Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][N:6]1[CH2:11][CH2:10][C:9]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:12][CH:8]2[CH2:7]1.O1CCOCC1>O>[CH3:5][N:6]1[CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([N:1]=[N+:2]=[N-:3])[CH:8]([OH:12])[CH2:7]1
Reactant: [N-]=[N+]=[N-]
Reactant: CN1CCC2(c3ccccc3)OC2C1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCC(N=[N+]=[N-])(c2ccccc2)C(O)C1

Procedure:
1.4 G. of sodium azide (NaN3) in 6 ml. of water was added to a solution of 3.6 g. of 1-methyl-4-phenyl-3,4-epoxypiperidine in 20 ml. of dioxane and the resulting combined solution refluxed for 2 hours. A further portion of 1.4 g. of NaN3 in 6 ml. of water was then added and the reaction mixture refluxed overnight. Upon cooling 3.2 g. of crystals of the desired 1-methyl-4-phenyl-4-azido-3-hydroxypiperidine were obtained, which had a melting point of 170°-71° C.
Reaction SMILES: [F:1][C:2]([CH3:35])([CH3:34])[CH:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:14]2[CH2:20][CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]([CH3:35])([CH3:34])[CH:3]([NH:8][C:9]([C:11]1[N:12]=[C:13]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:14]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][C:15]=12)=[O:10])[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)C(NC(=O)c1nc(-c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CCC2)C(C)(C)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)C(NC(=O)c1nc(-c2ccccc2)n2c1CNCCC2)C(C)(C)F
Reaction time: 1 h
Yield: 81.6 %

Procedure:
To 66D (178 mg, 0.37 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1.12 mL, 14.60 mmol). After 1 hour of stirring, the solution was concentrated under reduced pressure. The residue was brought to pH 8 with a saturated aqueous solution of sodium bicarbonate. The aqueous solution was extracted with dichloromethane. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to yield Compound 604 as a white solid (117 mg, 83%). 1H-NMR (400 MHz, (CD3)2SO) δ: 1.31 (d, 3H), 1.37 (d, 3H), 1.71 (m, 2H), 2.61 (d, 3H), 3.00 (m, 2H), 4.13 (m, 2H), 4.28 (m, 2H), 4.64 (dd, 1H), 7.52 (m, 5H), 7.81 (d, 1H), 8.24 (q, 1H). LCMS (+ESI) m/z 388.1 [M+H]+.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][PH3+].[Li]CCCC.[CH3:11][O:12][C@H:13]1[C@@H:18]([CH3:19])[CH2:17][O:16][C@@H:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:14]1=O>O1CCCC1.C(OCC)(=O)C>[CH3:2][O:3][C@H:4]1[C@@H:18]([CH3:19])[CH2:17][O:16][C@@H:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:14]1=[CH:13][O:12][CH3:11]
Reactant: CCCCCCCCC[C@@H]1OC[C@H](C)[C@H](OC)C1=O
Reactant: COC[PH3+]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCC[C@@H]1OC[C@H](C)[C@H](OC)C1=COC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a stirred suspension of methoxymethylphosphonium chloride (1,130 mg) in dry tetrahydrofuran (3 ml) there was added n-BuLi (1.9 ml, 1.6M in n-hexane) at 0° C. After the mixture was stirred at 0° C. for 30 min, a solution of (2S,4S,5S)-4-methoxy-5-methyl-2-nonyltetrahydro-2H-pyran-3-one (273 mg) in dry tetrahydrofuran (3 ml) was added to the resulting deep orange solution. After 30 min, the mixture was allowed to warm to room temperature, and stirred for an additional 2 hrs. The reaction was quenched by addition of saturated aqueous ammonium chloride solution. The mixture was extracted with diethyl ether, and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the residue by silica gel chromatography (n-hexane: ethyl acetate=10:1 as an eluent) gave (2S,4S,5S)-4-methoxy-5-methyl-3-methoxymethylene-2-nonyltetrahydro-2H-pyran (249 mg, 83% yield).
Reaction SMILES: [I:1][C:2]1[C:19]([C:20]([O:22]CC)=[O:21])=[C:5]2[CH2:6][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:8]3([CH2:11][CH2:10]3)[CH2:9][N:4]2[N:3]=1.[OH-].[Na+]>C(O)C.O>[C:15]([O:14][C:12]([N:7]1[C:8]2([CH2:10][CH2:11]2)[CH2:9][N:4]2[N:3]=[C:2]([I:1])[C:19]([C:20]([OH:22])=[O:21])=[C:5]2[CH2:6]1)=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: CCOC(=O)c1c(I)nn2c1CN(C(=O)OC(C)(C)C)C1(CC1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1Cc2c(C(=O)O)c(I)nn2CC12CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.7 %

