Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:16]([O:20][C:21]([NH:23][C@:24]([C:33]1[O:37][C:36]([C:38]2[CH:39]=[C:40]([N:46]([CH3:51])[S:47]([CH3:50])(=[O:49])=[O:48])[CH:41]=[C:42]([CH2:44]Br)[CH:43]=2)=[N:35][N:34]=1)([CH3:32])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C.O>[C:16]([O:20][C:21]([NH:23][C@:24]([C:33]1[O:37][C:36]([C:38]2[CH:39]=[C:40]([N:46]([CH3:51])[S:47]([CH3:50])(=[O:49])=[O:48])[CH:41]=[C:42]([CH2:44][O:5][CH:1]3[CH2:4][CH2:3][CH2:2]3)[CH:43]=2)=[N:35][N:34]=1)([CH3:32])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CN(c1cc(CBr)cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c1)S(C)(=O)=O
Reactant: OC1CCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1cc(COC2CCC2)cc(-c2nnc([C@@](C)(Cc3ccccc3)NC(=O)OC(C)(C)C)o2)c1)S(C)(=O)=O
Reaction time: 0.08 h

Procedure:
To a solution of cyclobutanol (0.009 mL, 0.115 mmol) in 0.26 mL DMF, cooled to 0° C., was added sodium bis(trimethylsilyl)amide dropwise. After stirring for 5 min, a solution of 3-(5-((R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(bromomethyl)-N-methyl-N-(methylsulfonyl)benzenamine (13.5 mg, 0.023 mmol) in 0.25 mL DMF was added and the reaction was stirred at 0° C. for 1 h. The reaction mixture was diluted with water, extracted with EtOAc and washed with brine. Drying, solvent evaporation and flash chromatography (15-55% EtOAc/hexanes) gave 3-(5-((R)-2-tert-butoxycarbonylamino-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl)-5-(cyclobutoxymethyl)-N-methyl-N-(methylsulfonyl)benzenamine. 1H NMR (CDCl3) δ 7.90 (d, J=9.0 Hz, 2H), 7.58 (s, 1H), 7.27 (m, 3H), 7.06 (m, 2H), 5.09 (bs, 1H), 4.47 (s, 2H), 4.05 (m, 1H), 3.57 (d, J=13.6 Hz, 1H), 3.43 (m, 1H), 3.38 (s, 3H), 2.90 (s, 3H), 2.24 (m, 2H), 2.02 (m, 2H), 1.73 (s, 3H), 1.56 (m, 2H), 1.42 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:10][CH2:9][CH:8]2[C:11](=[CH2:12])[CH:3]1[CH2:4][CH2:5][CH:6]([OH:13])[CH2:7]2.[C:15](OC(=O)C)(=[O:17])[CH3:16].O>P(=O)(O)(O)O.CCOCC>[C:15]([O:13][CH:6]1[CH2:5][CH2:4][CH:3]2[C:11](=[CH2:12])[CH:8]([CH2:9][CH2:10][C:2]2([CH3:14])[CH3:1])[CH2:7]1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: C=C1C2CCC(C)(C)C1CCC(O)C2
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCOCC
Product: C=C1C2CCC(C)(C)C1CCC(OC(C)=O)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 3-necked flask which was equipped with a reflux condenser, there were placed, under N2-atmosphere, 0.9 g (4.6 mmoles) of 7,7-dimethyl-10-methylene-bicyclo[4.3.1]decan-3-ol, 8 ml of acetic anhydride and 1 drop of phosphoric acid. The reaction mixture was stirred overnight at room temperature. Then 50 ml of H2O were added and the solution stirred one more night at room temperature. The resulting mixture was taken up in ether, washed to neutrality with brine and dried over Na2SO4. After filtration and concentration in vacuo, the product was distilled in a bulb-to-bulb apparatus at 150° C. (10 Pa). There were obtained 1.09 g of a colorless oil in 99% of the theoretical yield. The thus-obtained mixture was composed of 2 isomers (71/29) which were separated by gas chromatography on a chemically inert CARBOWAX® column having a length of 5 meters.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28](I)[CH:27]=[CH:26][C:25]=3[O:31][CH2:32][CH2:33][OH:34])[C:5]2=[CH:4][CH:3]=1.[CH3:36][C:37]([CH3:41])([CH3:40])[C:38]#[CH:39].C(N(CC)CC)C>CN(C)C=O.[Cu]I.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>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:35])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([C:39]#[C:38][C:37]([CH3:41])([CH3:40])[CH3:36])[CH:27]=[CH:26][C:25]=3[O:31][CH2:32][CH2:33][OH:34])[C:5]2=[CH:4][CH:3]=1
Reactant: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cc(I)ccc2OCCO)N1
Reactant: C#CC(C)(C)C
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: CC(C)(C)C#Cc1ccc(OCCO)c(C2NC(=O)CC(c3cccc(Cl)c3)C23C(=O)Nc2cc(Cl)ccc23)c1
Temperature: 80 °C
Yield: 29.6 %

