Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([O:10][CH2:11][CH2:12][CH3:13])=[CH:8][S:7][C:6]=1[NH:14][C:15]([N:17]([CH3:19])[CH3:18])=[O:16])=O.[OH-].[NH4+:21]>C(O)C>[CH3:18][N:17]([CH3:19])[C:15](=[O:16])[NH:14][C:6]1[S:7][CH:8]=[C:9]([O:10][CH2:11][CH2:12][CH3:13])[C:5]=1[C:3]([NH2:21])=[O:2]
Reactant: [NH4+]
Reactant: CCCOc1csc(NC(=O)N(C)C)c1C(=O)OC
Agent: [OH-]
Solvent: CCO
Product: CCCOc1csc(NC(=O)N(C)C)c1C(N)=O
Temperature: 40 °C
Yield: 51 %

Procedure:
A solution of 2-(3,3-Dimethyl-ureido)-4-propoxy-thiophene-3-carboxylic acid methyl ester ( ) in ethanol (6 mL) was treated with concentrated ammonium hydroxide (6 mL) in a sealed tube and heated to 40° C. for 5 hours. The mixture was then cooled, evaporated, acidified with a small amount of acetic acid and purified via radial chromatography on a 2 mm plate using hexanes/ethyl acetate (3/1) plus 2% methanol as eluent to afford a white solid (15 mg, 55.3 micromol, 51%) 1H NMR (CDCL3, 400 MHz) 1.03 (t, 3H, J=7.3 Hz), 1.81-1.88 (m, 2H), 3.04 (s, 6H), 3.97 (t, 2H, J=6.6 Hz), 5.33 (broad s, 1H), 5.55 (s, 1H), 7.50 (broad s, 1H), 12.00 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1)[CH3:2].C(O)(=O)C.[CH2:18]([O:25][C:26]1[CH:33]=[C:32]([I:34])[CH:31]=[CH:30][C:27]=1[CH:28]=O)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C([BH3-])#N.[Na+]>CN(C=O)C>[CH2:18]([O:25][C:26]1[CH:33]=[C:32]([I:34])[CH:31]=[CH:30][C:27]=1[CH2:28][NH:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])=[CH:11][CH:10]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCOc1cc(I)ccc1C=O
Reactant: CCOC(=O)Cc1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCCCCCOc1cc(I)ccc1CNc1ccc(CC(=O)OCC)cc1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
A solution of ethyl(4-aminophenyl)acetate (1.76 g, 9.84 mmol) and acetic acid (0.71 ml) in DMF (71 ml) is added to a solution of 2-heptyloxy-4-iodobenzaldehyde of Step c (3.1 g, 8.94 mmol), acetic acid (0.71 ml) in DMF (71 ml). The mixture is stirred for 12 hours and then 1.12 g of sodium cyanoborohydride (17.89 mmol) is added. The mixture is heated at 60° C. for 4 hours. The desired product is extracted by addition of ethyl ether. The organic phase is washed with brine and then with water, dried with magnesium sulfate and concentrated using a rotary evaporator. The product is purified by chromatography on a silica column, eluted with a heptane/ethyl acetate 9:1 mixture. After evaporation of the solvents, 4.11 g (96%) of the expected compound are recovered in the form of a yellow oil.
Reaction SMILES: Cl.Cl.[CH:3]1([CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[CH:12]2[N:7]([CH2:8]CCC2)[CH2:6][CH2:5][CH2:4]1.CN1CCCC(CO)C1>>[CH3:8][N:7]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:13][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:12]1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CC4CCCN5CCCCC45)CC3)cc12
Agent: CN1CCCC(CO)C1
Agent: Cl
Product: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CC4CCCN(C)C4)CC3)cc12

