Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@@H:10]1[C@@H:13]([C@@H:14]2[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C:15]2=[O:30])[NH:12][C:11]1=[O:31])[CH3:9])=[O:6])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH2:39]([O:42][C:43](=[O:47])[C:44](Cl)=[O:45])[CH:40]=[CH2:41]>ClCCl.C(OCC)(=O)C>[CH2:1]([O:4][C:5]([O:7][C@@H:8]([C@@H:10]1[C@@H:13]([C@@H:14]2[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25])[C:15]2=[O:30])[N:12]([C:44](=[O:45])[C:43]([O:42][CH2:39][CH:40]=[CH2:41])=[O:47])[C:11]1=[O:31])[CH3:9])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)C(=O)Cl
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N[C@@H]1[C@@H]1CCCC(CCO[Si](C)(C)C(C)(C)C)C1=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N(C(=O)C(=O)OCC=C)[C@@H]1[C@@H]1CCCC(CCO[Si](C)(C)C(C)(C)C)C1=O
Reaction time: 3 h

Procedure:
In dichloromethane (2.5 ml) was dissolved the (3S,4R)-3-[(R)-1-(allyloxycarbonyloxy)ethyl]-4-[(1S)-3-[2-(tert-butyldimethylsilyloxy)ethyl]-2-oxocyclohexan-1-yl]azetidin-2-one (0.56 g) obtained in Reference Example 3 and while the solution was stirred, a solution of triethylamine (0.7 ml) in dichloromethane (2.5 ml) was added. Then, a solution of allyloxyoxalyl chloride (0.55 g) in dichloromethane (2.5 ml) was added dropwise at -78° C. over a period of 10 minutes. The reaction mixture was stirred at -78° C. for 5 minutes and, then, at 0° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with phosphate buffer (pH 7) and aqueous sodium chloride in that order and, after addition of triethylamine (0.2 ml), dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by flash column chromatography (stationary phase: silica gel 15 g; ethyl acetate-hexane 1:6) to give allyl [(3S,4R)-3-[(R)-1-(allyloxycarbonyloxy)ethyl]-4-[(1S)-3-[2-(tert-butyldimethylsilyloxy)ethyl]-2-oxocyclohexan-1-yl]-2-oxoazetidin-1-yl]glyoxylate.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([OH:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:19][CH2:20][CH2:21]Br>C(O)(C)C>[C:12]1([C:10]2([OH:11])[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]3[CH2:19][CH2:20][CH2:21][N:1]=[C:2]23)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC1=Nc2ccccc2C1(O)c1ccccc1
Reactant: BrCCCBr
Solvent: CC(C)O
Product: OC1(c2ccccc2)C2=NCCCN2c2ccccc21

