Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].[CH2:8]([C:10]1[N:14]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[C:20]([C:25]4([O:31][CH3:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[N:21]3[CH3:24])=[C:17]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:16]=2)[C:13]2[CH:39]=[CH:40][CH:41]=[CH:42][C:12]=2[N:11]=1)[CH3:9].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>C1COCC1>[CH2:8]([C:10]1[N:14]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[C:20]([C:25]4([O:31][CH3:32])[CH2:30][CH2:29][N:28]([C:3](=[O:4])[C:2]([OH:1])([CH3:7])[CH3:6])[CH2:27][CH2:26]4)[N:21]3[CH3:24])=[C:17]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[N:16]=2)[C:13]2[CH:39]=[CH:40][CH:41]=[CH:42][C:12]=2[N:11]=1)[CH3:9]
Reactant: CC(C)(O)C(=O)O
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCNCC3)n(C)c2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCN(C(=O)C(C)(C)O)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.6 %

Procedure:
To a solution of 2-hydroxyisobutyric acid (49 mg, 0.47 mmol) in THF (3 mL) was added 2-(2-ethylbenzoimidazol-1-yl)-8-(4-methoxypiperidin-4-yl)-9-methyl-6-morpholin-4-yl-9H-purine (150 mg, 0.32 mmol), HOBt (47 mg, 0.35 mmol), NMM (77 μL, 0.69 mmol) and EDCI (91 mg, 0.47 mmol). The resulting mixture was allowed to stir at r.t. for 4 h then quenched with sat. aq. NH4Cl and extracted with DCM. The organic phase was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) then triturated with MeOH/H2O. The resulting solid was collected by filtration and dried in vacuo affording 800 (111 mg, 63%). LCMS (method G): RT 7.36 min, [M+H]+ 563.4. 1H NMR (DMSO, 400 MHz): δ 8.05-8.04 (1 H, m), 7.66-7.62 (1 H, m), 7.25-7.24 (2 H, m), 5.44 (1 H, s), 4.26 (6 H, brd s), 3.92 (3 H, s), 3.78 (4 H, t, J=4.52 Hz), 3.30-3.23 (4 H, m), 3.09 (3 H, s), 2.26-2.16 (2 H, m), 2.19-2.02 (2 H, m), 1.35-1.33 (9 H, m)
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][N:14]([C:16]([O:18]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:13][CH:12]([C:28]([O:30][CH3:31])=[O:29])[CH2:11]2)=[CH:6][CH:5]=1.[NH:34]1[CH2:39][CH2:38][S:37][CH2:36][CH2:35]1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[N:34]1([C:16]([N:14]2[CH2:15][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:3][C:2]([F:32])([F:33])[F:1])=[CH:5][CH:6]=3)[CH2:11][CH:12]([C:28]([O:30][CH3:31])=[O:29])[CH2:13]2)=[O:18])[CH2:39][CH2:38][S:37][CH2:36][CH2:35]1
Reactant: COC(=O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Reactant: C1CSCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Temperature: 150 °C

Procedure:
A solution of 10.3 g (17.9 mmol, purity 81%) of the compound from Example 54A in 1-methyl-2-pyrrolidone (65 ml) was admixed with 12.6 ml (13.7 g, 132 mmol) of thiomorpholine and 11.5 ml (8.56 g, 66.2 mmol) of N,N-diisopropylethylamine and then heated in 5 portions in a single-mode microwave (Emrys Optimizer) at 150° C. for 1 h. For workup, the reaction solutions were combined and purified directly by means of preparative HPLC. Yield: 5.63 g (71% of theory)
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH2:9][CH:10]=[CH2:11])[CH2:3][C@@H:4]([OH:7])[CH2:5][CH3:6].N1C=CC=CC=1.[C:18]1([CH3:28])[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:28][C:18]1[CH:23]=[CH:22][C:21]([S:24]([O:7][C@H:4]([CH2:3][CH:2]([CH3:1])[CH2:8][CH2:9][CH:10]=[CH2:11])[CH2:5][CH3:6])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: C=CCCC(C)C[C@@H](O)CC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCCC(C)C[C@H](CC)OS(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 79.5 %

