Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[C:24]([F:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([F:29])[C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:39])[CH2:41][OH:42])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: COc1cc(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f36) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:21]=[N:20][C:19]4[C:14]3=[N:15][CH:16]=[N:17][C:18]=4[C:22]3[CH:27]=[CH:26][C:25]([C:28]([NH:30][NH2:31])=[O:29])=[CH:24][CH:23]=3)[CH:7]=2)[CH2:3][CH2:2]1.[CH2:33](Cl)Cl>C(OC)(OC)OC.C(O)(=O)C>[CH:1]1([NH:4][C:5](=[O:32])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[CH:21]=[N:20][C:19]4[C:14]3=[N:15][CH:16]=[N:17][C:18]=4[C:22]3[CH:27]=[CH:26][C:25]([C:28]4[O:29][CH:33]=[N:31][N:30]=4)=[CH:24][CH:23]=3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(-c3ccc(C(=O)NN)cc3)ncnc21
Reactant: ClCCl
Solvent: COC(OC)OC
Solvent: CC(=O)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(-c3ccc(-c4nnco4)cc3)ncnc21
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
To a solution of N-Cyclopropyl-3-[6-(4-hydrazinocarbonyl-phenyl)-purin-9-yl]-4-methyl-benzamide (8.0 mg, 0.019 mmol) in 0.5 mL of trimethyl orthoformate was added three drop of acetic acid. The reaction mixture was stirred at 120° C. in microwave for 10 minutes. Then 0.5 mL of methylene chloride and 3 mL of hexanes were added. The product was collected by filtration to give a colorless solid (6.0 mg, 73%). HPLC tR=2.12 min; MS m/z 438 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]2[N:17]([CH:20]([CH3:22])[CH3:21])[N:18]=[CH:19][C:3]=12.Cl.[CH:24]12[O:31][CH:28]([CH2:29][CH2:30]1)[CH2:27][NH:26][CH2:25]2.C(N(CC)CC)C>C(O)C>[CH:20]([N:17]1[C:4]2=[N:5][C:6]([C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3)=[N:7][C:2]([N:26]3[CH2:25][CH:24]4[O:31][CH:28]([CH2:29][CH2:30]4)[CH2:27]3)=[C:3]2[CH:19]=[N:18]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1ncc2c(Cl)nc(-c3ccc([N+](=O)[O-])cc3)nc21
Reactant: C1CC2CNCC1O2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)n1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc([N+](=O)[O-])cc3)nc21
Temperature: 140 °C

Procedure:
A suspension of crude 4-chloro-1-isopropyl-6-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidine (2.5 mmol maximum) and 8-oxa-3-aza-bicyclo[3.2.1]octane hydrochloride (0.47 g, 3.1 mmol) in ethanol (12 mL) was treated with triethylamine (1.1 mL) and then heated for 20 minutes in the microwave reactor at 140° C. At the completion of the reaction, the mixture was refrigerated overnight before collection of the precipitate via Buchner filtration. The solid was washed with methanol and dried under house vacuum to provide 3-(1-isopropyl-6-(4-nitrophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane as a yellow powder (0.96 g, 97% over 2 steps). MS (ES+): 394.9, 396.0 (M+H)+
Reaction SMILES: F[C:2]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[N:6]=[CH:7][CH:8]=[C:9]2[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=12.N1C2=C(OC3C=CC(N)=CC=3[F:39])N=CC=C2C=C1>>[F:39][C:16]1[CH:15]=[C:3]([O:4][C:5]2[N:6]=[CH:7][CH:8]=[C:9]3[CH:13]=[CH:12][N:11]([CH3:14])[C:10]=23)[CH:2]=[CH:18][C:17]=1[NH2:19]
Reactant: Nc1ccc(Oc2nccc3cc[nH]c23)c(F)c1
Reactant: Cn1ccc2ccnc(Oc3ccc([N+](=O)[O-])cc3F)c21
Product: Cn1ccc2ccnc(Oc3ccc(N)c(F)c3)c21
Yield: 89 %