Procedure:
This compound is synthesized from the compound 161 (see example 127) and (1-Methyl-piperidin-3-yl)-methanol analogously to the method described in Example 127.
Reaction SMILES: [C-]#N.[K+].[C:4](=[O:7])([O-])[O-:5].[Na+].[Na+].[CH3:10][C:11]1[O:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.C(C=O)=O.Cl.C#N>O.O1CCOCC1>[CH3:15][C:14]1[O:17][C:11]([CH2:10][C:4]([OH:5])=[O:7])=[CH:12][CH:13]=1
Reactant: Cc1ccc(C=O)o1
Reactant: O=C([O-])[O-]
Agent: C#N
Agent: Cl
Agent: O=CC=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(CC(=O)O)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of potassium cyanide (12.2 g, 0.187 mol) and sodium carbonate (36 g, 0.338 mol) in water (250 ml) was added 5-methyl furfural (7.5 ml, 75 mmol) in 1,4-dioxane (12 ml) followed by glyoxal busulphite (3.0 g, 0.289 mol) and water (240 ml). After stirring for 21/2 hr at room temperature, the reaction was worked up by adding 5N HCl(aq) to the reaction mixture carefully (HCN↑) until the pH fell to ≈1-2. Stirring was continued for 1 hr after which time, no more gas was evolved.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:27])[C:10]2[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[C:12]([N+:24]([O-])=O)[CH:11]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.C(O)C.O.[Fe]>[NH2:24][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[S:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)=[O:27]
Reactant: O=C(Nc1ccc(Br)cc1)c1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: Nc1cc(C(=O)Nc2ccc(Br)cc2)ccc1Sc1ccc(O)cc1
Temperature: 25 °C
Yield: 75.9 %

Procedure:
A suspension of the product of Example 22A (409.9 mg, 0.9205 mmol) and iron powder (206 mg, 3.682 mmol) in acetic acid (7 mL) and ethanol (7 mL) was heated at reflux under a nitrogen atmosphere for 1 hour. The reaction was cooled to room temperature. The mixture was diluted with water (30 mL), the pH adjusted to 6 with solid sodium carbonate, and the aqueous extracted with ethyl acetate (2×50 mL). The combined organic extracts were washed with brine (25 mL), dried over sodium sulfate, filtered, and concentrated under vacuum to provide the title compound as a tan solid (290 mg, 0.6983 mmol, 76%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=[N+]=[N-])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.[CH:16]1([SH:21])[CH2:20][CH2:19][CH2:18][CH2:17]1.O>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[CH3:1][O:2][C:3](=[O:15])[CH:4]([S:21][CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1
Reactant: SC1CCCC1
Reactant: COC(=O)C(=[N+]=[N-])c1ccc(Cl)c(Cl)c1
Agent: [Rh]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)C(SC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
A solution of diazo-(3,4-dichloro-phenyl)-acetic acid methyl ester (Example 1; 193 mg, 0.79 mmol) in dichloromethane (10 mL) at 25° C. was treated with cyclopentyl mercaptan (0.21 mL, 1.97 mmol) followed by rhodium (II) acetate dimer (9 mg, 0.020 mmol) and the solution was stirred at 25° C. for 1 h. During this time no evolution of gas was detected, and examination of the black solution by thin layer chromatography indicated that only starting material was present. The reaction was heated to reflux and a second portion of rhodium (II) acetate dimer (10 mg, 0.024 mmol) was added and as the mixture was stirred at reflux for 110 min, a vigorous evolution of gas was observed. The reaction mixture was diluted with dichloromethane (10 mL), then was poured into water (15 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered and evaporated under reduced pressure. The residual oil was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 95/5 hexanes/ethyl acetate) to furnish rac-cyclopentylsulfanyl-(3,4-dichloro-phenyl)-acetic acid methyl ester (148 mg, 59% yield) as a colorless oil: EI-HRMS m/e calcd for C14H16Cl2SO2(M+) 318.0248, found 318.0244.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[C:7]([O:14][CH3:15])[CH:6]=1)[CH:2]([CH3:4])[CH3:3].[CH2:16]([O:23][C:24]1[C:33]([CH3:34])=[CH:32][C:27]([C:28]([NH:30][NH2:31])=O)=[CH:26][C:25]=1[CH3:35])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.CN(C)CCCN>C(Cl)Cl.C(OCC)C.N1C=CC=CC=1>[CH2:16]([O:23][C:24]1[C:25]([CH3:35])=[CH:26][C:27]([C:28]2[O:13][C:11]([C:9]3[CH:8]=[C:7]([O:14][CH3:15])[CH:6]=[C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[N:10]=3)=[N:31][N:30]=2)=[CH:32][C:33]=1[CH3:34])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(CC(C)C)nc(C(=O)O)c1
Reactant: Cc1cc(C(=O)NN)cc(C)c1OCc1ccccc1
Agent: CN(C)CCCN
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CC(C)C)nc(-c2nnc(-c3cc(C)c(OCc4ccccc4)c(C)c3)o2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
To a solution of 6-isobutyl-4-methoxy-pyridine-2-carboxylic acid (270 mg, 1.10 mmol), 4-benzyloxy-3,5-dimethyl-benzoic acid hydrazide (327 mg, 1.21 mmol) and DIPEA (455 mg, 3.52 mmol) in DCM (15 mL), PyBOP (858 mg, 1.65 mmol) is added at 0° C. The mixture is stirred for 30 min at rt, the reaction is diluted with diethyl ether and washed with 1 N aq. NaOH solution followed by 1 M aq. NaH2PO4 solution. The org. extract is dried over Na2SO4, filtered and concentrated to give the crude hydrazide intermediate; LC-MS: tR=1.00 min, [M+H]+=462.23. This material (1.13 g) is dissolved in DCM (15 mL) and pyridine (1 mL) and the mixture is cooled to 0° C. before trifluoromethanesulfonic anhydride (1.38 g, 4.89 mmol) is added dropwise. The mixture is warmed to rt and stirring is continued for 16 h. The reaction is quenched by adding 3-dimethylamino-1-propylamine (50 mg, 0.49 mmol). The mixture is washed twice with 1 N aq. NaH2PO4 solution followed by water, dried over Na2SO4, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 2-[5-(4-benzyloxy-3,5-dimethyl-phenyl)-[1,3,4]oxadiazol-2-yl]-6-isobutyl-4-methoxy-pyridine (414 mg) as a yellow oil; LC-MS: tR=1.15 min, [M+H]+=444.21.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:28])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[CH:14][C:13]=1[O:26][CH3:27].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:28])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=[O:20])=[CH:14][C:13]=1[O:26][CH3:27]
Reactant: COc1ccccc1NC(=O)Nc1ccc(CC(=O)OC(C)(C)C)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1OC
Yield: 81.5 %

