Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Si]([O:9][CH2:10][CH2:11][CH2:12][N:13]1[C:25]2[CH:24]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])[C:22]3[C:33](=[O:37])[NH:34][C:35](=[O:36])[C:21]=3[C:20]=2[C:19]2[CH:18]=[C:17]([O:38][CH3:39])[CH:16]=[CH:15][C:14]1=2)(C(C)(C)C)(C)C>C1COCC1.CO>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:23]1[C:22]2[C:33](=[O:37])[NH:34][C:35](=[O:36])[C:21]=2[C:20]2[C:19]3[CH:18]=[C:17]([O:38][CH3:39])[CH:16]=[CH:15][C:14]=3[N:13]([CH2:12][CH2:11][CH2:10][OH:9])[C:25]=2[CH:24]=1
Reactant: COc1ccc2c(c1)c1c3c(c(-c4ccccc4Cl)cc1n2CCCO[Si](C)(C)C(C)(C)C)C(=O)NC3=O
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c1c3c(c(-c4ccccc4Cl)cc1n2CCCO)C(=O)NC3=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
3N HCl (50 mL) was added to a solution of 6-(3-{[tert-Butyl(dimethyl) silyl]oxy}propyl)-4-(2-chlorophenyl)-9-methoxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (4.87 g, 8.85 mmol) prepared according to example 39 in 1:1 THF/methanol (200 mL). After stirring at room temperature for 2 h most of the solvents were removed in vacuo, the residue was extracted with ethyl acetate, washed well with water and the organic portion was concentrated to a volume of 60 mL. Petroleum ether was added to precipitate the product, which was filtered off and triturated several times with diethyl ether. The solid was crystallised from THF/petroleum ether and gave 4-(2-Chlorophenyl)-6-(3-hydroxypropyl)-9-methoxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (V; Ar=2-chlorophenyl, R10═CH2CH2CH2OH) (31)in a 3.77 g, 88% yield as a yellow powder; mp 228–230° C. 1H NMR δ [(CD3)2SO] 11.12 (br s, 1H), 8.52 (d, J=2.5 Hz, 1H), 7.80 (s, 1H), 7.70 (d, J=8.9 Hz, 1H), 7.58 (dd, J=8.1, 22 Hz, 1H), 7.53–7.42 (m, 3H), 7.31 (dd, J=8.9, 2.5 Hz, 1H), 4.63 (br, 1H), 4.53 (t, J=6.9 Hz, 2H), 3.91 (s, 3H), 3.40 (m, 2H), 1.91 (m, 2H). Found: C, 66.00; H, 4.23; N, 6.55. C24H19ClN2O4 requires C, 66.29; H, 4.40; N, 6.44.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.C([Sn](CCCC)(CCCC)[C:20]([O:22][CH2:23][CH3:24])=[CH2:21])CCC.[F-].[K+]>CN(C)C=O.O.CCOCC.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>[CH2:23]([O:22][C:20]([C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1)=[CH2:21])[CH3:24]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: C=C(OCC)c1nc(SC)ncc1C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (3.0 g, 12.89 mmol), tributyl(1-ethoxyvinyl)stannane (4.79 ml, 14.18 mmol) and bis(triphenylphosphine)palladium dichloride (0.452 g, 0.645 mmol) in N,N-dimethylformamide (43 mL) was heated to 70° C. for 1 hour. The mixture was cooled, treated with a solution of KF (1.5 g in 3 mL water) and stirred overnight at room temperature. The mixture was diluted with water and ether and filtered through diatomaceous earth. The layers were separated and the aqueous layer was extracted into ether. The combined extracts were rinsed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (0-20% gradient ethyl acetate in hexane) to provide the title compound. MS ESI(+) m/z 269.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([C@@H:13]([OH:21])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:7][CH2:6]1.[H-].[Na+].[CH3:24][CH2:25][CH2:26][CH2:27][C@@H:28](Br)[C:29]([OH:31])=[O:30].N#N>C1COCC1.CC(O)=O.CO>[CH3:1][O:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([C@@H:13]([O:21][C@@H:28]([CH2:27][CH2:26][CH2:25][CH3:24])[C:29]([OH:31])=[O:30])[CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:7][CH2:6]1
Reactant: COCOC1CCN(C(=O)[C@@H](O)Cc2ccccc2)CC1
Reactant: CCCC[C@@H](Br)C(=O)O
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCC[C@H](O[C@@H](Cc1ccccc1)C(=O)N1CCC(OCOC)CC1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 43 %

