Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.Cl[CH2:4][C:5]1[N:6]=[C:7]([C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)[S:8][CH:9]=1.[N+:16]([C:19]1[CH:23]=[N:22][NH:21][N:20]=1)([O-:18])=[O:17].CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[CH3:15][C:10]1([C:7]2[S:8][CH:9]=[C:5]([CH2:4][N:21]3[N:20]=[C:19]([N+:16]([O-:18])=[O:17])[CH:23]=[N:22]3)[N:6]=2)[O:14][CH2:13][CH2:12][O:11]1
Reactant: O=[N+]([O-])c1cn[nH]n1
Reactant: CC1(c2nc(CCl)cs2)OCCO1
Agent: N#N
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(c2nc(Cn3ncc([N+](=O)[O-])n3)cs2)OCCO1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 4-chloromethyl-2-(2-methyl-[1,3]dioxolan-2-yl)-thiazole (231 mg, 1.05 mmol) in DMF (1.5 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (100 mg, 0.88 mmol) in DMF (1.5 mL) pre-treated for 30 min with DIPEA (0.30 mL, 1.75 mmol) and the reaction mixture was stirred for 48 h at 50° C. Water (10 mL), followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over NaSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (6:4 hept-EA) gave the title compound as a pale yellow oil: TLC:rf (6:4 hept-EA)=0.33. LC-MS-conditions 02: tR=0.90 min, [M+H]+=298.23.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][N:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[CH3:14][C:15]1([CH3:36])[C:19]([CH3:21])([CH3:20])[O:18][B:17](C2C=CC(OC3C=CC=CC=3)=CC=2C)[O:16]1>>[CH3:10][N:9]([CH3:11])[CH2:8][CH2:7][O:6][C:5]1[CH:12]=[CH:13][C:2]([B:17]2[O:18][C:19]([CH3:21])([CH3:20])[C:15]([CH3:36])([CH3:14])[O:16]2)=[CH:3][CH:4]=1
Reactant: CN(C)CCOc1ccc(Br)cc1
Reactant: Cc1cc(Oc2ccccc2)ccc1B1OC(C)(C)C(C)(C)O1
Product: CN(C)CCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1

Procedure:
Prepared from [2-(4-bromo-phenoxy)-ethyl]-dimethyl-amine according to general Method I for borylation described above for preparation of 4,4,5,5-tetramethyl-2-(2-methyl-4-phenoxy-phenyl)-[1,3,2]dioxaborolane.
Reaction SMILES: CO[C:3](=[O:18])[CH:4]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=O.[CH3:19][O:20][C:21]([C:23]1[CH:27]=[C:26]([NH2:28])[NH:25][N:24]=1)=[O:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC1C=CC=CC=1>[CH3:19][O:20][C:21]([C:23]1[CH:27]=[C:26]2[NH:28][C:5]([C:7]3[O:8][CH:9]=[CH:10][CH:11]=3)=[C:4]([CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]3)[C:3](=[O:18])[N:25]2[N:24]=1)=[O:22]
Reactant: COC(=O)C(C(=O)c1ccco1)C1CCCCC1
Reactant: COC(=O)c1cc(N)[nH]n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Clc1ccccc1
Solvent: O
Product: COC(=O)c1cc2[nH]c(-c3ccco3)c(C3CCCCC3)c(=O)n2n1
Temperature: 120 °C
Yield: 32.1 %