Procedure:
To a stirred solution of tert-butyl 4-[N′-(2-methoxyphenyl)ureido]-3-methoxylphenyl-acetate (2.01 g, 5.20 mmol) in CH2Cl2 (15 ml) was added trifluoroacetic acid (10 ml), and the resulting mixture was heated under reflux for 30 min. The mixture was concentrated in vacuo. Water was added to the residue to give precipitate, which was collected by filtration. The crude solid was recrystallized from EtOH/hexane to give 4-[N′-(2-methoxyphenyl)ureido]-3-methoxy phenylacetic acid as white powder (1.40 g, 82%). mp 182–185° C.; 1H-NMR (CD3OD) δ 3.55 (s, 2 H), 3.88 (s, 3 H), 3.89 (s, 3 H), 6.80–6.99 (m, 5 H), 7.94 (d, J=8.4 Hz, 1 H), 8.00 (d, J=7.2 Hz, 1 H); MS (ESI) m/z 330 (M+).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=1[C:7]([NH:9][C:10]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])=[O:8])(=[O:3])[CH3:2].[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>>[C:1]([O:4][C:5]1[CH:23]=[CH:22][CH:21]=[CH:20][C:6]=1[C:7]([NH:9][C:10]1[CH:18]=[C:17]([NH:19][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=2[O:25][CH3:24])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])=[O:8])(=[O:3])[CH3:2]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CC(=O)Oc1ccccc1C(=O)Nc1cc(N)ccc1C(=O)O
Product: COc1ccccc1C(=O)Nc1ccc(C(=O)O)c(NC(=O)c2ccccc2OC(C)=O)c1

