Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24]([OH:26])=O)[CH2:9]2)=[O:7])[CH2:3]1.O[N:28]=[C:29]([NH2:36])[CH2:30][CH2:31][O:32][CH:33]([CH3:35])[CH3:34]>>[OH:1][CH:2]1[CH2:3][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=3)[CH2:11][CH:10]([C:24]3[O:26][N:36]=[C:29]([CH2:30][CH2:31][O:32][CH:33]([CH3:35])[CH3:34])[N:28]=3)[CH2:9]2)=[O:7])[CH2:5]1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Reactant: CC(C)OCCC(N)=NO
Product: CC(C)OCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CC(O)C3)C2)n1

Procedure:
100 mg (0.27 mmol) of the compound from Example 101A and 66 mg (0.40 mmol) of the compound from Example 65A were reacted according to the General Method 2. Yield: 28 mg (20% of theory)
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[CH2:10][C:9](=O)[NH:8][CH2:7]1)C.O.[OH-].[Na+]>C1COCC1.ClCCl>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([C:6]2([CH2:5][CH2:4][OH:3])[CH2:10][CH2:9][NH:8][CH2:7]2)[CH:17]=[CH:16][C:15]=1[O:18][CH3:19]
Reactant: CCOC(=O)CC1(c2ccc(OC)c(OC)c2)CNC(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2(CCO)CCNC2)cc1OC

Procedure:
Combined LiA1H4 (4.80 g, 127 mmol, 4 eq) and anhydrous THF (200 mL). Added portionwise, a slurry of [3-(3,4-dimethoxy-phenyl)-5-oxo-pyrrolidin-3-yl]-acetic acid ethyl ester (9.72 g, 31.6 mmol) in THF (100 mL). After the addition was complete, the reaction was heated at reflux overnight. Cooled in an ice/NaCl bath. Cautiously added H2O (4.8 mL), NaOH (4.8 mL, 15%), and H2O (19.2 mL). Filtered. Concentrated the filtrate to obtain a residue. Dissolved the residue in dichloromethane and dried over MgSO4, filtered, and concentrated the filtrate in vacuo to obtain a residue which was dried at 0.05 Torr overnight to give the title compound. This material was used without further purification.
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[C@@H:10]([CH2:21][CH3:22])[CH2:11][C:12]2=[O:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:23][CH3:24])[CH:4]=[CH:5]2.C([O-])([O-])=O.[K+].[K+].[N:31]#CBr>C(Cl)(Cl)Cl>[C:19]([N:18]1[CH2:17][CH2:16][C@:14]23[C:15]4[C:2]5[O:1][C@H:13]2[C:12](=[O:20])[CH2:11][C@H:10]([CH2:21][CH3:22])[C@H:9]3[C@H:8]1[CH2:7][C:6]=4[CH:5]=[CH:4][C:3]=5[O:23][CH3:24])#[N:31]
Reactant: N#CBr
Reactant: CC[C@H]1CC(=O)[C@@H]2Oc3c(OC)ccc4c3[C@@]23CCN(C)[C@H](C4)[C@H]13
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC[C@H]1CC(=O)[C@@H]2Oc3c(OC)ccc4c3[C@@]23CCN(C#N)[C@H](C4)[C@H]13
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
4,5α-Epoxy-8β-ethyl-3-methoxy-17-methylmorphinan-6one (5.00 g, 13.7 mmole; prepared in Part A) was dissolved in 50 ml chloroform. After the addition of K2CO3 (2.84 g, 20.6 mmole), the stirred suspension was treated dropwise with a solution of cyanogen bromide (1.95 g, 18.4 mmole) in 40 ml chloroform. The mixture was stirred at room temperature for 30 minutes and heated for 1.5 hours at reflux temperature. After cooling, the insoluble material was removed from the mixture by filtration and the filtrate was evaporated to a crystalline residue which was boiled with ethanol (30 ml). After chilling, the crystals were collected to give 4.30 g (92%) of white needles, mp sinters 194° C., melts 197°-198.5° C.
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH2:14][CH3:15])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11].[CH2:16]1[O:20][C:19]2[CH:21]=[C:22]([OH:25])[CH:23]=[CH:24][C:18]=2[O:17]1>>[CH2:16]1[O:20][C:19]2[CH:21]=[C:22]([O:25][CH2:2][CH:3]=[C:4]([CH2:14][CH3:15])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH:23]=[CH:24][C:18]=2[O:17]1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: CCC(=CCBr)CCC=C(C)CC(C)C
Product: CCC(=CCOc1ccc2c(c1)OCO2)CCC=C(C)CC(C)C

