) and the resulting reaction mixture was stirred for 19 h at 80° C. After addition of aqueous sodium thiosulfate (1 M, 500 mL) it was extracted with ethyl acetate (1000 mL). The combined organic layers were washed with aqueous sodium carbonate (saturated, 1000 mL), dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 20:80) afforded the title compound (9.00 g, 37%) as a white crystalline solid. MS: m/e=298.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH3:11][O:12][C:13](=[O:34])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22](Cl)[C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[S:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1>>[CH3:11][O:12][C:13](=[O:34])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:23]3[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[S:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(C(F)(F)F)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(Cl)c(Cl)c3)c3cc(C(F)(F)F)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-dichlorobenzylamine is reacted with 4-(4-chloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dichlorobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: C[Mg+].[Br-].[C:4]1(C)C=CC=CC=1.C1COCC1.[C:16]([C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=1)([CH3:19])([CH3:18])[CH3:17].[BH4-].[Na+]>C1COCC1.C(Cl)Cl.O.CO>[C:16]([C:20]1[N:21]=[CH:22][C:23]([CH:24]([NH2:25])[CH3:4])=[CH:26][CH:27]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1ccc(C#N)cn1
Reactant: Cc1ccccc1
Agent: C[Mg+]
Agent: [BH4-]
Agent: [Br-]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CC(N)c1ccc(C(C)(C)C)nc1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A solution of MeMgBr 1.4 M 75/25 toluene/THF (8.9 ml, 12.48 mmol) is added dropwise over 5 min to an ice cooled solution of 6-tert-butylnicotinonitrile (intermediate 21) (1 g, 6.24 mmol) in 15 mL of THF. The reaction is stirred for 6 hr and cooled with a dry ice bath. MeOH is then added dropwise followed by the incremental addition of NaBH4 (0.59 g, 15.9 mmol). The reaction is stirred over night, water and CH2Cl2 are then added and the resulting paste is filtered through celite and rinsed with CH2Cl2. The reaction is concentrated to remove the organics and extracted 3 times with ethyl acetate. The combined organic layers are extracted with 1 H HCl. The aqueous layer is basified with 28% NH4OH and extracted 3 times with ethyl acetate. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated. (Yield: 488 mg, 49%). 1H NMR (400 MHz, CDCl3) δ ppm 1.36 (s, 9 H) 1.40 (d, J=6.60 Hz, 3 H) 4.15 (q, J=6.60 Hz, 1H) 7.31 (d, J=8.20 Hz, 1 H) 7.63 (dd, J=8.20, 2.34 Hz, 1 H) 8.52 (d, J=2.34 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[C:14]([CH3:16])=O>>[CH2:19]([O:18][C:13](=[O:17])[C@H:14]([CH3:16])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]([F:10])([F:11])[F:12])[CH:4]=1)[CH3:20]
Reactant: CCOC(=O)C(C)=O
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Product: CCOC(=O)[C@H](C)Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Following General Procedure AA above and using 4-chloro-3-(trifluoromethyl)aniline (Aldrich) and ethyl pyruvate (Aldrich), the title compound was prepared.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:15]2[CH:14]=[C:13]([C:16]3[C:17]([O:23][CH2:24][CH3:25])=[N:18][CH:19]=[CH:20][C:21]=3[CH3:22])[CH:12]=[CH:11][C:10]=2[C:9]2[N:26]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:27]=[CH:28][C:8]=2[C:7]1=[O:35]>C(O)(C(F)(F)F)=O>[CH2:24]([O:23][C:17]1[C:16]([C:13]2[CH:12]=[CH:11][C:10]3[C:9]4[N:26]([CH:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[N:27]=[CH:28][C:8]=4[C:7](=[O:35])[NH:6][C:15]=3[CH:14]=2)=[C:21]([CH3:22])[CH:20]=[CH:19][N:18]=1)[CH3:25]
Reactant: CCOc1nccc(C)c1-c1ccc2c3c(cnn3C3CCOCC3)c(=O)n(Cc3ccc(OC)cc3OC)c2c1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1nccc(C)c1-c1ccc2c(c1)[nH]c(=O)c1cnn(C3CCOCC3)c12
Temperature: 65 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
[5-(2,4-dimethoxybenzyl)-4-oxo-1-(tetrahydro-2H-pyran-4-yl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinolin-7-yl]boronic acid obtained in Preparation Example 1 (70 mg) was dissolved in 1,4-dioxane (4 mL). 3-bromo-2-ethoxy-4-methylpyridine obtained in Preparation Example 44 (49 mg), Pd(PPh3)4 (8.7 mg), cesium carbonate (148 mg) and water (1 mL) were added to the solution, and the mixture was reacted using a microwave reactor at 130° C. for two hours. The reaction mixture was returned to room temperature and then partitioned by adding ethyl acetate. The organic layer was washed with brine and then dried over magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 30% to 50% to 80%) to give 5-(2,4-dimethoxybenzyl)-7-(2-ethoxy-4-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (55 mg). The 5-(2,4-dimethoxybenzyl)-7-(2-ethoxy-4-methylpyridin-3-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (55 mg) was dissolved in TFA (1 mL), and the mixture was stirred at 65° C. for two hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was neutralized by adding a saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with DCM. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 50% to 70% to 80% to 100%) to give the title compound (17 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:24])[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[N:18]=3)=[CH:16][C:10]=2[C:9]1=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[CH:28]=[C:29]([C:32](Cl)=[O:33])[S:30][CH:31]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:24])[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:32]([C:29]4[S:30][CH:31]=[C:27]([CH3:26])[CH:28]=4)=[O:33])[N:18]=3)=[CH:16][C:10]=2[C:9]1=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1c(-c2ccnc(N)n2)cc2c1CCN(C(=O)OC(C)(C)C)C2=O
Reactant: Cc1csc(C(=O)Cl)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1csc(C(=O)Nc2nccc(-c3cc4c(n3C)CCN(C(=O)OC(C)(C)C)C4=O)n2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.5 %

Procedure:
2-(2-Amino-pyrimidin-4-yl)-1-methyl-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (prepared as described in Example 9) (300 mg, 0.873 mmol) was suspended in dry pyridine under nitrogen atmosphere and sonicated for 2 minutes. 4-Methyl-thiophene-2-carbonyl chloride (0.142 mL, 1.135 mmol, 1.3 eq) and DMAP (10 mg, 0.087 mmol, 0.1 eq) were added and the mixture was stirred at room temperature for 3 hours. Pyridine was then evaporated and the residue was taken up with saturated aqueous NaHCO3 (10 mL) and extracted with ethyl acetate (3×10 mL). Combined organic layers were washed with brine (3×10 mL), dried over Na2SO4 and evaporated to dryness. The crude product was purified by chromatography on silica gel (gradient n-hexane/ethyl acetate 1:1 to pure ethyl acetate) to obtain 394 mg of 1-methyl-2-{2-[(4-methyl-thiophene-2-carbonyl)-amino]-pyrimidin-4-yl}-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester (85%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH2:12])[CH2:4][CH2:3]1.[NH2:13][C:14](N)=[O:15].N>>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:14]([NH2:13])=[O:15])[CH2:4][CH2:3]1
Reactant: NC(N)=O
Reactant: NC1CCC(=O)c2ccccc21
Agent: N
Product: NC(=O)NC1CCC(=O)c2ccccc21

Procedure:
Similarly, 1,2,3,4-tetrahydro-4-oxo-1-naphthylamine and excess urea are mixed and heated until ammonia evolution ceases. The solid product, 1,2,3,4-tetrahydro-4-oxo-1-naphthylurea, is washed with water, collected by filtration and dried.