Procedure:
The resultant compound of Example 82(b) (1.45 g, 4.95 mmol), in 10 ml THF was added dropwise to the cooled suspension of sodium hydride (60% dispersion in oil, 0.5 g, 11.2 mmol) in 4 ml THF (0°-5° C.). The suspension was stirred for 20 mins at 0°-5° C. and then warmed up to room temperature and stirred for additional 1 h. Solution of D-2-bromohexanoic acid in 6 ml THF was added dropwise to the cooled suspension (0°-5° C.) at N2 atmosphere. It was then allowed to warm up to room temperature and stirred overnight. Quenched with cold H2O and extracted with ethylacetate to remove undesired starting material. It was acidified with 1M sodium hydrogen sulfate and extracted with chloroform. After filtration and evaporation, the crude product was purified on silica gel, eluted with CH2Cl2 : CH3OH: AcOH (19.4=0.3:0.3) to obtain 0.79 g of desired acid (43% yield).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[CH:8]=[C:9]([C@H:14]2[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][N:15]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:10]=[CH:11][C:12]=1[F:13].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.C(N(CC)CC)C>O1CCCC1>[F:6][C:7]1[CH:8]=[C:9]([C@H:14]2[CH2:19][C@@H:18]([O:20][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:17][CH2:16][N:15]2[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C[C@@H]1c1ccc(F)c(F)c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C[C@@H]1c1ccc(F)c(F)c1
Yield: 102.2 %

Procedure:
Methanesulfonyl chloride (1.0 g, 3.2 mmol) was added to a mixture of (±)-1,1-dimethylethyl (2R,4S)-2-(3,4-difluorophenyl)-4-hydroxypiperidine-1-carboxylate (1.00 g, 3.0 mmol) (obtained by conducting reagent preparation 28 in the presence of di-tert-butyl dicarbonate) and triethylamine (0.70 g, 7.0 mmol), in tetrahydrofuran (25 mL) at 0° C., and the resulting mixture was at room temperature for two hours. The reaction mixture was then quenched with a cold mixture of water and ethyl acetate. The organic portion was separated, washed with 5% sodium hydroxide, 0.5M hydrochloric acid, water then brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (5% to 75% ethyl acetate in hexanes gradient) to give (±)-1,1-dimethylethyl (2R,4S)-2-(3,4-difluorophenyl)-4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (1.2 g, 88% yield). MS (EI) for C17H23F2NO5S: 392 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].[H-].[Na+].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14].C1([O-])C=CC=CC=1>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(O)ccc1Br
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
A solution of 4-bromo-3-methoxyphenol (5.00 g, 24.6 mmol, Chontech) in THF (50 ml) was added dropwise to a suspension of sodium hydride (1.08 g, 60% dispersion in mineral oil, 27 mmol) in THF (100 ml) over 10 min while cooling in ice. The reaction mixture was stirred at 0° C. for 30 min and then at room temperature for 60 min. Triisopropylsilyl chloride was added dropwise to the phenolate solution, and the reaction mixture was stirred at room temperature for 60 min. Water was added to the mixture while cooling in ice, and it was then extracted several times with ethyl acetate. The combined organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. Purification by chromatography on silica gel (mobile phase: 2-10% gradient of ethyl acetate in dichloromethane) afforded 8.67 g (98%) of the desired product.
Reaction SMILES: [CH:1]1([N:7]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([NH:18][CH2:19][C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:30]1(N[C@H]2CC[C@H](C)CC2)[CH2:35]CCC[CH2:31]1.[CH3:44]OC([C@H]1CCCN1S(C1SC(N)=NC=1)(=O)=O)=O>>[CH:24]1([N:7]([C@H:1]2[CH2:2][CH2:3][C@H:4]([CH3:44])[CH2:5][CH2:6]2)[C:8](=[O:23])[NH:9][C:10]2[S:11][C:12]([S:15]([N:18]3[CH2:35][CH2:30][CH2:31][C@@H:19]3[C:20]([OH:22])=[O:21])(=[O:16])=[O:17])=[CH:13][N:14]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COC(=O)[C@H]1CCCN1S(=O)(=O)c1cnc(N)s1
Reactant: O=C(O)CNS(=O)(=O)c1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: C[C@H]1CC[C@H](NC2CCCCC2)CC1
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(S(=O)(=O)N3CCC[C@@H]3C(=O)O)s2)C2CCCCC2)CC1