Procedure:
By the procedure of Example 1, 1-bromo-3-ethyl-7,9-dimethyl-2,6-decadiene is reacted with sesamol to obtain 1,2-(methylenedioxy-4-[(3-ethyl-7,9-dimethyl-2,6-decadienyl)-oxy]-benzene; nD24 = 1.5190.
Reaction SMILES: [N:1]([C:4]1[CH:82]=[CH:81][C:7]([CH2:8][O:9][C:10]([NH:12][C@@H:13]([CH2:74][S:75][S:76][C:77]([CH3:80])([CH3:79])[CH3:78])[C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][C@@H:21]([NH:66]C(OC(C)(C)C)=O)[C:22]([O:24][C@H:25]2[C@@H:29]([OH:30])[C@H:28]([N:31]3[CH:39]=[N:38][C:37]4[C:32]3=[N:33][CH:34]=[N:35][C:36]=4[NH2:40])[O:27][C@H:26]2[CH2:41][O:42][P:43]([O:46][C@H:47]2[CH2:51][C@H:50]([N:52]3[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]3=[O:59])[O:49][C@@H:48]2[CH2:60][O:61][P:62]([OH:65])([OH:64])=[O:63])([OH:45])=[O:44])=[O:23])=[O:15])=[O:11])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].FC(F)(F)C(O)=O>ClCCl>[NH2:66][C@H:21]([CH2:20][CH2:19][CH2:18][CH2:17][NH:16][C:14](=[O:15])[C@@H:13]([NH:12][C:10]([O:9][CH2:8][C:7]1[CH:81]=[CH:82][C:4]([N:1]=[N+:2]=[N-:3])=[CH:5][CH:6]=1)=[O:11])[CH2:74][S:75][S:76][C:77]([CH3:80])([CH3:79])[CH3:78])[C:22]([O:24][C@H:25]1[C@@H:29]([OH:30])[C@H:28]([N:31]2[CH:39]=[N:38][C:37]3[C:32]2=[N:33][CH:34]=[N:35][C:36]=3[NH2:40])[O:27][C@H:26]1[CH2:41][O:42][P:43]([O:46][C@H:47]1[CH2:51][C@H:50]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:49][C@@H:48]1[CH2:60][O:61][P:62]([OH:65])([OH:64])=[O:63])([OH:45])=[O:44])=[O:23]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCCNC(=O)[C@H](CSSC(C)(C)C)NC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)SSC[C@H](NC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)NCCCC[C@@H](N)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 27.6 %

Procedure:
A solution of (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 6-((R)-2-((((4-azidobenzyl)oxy)carbonyl)amino)-3-(tert-butyldisulfanyl)propanamido)-2-((tert-butoxycarbonyl)amino)hexanoate (Compound tk25) (6.7 mg, 5.44 μmol) in dichloromethane (0.4 mL) was cooled in an ice bath, after which trifluoroacetic acid (0.1 mL) was added and the mixture was stirred at room temperature for 25 minutes. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-amino-6-((R)-2-((((4-azidobenzyl)oxy) carbonyl)amino)-3-(tert-butyldisulfanyl)propanamido)hexanoate (Lys(Acbz-Cys(StBu))-pdCpA) (Compound tk26) (1.7 mg, 28%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([N-]C(C)C)(C)C.[Li+].[F:17][C:18]([F:25])([F:24])[C:19](OCC)=[O:20].O>O1CCCC1>[Br:1][C:2]1[C:3]([F:8])=[C:4]([C:19](=[O:20])[C:18]([F:25])([F:24])[F:17])[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccccc1Br
Reactant: CCOC(=O)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(c1cccc(Br)c1F)C(F)(F)F
Yield: 30.7 %