Procedure:
To a solution of (S)-5-methylnon-8-en-3-ol (9.5 g, 60.8 mmole) in DCM (100 mL) was added pyridine (20 mL) followed by DMAP (0.74 g, 6.08 mmole) and the solution was stirred for 10 min. p-Toluenesulfonyl chloride (17.39 g, 91 mmole) was added to the reaction mass at 0° C. The reaction mass was allowed to come to room temperature and stirred for overnight. Solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (100 mL). The organic solution was washed with aqueous 1.5 N HCl solution, saturated bicarbonate solution, brine solution, dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound (15 g, 79%). The crude compound was taken to the next step without further purification. MS: MS m/z 328.4 (M++18).
Reaction SMILES: [C:1]([C:4]1[C:5]([N:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH:7][C:8]=1[CH3:9])(=[O:3])[CH3:2].[CH2:24](I)[CH2:25][CH3:26]>>[C:1]([C:4]1[C:5]([N:16]=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([CH2:24][CH2:25][CH3:26])[C:8]=1[CH3:9])(=[O:3])[CH3:2]
Reactant: CCCI
Reactant: CC(=O)c1c(C)[nH]c(-c2ccccc2)c1N=Cc1ccccc1
Product: CCCn1c(C)c(C(C)=O)c(N=Cc2ccccc2)c1-c1ccccc1

Procedure:
Starting from the compound of Example 46 and propyl iodide, and using procedure (a) of Example 49, 4-acetyl-3-benzylideneamino-5-methyl-2-phenyl-1-propylpyrrole is obtained as an oily substance. This compound is hydrolyzed as in procedure (b) of Example 49. Yield of the title compound: 50%, m.p. 113°-115° C. (from ethanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([S:16][CH3:17])[C:4]=1[C:5]([OH:7])=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:51][CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][C:53]1=[O:58]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([S:16][CH3:17])[C:4]=1[C:5]([NH:51][CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][C:53]1=[O:58])=[O:7]
Reactant: NC1CCCCC1=O
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-benzoic acid (intermediate A, 400 mg, 1.5 mmol) was dissolved in 10 mL dimethylformamide. N,N-Diisopropyl ethyl amine (505 mg, 3.9 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (571 mg, 1.5 mmol) were added. After 5 minutes of stirring at room temperature 2-amino-cyclohexanone (CAS 6946-05-0) (247 mg, 1.6 mmol) was added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated off. The residue was taken up in 2N sodium carbonate solution and ethyl acetate and was extracted three times with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (heptane/ethyl acetate 1:0→0:1) yielded 2-methoxy-6-methylsulfanyl-N-(2-oxo-cyclohexyl)-4-trifluoromethyl-benzamide as a white foam (370 mg, 68%), MS: m/e=362.2 [(M+H)+].
Reaction SMILES: [OH:1][CH:2]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)=[CH2:10])[C:3]([O:5]C(C)C)=[O:4].[K].O>C(O)(C)C>[CH3:10][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:15][CH:16]=1)[C:2](=[O:1])[C:3]([OH:5])=[O:4]
Reactant: C=C(c1ccc(C2CCCCC2)cc1)C(O)C(=O)OC(C)C
Agent: [K]
Solvent: O
Solvent: CC(C)O
Product: CC(C(=O)C(=O)O)c1ccc(C2CCCCC2)cc1
Yield: 83 %

Procedure:
3.0 Grams of isopropyl 2-hydroxy-3-(4-cyclohexylphenyl)-3-butenoate was dissolved in 50 ml of anhydrous isopropyl alcohol. Separately, 1.1 g of metalic potassium was dissolved in 100 ml of anhydrous isopropyl alcohol. The two solutions thus prepared were combined together, and the combined solution was refluxed for 20 minutes. To the solution was then added 2 ml of water, and the mixture was further refluxed for 5 minutes. Thereafter, the isopropyl alcohol was removed from the mixture by distillation under reduced pressure. The residue was charged with water, and insoluble matter was removed therefrom by extraction with ethyl acetate. The extraction mother liquor was acidified with hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate layer was successively washed with water and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The ethyl acetate was removed by distillation under reduced pressure to obtain crude crystals. The crude crystals were recrystallized from benzene-hexane to obtain 2.15 g of 3-methyl-3-(4-cyclohexylphenyl)-pyruvic acid, m.p. 100.6°-102.5° C. The yield was 83%.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[C:13]3=[C:14]([Cl:22])[CH:15]=[N:16][C:17]4[CH:18]=[CH:19][C:20](=[O:21])[N:11]([C:12]=43)[CH2:10]2)[CH2:4][C@H:3]1[OH:23].[O:24]=[C:25]1[CH2:30][S:29][C:28]2[CH:31]=[CH:32][C:33]([C:35](O)=[O:36])=[N:34][C:27]=2[NH:26]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:22][C:14]1[CH:15]=[N:16][C:17]2[CH:18]=[CH:19][C:20](=[O:21])[N:11]3[CH2:10][CH:9]([CH2:8][N:5]4[CH2:6][CH2:7][C@H:2]([NH:1][C:35]([C:33]5[CH:32]=[CH:31][C:28]6[S:29][CH2:30][C:25](=[O:24])[NH:26][C:27]=6[N:34]=5)=[O:36])[C@H:3]([OH:23])[CH2:4]4)[C:13]=1[C:12]=23
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Reactant: N[C@H]1CCN(CC2Cn3c(=O)ccc4ncc(Cl)c2c43)C[C@H]1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CSc2ccc(C(=O)N[C@H]3CCN(CC4Cn5c(=O)ccc6ncc(Cl)c4c65)C[C@H]3O)nc2N1
Yield: 59 %

Procedure:
The free base of the title compound was synthesised from racemic 4-{[(3R,4S)-4-amino-3-hydroxy-1-piperidinyl]methyl}-3-chloro-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one (79 mg), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (for a synthesis see WO2003087098, Example 301(b)) (50 mg), triethylamine (0.066 ml) and HATU (95 mg) in DMF (2 ml) according to the general method of Example 9 in 59% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=O)[CH:18]([CH3:20])[CH3:19])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:23][OH:24].[OH-].[Na+].Cl>CCO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17](=[N:23][OH:24])[CH:18]([CH3:20])[CH3:19])=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(C)C(=O)c1c(-c2ccc(F)cc2)nn2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C(=NO)c1c(-c2ccc(F)cc2)nn2ccccc12
Temperature: 0 °C
Yield: 68.1 %

Procedure:
To a solution of 2.3 g (8.15 mmol) of 1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one in 32 ml of anhydrous EtOH was added 2.26 g of hydroxylamine hydrochloride, followed by a solution of 1.63 g (8.15 mmol) NaOH in 5 ml water dropwise. The mixture was stirred and refluxed over night. After cooling, the solution was poured into a solution of 4.8 ml 6N HCl in 100 ml ice water with stirring for 30 minutes. The mixture was extracted with ethyl acetate three times. The combined organic phases were washed with brine and dried over MgSO4. After solvent evaporation under vacuum, 4.6 g of crude product was obtained. Purification on an aluminum oxide column with hexane-dichloromethane-ethyl acetate as eluant afforded 1.65 g (67%) of 1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime. Compound 1019.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:9]=[CH:8][CH:7]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[OH:4][CH2:5][C:6]1[N:11]=[C:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)OCc1cccc(C(=O)OC(C)(C)C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)c1cccc(CO)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 3.0 g of t-butyl 6-acetoxymethylpyridine-2-carboxylate were added 330 mg of potassium carbonate, 20 mL of methanol and 20 mL of water, and the mixture was stirred at room temperature for 3 hours. The methanol was removed under reduced pressure, then the residue was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed. The residue was purified by chromatography on silica gel (chloroform-ethanol 50:1) to give t-butyl 6-hydroxymethylpyridine-2-carboxylate as a yellow powder.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:29]=[CH:28][C:17]2[C@:18]3([CH3:27])[C@@H:23]([CH2:24][CH2:25][C:16]=2[CH:15]=1)[NH:22][C:21](=[O:26])[CH2:20][CH2:19]3)([O-:3])=[O:2].[C:30](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:30][N:22]1[C@H:23]2[C@@:18]([CH3:27])([C:17]3[CH:28]=[CH:29][C:14]([C:5]4[CH:6]=[CH:7][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:9][C:4]=4[N+:1]([O-:3])=[O:2])=[CH:15][C:16]=3[CH2:25][CH2:24]2)[CH2:19][CH2:20][C:21]1=[O:26]
Reactant: CC(C)(C)O
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccc(C(F)(F)F)cc3[N+](=O)[O-])ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(C(F)(F)F)cc4[N+](=O)[O-])cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(2-nitro-4-trifluoromethylphenyl )-10b-methyl -1,2,3,4, 4a, 5,6,10b-octahydrobenzo[f]quinolin-3-one (48 mg, 0.12 mmol), 0.3 mL of t-butanol, and potassium t-butoxide (40 mg, 0.36 mmol). Methyl iodide (0.022 mL, 0.36 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 38 mg (76%) of the title compound as an off- white solid. mp 55°-57°. FDMS: m/e =418. α[D]589 =+60.50 (c=0.16, methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[F:17])=[C:4](I)[CH:3]=1.C([Mg]Cl)(C)C.[B:24](OC)([O:27]C)[O:25]C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[F:17])=[C:4]([B:24]([OH:27])[OH:25])[CH:3]=1
Reactant: COB(OC)OC
Reactant: Fc1cc(Cl)ccc1COc1ccc(Cl)cc1I
Agent: CC(C)[Mg]Cl
Product: OB(O)c1cc(Cl)ccc1OCc1ccc(Cl)cc1F

Procedure:
As for reaction 1, using 90.5 g 4-chloro-1-{[(4-chloro-2-fluorophenyl)methyl]oxy}-2-iodobenzene, 228 ml isopropylmagnesium chloride and 47.42 g trimethyl borate. Yield 66.8 g. NMR showed trace impurities. LCMS OK.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][N:11]([S:13]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]1[C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1)(=O)=O.[NH:34]1[CH2:39][CH2:38][NH:37][CH2:36][C:35]1=[O:40].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=O>[S:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[S:13]([N:11]1[CH2:10][CH2:9][N:8]([C:21]2[CH:22]=[CH:23][C:24]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[CH:25][CH:26]=2)[C@@H:7]([CH2:6][N:37]2[CH2:38][CH2:39][NH:34][C:35](=[O:40])[CH2:36]2)[CH2:12]1)(=[O:14])=[O:15]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2COS(C)(=O)=O)cc1)C(F)(F)F
Reactant: O=C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)C[C@@H]2CN2CCNC(=O)C2)cc1)C(F)(F)F
Temperature: 130 °C
Yield: 44.7 %

Procedure:
((2R)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl methanesulfonate (100 mg, 0.189 mmol, Intermediate B) was combined with piperazin-2-one (18.9 mg, 0.189 mmol, Alfa-Aesar) and potassium carbonate (78 mg, 0.57 mmol, Sigma-Aldrich, St. Louis, Mo.) in acetonitrile (1.89 mL) and heated at 130° C. for 30 min. After the reaction was allowed to cool to room temperature, the mixture was diluted with EtOAc and the solids were removed by filtering through a 0.2 μm millipore Millex-FG filter (Millipore, Billerica, Mass.). After concentration of the filtrate, the crude residue was purified by silica gel chromatography (0 to 7% MeOH in CH2Cl2) followed by purification via reverse-phase HPLC (Phenomenex Gemini-NX 10μ, 110 Å, AXIA packed column, 100×50 mm, 60 mL/min, 10-95% CH3CN/H2O, 0.1% TFA, 10 min gradient). The collected fractions were partitioned between CH2Cl2 and saturated aqueous NaHCO3 and then the organic extracts were dried (Na2SO4), filtered and concentrated. The residue was taken up in MeOH and was passed through an AccuBond SPE SCX cartridge eluting with 2M ammonia in MeOH to give the title compound (45 mg) as a mixture of two isomers.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]O)=[CH:4][CH:3]=1.P(Br)(Br)[Br:12]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][Br:12])=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCCc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: Fc1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 64.8 %

Procedure:
To a solution of 2-(4-fluorophenyl)ethyl alcohol (13.4 mL, 107 mmol) in dry toluene (150 mL) at 0° C. was added phosphorous tribromide (21.1 mL, 224 mmol). The resulting mixture was stirred at ambient temperature for 5 days and then recooled to 0° C. and crushed ice (200 g) added. The aqueous layer was extracted with ether (2×120 mL) and the combined organic extracts were then washed with saturated aqueous sodium bicarbonate solution (2×30 mL), dried (MgSO4) and concentrated in vacuo. Distillation afforded 2-(4-fluorophenyl)ethyl bromide as a colorless oil (14.08 g, 31%); b.p. 103° C. @ 12 mm Hg.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:6][N:7]([C:25]([O:27][CH3:28])=[O:26])[C@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=2)[NH:11][C@@H:10]([CH:22]2[CH2:24][CH2:23]2)[CH2:9]1.[C:38](Cl)([Cl:40])=[O:39]>C1(C)C=CC=CC=1>[F:33][C:32]([F:34])([F:35])[C:30]1[CH:29]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:36])[F:37])[CH:31]=1)[CH2:6][N:7]([C:25]([O:27][CH3:28])=[O:26])[C@H:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=2)[N:11]([C:38]([Cl:40])=[O:39])[C@@H:10]([CH:22]2[CH2:24][CH2:23]2)[CH2:9]1
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)Nc2ccc(C(F)(F)F)cc21
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1C[C@H](C2CC2)N(C(=O)Cl)c2ccc(C(F)(F)F)cc21

Procedure:
A solution of cis-4-[(3,5-bis-trifluoromethyl-benzyl)-methoxycarbonyl-amino]-2-cyclopropyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline (Example 102A) (180 mg, 0.33 mmol) in 2 mL of a 1.93M solution of phosgene in toluene was heated to reflux for 1 h. Excess phosgene was removed by purging with nitrogen, and the resulting solution was concentrated to afford the crude title product (208 mg) which was used without further purification. MS m/z 621 (M+19+); 1H NMR (CDCl3) δ 0.2 (m, 1H), 0.45 (m, 2H), 0.55 (1H), 0.75 (m, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[N:4]=1.[C:11]1([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[Na+]>C1COCC1.O>[C:11]1([C:17]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:18][C@H:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[N:4]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: COc1cccc(CBr)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1cccc(OC)n1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.8 %

Procedure:
To a 100-mL round-bottomed flask was added 2-(bromomethyl)-6-methoxypyridine (1.33 g, 6.58 mmol), 2-(bromomethyl)-6-methoxypyridine (1.33 g, 6.58 mmol), ethyl N-(diphenylmethylene)glycinate (1.76 g, 6.58 mmol, Acros, N.J.) and 5N sodium hydroxide (6.58 mL, 32.9 mmol) in THF (30 mL). The reaction mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×50 mL). The organic extract was washed with saturated NaCl (30 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 10% EtOAc/hexanes to give ethyl N-(diphenylmethylidene)-3-(6-methoxy-2-pyridinyl)alaninate (1.86 g) as a colorless oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]([NH2:22])=[N:20][CH:21]=2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+].Br[CH:29]([CH3:40])[C:30]([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=1[F:39])=O>C(O)C>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:29]([CH3:40])=[C:30]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=4[F:39])[N:22]=3)[CH:21]=2)[CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(Br)C(=O)c1ccc(F)cc1F
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(-c2ccc(N)nc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1c(-c2ccc(F)cc2F)nc2ccc(-c3cccc(CO[Si](C)(C)C(C)(C)C)c3)cn12
Temperature: 80 °C
Yield: 49.6 %

Procedure:
300 mg of 5-[3-(tert-butyldimethylsilanyloxymethyl)phenyl]pyridin-2-ylamine dissolved in 5 ml of ethanol are placed in a screw reactor. 200 mg of sodium hydrogen carbonate and 470 mg of 2-bromo-1-(2,4-difluorophenyl)propan-1-one are added thereto. The reactor is closed and heated at 80° C. for 20 h. After cooling, the reaction mixture is concentrated under reduced pressure. The residue obtained is purified by silica gel chromatography, elution being carried out with a heptane/ethyl acetate mixture. 220 mg of compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[Cl:25][C:26]1[CH:35]=[CH:34][C:29](/[CH:30]=[CH:31]/[CH:32]=O)=[CH:28][CH:27]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:25][C:26]1[CH:35]=[CH:34][C:29](/[CH:30]=[CH:31]/[C@H:32]2[O:21][CH2:20][C@H:19]([S:18][C@H:16]([CH3:17])[C@:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])([OH:24])[CH2:10][N:11]3[CH:15]=[N:14][CH:13]=[N:12]3)[CH2:22][O:23]2)=[CH:28][CH:27]=1
Reactant: O=C/C=C/c1ccc(Cl)cc1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/c2ccc(Cl)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
In 14 ml of methylene chloride were dissolved 294 mg (0.82 mmol) of (2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol as described in Reference example 2 and 191 mg (1.15 mmol) of trans-4-chlorocinnamaldehyde [Bull. Chem. Soc. Japan 52 555 (1979)], and 233 mg (1.23 mmol) of p-toluenesulfonic acid monohydrate and 1.5 g of molecular sieves 4A were added thereto, followed by stirring of the resulting mixture for 1 hour and 15 minutes. An aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the mixture was stirred for 10 minutes, followed by removal of the molecular sieves by filtration. The organic layers were collected and dried to distil off the solvent under reduced pressure. The thus obtained oil was subjected to column chromatography using 15 g of silica gel and eluted with a mixed solvent hexane-ethyl acetate (3:2) to obtain 280 mg (yield: 67%) of the desired title compound, trans isomer (A) as an oil. Further, the oil was eluted with a mixed solvent of hexane-ethyl acetate (1:1) to obtain 35 mg (yield: 8%) of the cis isomer (B) as an oil.