Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([O:17][CH2:18]C)=[O:16])[CH:10]=2)=[CH:5][CH:4]=1)=O.[CH3:20]/C(/[O-])=C(/P(OC)(OC)=O)\[N+]#N.C([O-])([O-])=O.[K+].[K+]>CO.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=2)=[CH:7][CH:8]=1)#[CH:20]
Reactant: COP(=O)(OC)/C([N+]#N)=C(/C)[O-]
Reactant: CCOC(=O)c1cc(-c2ccc(C=O)cc2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1ccc(-c2ccnc(C(=O)OC)c2)cc1
Reaction time: 5 h
Yield: 33.7 %

Procedure:
To a stirring solution of compound 2.5 (12.7 g, 50 mmol) in CH3OH (300 mL) was added the Bestmann reagent (14.4 g, 75 mmol) followed by K2CO3 (20.8 g, 150 mmol) and the reaction was stirred for 5 hr. The reaction mixture was diluted with water (500 mL) and extracted with Et2O (3×300 mL). The combined organic layers were dried and concentrated under reduced pressure to give a crude, which was purified by flash chromatography (silica gel/PE:Et2O 10:1-5:1) to give methyl 4-(4-ethynylphenyl)picolinate (2.6, 4.0 g, 33.9%) as a white solid.
Reaction SMILES: Cl.[CH:2]1[C:12]2[C:11]([NH2:13])=[N:10][C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23]N[CH2:21][CH2:20]1.C(N(CC)C(C)C)(C)C.CS(C)=O>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:18][N:19]1[CH2:24][CH2:23][N:13]([C:11]2[C:12]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=3[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[N:10]=2)[CH2:21][CH2:20]1
Reactant: NC1=Nc2ccccc2Nc2ccccc21
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: CN1CCN(C2=Nc3ccccc3Nc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 44.8 %

Procedure:
Combine 5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (600.0 mg, 2.44 mmol), N-methylpiperazine (1.47 g, 14.65 mmol), N,N-diisopropylethylamine (315.6 mg, 2.44 mmol), DMSO (1.0 ml), and toluene (4.0 ml). Stir and beat the mixture at 110° C. After 21 hours, cool the mixture to ambient temperature and stir it overnight. Dilute the mixture with ethyl acetate and wash the organic layer with 0.1N NaOH and brine. Dry (sodium sulfate) and concentrate the organic layer to residue. Purify the residue on silica gel using dichloromethane/methanol (90:10) to give 319.7 mg (45%) of a tan foam: mp 173° C. –179° C., dec; mass spectrum (ion spray): m/z=293.1 (M+1).
Reaction SMILES: [BrH:1].N[C:3]1[C:11]2[C:10](=[O:12])[N:9]3[CH2:13][CH2:14][S:15][C:8]3=[N:7][C:6]=2[N:5]([CH3:16])[N:4]=1.N([O-])=O.[Na+]>O>[Br:1][C:3]1[C:11]2[C:10](=[O:12])[N:9]3[CH2:13][CH2:14][S:15][C:8]3=[N:7][C:6]=2[N:5]([CH3:16])[N:4]=1
Reactant: Br
Reactant: Cn1nc(N)c2c(=O)n3c(nc21)SCC3
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cn1nc(Br)c2c(=O)n3c(nc21)SCC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
In a mixture of 52 ml of an aqueous solution of hydrogen bromide and 36 ml of water was dissolved 4.00 g (17.9 mmol) of Compound 13 prepared in Example 10, and 1.24 g (17.9 mmol) of sodium nitrite was added to the solution under ice-cooling, followed by stirring for 30 minutes. Then, a solution of 3.08 g (21.5 mmol) of cuprous bromide in 36 ml of an aqueous solution of hydrogen bromide was added thereto and the temperature of the mixture was raised slowly to room temperature, followed by stirring for one hour. The precipitated crystals were collected by filtration and washed with water. The crystals were then subjected to silica gel column chromatography and eluted with chloroform to give 3.51 g (68%) of Compound 25. The compound was recrystallized from chloroform/ethanol for purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][N:12]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=1.[NH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>>[OH:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][CH2:29][NH:28][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=3)[CH2:11][N:12]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=2)=[CH:32][CH:33]=1
Reactant: CS(=O)(=O)N(CCc1ccccn1)Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccc(O)cc1