Procedure:
Starting from the compound 264 and following the procedure described above for the synthesis of amine 261 (scheme 59, step 3, example 218), title compound 265 was obtained in 89% yield as an off-white solid. MS (m/z): 258.1 (M+H) (found).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[CH:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH:30]([CH3:32])[CH3:31])[CH3:22])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si](C(C)(C)C)(C)C)[CH2:37]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[CH:21]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH:30]([CH3:32])[CH3:31])[CH3:22])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([OH:43])[CH2:37]2)=[CH:10]1
Reactant: CC(Oc1ccccc1C(C)C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(Oc1ccccc1C(C)C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 53.9 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 1.31 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(2-isopropylphenoxy)propionyloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 130, above] and 35.4 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 488 mg of the title compound as white crystals, melting at between 138° and 141° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].ClCCl>[CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cc2ccc(CO)cc2)o1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1ccc(Cc2ccc(C=O)cc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.4 %

Procedure:
To a mixture of (4-(5-methyl-furan-2-ylmethyl)-phenyl)-methanol (350 mg, 1.7 mmol) obtained in Manufacturing Example 46-1-2 and dichloromethane (10 mL) was added manganese dioxide (3.5 g, 4.7 mmol) at room temperature, which was stirred overnight at room temperature. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:6) to obtain the title compound (100 mg, 29%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[CH3:9].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.CCO.C(=O)([O-])[O-].[Na+].[Na+].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>[Cl:1][C:2]1[CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(I)cc1Cl
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1ccc(-c2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To a suspension of tetrakis(triphenylphosphine)palladium (213 mg) in toluene (7 ml) was added 2-chloro-4-iodotoluene (2.33 g) at room temperature. The mixture was stirred at room temperature for 30 min, and thereto were added a solution of phenylboronic acid (1.35 g) in EtOH (2 ml) and 2M aqueous sodium carbonate solution (9.25 ml), and the mixture was refluxed under heating. After 3 hr, the reaction mixture was cooled and the organic layer was separated. The aqueous layer was extracted with hexane (4 ml). The organic layers were combined, washed with saturated aqueous sodium hydrogencarbonate solution (4 ml) and saturated brine (4 ml), and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated, and hexane (10 ml) and silica gel (4 g) were added to the residue (2.11 g). The mixture was stirred at room temperature for 1 hr. Silica gel was filtered off and the filtrate was concentrated to give 2-chloro-4-phenyltoluene as a pale-brown oil (1.86 g, 99.4%).
Reaction SMILES: [OH:1][CH2:2][C:3]([O:14][CH2:15][CH2:16][CH3:17])([CH3:13])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>C(Cl)Cl>[CH3:18][S:19]([O:1][CH2:2][C:3]([O:14][CH2:15][CH2:16][CH3:17])([CH3:13])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5])(=[O:21])=[O:20]
Reactant: CCCOC(C)(CO)C(=O)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCOC(C)(COS(C)(=O)=O)C(=O)c1ccc(Cl)cc1
Temperature: -40 °C
Yield: 42.1 %

Procedure:
To 11 g (44 mmole) of crude 2-hydroxymethyl-2-propoxy-4'-chloropropiophenone (Example 96d) in 50 ml of methylene chloride was added 4.5 g (39 mmole) of methanesulfonyl chloride. The mixture was cooled to -40° C. and then 6.0 g (60 mmole) of triethylamine was slowly added. The mixture was allowed to warm to room temperature over 1 hour and was then washed with water, dilute aqueous hydrochloric acid, and brine. It was then dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo, and chromatographed over silica gel using diethyl ether and hexanes to yield 5.5 g of the title compound, an oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C@H:10]1[CH2:14][C@@H:13]([F:15])[CH2:12][NH:11]1.Br[C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:19]2[CH:18]=1>>[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C@H:10]1[CH2:14][C@@H:13]([F:15])[CH2:12][N:11]1[C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:19]2[CH:18]=1
Reactant: CCOC(=O)c1cnn2ccc(Br)cc12
Reactant: Fc1ccc(F)c([C@H]2C[C@@H](F)CN2)c1
Agent: Cl
Product: CCOC(=O)c1cnn2ccc(N3C[C@H](F)C[C@@H]3c3cc(F)ccc3F)cc12