Procedure:
A solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-iodo-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.15 g, 0.24 mmol) prepared in Example 190c in anhydrous N,N-dimethylformamide (10 mL) was added CuI (3 mg), 3,3-dimethyl-1-butyne (19.7 mg, 2.4 mmol) (Aldrich), and triethylamine (1 mL, 7.2 mmol). The mixture was degassed under nitrogen for 5 min, then dichlorobis(triphenylphosphine)palladium (8.4 mg, 0.012 mmol) (Strem) was added and the reaction mixture was heated at 80° C. under nitrogen for 0.5 h. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over MgSO4 and concentrated. The residue was purified with chromatography to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-(3,3-dimethyl-1-butynyl)-2-(2-hydroxy-ethoxy)-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield: 41 mg, 30%).
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:31])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)[C:5]1=[O:30])[CH:2]=C.I([O-])(=O)(=O)=[O:33].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:6]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][N:25]=3)[C:5](=[O:30])[C@:4]([CH2:1][CH:2]=[O:33])([CH3:31])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2ccncn2)C1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@]1(CC=O)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2ccncn2)C1=O
Reaction time: 0.08 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pyrimidin-4-yl)piperidin-2-one (Example 110, Step B) (60 mg, 0.13 mmol) in a mixture of tetrahydrofuran (2.7 mL) and water (880 μL) was added osmium tetroxide (1.7 mg, 6.6 μmol). After 5 minutes, sodium periodate (89 mg, 0.46 mmol) was added and the reaction mixture was stirred for 14 hours. The reaction mixture was filtered through Celite® (J. T. Baker, Phillipsberg, N.J., diatomaceous earth) and washed with EtOAc and water. The organic layer was washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography (0 to 75% EtOAc/hexanes, gradient elution) provided the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[C:7]([OH:15])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4].F[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[CH2:1]([C:5]1[C:6]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[C:7]([O:15][C:24]2[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2ccccc2c(O)c1-c1ccc(F)cc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCCCc1cc2ccccc2c(Oc2ccc(C=O)cc2)c1-c1ccc(F)cc1
Yield: 78 %

