Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[NH:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CC(C)=O>[Cl:7][C:8]1[N:12]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[N:9]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Cn1c(Cl)nc2ccccc21
Yield: 88.5 %

Procedure:
In a round bottomed flask are added K2CO3 (9.34 g, 67.7 mmol), 2-chlorobenzimidazole (5.16 g, 33.8 mmol) and tert-butyl bromoacetate (6.6 g, 5 ml, 33.8 mmol) in acetone (100 ml). The resulting suspension is refluxed for 1 h. The crude mixture is filtered through a filter paper and water (100 ml) is added. The resulting aqueous phase is extracted three times with Et2O. The combined organic phases are washed with brine and dried over MgSO4. The solvent is evaporated under reduced pressure yielding the title compound (7.98 g) in 88% as a white powder: tR=2.20 min (LC-2), ESI-MS (pos.): m/z 267.2 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 1.48 (s, 9H, tBu), 4.92 (s, 2H, CH2CO2), 7.24-7.40 (m, 3Harom), 7.76-7.80 (m, 1Harom). Intermediate 2-IIa and 2-IIb tert-Butyl (2-chloro-5-nitro-benzoimidazol-1-yl)-acetate and its 6-nitro regioisomer are prepared according to the same procedure (yield 93%): tR=6.68 min (LC-1), ESI-MS (pos.): m/z 312.08 [M+H]+, 310.28 [M−H]+; 1H-NMR (CDCl3): δ (ppm) 1.50 (s, 9H, tBu), 1.52 (s, 9H, tBu), 5.04 and 5.06 (s, 2H, CH2CO2), 7.38 (d, 1Harom), 7.86 (d, 1 Harom), 8.32-8.40 (m, 3Harom), 8.96 (m, 1Harom).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:32][CH:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[C:14](=O)[CH2:15][CH2:16][C:17]([C:19]3[S:20][C:21]([CH:24]4[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25]4)=[CH:22][N:23]=3)=O)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+:43]>C(O)(=O)C.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:14]3[NH:43][C:17]([C:19]4[S:20][C:21]([CH:24]5[CH2:28][O:27][C:26]([CH3:29])([CH3:30])[O:25]5)=[CH:22][N:23]=4)=[CH:16][CH:15]=3)[CH2:32][CH:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: CC1(C)OCC(c2cnc(C(=O)CCC(=O)C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)s2)O1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC1(C)OCC(c2cnc(-c3ccc(C(CC4CCOCC4)c4ccc(S(=O)(=O)C5CC5)cc4)[nH]3)s2)O1
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 66.6 %

Procedure:
To a solution of 5-[4-(cyclopropylsulfonyl)phenyl]-1-[5-(2,2-dimethyl-1,3-dioxolan-4-yl)-1,3-thiazol-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (730 mg) in acetic acid (15 mL) was added ammonium acetate (1.60 g), and the mixture was stirred at 110° C. for 45 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (470 mg, yield 67%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). MS: 543 (MH+).
Reaction SMILES: O[C@@H:2]([CH3:23])[C@@H:3]([NH:7][C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:9])[C:4]([OH:6])=[O:5].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:17]1([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:8](=[O:9])[NH:7][C@H:3]2[C:4](=[O:6])[O:5][C@H:2]2[CH3:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@H](O)[C@@H](NC(=O)OCCCCCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1OC(=O)[C@@H]1NC(=O)OCCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 50.4 %

Procedure:
Under nitrogen atmosphere at 0° C., to a stirred mixture of (2R,3S)-3-hydroxy-2-(6-phenylhexoxycarbonylamino)-butanoic acid (0.25 g, 0.78 mmol) in dry CH2Cl2 (25 mL), Et3N (0.33 mL, 2.35 mmol) and subsequently TBTU (0.30 g, 1.2 mmol) were added. The mixture was left stirring 1 h at 0° C. and 15 h rt. Upon full conversion of the starting material, the organics were removed under reduced pressure, and the resulting crude product absorbed over silica gel and purified by typical column chromatography, eluting with Cy/AcOEt (from 100:0 to 0:100) to afford the title compound (0.12 g, 50%) as white solid. MS (ESI) m/z: 306 [M−H]+; (ESI) m/z: 304 [M−H]−. 1H NMR (DMSO-d6): δ 1.26-1.39 (m, 4H), 1.34 (d, J=6.4 Hz, 3H), 1.48-1.65 (m, 4H), 2.54-2.61 (m, 2H), 3.91-4.06 (m. 2H), 4.84 (dq, J=6.3 Hz, 1H), 5.41 (dd, J=6.1, 9.4 Hz, 1H), 7.11-7.31 (m, 5H), 8.19 (d, J=9.4 Hz, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(Oc2ccccc2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(Oc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.2 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-phenoxybenzamido)-4-phenylbenzoate (0.049 g) in methanol (1.5 mL) and ethyl acetate (1.5 mL), 10% palladium-carbon (0.025 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture, 10% palladium-carbon (0.050 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. Ethyl acetate was added to the reaction mixture, and the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure, and hexane was added to the obtained residue. The solid substance was collected by filtration to obtain 0.017 g of tert-butyl 2-(2-hydroxy-5-phenoxybenzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH:17]2[CH2:21][N:20]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=3)[C:19](=[O:33])[N:18]2[CH3:34])=[CH:10][C:9]=1[CH:35]=[CH2:36])([CH3:6])[CH3:5]>C(O)C>[CH3:1][O:2][C:3](=[O:37])[C:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH:17]2[CH2:21][N:20]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]([CH3:30])([CH3:31])[CH3:32])=[CH:27][CH:28]=3)[C:19](=[O:33])[N:18]2[CH3:34])=[CH:10][C:9]=1[CH2:35][CH3:36])([CH3:5])[CH3:6]
Reactant: C=Cc1cc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)ccc1OC(C)(C)C(=O)OC
Solvent: CCO
Product: CCc1cc(CCCC2CN(Cc3ccc(C(C)(C)C)cc3)C(=O)N2C)ccc1OC(C)(C)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-vinyl-phenoxy)-2-methyl-propionic acid methyl ester (0.110 g, 0.217 mmole) was dissolved in absolute ethanol (4 mL). After purged the solution with N2 for 15 min, 10% Pd/C (0.040 g). The reaction was stirred under a hydrogen balloon at room temperature for 2 hours. The catalyst was removed through filtration, and solvent was removed on rota-vapor to provide a colorless oil (0.110 g, 100%). Mass [EI+] 509 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([CH3:37])=[CH:34][C:35]=2[CH3:36])[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:36][C:35]1[CH:34]=[C:33]([CH3:37])[N:32]=[CH:31][C:30]=1[C:26]1[CH:25]=[C:24]([C:22]2[CH2:21][C:20](=[O:38])[NH:19][C:9]3[CH:10]=[C:11]([C:15]([F:16])([F:17])[F:18])[C:12]([CH3:14])=[CH:13][C:8]=3[N:7]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cc(C)c(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (2-{3-[3-(4,6-dimethyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M225) (312 mg, 0.576 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (182 mg, 75%).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:20]([O:22]CC)=[O:21])[CH:12]([C:16]([F:19])([F:18])[F:17])[O:13]2)=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].Cl>C1COCC1.C(O)C.O>[CH2:1]([NH:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:20]([OH:22])=[O:21])[CH:12]([C:16]([F:19])([F:17])[F:18])[O:13]2)=[CH:8][CH:7]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)C1=Cc2ccc(NCC(C)C)cc2OC1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CNc1ccc2c(c1)OC(C(F)(F)F)C(C(=O)O)=C2
Temperature: 55 °C
Reaction time: 18 h
Yield: 20.6 %

Procedure:
The ethyl 7-(isobutylamino)-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.53 g, 1.54 mmole) was dissolved in a mixture of THF (5.0 mL) and ethanol (5.0 mL). 2.5N sodium hydroxide (1.54 mL) was added and the reaction was heated to 55° C. (oil bath) for 3 hours. The reaction was cooled to room temperature and stirred for 18 hours. The solution was condensed in vacuo to give a yellow oil. The oil was redissolved in water (20 mL), acidified with 2.4 N HCl to pH around 1 and extracted with EtOAc (2×20 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil which was subject to prep HPLC (reverse phase) and eluted with 50-95% ACN/ water with 0.05% TFA to give a yellow solid (0.1 g, 21%). ESHRMS m/z 314.1023 (M−H, C15H15O3F3N, Calc'd 314.0999). 1H NMR (CDCl3/400 MHz) 7.78 (s, 1H), 7.01 (s, 1H), 6.24 (s, 2H), 5.60 (q, 1H, J=7.0 Hz), 2.97 (m, 2H), 1.91 (m, 1H), 0.98 (m, 6H).
Reaction SMILES: C(OC(=O)N)(C)(C)C.B(O)O.[C:12]([O:16][C:17](=[O:27])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)([CH3:15])([CH3:14])[CH3:13].C(OC([NH:35][CH2:36][C:37]1[CH:38]=[CH:39][C:40](F)=C(B(O)O)C=1)=O)(C)(C)C.ClC1C=CN=CC=1.BrC1C=CN=CC=1>>[C:12]([O:16][C:17](=[O:27])[NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[C:24]([C:38]2[CH:37]=[CH:36][N:35]=[CH:40][CH:39]=2)[CH:25]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(F)c(B(O)O)c1
Agent: Brc1ccncc1
Agent: CC(C)(C)OC(N)=O
Agent: Clc1ccncc1
Product: CC(C)(C)OC(=O)NCc1ccc(F)c(-c2ccncc2)c1

Procedure:
The present invention is directed to an improved method for preparing 4-fluoro-3-piperidin-4-yl-benzyl)-carbamic acid tert-butyl ester (I); more particularly, to its synthesis in three steps. The first step comprises a boronic acid formation by treatment of (4-fluoro-benzyl)-carbamic acid tert-butyl ester under boronation conditions. The second step involves reacting the resultant 5-((tert-butoxycarbonyl)aminomethyl)-2-fluorobenzeneboronic acid of the first step with a 4-halo-pyridine such as 4-chloro-pyridine or 4-bromo-pyridine under Suzuki coupling conditions to yield (4-fluoro-3-pyridin-4-yl-benzyl)-carbamic acid tert-butyl ester. The third step involves employing selective hydrogenation conditions on the product of the second step to yield compound I. The invention is also directed to the intermediates 5-((tert-butoxycarbonyl)aminomethyl)-2-fluorobenzeneboronic acid (compound 11), and (4 fluoro-3-pyridin-4-yl-benzyl)-carbamic acid tert-butyl ester (compound 13).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)=[N+]=[N-]>C(OCC)(=O)C.CO.[C].[Pd]>[NH2:1][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2
Reactant: [N-]=[N+]=NCCCOc1ccc2[nH]c(=O)ccc2c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: NCCCOc1ccc2[nH]c(=O)ccc2c1
Yield: 94 %

Procedure:
To a solution of 6-(3-azidopropoxy)carbostyril (17.5 g) in a mixture of ethyl acetate-methanol (1:1, 700 ml) is added 10% palladium-carbon (1.75 g), and the mixture is subjected to hydrogenation at room temperature under atmospheric pressure. After the reaction is complete, the catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to remove the solvent. The resulting residue is washed with diethyl ether to give 6-(3-aminopropoxy)carbostyril (14.7 g) as a white powder.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]#[N:33])[CH2:28][CH2:27]1.CC(C)([O-])C.[Na+]>CC(O)=O.CC(P(C(C)(C)C)C1C(C2[C-]=CC=CC=2)=CC=CC=1)(C)C.[Pd]>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([N:26]4[CH2:31][CH2:30][CH:29]([C:32]#[N:33])[CH2:28][CH2:27]4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]2)[N:15]=1
Reactant: N#CC1CCNCC1
Reactant: CN1CCN(c2cc(N3CCc4ccc(Br)cc4C3)nc(N)n2)CC1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1[c-]cccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CC(=O)O
Product: CN1CCN(c2cc(N3CCc4ccc(N5CCC(C#N)CC5)cc4C3)nc(N)n2)CC1
Temperature: 120 °C

Procedure:
A mixture of 4-(7-bromo-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (40 mg, 0.1 mmol), piperidine-4-carbonitrile (22 mg, 0.20 mmol, Oakwood, Cat. No. 024547), sodium tert-butoxide (23 mg, 0.24 mmol), 2-(2′-di-tert-butylphosphine)biphenyl palladium(II) acetate (2.8 mg, 0.0060 mmol, Aldrich, Cat. No. 655414) in 1,4-dioxane (1 mL) was degassed with nitrogen and then heated at 120° C. overnight. The reaction mixture was cooled to r.t. and concentrated under reduced pressure. The residue was dissolved in MeOH and purified by RP-HPLC (pH=10) to afford the desired compound. LCMS (M+H)+: m/z=433.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[CH2:13][OH:14])=[CH:4][CH:3]=1.CN(C)C=O.C1C(=O)N([Br:27])C(=O)C1>CC(=O)OCC>[Br:27][C:11]1[S:10][C:9]([CH2:13][OH:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1sccc1-c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCc1sc(Br)cc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed [3-(4-chlorophenyl)thiophen-2-yl]methanol (3.6 g, 16.02 mmol, 1.00 equiv), N,N-dimethylformamide (20 mL). This was followed by the addition of NBS (2.85 g, 16.01 mmol, 1.00 equiv) portions at −5° C. The resulting solution was stirred for 2 h at room temperature (20 degree C.). The resulting solution was diluted with 100 mL of EA. The resulting mixture was washed with 3×30 mL of brine. The mixture was dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 4.8 g (99%) of [5-bromo-3-(4-chlorophenyl)thiophen-2-yl]methanol as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:6]2[C:11]([C:12]=1[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=1)=[O:14])=[CH:10][CH:9]=[C:8]([O:25][CH:26]([CH3:28])[CH3:27])[CH:7]=2)(=O)[CH3:2].[CH3:36][O:37][NH2:38].Cl>>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[F:23])[CH2:16][NH:15][C:13]([C:12]1[C:11]2[C:6](=[CH:7][C:8]([O:25][CH:26]([CH3:27])[CH3:28])=[CH:9][CH:10]=2)[N:5]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[C:4]=1/[C:1](=[N:38]/[O:37][CH3:36])/[CH3:2])=[O:14]
Reactant: CC(=O)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC(C)C)cc2n1Cc1ccccn1
Reactant: CON
Agent: Cl
Product: CO/N=C(\C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OC(C)C)cc2n1Cc1ccccn1

Procedure:
The title compound was prepared from 2-acetyl-N-(3,4-difluorobenzyl)-6-isopropoxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 109) and MeONH2.HCl by General Procedure Q.
Reaction SMILES: O.[OH-].[Li+].[F:4][CH:5]([F:33])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([O:21][C:22]2[CH:27]=[N:26][C:25]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])=[CH:24][N:23]=2)[CH:20]=1)[C:14]([O:16]C)=[O:15])[CH3:9]>O.C1COCC1>[F:33][CH:5]([F:4])[O:6][CH2:7][C@@H:8]([O:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([O:21][C:22]2[CH:27]=[N:26][C:25]([C:28](=[O:32])[N:29]([CH3:30])[CH3:31])=[CH:24][N:23]=2)[CH:20]=1)[C:14]([OH:16])=[O:15])[CH3:9]
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@@H](C)COC(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](COC(F)F)Oc1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.3 %

Procedure:
Lithium hydroxide monohydrate (45 mg, 1.06 mol) in water (5 mL) was added to a solution of methyl 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-benzoate (0.3 g, 0.71 mmol) in THF (10 mL) and stirred at RT for 20 hours. The THF was removed in vacuo and the aqueous layer was washed with ethyl acetate (50 mL) to remove any impurities. The aqueous layer was acidified and extracted into ethyl acetate (2×50 mL) then the combined organics washed with brine (50 mL), dried (MgSO4) and the solvent removed in vacuo to give the desired compound (0.22 g).
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:34])[CH:7]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[C:6]2[C:14]([CH3:33])=[C:15]([N:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[C:16]([CH3:19])=[C:17]([CH3:18])[C:5]=2[O:4]1.CO.[OH-].[Na+]>C(OCC)(=O)C.C1COCC1>[CH3:2][C:3]1([CH3:34])[CH:7]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[C:6]2[C:14]([CH3:33])=[C:15]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:16]([CH3:19])=[C:17]([CH3:18])[C:5]=2[O:4]1
Reactant: Cc1c(C)c(N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2N1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2N1CCCCC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
A solution of 4N hydrogenchloride in ethyl acetate solution (10 ml) was added to a solution of tert butyl 4-(2,2,4,6,7-pentamethyl-3-piperidino-2,3-dihydro-1-benzofuran-5-yl)piperazine carboxylate (1.37 g, 3 mmol) obtained in Example 133 in THF (10 mL)-methanol (10 ml) and the mixture was stirred at 60° C. for 3 hours. After the reaction mixture was cooled to 0° C., the resulting mixture was made weakly alkaline using 1N sodium hydroxide and extracted with ethyl acetate. The organic extract was washed saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified with basic silica gel column chromatography (ethyl acetate) to obtain 0.89 g (yield 83%) of the title compound as an amorphous powder.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1.[CH3:17][NH:18][CH2:19][CH3:20]>CCO>[CH3:17][N:18]([CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[C:10]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:11]=[CH:12][C:6]=2[CH2:5][O:4]1)[CH2:19][CH3:20]
Reactant: CCNC
Reactant: CS(=O)(=O)c1ccc2c(c1)OC(CBr)OC2
Solvent: CCO
Product: CCN(C)CC1OCc2ccc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 22 using 2-(bromomethyl)-7-(methylsulfonyl)-4H-1,3-benzodioxine (30 mg, 0.10 mmol), N-methylethanamine (0.50 ml, 5.8 mmol) and EtOH (1.0 ml). MS m/z (rel. intensity, 70 eV) 285 (M+, 1), 77 (4), 73 (5), 72 (bp), 51 (3).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[CH:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[F:14][C:15]1[CH:16]=[C:17](Br)[CH:18]=[C:19]([F:22])[C:20]=1[F:21].C(N(CC)CC)C>C(OC)(C)(C)C.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.[Cu]I>[F:14][C:15]1[CH:16]=[C:17]([C:13]#[C:12][C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:11][CH:10]=2)[CH:18]=[C:19]([F:22])[C:20]=1[F:21]
Reactant: C#Cc1ccc(OCCCC)cc1
Reactant: Fc1cc(Br)cc(F)c1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(C#Cc2cc(F)c(F)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.4 mmol of bis(triphenylphosphine)palladium(II) chloride and 0.2 mmol of CuI are added at room temperature to a mixture of 0.02 m of 4-butoxyphenylacetylene, 0.02 m of 3,4,5-trifluorobromobenzene and 50 ml of triethylamine. The reaction mixture is stirred at room temperature for 2 hours, diluted with methyl tert.-butyl ether and filtered with suction, and the solution is evaporated. Purification by chromatography and/or crystallization gives 3,4,5-trifluoro-4'-butoxytolan.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[S:15])[C:8]([CH3:14])=[CH:9][N:10]2[CH3:13])=[CH:5][CH:4]=1.Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=[S:15])[C:8]([CH3:14])=[CH:9][N:10]2[CH3:13])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(=S)c(C)cn(C)c2c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cn(C)c2cc(O)ccc2c1=S

Procedure:
A mixture of 7-methoxy-1-methyl-3-methylthio-4-quinolone (8.23 g.) glacial acetic acid (75 ml.) and hydrobromic acid (75 ml.) was stirred and boiled under reflux for 2 days. The mixture was cooled and poured into saturated aqueous sodium bicarbonate (500 ml.). The resulting precipitate was collected by filtration and dried to give 7-hydroxy-1-methyl-3-methylthio-4-quinolone, m.p. 285°-288°.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([S:14]([C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23]CC)=[O:22])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH:5]=[CH:4][C:3]1=2.[Li+].[OH-].CO>O1CCCC1>[CH3:1][C:2]1([CH3:28])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([S:14]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:26][CH:27]=3)(=[O:16])=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(S(=O)(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(S(=O)(=O)c3ccc(C(=O)O)cc3)ccc21
Temperature: 55 °C
Yield: 93.4 %

Procedure:
To a solution of 95 mg (0.23 mmol) of ethyl 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylsulfonyl)benzoate (Compound 4) in 4.0 mL of tetrahydrofuran was added 1.0 mL of LiOH (2.6N aqueous solution) and 1.4 mL of MeOH. The solution was heated at 55° C. for 2.5 h, cooled to room temperature and concentrated in vacuo. The residue was diluted with brine, acidified to pH=1 using 10% HCl and extracted with ether (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered and the solvents were removed in vacuo to give the title compound as a white solid (80 mg, 91%):