Procedure:
The title compound (Int-74) was prepared by the method similar to that for Int-84 using (2R,4R)-2-(2,5-difluorophenyl)-4-fluoropyrrolidine hydrochloride (Int-48) and Ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate to afford as yellow liquid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:18]1[C:22]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27](=[O:32])[CH2:26]3)=[CH:21][N:20]=[CH:19]1>>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([S:8]([C:5]2[CH:4]=[CH:3][C:2]([C:26]3[C:25]4[C:29](=[CH:30][CH:31]=[C:23]([C:22]5[O:18][CH:19]=[N:20][CH:21]=5)[CH:24]=4)[NH:28][C:27]=3[OH:32])=[N:7][CH:6]=2)(=[O:10])=[O:9])[CH2:12][CH2:13]1
Reactant: CN1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Reactant: O=C1Cc2cc(-c3cnco3)ccc2N1
Product: CN1CCN(S(=O)(=O)c2ccc(-c3c(O)[nH]c4ccc(-c5cnco5)cc34)nc2)CC1
Yield: 1 %

Procedure:
The title compound was prepared as described for Example 101 using 1-[(6-chloropyridin-3-yl)sulfonyl]-4-methylpiperazine (described in: Thunus L., Annales Pharmaceutiques Francaises 1977, 35, 197-203) and 5-(1,3-oxazol-5-yl)-1,3-dihydro-2H-indol-2-one. The crude product was purified on a silica gel column using chloroform/methanol/conc NH3(aq), (100:10:1), as the eluent followed by trituration in ethyl acetate. Yield: 1% of the title compound: MS (ES) m/z 441 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:21][N:22]1[CH:26]=[CH:25][C:24]([C:27](Cl)=[O:28])=[N:23]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:27]([C:24]3[CH:25]=[CH:26][N:22]([CH3:21])[N:23]=3)=[O:28])[CH2:19][CH2:20]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: Cn1ccc(C(=O)Cl)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)c2ccn(C)n2)CC1
Reaction time: 2 h

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with 1-methyl-1H-pyrazole-3-carbonyl chloride (0.022 g, 0.16 mmol) and triethylamine (0.058 mL, 0.41 mmol) in methylene chloride (1.0 mL) at room temperature and the resulting mixture was stirred for 2 hrs. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired porduct (32 mg, 78%). LCMS calculated for C20H21ClN5O2 (M+H)+: m/z=398.1; Found: 398.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH:10][C:11]1[S:12][C:13]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)([CH3:17])[C:14](=[O:16])[N:15]=1)[CH3:9].[OH-:26].[K+].Cl>CC(O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([NH:10][C:11]1[S:12][C:13]([C:18]2[CH:19]=[CH:20][C:21]([C:22]([NH2:23])=[O:26])=[CH:24][CH:25]=2)([CH3:17])[C:14](=[O:16])[N:15]=1)[CH3:9]
Reactant: C[C@H](NC1=NC(=O)C(C)(c2ccc(C#N)cc2)S1)c1ccccc1F
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: C[C@H](NC1=NC(=O)C(C)(c2ccc(C(N)=O)cc2)S1)c1ccccc1F
Temperature: 85 °C
Reaction time: 1 h

Procedure:
The mixture of 4-(2-((S)-1-(2-fluorophenyl)ethylamino)-5-methyl-4-oxo-4,5-dihydrothiazol-5-yl)benzonitrile (0.080 g, 0.23 mmol) and potassium hydroxide (VWR, 0.17 g, 2.9 mmol) and t-BuOH (2 mL) was gradually heated to 85° C. The solid gradually dissolved and the mixture became a solution. After 1 h, the reaction was added to 2N HCl until the pH was ca. 7-8. The mixture was extracted three times with CH2Cl2, and the combined organic layers was dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by silica gel chromatography. MS: 372 (M+1), 370 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@@H:23]2[CH2:25][O:24]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH:26]([NH2:29])([CH3:28])[CH3:27].CN1CCCC1=O.Cl>[Cl-].[Na+].O.ClCCl>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@@H:23]([OH:24])[CH2:25][NH:29][CH:26]([CH3:28])[CH3:27])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2)=[O:5]
Reactant: CC(C)N
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(C[C@@H]2CO2)ccc1Cl
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: ClCCl
Product: CC(C)NC[C@H](O)Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
2-Chloro-5-[(2R)-2-oxiranylmethyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 5c) (133 mg), isopropylamine (3 mL) and 1-methyl-2-pyrrolidinone (5 mL) were heated together at 80° C. in a sealed tube for 22 hours, cooled and poured into brine (50 mL), extracted into ethyl acetate (3×50 mL), washed with brine (3×50 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil. This was purified by Waters' MCX resin and then by column chromatography eluting with 19:1:0.1 dichloromethane/methanol/ammonia. The oil obtained was dissolved in dichloromethane (5 mL) and 1M ethereal hydrogen chloride (4 mL) was added. The mixture was concentrated to give the titled compound as a solid (85 mg).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]([C:14]2[N:15]=[CH:16][N:17](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:18]=2)=[CH2:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2>C(O)(C(F)(F)F)=O.[Pd]>[NH:17]1[CH:18]=[C:14]([CH:12]([C:3]2[C:2]([CH3:1])=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[N:10]3)=[CH:5][CH:4]=2)[CH3:13])[N:15]=[CH:16]1
Reactant: C=C(c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc2cccnc2c1C
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(C)c2c[nH]cn2)ccc2cccnc12
Yield: 78.3 %

