Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][CH:8]=1)=[CH2:6])[CH3:2].[F:17][C:18]([F:22])=[C:19]([F:21])[F:20]>CC1C2C(C)(C)C(C2)CC=1.C1C=CC=CC=1>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2([C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH2:6][C:18]([F:22])([F:17])[C:19]2([F:21])[F:20])=[CH:8][CH:9]=1)[CH3:15]
Reactant: C=C(C(=O)OCC)c1ccc(OCC)cc1
Reactant: FC(F)=C(F)F
Agent: CC1=CCC2CC1C2(C)C
Solvent: c1ccccc1
Product: CCOC(=O)C1(c2ccc(OCC)cc2)CC(F)(F)C1(F)F
Reaction time: 17 h
Yield: 75 %

Procedure:
2-(4-ethoxyphenyl)propenoic acid ethyl ester (13.2 g) was mixed with benzene (7.5 ml), α-pinene (2 drops) N-ethyldiisopropyl amine (2 drops) and tetrafluoroethylene (15.5 ml) and heated to 150°-155° for 24 hours then 155°-60° C. for 17 hours. After evaporation of volatile materials the residue (16.6 g) was dissolved in dichloromethane and chromatographed on a column of silica gel to give the ester as a colourless oil 14.5 g (75%). Analysis: C: 56.47%, H: 5.24%, F: 23.4%. C15H16F4O3 requires C: 56.25%, H: 5.04%, F: 23.7%.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].Br[CH2:28][CH2:29][C:30]#[N:31]>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:28][CH2:29][C:30]#[N:31])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: N#CCCBr
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCC#N)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was synthesized from Compound 157 and 3-bromopropionitrile using an analogous procedure to that outlined in the preparation of Compound 205.11-1 NMR (400 MHz, MeOD) δ ppm 1.28 (d, J=14.65 Hz, 2H) 1.28 (s, 2H) 2.30 (s, 3H) 3.10 (t, J=6.69 Hz, 2H) 5.12 (t, J=6.82 Hz, 2H) 7.00-7.05 (m, 2H) 7.53 (dd, J=2.02, 0.76 Hz, 1H) 7.81 (t, J=7.45 Hz, 1H) 7.92 (ddd, J=7.89, 1.45, 1.26 Hz, 1H) 8.02 (dt, J=7.83, 1.52 Hz, 1H) 8.10 (t, J=1.89 Hz, 1H) 8.26 (d, J=2.02 Hz, 1H) [M+H] calc'd for C23H21N3O3S, 421; found, 421.
Reaction SMILES: [NH2:1][CH:2]([CH2:11][CH3:12])[CH:3]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)[OH:4].[O:13]=[C:14](Cl)OC(Cl)(Cl)Cl>C(Cl)Cl>[CH2:11]([CH:2]1[CH:3]([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=2)[O:4][C:14](=[O:13])[NH:1]1)[CH3:12]
Reactant: CCC(N)C(O)c1cccnc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCC1NC(=O)OC1c1cccnc1
Yield: 58 %

Procedure:
To a solution of 2-amino-1-pyridin-3-yl-butan-1-ol (150 mg, 0.90 mmol) in CH2Cl2 (5 mL) was added under argon NEt3 (314 μL, 5.63 mmol) at 0° C. Then, diphosgene was added over a period of 5 minutes and the temperature was allowed to warm from 0° C. to room temperature within 2 hours. The reaction mixture was quenched with ice cold water and a 2 M solution of Na2CO3, extracted with CH2Cl2, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using EtOAc in heptane from 0% to 100% in order to give the title compound (100 mg, 58%) as a mixture of diastereoisomers A and B. LC-MS: [M+H] 193.1; Rt 0.43 min; (LCMS method 1). A) 1H NMR (400 MHz, CHCl3-d): 8.70-8.62 (m, 1H), 8.60-8.56 (m, 1H), 7.76-7.71 (m, 1H), 7.42-7.35 (m, 1H), 5.78 (d, 1H), 4.08-3.98 (m, 1H), 1.21-1.05 (m, 2H), 0.84 (t, 3H). B) 1H NMR (400 MHz, CHCl3-d): 8.70-8.62 (m, 2H), 7.80-7.76 (m, 1H), 7.42-7.35 (m, 1H), 5.21 (d, 1H), 3.75-3.68 (m, 1H), 1.89-1.69 (m, 2H), 1.05 (t, 3H).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[C:7]([CH:16]([O:18][CH2:19][C:20]3([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH3:17])[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][N:4]=1)#[N:2].FC(F)(F)C(O)=O.C(Cl)Cl>>[C:33]1([C:20]2([CH2:19][O:18][CH:16]([C:7]3[CH:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=[C:11]4[C:6]=3[NH:5][N:4]=[C:3]4[C:1]#[N:2])[CH3:17])[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc2c(C#N)n[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc2c(C#N)n[nH]c12

Procedure:
(±)-tert-Butyl 4-((1-(3-cyano-5-(trifluoromethyl)-1H-indazol-7-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate (40 mg, 0.08 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvent was evaporated to afford 25 mg (77%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.89 (s, 1H), 7.54 (d, J=1.8 Hz, 1H), 7.37-7.40 (m, 2H), 7.30-7.32 (m, 3H), 7.69 (m, 1H), 4.49 (q, J=6.7 Hz, 1H), 3.40 (q, J=9.2 Hz, 1H), 3.29 (d, J=9.2 Hz, 1H), 2.87-2.93 (m, 2H), 2.67-2.77 (m, 2H), 2.07-2.26 (m, 2H), 1.78-1.93 (m, 2H), 1.41 (m, 3H); 13C-NMR (126 MHz, CDCl3) δ ppm 143.2, 138.4, 129.4, 129.1, 127.2, 127.0, 126.0 (q, J=32.6 Hz), 124.7, 124.1 (q, J=273 Hz), 121.0, 120.3, 116.6, 77.3, 50.6, 42.4, 41.7, 33.1, 22.3. Mass spec.: 429.13 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:9][CH:8]=1)=[O:5].O1CCCCC1[O:27][CH2:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][N:30]=1>CCO>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:1]=[C:33]2[C:32]2[CH:31]=[N:30][C:29]([CH2:28][OH:27])=[CH:36][CH:35]=2)=[CH:8][CH:9]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: O=Cc1ccc(COC2CCCCO2)nc1
Reactant: CCC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Solvent: CCO
Product: CCC(C)c1ccc(-n2c(-c3ccc(CO)nc3)nc3ccccc3c2=O)cc1
Yield: 40 %

Procedure:
2-amino-N-(4-sec-butylphenyl)benzamide (0.250 g, 0.92 mmol) and 6-((tetrahydro-2H-pyran-2-yloxy)methyl)nicotinaldehyde (0.77 mmol) were mixed in anyhydrous EtOH (40 mL) and anyhydrous CuCl2 (0.310 g, 2.3 mmol) was added. After heating at reflux for 1.5 hours, and concentrating, ethyl acetate (150 mL) was added, the mixture was washed with water (2×125 mL), dried (MgSO4), filtered, and concentrated. Flash chromatograph on silica gel, eluting with 50% ethyl acetate/heptane to 100% ethyl acetate, plus re-chromatographing with 30% ethyl acetate/CH2Cl2 to 100% ethyl acetate, afforded the title compound as a white solid (40%). 1H-NMR (300 MHz, DMSO-6): δ8.47 (d, J=1.6 Hz, 1H), 8.21 (d, J=7.8 Hz, 1H), 7.89-7.94 (m, 1H), 7.79 (d, J=7.9 Hz, 1H), 7.60-7.72 (m, 2H), 7.26-7.29 (m, 3H), 7.14-7.18 (m, 2H), 5.42 (t, J=5.8 Hz, 1H), 4.45 (d, J=5.7 Hz, 2H), 2.55-2.64 (m, 1H), 1.37-1.58 (m, 2H), 1.15 (d, J=6.9 Hz, 3H), 0.64 (t, J=7.3 Hz, 3H). MS (APCI) m/z: 386 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](S(C)(=O)=O)[N:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH2:31].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[NH2:17][C:12]1[C:11]2[C:15](=[CH:16][C:8]([C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([NH:31][CH2:30][CH2:29][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[Cl:22])[CH:5]=3)=[CH:9][CH:10]=2)[NH:14][N:13]=1
Reactant: NCCc1ccccc1Cl
Reactant: CS(=O)(=O)c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCCc2ccccc2Cl)cc(-c2ccc3c(N)n[nH]c3c2)n1
Temperature: 160 °C
Yield: 39.9 %

Procedure:
A mixture of 6-[2-amino-6-(methylsulfonyl)-4-pyrimidinyl]-1H-indazol-3-amine (300 mg, 0.99 mmol), 2-(2-chlorophenyl)ethanamine (300 mg, 1.94 mmol), and Hunig's base (2 mL) in NMP (3 mL) was heated for 2 hours at 160° C. in a BiotageInitiator® microwave synthesizer. Upon cooling, the mixture was decanted to remove the solids, and the resulting solution was concentrated to dryness. The crude material was purified by RPHPLC to afford the title compound (150 mg) as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 2.99 (t, J=8 Hz, 2H), 3.52-3.53 (m, 2H), 5.39 (s, 2H), 6.03 (s, 2H), 6.29 (s, 1H), 7.03 (s, 1H), 7.24-7.46 (m, 5H), 7.71 (d, J=8.0 Hz, 1H), 7.85 (s, 1H), 11.53 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:11])[C:3]=1[Br:12].[CH3:13][Mg+].[Br-]>>[NH2:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([CH:6]([OH:7])[CH3:13])=[C:4]([F:11])[C:3]=1[Br:12]
Reactant: Cc1cc(C=O)c(F)c(Br)c1N
Reactant: C[Mg+]
Agent: [Br-]
Product: Cc1cc(C(C)O)c(F)c(Br)c1N

Procedure:
Using the method of Example 19, 4-amino-3-bromo-2-fluoro-5-methylbenzaldehyde is reacted with MeMgBr to afford the title compound.
Reaction SMILES: [C:1]([O:15]C)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[NH2:17][NH2:18]>C(O)C>[C:1]([NH:17][NH2:18])(=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCC(=O)OC
Reactant: NN
Solvent: CCO
Product: CCCCCCCCCCCCC(=O)NN

Procedure:
A solution of tridecanoic acid, methyl ester (24.63 g, 0.1078 mol), and anhydrous hydrazine (3.40 mL, 0.108 mol) in absolute ethanol (150 mL) was stirred at room temperature for 24 hours, then refluxed 2 days. The solution was allowed to cool, and the solid that crystallized was filtered off, washed, and dried in vacuo; yield 18.6 g (75%); mp 101°-104° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[CH2:7][C:8]3[C:9]([N:28]=[CH:29][N:30]=3)=[CH:10][C:11]=2[C:12]=1[N:13]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=1)C=O)#[N:2].C(=O)([O-])[O-].[K+].[K+]>CO.O.CC(O)=O>[CH3:27][O:26][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([O:22][CH3:23])[C:19]=1[O:24][CH3:25])[NH:13][C:12]1[C:11]2[CH:10]=[C:9]3[N:28]=[CH:29][N:30]=[C:8]3[CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: COc1cc(N(C=O)c2c(C#N)cnc3c2C=C2N=CN=C2C3)cc(OC)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc(Nc2c(C#N)cnc3c2C=C2N=CN=C2C3)cc(OC)c1OC
Yield: 68.4 %

Procedure:
A suspension of 138.6 mg (0.34 mmol) of 7-cyanoimidazo[4,5-g]quinolin-8-yl(3,4,5-trimethoxyphenyl)formamide and 229.1 mg (1.66 mmol) of potassium carbonate in 10 mL of methanol is refluxed for 2 hours. After cooling, the solution is diluted with water and neutralized to pH 7 with AcOH. The precipitate is collected by filtration and washed with water, diethyl ether and ethyl acetate. After drying in vacuo, this yields a crude product. Purification of the crude product by flash chromatography (elution with 95:5 methylene chloride/methanol) yields 87.3 mg (68.5%) of the final product as a yellow solid, mp>260° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[CH3:16]O>S(=O)(=O)(O)O>[CH3:16][O:14][C:13](=[O:15])[CH2:12][C:4]1[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([F:1])[CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1ccc(C(F)(F)F)c(F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of 3-fluoro-4-(trifluoromethyl)phenylacetic acid (2.50 g, 11.25 mmol) in methanol (25 mL) was treated slowly with 4 drops of concentrated sulfuric acid. The resulting reaction mixture was heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded (3-fluoro-4-trifluoromethyl-phenyl)-acetic acid methyl ester (2.58 g, 97%) as a colorless oil: EI-HRMS m/e calcd for C10H8F4O2 (M+) 236.0460, found 236.0457.
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:18]3[CH:30]=[CH:29][N:28]=[C:19]3[S:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:13][CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl>[C:1]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[N:18]3[CH:30]=[CH:29][N+:28]([O-:39])=[C:19]3[S:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:15][CH2:16]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(OCc1ccccc1)N1CCN(C2=Nc3ccccc3Sc3nccn32)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCN(C2=Nc3ccccc3Sc3n2cc[n+]3[O-])CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To the solution of 0.5 g of 5-(4-carbobenzoxypiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine in 5 ml of methylene chloride, cooled at 0° C., is added dropwise a solution of 0.26 g of m-chloroperbenzoic acid dissolved in 2 ml of methylene chloride. The mixture is stirred at 0° C. for 1.5 hrs., the solids are filtered, and the filtrates are washed with 10% aqueous potassium carbonate and water, then dried over magnesium sulfate and evaporated to dryness to give 5-(4-carbobenzoxypiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine 1-oxide.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][NH:3][CH2:2]1.[C:6]([NH:13][C@H:14]([C:22](O)=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>>[C:9]([O:8][C:6](=[O:7])[NH:13][C@@H:14]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22](=[O:23])[N:3]1[CH2:4][CH2:5][S:1][CH2:2]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C1CSCN1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCSC1

Procedure:
Thiazolidine (38 mmol) and Boc-L-phenylalanine (19 mmol) were coupled according to Procedure A (0-25° C. reaction temperature, washed with acid then base) and the product used without further purification. Yield 5.5 g, 86%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[O:5][CH:6]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[OH-].[Na+]>O.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)[O:5][CH:6]=1
Reactant: O=Cc1cc(Br)co1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CN1CCN(Cc2cc(Br)co2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of 4-bromofuran-2-carbaldehyde (2.10 g, 12.0 mmol) and THF (10 mL) that was cooled in an ice bath was added 1-methylpiperazine (1.60 ml, 14.4 mmol) dropwise, followed by sodium triacetoxyborohydride (3.81 g, 18.0 mmol) in 3 portions as solid. Acetic acid (0.343 ml, 6.00 mmol) was added, and the reaction was stirred for 18 hours at ambient temperature. The dark mixture was diluted with water (10 mL) and basified to pH>12 by addition of 5N NaOH. The mixture was extracted with diethyl ether (3×50 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated in vacuo. The resulting black oil (2.10 g, 66%) was carried forward without purification.
Reaction SMILES: B1([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)C2CCCC1CCC2.Br[C:18]1[C:23]2[O:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH:26]3[C:22]=2[CH:21]=[C:20]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=2[Cl:45])[CH:19]=1.C([O-])([O-])=O.[K+].[K+]>O>[CH2:10]([C:18]1[C:23]2[O:24][CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[CH2:27][CH:26]3[C:22]=2[CH:21]=[C:20]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=2[Cl:45])[CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC2Oc3c(Br)cc(-c4ccc(Cl)cc4Cl)cc3C2C1
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2Oc3c(Cc4ccccc4)cc(-c4ccc(Cl)cc4Cl)cc3C2C1
Temperature: 65 °C
Reaction time: 6 h
Yield: 77 %

Procedure:
B-Benzyl-9-BBN (1.3 mL 0.5 M sol in THF, 0.650 mmol) was added to degassed DMF (3 mL), followed by sequential addition of tert-butyl 6-bromo-8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate (0.255 g, 0.511 mmol), catalyst Cl2PdDPPF (0.018 g, 0.022 mmol) and K2CO3 (0.220 g, 1.592 mmol). The reaction mixture was stirred under N2 at 65° C. for 6 h. The reaction mixture was poured into water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography (14% EtOAc/Hexane) and tert-butyl 6-benzyl-8-(2,4-dichlorophenyl)-3,4,4a,9b-tetrahydro[1]benzofuro[3,2-c]pyridine-2(1H)-carboxylate was obtained in 77% yield (0.200 g, 0.392 mmol). MS (ESI+) for C29H29Cl2NO3 m/z 510.1 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[C:23]([CH3:24])=[CH:22][C:7]2[NH:8][C:9]([S:11][CH2:12][C:13]3[C:18]4[O:19][CH2:20][O:21][C:17]=4[CH:16]=[CH:15][N:14]=3)=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:33])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.C(=O)([O-])O.[Na+]>[C:1]([C:4]1[C:23]([CH3:24])=[CH:22][C:7]2[NH:8][C:9]([S:11]([CH2:12][C:13]3[C:18]4[O:19][CH2:20][O:21][C:17]=4[CH:16]=[CH:15][N:14]=3)=[O:33])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1cc2nc(SCc3nccc4c3OCO4)[nH]c2cc1C
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)c1cc2nc(S(=O)Cc3nccc4c3OCO4)[nH]c2cc1C
Temperature: 25 °C

Procedure:
5-Acetyl-6-methyl-2-[[(3,4-methylenedioxy-2pyridinyl)methyl]thio]-1H-benzimidazole (140 mg, 0,41 mmol) was dissolved in methylene chloride (20 ml) and sodium hydrogen carbonate (5 ml,1M). The mixture was stirred at ambient temperature and MCPBA (100 mg, 0.41 mmol, 70%) dissolved in methylene chloride (10 ml) was added portionwise. After 10 min sodium thiosulphate (100 mg) was added whereupon the phases were separated. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica (CH2Cl2 /MeOH/NH3, 97.5: 2.5: sat.) Yield: 90 mg (61%) of the title compound. Mp: 178°-180° C. (dec., uncorr.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:14])[CH2:9][CH:10]([NH2:13])[CH2:11][NH2:12])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[N:21]#[C:22]Br>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([CH2:9][CH:10]2[CH2:11][NH:12][C:22]([NH2:21])=[N:13]2)[CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CBr
Reactant: CN(CC(N)CN)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(CC1CNC(N)=N1)c1cccc(Cl)c1
Reaction time: 1 h
Yield: 27.9 %

Procedure:
N1-(3-Chloro-phenyl)-N1-methyl-propane-1,2,3-triamine (0.321 g, 1.5 mmol) was dissolved in tetrahydrofurane (5 ml) and potassium carbonate (0.249 g, 1.8 mmol) was added. Under cooling with an ice-bath a solution of cyanogen bromide (0.191 g, 1.8 mmol) in tetrahydrofurane (5 ml) was added dropwise. The cooling bath was removed and stirring was continued for one hour. Ethyl acetate (50 ml) and water (20 ml) were added and the organic layer was separated. The mixture was extracted again with ethyl acetate. The combined organic layers were dried over magnesium sulfate and evaporated. The residue was recrystallised from ethyl acetate to yield 0.1 g (28%) of a white solid; MS (ISP): 239.2 ((M+H)+).
Reaction SMILES: OC1C=C(C2C=NC=CC=2)OC2(CCN([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[C:14]([CH3:22])[CH:13]=3)=[O:11])CC2)C1>C(O)C.[Pd]>[CH:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:10]=[O:11])=[CH:13][C:14]=1[CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CC(O)C=C(c2cccnc2)O3)ccc1OC(C)C
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C=O)ccc1OC(C)C
Reaction time: 8 h
Yield: 102.7 %

Procedure:
[8-hydroxy-10-(3-pyridyl)-11-oxa-3-azaspiro[5.5]undec-9-en-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (1.20 g, 2.84 mmol) was dissolved in ethanol. Under nitrogen, palladium (90.7 mg, 0.09 mmol) (10 wt % on carbon, wet) was added. The reaction system was flushed with hydrogen gas, and the mixture was stirred under a balloon of hydrogen gas overnight. The reaction mixture was filtered through a pad of celite. The concentrated filtrate was purified by column chromatography (70-100% ethyl acetate/hexane) to provide cis-8-hydroxy-10-(3-pyridyl)-11-oxa-3-azaspiro[5.5]undecan-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (520 mg) as a white foaming solid. 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.57 (d, J=4.2 Hz, 1H), 7.80 (d, J=7.5 Hz, 1H), 7.37 (s, 1H), 7.19 (d, J=8.5 Hz, 2H), 6.80 (d, J=8.1 Hz, 1H), 4.65 (br s, 1H), 4.55 (dt, J=12.1, 6.0 Hz, 1H), 4.40 (br s, 1H), 4.17 (br s, 1H), 3.75-3.01 (m, 3H), 2.27-2.12 (m, 2H), 2.19 (s, 3H), 2.13-1.93 (m, 2H), 1.84-1.39 (m, 4H), 1.34 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 424.24, found 425.4 (M+1)+; Retention time: 1.13 minutes (3 min run).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12](Br)[CH:13]=1)(=[O:3])[CH3:2].[CH3:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[C:32]([CH3:36])[C:33]=1[O:34][CH3:35]>>[C:1]([O:4][C@@H:5]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:17]([O:23][C:24](=[O:26])[CH3:25])[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:30]2[CH:31]=[C:32]([CH3:36])[C:33]([O:34][CH3:35])=[C:28]([CH3:27])[CH:29]=2)[CH:13]=1)(=[O:3])[CH3:2]
Reactant: COc1c(C)cc(B(O)O)cc1C
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cncc(Br)c1
Product: COc1c(C)cc(-c2cncc(O[C@@H]3SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c2)cc1C

Procedure:
By following a procedure analogous to Example 27 starting from 5-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside and 3,5-dimethyl-4-methoxyphenylboronic acid, 5-(3,5-dimethyl-4-methoxyphenyl)-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside is obtained in the form of a white solid (yield=52%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].[CH2:22](OCC)[CH3:23]>COCCOC.O>[CH:22]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15])=[CH2:23]
Reactant: COc1ccc2ncc(C#N)c(Cl)c2n1
Reactant: CCOCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C=Cc1c(C#N)cnc2ccc(OC)nc12
Temperature: 90 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 4-chloro-6-(methyloxy)-1,5-naphthyridine-3-carbonitrile (280 mg, 1.28 mmol), potassium carbonate (885 mg, 6.4 mmole), tetrakis-triphenylphosphine (30 mg, 0.026 mmole) in DME/H2O (20 mL, 3:1) was added 2,4,6-trivinylcycloborane-pyridine complex (154 mg, 0.64 mmole). After stirring for 1 h at 90° C., another batch of tetrakis-triphenylphosphine (30 mg, 0.026 mmol) was added. After refluxing for another 1.5 h, the mixture contents were cooled down to room temperature and extrated with diethyl ether. The ether fractions were combined, concentrated and purified by column chromatography (silica, 0-10% ethyl acetate in hexane) to give the title compound as a light yellow solid (176 mg, 65%): LC/MS (ES) m/e 212 (M+H)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([O:16][C:17]([N:19]1[CH2:23][CH:22]=[CH:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].O>C(Cl)(Cl)Cl>[C:12]([O:16][C:17]([N:19]1[CH2:23][CH:22]2[O:9][CH:21]2[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC=CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC2OC2C1
Yield: 58.8 %

Procedure:
2.96 g (0.012 mole) of 70% aqueous m-chloroperbenzoic acid were added to a solution of 1.69 g (0.01 mole) of 1-t-butoxycarbonyl-3-pyrroline [prepared as described in Step (a) above] in 10 ml of chloroform, whilst ice-cooling, and the mixture was stirred with ice-cooling for 8 hours and then with water-cooling for 15 hours. At the end of this time, the reaction mixture was extracted with toluene and the extract was washed, in turn, with an aqueous solution of sodium bicarbonate, a 0.1N aqueous solution of sodium thiosulfate and water. It was then dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The residue was subjected to silica gel column chromatography eluted with a 1:5 by volume mixture of ethyl acetate and toluene, to afford 1.09 g of 1-t-butoxycarbonyl-3,4-epoxypyrrolidine as a colorless oily substance.