Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O[CH2:16][CH:17]([NH:21]C(=O)OC(C)(C)C)[CH:18]([CH3:20])[CH3:19]>>[NH2:21][CH:17]([CH:18]([CH3:20])[CH3:19])[CH2:16][N:12]1[CH:13]=[CH:14][C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:11]1
Reactant: CC(C)C(CO)NC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(-c2cc[nH]n2)cc1Cl
Product: CC(C)C(N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Yield: 22 %

Procedure:
The title compound was prepared using the method of Example 34(c) starting from 2-chloro-4-(1H-pyrazol-3-yl)benzonitrile (0.2 g; 0.98 mmol) and tert-butyl 1-hydroxy-3-methylbutan-2-ylcarbamate (0.22 g; m 1.09 mmol). Yield 22%. 1H-NMR (400 MHz; CDCl3): δ 1.02 (m, 6H), 1.71 (m, 1H), 3.14 (m, 1H), 3.95 (m, 1H), 4.27 (m, 1H), 6.61 (d, 1H), 7.51 (d, 1H), 7.66 (d, 1H), 7.77 (dd, 1H), 7.97 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:9]=1[C:10](Cl)=[O:11]>C(O)(=O)C>[F:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:9]=1[C:10]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:11]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: C1CNCCN1
Solvent: CC(=O)O
Product: O=C(c1c(F)cccc1F)N1CCNCC1
Temperature: 40 °C