Procedure:
A solution of 8-methyl-7-[1-(1-trityl-1H-imidazol-4-yl)vinyl]quinoline (Intermediate M5) (2.14 g, 4.49 mmol) in TFA (40 mL) was reduced by action of 10% Pd/C (0.51 g) under H2 (45-50 psi) for 16 h at rt. The mixture was filtered through celite and the solvent was removed under vacuum. The residue was purified by chromatography on silica gel with 24% NH3-MeOH:CH2Cl2 to give 7-[1-(1H-imidazol-4-yl)ethyl]-8-methylquinoline (Intermediate M6) 834 mg, (79%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[F:23]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1n[nH]c(=O)c(-c2cc(F)ccc2F)c1-c1ccc(Cl)cc1
Product: Cc1nnc(Cl)c(-c2cc(F)ccc2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
2.86 g of 5-(4-chlorophenyl)-4-(2,5-difluorophenyl)-6-methyl-2H-pyridazin-3-one and 6.5 g of phosphorus oxychloride were mixed and stirred at 110° C. for 1 hour. The reaction mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated. The residue was subjected to silica gel column chromatography (elution solvent; hexane:ethyl acetate=3:1, to obtain 2.89 g of 3-chloro-5-(4-chlorophenyl)-4-(2,5-difluorophenyl)-6-methyl pyridazine (hereinafter, referred to as compound (xiii) of the present invention).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[NH:16][C@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]3[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=3)[CH2:18]2)[CH:4]=1)=[O:2].[BH4-].[Na+]>C1COCC1>[OH:2][CH2:1][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([NH:9][C@@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]2[NH:16][C@H:17]2[CH2:22][CH2:21][CH2:20][N:19]([C:23]3[CH:24]=[CH:25][C:26]([C:27]#[N:28])=[CH:29][CH:30]=3)[CH2:18]2)[CH:4]=1
Reactant: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3Nc3cc(C=O)ccn3)C2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3Nc3cc(CO)ccn3)C2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 21.8 %

Procedure:
To a round bottom flask was added 4-((S)-3-(((1R,2R)-2-((4-formylpyridin-2-yl)amino)cyclohexyl)amino)piperidin-1-yl)benzonitrile (100 mg, 0.248 mmol) and THF (1 mL). The reaction was cooled to 0° C. and NaBH4 (9.38 mg, 0.248 mmol) was added to the reaction. The reaction was stirred at 0° C. for 2 hrs. The reaction was quenched with 1N NH4Cl (0.5 ml) and then diluted with EtOAc (30 ml). The organics was washed with water (2×15 ml) and saturated NaCl solution (15 ml). The organic layer dried over MgSO4, filtered and concentrated. The residue was purified using ISCO system (0-100% EtOAc/Hex) to give 4-((S)-3-(((1R,2R)-2-((4-(hydroxymethyl)pyridin-2-yl)amino)cyclohexyl)amino)piperidin-1-yl)benzonitrile (23 mg, 0.054 mmol, 21.74% yield) as white solid. Anal. Calcd. for C24H31N5O m/z 405.3, found: 406.2 (M+H)+; 1H NMR (400 MHz, METHANOL-D4) δ ppm 8.07-7.97 (m, 1H), 7.45 (d, J=8.8 Hz, 2H), 6.93 (d, J=9.3 Hz, 3H), 6.62-6.51 (m, 1H), 4.60 (s, 2H), 3.86-3.75 (m, 1H), 3.71-3.62 (m, 1H), 3.37-3.33 (m, 1H), 2.95-2.84 (m, 1H), 2.83-2.59 (m, 3H), 2.16-2.04 (m, 2H), 2.01-1.92 (m, 1H), 1.82-1.72 (m, 2H), 1.68-1.55 (m, 1H), 1.45-1.23 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].[Br:12]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>ClC(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][Br:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccccc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccccc1CBr
Temperature: 0 °C