Procedure:
To a stirred solution of Intermediate 350D (0.500 g, 1.118 mmol) in ethanol (10 mL) and water (1 mL) was added NaOH (0.369 g, 9.21 mmol) and the resulting solution was stirred at RT for 12 h. The volatiles were removed under reduced pressure and the residue was acidified with an aqueous solution of 1.5 N HCl. The solid product separated was filtered through a Buchner funnel and dried under vacuum to afford Intermediate 350E as a white solid (0.43 g, 90%). MS(ES): m/z=420 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ ppm 6.19 (br. s., 1H), 4.92 (br. s., 2H), 4.06 (br. s., 2H), 1.48 (s, 9H), 1.19 (br. s., 2H), 1.01-0.83 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C@@H:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>O1CCCC1>[C:16]1([C@H:14]([N:10]2[CH2:11][CH2:12][O:13][C@@H:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:29](=[O:31])[CH3:30])=[CH:7][CH:6]=3)[CH2:9]2)[CH3:15])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(=O)Cl
Reactant: C[C@H](c1ccccc1)N1CCO[C@@H](c2ccc(N)cc2)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc([C@H]2CN([C@H](C)c3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of (2S)-2-(4-aminophenyl)-4-((1R)-1-phenylethyl)morpholine (7.9 g, 28 mmol) and triethylamine (8.5 g, 84 mmol) in tetrahydrofuran (180 ml) was added acetyl chloride (4.4 g, 56 mmol). The mixture was stirred at room temperature for 2 hours and partitioned between water and chloroform. The organic extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the precipitated crystals were collected by filtration, washed with isopropyl ether to give N-(4-((2S)-4-((1R)-1-phenylethyl)morpholin-2-yl)phenyl)-acetamide (6.47 g, 71%) as yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:18]1[CH:23]=[CH:22][C:21]([CH2:24]Br)=[CH:20][CH:19]=1>CN(C=O)C.CCOC(C)=O>[CH2:24]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1)[C:21]1[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CCc2ccc(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 92 %

Procedure:
To a stirred solution of 6-hydroxy-2,3-dihydroinden-1-one (30 g, 0.203 mol) in 300 mL DMF was added K2CO3 (70 g, 0.507 mol), followed by addition of BnBr (38.2 g, 0.225 mol) dropwise at 0° C. The mixture was allowed to warm to ambient temperature and stirred for 20 h. The mixture was diluted with EtOAc (500 mL), then filtered to remove the solid. The filtrate was washed with brine (200 mL×5), dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulted solid was recrystallized in ether to give the title compound (44.5 g, 92%) as a white solid. 1H-NMR (600 MHz, CDCl3) δ 7.47-7.46 (m, 2H), 7.44-7.39 (m, 3H), 7.38-7.35 (m, 1H), 7.31-7.30 (m, 2H), 5.12 (s, 2H), 3.11-3.09 (m, 2H), 2.76-2.74 (m, 2H) ppm.
Reaction SMILES: C1(O)C=CC=CC=1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[N+](=[C:19]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:26]=2)[O:21][CH2:20]1)=[N-]>>[CH2:31]([O:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH:19]([O:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1)[C:28]2=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1ccc(O)cc1
Reactant: [N-]=[N+]=C1COc2ccc(OCc3ccccc3)cc2C1=O
Solvent: Oc1ccccc1
Product: COc1ccc(OC2COc3ccc(OCc4ccccc4)cc3C2=O)cc1

Procedure:
Replacing the phenol with a molar equivalent of 4-methoxyphenol, the method of Example 9 was employed to convert 3-diazo-6-benzyloxy-4-chromanone (22 g) to present title product, 6.8 g, m.p. 98°-100° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([CH2:7][N:8]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1.[CH3:42][O:43][CH2:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][C:50]([NH:53][C:54](=O)[O:55]C2C=CC([N+]([O-])=O)=CC=2)=[CH:49][CH:48]=1.CCN(CC)CC>C(Cl)Cl>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH:30][C:54]([NH:53][C:50]5[CH:49]=[CH:48][C:47]([O:46][CH2:45][CH2:44][O:43][CH3:42])=[CH:52][CH:51]=5)=[O:55])=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=[CH:37][CH:36]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(N)nc3)n2)cc1
Reactant: COCCOc1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOc1ccc(NC(=O)Nc2ccc(Nc3ncc(Cl)cc3-c3nc(C)nc(N(Cc4ccc(OC)cc4)Cc4ccc(OC)cc4)n3)cn2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.4 %