Procedure:
By the procedure similar to that described in Example 23, 2-(2' -acetoxybenzamido)-4-aminobenzoic acid and 2-methoxybenzoylchloride were allowed to react and were treated to obtain crude crystals. Recrystallization from ethanol gave 2-(2'-acetoxybenzamido)-4-(2'-methoxybenzamido)-benzoic acid having a melting point between 197° - 198°C.
Reaction SMILES: C(NC(C)C)(C)C.[C:8]([O:13]C)(=[O:12])[CH:9]([CH3:11])[CH3:10].Cl[CH2:16][C:17]1[N:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:20][C:21]=1[CH3:22].[NH4+].[Cl-]>CCCCCC.C1COCC1.CN1C(=O)N(C)CCC1>[CH3:10][C:9]([CH3:11])([CH2:16][C:17]1[N:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:20][C:21]=1[CH3:22])[C:8]([OH:13])=[O:12]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: COC(=O)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CC(C)(C)C(=O)O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
n-Buthyllithium (1.6M in hexane, 5.05 ml) was added dropwise to a solution of diisopropylamine (1.16 ml) in THF (30 ml) at 0° C. under argon. The resulting mixture was stirred for another 15 minutes before it was cooled to −78° C. and a solution of methyl isobutyrate (0.84 ml) in THF (3 ml) was added dropwise. After the addition was completed, the reaction mixture was allowed to warm to 0° C. and than again cooled to −78° C. At this temperature a solution of 4-chloromethyl-5-methyl-2-phenyl-oxazole [CAS 103788-61-0, commercially available] (1.17 g) in THF (6 ml) and DMPU (7.7 ml) was added. Stirring was continued for another 30 minutes before a saturated NH4Cl solution (1 ml) was added. Then the THF was removed in vacuo and water was added to the remaining residue. This mixture was extracted with ether and the combined organic extracts were washed with water and brine and dried (MgSO4). After evaporation of the solvent the crude alkylation product (1.46 g) was dissolved in THF (20 ml) and LiOH solution (1M, 14.5 ml) was added. The reaction mixture was stirred overnight, concentrated and washed with ether. Then the pH was adjusted to 1 by addition of 3N HCl and the resulting suspension was extracted with ether. Finally the combined extracts were washed with water and brine, dried (MgSO4) and the solvent was removed in vacuo. The product was obtained as a white solid (1.33 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:11])[CH:9]=[O:10])([CH3:4])([CH3:3])[CH3:2].[I-].[CH3:21][S+](C)C.[OH-].[K+]>C(#N)C.O.CCOC(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C@@:8]([CH3:11])([CH:9]1[CH2:21][O:10]1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(C=O)Cc1ccccc1
Reactant: C[S+](C)C
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@](C)(Cc1ccccc1)C1CO1
Temperature: 60 °C

Procedure:
To a solution of N-(tert-butyl((1R)-1-benzyl-1-methyl-2-oxoethyl)carbamate (Intermediate XLIX, 1 g, 3.80 mmol) in acetonitrile (15 mL) was added 6 drops water, trimethylsulfonium iodide (775 mg, 3.80 mmol) and potassium hydroxide (511 mg, 9.11 mmol). The reaction was stirred at 60° C., sealed, for 1.5 h, additional trimethylsulfonium iodide (775 mg, 3.80 mmol) and potassium hydroxide (511 mg, 9.11 mmol) were added and the reaction was stirred at 60° C., sealed, for 3 h. the reaction mixture was diluted with EtOAc, washed with sat'd aq NaHCO3, brine, dried over sodium sulfate, and concentrated in vacuo to provide tert-butyl((1R)-1-methyl-1-oxiran-2-yl-2-phenylethyl)carbamate as an oil. MS (ES, M+H) 278.
Reaction SMILES: O=O.[C:3]([S:6][C@H:7]1[N:10]([C:11](=C(C)C)[C:12]([O:14][CH3:15])=[O:13])[C:9](=[O:19])[C@@H:8]1[Cl:20])(=[O:5])[CH3:4].P(OC)(OC)OC>C(OCC)(=O)C>[C:3]([S:6][C@H:7]1[N:10]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:9](=[O:19])[C@@H:8]1[Cl:20])(=[O:5])[CH3:4]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H](Cl)[C@H]1SC(C)=O
Agent: COP(OC)OC
Agent: O=O
Solvent: CCOC(C)=O
Product: COC(=O)CN1C(=O)[C@H](Cl)[C@H]1SC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 56.4 %