Procedure:
2-Amino-3-phenyl-3H-indol-3-ol (2.24 g) was heated under reflux with isopropanol (20 ml) and 1,3-dibromopropane (2.0 g) for 20 hours. The reaction mixture was evaporated to 10 ml and diluted with a little ether. The title compound was obtained as its hydrobromide salt 0.73 g., m.p. 260°-262°C (decomp.) and could be recrystallized from methanol, ethanol or isopropanol with or without the addition of ethyl acetate or ether.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)=[C:4]([NH2:16])[C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][C:7]=1[CH3:8].[CH2:29]([O:31][CH2:32][C:33](Cl)=O)[CH3:30]>N1C=CC=CC=1.Cl.N1C=CC=CC=1>[CH2:29]([O:31][CH2:32][C:33]1[N:17]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[C:3]2[C:2]([CH3:1])=[C:7]([CH3:8])[N:6]=[C:5]([O:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:4]=2[N:16]=1)[CH3:30]
Reactant: CCOCC(=O)Cl
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCOCCCc2nccs2)c1C
Agent: Cl
Solvent: c1ccncc1
Product: CCOCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCOCCCc1nccs1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
Under a nitrogen atmosphere, a solution of 5,6-dimethyl-2-phenoxy-N4-{2-[3-(1,3-thiazol-2-yl)propoxy]ethyl}pyridine-3,4-diamine (4.12 g, 10.3 mmol) and pyridine hydrochloride (0.024 g, 0.21 mmol) in pyridine (30 mL) was cooled to 7° C. Ethoxyacetyl chloride (1.33 g, 10.9 mmol) was added, and the reaction was stirred for 30 minutes. The cloudy solution was then heated at 100° C. for 20 hours and then allowed to cool to room temperature. The volatiles were removed under reduced pressure, and the residue was partitioned between water and dichloromethane. The organic layer was washed with potassium carbonate (2×50 mL) and brine (2×50 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting oil was triturated with heptane to provide a solid that was isolated by filtration. 2-(Ethoxymethyl)-6,7-dimethyl-4-phenoxy-1-{2-[3-(1,3-thiazol-2-yl)propoxy]ethyl}-1H-imidazo[4,5-c]pyridine (3.68 g) was obtained as a tan solid.
Reaction SMILES: [CH3:1][C:2]([CH3:46])([CH3:45])[CH2:3][O:4][C:5](=[O:44])[N:6]=[C:7]([NH2:43])[C:8]1[CH:13]=[CH:12][C:11]([NH:14][CH:15]([C:29]2[N:33]=[C:32]([O:34][CH2:35]Cl)[N:31]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:30]=2)[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][CH2:26][OH:27])[C:17]=2[F:28])=[CH:10][CH:9]=1.[I-].[Na+].C(=O)([O-])O.[K+].[CH:54]1([O:60][C:61](=[O:68])[C:62]([CH3:67])([CH3:66])[C:63]([OH:65])=[O:64])[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1>O.C(OCC)(=O)C.CN(C=O)C>[CH:54]1([O:60][C:61](=[O:68])[C:62]([CH3:66])([CH3:67])[C:63]([O:65][CH2:35][O:34][C:32]2[N:31]([C:37]3[N:42]=[CH:41][CH:40]=[CH:39][N:38]=3)[N:30]=[C:29]([CH:15]([NH:14][C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH2:43])=[N:6][C:5]([O:4][CH2:3][C:2]([CH3:46])([CH3:45])[CH3:1])=[O:44])=[CH:9][CH:10]=3)[C:16]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][CH2:26][OH:27])[C:17]=3[F:28])[N:33]=2)=[O:64])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59]1
Reactant: CC(C)(C(=O)O)C(=O)OC1CCCCC1
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2nc(OCCl)n(-c3ncccn3)n2)c1
Agent: O=C([O-])O
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)OCC(C)(C)C)cc2)c2nc(OCOC(=O)C(C)(C)C(=O)OC3CCCCC3)n(-c3ncccn3)n2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.3 %