Procedure:
To a solution of 1-bromo-2-fluorobenzene (5.0 g, 28.6 mmol) in dry tetrahydrofuran (50 ml) under nitrogen, at −78° C. was added lithium diisopropylamide (2.0 M in hexane, 15.7 ml, 31.4 mmol). The mixture was stirred for 5 minutes after which ethyl trifluoroacetate (3.76 ml, 31.4 mmol) was added and the stirring was continued at −78° C. for an additional hour. The reaction mixture was brought to ambient temperature and water (50 ml) was added. The phases were separated and the aqueous phase extracted with ethylacetate (3×100 ml). The combined organic phases was dried (MgSO4) and evaporated to dryness to give an oil. The residue was purified by flash column chromatography (isooctane) to give the title compound (2.38 g). MS m/z (relative intensity, 70 eV) 272 (M+, 11), 270 (M+, 11), 203 (97), 201 (bp, 173 (46).
Reaction SMILES: [H-].[Na+].[C:3](=[N:6][OH:7])([NH2:5])[CH3:4].[C:8]1([CH2:18][C:19]([NH:21][C:22]2[CH:26]=[CH:25][S:24][C:23]=2[C:27](OC)=O)=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1>C1COCC1.C(OCC)(=O)C>[CH3:4][C:3]1[N:5]=[C:27]([C:23]2[S:24][CH:25]=[CH:26][C:22]=2[NH:21][C:19](=[O:20])[CH2:18][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[CH:10][CH:9]=2)[O:7][N:6]=1
Reactant: COC(=O)c1sccc1NC(=O)Cc1cccc2ccccc12
Reactant: CC(N)=NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1noc(-c2sccc2NC(=O)Cc2cccc3ccccc23)n1
Reaction time: 1 h

Procedure:
Sodium hydride (60% dispersion, 15 mg, 0.39 mmol) was added to a solution of acetamide oxime (29 mg, 0.39 mmol) in THF (1 mL). The resulting mixture was stirred at room temperature for 10 minutes after which a solution of methyl 3-(2-(naphthalen-1-yl)acetamido)thiophene-2-carboxylate (107 mg, 0.33 mmol) in THF (1 mL) was added. The reaction mixture was stirred for 1 h and was subsequently diluted with ethyl acetate (10 mL). The resulting solution was washed with brine (5 mL) and the organic phase was then dried (Na2SO4), filtered and concentrated under vacuum. The residue was dissolved in THF (1 mL) and HCl (1 mL of a 10% aqueous solution) was added. The mixture was stirred for 20 minutes after which ethyl acetate (10 mL) was added. The resulting solution was washed with brine (5 mL) and the organic phase was then dried (Na2SO4), filtered, concentrated under vacuum and the residue was purified by preparative HPLC to give N-(2-(3-methyl-1,2,4-oxadiazol-5-yl)thiophen-3-yl)-2-(naphthalen-1-yl)acetamide. Retention time (min)=9.533, method [7], MS (ESI) 350.1 (M+H). 1H NMR (300 MHz, CDCl3) δ 10.10 (s, 1H), 8.26 (d, J=5.4 Hz, 1H), 8.03 (d, J=9.3 Hz, 2H), 7.59-7.49 (m, 5H), 4.27 (s, 2H), 2.14 (s, 3H).
Reaction SMILES: CN1CCOCC1.[O:8]=[C:9]([O:25][CH2:26][CH2:27][CH3:28])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]=1[CH2:20][CH2:21][C:22]([OH:24])=O.ClC(OCC)=O.[N+:35](=[CH2:37])=[N-:36]>C1COCC1>[N+:35](=[CH:37][C:22](=[O:24])[CH2:21][CH2:20][C:12]1[NH:13][C:14]2[C:19]([C:11]=1[CH2:10][C:9]([O:25][CH2:26][CH2:27][CH3:28])=[O:8])=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N-:36]
Reactant: C=[N+]=[N-]
Reactant: CCCOC(=O)Cc1c(CCC(=O)O)[nH]c2ccccc12
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CCCOC(=O)Cc1c(CCC(=O)C=[N+]=[N-])[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
N-methylmorpholine (1.1 equiv.) was added dropwise over 1 h to a stirred, 0° C. mixture of 3-[3-(2-oxo-2-propoxyethyl)-1H-indol-2-yl]propanoic acid from Step 3 and ethyl chloroformate (1.11 equiv.) in THF (0.4 M). The reaction temperature was closely monitored during the addition and was not allowed to go over +2° C. The mixture was stirred at 0° C. an additional 30 min. A white precipitate formed rapidly. Diazomethane (0.3 M in Et2O, 1.8 equiv.) was added and the final mixture was stirred for 2 h at 0° C. The mixture was filtered and the supernatant was concentrated under vacuum (with AcOH put in the vacuum trap to quench excess diazomethane). The residue was purified by column chromatography on silica gel using automatized gradiant pump system CombiFlashRF (Teledyne ISCO) eluting with EtOAc/Hexane(10:90 to 60:40) to give the title compound (63%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:28])=O>C1COCC1.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:9]=[CH:8][C:4]=1[C:5]([Cl:28])=[O:6]
Reactant: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
2-Methoxy-4-(1-Boc-4-piperidyloxy)benzoic acid (3.2 g, 9.1 mmol) was dissolved in THF (35 ml). Thionyl chloride (1 ml, 1.63 g, 13.7 mmol) was added dropwise, followed by 2 drops of pyridine. The mixture was stirred at ambient temperature under nitrogen for 4.5 hours, then concentrated in vacuo. The residue was reconcentrated from ether to give 2-methoxy-4-(1-Boc-4-piperidyloxy)benzoyl chloride.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Fe].CC(O)=O>[NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1c(-c2ccccc2)cccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1cccc(-c2ccccc2)c1N
Temperature: 60 °C
Reaction time: 1 h

