Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[N:14]1([CH2:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8](=[O:13])[CH2:7]3)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: O=C1Cc2cc(CCCl)ccc2N1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Cc2cc(CCN3CCOCC3)ccc2N1
Yield: 31 %

Procedure:
A solution of 5-(2-chloroethyl)-2-oxindole (2.3 g), morpholine (1.2 mL) and diisopropylethylamine (1.2 mL) in dimethylsulfoxide (10 mL) was stirred overnight at 100° C. The mixture was cooled, poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried and evaporated. The residue was chromatographed (silica gel, 5% methanol in chloroform) to give 0.9 g (31%) of 5-(2-morpholin-4-ylethyl)-2-oxindole as a white solid.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][C:28]=1[C:36]([F:39])([F:38])[F:37].Cl>CN(C=O)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:35])=[CH:29][C:28]=1[C:36]([F:37])([F:38])[F:39]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CN(C)C=O
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)ccc3C2=O)C(=O)N1
Temperature: 0 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
TEA (0.28 g, 2.8 mmol) was added to a mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.5 g, 1.4 mmol) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (0.31 g, 1.4 mmol) in DMF (30 mL) at 0° C. The mixture stirred at 0° C. for 3 h, and then 4% aqueous HCl (30 mL) was added. The solid precipitate was filtered and dried in vacuo providing 1-(4-chloro-3-trifluoromethyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid, (0.57 g, 86% yield); mp 261-263° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 8.57 (98.52%); 1H NMR (DMSO-d6) δ 1.98-2.02 (m, 1H), 2.13-2.46 (m, 1H), 2.58-2.63 (m, 1H), 2.86-2.98 (m, 1H), 4.28-4.48 (m, 4H), 5.11 (dd, 1H, J=13.2 Hz, J=5.1 Hz), 6.98 (t, 1H, J=6.0 Hz), 7.45 (d, 1H, J=8.1 Hz), 7.54 (d, 2H, J=11.7 Hz), 7.61 (dd, 1H, J=8.7 Hz, J=2.1 Hz), 7.70 (d, 1H, J=7.8 Hz), 8.09 (d, 1H, J=2.4 Hz), 9.18 (s, 1H), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.2, 42.8, 47.1, 51.6, 116.2 (q, J=5.6 Hz), 121.5, 121.9, 122.4, 122.8 (q, J=271 Hz), 122.9, 126.6 (q, J=30 Hz), 126.9, 130.3, 131.8, 140.0, 142.4, 144.5, 154.9, 167.9, 171.0, 172.8; LCMS: MH=495, 497; Anal. Calcd for C22H18ClF3N4O4+0.1H2O: C, 53.20; H, 3.69; N, 11.28. Found: C, 52.83; H, 3.47; N, 11.15.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCO>[CH2:12]([O:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: OCc1ncccc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: OCc1ncccc1OCc1ccccc1
Temperature: 25 °C
Yield: 65 %

Procedure:
To a solution of 3-hydroxy-2-(hydroxymethyl)pyridine (10.00 g) and KOH (7.00 g) in anhydrous EtOH was added benzyl bromide (7.30 mL) at room temperature under stirring. The reaction mixture was heated to reflux for 24 h, then cooled to rt and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) DCM/MeOH) to give the title compound as a pale yellow solid (7.50 g, 65.00%), HPLC: 95.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 216.4 (M+1); 1H NMR (400 MHz, CDCl3) δ: 4.39 (br s, 1H), 4.82 (s, 2H), 5.11 (s, 2H), 7.16-7.17 (m, 2H), 7.34-7.40 (m, 5H), 8.15-8.17 (m, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:15]([OH:17])=O)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=1.[NH2:18][C@@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21]>>[C:20]([C@@H:19]([NH:18][C:15]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:6]=1)=[O:17])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:21])[NH2:22]
Reactant: O=C(O)c1ccc(Cl)c(-c2cccc(Cl)c2)n1
Reactant: CC(C)C[C@H](N)C(N)=O