Procedure:
To a mixture of [1-amino-1-[4-({(5-chloromethoxy-1-pyrimidin-2-yl-1H-[1,2,4]triazol-3-yl)-[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]methyl}amino)phenyl]methylidene]carbamic acid 2,2-dimethylpropyl ester (Example 2b, 80 mg) and DMF (5 mL), sodium iodide (183 mg), potassium hydrogen carbonate (85.5 mg), and 2,2-dimethylmalonic acid monocyclohexyl ester (261 mg) were added, and the resulting mixture was stirred at room temperature for 3 days. Ethyl acetate (30 mL) and water (10 mL) were added to the mixture, and the resulting mixture was shaken, after which the organic layer was collected. Ethyl acetate (20 mL) was added to the aqueous layer, and the resulting mixture was shaken, after which the organic layer was collected. All the organic layers were combined, washed with saturated aqueous sodium chloride solution (10 mL), and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of heptane-ethyl acetate) to obtain the captioned compound (97.9 mg).
Reaction SMILES: C([O:3][CH2:4][CH2:5][CH2:6][N:7]1[C:12](=[O:13])[C:11]2[C:14]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[C:15](Br)[CH:16]=[N:17][C:10]=2[N:9]([CH3:24])[C:8]1=[O:25])=O.[Cl:26][C:27]1[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C)CCC(O)=O>O1CCOCC1.C(Cl)Cl.O.[Cu]I>[Cl:26][C:27]1[CH:28]=[C:29]([CH:30]=[CH:31][CH:32]=1)[O:33][C:15]1[CH:16]=[N:17][C:10]2[N:9]([CH3:24])[C:8](=[O:25])[N:7]([CH2:6][CH2:5][CH2:4][OH:3])[C:12](=[O:13])[C:11]=2[C:14]=1[CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23]
Reactant: CC(C)CCc1c(Br)cnc2c1c(=O)n(CCCOC=O)c(=O)n2C
Reactant: Oc1cccc(Cl)c1
Agent: [Cu]I
Agent: CN(C)CCC(=O)O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)CCc1c(Oc2cccc(Cl)c2)cnc2c1c(=O)n(CCCO)c(=O)n2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
To a solution of 3-(6-bromo-5-isopentyl-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propyl formate (42 mg, 0.109 mmol) in dioxane (2 mL) was added 3-chlorophenol (28 mg, 0.218 mmol), CuI (6 mg, 0.0327 mmol), Cs2CO3 (71 mg, 0.218 mmol) and 3-(dimethylamino)propanoic acid (3 mg, 0.0327 mmol). The reaction was stirred at 130° C. (MW) for 2 h, cooled to RT then diluted with DCM (10 mL) and water (10 mL). The organic layer was dried over Na2SO4, and concentrated to a residue which was purified by Prep HPLC to give 6-(3-chlorophenoxy)-3-(3-hydroxypropyl)-5-isopentyl-1-methylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (8 mg, 15.5% yield) as a white solid. 1H NMR (DMSO-d6) δ: 8.57 (s, 1H), 7.39 (t, J=8.4 Hz, 1H), 7.17 (d, J=9.2 Hz, 1H), 7.02-7.00 (m, 1H), 6.93 (dd, J=8.0, 2.4 Hz, 1H), 4.50 (t, J=5.2 Hz, 1H), 4.00 (t, J=7.2 Hz, 2H), 3.58 (s, 3H), 3.45-3.50 (m, 2H), 3.15-3.10 (m, 2H), 1.77-1.72 (m, 2H), 1.57-1.52 (m, 1H), 1.23-1.34 (m, 2H), 0.82 (d, J=6.8 Hz, 6H). LCMS: MH+ 432 and TR=3.366 min.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:19](N)=[NH:20].[OH-].[Na+]>>[CH3:14][O:13][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[O:11][CH3:12])[N:1]=[CH:19][NH:20][C:4]2=[O:5]
Reactant: COc1cc(N)c(C(=O)O)cc1OC
Reactant: N=CN
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc2nc[nH]c(=O)c2cc1OC
Temperature: 140 °C
Yield: 75.4 %

Procedure:
A mixture of 2-amino-4,5-dimethoxybenzoic acid (1.0 g, 5.08 mmol) and formamidine acetate (4.50 g, 43.3 mmol) was disposed in a 50 mL ball. The solid mixture was heated at 140° C. in a silicone bath for eight hours. During heating, the fusion of solids happened, and then the resolidification of the reaction environment. The mixture was left cooling, and then a NaOH solution was added to it (0.33 mol.L−1) until pH was adjusted to 8. The grayish pink solid was collected through filtering in a Büchner funnel, washed with water (3×10 mL), and dried in vacuum to provide the desired compound (0.79 g, 3.83 mmol, 76%), which was used without purification in the next stage: m.p. 296-298° C. (Lit. (Bridges et al., J. Med. Chem. 1996, 39, 267), m.p. 295-298° C.).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.CCN(CC)CC.[C:24](Cl)(=[O:27])[CH:25]=[CH2:26].O>C(Cl)Cl>[C:24]([NH:1][CH2:2][CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1)(=[O:27])[CH:25]=[CH2:26]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)NCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 48.5 %