Procedure:
A mixture of 1.1 g (4.4 mmol) of 2-cyclohexyl-3-furan-2-yl-3-oxo-propionic acid methyl ester, 0.592 g (4.2 mmol) of 5-amino-1H-pyrazole-3-carboxylic acid methyl ester, 76 mg (0.4 mmol, 10 mol %) of p-toluenesulfonic acid monohydrate (PTSA), and 50 mL of chlorobenzene was heated at 120° C. overnight. The reaction mixture was then concentrated to a residue which was chromatographed on silica gel (7% methanol in dichloromethane) to afford 0.46 g (32% yield) of desired 6-cyclohexyl-5-furan-2-yl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester as indicated by 1H NMR; LC-MS—calcd for C18H19N3O4 [M++H]+: 342.14, found: 342.3.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:25])=[O:24])=[C:19]([OH:26])[CH:18]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:26][C:19]1[CH:18]=[C:17]([CH3:16])[CH:22]=[CH:21][C:20]=1[C:23](=[O:24])[CH3:25]
Reactant: CC(=O)c1ccc(C)cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc(C)ccc3C(C)=O)c2cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 21.1 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (116 mg), 2-hydroxy-4-methylacetophenone (300 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (37 mg, yield 6%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[C:3]=1[CH2:23][C:24]([O:26][CH3:27])=[O:25].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:38]1[CH2:42]OC[CH2:39]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)[C:3]=1[CH:23]([CH2:39][CH2:38][CH3:42])[C:24]([O:26][CH3:27])=[O:25]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CC=CC=C3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CC=CC=C3
Yield: 80 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(p-tolyl)-5H-cyclohepta[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.510 g; 1.3 mmol), LHMDS 1N in THF (1.44 mL; 1.44 mmol), 1-iodopropane (0.215 mL; 1.95 mmol) in DMF (4 mL) for 5 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.434 g (79%) of the title compound as a yellow solid.
Reaction SMILES: [O:1]=[C:2]([O-:13])[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])O)[OH:4].O=C([O-])[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[Na+].[Cl-].[Mg+2].[Cl-].Cl>C(O)C(N)(CO)CO>[CH2:5]([C:3]([C:2]([OH:13])=[O:1])=[O:4])[C@H:7]([OH:8])[C@H:9]([OH:10])[CH2:11][OH:12]
Reactant: O=C([O-])[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: [Cl-]
Product: O=C(O)C(=O)C[C@H](O)[C@H](O)CO
Reaction time: 2 h

Procedure:
Samples of the purified gluconate dehydratase solution prepared in Example 3, which was dissolved in the 30 mM Tris buffer (pH 8.5) containing 1 mM sodium D-gluconate and 1 mM magnesium chloride, were allowed to stand for 30 minutes, 2 hours, or 12 hours at 4, 20, 30, 40, 50, 55, 60, 65, or 70° C. Another sample was allowed to stand at 4° C. for 7 days and 30 days. Then, each sample subjected to heat treatment as above was reacted with 1 mL of a liquid containing 1 μmmol of Tris buffer (pH 8.5), 40 μmol of sodium D-gluconate, and 1 μmol of magnesium chloride at 37° C. After 10 minutes, 200 μL of 1 M hydrochloric acid solution was added to the reaction mixture to stop the reaction. Then, the amount of 2-keto-3-deoxy-D-gluconic acid produced was determined by high-performance liquid chromatography, and the reaction rate was calculated. The results are shown in Table 2 by relative activities to the enzyme activity before heat treatment which is represented as 100. The activity of 100% was maintained after treatment at 55° C. for 2 hours, and it is also stably maintained for 30 days at 4° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:6]=1)=O.[BH4-].[Na+]>CCO>[N:14]1([CH2:13][CH2:12][CH2:11][O:10][C:7]2[CH:6]=[C:5]([CH2:3][OH:2])[O:9][N:8]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1cc(OCCCN2CCCCC2)no1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc(OCCCN2CCCCC2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
To a solution of 3-(3-piperidin-1-yl-propoxy)-isoxazole-5-carboxylic acid methyl ester (0.200 g, 0.750 mmol) in EtOH (15 mL) was added NaBH4 (0.358 g, 11.2 mmol) was slowly over 30 min. The reaction mixture was heated at reflux overnight, then was cooled to rt and quenched by the addition of 1 N NaOH (10 mL). The mixture was stirred for 1 h, and then was extracted with DCM (3×30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to yield the desired alcohol (0.177 g, 99%). MS (ESI): exact mass calcd. for C12H20N2O3, 240.15; m/z found, 241.3 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[N:26]1([C:31]2[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=2)[NH2:34])[CH:30]=[CH:29][N:28]=[CH:27]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([NH:34][C:33]3[CH:35]=[CH:36][CH:37]=[C:31]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)[CH:32]=3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Nc1cccc(-n2ccnc2)c1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)Nc3cccc(-n4ccnc4)c3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 3-(1H-imidazol-1-yl)aniline and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].Cl[C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]2[C:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][NH:15][C:7]=12>C1(C)C(C)=CC=CC=1>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:13]2[C:8]3=[N:9][C:10]([CH3:12])=[CH:11][C:6]([NH:4][CH2:3][CH2:1][OH:2])=[C:7]3[NH:15][N:14]=2)=[CH:21][CH:20]=1
Reactant: NCCO
Reactant: Cc1cc(Cl)c2[nH]nc(-c3ccc(Cl)cc3)c2n1
Solvent: Cc1ccccc1C
Product: Cc1cc(NCCO)c2[nH]nc(-c3ccc(Cl)cc3)c2n1