Procedure:
3-Butyl-2-(4-fluorophenyl)-1-naphthalenol (166) (0.25 g, 0.83 mmol) and 4-fluorobenzaldehyde was heated with Cs2CO3 in DMSO at 100° C. to give 0.26 g (78%) of the title compound (167) as a colorless viscous oil. 1H NMR (400 MHz, CDCl3): δ 0.78 (t, J=7.3 Hz, 3H), 1.20-1.30 (m, 2H), 1.40-1.50 (m, 2H), 2.56 (t, J=7.9 Hz, 2H), 6.68 (d, J=8.6 Hz, 2H), 6.95 (t, J=8.7 Hz, 2H), 7.06-7.14 (m, 2H), 7.40 (t, J=7.6 Hz, 1H), 7.51 (t, J=7.2 Hz, 1H), 7.63 (d, J=8.6 Hz, 2H), 7.71 (s, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.87 (d, J=8.2 Hz, 1H), 9.81 (s, 1H). LCMS (ESI): m/z 399 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:12])([F:11])[F:10].[Cl:13][S:14](O)(=[O:16])=[O:15]>ClCCl.CCCCCCC.ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([S:14]([Cl:13])(=[O:16])=[O:15])[CH:5]=[CH:4][C:3]=1[O:8][C:9]([F:11])([F:10])[F:12]
Reactant: FC(F)(F)Oc1ccccc1Br
Reactant: O=S(=O)(O)Cl
Solvent: CCCCCCC
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(OC(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
2.0 g of 1-bromo-2-(trifluoro-methoxy)benzene (8.3 mmol) were dissolved in 30 ml of dichloromethane. At 0-5° C., 1.06 g of chlorosulfonic acid (9.13 mmol), dissolved in 3 ml of dichloromethane, were added dropwise. The reaction mixture was stirred for 30 min at room temperature. Additional 5.5 equivalents of chlorosulfonic in dichloromethane were added to drive the reaction to completion. Standard work-up was followed and silica gel chromatography with n-heptane-dichloromethane (6:4) as eluent gave 2.19 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[O:6][C:7]3([C:32]4[N:33]([CH:34]=[CH:35][CH:36]=4)[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]2[CH2:27][O:26]C(C)(C)[O:24]2)=[C:17]([O:30][CH3:31])[CH:16]=1)=[O:14])[CH2:9][CH2:8]3.O.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[O:6][C:7]3([C:32]4[N:33]([CH:34]=[CH:35][CH:36]=4)[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@@H:23]([OH:24])[CH2:27][OH:26])=[C:17]([O:30][CH3:31])[CH:16]=1)=[O:14])[CH2:9][CH2:8]3
Reactant: COc1cc(C(=O)N2CCC3(CC2)Oc2ccc(Cl)cc2-n2cccc23)ccc1OC[C@@H]1COC(C)(C)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2ccc(Cl)cc2-n2cccc23)ccc1OC[C@@H](O)CO
Temperature: 80 °C

Procedure:
(R)-(8-Chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-3-methoxyphenyl)methanone (41 mg, 0.076 mmol) and 4-methylbenzenesulfonic acid hydrate (2.9 mg, 0.015 mmol) were dissolved in MeOH (760 μL) and H2O (76 μL) was added. The reaction mixture was heated at 80° C. for 45 min. The mixture was filtered and the residue was purified by reverse phase HPLC using 5 mM HCl/H2O and MeOH to yield (S)-(8-chlorospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-(2,3-dihydroxypropoxy)-3-methoxyphenyl)methanone. ESI-MS m/z calc. 498.2. found 499.3 (M+1)+; Retention time: 4.72 minutes (15 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[O:22]=[C:23]1[N:27]([CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:26][CH2:25][N:24]1[C:34](Cl)=[O:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:34]([N:24]3[CH2:25][CH2:26][N:27]([CH:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[C:23]3=[O:22])=[O:35])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cn1
Reactant: O=C(Cl)N1CCN(C2CCOCC2)C1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccnc(Cl)c2)cn1)N1CCN(C2CCOCC2)C1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 118.9 %

Procedure:
A 0° C. mixture of Example A5 (1 g, 4.51 mmol) and pyridine (1.1 mL, 13.6 mmol) in DCM (25 mL) was treated with a solution of Example B2 (1.680 g, 7.22 mmol) in DCM (8 mL), warmed to RT and stirred 45 min. The mixture was concentrated to dryness, the residue treated with DCM and Et2O, sonicated and the resulting solid collected via filtration. The solid was dissolved in DCM, washed with water, the aqueous layer back-extracted with DCM (3×) and the combined organics were dried over Na2SO4 and concentrated to dryness to afford N-(5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (2.24 g, 119%) which was used without further purification. MS (ESI) m/z: 418.1 (M+H+).
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2)#[N:4].[CH3:20][N:21]([CH3:25])[CH2:22][CH2:23]Cl.O>CN(C)C=O>[C:3]([C:5]1([CH2:23][CH2:22][N:21]([CH3:25])[CH3:20])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2)#[N:4]
Reactant: CN(C)CCCl
Reactant: N#CC1c2ccccc2COc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCC1(C#N)c2ccccc2COc2ccccc21
Yield: 42 %