Procedure:
To a stirred mixture of tert-butyl 4-(2-aminoethyl)piperidine-1-carboxylate (1.0 g, 4.38 mmol) in DCM (20 mL) at 0° C., Et3N (1.33 g, 13.14 mmol) was added and the resulting mixture was stirred at 0° C. for 5 min. To this mixture, a solution of acryloyl chloride (0.39 g, 4.38 mmol) in DCM (5 mL) was added dropwise. The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was poured into water (20 mL) and extracted with DCM (30 mL×3). The combined organic layer was washed with brine (15 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10-50% ethyl acetate/dichloroethane) to afford the desired product (0.6 g, 50% yield) as a solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH3:17])[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:18]([O:21][CH2:22][C:23]1[C:24]([N:32]2[N:41]=[CH:40][C:39]3[C:34](=[C:35]([F:46])[CH:36]=[C:37]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:38]=3)[C:33]2=[O:47])=[N:25][CH:26]=[CH:27][C:28]=1B(O)O)(=[O:20])[CH3:19].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:18]([O:21][CH2:22][C:23]1[C:24]([N:32]2[N:41]=[CH:40][C:39]3[C:34](=[C:35]([F:46])[CH:36]=[C:37]([C:42]([CH3:44])([CH3:43])[CH3:45])[CH:38]=3)[C:33]2=[O:47])=[N:25][CH:26]=[CH:27][C:28]=1[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][N:14]([CH2:16][CH3:17])[CH:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OCc1c(B(O)O)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: CCn1cc(Nc2nc(Br)cn(C)c2=O)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CCn1cc(Nc2nc(-c3ccnc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3COC(C)=O)cn(C)c2=O)cn1
Temperature: 100 °C
Yield: 53.9 %

Procedure:
A 50-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 123c (151 mg, 0.51 mmol), 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-ylboronic acid 116c (206 mg, 0.50 mmol), PdCl2(dppf) (22 mg, 0.030 mmol), K3PO4 (216 mg, 1.02 mmol), sodium acetate (84 mg, 1.02 mmol), acetonitrile (10 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 3 h. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:3 petroleum/ethyl acetate to afford 123d as a yellow solid (158 mg, 53%). MS-ESI: [M+H]+ 587.2
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[CH:11]=[O:12].C1(C)C=CC=CC=1.[OH-:20].[Na+].OO>O>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:9])[F:10])[C:3]=1[C:11]([OH:20])=[O:12]
Reactant: Cn1nc(C(F)F)c(C=O)c1Cl
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cn1nc(C(F)F)c(C(=O)O)c1Cl
Temperature: 50 °C
Reaction time: 7 h
Yield: 49 %

Procedure:
In a 500 ml flask, 6.0 g (31 mmol) of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde are added to 30 ml of toluene. A solution of 2.4 g (62 mmol) of sodium hydroxide in 6 ml of water is added to the reaction mixture, followed by 103 ml of a 30% solution of hydrogen peroxide in water, whilst keeping the temperature below 37° C. After the end of the addition, the reaction mixture is stirred at 50° C. for 7 hours. Once the reaction mixture is back to room temperature, the two phases are separated and the organic phase is extracted with 100 ml of water. The combined aqueous phases are acidified to pH 2 with aqueous hydrochloric acid. The resulting white precipitate is filtered, washed twice with 20 ml of water, and dried to yield 3.2 g of 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm: 3.78 (s, 3H); 7.12 (t, 1H, JHF=53.60 Hz) 13.19 (s, 1H); IR (KBr): 1688 cm−1 (C═O); 2200-3200 cm−1 broad (hydrogen bond).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[N:5]=[CH:4]1.C(N(CC)CC)C.[Cl:19][C:20]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:21]=1[CH2:22][N:23]=[C:24]=[O:25]>C(O)C>[Cl:19][C:20]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:21]=1[CH2:22][NH:23][C:24]([N:8]1[CH2:9][CH2:10][C:11]2[NH:3][CH:4]=[N:5][C:6]=2[CH2:7]1)=[O:25]
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Reactant: c1nc2c([nH]1)CCNC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCc1ccc(Cl)cc1Cl)N1CCc2[nH]cnc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 36.2 %