Product: CS(=O)(=O)N(CCc1ccccn1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 17 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 504. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.5 (d, 1H) 8.3 (d, 1H) 7.9 (m, 2H) 7.6 (m, 1H) 7.4 (m, 2H) 7.2 (m, 2H) 7.0 (d, 2H) 6.9 (d, 1H) 6.7 (d, 2H) 5.4 (s, br, 1H) 4.4 (s, 2H) 3.7 (m, 2H) 3.6 (m, 2H) 3.0 (m, 2H) 2.8 (m, 2H) 2.8 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=[C:6]([Br:8])[CH:7]=1.N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClC(Cl)C>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:24]([CH3:23])(=[O:26])=[O:25])[CH:3]=[C:4]([C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(Br)cc(C(=O)c2cccnc2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
To a stirred solution of 0.200 grams of (3-amino-5-bromo-phenyl)-pyridin-3-yl-methanone (0.72 mmol) in 10 mL of dichloroethane was added 0.87 mL (10.82 mmol) of pyridine followed by the addition of 0.56 mL (7.2 mmol) of methanesulfonyl chloride. The reaction was stirred at 80° C. for 2 hours. The volatiles were removed under reduced pressure affording material which was flash chromatographed (25% EtOAc/hexane to 1:1 EtOAc:hexane to 100% EtOAc) to give 0.150 grams of N-[3-bromo-5-(pyridine-3-carbonyl)-phenyl]-methanesulfonamide.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:11][CH2:10][N:9]2[CH:18]=1)([O:3][CH2:4][CH3:5])=[O:2].Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].[OH-].[Na+]>CC(C)=O.O>[C:1]([C:6]1[CH:7]=[C:8]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10][N:9]2[CH:18]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)c1cc2n(c1)CNc1ccccc1-2
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)c1cc2n(c1)CN(C(=O)OCC)c1ccccc1-2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of the product of Example IV (1.2 g, 0.005 m) and ethyl chloroformate (6.0 g, 0.0553 m) in acetone (20 ml) and H2O (50 ml) was treated with NaOH (0.1 ml aq. 30%) and the mixture stirred at room temperature for 15 min. The acetone was removed in vacuo and the aqueous residue cooled in an ice-bath. A solid formed and this was filtered, washed with water, and dried in vacuo. The crude product (1.0 g) was crystallized from methanol to afford the desired product; m.p. 80°-82° C.
Reaction SMILES: C(=[N:4][O:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14]COC)[C:7]=1[C:8]#[N:9])(C)C>CO>[NH2:9][C:8]1[C:7]2[C:10]([OH:14])=[CH:11][CH:12]=[CH:13][C:6]=2[O:5][N:4]=1
Reactant: COCOc1cccc(ON=C(C)C)c1C#N
Solvent: CO
Product: Nc1noc2cccc(O)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
2-[(Isopropylidenamino)oxy]-6-methoxymethoxybenzonitrile of Example 1(c) (9.91 g, 0.0423 mole) was dissolved in 100 ml of methanol and then 100 ml of freshly prepared saturated HCl-ether was added. After stirring overnight (about 16 hours) at room temperature the reaction mixture was concentrated under reduced pressure and the residue triturated with CH2Cl2 and filtered. Recrystallization from methanol-water gave 5.62 g (89%) of 3-amino-4-hydroxy-1,2-benzisoxazole, mp 255° (d).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].I[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1>[Cu]>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]([C:2]2[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)c1cccc(I)c1
Reactant: Cc1ccc(I)cc1
Agent: [Cu]
Product: COC(=O)c1cccc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