Product: CC(C)C[C@H](NC(=O)c1ccc(Cl)c(-c2cccc(Cl)c2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-6-(3-chloro-phenyl)-pyridine-2-carboxylic acid (Example 58 c) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (EI): m/e=380.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16]Br)[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C-:19]#[N:20].[Na+]>C(#N)C.[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(OCC)(=O)C>[C:19]([CH2:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][N:7]([CH3:8])[C:6](=[O:18])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])#[N:20]
Reactant: CN(Cc1cccc(CBr)c1)C(=O)OC(C)(C)C
Reactant: [C-]#N
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN(Cc1cccc(CC#N)c1)C(=O)OC(C)(C)C

Procedure:
tert-Butyl-N-[3-(bromomethyl)benzyl]-N-methylcarbamate (preparation 13) (3.2 g, 10.18 mmol) was dissolved in acetonitrile (50 ml) and treated with sodium cyanide (1.23 g, 25.10mmol) followed by benzyl triethylammonium bromide (220 mg, 0.8 mmol) and the resultant mixture stirred at room temperature for 4 days. The resultant slurry was diluted with ethyl acetate (200 ml) washed with water, sat aq brine and dried over MgSO4. Removal of the drying agent by filtration followed by evaporation of the solvent gave a pale yellow solid which was purified by chromatography (SiO2, eluting with 100% CH2Cl2) to give the desired product with a trace of impurity (3.0 g). 1H NMR (CDCl3) δ 1.50 (s, 9H), 2.80 (s, b, 3H), 3.75 (s, 2H), 4.40 (s, 2H), 7.20 (m, 3H), 7.35 (t, 1H). LRMS m/z=278.1 (M+18)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Mg].[CH3:11][C:12]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[CH:17]=1)([CH3:15])[C:13]#N.CC[O:28]CC>>[CH3:15][C:12]([C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[CH:17]=1)([C:13](=[O:28])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11]
Reactant: COc1cc(OC)cc(C(C)(C)C#N)c1
Reactant: CCOCC
Reactant: BrCCc1ccccc1
Agent: [Mg]
Product: COc1cc(OC)cc(C(C)(C)C(=O)CCc2ccccc2)c1

Procedure:
To a solution of the Grignard reagent prepared from 2-phenylbromoethane (5.5 g.), magnesium (0.8 g.) and dry ether (60 ml.) is added a solution of 2-methyl-2-(3,5-dimethoxyphenyl)propionitrile (2.75 g.) in dry ether (20 ml.). The ether is distilled off and replaced by dry benzene (50 ml.) and the mixture refluxed for 48 hours. It is then decomposed by careful treatment with dilute sulfuric acid and heated on a steam bath for one hour. The mixture is then extracted with ether, the extract dried (MgSO4) and concentrated to an oil. Distillation of the oil in vacuo affords 2-methyl-2-(3,5-dimethoxyphenyl)-5-phenyl-3-pentanone; b.p. 168° C./0.2 mm. (Yield: 2.32 g., 60%)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]2[N:11]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[NH:33][N:32]=[N:31][N:30]=4)=[CH:19][CH:18]=3)[C:12]([CH2:14][CH3:15])=[N:13][C:8]2=[C:7]([CH3:34])[CH:6]=1.[C:35](Cl)([CH3:37])=[O:36].C(N(CC)CC)C>C1COCC1>[C:35]([NH:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]2[N:11]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]4[NH:33][N:32]=[N:31][N:30]=4)=[CH:21][CH:22]=3)[C:12]([CH2:14][CH3:15])=[N:13][C:8]2=[C:7]([CH3:34])[CH:6]=1)(=[O:36])[CH3:37]
Reactant: CC(=O)Cl
Reactant: CCc1nc2c(C)cc(NCCN)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1nc2c(C)cc(NCCNC(C)=O)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 1 h

Procedure:
To 5-(2-aminoethyl)amino-2-ethyl-7-methyl-3-(2'-(tetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine (20 mg) in THF (1 mL) at °C. was added AcCl (3.4 μL) and triethylamine (18 μL). After 1 h, the solvent was evaporated and the residue was purified (SiO2, 80:20:1 CHCl3, MeOH, NH4OH) to give 17 mg of the title compound. 1H NMR (300 MHz, CD3OD) δ7.63-7.45 (m, 4H), 7.18-7.04 (AB q, 4H), 6.33 (s, 1H), 5.43 (s, 2H), 3.47 (t, 2H, J=5 Hz), 3.38 (t, 2H, J=5 Hz), 2.86 (q, 2H, J=7.8 Hz), 2.47 (s, 3H), 1.90 (s, 3H), 1.22 (t, 3H, J=7.8 Hz).