Procedure:
Charge acetic acid (5 L) to a 22 L flask. Place the reaction in an ice-water bath. Add piperazine (355.00 g, 2.0 equiv; 4.06 moles) in portions with stirring, and increase temperature to ˜40° C. Add another 5 L of acetic acid. Stir until mixture becomes a solution. Adjust cooling bath to ˜13° C. Add 2,6-difluorobenzoyl chloride (355.00 g, 1.00 equiv; 2.01 moles; 253.39 mL) drop wise over a 2 hours period, while maintaining reaction temperature at approximately 13-15° C. Stir overnight. Concentrate under reduced pressure and dissolve residue in 2 L of ice water. Cool flask in an ice water bath. Add 5 N NaOH to adjust pH to 7.5 while maintaining the reaction temperature below 30° C. Filter at ˜10° C. Extract product from filtrate with dichloromethane (4×2 L). Remove solvent under reduced pressure. Dissolve the solid in 1.5 L of methanol at room temperature and filter. Concentrate the methanol solution, then solvent exchange with toluene 2.0 L, afforded pure product. Filter to obtain (2,6-difluorophenyl)-piperazin-1-yl-methanone. Concentrate filtrate and filter again to obtain additional product (total 400 g).
Reaction SMILES: [H][H].[O:3]1[CH2:8][CH:7]=[C:6]([C:9]2[CH:10]=[C:11]3[N:27]([CH3:28])[CH:26]=[CH:25][C:12]3=[N:13][C:14]=2[C@@H:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:16])[CH2:5][CH2:4]1>CO.[OH-].[OH-].[Pd+2]>[CH3:28][N:27]1[C:11]2[C:12](=[N:13][C:14]([C@@H:15]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH3:16])=[C:9]([CH:6]3[CH2:7][CH2:8][O:3][CH2:4][CH2:5]3)[CH:10]=2)[CH:25]=[CH:26]1
Reactant: [H][H]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccn(C)c2cc1C1=CCOCC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccn(C)c2cc1C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 100 mL round-bottom flask fitted with a 3-way valve and a hydrogen-filled balloon, were added (S)-tert-butyl (1-(6-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)carbamate (1.23 g, 3.44 mmol) in MeOH (20 mL) along with palladium hydroxide on carbon (0.097 g, 0.688 mmol). The flask was evacuated and hydrogen introduced via the three-way valve. The reaction mixture was stirred overnight at RT. The next day an additional equivalence of Pd(OH)2 was added and the reaction mixture was stirred overnight. The reaction mixture was subsequently diluted with EtOAc, filtered through a pad of Celite, and concentrated to give the title compound as a yellow oil, which was used without further purification.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]3[O:19][CH:18]=[C:17](Br)[C:16]=3[CH:21]=1)=[O:11])[CH2:2]2.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[CH3:35][Si:36]([C:39]#[CH:40])([CH3:38])[CH3:37]>O1CCOCC1.CCOC(C)=O.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]3[O:19][CH:18]=[C:17]([C:40]#[C:39][Si:36]([CH3:38])([CH3:37])[CH3:35])[C:16]=3[CH:21]=1)=[O:11])[CH2:2]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1ccc2occ(Br)c2c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: N#Cc1ccccc1
Product: C[Si](C)(C)C#Cc1coc2ccc(C(=O)N[C@H]3CN4CCC3CC4)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-bromo-1-benzofuran-5-carboxamide (350 mg, 1.0 mmol) is combined with bis(benzonitrile)palladium dichloride (57 mg, 0.15 mmol), cuprous iodide (19 mg, 0.10 mmol), tri(t-butyl)phosphine (658 μL, 0.325 mmol), trimethylsilylacetylene (170 μL, 1.2 mmol), and DIA (168 μL, 1.2 mmol) in dioxane (3 ml) in a dry flask under nitrogen. The reaction is stirred overnight at RT, is diluted with EtOAc (25 ml), is washed with 1:1:0.1 NaCl/water/conc. NH4OH (4×25 ml), and the organic layer is dried (K2CO3). The volatiles are removed in vacuo and the residue is chromatographed over 30 g silica gel (230-400 mesh) eluting with 7% MeOH/CHCl3+1% conc. NH4OH. The appropriate fractions are combined and concentrated to afford 268 mg (73%) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-[(trimethylsilyl)ethynyl]-1-benzofuran-5-carboxamide as a pale foam. HRMS (ESI) calcd for C21H26N2O2SI+H: 367.1841, found 367.1852 (M+H)+.
Reaction SMILES: [F:1][CH:2]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[CH:3]1[NH:13][O:14][CH3:15].C(N(CC)CC)C.[F:23][CH:24]([F:34])[C:25]1[C:29]([C:30](Cl)=[O:31])=[CH:28][N:27]([CH3:33])[N:26]=1>ClCCl>[F:1][CH:2]1[CH2:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[CH:3]1[N:13]([O:14][CH3:15])[C:30]([C:29]1[C:25]([CH:24]([F:34])[F:23])=[N:26][N:27]([CH3:33])[CH:28]=1)=[O:31]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: CONC1c2ccccc2CCCC1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C(=O)c1cn(C)nc1C(F)F)C1c2ccccc2CCCC1F
Temperature: 20 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
To a stirred solution of N-(6-fluoro-6,7,8,9-tetrahydro-5-H-benzocyclohepten-5-yl)-O-methyl-hydroxylamine (0.100 g; 0.48 mmol), prepared as described in example P2b and triethylamine (0.073 ml; 0.53 mmol) in dichloromethane (1 ml) under nitrogen at 0° C. was added drop wise 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride (0.093 g; 0.48 mmol). The reaction mixture was stirred at 20° C. for 15 h under nitrogen. The solvent was removed in vacuo to afford a sticky oil which was subject to flash chromatography (eluant: c-hexane/ethyl acetate 95:5 to 0:100) to afford 0.134 g (76% of theory) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (6-fluoro-6,7,8,9-tetrahydro-5-H-benzocyclohepten-5-yl)-methoxy-amide as an oil.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:19])[NH:9][C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([Br:18])[N:11]=1)([CH3:6])([CH3:5])[CH3:4].I[CH3:21].[NH4+].[Cl-]>CC1OCCC1.O>[C:3]([O:7][C:8](=[O:19])[N:9]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([Br:18])[N:11]=1)[CH3:21])([CH3:6])([CH3:4])[CH3:5]
Reactant: CI
Reactant: COc1ccc(Br)nc1NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: O
Solvent: CC1CCCO1
Product: COc1ccc(Br)nc1N(C)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 90.5 %

Procedure:
NaH (60% in oil, 1.90 g, 47.5 mmol) was added to cooled (5° C.) anhydrous 2-MeTHF (120 mL) under argon, followed by a solution of tert-butyl(6-bromo-3-methoxypyridin-2-yl)carbamate (4.80 g, 15.8 mmol) in anhydrous 2-MeTHF (40 mL) slowly, maintaining the reaction temperature below 15° C. Once the addition was complete the reaction was stirred for 15 min prior to addition of iodomethane (2.76 mL, 44.3 mmol). After stirring at rt for 21 h, further iodomethane (2.76 mL, 44.3 mmol) was added and the reaction mixture stirred at rt for 1 d. After cooling to 5° C. saturated aqueous NH4Cl and H2O (1:1, 160 mL) was added with caution. The mixture was stirred at rt for 15 min, the phases were separated and the aqueous phase extracted with EtOAc (2×200 mL). The combined organic phases were washed with brine, dried (Na2SO4) and concentrated in vacuo before purification by gradient flash chromatography, eluting with 5-25% EtOAc in heptane yielded tert-butyl(6-bromo-3-methoxypyridin-2-yl)(methyl)carbamate (4.52 g, 14.3 mmol) as a colourless oil.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]=[N+:14]=[N-:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CCN(C(C)C)C(C)C.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]=[N+:14]=[N-:15])[CH2:10][C@H:9]1[C:16]([N:32]1[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]1)=[O:18])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N=[N+]=[N-])C[C@H]1C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)[C@@H]2C[C@H](N=[N+]=[N-])CN2C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.5 %