To a stirred solution of 25.2 g of methyl 3-iodobenzoate and 21.0 g of 4-iodotoluene at 180°-190° under nitrogen was added 30.3 g of copper powder portionwise over 1 hour. When approximately one-third of the copper had been added, the reaction initiated and the temperature increased spontaneously to 240°. The mixture was allowed to cool to 210°, then was held at 210° during the addition of the remaining copper and for an additional hour. The mixture was allowed to cool to room temperature and was filtered employing benzene as solvent; the resulting filtrate was concentrated in vacuum to provide the crude product. Column chromatography on silica gel (elution=50-100% benzene/hexane) followed by distillation furnished 7.60 g of methyl 4'-methylbiphenyl-3-carboxylate [bp: 114°-115° C. (0.025 torr)] as a colorless oil; NMR (200 MHz, CDCl3): δ 8.27 (br S, 1H); 7.99 (d, 1H); 7.77 (d, 1H); 7.50 (t, 1H); 7.39 (A2B2, 4H); 3.94 (s, 3H); 2.41 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C@@H:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[OH:11])[CH:3]=1.[F:18][C:19]1([F:37])[O:23][C:22]2[CH:24]=[CH:25][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:21]=2[O:20]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[F:37][C:19]1([F:18])[O:20][C:21]2[CH:27]=[CH:26][C:25]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C@@H:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[OH:11])[CH:3]=3)=[CH:24][C:22]=2[O:23]1
Reactant: CC1(C)OB(c2ccc3c(c2)OC(F)(F)O3)OC1(C)C
Reactant: O[C@@H](CNc1cc(Cl)ncn1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: O[C@@H](CNc1cc(-c2ccc3c(c2)OC(F)(F)O3)ncn1)c1ccccc1
Temperature: 100 °C
Yield: 82.6 %

Procedure:
(1R)-2-[(6-Chloropyrimidin-4-yl)amino]-1-phenylethanol (75 mg, 0.30 mmol), 2,2-difluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzo[1,3]dioxole (85 mg, 0.30 mmol), Pd(OAc)2 (1.3 mg, 0.006 mmol, 2 mol %), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (S-Phos) (4.9 mg, 0.012 mmol, 4 mol %) and K3PO4 (191 mg, 0.900 mmol) were dissolved in dioxane (1.0 mL), which had been degassed by bubbling N2 into the solvent and water (0.1 mL) in a sealed tube. The tube was flushed with N2 and heated at 100° C. for 16 h before cooling to rt and filtering through a pad of celite. The celite was washed with CH2Cl2 (5 mL) and the filtrate concentrated to dryness. The crude material was purified by (FCC) to yield the title compound (92 mg, 83%). MS (ESI): mass calcd. for C19H15F2N3O3, 371.11; m/z found, 372.1 [M+H]+. 1H NMR (CDCl3): 8.64 (s, 1H), 7.73-7.71 (m, 2H), 7.43-7.37 (m, 4H), 7.34-7.30 (m, 1H), 7.14-7.12 (m, 1H), 6.65 (d, J=1.1 Hz, 1H), 5.31-5.25 (br hump, 1H), 5.01-4.99 (m, 1H), 3.91-3.85 (br hump, 1H), 3.64-3.59 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C@@:3]12[CH2:9][C@@H:8]1[CH2:7][C@H:6]1[C@H:10]3[C@H:19]([CH2:20][CH2:21][C@:4]21[CH3:5])[C:18]1[CH2:17][CH2:16][C:15](=[O:22])[CH2:14][C:13]=1[CH2:12][CH2:11]3.C1C=C[NH+]=CC=1.Br[Br-]Br>N1C=CC=CC=1>[CH3:1][O:2][C@@:3]12[CH2:9][C@@H:8]1[CH2:7][C@H:6]1[C@H:10]3[C:19]([CH2:20][CH2:21][C@:4]21[CH3:5])=[C:18]1[C:13](=[CH:14][C:15](=[O:22])[CH2:16][CH2:17]1)[CH2:12][CH2:11]3
Reactant: CO[C@@]12C[C@@H]1C[C@H]1[C@@H]3CCC4=C(CCC(=O)C4)[C@H]3CC[C@@]12C
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Product: CO[C@@]12C[C@@H]1C[C@H]1[C@@H]3CCC4=CC(=O)CCC4=C3CC[C@@]12C
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
9.5 g of 17beta-methoxy-16alpha,17alpha-methylene-estr-5(10)-en-3-one (crude product) is dissolved in 130 ml of pyridine and then, with cooling (-5° C.), mixed with 11.5 of pyridine hydrobromide perbromide within 5 minutes. Then, the cooling is removed and the reaction solution warming slowly to room temperature is stirred for about 30 minutes, and then mixed with 3 ml of methylbutene and an excess bromation agent is consumed. Then, it is stirred for 4 hours at room temperature and then stirred into ice water, and the steroid precipitates in oily crystalline form. For complete crystallization, it is stored for 16 hours in the refrigerator and the steroid is fritted. 8 g of crystalline crude product is obtained. After extraction with methylene chloride and chromatography on neutral aluminum oxide with benzene/ethyl acetate (20:1 to 9:1), about 1 g of dienone can be obtained from the filtrate, dienone which can be crystallized from acetone/n-hexane (total yield 9 g). Melting point: 117° C. to 121° C., [α]D =-203°.