Procedure:
2-Amino-3-nitrobiphenyl d (0.613 g, 2.86 mmol) was purged under nitrogen for 30 minutes then HOAc (5 mL) was added followed by iron powder (0.4895 g, 8.76 mmol). The sample was heated at 60° C. for 30 minutes then HOAc (5 mL) was added. The sample was stirred at 60° C. for 1 hour then poured into ice. The sample was extracted with EtOAc (3×100 mL). The EtOAc extracts were washed with saturated NaHCO3 (3×100 mL. The EtOAc layer was dried over MgSO4, filtered, and concentrated to give 2,3-diaminobiphenyl e (0.439 g, 2.38 mmol, 83%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15](=O)[C:14](=[CH:17][N:18]([CH3:20])C)[CH2:13][CH2:12][CH2:11][C:8]=2[NH:9][CH:10]=1)=[O:5])[CH3:2].C(O)(=O)C.C(N)=[NH:26]>CCO.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[C:15]3[N:26]=[CH:20][N:18]=[CH:17][C:14]=3[CH2:13][CH2:12][CH2:11][C:8]=2[NH:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: N=CN
Reactant: CCOC(=O)c1c[nH]c2c1C(=O)C(=CN(C)C)CCC2
Solvent: CCO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1c[nH]c2c1-c1ncncc1CCC2
Temperature: 120 °C
Reaction time: 4 h
Yield: 77.5 %