Procedure:
To a solution of 2-methylbenzoic acid methyl ester (33.0 g) in tetrachlorocarbon (440 ml) were added N-bromosuccinimide (43.0 g) and AIBN (2,2′-azobisisobutyronitrile, 361 mg) and the mixture was refluxed for 30 minutes. The reaction mixture was cooled down to 0° C. and cinnamoic acid that appeared were filtered off and the filtrate was concentrated. The residue was purified by distillation under reduced pressure to give the title compound having the following physical data (28.0 g, colorless oil).
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:10][C:11]1[CH:23]=[CH:22][C:14]2[C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:16][O:17][C:13]=2[CH:12]=1>CO>[C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:10][C:11]1[CH:23]=[CH:22][C:14]2[C@H:15]([CH2:18][C:19]([OH:21])=[O:20])[CH2:16][O:17][C:13]=2[CH:12]=1
Reactant: O=C(O)Cc1coc2cc(O)ccc12
Agent: C[C@@H](N)c1ccccc1
Solvent: CO
Product: O=C(O)C[C@@H]1COc2cc(O)ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
A solution of (6-hydroxy-1-benzofuran-3-yl)acetic acid (1R)-1-phenylethylamine salt (8.16 g) and dichloro[(+)-1,2-bis((2R,5R)-2,5-diisopropylphosphorano)benzene]ruthenium (II)—N,N-dimethylformamide complex (1.3 mg) in dehydrated methanol (50 ml) was stirred at 35° C. for 26 hr under a hydrogen atmosphere (1.1 MPa). After concentration, the residue was dissolved in a mixed solvent of methanol (25.0 mL)-water (3.7 mL) at around 55° C. After adding toluene (225 mL) at the same temperature, the mixture was stirred at 25° C. for 20 hr and at 0° C. for 1 hr. The precipitated crystals were collected by filtration, washed with toluene (25 mL), and dried at 50° C. under reduced pressure to give a crude product (6.65 g). The crude product was subjected to a similar recrystallization method using a mixed solvent of methanol (20.0 mL)-water (3.0 mL) and diisopropyl ether (180 mL) to give a crude product (6.16 g). The crude product was subjected to a similar recrystallization method using a mixed solvent of methanol (18.5 mL)-water (2.8 mL) and diisopropyl ether (166 mL) to give the title compound (5.81 g) as white crystals. 99.7% de.
Reaction SMILES: [OH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:17])[CH:10]=[CH:11][CH:12]=3)[O:7][C:6]=2[C:5]([CH2:18][CH:19]=[CH2:20])=[C:4]([OH:21])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:28]([O:21][C:4]1[CH:3]=[C:2]([OH:1])[C:15]2[C:14](=[O:16])[C:13]3[C:8]([O:7][C:6]=2[C:5]=1[CH2:18][CH:19]=[CH2:20])=[C:9]([O:17][CH2:18][C:5]1[CH:6]=[CH:15][CH:2]=[CH:3][CH:4]=1)[CH:10]=[CH:11][CH:12]=3)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: C=CCc1c(O)cc(O)c2c(=O)c3cccc(O)c3oc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCc1c(OCc2ccccc2)cc(O)c2c(=O)c3cccc(OCc4ccccc4)c3oc12
Temperature: 110 °C
Yield: 160.7 %

Procedure:
To a solution of xanthone 5 (48 g, 168 mmol) in dry DMF was added potassium carbonate (46 g, 336 mmol) and benzyl bromide (90 g, 526 mmol) and the mixture was heated to 110° C. for 8 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (1.4L) and the remaining potassium carbonate was destroyed with 2M Sulfuric acid. The organic layer was washed with brine (2×500 mL), dried over magnesium sulfate and concentrated in vacuo to afford the xanthone 6 as a solid (63 g, 135 mmol, 81%).