Procedure:
Sodium hydride (5.0 g; 0.10 mole) is added portionwise with cooling (5°-10° C.) under a nitrogen atmosphere to a solution of 11-cyano-6,11-dihydrodibenz[b,e]oxepin of Example 1A, (20.0 g; 0.09 mole) in dry DMF (200 ml). After thirty minutes, effervescence ceases and 2-dimethylaminoethyl chloride (10.0 g; 0.09 mole) in dimethyl formamide [DMF] (200 ml) is added dropwise. Stirring is continued at 80° C. for sixteen hours. The reaction is cooled and poured into three liters of water. After extraction with ether, the ether is re-extracted with 1 N HCl, and the combined aqueous extracts are made basic with 50% NaOH. After extracting with ether and drying (K2CO3), the solvent is removed in vacuo to provide an oil which is chromatographed on an alumina column. The resulting oil crystallizes upon standing and trituration with hexane yields 11.0 g (42%) of a solid of 11-cyano-11-[2-(dimethylamino)ethyl]-6,11-dihydrodibenz[ b,e]oxepin (m.p. 63°-65° C.),
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([OH:13])=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+].[CH2:33](O)[CH2:34][CH:35]([CH3:37])[CH3:36]>S(=O)(=O)(O)O>[CH3:36][CH:35]([CH3:37])[CH2:34][CH2:33][O:12][C:11]([C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[C:2]([NH2:1])[CH:10]=2)=[O:13]
Reactant: CC(C)CCO
Reactant: Nc1cc2[nH]c(C(=O)O)cc2cc1OCc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)CCOC(=O)c1cc2cc(OCc3ccccc3)c(N)cc2[nH]1
Temperature: 115 °C
Reaction time: 0.17 h

Procedure:
6-Amino-5-benzyloxy-1H-indole-2-carboxylic acid is suspended in isopentanol (10 mL) and concentrated sulfuric acid (10 drops) is added. The mixture is stirred at 115° C. for 10 min and then stirred at 90° C. for 3 h. Ethyl acetate is added and the mixture is neutralized with saturated sodium bicarbonate. The mixture is then washed with saturated NaCl (3×) and water (1×), dried over MgSO4, filtered, and concentrated to afford 6-amino-5-benzyloxy-1H-indole-2-carboxylic acid 3-methyl-butyl ester.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6]Cl)=[O:3].[NH2:8][C:9]1[CH:10]=[C:11]([C:26]2[CH:31]=[CH:30][C:29]([C@@H:32]([OH:36])[CH:33]([F:35])[F:34])=[CH:28][CH:27]=2)[CH:12]=[C:13]([NH:15][C:16]2[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[F:35][CH:33]([F:34])[C@@H:32]([C:29]1[CH:30]=[CH:31][C:26]([C:11]2[CH:12]=[C:13]([NH:15][C:16]3[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=3)[CH:14]=[C:9]([N:8]3[CH2:6][CH2:5][O:4][C:2]3=[O:3])[CH:10]=2)=[CH:27][CH:28]=1)[OH:36]
Reactant: Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc([C@@H](O)C(F)F)cc2)c1
Reactant: O=C(Cl)OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C1OCCN1c1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2ccc([C@@H](O)C(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloroethyl chloroformate (12.58 μL, 0.122 mmol) was slowly added to a stirred, cooled (0° C.) mixture of (1R)-1-(3′-amino-5′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-4-yl)-2,2-difluoroethanol (40 mg, 0.097 mmol) and potassium carbonate (33.7 mg, 0.244 mmol) in acetonitrile (0.5 mL). The mixture was stirred at room temperature for 1 hour. The mixture was then heated and stirred at 80° C. for 3 hours, then allowed to cool to room temperature. The mixture was diluted with ethyl acetate and concentrated in vacuo. Purification via silica gel column chromatography (20-80% ethyl acetate in hexanes) to give 3-(4′-[(1R)-2,2-difluoro-1-hydroxyethyl]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-yl)-1,3-oxazolidin-2-one as a colorless solid. MS ESI calc'd. for C22H18F5N4O3 [M+H]+ 481, found 481. 1H NMR (500 MHz, DMSO-d6): δ 10.39 (s, 1H); 8.85 (d, J=4.9 Hz, 1H); 8.01 (s, 1H); 7.88 (s, 1H); 7.64 (d, J=7.8 Hz, 2H); 7.55 (t, J=8.9 Hz, 3H); 7.31 (d, J=4.8 Hz, 1H); 6.27 (d, J=4.8 Hz, 1H); 6.07 (td, J=55.5, 3.9 Hz, 1H); 4.83 (s, 1H); 4.48 (t, J=7.8 Hz, 2H); 4.13 (t, J=7.9 Hz, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:14]=[CH:13][C:8]([CH2:9][N:10]=[C:11]=[S:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:15]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1)([O-])=O>ClCCl>[NH2:15][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:11]([NH:10][CH2:9][C:8]2[CH:13]=[CH:14][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=2)=[S:12])=[CH:20][CH:19]=1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)c1ccc(CN=C=S)cc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CNC(=S)NCc2ccc(N)cc2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 85.9 %