Reaction SMILES: Cl.[CH3:2][N:3](C)[CH:4]1[CH2:18][C:7]2[C:8]3[NH:9][C:10](=[O:17])[C:11](=[O:16])[NH:12][C:13]=3[CH:14]=[CH:15][C:6]=2[CH2:5]1.[N+:20]([O-])([OH:22])=[O:21]>FC(F)(F)C(O)=O>[CH3:2][NH:3][CH:4]1[CH2:18][C:7]2[C:8]3[NH:9][C:10](=[O:17])[C:11](=[O:16])[NH:12][C:13]=3[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[C:6]=2[CH2:5]1
Reactant: O=[N+]([O-])O
Reactant: CN(C)C1Cc2ccc3[nH]c(=O)c(=O)[nH]c3c2C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CNC1Cc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 8-dimethylamino-4,7,8,9-tetrahydro-1H-cyclopenta[f]quinoxaline-2,3-dione hydrochloride (0.39 g) in trifluoroacetic acid was cooled in an ice bath and then treated with fuming nitric acid (1 mL). After stirring for 1 h, the mixture was warmed to room temperature for 3 h. The solvent was evaporated and the residue suspended in methanol. The resulting yellow solid was collected by filtration and dried. Calc'd for C12H12 N4O4.CH4O3S: C, 41.93; H, 4.33; N, 15.05; found: C, 39.56; H, 4.11; N, 13,61. Ms M+1 (277).
Reaction SMILES: [OH:1][CH:2]1[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]([C:10]2([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]2)[CH:3]1[O:19][CH3:20].O1CCCC1.[H-].[Na+].Cl[C:29]([O:31][CH2:32][CH:33]([CH3:35])[CH3:34])=[O:30]>C(OCC)C>[CH2:32]([O:31][C:29]([O:1][CH:2]1[CH2:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH:4]([C:10]2([CH3:18])[CH:12]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[O:11]2)[CH:3]1[O:19][CH3:20])=[O:30])[CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)COC(=O)Cl
Reactant: COC1C(O)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC1C(OC(=O)OCC(C)C)CCC2(CO2)C1C1(C)OC1CC=C(C)C
Yield: 26.7 %

Procedure:
To a solution of 6-hydroxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (14.1 mg) in freshly distilled tetrahydrofuran (0.5 ml) was added sodium hydride (6.0 mg, 60% oil dispersion) in one portion at 5° C. The mixture was stirred for half an hour at the same temperature and then isobutyl chloroformate (7 mg) was added thereto. The reaction mixture was stirred for 2 hours at ambient temperature and then diluted with diethyl ether. The organic layer was washed with brine, dried, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (elution by diethyl ether/n-hexane=1/3) to yield 6-isobutoxycarbonyloxy-5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]octane (5.1 mg) as an oil.
Reaction SMILES: I[C:2]1[O:3][C:4]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.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]>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[O:3][C:2]([C:21]3[S:20][CH:24]=[CH:23][CH:22]=3)=[N:6][C:5]=2[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:13][CH:14]=1
Reactant: CCOC(=O)c1nc(I)oc1-c1ccc(OC)cc1
Reactant: OB(O)c1cccs1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CCOC(=O)c1nc(-c2cccs2)oc1-c1ccc(OC)cc1
Temperature: 150 °C

Procedure:
To a mixture of ethyl 2-iodo-5-(4-methoxyphenyl)oxazole-4-carboxylate (0.100 g, 0.27 mmol) and 2-thiophenyl boronic acid (0.069 g, 0.54 mmol) in acetonitrile (2 mL) was added a solution of Pd(dppf)2Cl2 (0.010 g, 0.012 mmol) in acetonitrile (0.2 mL) followed by 1M aqueous sodium carbonate solution (0.535 mL, 0.54 mmol). The resulting reaction mixture was heated at 150° C. in the microwave for 15 minutes and the solvent was then removed in vacuo. The residue was purified by silica gel column chromatography using a gradient of 4-90% EtOAc in hexanes to afford ethyl 5-(4-methoxyphenyl)-2-(thiophen-2-yl)oxazole-4-carboxylate which was used without further purification. LCMS (1) Rt: 2.45 min; m/z (ES+) 330.