Procedure:
Prepared in a similar manner to [2-(3,3-dicyclohexyl-ureido)-thiazole-5-sulfonylamino]-acetic acid via cyclohexyl-(trans-4-methyl-cyclohexyl)-amine and (R)-1-(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].[C:10]1([CH3:22])[CH:15]=[CH:14][C:13]([S:16]([N:19]=[C:20]=[O:21])(=[O:18])=[O:17])=[CH:12][CH:11]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20]([NH:19][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:22])=[CH:11][CH:12]=2)(=[O:18])=[O:17])=[O:21])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)ccc1Br
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2ccc(Br)c(C)c2)cc1
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of 5.58 g of 4-bromo-3-methyl-aniline in 20 ml of toluene and 5 ml of methylene chloride was added to a solution of 5.91 g of p-toluene-sulfonyl isocyanate in 50 ml of toluene and 10 ml of methylene chloride under a nitrogen atmosphere. The mixture was stirred overnight and filtered, providing 9.19 g of the title product, m.p. 178°-180° C.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13](O)=[O:14])[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]([C:6]=23)=[N:4][CH:3]=1.Cl.[NH:23]1[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH2:25][CH2:24]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C)C1C=CN=CC=1.CN(C=O)C>[O:29]=[S:26]1(=[O:30])[CH2:27][CH2:28][N:23]([C:13]([C@H:12]([N:9]2[C:8](=[O:19])[C:7]3=[CH:20][NH:21][C:5]4[C:6]3=[C:11]([C:2]([F:1])=[CH:3][N:4]=4)[CH2:10]2)[CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:24][CH2:25]1
Reactant: O=S1(=O)CCNCC1
Reactant: CC(C)[C@H](C(=O)O)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)[C@H](C(=O)N1CCS(=O)(=O)CC1)N1Cc2c(F)cnc3[nH]cc(c23)C1=O
Yield: 47 %

Procedure:
To an 8 mL scintillation vial equipped for stirring was added (R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid (15 mg, 0.051 mmol). DMF (0.5 mL), thiomorpholine 1,1-dioxide hydrochloride (8.84 mg, 0.51 mmol), HOBt (11.83 mg, 0.077 mmol), EDC (14.81 mg, 0.077 mmol) and N,N-dimethylpyridin-4-amine (9.44 mg, 0.077 mmol) were added and the solution was stirred at 25° C. for 4 h. The reaction mixture was purified via preparative mass trigger LC-MS (AcCN/H2O, 20-50%). The fractions were collected and lyophilized to afford the title compound as a white solid (9.8 mg, 46.6%). 1H NMR (400 MHz, CD3OD) δ 0.92 (d, J=6.82 Hz, 3 H) 1.02 (d, J=6.32 Hz, 3 H) 2.60 (dt, J=10.61, 6.57 Hz, 1 H) 2.90-3.03 (m, 1 H) 3.03-3.25 (m, 3 H) 3.86-4.01 (m, 1 H) 4.13 (ddd, J=14.78, 8.59, 2.40 Hz, 1 H) 4.21-4.41 (m, 2 H) 4.92-5.06 (m, 1 H) 5.06-5.18 (m, 1 H) 5.57 (d, J=10.61 Hz, 1 H) 7.89 (s, 1 H) 8.18 (d, J=3.28 Hz, 1 H). [M+H] calc'd for C18H21FN4O4S, 409; found, 409.3.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([N+:16]([O-])=O)[CH:9]=2)[CH:3]=1>C(O)C.O1CCCC1.[Pd]>[CH3:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=2)=[CH:9][C:10]=1[NH2:16]
Reactant: COc1ccc(-c2cc(C)ccn2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(-c2cc(C)ccn2)cc1N
Yield: 99.9 %