Procedure:
A mixture of N5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-yl)pyridine-2,5-diamine (Example 4, step 2, 0.158 g, 0.277 mmol) and 4-nitrophenyl 4-(2-methoxyethoxy)phenylcarbamate (0.118 g, 0.354 mmol) in DCM (3 mL) was stirred at rt for 3 days. Et3N (0.20 mL) was added followed by 4-nitrophenyl 4-(2-methoxyethoxy)phenylcarbamate (0.142 g, 0.428 mmol). The reaction mixture was stirred at rt for 2 h. The yellow solid was collected and washed with DCM to give 0.176 g of crude 1-(5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-ylamino)pyridin-2-yl)-3-(4-(2-methoxyethoxy)phenyl)urea, which was taken into the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([O:20][CH2:21][CH2:22][O:23]C4CCCCO4)[C:14]=3[F:30])O)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][C:13]3[C:14]([F:30])=[C:15]([CH:16]=[CH:17][C:18]=3[F:19])[O:20][CH2:21][CH2:22][OH:23])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: OC(c1c(F)ccc(OCCOC2CCCCO2)c1F)c1c[nH]c2ncc(Br)cc12
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: OCCOc1ccc(F)c(Cc2c[nH]c3ncc(Br)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.2 %

Procedure:
To (5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,6-difluoro-3-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl-methanol (542, 0.22 g, 0.46 mmol) in acetonitrile (6.0 mL) were added trifluoroacetic acid (0.14 mL, 1.8 mmol) and triethylsilane (0.29 mL, 1.8 mmol). The reaction was stirred at room temperature overnight. The filtrate was concentrated and purified by silica gel column chromatography eluting with 35% ethyl acetate in hexane to give the compound as a white solid (P-1392, 62 mg, 35%). MS (M+H+)+=383.1, 385.1.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6](O)[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:15])=O.P(Cl)(Cl)(Cl)(Cl)Cl.[OH-].[NH4+]>>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:15])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ncc([N+](=O)[O-])c(O)c1C
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1ncc([N+](=O)[O-])c(Cl)c1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2,3-Dimethyl-4-hydroxy-5-nitropyridine (26.8 g, 0.16 mol) prepared in Step 3 was added to 85 ml of phosphorus oxychloride. Phosphorus pentachloride (33.3 g, 0.16 mol) was added to the reaction mixture, which was then refluxed under stirring for 2 hours. The reaction mixture was left overnight at room temperature, added to ice water, brought to pH 5 with 28% ammonium hydroxide, and then extracted with ether. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated to give 28.3 g of the titled compound.
Reaction SMILES: [C:1]1([CH:9]=[C:7]([OH:8])[CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].O=[C:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[C:17](OCC)=[O:18]>S(=O)(=O)(O)O>[OH:2][C:1]1[C:9]2[C:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:17](=[O:18])[O:8][C:7]=2[CH:6]=[C:4]([OH:5])[CH:3]=1
Reactant: Oc1cc(O)cc(O)c1
Reactant: CCOC(=O)C1CCCCC1=O
Agent: O=S(=O)(O)O
Product: O=c1oc2cc(O)cc(O)c2c2c1CCCC2
Temperature: 0 °C

Procedure:
Phloroglucinol (1 g) and ethyl 2-oxocyclohexane carboxylate (1.32 g) were stirred in 75% sulfuric acid (10 ml) overnight, the mixture poured into ice water and filtered Yield: 1.55 g.
Reaction SMILES: Br.[NH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([Br:19])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1.[CH3:20][C:21]1([CH3:27])[CH2:25][CH2:24][O:23][C:22]1=[O:26].C[Al](C)C.O>C1COCC1>[Br:19][C:8]1[C:7]2[C:6]3[C:14](=[CH:15][C:3]([NH:2][C:22](=[O:26])[C:21]([CH3:27])([CH3:20])[CH2:25][CH2:24][OH:23])=[CH:4][CH:5]=3)[NH:13][C:12]=2[C:11]([C:16]([NH2:18])=[O:17])=[CH:10][CH:9]=1
Reactant: CC1(C)CCOC1=O
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(N)ccc12
Agent: Br
Agent: C[Al](C)C
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CCO)C(=O)Nc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Temperature: 50 °C
Yield: 46 %