Procedure:
A mixture of ethanolamine (5 ml) and 7-chloro-5-methyl-3-(4-chlorophenyl)-1H-pyrazolo[4,3-b]pyridine (D16) (0.6 g) were heated under reflux in xylene (10 ml) under nitrogen for 48 h. The mixture was evaporated to dryness in vacuo and dissolved in a mixture of water (40 ml) and methanol (60 ml). The pH of the solution was adjusted to ca. 12 with 10% sodium hydroxide solution and then the solution was evaporated to one third volume in vacuo. The resulting precipitate (0.6 g) was collected, washed with water, and recrystallised from ethyl acetate-methanol (trace) to afford the title compound (0.42 g), m.p. 222°-224° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+].[C:29]([Si:33]([CH3:50])([CH3:49])[O:34][CH:35]1[CH2:40][CH2:39][C:38](OS(C(F)(F)F)(=O)=O)=[CH:37][CH2:36]1)([CH3:32])([CH3:31])[CH3:30]>C1(C)C=CC=CC=1.CCOC(C)=O.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.CCO>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:38]2[CH2:39][CH2:40][CH:35]([O:34][Si:33]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:49])[CH3:50])[CH2:36][CH:37]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(B(O)O)cc1)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC1CC=C(OS(=O)(=O)C(F)(F)F)CC1
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: [Cl-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC1CC=C(c2ccc(NC(=O)OCc3ccccc3)cc2)CC1
Temperature: 100 °C
Yield: 97.9 %

Procedure:
4-Benzyloxycarbonylamino-benzene boronic acid (1.42 g, 5.25 mmol, 1.5 equiv.) and LiCl (420 mg, 10.5 mmol, 3 equiv.) was placed in a 25 mL round bottom flask. To this was added Na2CO3 (2M) (7 mL) and EtOH (7 mL) to form a nice suspension. To this was transferred a solution of trifluoromethanesulfonic acid 4-(tert-butyl-dimethyl-silanyloxy)-cyclohex-1-enyl ester (1.26 g, 3.5 mmol, 1 equiv.) in toluene (18 mL). This suspension was subjected to a vacuum/nitrogen exchange three times. Pd(PPh3)4 (CAS 14221-01-3) (203 mg, 0.05 mmol, 7.5 mol %) was then added. The brown mixture was heated in an oil bath at 100° C. (external) for 50 min when the suspension became dark. At which time the TLC showed that the reaction was complete. The reaction was diluted with EtOAc (20 mL) and water (10 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (10 mL×2). The combined EtOAc extracts were washed with sodium bicarbonate (5 mL), brine (5 mL), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo to obtain a crude product. This was purified on a silica gel column eluted with 30% EtOAc in heptane to afford 1.5 g (98% yield) of the title compound as a crystalline white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11]C(=O)OC(C)(C)C)[CH2:9][CH3:10])=[C:4]([F:19])[C:3]=1[C:20]([C:22]1[CH:23]=[N:24][C:25]([NH:28]CC2C=CC(OC)=CC=2)=[CH:26][CH:27]=1)=[O:21].FC(F)(F)C(O)=O>ClCCl>[NH2:11][C@@H:8]([C:5]1[C:4]([F:19])=[C:3]([C:2]([Cl:1])=[CH:7][CH:6]=1)[C:20]([C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[N:24][CH:23]=1)=[O:21])[CH2:9][CH3:10]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(NCc3ccc(OC)cc3)nc2)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2ccc(N)nc2)c1F
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
Step 8—To a solution of the tert-butyl N-[(1R)-1-[4-chloro-2-fluoro-3-(6-{[(4-methoxyphenyl)methyl]-amino}pyridine-3-carbonyl)phenyl]propyl]carbamate (109 g) in dichloromethane (2 vol) was carefully added trifluoroacetic acid (1 vol) at room temperature. The dichloromethane was removed under vacuum, additional trifluoroacetic acid (2 vol) was added and the mixture was stirred for 10 minutes before increasing the temperature to 70° C. and stirring overnight. The mixture was allowed to cool then poured slowly into a stirred mix of TBME (15 vol) and water (15 vol). The phases were separated and the remaining emulsion was filtered through GFA paper. The TBME layer was extracted into 2M HCl (2×3 vol) and the combined acidic extracts were basified (˜pH 12) and extracted with TBME (5×5 vol). The combined organic liquors were dried (Na2SO4) and concentrated to produce an oil/foam. The material was triturated with EtOAc to give 5-{3-[(1R)-1-aminopropyl]-6-chloro-2-fluorobenzoyl}pyridin-2-amine as a fine yellow powder 53.5 g, 84%. (Data for this compound are in Example 1).
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([O:10]CC)=[O:9])[CH:4]=1.[OH-].[Na+].Cl.[CH2:16]([OH:18])[CH3:17]>>[CH2:16]([O:18][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([OH:10])=[O:9])[CH:4]=1)[CH3:17]
Reactant: CCO
Reactant: CCOC(=O)c1cc(CBr)on1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOCc1cc(C(=O)O)no1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To an oily suspension of ethyl 5-(bromomethyl)isoxazole-3-carboxylate (0.680 g; 2.91 mmol) in aqueous 1M sodium hydroxide (6.4 mL; 6.4 mmol) was added 1 mL of ethanol. The oily suspension immediately transformed to a white solid suspension. The mixture was stirred overnight at room temperature. The pH of the solution was adjusted between 2 and 3 by addition of 6N hydrochloric acid. The solution was extracted with ethyl acetate. Organic extracts were dried over magnesium sulfate and evaporated to afford 0.189 g (38%) of 5-(ethoxymethyl)isoxazole-3-carboxylic acid as a white solid which was directly used in the next step.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl[C:15]1[CH:16]=[CH:17][C:18]2[S:22][CH:21]=[C:20]([N:23]3[C:35]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[C:29]4[C:24]3=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:19]=2[CH:36]=1>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.O1CCCC1>[S:22]1[CH:21]=[C:20]([N:23]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[C:30]3[C:35]2=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:19]2[CH:36]=[C:15]([N:12]3[C:13]4[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=4[C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:16]=[CH:17][C:18]1=2
Reactant: Clc1ccc2scc(-n3c4ccccc4c4ccccc43)c2c1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc2c(c1)c1ccccc1n2-c1ccc2scc(-n3c4ccccc4c4ccccc43)c2c1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
In a 250 mL 2-neck round flask, 5 mL of tetrahydrofuran (THF) was poured to carbazole (0.75 g, 4.5 mmol). Then, a 2.5Mn-butyllithium/hexane solution (1.8 ml) was gradually added to the mixture in an ice bath. This mixture solution was stirred at room temperature for minutes, and then 9-(5-chlorobenzothiophen-3-yl)carbazole (1.5 g, 4.5 mmol) and tetrakis(triphenylphosphine)palladium(0) (Pd(pph3)4) (0.024 g) were poured to the mixture solution, the resulting mixture was dissolved in and tetrahydrofuran, and reacted at 80° C. After the reaction, the precipitate was filtered and recrystallized with dichloromethane and methanol, thereby giving 1.71 g of a product (82%).
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[CH2:14]([O:21][C:22](ON1C(=O)CCC1=O)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.O>CN(C=O)C>[CH2:14]([O:21][C:22]([N:2]1[CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:1]1)=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Reaction time: 12 h
Yield: 96.9 %

Procedure:
To a stirred solution of 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (20.0 g, 116.2 mmole) in dry DMF (150 mL) at RT was added N-(benzyloxycarbonyloxy)succinimide (31.84 g, 127.76 mmole) and triethylamine (13.0 g. 127.76 mmole). After 12 h, the reaction contents were poured into H2O (150 mL) and extracted with EtOAc (2×200 mL). The combined organic phases were washed sequentially with H2O and brine, then were dried over Na2SO4. Concentration under reduced pressure gave a yellow oil. Purification on silica (hexanes/EtOAc, 4:1) afforded the title compound (34.48 g. 97%) as a white solid: MS (ES) m/e 307 (M+H)+.
Reaction SMILES: [OH:1]O.[NH:3]1[C:14]2[C:6](=[CH:7][CH:8]=[C:9]3[C:13]=2[CH2:12][CH2:11][CH2:10]3)[C:5](=[O:15])C1=O.[OH-].[Na+].Cl>O>[NH2:3][C:14]1[C:6]([C:5]([OH:15])=[O:1])=[CH:7][CH:8]=[C:9]2[C:13]=1[CH2:12][CH2:11][CH2:10]2
Reactant: OO
Reactant: O=C1Nc2c(ccc3c2CCC3)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(C(=O)O)ccc2c1CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Add 30% aqueous hydrogen peroxide solution (5 mL) in water (44 mL) to a solution of 1,6,7,8-Tetrahydro-1-aza-as-indacene-2,3-dione (3.80 mg, 20.3 mmol) and NaOH (5.03 g, 126 mmol) in water (97 mL) over a period of 30 minutes, stir the mixture at room temperature for 1 h. Acidulate with 1N hydrochloric acid, filter the solid, wash with water and dry to afford 4-amino-indan-5-carboxylic acid (3.13 g, 87%). Dissolve 4-amino-indan-5-carboxylic acid (3.07 g, 17.3 mmol) in ethyl acetate (87 mL) and ethanol (87 mL) and add (trimethylsilyl) diazomethane (17.3 mL, 34.6 mmol, 2 M in hexanes) at room temperature and stir the solution for 1 h. Remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (2.50 g, 76%). 1H NMR (MeOD, 300 MHz) δ 2.12 (quintuplet, J=7.6 Hz, 2H), 2.75 (t, J=7.5 Hz, 2H), 2.89 (t, J=7.5 Hz, 2H), 3.83 (s, 3H), 6.53 (d, J=8.1 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H). MS (ES+): 192 (M+H).
Reaction SMILES: [CH2:1](N)C1C=CC=CC=1.C(N)CC1C=CC=CC=1.[CH3:18][S:19][C:20]1[NH:25][C:24](=[O:26])[N:23]=[C:22]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:21]=1>>[CH3:1][N:25]1[C:20]([S:19][CH3:18])=[N:21][C:22]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[N:23][C:24]1=[O:26]
Reactant: NCc1ccccc1
Reactant: CSc1nc(-c2ccncc2)nc(=O)[nH]1
Agent: NCCc1ccccc1
Product: CSc1nc(-c2ccncc2)nc(=O)n1C

Procedure:
By analogy with the method described in example 1 (step 1.2), using benzylamine (commercially available) in place of phenethylamine and 6-Methylsulfanyl-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one (synthesis as described in U.S. Pat. No. 4,406,897) in place of 1-Methyl-6-methylsulfanyl-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one, to afford the product which was transformed into the hyrdochloride salt in the usual manner to give 0.15 g (47%) of a white solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:13][C:14](=O)[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:8][CH:7]=1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:21]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][CH:8]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCCc1ccc(-c2cc3ccccc3c(=O)[nH]2)cc1
Product: COCCCc1ccc(-c2cc3ccccc3c(Cl)n2)cc1

Procedure:
The resulting 3-[4-(3-methoxypropyl)phenyl]isoquinolin-1-one (1.85 g) was reacted with phosphorus oxychloride (20 ml) according to the method of Example 10-2, to give 1-chloro-3-[4-(3-methoxypropyl)phenyl]isoquinoline. The resulting compound was reacted, as it was, with N-ethylpiperazine (6 ml) at 100° C. overnight. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and purified water. The resulting ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.63 g of the free compound of the title compound as a pale yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:11](=[O:32])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([O:25][C:26]([CH3:31])([CH3:30])[C:27]([NH2:29])=[O:28])=[CH:14][CH:13]=2)(C)(C)C.[ClH:38]>C(OCC)(=O)C>[ClH:38].[NH2:7][CH2:8][C:9]1[N:10]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:11](=[O:32])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([O:25][C:26]([CH3:31])([CH3:30])[C:27]([NH2:29])=[O:28])=[CH:14][CH:13]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(OC(C)(C)C(N)=O)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(OC(C)(C)C(N)=O)ccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
Tert-butyl[6-(2-amino-1,1-dimethyl-2-oxoethoxy)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.15 g, 0.3 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml). The solution was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate to give 2-{[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]oxy}-2-methylpropanamide hydrochloride (0.12 g, 92.3%) crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[N:5]=[CH:4][N:3]=1.[NH3:13]>C(O)(C)C>[N:8]1([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH2:13])[CH:7]=2)[CH:12]=[CH:11][CH:10]=[N:9]1
Reactant: Clc1cc(-n2cccn2)ncn1
Reactant: N
Solvent: CC(C)O
Product: Nc1cc(-n2cccn2)ncn1
Reaction time: 96 h
Yield: 98.4 %

Procedure:
A solution of 4-chloro-6-(1H-pyrazol-1-yl)pyrimidine (1.31 g, 7.25 mmol) in 2 M ammonia (20 mL, 40.0 mmol)/isopropanol was heated at 80° C. in a sealed vial for 24 h. The reaction was stored at room temperature for 4 days. The solid precipitate was filtered and dried to give 6-(1H-pyrazol-1-yl)pyrimidin-4-amine (1.15 g, 98% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (1H, dd, J=2.52, 0.50 Hz), 8.30 (1H, d, J=0.76 Hz), 7.82 (1H, d, J=1.01 Hz), 7.19 (2H, br. s.), 6.88 (1H, d, J=1.01 Hz), 6.55 (1H, dd, J=2.64, 1.64 Hz). LCMS: RT=0.52 min, MH+=162.1.