Procedure:
To a mixture of 4,5,6,7-tetrahydroimidazo[4,5-c]pyridine dihydrochloride (0.50 g, 2.55 mmol), ethanol (10 mL) and triethylamine (1.10 mL, 7.89 mmol), 2,4-dichlorobenzyl isocyanate (0.52 g, 2.57 mmol) was added. The resulting mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was distributed between water (20 mL) and ethyl acetate (75 mL). The organic phase was washed with water (10 mL) and brine (10 mL), dried (MgSO4) and concentrated under reduced pressure. The residue was triturated in diethylether (50 mL) and the crude product was filtered off. Recrystallization from acetone (25 mL) gave 0.30 g (37%) of the title urea as a colourless solid.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:12][C@@H:11](O)[C@@H:10]1[NH:33][C:34]([N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1)=[S:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:1]([O:8][C@@H:9]1[C@H:10]2[N:33]=[C:34]([N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[S:35][C@H:11]2[CH2:12][C@H:13]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:14]1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@@H]1C[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1NC(=S)N1CCCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(COC[C@H]2C[C@@H]3SC(N4CCCC4)=N[C@@H]3[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 83.4 %

Procedure:
To a solution of N-((1S,2R,3R,4R,6R)-2,3-bis(benzyloxy)-4-((benzyloxy)methyl)-6-hydroxycyclohexyl)pyrrolidine-1-carbothioamide (0.260 g, 0.464 mmol) and triphenylphosphine (0.183 g, 0.700 mmol) in anhydrous THF (6.0 mL) was added DIAD (0.131 g, 0.650 mmol). After addition the mixture was stirred at room temperature for 60 h. The solvent was evaporated under reduced pressure, and the residue was purified on silica gel by automatic flash column chromatography (EtOAc/hexanes, 1:10 to 1:4), affording as a colorless oil (0.21 g, 84%). 1H NMR (400 MHz, CDCl3) δ 7.43-7.42 (m, 2H), 7.34-7.23 (m, 13H), 4.95 (d, J=11.6 Hz, 1H), 4.86 (d, J=11.0 Hz, 1H), 4.76 (d, J=11.6 Hz, 1H), 4.56 (d, J=11.0 Hz, 1H), 4.50-4.43 (m, 2H), 3.80 (d, J=7.6 Hz, 1H), 3.78-3.76 (m, 2H), 3.68 (dd, J=4.0, 9.0 Hz, 1H), 3.57-3.43 (m, 4H), 3.13 (d, J=6.2 Hz, 1H), 2.89-2.88 (m, 1H), 2.28-2.23 (m, 1H), 2.05-2.02 (m, 1H), 2.00-1.90 (m, 4H), 1.87-1.82 (m, 1H).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[S:3][C:4]3[CH2:5][C:6]4[C:12]([C:13]5[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=5)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[C:7]=4[C:8]=3[CH:9]=2)=[CH:33][CH:32]=1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2cc3c(s2)Cc2c(-c4ccc(OC)cc4)nn(COCC[Si](C)(C)C)c2-3)cc1
Temperature: 100 °C
Yield: 76 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.76 g, 1.5 mmol), 2-(4-Methoxy-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.36 g, 2.3 mmol), Na2CO3 (2 M, 3.7 mL), and Pd(PPh3)2Cl2 (150 mg, 0.012 mmol) in toluene/ethanol (1:1, 10 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 2,6-Bis-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as orange solid in 76% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH:27]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([Cl:15])=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=2)[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(Cl)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2ccncc2)c1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-fluoro-phenyl)-carbamic acid tert-butyl ester (Example J5) (235 mg, 0.9 mmol) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a pink powder (272 mg).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]([C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=2)(SC2C=CC=CC=2)[C:9]2[C:4](=[CH:5][C:6]([O:30][CH3:31])=[CH:7][CH:8]=2)[CH2:3]1.[BH4-].[Na+]>CO.O1CCCC1.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][N:2]1[C:11](=[O:12])[CH:10]([C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=2)[C:9]2[C:4](=[CH:5][C:6]([O:30][CH3:31])=[CH:7][CH:8]=2)[CH2:3]1
Reactant: COc1cc(OC)cc(C2(Sc3ccccc3)C(=O)N(C)Cc3cc(OC)ccc32)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(OC)cc(C2C(=O)N(C)Cc3cc(OC)ccc32)c1
Yield: 72.1 %

