Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[C:6]([C:10]3[C:11](=[O:36])[NH:12][C:13](=[O:35])[C:14]=3[C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][C:22]=4F)[N:17]([CH:25]4[CH2:34][CH2:33][C:28]5(OCC[O:29]5)[CH2:27][CH2:26]4)[CH:16]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.Cl>O1CCCC1>[O:1]1[C:5]2[C:6]([C:10]3[C:11](=[O:36])[NH:12][C:13](=[O:35])[C:14]=3[C:15]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]([CH:25]4[CH2:34][CH2:33][C:28](=[O:29])[CH2:27][CH2:26]4)[CH:16]=3)=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C1NC(=O)C(c2cn(C3CCC4(CC3)OCCO4)c3cccc(F)c23)=C1c1cccc2ccoc12
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCC(n2cc(C3=C(c4cccc5ccoc45)C(=O)NC3=O)c3ccccc32)CC1
Temperature: 25 °C

Procedure:
Dissolve 3-(Benzofur-7-yl)-4-[1-(1,4-dioxa-spiro[4.5]dec-8-yl)-4-fluoro-1H-indol-3-yl]pyrrole-2,5-dione (1.40 g, 2.88 mmol) in tetrahydrofuran (20 mL) and stir at room temperature. Add 1N hydrochloric acid (20 mL) and heat the reaction to reflux for 24 h. Upon completion, Filter the product, rinse with cold water, and dry under vaccuum. The orange solid is used without further purification, 1.1 g (87%). MS (ES, m/z): 443.18(M++1), 441.13(M+−1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][S:8]([CH2:11]P(C1C=CC=CC=1)(C1C=CC=CC=1)=O)(=[O:10])=[O:9])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.[Si:38]([O:45][C@H:46]1[CH2:50][C@H:49]([N:51]2[C:55]3[N:56]=[CH:57][N:58]=[C:59]([NH:60][C@@H:61]4[C:69]5[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=5)[CH2:63][CH2:62]4)[C:54]=3[CH:53]=[CH:52]2)[CH2:48][C@H:47]1[CH:70]=O)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39]>C1COCC1>[C:1]([O:5][C:6](=[O:26])[NH:7][S:8](/[CH:11]=[CH:70]/[C@@H:47]1[CH2:48][C@@H:49]([N:51]2[C:55]3[N:56]=[CH:57][N:58]=[C:59]([NH:60][C@@H:61]4[C:69]5[C:64](=[CH:65][CH:66]=[CH:67][CH:68]=5)[CH2:63][CH2:62]4)[C:54]=3[CH:53]=[CH:52]2)[CH2:50][C@@H:46]1[O:45][Si:38]([C:41]([CH3:43])([CH3:44])[CH3:42])([CH3:39])[CH3:40])(=[O:10])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)CP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@H]1C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NS(=O)(=O)/C=C/[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
tert-Butyl{[(diphenylphosphoryl)methyl]sulfonyl}carbamate (602 mg, 1.45 mmol) was dissolved in THF (50.0 mL) under an atmosphere of argon, a 1.60 M solution of n-butyllithium in hexane (1.81 mL, 2.89 mmol) was added at −50° C., and the resultant mixture was stirred for 1 h. A solution of (1R,2S,4R)-2-{[tert-butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentanecarbaldehyde (300 mg, 0.60 mmol) in THF (8.0 mL) was added to the mixture, and the resulting mixture was stirred for 30 min at room temperature. After quenching by addition of water (200 mL), the mixture was extracted with EtOAc (100 mL×3). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography eluting with a gradient of 10 to 60% EtOAc in hexane to afford the title compound (84.0 mg, 21%). LC/MS: Rt=1.90 min, ES+ 654 (FA standard).
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][C:5]3[C:10]([CH:2]12)=[CH:9][C:8]([F:11])=[C:7]([F:12])[CH:6]=3>C(O)C.[Pd]>[F:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[F:12])[CH2:4][CH:3]([OH:1])[CH2:2]2
Reactant: Fc1cc2c(cc1F)C1OC1C2
Agent: [Pd]
Solvent: CCO
Product: OC1Cc2cc(F)c(F)cc2C1
Yield: 59.4 %