Procedure:
A suspension of 4-(4-methylpyridin-2-yl)-2-nitro anisole (347 mg) in ethanol (3.5 ml) and tetrahydrofuran (3.5 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 120 mg) under a hydrogen atmosphere for 1 hour. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 2-methoxy-5-(4-methylpyridin-2-yl)aniline (304 mg).
Reaction SMILES: C(O[CH:5]1[CH2:31][C:30](=[O:32])[CH:29]([CH2:33][CH:34]=[CH2:35])[CH:28]=[C:27]([CH3:36])[CH2:26][CH:25]([CH3:37])[CH2:24][CH:23]([O:38][CH3:39])[CH:22]2[O:40][C:18]([OH:44])([CH:19]([CH3:43])[CH2:20][CH:21]2[O:41][CH3:42])[C:17](=[O:45])[C:16](=[O:46])[N:15]2[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[C:9](=[O:47])[O:8][CH:7]([C:48]([CH3:76])=[CH:49][CH:50]2[CH2:55][CH2:54][CH:53]([O:56][Si:57]([C:70]([CH3:73])([CH3:72])[CH3:71])([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[CH:52]([O:74][CH3:75])[CH2:51]2)[CH:6]1[CH3:77])(=O)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.C(OCC)C>[CH2:33]([CH:29]1[CH:28]=[C:27]([CH3:36])[CH2:26][CH:25]([CH3:37])[CH2:24][CH:23]([O:38][CH3:39])[CH:22]2[O:40][C:18]([OH:44])([CH:19]([CH3:43])[CH2:20][CH:21]2[O:41][CH3:42])[C:17](=[O:45])[C:16](=[O:46])[N:15]2[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14]2)[C:9](=[O:47])[O:8][CH:7]([C:48]([CH3:76])=[CH:49][CH:50]2[CH2:55][CH2:54][CH:53]([O:56][Si:57]([C:70]([CH3:73])([CH3:72])[CH3:71])([C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH:52]([O:74][CH3:75])[CH2:51]2)[CH:6]([CH3:77])[CH:5]=[CH:31][C:30]1=[O:32])[CH:34]=[CH2:35]
Reactant: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)C(OC)C3)C(C)C(OC(C)=O)CC1=O)C(C)CC2OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)C(OC)C3)C(C)C=CC1=O)C(C)CC2OC
Reaction time: 3 h
Yield: 72.5 %

Procedure:
To a solution of 14-acetoxy-17-allyl-12-[2-(4-tert-butyl-diphenylsilyloxy-3-methoxycyclohexyl)-1-methylvinyl]-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (43.8 mg) in tetrahydrofuran (1.5 ml) was added potassium carbonate (ca 100 mg) at room temperature and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was diluted with diethyl ether and the resulting solution was washed with a saturated aqueous ammonium chloride, water and an aqueous sodium chloride successively, and dried over sodium sulfate. The resulting solution was concentrated under reduced pressure and the residue was purified on silica gel thin layer chromatography (developing solvent: diethyl ether and hexane, 3:2 v/v) to give 17-allyl-12-[2-(4-tert-butyl-diphenylsilyloxy-3-methoxycyclohexyl)-1-methylvinyl]-1-hydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacosa-14,18-diene-2,3,10,16-tetraone (30 mg).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:4][CH2:3]1.[CH3:36][S:37]([CH3:39])=O.C(OC(=O)C)(=O)C>O>[CH3:36][S:37][CH2:39][O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:4][CH2:3]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Reactant: CS(C)=O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCSC)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (2.0 g), dimethyl sulfoxide (30 mL) and acetic anhydride (10 mL) was stirred at room temperature for 14 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.3 g, 59%).
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][Si:5]([O:12][CH2:13]C)([O:9][CH2:10]C)[O:6][CH2:7]C.[CH2:15]([C:17]([CH3:19])=[O:18])C.[OH2:20]>>[CH2:15]([O:20][CH2:2][CH2:3][CH2:4][Si:5]([O:6][CH3:7])([O:9][CH3:10])[O:12][CH3:13])[CH:17]1[O:18][CH2:19]1
Reactant: CCC(C)=O
Reactant: O
Reactant: CCO[Si](CCCN)(OCC)OCC
Product: CO[Si](CCCOCC1CO1)(OC)OC
Reaction time: 1 h

Procedure:
Into a sealable, glass container were charged 50 g of γ-aminopropyl-triethoxysilane (0.226 mole) and 50 g (0.694 mole) methyl ethyl ketone. The mixture was allowed to stand one hour to permit the ketimine to form. Then 106.8 g (0.4525 mole) of γ-glicidoxypropyl-trimethoxysilane, 117.2 g of methyl ethyl ketone (1.63 mole) and 12.4 g (0.678 mole) distilled water were added to the ketimine mixture (representing a molar ratio of water per siloxane group of 0.68). The non-volatile solids content was 45 wt. % of the total coating composition, which was composed of the first component, or ketimine, and the second component (formed via partial hydrolysis of the γ-glycidoxypropyl-trimethoxysilane). The coating composition was allowed to age for about one hour, and then a sample was drawn down onto a degreased panel of polyallyl diglycol carbonate with a #22 wire wound coating rod. The coating was cured by baking at 15 hours at 80° C. The adhesion, as tested by ASTM D3359, was 100%. The scratch resistance on a Gardner Labs Scratch and Adhesion Tester was 148 g. The surface, when rubbed 100 times at 40 psi with 000 steel wool exhibited 1 or 2 scratches, but no scratches after 100 rubs at 30 psi. The usable pot life was 16-18 hours.
Reaction SMILES: O.O.O.O.O.O.[NH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl.Cl.N1CCNCC1.Br[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1>CO>[N:7]1([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: C1CNCCN1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(CN2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64 %