Procedure:
A solution of 2-methyl-4-(3,5-dimethoxyphenyl)-4-(phenylsulfanyl)-7-methoxy-1,4-dihydro-3(2H)-isoquinolone (2.4 g) and nickel chloride hexahydrate (8.8 g) in methanol-tetrahydro-furan (3:1, 100 ml) was cooled to 0° C. Sodium borohydride (4.2 g) was added in small portions during 30 minutes at a temperature not exceeding 5° C. The slurry was filtered and the filtrate concentrated to dryness. The residue was partitioned between dichloromethane (200 ml) and aqueous sodium hydroxide (2M, 200 ml). The organic phase was dried and concentrated to dryness leaving crude 2-methyl-4-(3,5-dimethoxyphenyl)-7-methoxy-1,4-dihydro-3(2H)-isoquinolinone (1.3 g). Crystallization from methanol afforded the pure compound, m.p. 137-139
Reaction SMILES: [C:1]1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[CH3:13][S-:14].[Na+].[Cl-].[Na+]>CO>[CH3:1][C:2]1[C:13](=[S:14])[C:6]2[C:5]([C:4](=[O:11])[CH:3]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: C[S-]
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC1=CC(=O)c2ccccc2C1=S
Reaction time: 8 h
Yield: 14 %

Procedure:
0.617 mM 1,4-naphtoquinone was dissolved in 30 ml of methanol in 100 ml one-neck round flask, and 1.54 mM sodium thiomethoxide was added thereto and stirred overnight. 50 ml of saturated sodium chloride solution was added to the reaction mixture, followed by extraction three times with 50 ml of chloroform, and an organic layer was dehydrated with an anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was re-crystallized with methanol to produce 2-methylthio-1,4-naphthoquinone that was yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([CH3:16])[N:9]=[CH:10]2.[Br:18]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([CH2:16][Br:18])[N:9]=[CH:10]2
Reactant: COC(=O)Cc1c(Cl)ccc2cnc(C)cc12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Cc1c(Cl)ccc2cnc(CBr)cc12
Temperature: 40 °C
Yield: 40 %

Procedure:
To a solution of (6-Chloro-3-methyl-isoquinolin-5-yl)-acetic acid methyl ester (1.9 g, 7.63 mmol) in tetrachloromethane (190 mL) was added N-bromosuccinimide (1.36 g, 7.63 mmol). The reaction mixture was heated to 40° C. for 1 h under simultaneous irradiation by a 300 W UV lamp, filtered and the filtrate concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, cyclohexane/EtOAc 80:20) to afford the title compound as a white powder (1.00 g, 3.05 mmol, 40%). MS (ES+): 328 (M(C13H1179Br35ClNO2)+H)+.