Reaction SMILES: [CH:1]1([C:6]2([CH3:19])[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11]([SH:15])[CH:12]=3)[C:7]2=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30]CC)=[O:29]>CN(C=O)C>[O:18]=[C:7]1[C:8]2[C:13](=[CH:12][C:11]([S:15][CH2:27][C:28]([OH:30])=[O:29])=[C:10]([Cl:16])[C:9]=2[Cl:17])[CH2:14][C:6]1([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH3:19]
Reactant: CCOC(=O)CBr
Reactant: CC1(C2CCCC2)Cc2cc(S)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C2CCCC2)Cc2cc(SCC(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
(1-Oxo-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanylthio)acetic acid is prepared following substantially the same procedure described in Example 10, Step F, using the following substances: 2-cyclopentyl-2-methyl-5-mercapto-6,7-dichloro-1-indanone (3.47 g., 0.01 mole), DMF (40 ml.), potassium carbonate (2.78 g., 0.02 mole) and ethyl bromoacetate (2.9 g., 0.02 mole).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH3:6][C:7]1([CH3:23])[CH2:11][NH:10][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[N:8]1.BrCCCC.O>CCCCCC.C1C=CC=CC=1>[CH3:6][C:7]1([CH3:23])[CH2:11][N:10]([CH2:1][CH2:2][CH2:3][CH3:4])[C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[N:8]1
Reactant: [Li]CCCC
Reactant: CCCCCCCCCCCC1=NC(C)(C)CN1
Solvent: CCCCCC
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCCC1=NC(C)(C)CN1CCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
22 ml (55 mmoles) of a 2.5M solution of butyl lithium in hexane are added to 12.62g (50 mmoles) of 4,4-dimethyl-2-undecyl-2-imidazoline in 50 ml of anhydrous benzene at a temperature kept at around 20° C. The mixture is then stirred for 2 hours at ambient temperature (15° to 20° C.). 8.22 g (60 mmoles) of 1 -bromobutane is then added dropwise to the reaction mixture, keeping the temperature at around 20° C. The reaction mixture is then stirred at ambient temperature until it is homogeneous, after which it is refluxed for 3 hours. After cooling, 50 ml of water is added, the mixture is stirred for half hour, decanted and extracted with 100 ml of ether. After drying over magnesium sulfate the solvent is removed in vacuo and the oil is distilled at reduced pressure to give 10.34 g (67%) of the product.
Reaction SMILES: O=C(C1N(C)N=C(C)C=1C)C(C1C=CC(C(C)(C)C)=CC=1)C#N.C(=O)([O-])[O-].[K+].[K+].C(Cl)(=O)C(C)(C)C.[CH3:37][C:38]([CH3:68])([CH3:67])[C:39]([O:41]/[C:42](/[C:59]1[N:63]([CH3:64])[N:62]=[C:61]([CH3:65])[C:60]=1[CH3:66])=[C:43](\[C:46]1[C:50]([CH2:51][CH3:52])=[N:49][N:48]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[N:47]=1)/[C:44]#[N:45])=[O:40]>>[CH3:67][C:38]([CH3:37])([CH3:68])[C:39]([O:41]/[C:42](/[C:59]1[N:63]([CH3:64])[N:62]=[C:61]([CH3:65])[C:60]=1[CH3:66])=[C:43](/[C:46]1[C:50]([CH2:51][CH3:52])=[N:49][N:48]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[N:47]=1)\[C:44]#[N:45])=[O:40]
Reactant: CCc1nn(-c2ccccc2)nc1/C(C#N)=C(\OC(=O)C(C)(C)C)c1c(C)c(C)nn1C
Agent: CC(C)(C)C(=O)Cl
Agent: Cc1nn(C)c(C(=O)C(C#N)c2ccc(C(C)(C)C)cc2)c1C
Agent: O=C([O-])[O-]
Product: CCc1nn(-c2ccccc2)nc1/C(C#N)=C(/OC(=O)C(C)(C)C)c1c(C)c(C)nn1C
Temperature: 60 °C
Reaction time: 3 h
Yield: 78.6 %

Procedure:
In a 10 L-reaction flask, 223 g (0.639 mol) of 3-oxo-2-(4-tert-butylphenyl)-3-(1,3,4-trimethylpyrazol-5-yl)propionitrile and 4456 g of 1,4-doxane were added, 97.2 g (0.351 mol) of potassium carbonate was added thereto, then the temperature was raised to 60° C., and the resulting mixture was stirred for 3 hours. In order to remove water formed as a by-product, 486 g of the solvent was distilled off under a reduced pressure, then 92.5 g (0.767 mol) of pivaloyl chloride was dropwise at 60° C. over 1 hour. After reacting for 2 hours, 1,4-dioxane being a solvent was distilled off, then 456 g of toluene was added and dissolved. The resulting solution was washed two times with 446 g of water to obtain a toluene solution containing 217 g (yield 78.6%) of (2Z)-3-(2,2-dimethylpropanoyloxy)-2-(5-ethyl-2-phenyl-1,2,3-triazol-4-yl)-3-(1,3,4-trimethylpyrazol-5-yl)acrylonitrile and 43 9 (yield 15.5%) of (2E)-3-(2,2-dimethylpropanoyloxy)-2-(5-ethyl-2-phenyl-1,2,3-triazol-4-yl)-3-(1,3,4-trimethylpyrazol-5-yl)acrylonitrile. After distilling off toluene under a reduced pressure, the residue was dissolved in 780 g of acetonitrile, and crystallization was carried out by gradually cooling to 0° C. After filtering, the resulting crystal was washed with 260 g of acetonitrile, then dried to obtain 166 g (yield 63.1%) of (2Z)-3-(2,2-dimethylpropanoyloxy)-2-(5-ethyl-2-phenyl-1,2,3-triazol-4-yl)-3-(1,3,4-trimethylpyrazol-5-yl)acrylonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][N:6]3[C:7]=2[C:3]=1[C:4]1[CH2:19][CH2:18][CH2:17][C:5]=13.C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][N:6]3[C:7]=2[C:3]=1[CH:4]1[CH2:19][CH2:18][CH2:17][CH:5]13
Reactant: CN1CCc2ccc(Cl)c3c4c(n(c23)CC1)CCC4
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CCc2ccc(Cl)c3c2N(CC1)C1CCCC31
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
To a solution of 8-chloro-3-methyl-2,3,4,5,10,11-hexahydro-1H,9H-cyclopenta[b][1,4]diazocino[7,8,1-hi]indole (0.20 g, 0.73 mmole) in acetic acid (50 mL) was added sodium cyanoborohydride (0.45 g, 6.80 mmole) and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was diluted with methylene chloride (200 mL) and washed with aqueous sodium hydroxide (1N, 150 mL), saturated sodium chloride (150 mL), dried (sodium sulfate) and concentrated. Purification by flash column chromatography (silica gel, 1.5% methanol in methylene chloride) provided 0.13 g of the title compound as a colorless oil. The oil was further treated with one equivalent of fumaric acid in ethanol to form a fumarate salt, mp 179-181° C. MS (ES) m/z 277.10 ([M+H]+).
Reaction SMILES: C([S:4][CH:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:19]([O:21][CH3:22])=[O:20])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH2:7]/[C:6]/1=[CH:23]\[C:24]([O:26][CH2:27]C)=[O:25])(=O)C.Cl>CO>[ClH:18].[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:11]([N:8]1[CH2:9][CH2:10][CH:5]([SH:4])/[C:6](=[CH:23]/[C:24]([O:26][CH3:27])=[O:25])/[CH2:7]1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: CCOC(=O)/C=C1\CN(C(C(=O)OC)c2ccccc2Cl)CCC1SC(C)=O
Agent: Cl
Solvent: CO
Product: COC(=O)/C=C1\CN(C(C(=O)OC)c2ccccc2Cl)CCC1S
Reaction time: 8 h

Procedure:
1.22 g of the (E)-4-acetylthio-1-(2-chloro-α-methoxycarbonylbenzyl)-3-ethoxycarbonylmethylidenepiperidine obtained in the above-described step (a) were dissolved in 50 ml of methanol was dissolved. An appropriate amount of hydrogen chloride gas was blown through the resulting solution and the resulting mixture was allowed to stand overnight at room temperature. The residue after the removal of the solvent under reduced pressure was crystallized from diethyl ether, whereby 1.25 g of a mixture of (E)-1-(2-chloro-α-methoxycarbonylbenzyl)-3-ethoxycrbonylmethylidene-4-mercaptopiperidine hydrochloride and (E)-1-(2-chloro-α-methoxycarbonylbenzyl)-4-mercapto-3-methoxycarbonylmethylidene-piperidine hydrochloride was obtained.