Procedure:
A mixtue of 38 g. (0.2 mole) piperazine hexahydrate, 28 g. (0.2 mole) piperazine dihydrochloride and 150 ml. methanol is mixed, while stirring at ambient temperature, with 45 g. (0.2 mole) methyl 4-bromomethylbenzoate. The reaction mixture is left to stand for 2 days and suction filtered from the precipitate. The clear solution is evaporated and the residue is recrystallised from ethanol to give 39 g. (64%) of the desired compound as a monohydrochloride; m.p. 226°-227° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[NH4+].[Cl-].I[CH2:15][C:16]([CH3:18])=[CH2:17]>C1COCC1.[Zn]>[Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([OH:5])[CH2:17][C:16]([CH3:18])=[CH2:15]
Reactant: O=C(CCCl)c1ccccc1
Reactant: C=C(C)CI
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: C=C(C)CC(O)(CCCl)c1ccccc1
Reaction time: 1 h
Yield: 75.6 %

Procedure:
A solution of 3-chloro-1-phenylpropan-1-one (16.8 g, 0.1 mol) in THF (50 mL) was added to a well-stirred suspension of zinc powder (13 g, 0.2 mol) in a mixture of satd aq NH4Cl solution (260 mL) and THF (65 mL). A solution of 3-iodo-2-methylprop-1-ene (36.4 g, 0.2 mol) in THF (50 mL) was added dropwise. The reaction was mildly exothermic, and the mixture began to reflux spontaneously. After refluxing had ceased, the mixture was stirred for 1 h. TLC showed the 3-chloro-1-phenylpropan-1-one had not reacted completely. A solution of 3-iodo-2-methylprop-1-ene (18.2 g, 0.1 mol) in THF (30 mL) was added, and the mixture was stirred at rt overnight. The mixture was extracted with EtOAc (2×500 mL). The combined organic layer was dried and concentrated. The residue was purified by column chromatography on silica gel eluted with petroleum ether/EtOAc 50:1→30:1→5:1, to give 1-chloro-5-methyl-3-phenylhex-5-en-3-ol (17 g, yield 76%) as an oil. 1H NMR (CDCl3): δ1.28 (s, 3H), 2.31 (m, 2H), 2.54 (m, 2H), 2.68 (d, 1H), 3.15 (m, 1H), 3.58 (m, 1H), 4.78 (m, 1H), 4.93 (m, 1H), 7.27 (t, 1H), 7.38 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[O:18][CH:17]([CH2:20][NH:21]C(=O)OCC3C=CC=CC=3)[CH2:16][C:15]=2[CH:14]=[CH:13][CH:12]=1>[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[O:18][CH:17]([CH2:20][NH2:21])[CH2:16][C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2cccc3c2OC(CNC(=O)OCc2ccccc2)C3)c(OC)c1
Agent: [Pd]
Product: COc1ccc(-c2cccc3c2OC(CN)C3)c(OC)c1
Yield: 82.3 %

Procedure:
Treatment of (−)-benzyl {[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (0.638 g, 1.52 mmol) with palladium on carbon (0.066 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 0.357 g (73%) of (+)-1-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a pale yellow solid, hydrochloride salt. [α]D25=+1.16 (c 10.0 in methanol); mp 166-168° C.; Anal. calcd. for C17H19NO3HCl: C, 63.45; H, 6.26; N, 4.35. Found: C, 61.94; H, 6.85; N, 3.76.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH:11]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH3:12])[C:5]([OH:7])=O.[F:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[NH2:28]>C1COCC1>[C:17]([O:16][C:14](=[O:15])[NH:13][CH:11]([C:10]1[CH:9]=[CH:8][C:4]([C:5](=[O:7])[NH:28][C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[F:21])=[CH:3][C:2]=1[Br:1])[CH3:12])([CH3:20])([CH3:19])[CH3:18]
Reactant: Nc1ccncc1F
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)O)cc1Br
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ccncc2F)cc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromo-4-(1-tert-butoxycarbonylamino-ethyl)-benzoic acid (8352 μmol) in dry THF (20 ml) was added Ghosez reagent (2 eq.). The mixture was stirred at RT for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in dry pyridine (20 ml) and 3-fluoro-pyridin-4-ylamine (1.2 eq) was added. The reaction mixture was stirred at RT for 2.5 hours. The pyridine was removed under reduced pressure. The residue was dissolved in 1N Na2CO3 and extracted with EtOAc. The combined organic layers were washed with 1N NaHCO3, citric acid and water. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. The compound was purified by column chromatography (silicagel, DCM/MeOH gradient).