Procedure:
4-t-Butylbenzylisothiocyanate (100 mg) was dissolved in dichloromethane (3 ml) and then cooled to 0° C. To the solution was added 4-nitrobenzylamine (75 mg), followed by stirring at room temperature for 6 hours. After the completion of the reaction, dichloromethane was evaporated therefrom under reduced pressure and the residue was dissolved in methanol (3 ml). To the solution was added catalytic amount of 5% platinum/carbon and the mixture was subjected to hydrogenation reaction under atmospheric pressure. After the completion of the reaction, the methanol was evaporated under reduced pressure and the obtained residue was column-chromatographed (hexane/ethyl acetate=1/1) to yield the compound 9a (137 mg, 85%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:7][C:6]([CH2:8][CH2:9][CH3:10])=[N:5][C:4]=1[N:11]1[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]1[CH3:17]>C1COCC1.O=[Mn]=O>[CH3:17][C:12]1[N:11]([C:4]2[N:5]=[C:6]([CH2:8][CH2:9][CH3:10])[NH:7][C:3]=2[CH:2]=[O:1])[C:15]([CH3:16])=[CH:14][CH:13]=1
Reactant: CCCc1nc(-n2c(C)ccc2C)c(CO)[nH]1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: CCCc1nc(-n2c(C)ccc2C)c(C=O)[nH]1
Yield: 74.8 %

Procedure:
To a solution of 5-(hydroxy-methyl)-2-propyl-4-(2,5-dimethyl-1H-pyrrol-1-yl)imidazole (Example 48, 6.0 g, 0.026 mol) in dry THF (125 mL) was added MnO2 (11.2 g, 0.13 mol) and the reaction mixture refluxed for 4 hours under an atmosphere of nitrogen. The reaction mixture was cooled, filtered through celite, and the resulting filtrate evaporated under reduced pressure. Purification by flash chromatography (silica; 2:1 hexane ethyl acetate) gave the title compound 4-(2,5-dimethyl-1H-pyrrol 1-yl)-2-propylimidazole-5-carboxaldehyde (4.5 g, 75%), mp 119°-121° C.
Reaction SMILES: C(OC(=O)C[CH2:8][C:9]1[C:14](C)=[CH:13][C:12]([C:16](=[NH:19])[NH:17][OH:18])=[CH:11][C:10]=1C)(C)(C)C.[OH:22]CC1C=CC(C#N)=CC=1>>[OH:18][NH:17][C:16](=[NH:19])[C:12]1[CH:13]=[CH:14][C:9]([CH2:8][OH:22])=[CH:10][CH:11]=1
Reactant: N#Cc1ccc(CO)cc1
Reactant: Cc1cc(C(=N)NO)cc(C)c1CCC(=O)OC(C)(C)C
Product: N=C(NO)c1ccc(CO)cc1

Procedure:
The title compound is prepared in analogy to 3-[4-(N-hydroxycarbamimidoyl)-2,6-dimethyl-phenyl]-propionic acid tert-butyl ester (step g) starting from 4-hydroxymethyl-benzonitrile; LC-MS: tR=0.21 min, [M+1]+=167.04.
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[O:14]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17][CH2:16][CH2:15]1.[C:25](=[O:27])=[O:26]>CCCCCC.O>[O:14]1[C:20]2[C:21]([C:25]([OH:27])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: c1ccc2c(c1)CCCCO2
Reactant: O=C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: O=C(O)c1cccc2c1OCCCC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To 17.6 ml n-butyllithium (2.5M, 0.044 mol) in 63 ml hexane is added dropwise (0.044 mol) 5.1 g tetramethylethylenediamine (TMEDA) and 5 g (0.034 mol) of 2,3,4,5-tetrahydro-1-benzoxepin. The reaction mixture is stirred overnight. The reaction mixture is then chilled to 0° C. and carbonated with dry ice for an hour. Water (110 ml) is added and the mixture is filtered and the aqueous phase acidified with 4N HCl. The resultant oil is extracted into methylene chloride and dried (MgSO4). After filtering and concentrating in vacuo, 2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid results as a tan solid.
Reaction SMILES: [Cl-:1].[NH2:2][N+:3]1[CH:7]=[CH:6][N:5]([NH2:8])[C:4]=1[CH2:9][CH3:10].[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=1)([O-:13])=[O:12]>C(O)(=O)C>[Cl-:1].[NH2:2][N+:3]1[CH:7]=[CH:6][N:5]([N:8]=[C:20]([CH3:21])[C:17]2[CH:16]=[CH:15][C:14]([N+:11]([O-:13])=[O:12])=[CH:19][CH:18]=2)[C:4]=1[CH2:9][CH3:10]
Reactant: CCc1n(N)cc[n+]1N
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCc1n(N=C(C)c2ccc([N+](=O)[O-])cc2)cc[n+]1N
Reaction time: 48 h

Procedure:
A solution of 3.24 g (20 mmol) of 1,3-diamino-2-ethylimidazolium chloride and 16.5 g (100 mmol) of p-nitroacetophenone in 150 ml of glacial acetic acid is left to stand for 2 days, concentrated and the residue is crystallized from ethanol/ether. The crystals are placed on a column loaded with 50 g of silica gel. The material eluted with methylene chloride/methanol (7:3) is recrystallized from ethanol. There is obtained 1-amino-2-ethyl-3-[(α-methyl-p-nitrobenzylidene)amino]-imidazolium chloride of melting point 201°-203°.
Reaction SMILES: [C:1]([CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[C:10]([O:14][CH3:15])[CH:11]=2)[CH2:6][N:5]1[CH3:18])([OH:3])=[O:2].Cl.[CH3:20][CH2:21]O>>[C:1]([CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[C:10]([O:14][CH3:15])[CH:11]=2)[CH2:6][N:5]1[CH3:18])([O:3][CH2:20][CH3:21])=[O:2]
Reactant: COc1cc2c(cc1OC)CN(C)C(C(=O)O)C2
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C1Cc2cc(OC)c(OC)cc2CN1C

Procedure:
The resulting tetrahydroisoquinoline derivative of formula 30 is then esterified with a suitable lower alkanol by standard means to produce a tetrahydroisoquinoline ester of formula 31 (step 2). For example, 3-carboxy-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (30) is treated with HCl in EtOH to produce 3-carboethoxy-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (31).