Reaction SMILES: CN(C=O)C.[OH:6][C:7]1[CH:16]=[C:15]([OH:17])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)/[CH:25]=[C:26](/[CH2:28][CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])\[CH3:27]>O>[CH3:27]/[C:26](/[CH2:28][CH2:29][CH:30]=[C:31]([CH3:33])[CH3:32])=[CH:25]\[CH2:24][O:17][C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([OH:6])[CH:16]=1
Reactant: CC(C)=CCC/C(C)=C/CBr
Reactant: COC(=O)c1ccc(O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC/C=C(\C)CCC=C(C)C)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
In 80 m of DMF were poured 13.1 g (78.0 mmol) of methyl 2,4-dihydroxybenzoate and 18.9 g (86.9 mmol) of potassium carbonate, and 12.0 g (86.9 mmol) of geranyl bromide was added thereto dropwise at 5° C. After the addition, the mixture was stirred at room temperature for 1 hour, poured into 300 ml of water, and extracted with 250 ml of ethyl acetate. The extract was washed with water and a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated. The resulting crude product was purified by column chromatography to obtain 18.1 g (yield: 75%) of methyl 4-{(2E)-3,7-dimethylocta-2,6-dienyloxy}-2-hydroxybenzoate represented by the following chemical formula (hereinafter referred to as compound 31) as a colorless, clear and oily substance. The analytical results are shown below. ##STR52##
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([OH:32])=[CH:4][N:3]=1.[CH3:33][O:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=1B(O)O>>[OH:32][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])[CH:7]=2)[C:2]([C:36]2[CH:37]=[CH:38][C:39]([C:41]([F:44])([F:43])[F:42])=[CH:40][C:35]=2[O:34][CH3:33])=[N:3][CH:4]=1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncc(O)c3c2)c(OC)c1
Product: COc1cc(C(F)(F)F)ccc1-c1ncc(O)c2cc(S(=O)(=O)Nc3nccs3)ccc12

Procedure:
Example 232 was synthesized in a similar manner to Example 228, except that 1-chloro-N-(2,4-dimethoxybenzyl)-4-hydroxy-N-(thiazol-2-yl)isoquinoline-6-sulfonamide and (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid were used as the coupling partners. The final compound was purified via column chromatography (12 g silica gel column, gradient elution 0 to 5% MeOH:DCM) to afford 4-hydroxy-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.89 (s, 1H), 11.03 (s, 1H), 8.64 (d, J=1.4 Hz, 1H), 8.24 (s, 1H), 7.84 (dd, J=1.8, 8.9 Hz, 1H), 7.60 (d, J=8.9 Hz, 1H), 7.55-7.49 (m, 1H), 7.48-7.42 (m, 2H), 7.28 (d, J=4.6 Hz, 1H), 6.86 (d, J=4.5 Hz, 1H), 3.73 (s, 3H). m/z (ESI) 482.2 (M+H)+.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[CH2:13]([N:29]1[CH:33]=[CH:32][CH:31]=[CH:30]1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH2:13]([N:29]1[CH:30]=[CH:31][CH:32]=[C:33]1[C:3]1[C:4](=[O:11])[C:5]2[C:10]([C:1](=[O:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: CCCCCCCCCCCCCCCCn1cccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCn1cccc1C1=CC(=O)c2ccccc2C1=O
Yield: 41 %

Procedure:
6.32 millimol of 1,4-naphthoquinone and 3.16 millimol of N-hexadecylpyrrole were stirred in 50 ml of chloroform in a round-bottomed flask for 5 hours at room temperature, the reaction being catalysed by addition of a few milligrams of para-toluenesulphonic acid. The reaction medium was diluted with 50 ml of chloroform and then washed four times with 50 ml of water and finally with saturated aqueous NaCl solution. The resulting organic phase was dried over Na2SO4 and then concentrated under vacuum. The product 2-(1-hexadecyl-1H-pyrrol-2-yl)-[1,4]-naphthoquinone was thus isolated in a yield of 41% after purification by chromatography on a column of silica.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]=C)=[CH:6][C:3]=1[C:4]#[N:5].I([O-])(=O)(=O)=[O:14].[Na+].[OH2:19]>C(Cl)(Cl)(Cl)Cl.C(#N)C.C(Cl)Cl.O.[Ru]=O>[C:4]([C:3]1[CH:6]=[C:7]([CH2:10][C:11]([OH:14])=[O:19])[CH:8]=[CH:9][C:2]=1[F:1])#[N:5]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCc1ccc(F)c(C#N)c1
Reactant: O
Agent: O=[Ru]
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CC#N
Product: N#Cc1cc(CC(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 2-fluoro-5-(prop-2-en-1-yl)benzonitrile (1.9 g, 11.8 mmol) in CCl4 (25 mL), acetonitrile (25 mL) and water (38 mL) was added sodium periodate (8.83 g, 41.3 mmol) and ruthenium oxide hydrate (200 mg) and the resulting mixture was stirred at ambient temperature overnight. The mixture was diluted with 100 mL DCM and 100 mL of water. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified with silica gel column chromatography afford crude (3-cyano-4-fluorophenyl)acetic acid.