Procedure:
Ozonised oxygen was bubbled through a solution of methyl 2-[(3S,4R)-4-acetylthio-3-chloro-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (7.6 g, 0.026 mol) in ethyl acetate (300 ml) at -65 to -70° C. until a permanent blue colour was obtained. Excess ozone was removed by the passage of oxygen, then trimethyl phosphite (30.7 ml, 0.26 mol) was added dropwise. After 15 minutes the solution was allowed to warm to room temperature and stirred for 19 hr. The solvents were evaporated and the residue reevaporated twice from toluene, then disolved in ethyl acetate (175 ml) and stirred vigourously with a solution of p-toluenesulphonic acid (1.14 g) in water (60 ml). After dilution with water the organic layer was separated and the aqueous layer further extracted with ethyl acetate. The combined organic extracts were washed successively with saturated aq. sodium hydrogen carbonate and brine, dried (MgSO4) and evaporated. Purification by flash chromatography (silica, pet. ether-ethyl acetate) gave the title compound as a colourless solid 3.69 g (56%, m.p. 82-83° C.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(O)(=O)C>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:19][CH:20]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(c2ccc(C(F)(F)F)cc2)CCN(Cc2ccccc2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Yield: 80.8 %

Procedure:
A mixture of 1-benzyl-4-(4-trifluoromethylphenyl)piperidin-4-ol (692 mg, 2.06 mmol) prepared in Reference Example 95, concentrated hydrochloric acid (4.5 ml) and acetic acid (10 ml) was heated under reflux overnight. The reaction mixture was allowed to return to room temperature, and diluted with methylene chloride. The mixture was washed with water, 10% sodium hydroxide aqueous solution and brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/acetone=4/1) to afford 1-benzyl-4-(4-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine (528 mg, yield 80%) as a pale yellow crystalline powder.
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[C:7]([C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][CH:18]=3)[N:15]([C:19](=[O:21])[CH3:20])[C@@H:14]([CH3:22])[CH2:13][NH:12]4)[CH:6]=[N:5]2)[CH2:3][CH2:2]1.Cl[C:24]1[O:25][C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)(C)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[N:12]1[C:11]2[C:16](=[CH:17][CH:18]=[C:9]([C:7]3[CH:6]=[N:5][N:4]([CH:1]4[CH2:3][CH2:2]4)[CH:8]=3)[CH:10]=2)[N:15]([C:19](=[O:21])[CH3:20])[C@@H:14]([CH3:22])[CH2:13]1
Reactant: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)cc2NC[C@@H]1C
Reactant: Clc1nc2ccccc2o1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: CC(=O)N1c2ccc(-c3cnn(C4CC4)c3)cc2N(c2nc3ccccc3o2)C[C@@H]1C
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 87.8 %