Procedure:
A mixture of 5-dimethylaminomethylene-4-oxo-1,4,5,6,7,8-hexahydro-cyclohepta [b]pyrrole-3-carboxylic acid ethyl ester (840 mg) and formamidine acetate (956 mg, 9.1 mmol) in EtOH (10 mL) is stirred at 120° C. for 4 h. After cooling, the reaction mixture is diluted with CH2Cl2 and washed with half saturated aq NaHCO3 (25 mL), H2O (25 mL), and brine (25 mL) The aqueous washes are reextracted once with CH2Cl2, and the combined extracts are dried over K2CO3 and concentrated. The crude material is purified by flash chromatography on silica gel. Elution with 30:1 CHCl3-MeOH followed by 20:1 CHCl3-MeOH and finally 15:1 CHCl3-MeOH afforded 606 mg (77%) of 3,4,5,6-tetrahydro-3,8,10-triaza-benzo[e]azulene-1-carboxylic acid ethyl ester as a light yellow solid. 1H NMR (CDCl3, 300 MHz) δ9.30 (br s, 1H), 9.02 (s, 1H), 8.43 (s, 1H), 7.24 (d, J=2.7 Hz, 1H), 4.26 (q, J=7.2 Hz, 2H), 2.78 (t, J=7.2 Hz, 2H) 2.70 (m, 2H), 2.12 (m, 2H), 1.26 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.Br[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([C:24]#[N:25])[CH:23]=1>O>[CH3:1][C:2]1([CH3:16])[O:3][C:4](=[O:15])[NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH:23]=3)[C:24]#[N:25])=[CH:8][C:7]1=2
Reactant: N#Cc1cncc(Br)c1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Solvent: O
Product: CC1(C)OC(=O)Nc2ccc(-c3cncc(C#N)c3)cc21

Procedure:
Prepared from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 3-bromo-5-cyanopyridine according to Procedure B. Off-white solid: mp 290-291° C.; 1H-NMR (DMSO-d6) δ 10.41 (s, 1H, D2O exchangeable), 9.21 (d, 1H, J=2.2 Hz), 8.97 (d, 1H, J=1.7 Hz), 8.68 (t, 1H, J=2.1 Hz), 7.76 (m, 2H), 7.01 (d, 1H, J=8.2 Hz), 1.70 (s, 6H); MS (ESI) m/z 278 (M−H, 96%). Anal. Calc. For C16H13N3O2.0.2 H2O: C, 67.94; H, 4.77; N, 14.85. Found: C, 68.04; H, 4.70; N, 14.58.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][CH2:4][C@@H:3]([C:7](OC)=[O:8])[CH2:2]1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[CH:7]([C@@H:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2]1)=[O:8]
Reactant: COC(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C=O)C1
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
To a solution of (R)-1-tert-butyl 3-methyl piperidine-1,3-dicarboxylate (1.9 g, 7.3 mmol) in 60 mL DCM was slowly added DIBAL-H (22 mL, 1M in cyclohexane, 22 mmol) at −70° C. The mixture was further stirred at −70° C. for 20 min and the temperature was slowly raised to 0° C. over a period of 20 min. The reaction was quenched by pouring 4% aqueous H2SO4 (30 mL) and followed extraction with DCM (3×30 mL). The combined DCM layers were washed with 30 mL 4% aqueous H2SO4, 20 mL brine twice and dried over Na2SO4. The solvent was removed under reduced pressure and the product isolated by flash column chromatography eluting with 0% to 50% ethyl acetate/hexane gradient solvent to give the title compound, 732 mg, as colorless oil.
Reaction SMILES: [CH2:1]([O:5][CH:6]=[C:7]([CH:10]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])[O:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:8]#[N:9])[CH2:2][CH2:3][CH3:4].[CH3:21][CH2:22][CH2:23][CH2:24][O-:25].[Na+].S(=O)(=O)(O)O>C(O)CCC>[CH2:17]([O:16][CH:10]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]([CH:6]([O:25][CH2:24][CH2:23][CH2:22][CH3:21])[O:5][CH2:1][CH2:2][CH2:3][CH3:4])[C:8]#[N:9])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC[O-]
Reactant: CCCCOC=C(C#N)C(OCCCC)OCCCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCCCO
Product: CCCCOC(OCCCC)C(C#N)C(OCCCC)OCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 277.8 %

Procedure:
In 100 ml of n-butanol was dissolved 8.49 g (30 mmoles) of 2-n-butoxymethylene-3,3-di-n-butoxypropanenitrile. To the resulting solution was added 0.87 g (9 mmoles) of sodium n-butylate at room temperature, and the mixture was stirred at room temperature for one hour. Then, the reaction mixture was neutralized with a solution of sulfuric acid in butanol and the resulting inorganic salt was removed by filtration. The filtrate was distilled under reduced pressure to obtain 9.10 g (25 mmoles) of 2-di-n-butoxymethyl-3,3-di-n-butoxypropanenitrile as a colorless transparent oil boiling at 170°-175° C./2 mmHg.
Reaction SMILES: [CH:1]#[C:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:9][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:2]#[C:1][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#CC(O)CCCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCC(O)C#Cc1cccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2

Procedure:
Using Method C above, rac-1-octyn-3-ol (61 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (146 mg, 0.4 mmol) (Starting Material 2 supra) using (Ph3P)2PdCl2 (20 mg) and CuI (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield rac-(Z)-1,3-dihydro-4-(3-hydroxy-1-octynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 88 mg, 60%).
Reaction SMILES: [CH2:1]([S:7][CH:8]=[CH:9][C:10](OC)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CC(C[AlH]CC(C)C)C>CCCCCC>[CH2:1]([S:7][CH:8]=[CH:9][CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCSC=CC(=O)OC
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Product: CCCCCCSC=CCO

Procedure:
To a cooled (5°) solution of the above methyl 3-(hexylthio)-2-propenoate (0.84 g, 4.2 mmol) in 5 ml of hexane is added dropwise 10.7 ml (9.7 mmol) of a DIBAL solution (0.91 M/hexane). After addition is complete, the ice bath is removed. Aqueous methanol (3 ml MeOH:2 ml H2O) is added dropwise, followed by ether, and the reaction mixture is filtered, washed with ether and then stripped of solvent to give 3-hexylthio-2-propenol.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:33])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21](Cl)[C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1>>[CH3:10][O:11][C:12](=[O:33])[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=3)[C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[S:25][C:23]=3[N:24]=2)=[CH:15][CH:14]=1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(C(F)(F)F)sc3n2)cc1
Reactant: NCc1ccc(F)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(F)cc3)c3cc(C(F)(F)F)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 4-fluorobenzylamine is reacted with 4-(4-chloro-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(4-fluorobenzylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([C:13]([CH3:15])=[CH2:14])[CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.O[C:17]1C=C(C(CC=C)CC(OC)=O)C=CC=1>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]([C:13]([CH3:15])=[CH2:14])[CH2:9][C:10]([O:12][CH3:17])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC(CC(=O)OC)c1cccc(O)c1
Reactant: C=C(C)C(CC(=O)O)c1cccc(O)c1
Product: C=C(C)C(CC(=O)OC)c1cccc(O)c1
Yield: 83 %

Procedure:
Compound 48.2 (0.63 g, 3.1 mmol) was esterified according to the method described for preparation of 43.3 to afford 48.3 (0.56 g, 83%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[NH2:12][CH:13]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[C:14]([NH:16][C:17]1([C:24]#[N:25])[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1)=[O:15]>>[C:24]([C:17]1([NH:16][C:14](=[O:15])[CH:13]([NH:12][C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=2)[CH2:26][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]1)#[N:25]
Reactant: CN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Product: CN1CCC(C#N)(NC(=O)C(CC2CCCCC2)Nc2nccc(C(F)(F)F)n2)CC1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl pyrimidine and 2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide according to the procedure from Example 90. MS, m/z 439.5=M+1.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1.[Cu][C:13]#[N:14].[C-]#N.[Na+]>CN1CCCC1=O>[C:13]([C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([CH3:11])[C:5]2=[CH:4][CH:3]=1)#[N:14]
Reactant: N#C[Cu]
Reactant: Cc1nccn2c(Br)ccc12
Agent: [C-]#N
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1nccn2c(C#N)ccc12
Temperature: 150 °C
Reaction time: 5 h
Yield: 78.1 %

Procedure:
To a solution of 4.3 g of 6-bromo-1-methylpyrrolo[1,2-a]pyrazine dissolved in 50 ml of N-methylpyrrolidone was added 4.5 g of copper(I) cyanide. The resulting solution was stirred at 150° C. for 5 hours, and then cooled to room temperature. To the reaction mixture was added 100 ml of sodium cyanide solution; and the resulting solution was extracted with ethyl acetate(100 ml×3). The organic layer was concentrated to dryness to obtain 2.5 g of title compound.