Procedure:
Impure 1,2-epoxy-5,6-difluoroindane (4.5 g) was dissolved in 100 mL of ethanol and hydrogenated over 10% palladium on carbon (450.mg) for 15 hours. The mixture was filtered and evaporation gave 5,6-difluoro-2-hydroxyindane (2.72 g, 15.9 mmol), m.p. 57°-58° C.
Reaction SMILES: S(=O)(=O)(O)O.[C:6](O)(=[O:15])[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)O.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH2:27])=[O:26])=[CH:20][CH:19]=1>>[O:15]=[C:6]1[CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:23]2[CH:22]=[C:21]([CH2:24][C:25]([NH2:27])=[O:26])[CH:20]=[CH:19][C:18]=2[O:17]1
Reactant: NC(=O)Cc1ccc(O)cc1
Reactant: O=C(O)C(O)c1ccccc1
Agent: O=S(=O)(O)O
Product: NC(=O)Cc1ccc2c(c1)C(c1ccccc1)C(=O)O2
Temperature: 80 °C
Yield: 20 %

Procedure:
190 ml of 80% strength sulfuric acid solution are added to a mixture of 16 g of mandelic acid and 15 g of 4-hydroxyphenylacetamide [J. Am. Chem. Soc. (1946) p. 2633]. The medium is heated very rapidly to 80° C. and immediately hydrolyzed using 600 g of ice. The aqueous phase is extracted with 3 times 200 ml of chloroform and the organic phase washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product obtained is recrystallized in chloroform.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:19])=[C:12]([CH2:17][NH2:18])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br-].[CH2:21]([Zn+])[CH2:22][CH2:23][CH3:24]>C1COCC1.CCOC(C)=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>[CH2:21]([C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:19])=[C:12]([CH2:17][NH2:18])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCC[Zn+]
Reactant: NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Temperature: 60 °C
Yield: 74.7 %

Procedure:
To a solution of ({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amine (300 mg, 0.822 mmol) and tetrakis(triphenylphosphine)palladium(0) (950 mg, 0.822 mmol) in THF (4 ml) was added n-butyl zinc bromide (0.5 M solution in THF) (1.644 ml, 0.822 mmol) and the reaction mixture was heated at 60° C. for one hour. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give ({3-[(3-butyl-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)amine (210 mg, 0.614 mmol, 75% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.43 (s, 2H), 6.97 (s, 1H), 6.68 (s, 1H), 6.64 (s, 1H), 3.71 (s, 2H), 2.50 (t, 2H), 1.88 (br. s., 2H), 1.45 (quin, 2H), 1.14-1.29 (m, 2H), 0.82 (t, 3H).
Reaction SMILES: Cl[C:2]1[N:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5].[CH:14]1([CH2:19][NH:20][CH2:21][CH3:22])[CH2:18][CH2:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH:14]1([CH2:19][N:20]([C:2]2[N:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=2[C:4]#[N:5])[CH2:21][CH3:22])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCNCC1CCCC1
Reactant: Cc1nc(Cl)c(C#N)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCN(CC1CCCC1)c1nc(C)c([N+](=O)[O-])cc1C#N
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A mixture of 2-chloro-6-methyl-5-nitronicotinonitrile (997 mg, 5.05 mmol), N-(cyclopentylmethy)-N-ethylamine (770 mg, 6.05 mmol), and K2CO3 (1.7 g, 12.3 mmol) in toluene (20 mL) is heated to 110° C. After stirring for 3 hours, the reaction mixture is filtered to remove the resulting precipitate. The filtrate is diluted with EtOAc and washed with H2O and brine. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica-gel column chromatography to give 2-[N-(cyclopentylmethyl)-N-ethylamino]-6-methyl-5-nitronicotinonitrile as orange oil.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][O:6][C@H:5]([CH2:9][N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)[CH2:4]1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([N:3]1[CH2:8][CH2:7][O:6][C@H:5]([CH2:9][N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)[CH2:4]1)[CH3:2]
Reactant: CCN1CCO[C@H](CN2CCN(C(=O)OC(C)(C)C)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN1CCO[C@H](CN2CCNCC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl 4-((2R)-4-ethylmorpholin-2-ylmethyl)piperazinecarboxylate (0.50 g, 1.60 mmol) prepared according to Process Step 1 was dissolved in dichloromethane (5 mL), and the solution was mixed with trifluoroacetic acid (2 mL) added dropwise under ice-cooling. After stirring at room temperature for one hour, the solvent was distilled off under reduced pressure. The resulting yellow oil was dissolved in dioxane (6 mL), and the solution was mixed with triethylamine (3 mL) to thereby yield (2R)-4-ethyl-2-(piperazinylmethyl)morpholine.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].FC(F)(F)S([O:16][CH2:17][C:18]([F:29])([F:28])[CH2:19]OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:28][C:18]1([F:29])[CH2:17][O:16][C:9]2[CH:2]=[CH:3][C:4]([CH:5]=[O:6])=[CH:7][C:8]=2[O:10][CH2:19]1
Reactant: O=Cc1cc(O)cc(O)c1
Reactant: O=S(=O)(OCC(F)(F)COS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=Cc1ccc2c(c1)OCC(F)(F)CO2
Temperature: 50 °C

Procedure:
A mixture of 2 g of 3,5-dihydroxybenzaldehyde, 6 g of 2,2-difluoropropane-1,3-diyl bis(trifluoromethanesulfonate) and 12 g of cesium carbonate in 100 mL of anhydrous acetonitrile was heated under nitrogen to 50° C. overnight. The mixture was allowed to cool, then filtered and concentrated under reduced pressure. The residue was partitioned between 250 mL of ethyl acetate and 100 mL of saturated sodium carbonate then dried over magnesium sulfate and concentrated under reduced pressure. Purification by flash chromatography (0-25% ethyl acetate in hexanes) gave the product as colorless oil. MS (m+1)=215.1; 1H NMR (400 MHz, CDCl3) 9.85 (s, 1H), 7.6 (m, 2H), 7.1 (d, 1H), 4.48 (m, 4H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(C(C)C)CC)(C)C.[F:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[F:42])[C:36](Cl)=[O:37]>C(Cl)Cl>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:36](=[O:37])[C:35]3[CH:39]=[CH:40][C:41]([F:42])=[C:33]([F:32])[CH:34]=3)[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccc(F)c(F)c4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.16 mmol) in CH2Cl2 (60 ml), was added diisopropylethylamine (0.94 mL, 5.4 mmol) and 3,4-difluorobenzoyl chloride (0.5 g, 2.8 mmol). The mixture was stirred at room temperature overnight and a suspension was obtained. The reaction mixture was quenched with MeOH (1 mL) and was filtered. The solid was rinsed with CH2Cl2 (5 mL) and then dissolved in acetone (4 mL). Ether (10 mL) and hexane (10 mL) were added to the solution and the resulting suspension was filtered to afford N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3,4-difluoro-benzamide as a white solid (0.7 g, 75%): mp, 218-220° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=4.1 min. (99%); 1H NMR (DMSO-d6): δ 2.06-2.11 (m, 1H), 2.51-2.64 (m, 2H), 2.87-2.93 (m, 1H), 4.95 (d, J=5.8 Hz, 2H), 5.15-5.21 (dd, J=5, 12 Hz, 1H), 7.55-8.01 (m, 6H), 9.26 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 21.96, 30.92, 39.20, 48.86, 116.77, 116.65, 116.89, 117.51, 117.74, 121.95, 124.75, 124.80, 124.85, 124.89, 127.18, 131.28, 131.32, 131.39, 131.53, 133.15, 134.82, 138.86, 147.42, 147.59, 149.70, 149.87, 150.68, 150.85, 153.02, 153.19, 164.45, 166.93, 167.49, 169.81, 172.74. Anal Calcd for C21H15F2N3O5: C, 59.02; H, 3.54; N, 9.83; F, 8.89. Found: C, 59.12; H, 3.60; N, 9.68; F, 8.86.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([NH:9][N:10]=[CH:11][C:12](=O)[C:13]([F:16])([F:15])[F:14])=[C:4]([F:18])[CH:3]=1.[C:19]([CH2:24][CH:25]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OCC)=[O:20]>O1CCCC1>[F:18][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([OH:8])=[CH:6][C:5]=1[N:9]1[C:19](=[O:20])[C:24]([CH3:25])=[C:12]([C:13]([F:16])([F:15])[F:14])[CH:11]=[N:10]1
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(C=NNc1cc(O)c(Cl)cc1F)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1c(C(F)(F)F)cnn(-c2cc(O)c(Cl)cc2F)c1=O
Yield: 60.2 %

Procedure:
Then, 12.9 g of 3,3,3-trifluoro-2-oxopropanal 1-(4-chloro-2-fluoro-5-hydroxyphenylhydrazone) and 22.3 g of carbethoxyethylidenetriphenylphosphorane were dissolved in 110 ml of tetrahydrofuran, and the solution was heated under reflux for 3 hours. The solvent was distilled out under reduced pressure, and the residue was subjected to silica gel chromatography, which afforded 8.8 g of 2-(2-fluoro-4-chloro-5-hydroxyphenyl)-4-methyl-5-trifluoromethylpyridazin-3-one (compound 1-391).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[N:18][C:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:16]2[C:27]1[CH:28]=[C:29]([NH2:33])[CH:30]=[CH:31][CH:32]=1>C(#N)C>[Cl:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[N:18][C:17]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[C:16]2[C:27]1[CH:28]=[C:29]([NH:33][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[CH:30]=[CH:31][CH:32]=1
Reactant: Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reactant: O=C=Nc1ccccc1
Solvent: CC#N
Product: O=C(Nc1ccccc1)Nc1cccc(-c2c(-c3ccccc3)nnc3c(Cl)cccc23)c1
Reaction time: 3 h
Yield: 73 %

Procedure:
Phenyl isocyanate (0.075 g, 0.63 mmol) was added to a stirred solution of 3-(8-chloro-3-phenyl-cinnolin-4-yl)-phenylamine (0.025 g, 0.076 mmol) in 5 mL of ACN at room temperature. The reaction mixture was stirred for 3 hours and concentrated. The residue was purified by silica gel chromatography using 5-50% EtOAc/hexanes as eluent to provide 0.025 g of the title compound as a gray solid. HRMS (ESI, [M+H]+) 451.1310.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C@@H:19]([NH2:22])[C@H:18]([OH:23])[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C@@H:19]([NH:22][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:18]([OH:23])[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC[C@@H](NCc2ccccc2)[C@H](O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
Add benzaldehyde (0.24 mol, 26.3 g) to a solution of racemic trans-4-amino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.24 mol, 53.7 g), and acetic acid (92 mL) in ethanol (400 mL) and stir the reaction mixture at room temperature for 30 min. Add sodium cyanoborohydride (0.49 mol, 31.2 g) and stir the reaction mixture for 3 h. Quench the reaction mixture with sodium bicarbonate solution and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate. Dissolve the residue in a minimum amount of dichloromethane and add 0.1 N aqueous hydrochloric acid to maintain the pH between 4-5. Discard the organic layer. Wash the acidic aqueous layer three times with dichloromethane and discard the organic layer. Adjust the pH of the aqueous layer between 10-12 and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (35.7 g, 46%) as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.35-1.40 (m, 2H), 1.45 (s, 9H), 2.05 (br s 1H), 2.43 (t, 1H), 2.57 (t, 1H), 2.69 (br s, 1H), 3.27 (br s, 1H), 3.70 (d, 1H), 3.94 (d, 1H), 4.15 (br s, 1H), 4.26 (d, 1H), 7.23-7.29 (m, 1H), 7.30-7.32 (m, 2H), 7.33-7.36 (m, 2H).
Reaction SMILES: [BrH:1].[CH2:2]([O:4][C:5](=[O:20])[CH:6]([C:18]#[N:19])[CH:7]1[CH2:16][CH2:15][C:14]2[CH:13]=[N:12][CH:11]=[CH:10][C:9]=2[C:8]1=O)[CH3:3]>C(O)(=O)C.C(OCC)C>[BrH:1].[CH2:2]([O:4][C:5]([C:6]1[C:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[N:12][CH:11]=[CH:10][C:9]=3[C:8]=2[NH:19][C:18]=1[Br:1])=[O:20])[CH3:3]
Reactant: CCOC(=O)C(C#N)C1CCc2cnccc2C1=O
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)c1c(Br)[nH]c2c1CCc1cnccc1-2
Yield: 89 %

Procedure:
To stirred, cold (4° C.) 33% HBr in acetic acid (27 mL), cyano-(5-oxo-5,6,7,8-tetrahydro-isoquinolin-6-yl)-acetic acid ethyl ester 8C (7 mmol), dissolved in acetic acid (22 mL) and diethyl ether (22 mL), was added dropwise. The mixture was stirred at rt for 15 h. The yellow precipitate was filtered and repeatedly washed with diethyl ether affording the title product in 89% yield. ESI (+) MS: m/z 322 (MH+). 1H NMR: 1.32 (t, J=7.19, 3H), 3.02-3.33 (m, 4H), 4.17-4.31 (m, 2H), 7.89 (d, J=6.22, 1H), 8.61-8.64 (m, 1H), 8.65-8.70 (m, 1H), 13.49 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][N:7]=1.[C:9]([O-])([O-])=O.[Cs+].[Cs+].CI>CC#N>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH3:9])[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1ccc(Cl)n[nH]1
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: Cn1nc(Cl)ccc1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 749.4 %

Procedure:
To a solution of 6-chloropyridazin-3(2H)-one (780 mg, 6 mmol) in CH3CN (40 mL) was added Cs2CO3 (3.9 g, 12 mmol) and CH3I (1 mL, 12 mmol) and the reaction mixture was stirred at 70° C. overnight. Solid was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/EA=3/1) to afford the title compound as orange oil (6.5 g, 75%). [LCMS: Rt=1.43 min, m/z 145.1 (M+H)+].
Reaction SMILES: C(N1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([B:16]([OH:18])[OH:17])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(C)C.BrC1C=CC(N2CC[CH:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)CC2)=CC=1>>[O:35]1[CH2:36][CH2:37][N:32]([CH:29]2[CH2:5][CH2:6][N:7]([C:10]3[CH:11]=[CH:12][C:13]([B:16]([OH:17])[OH:18])=[CH:14][CH:15]=3)[CH2:8][CH2:9]2)[CH2:33][CH2:34]1
Reactant: CC(C)N1CCN(c2ccc(B(O)O)cc2)CC1
Reactant: Brc1ccc(N2CCC(N3CCOCC3)CC2)cc1
Product: OB(O)c1ccc(N2CCC(N3CCOCC3)CC2)cc1
Yield: 40 %

Procedure:
The title compound was synthesized according to the synthesis of 4-(4-isopropylpiperazin-1-yl)phenylboronic acid, except substituting 4-(1-(4-bromophenyl)piperidin-4-yl)morpholine (250 mg, 0.77 mmol). The aqueous layer was washed with EtOAc and concentrated. The residue was triturated with THF and the filtrate was concentrated to give the title compound as a yellow solid (87 mg, 40%). 1H NMR (400 MHz, MeOD) δ 7.58 (br s, 2H), 6.93 (d, J=7.5 Hz, 2H), 3.85-3.82 (m, 2H), 3.72 (br s, 4H), 2.72 (t, J=12.3 Hz, 2H), 2.63 (br s, 4H), 2.40-2.34 (m, 1H), 2.01-1.98 (m, 2H), 1.62-1.54 (m, 2H); MS ESI 291.1 [M+H]+, calcd for [C15H23BN2O3+H]+ 291.18.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)=[C:22]=[O:23]>CN(C=O)C>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([NH:21][C:22]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:23])=[CH:25][CH:26]=1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Reactant: COc1ccc(N=C=O)cc1
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)N2CCC(c3ncnc4cc(OC)c(OC)cc34)CC2)cc1
Yield: 55.7 %

Procedure:
To a solution of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (30 mg, 0.110 mmol), as prepared in Example 1d, in DMF (1 mL) was treated with 1-isocyanato-4-methoxy-benzene (24.5 mg, 0.164 mmol) at RT overnight. The reaction was then partitioned between EtOAc (10 mL) and H2O (10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a yellow solid (25.9 mg, 56%). 1H NMR (300 MHz, CDCl3) δ 9.10 (s, 1H), 7.29 (m, 4H), 6.88 (m, 2H), 6.30 (br s, NH), 4.30-4.26 (m, 2H), 4.08 (s, 6H), 3.80 (s, 3H), 3.61 (m, 1H), 3.17 (m, 2H), 2.19-2.14 (m, 2H), 2.03-1.97 (m, 2H); LC/MS (ESI): calcd mass 422.2, found 423.3 [M+1]+.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.[Cl:19][C:20]1[C:25]2[CH:26]=[N:27][NH:28][C:24]=2[CH:23]=[CH:22][N:21]=1>ClCCl>[Cl:19][C:20]1[C:25]2[CH:26]=[N:27][N:28]([CH:18]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:24]=2[CH:23]=[CH:22][N:21]=1
Reactant: Clc1nccc2[nH]ncc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: Clc1nccc2c1cnn2C1CCCCO1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
p-Toluenesulfonic acid monohydrate (2.4 g, 13 mmol) and 3,4-dihydro-2H-pyran (99%, 45 mL, 520 mmol) were sequentially added to a suspension of 4-chloro-1H-pyrazolo[4,3-c]pyridine (20.0 g, 130 mmol) in dichloromethane (400 mL). The reaction mixture was allowed to stir at room temperature for 24 hours, at which time it was washed with saturated aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Eluents: 10%, then 30%, then 50% ethyl acetate in heptane) afforded the product as a white solid. Yield: 27.51 g, 115.7 mmol, 89%. LCMS m/z 238.1 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J=6.0 Hz, 1H), 8.16 (d, J=0.9 Hz, 1H), 7.47 (dd, J=6.0, 0.9 Hz, 1H), 5.73 (br dd, J=9.0, 2.7 Hz, 1H), 3.97-4.04 (m, 1H), 3.72-3.80 (m, 1H), 2.43-2.53 (m, 1H), 2.07-2.20 (m, 2H), 1.65-1.85 (m, 3H).
Reaction SMILES: Cl.[C:2]([N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:9]([C:18]2[S:19][CH:20]=[C:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:22]=2)[CH:8]=[N:7]1)([CH3:5])([CH3:4])[CH3:3].[C:29]([C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1)#[N:30]>>[C:2]([N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:9]([C:18]2[S:19][CH:20]=[C:21]([CH:23]3[CH2:24][CH2:25][N:26]([C:35]([C:34]4[CH:38]=[CH:39][C:31]([C:29]#[N:30])=[CH:32][CH:33]=4)=[O:36])[CH2:27][CH2:28]3)[N:22]=2)[CH:8]=[N:7]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)n1ncc(-c2nc(C3CCNCC3)cs2)c1-c1ccc(F)cc1
Agent: Cl
Product: CC(C)(C)n1ncc(-c2nc(C3CCN(C(=O)c4ccc(C#N)cc4)CC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 4-{2-[1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl]-1,3-thiazol-4-yl}piperidine monohydrochloride and 4-cyanobenzoic acid and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.