Procedure:
A mixture of (S)-1-(6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.040 g, 0.135 mmol), 2-chlorobenzo[d]oxazole (0.031 mL, 0.270 mmol), tris(dibenzylideneacetone)dipalladium (0.012 g, 0.013 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.016 g, 0.027 mmol), and cesium carbonate (0.088 g, 0.270 mmol) in t-butanol (2.0 mL) was heated in the microwave at 80° C. for 1.5 h. Additional portions of Xantphos (0.016 g, 0.027 mmol), tris(dibenzylideneacetone)dipalladium (0.012 g, 0.013 mmol), and 2-chlorobenzo[d]oxazole (0.031 ml, 0.270 mmol) were added, and the mixture stirred at 100° C. for 2.5 h. The reaction mixture was filtered through Celite and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 50-100% ethyl acetate-hexane) to afford (S)-1-(4-(benzo[d]oxazol-2-yl)-6-(1-cyclopropyl-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.049 g, 88%) as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.89-1.03 (m, 2 H), 1.03-1.11 (m, 5 H), 2.18 (s, 3 H), 3.76 (tt, J=7.44, 3.85 Hz, 1 H), 4.01 (br d, J=10.26 Hz, 1 H), 4.07-4.19 (m, 1 H), 5.08 (br s, 1 H), 7.13-7.37 (m, 3 H), 7.53 (dd, J=18.03, 7.48 Hz, 3 H), 7.85 (s, 1 H), 8.24 (s, 1 H), 8.38 (d, J=2.05 Hz, 1H). MS (ESI, pos. ion) m/z 414 [M+1]+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:9][N:8]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH2:23][CH2:22]2)=[O:20])[CH2:7]1)=O)C.[Li+].[BH4-]>CO>[Cl:18][C:13]1[CH:12]=[C:11]([CH:10]2[CH:6]([CH2:4][OH:3])[CH2:7][N:8]([C:19]([N:21]3[CH2:22][CH2:23][N:24]([S:27]([CH3:30])(=[O:28])=[O:29])[CH2:25][CH2:26]3)=[O:20])[CH2:9]2)[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: CCOC(=O)C1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)CC1c1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: CS(=O)(=O)N1CCN(C(=O)N2CC(CO)C(c3ccc(Cl)c(Cl)c3)C2)CC1
Reaction time: 48 h
Yield: 80.7 %

Procedure:
To a stirred solution of (3SR,4RS)-4-(3,4-dichloro-phenyl)-1-(4-methanesulfonyl-piperazine-1-carbonyl)-pyrrolidine-3-carboxylic acid ethyl ester (2.39 g, 5.00 mmol) in MeOH (80 mL) at RT was added LiBH4 (434 mg, 19.9 mmol). After 2 hours a second portion of LiBH4 (1.30 g, 59.7 mmol) was added and stirring was continued for 2 days. The reaction mixture was poured on H2O, extracted with EtOAc and the combined organic phases were dried over Na2SO4. Flash chromatography (SiO2, EtOAc, then EtOAc/MeOH 9:1) yielded the title product (1.76 g, 81%) as a white solid. ES-MS m/e: 436.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:28])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1]([O:5][C:6]([C:7]1[CH:8]=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][Br:28])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(-c2cccc(C(=O)OC(C)(C)C)c2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1cccc(-c2ccc(CBr)cc2)c1
Temperature: 25 °C
Yield: 85.1 %

Procedure:
To a solution of tert-Butyl-3-(4-tolyl)benzoate (60 g, 0.22 mol) in CCl4 (800 mL) were added NBS (47.8 g, 0.268 mol) and benzoylperoxide (10 g) and the reaction mixture was refluxed overnight. Cooled to RT and filtered. The filtrate was concentrated to give 4-(3-tert-butoxy carbonyl phenyl)benzyl bromide (65 g, 84%).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Na+].[CH:11](=O)[CH:12]([CH3:14])[CH3:13]>[Cl-].[Na+].O>[CH:11](=[C:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:1]1=[O:7])[CH:12]([CH3:14])[CH3:13]
Reactant: O=C1CCCCC1
Reactant: CC(C)C=O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C=C1CCCCC1=O
Reaction time: 1 h
Yield: 40 %

Procedure:
Into a 8 liter reaction vessel are placed 3400 grams cyclohexanone, 250 grams of water and 80 grams of sodium hydroxide. Over a period of one hour while maintaining the reaction mass at 50°-75° C., 1400 grams (19.4 moles) of isobutyraldehyde is added to the reaction mass. The reaction mass is stirred for a period of one hour. At the end of the one hour period, an equal volume of brine is added to the reaction mass. The organic phase is separated from the aqueous phase and the organic phase is washed with two volumes of brine. 500 ml Toluene is added to the organic phase and the water is azeotroped from the reaction mass. The reaction mass is then distilled yielding 1180 grams of product, the distillation taking place on a 2" splash column yielding the following fractions: