Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12]C)=[O:11].[OH-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([OH:12])=[O:11]
Reactant: COC(=O)c1cccc(-c2ccccn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cccc(-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 161.4 %

Procedure:
To a solution of methyl 3-(pyridin-2-yl)benzoate (300 mg, 1.40 mmol) in MeOH (3 mL) was added aqueous NaOH (1 mL, 0.4M). The mixture was stirred at room temperature for 3 h. The reaction solution was concentrated and the residue dissolved in water and adjust pH to 5-6 with 2N of HCl. The solution was extracted with EtOAc (3×20 mL) and the combined organic layers concentrated to give the desired crude product (450 mg, Yield 90%) which was used in the next step without further purification. LCMS (m/z): 200.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([N+:12]([O-])=O)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[Cl:1][C:2]1[C:11]2[C:6](=[C:7]([NH2:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cccc2c(Cl)nccc12
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cccc2c(Cl)nccc12
Temperature: 70 °C

Procedure:
A solution (40 ml) of 1-chloro-5-nitroisoquinoline (2.23 g, synthesized according to the method described in J. Med. Chem. 45, 3, 740 (2002)) in ethyl acetate was added with tin(II) chloride dihydrate (12.39 g, Wako Pure Chemical Industries) at room temperature and stirred with heating at 70° C. for 1 hour. The reaction mixture was cooled to room temperature, then added with ice (200 g) and stirred for 0.5 hour. The reaction mixture was filtered through Celite and extracted three times with ethyl acetate (200 ml for each time), and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain the title compound (749 mg).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([CH:10]([C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH3:11])[CH:7]=[CH:6][C:5]=12.C1C(=O)N([Br:34])C(=O)C1>C(Cl)Cl>[Br:34][C:3]1[N:4]2[CH:9]=[C:8]([CH:10]([C:12]3[N:16]4[N:17]=[C:18]([C:21]5[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=5)[CH:19]=[CH:20][C:15]4=[N:14][CH:13]=3)[CH3:11])[CH:7]=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: CC(c1ccc2nccn2c1)c1cnc2ccc(-c3cnn(C)c3)nn12
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CC(c1ccc2ncc(Br)n2c1)c1cnc2ccc(-c3cnn(C)c3)nn12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(rac)-3-(1-Imidazo[1,2-a]pyridin-6-yl-ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazine (Example 293, 607 mg, 1.768 mmol) was dissolved in DCM (18 mL) and NBS (346 mg, 1.944 mmol) was added. It was stirred at rt for 30 min then the solvent was removed. The residue was purified by flash chromatography (CombiFlash® Companion System®, with RediSep® silica gel column, 0 to 20% MeOH in DCM). Combined fractions were concentrated to give the title compound as a yellow solid (tR 0.7 min (conditions 2), MH+=422, 1H-NMR in DMSO-d6: 8.47 (s, 1H); 8.37 (s, 1H); 8.04 (m, 2H); 7.78 (s, 1H); 7.67 (s, 1H); 7.54 (d, 1H); 7.47 (d, 1H); 7.32 (d, 1H); 4.81 (q, 1H); 3.89 (s, 3H); 1.80 (d, 3H)).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[C:8](OC)=[O:9].CO.O>ClCCCl>[F:3][C:4]1[C:16]([F:17])=[C:15]([F:18])[CH:14]=[CH:13][C:5]=1[NH:6][C@@H:7]([CH3:12])[CH2:8][OH:9]
Reactant: COC(=O)[C@H](C)Nc1ccc(F)c(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CO
Product: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reaction time: 1 h

Procedure:
At room temperature, sodium borohydride (35.7 mg) was suspended in 1,2-dichloroethane (EDC, 0.2 ml). Then a solution (0.8 ml) of methyl (2S)-2-(2,3,4-trifluoroanilino)propionate (200 mg, 99.8% ee) in EDC was added to the solution. After adding methanol (137.4 mg), the liquid reaction mixture was stirred for 1 hour. Then water was added to the liquid reaction mixture followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography to thereby give 159.8 mg (99.8% ee) of the title compound as an oily substance. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 51.
Reaction SMILES: [CH3:1][Si:2]([CH3:16])([C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]>C(O)C.C(OCC)(=O)C.[OH-].[OH-].[Pd+2]>[CH3:16][Si:2]([CH3:1])([CH2:10][CH2:11][Si:12]([CH3:13])([CH3:14])[CH3:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9]
Reactant: C[Si](C)(C)C#C[Si](C)(C)CCCCCCO
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CC[Si](C)(C)CCCCCCO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of compound 16 (18.18 g, 0.071 mol) and palladium hydroxide on charcoal (2.46 g, 2.13 mmol) in ethanol and ethyl acetate (120 ml, 1:1) was stirred under an atmosphere of hydrogen for 24 h at room temperature. The reaction mixture was filtered (celite) and the solvent roved in vacuo to yield a clear oil.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH3:16][C:17](=[O:22])[CH2:18][C:19](=[O:21])[CH3:20].C(O)(=O)C.N1CCCCC1>ClCCl>[N+:11]([C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[C:18]([C:17](=[O:22])[CH3:16])[C:19](=[O:21])[CH3:20])=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:10]=1)([O-:13])=[O:12]
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1C(F)(F)F
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)C(=Cc1ccc([N+](=O)[O-])cc1C(F)(F)F)C(C)=O

Procedure:
1 g (4.56 mmol) of 2-trifluoromethyl-4-nitrobenzaldehyde, 0.51 ml (5.02 mmol) of 2,4-pentanedione, 0.4 ml (6.85 mmol) of acetic acid and 90 μl (0.91 mmol) of piperidine in 20 ml of anhydrous dichloromethane are stirred under reflux with a water trap for 24 h. After cooling, the reaction solution is washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue (1.28 g) is reacted in the next stage without further purification.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl[S:7]([C:10]1[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8]>ClCCl>[C:1]([NH:5][S:7]([C:10]1[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(=O)OC)c(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)OC)c(S(=O)(=O)NC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
At 5° C., 59.1 g (0.81 mol) of tert-butylamine were added dropwise to a solution of 118.3 g (0.4 mol) of crude dimethyl chlorosulfonylterephthalate (from Example A1) in 500 ml of dichloromethane, and the mixture was stirred at room temperature for another 1 h. The reaction solution was washed with water, dried and concentrated. Trituration of the crude product with heptane gave 106.7 g (81% of theory) of dimethyl tert-butylsulfamoylterephthalate of m.p. 132-134° C.
Reaction SMILES: [C:1]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:18])=[CH:10][CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:25][I:26]>CC(C)=O>[I-:26].[CH3:25][N+:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17](=[O:18])[NH:16][CH2:15][CH2:14][C:11]2[CH:12]=[CH:13][C:8]([O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:9][CH:10]=2)[CH:20]=1
Reactant: CC(C)(C)C(=O)Oc1ccc(CCNC(=O)c2cccnc2)cc1
Reactant: CI
Solvent: CC(C)=O
Product: C[n+]1cccc(C(=O)NCCc2ccc(OC(=O)C(C)(C)C)cc2)c1
Product: [I-]

Procedure:
To a solution of 1.63 g (5 mmol) of the product of Example 26 in 10 ml of acetone, 1.41 g (10 mmol) methyl iodide were added and the mixture was refluxed overnight while stirring. The acetone layer was separated by decantation and the yellowish, oily residue was crystallized from methanol/ether.
Reaction SMILES: [CH:1](=[O:5])[CH:2](C)[CH3:3].[NH:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([N:22]3[CH2:30][C:29]4[CH:28]=[CH:27][N:26]=[CH:25][C:24]=4[CH2:23]3)=[O:21])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.N1CC=C(C2C=CC(NC(N3CC4C(=CC=CC=4)C3)=O)=CC=2)[CH2:33][CH2:32]1>>[O:5]1[CH2:1][CH2:2][CH2:3][CH:32]1[CH2:33][N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]([N:22]3[CH2:30][C:29]4[CH:28]=[CH:27][N:26]=[CH:25][C:24]=4[CH2:23]3)=[O:21])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1
Reactant: CC(C)C=O
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccccc2C1
Reactant: O=C(Nc1ccc(OC2CCNCC2)cc1)N1Cc2ccncc2C1
Product: O=C(Nc1ccc(OC2CCN(CC3CCCO3)CC2)cc1)N1Cc2ccncc2C1

Procedure:
The title compound was prepared as described in Example 429, substituting tetrahydrofuran-2-carbaldehyde for isobutyraldehyde and N-(4-(piperidin-4-yloxy)phenyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide for N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, Pyridine-d5. Temp=90° C.) δ ppm 8.53-8.59 (m, 2H) 8.07 (s, 1H) 7.73 (d, J=9.16 Hz, 2H) 7.10 (d, J=5.49 Hz, 1H) 6.97-7.02 (m, 2H) 4.80-4.87 (m, 4H) 4.03 (d, J=11.60 Hz, 1H) 3.77-3.84 (m, 1H) 3.61-3.69 (m, 1H) 2.88 (d, J=41.81 Hz, 2H) 2.25-2.63 (m, 4H) 1.97 (s, 2H) 1.77-1.91 (m, 4H) 1.64-1.76 (m, 2H) 1.44-1.58 (m, 1H); MS (APCI(+)) m/e 423 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[S:17][C:18]([C:27]([F:30])([F:29])[F:28])=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:20]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1)(OC)=[O:2].CC(C[AlH]CC(C)C)C>C(Cl)Cl>[OH:2][CH2:1][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[S:17][C:18]([C:27]([F:30])([F:29])[F:28])=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:20]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(-c2noc(-c3cc(-c4ccccc4)c(C(F)(F)F)s3)n2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: OCc1ccc(-c2noc(-c3cc(-c4ccccc4)c(C(F)(F)F)s3)n2)cc1
Reaction time: 1 h
Yield: 88.8 %

Procedure:
A solution of 390 mg (0.91 mmol) of 3-[4-(carbomethoxy)phenyl]-5-(4-phenyl-5-trifluoromethyl-2-thienyl)-1,2,4-oxadiazole (from Step D) in 10 mL of CH2Cl2 at −78° C. was treated with 2.7 mL of 1.0 M DIBALH solution in CH2Cl2. The resulting solution was stirred cold for 1 h, then quenched with 5 mL of sat'd Rochelle salt solution. The mixture was partitioned between 100 mL CH2Cl2 and 50 mL of 1 N NaOH. The organic layer was separated, dried and concentrated. Chromatography on a Biotage 40 S cartridge using 4:1 v/v hexanes/EtOAc (1L) as the eluant afforded 325 mg (89%) of the title compound: 1H NMR (500 Mhz) δ 1.80 (app s, 1H), 4.80 (d, J=4.0, 2H), 7.46-7.48 (5H), 7.52 (d, J=8.0, 2H), 7.91 (q, J=1.5, 1H), 8.14 (d, J=8.0, 2H).
Reaction SMILES: [C:1]1([CH2:7][C:8]([N:10]2[CH2:17][CH2:16][CH2:15][C@H:11]2[C:12](O)=O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CC[O:22]CC1.ClC(OCC(C)C)=O.[NH2:33][CH2:34][C:35]([NH2:38])([CH3:37])[CH3:36]>O.C(Cl)(Cl)Cl>[NH2:38][C:35]([CH3:37])([CH3:36])[CH2:34][N:33]1[CH2:12][CH2:11][CH2:15][C@H:16]1[C:17]([NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:22]
Reactant: CN1CCOCC1
Reactant: CC(C)(N)CN
Reactant: O=C(O)[C@@H]1CCCN1C(=O)Cc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(N)CN1CCC[C@H]1C(=O)NC(=O)Cc1ccccc1
Temperature: -23 °C
Reaction time: 0.08 h

Procedure:
A mixture of N-phenylacetyl-proline (17.4 g.), N-methylmorpholine (7.85 ml.) and analytical grade chloroform (60 ml.) was stirred at room-temperature for 5 minutes. After cooling to -23° C., isobutyl chloroformate (9.23 ml.) was added rapidly during 1 minute. An exothermic reaction occurred and the temperature rose to -15° C. After a further 1 minute of stirring, 1,2-diamino-2-methylpropane (7.86 ml.) was added rapidly and the temperature was allowed to rise to room-temperature with stirring during 2 hours. The mixture was then poured into water (50 ml.) and the organic layer separated and discarded. The aqueous layer was basified (solid potassium carbonate) and extracted with chloroform (4×100 ml.). The chloroform extracts were dried (MgSO4) and evaporated under high vacuum to give N1 -(2-amino-2-methylpropyl)-N2 -phenylacetylprolinamide as an oil (15.5 g.); NMR (δ) (CDCl3): 7.7-6.7 (6H, complex, aromatic H+NHCO); 4.5 (1H, complex, =N--CH--CO); 3.8-2.7 (6H, complex CH2N+PhCH2); 3.65 (singlet, PhCH2); 2.4-1.6 (6H, complex, CH2CH2CH+NH2); and 1.0 [6H, singlet, C(CH3)2 ].
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[CH2:8]1.[O:21]1[CH2:26][CH2:25][CH:24](N)[CH2:23][CH2:22]1.[CH3:28][N:29]1CCOCC1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CO.CN(C=O)C>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:29][CH2:28][CH:24]3[CH2:25][CH2:26][O:21][CH2:22][CH2:23]3)=[O:17])=[CH:19][CH:20]=2)[CH2:8]1
Reactant: NC1CCOCC1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc(C(=O)O)cc2)C1
Reactant: CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc(C(=O)NCC3CCOCC3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
4-((2S,3′S)-2-Methyl-[1,3′]bipyrrolidinyl-1′-yl)-benzoic acid (0.17 g, 0.625 mmol) was dissolved in DCM (4 mL) and DMF (2 mL) and the solution was cooled to an ice-water bath. To this solution was added a solution of tetrahydropyran-4-yl amine (0.1 g, 0.86 mmol, 1 equiv.) in 1 mL of DCM, followed by N-methylmorpholine (0.2 mL, 3 equiv.), 1-Hydroxylbenzotriazole (HOBT) (0.11 g, 1.3 equiv.), sequentially, and finally EDC.HCl (0.104 g, 1.3 equiv.). The resultant clear light brown solution was stirred at r.t. overnight. TLC (10% MeOH in DCM) and LC/MS detected the product peak at retention time of 2.152 min with MS 372.35. The reaction was quenched with saturated sodium bicarbonate aqueous solution (10 mL) and 10 mL of DCM. The two layers were separated, and the aqueous layer was extracted with DCM (15 mL×2). The combined DCM extracts were washed with sodium bicarbonate (10 mL), and brine (10 mL), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo to get 0.17 g (74%) of the titled compound as a solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[S:12])([CH3:3])[CH3:2].[CH2:13]([NH:15][CH2:16][C:17](O)=[O:18])[CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:13]([N:15]1[CH2:16][C:17](=[O:18])[N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])[C:11]1=[S:12])[CH3:14]
Reactant: CC(C)c1ccccc1N=C=S
Reactant: CCNCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CC(=O)N(c2ccccc2C(C)C)C1=S
Yield: 42.9 %

Procedure:
The title compound was prepared by the procedure described in Example 9 using 15.42 g of 2-isopropylphenyl-isothiocyanate, 16.05 g of N-ethyl glycine, 12 g of triethyl amine, and 200 mL of chloroform. Purification was achieved by flash chromatography on silica gel (5-20% ethyl acetate in hexane). Crystallization from ethanol afforded the title compound (9.8 g) as a white solid, m.p. 125°-127° C. Anal. Calcd. for. C14H18N2OS: C, 64.09; H, 6.91; N, 10.68. Found: C, 64.19 H, 6.93; N, 10.71. Mass spectrum (EI, M.+) m/z 262.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12].C1(C)C=CC=CC=1.CO.[H][H]>[Rh].C(O)(=O)C>[OH:1][CH:2]([CH:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12]
Reactant: [H][H]
Reactant: COc1cccc(C(O)c2ccncc2)c1OC
Agent: [Rh]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CO
Product: COc1cccc(C(O)C2CCNCC2)c1OC
Yield: 96 %

Procedure:
Into a suitable inerted reactor was charged 118 kg (481 mol) of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]pyridine (10) as a toluene wet cake and 23.6 kg of 5% rhodium on carbon catalyst at 25° C. To the slurry was then added 850 kg of methanol and 29 kg of glacial acetic acid. The reactor was then pressurized to about 100 psi with hydrogen for about 4-12 hours1 at 40° C. The catalyst was removed by filtration and the reactor and the catalyst were rinsed with 150 kg of methanol.2 The reactor rinse filtrate and the reaction mixture filtrate were combined. The concentration of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]piperidine (11) is typically about 10 wt %, affording about 116 kg of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]piperidine (11) (96% yield)3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]=1[NH2:15].C(OC([NH:23][C@@H:24]([CH3:28])[C:25](O)=O)=O)(C)(C)C.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[F:1][C:2]1[C:3]2[N:15]=[C:25]([C@@H:24]([NH2:23])[CH3:28])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1c(F)cccc1Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](N)c1nc2c(F)cccc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
A mixture of 3-fluoro-N1-phenylbenzene-1,2-diamine (440 mg, 2.18 mmol), (S)-2-tertbutoxycarbonylaminopropionic acid (454 mg, 2.40 mmol), HOAt (327 mg, 2.40 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (460 mg, 2.40 mmol) and 4-methylmorpholine (0.527 mL, 4.79 mmol) in anhydrous DCM (20 mL) was stirred at RT for 2 h. The reaction mixture was diluted with DCM (100 mL) and washed with a saturated solution of NaHCO3. The organic layer was then dried and concentrated in vacuo. The resulting residue was dissolved in AcOH (10 mL) and heated to 70° C. for 2 h and then to 80° C. for 20 h. After cooling to RT, TFA (20 mL) was added and the mixture was stirred at RT for 1 h and 20 min. Volatiles were then removed in vacuo and the residue was dissolved in DCM (100 mL) and washed with a saturated solution of NaHCO3. The organic layer was then washed with brine, dried (Na2SO4) and then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in TBME) affording (S)-1-(4-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine as a brown oil (396 mg, 71%). LCMS: RT 2.01 min [M−NH2]+ 239.1.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH2:26][OH:27].[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(C(C)C)CC)(C)C>ClCCl>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[CH2:26][O:27][S:29]([CH3:28])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(CO)cc(OC)c21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(COS(C)(=O)=O)cc(OC)c21
Temperature: 0 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
A mixture of 100 mg (0.23 mmol) [4-bromo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-yl]-methanol, 26 μl (0.33 mmol) methanesulfonyl chloride and 60 μl (0.35 mmol) diisopropylethylamine in 4 ml dichloromethane is stirred at 0° C. for 2 h. The reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo to afford 120 mg of the title compound as an oil that is used directly in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]=[CH:7][C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]2[OH:22].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH2:30][OH:31]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]([CH2:29][CH2:30][OH:31])[CH:7]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22]
Reactant: OCCBr
Reactant: CCOC(=O)c1cnc2cc(-n3cccc3)c(F)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCO)c2cc(-n3cccc3)c(F)cc2c1=O
Temperature: 60 °C
Yield: 45.9 %

Procedure:
A mixture of 2 g (0.0076 mol) of ethyl 6-fluoro-7-(pyrrol-1-yl)-4-hydroxyquinoline-3-caboxylate and 1.85 g (2×0.0076 mol) of potassium carbonate in 20 ml of dimethylformamide is heated for 30 minutes at 60° C. and left to cool, 3.35 g (4×0.0076 mol) of ethylene bromohydrin are added, the mixture is heated at 80°-90° C. for 10 hours, active carbon is added, the mixture is filtered hot, the filtrate is evaporated to dryness, water is added and the precipitate formed is filtered off and washed with water. It is recrystallized from dimethylformamide to give 1.2 g of a solid melting at 237°-239° C.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:10]=[N:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:13][CH:14]=2)[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C>ClCCl.CS(C)=O>[CH:1]1([C:7]([C:9]2[CH:14]=[N:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)=[N:11][CH:10]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OC(c1cnc(-c2ccc(C(F)(F)F)cc2)nc1)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C(c1cnc(-c2ccc(C(F)(F)F)cc2)nc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of (+/−)-cyclohexyl{2-[4-(trifluoromethyl)phenyl]pyrimidin-5-yl}methanol (0.440 g, 1.31 mmol) in dichloromethane (4.8 ml), dimethyl sulfoxide (3.7 ml) and triethylamine (0.911 ml, 6.54 mmol) was cooled to 0° C. Sulfur trioxide pyridine complex (0.625 g, 3.92 mmol) was added in portions and the mixture stirred at 0° C. for 1 hour then slowly raised to ambient temperature over 12 hours. The reaction was quenched with water and diluted with diethylether. The aqueous layer was extracted with diethylether and the combined organic layers were washed with brine. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo, affording a crude solid. This material was used without further purification.
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-])(=O)=O)=CC=1.[CH2:14]1[O:24][C:17]2([CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]2)[O:16][CH2:15]1.CC(C)([O-])C.[K+].O>COCCOC.C(O)C>[O:16]1[C:17]2([CH2:22][CH2:21][CH:20]([C:10]#[N:11])[CH2:19][CH2:18]2)[O:24][CH2:14][CH2:15]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: N#CC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
p-Toluenesulfonylmethylisocyanide (27.0 g) was added at room temperature to a solution of 1,4-cyclohexanedione monoethyleneketal (16.6 g) in 1,2-dimethoxyethane (133 ml) and ethanol (13 ml). Then, potassium tert-butoxide was added under ice cooling over an hour, and stirred at room temperature for three hours. After completion of the reaction, water was added and extracted with ethyl acetate three times. The organic layer was dried over anhydrous sodium sulfate and concentrated. The resulting residue was purified with silica gel column chromatography (n-hexane/ethyl acetate) to give 1,4-dioxaspiro[4,5]decane-8-carbonitrile (12.8 g) as a colorless oil.