Reaction SMILES: [C:1](NC(N)=N)#[N:2].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]=[C:15]=[N:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[Cl:24])=[C:10]([O:25][Si](C(C)(C)C)(C)C)[C:9]=1[S:33]([N:36]([CH3:38])[CH3:37])(=[O:35])=[O:34].[N:39]#CN.C(N(CC)C(C)C)(C)C.[F-].[Cs+]>>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]([C:1]#[N:2])[C:15]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[Cl:24])=[NH:39])=[C:10]([OH:25])[C:9]=1[S:33]([N:36]([CH3:37])[CH3:38])(=[O:35])=[O:34]
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N=C=Nc2ccc(F)cc2Cl)c1O[Si](C)(C)C(C)(C)C
Reactant: N#CNC(=N)N
Reactant: N#CN
Agent: [Cs+]
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(N(C#N)C(=N)Nc2ccc(F)cc2Cl)c1O
Yield: 50 %

Procedure:
Following the general procedure for cyanoguanidine formation outlined in example 12, N-[4-chloro-2-tert-butyldimethylsilyloxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]N′-(2-chloro4-fluorophenyl)carbodiimide (420 mg, 0.81 mmol), cyanamide (136 mg, 3.24 mmol) and N,N-diisopropylethylamine (126 mg, 1.62 mmol) were reacted, followed by desilylation with Cesium fluoride (148 mg, 1.62 mmol) to form the desired product (180 mg, 50%). EI-MS m/z 446.2 (M+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.Cl.CN(C)CCCN=C=NCC.[Si:21]([O:28][C@H:29]([C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[C:47]([CH2:52][OH:53])[CH:46]=1)[CH2:30][NH:31][C:32]([CH3:44])([CH3:43])[CH2:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](O)=[O:38])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[NH3:1].[Si:21]([O:28][C@H:29]([C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[C:47]([CH2:52][OH:53])[CH:46]=1)[CH2:30][NH:31][C:32]([CH3:44])([CH3:43])[CH2:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([NH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)=[O:38])([C:24]([CH3:25])([CH3:26])[CH3:27])([CH3:23])[CH3:22]
Reactant: CC(C)(Cc1cccc(C(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Reactant: NCCN1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(Cc1cccc(C(=O)NCCN2CCCC2)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Product: N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(2-Aminoethyl)pyrrolidine (83 μL, 0.63 mmol) was added to a mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (122 mg, 0.63 mmol), 3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxy methyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid (preparation 37) (200 mg, 0.42 mmol), 1-hydroxybenzotriazole hydrate (63 mg, 0.47 mmol) and N,N-diisopropylethylamine (88 □L, 0.63 mmol) in N,N-dimethylformamide (5 mL). The resulting solution was stirred for 18 hours at room temperature. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate (50 mL) and saturated sodium hydrogen carbonate solution (10 mL). The aqueous layer was separated and re-extracted with dichloromethane (30 mL), and the combined organic solution was dried (sodium sulfate) and concentrated in vacuo to give a yellow oil. The oil was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia, 100:0:0 to 75:25:2 to afford the title compound as a pale yellow solid. 1H NMR (400 MHz, CD3OD) δ: 7.69 (2H, m) 7.40-7.31 (2H, m), 7.26 (1H, m), 7.14-7.03 (1H, dd), 6.85 (1H, d), 4.69 (1H, m), 4.62 (2H, m), 3.58 (2H, m), 2.89-2.59 (10H, m), 1.82-1.79 (4H, m), 1.12 (3H, s), 1.07 (3H, s), 0.79 (9H, s), −0.01 (3H, s), −0.21 (3H, s) ppm; LRMS APCI m/z 570 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N+:16]([O-])=[CH:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.[CH3:35][O+:36](C)C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>C(Cl)Cl.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH2:35][OH:36])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[O+](C)C
Reactant: Cc1cccc(-c2nc(-c3ccc(S(C)(=O)=O)cc3)sc2-c2cc[n+]([O-])cc2)c1
Agent: F[B-](F)(F)F
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: Cc1cccc(-c2nc(-c3ccc(S(C)(=O)=O)cc3)sc2-c2ccnc(CO)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a solution of 4-[4-(3-methylphenyl)-2-(4-methylsulfonylphenyl)-1,3-thiazol-5-yl]pyridine N-oxide (0.43 g, 1.0 mmol) in methylene chloride (10 mL) was added trimethyloxonium tetrafluoroborate (0.17 g, 1.2 mmol), and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, and methanol (15 mL) was added to the residue. To the mixture was added a solution of ammonium persulfate (0.05 g, 0.22 mmol) in water (1 mL) under reflux, and the mixture was heated to reflux for 30 minutes. A solution of ammonium persulfate (0.03 g, 0.11 mmol) in water. (1 mL) was added to the reaction mixture, and the mixture was further heated to reflux for 13 hours. The reaction mixture was cooled to room temperature, then, concentrated under reduced pressure. To the residue was added an aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extracts were washed with brine, dried over magnesium sulfate, and filtrated and concentrated under reduced pressure. The residued was purified by column chromatography (filler: Chromatorex NH DM1020 (trade name, manufactured by Fuji Silysia Chemical Ltd.), ethyl acetate) to obtain a title compound (0.26 g, yield 61%).