Procedure:
A mixture of 7-amino-4-bromo-9H-carbazole-1-carboxamide hydrobromide (Example 54-2, 500 mg, 1.299 mmol) and 3,3-dimethyldihydrofuran-2(3H)-one (222 mg, 1.948 mmol) in THF (10 mL) was treated with trimethylaluminum (2 M in toluene, 562 mg, 7.79 mmol) dropwise at rt. The mixture was heated at 50° C. for 1.5 h, cooled to rt and treated with water. The mixture was filtered through Celite and the solids were washed thoroughly with DCM and methanol. The filtrate was washed with water, dried and concentrated, and the residue was purified by column chromatography (eluting with a gradient from DCM to 10% ammonia-methanol-DCM) to provide 4-bromo-7-(4-hydroxy-2,2-dimethylbutanamido)-9H-carbazole-1-carboxamide as a yellow solid (250 mg, 46%). Mass spectrum m/z 418, 420 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3[C:16]4[CH2:29][CH2:28][CH2:27][C:17]=4[C:18](=[O:26])[NH:19][C:20]=3[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])=[CH:10][CH:9]=1)(=[O:7])=[O:6].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>O1CCCC1>[CH3:37][S:38]([O:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]3[C:16]4[CH2:29][CH2:28][CH2:27][C:17]=4[C:18](=[O:26])[NH:19][C:20]=3[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])=[CH:10][CH:9]=1)(=[O:7])=[O:6])(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2[nH]c(=O)c3c(c2c1-c1ccc(S(=O)(=O)NCCO)cc1)CCC3
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2[nH]c(=O)c3c(c2c1-c1ccc(S(=O)(=O)NCCOS(C)(=O)=O)cc1)CCC3
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.6 %

Procedure:
To a stirred solution of N-(2-hydroxyethyl)-4-(8-methoxy-4-oxo-2,3,4,5-tetrahydro-1H-cyclopenta[c]quinolin-9-yl)benzenesulfonamide (230 mg, 0.555 mmol) and triethylamine (168 mg, 1.66 mmol) in anhydrous tetrahydrofuran (10 mL) was added methane sulfonyl chloride (88 mg, 0.666 mmol). The reaction mixture was stirred for 20 h at room temperature. After this time the reaction mixture was filtered to remove a white precipitate, which was washed with tetrahydrofuran (30 mL). The filtrate was concentrated under reduced pressure to an orange solid. The residue was purified by flash chromatography to afford the desired product as a brown solid (141 mg, 51%). ESI MS m/z 493 [C22H24N2O7S2+H]+
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[OH:17])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:18]1([CH:16]([OH:17])[CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(O)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC(CCC1CCNCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 117.4 %

Procedure:
To a solution of 1.48 g (4.66 mmol) of 1-t-butoxycarbonyl-4-(3-phenyl-3-hydroxypropyl)piperidine in 8 mL of CH2Cl2 at rt was added 2 mL of trifluoroacetic acid. After stirring for 2 h at rt, the reaction mixture was poured into 100 mL of sat'd NaHCO3 solution and extracted with CH2Cl2. The combined organic fractions were dried over MgSO4, filtered and the filtrate was concentrated to give 1.2 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:54])[C@@H:4]([NH:21][C:22]([C@@H:24]1[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]5[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=5)=[CH:40][CH:39]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26][NH:25]1)=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[C:14]=2[CH3:20])=[CH:8][CH:7]=1.[N:55]([CH:58]1[CH2:61][CH2:60][CH2:59]1)=[C:56]=[O:57]>>[CH3:1][O:2][C:3](=[O:54])[C@@H:4]([NH:21][C:22]([C@@H:24]1[CH2:33][C:32]2[CH:31]=[C:30]3[O:34][CH2:35][C@H:36]([C:38]4[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]5[CH:51]=[CH:50][C:49]([Cl:52])=[C:48]([Cl:53])[CH:47]=5)=[CH:40][CH:39]=4)[O:37][C:29]3=[CH:28][C:27]=2[CH2:26][N:25]1[C:56](=[O:57])[NH:55][CH:58]1[CH2:61][CH2:60][CH2:59]1)=[O:23])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[C:14]=2[CH3:20])=[CH:10][CH:11]=1
Reactant: O=C=NC1CCC1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Product: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)NC1CCC1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester (30 mg) was reacted with Isocyanato-cyclobutane according to General Procedure AD and I to give (S)-2-({(3S,8S)-7-cyclobutylcarbamoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester. This ester was hydrolyzed according to General Procedure B to give the title compound (12 mg). LCMS (m/z): 852.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]1([C@H:7]2[CH2:12][CH2:11][C@H:10]([CH2:13][O:14][S:21]([C:18]3[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=3)(=[O:23])=[O:22])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCC(c2ccccc2)CC1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@H](c3ccccc3)CC2)cc1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
The compound (III) (50 g, 0.268 mol) obtained in the first step was dissolved in dry pyridine (110 ml) and the solution was cooled to 5° C. or lower. To this solution was dropwise added a solution of p-toluenesulfonic acid chloride (50.1 g, 0.263 mol) dissolved in dry toluene (70 ml), in small portions through a dropping funnel so that the reaction temperature did not exceed 10° C. After completion of the dropwise addition, the cooling bath was removed and the reaction mixture was agitated at room temperature for 4 hours, followed by adding water (100 ml) and toluene (300 ml) and stirring. The mixture was transferred into a separating funnel and the toluene layer was washed twice with 6N-HCl aqueous solution (100 ml), then once with water (200 ml), further twice with 2N-NaOH aqueous solution (100 ml) and then four times with water (200 ml). Toluene was distilled off under reduced pressure and the resulting crystals were recrystallized from toluene (90 ml), followed by separating the crystals by filtration to obtain p-toluenesulfonic acid (trans-4-phenylcyclohexylmethyl) ester (IV) (77 g) having a melting point of 108.0°~108.7° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:30]2[CH:34]=[C:33]([CH3:35])[S:32][CH:31]=2)O1>>[CH3:35][C:33]1[S:32][CH:31]=[C:30]([C:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][CH:8]=2)[CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cs1
Product: Cc1cc(C2=CCN(C(=O)OC(C)(C)C)CC2)cs1
Yield: 69.4 %

Procedure:
tert-Butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-5,6-dihydropyridine-1(2H)-carboxylate (1.66 g, 5.00 mmol) and a crude product of 4,4,5,5,-tetramethyl-2-(5-methylthiophen-3-yl)-1,3,2-dioxaborolane (3.40 g) were used to obtain a crude product of the title compound (970 mg) by synthesis in a similar manner to Reference Synthesis Example 139.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[C:16]3[N:15]=[C:14]([CH3:17])[C:13](=[O:18])[NH:12][C:11]=3[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[S:21][CH3:22].[C:23]([C:27]1[CH:31]=[C:30]([N:32]=[C:33]=[O:34])[N:29]([C:35]2[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[N:39][CH:40]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([O:6][C:7]3[C:16]4[N:15]=[C:14]([CH3:17])[C:13](=[O:18])[NH:12][C:11]=4[N:10]=[CH:9][CH:8]=3)=[CH:4][C:3]=2[S:21][CH3:22])=[O:34])[N:29]([C:35]2[CH:40]=[N:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[N:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CSc1cc(Oc2ccnc3[nH]c(=O)c(C)nc23)ccc1N
Reactant: COc1ccc(-n2nc(C(C)(C)C)cc2N=C=O)cn1
Product: COc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)c(C)nc34)cc2SC)cn1
Yield: 35 %

Procedure:
Method F2 was used with 8-(4-amino-3-(methylthio)phenoxy)-2-methylpyrido[2,3-b]pyrazin-3(4H)-one and 5-(3-tert-butyl-5-isocyanato-1H-pyrazol-1-yl)-2-methoxypyridine to afford the title compound (33 mg, 35%) as a white powder.
Reaction SMILES: IC.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]3[N:18]=[C:19]([CH2:22][O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:20]([OH:21])=[C:14]3[CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[C:30]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]3[N:18]=[C:19]([CH2:22][O:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:20]([O:21][CH3:30])=[C:14]3[CH2:13]2)=[O:11])=[CH:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)c(O)c2C1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1c(COc2ccccc2)nn2c1CN(C(=O)c1ccc(F)cc1)CC2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 25.2 %

Procedure:
Iodomethane (0.005 mL, 0.08 mmol) was added to a stirred suspension of (4-fluoro-phenyl)-(3-hydroxy-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone (19 mg, 0.052 mmol) and Cs2CO3 (0.034 g, 0.1 mmol) in DMF (0.5 mL). The mixture was stirred at room temperature for 45 minutes and the solvent was evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 100/0). The desired fractions were collected and the solvents evaporated in vacuo to yield (4-fluoro-phenyl)-(3-methoxy-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone (5 mg, 25% yield) as a colourless oil. C21H20FN3O3 1H NMR (400 MHz, CDCl3) δ ppm 3.78 (br. s., 3H), 4.01 (br. s., 2H), 4.20 (br. s., 2H), 4.80 (br. s., 2H), 5.02 (s, 2H), 6.93-7.00 (m, 1H), 7.03 (d, J=7.9 Hz, 2H), 7.16 (t, J=8.7 Hz, 2H), 7.27-7.34 (m, 2H), 7.46-7.53 (m, 2H).