Reaction SMILES: [C:1]1([C:7]23[CH2:14][CH2:13][C:10]([CH2:15][C:16]([O:18][CH3:19])=[O:17])([CH2:11][CH2:12]2)[CH2:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C23CCC(C(C)C(OC)=O)(CC2)CC3)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[Br:44][C:45]([CH3:50])([CH3:49])[C:46](Br)=[O:47]>C(Cl)Cl>[Br:44][C:45]([CH3:50])([CH3:49])[C:46]([C:4]1[CH:3]=[CH:2][C:1]([C:7]23[CH2:8][CH2:9][C:10]([CH2:15][C:16]([O:18][CH3:19])=[O:17])([CH2:13][CH2:14]2)[CH2:11][CH2:12]3)=[CH:6][CH:5]=1)=[O:47]
Reactant: COC(=O)CC12CCC(c3ccccc3)(CC1)CC2
Reactant: CC(C)(Br)C(=O)Br
Agent: COC(=O)C(C)C12CCC(c3ccccc3)(CC1)CC2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CC12CCC(c3ccc(C(=O)C(C)(C)Br)cc3)(CC1)CC2
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To an ice water cooled solution of crude methyl (4-phenylbicyclo[2.2.2]oct-1-yl)acetate (Intermediate 16; 961 mg, 3.53 mmol) in DCM (10 mL) was added aluminium chloride (1.4 g, 10.58 mmol) followed by the dropwise addition of 2-bromoisobutyryl bromide (0.45 mL, 3.53 mmol). The reaction mixture was allowed to stir at ˜0° C. for ˜40 mins, it was then poured onto ice-water (˜100 mL). The organic phase was separated and the aqueous phase washed with DCM (3×50 mL), the organic washings were combined, dried (MgSO4) and concentrated to leave a yellow gum. This was purified on a 120 g silicyle silica cartridge, loading in DCM and eluting with 0-10%-20% isohexane-EtOAc, the product eluting at 10% EtOAc. The mixed fractions were combined and recolumned on a 120 g silica cartridge as described above; to yield the title compound as a white solid, (705 mg 1.67 mmol, 47%). 1H NMR (CDCl3) δ 1.09 (d, 3H), 1.50-1.57 (m, 3H), 1.67-1.74 (m, 3H), 1.82-1.86 (m, 6H), 2.03 (s, 6H), 2.27 (q, 1H), 3.67 (s, 3H), 7.37 (d, 2H), 8.11 (d, 2H); GC-MS CI m/e MH+ 421.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([N:13]4[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21](=O)[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.[O:26]1[CH:30]=[CH:29][C:28]([NH2:31])=[N:27]1.[B][B][B][B][B][B][B][B][B][B].Cl>CO.C(O)(=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[N:10]=[C:11]([N:13]4[CH2:18][CH2:17][CH:16]([O:19][CH2:20][CH:21]([NH:31][C:28]5[CH:29]=[CH:30][O:26][N:27]=5)[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1
Reactant: Nc1ccon1
Agent: Cl
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Solvent: CC(=O)O
Product: CC(COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1)Nc1ccon1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-({1-[6-(cyclopropylmethoxy)-1,3-benzoxazol-2-yl]piperidin-4-yl}oxy)propan-2-one (400 mg) and isoxazol-3-amine (0.129 mL) in methanol (6 mL) and acetic acid (0.300 mL) was added decaborane (213 mg), and the mixture was stirred at room temperature for 3 hr. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min, and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (hexane/ethyl acetate). The obtained residue was applied to preparative HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)). Saturated aqueous sodium hydrogen carbonate solution was added to the obtained fraction, and the mixture was extracted with ethyl acetate and the extract was dried over anhydrous sodium sulfate. The residue was concentrated under reduced pressure to give the title compound (126 mg).