Procedure:
(2S,4S)-1-Boc-4-azidopyrrolidine-2-carboxylic acid (9.5 g, 35 mmol) obtained in Step A was dissolved in DMF (30 mL). After DIPEA (1.15 mL, 6.70 mmol) was added thereto, 1-methylpiperazine (5.81 mL, 52.5 mmol), HOBT (7 g, 52.5 mmol) and EDC (10.2 g, 52.5 mmol) were added thereto, in turn. The reaction solution was stirred for 12 hours at room temperature and concentrated in vacuo. The residue was diluted with EtOAc and washed with saturated NaHCO3 aqueous solution, water and 1N HCl. The extracted organic solution was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (eluent: MC/MeOH=10/1) to give the title compound (11.67 g, 93%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[N:20]1([CH2:25][C:26]2([OH:31])[CH2:30][CH2:29][NH:28][CH2:27]2)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:28]4[CH2:29][CH2:30][C:26]([CH2:25][N:20]5[CH2:24][CH2:23][CH2:22][CH2:21]5)([OH:31])[CH2:27]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: OC1(CN2CCCC2)CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCC(O)(CN4CCCC4)C3)c(F)cc2c1=O

Procedure:
1-Cyclopropyl-6,7-diflouro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid and 3-(1-pyrrolidinylmethyl)-3-hydroxy-pyrrolidine are reacted according to example 1, yielding 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7[3-(1-pyrrolidinylmethyl)-3-hydroxy- 1-pyrrolidinyl]-3-quinoline carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[NH:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[C:35]1[NH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.C(N(CC)C(C)C)(C)C.N>C(OCC)(=O)C.ClCCl.CO.C(OCC)(=O)C.C(#N)C>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:47]2[CH2:46][CH2:45][CH:44]([NH:43][C:35]3[NH:34][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=4[N:36]=3)[CH2:49][CH2:48]2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)=[O:7]
Reactant: c1ccc2[nH]c(NC3CCNCC3)nc2c1
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Agent: I
Agent: N
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) (2.51 g, 5.4 mmol), (1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydriodic acid salt (3.07 g, 6.5 mmol), N,N-diisopropylethylamine (4.8 mL, 27.6 mmol), and acetonitrile (70 mL). Heat to reflux. After 18 hours, cool to ambient temperature, dilute the reaction mixture with ethyl acetate, and extract with water and brine. Separate the organic layer, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 305 methanol/ethyl acetate containing concentrated aqueous ammonia 22 mL/3L. Evaporate the product containing fractions to give a residue. Combine the residue and dichloromethane, filter and evaporate in vacuo to give the title compound: Rf=0.17 (silica gel, 30% methanol/ethyl acetate).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]([F:28])([F:27])[F:26])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22](O)=[O:23])=[C:15]3[N:14]=2)[CH:7]=1.[Cl-].[NH4+:30]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:25]([F:27])([F:28])[F:26])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([NH2:30])=[O:23])=[C:15]3[N:14]=2)[CH:7]=1
Reactant: [NH4+]
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3C(F)(F)F)nc12
Agent: [Cl-]
Product: NC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3C(F)(F)F)nc12
Yield: 78 %

Procedure:
Prepared by the method described in Example 1 using (R)-5-(2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation M) and ammonium chloride. The crude material was purified by reverse phase HPLC (0-60% acetonitrile/water) to yield the title compound (23 mg, 78% yield). MS (apci) m/z=394.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=2)[CH:6]=1)=[O:4].[Sn](Cl)Cl.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[O:12][CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2cccc([N+](=O)[O-])c2)cc2c1OCC2
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2cccc(N)c2)cc2c1OCC2
Yield: 80.4 %

Procedure:
5-(3-Nitrophenyl)-2,3-dihydro-7-benzofurancarboxylic acid methyl ester (650 mg) and tin(II) chloride (2.3 g) in ethyl acetate (28 mL) were heated at 70° C. for 16 h. The mixture was allowed to cool and poured onto ice. The pH was adjusted to 7-8 by addition of saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, treated with charcoal and dried over sodium sulfate. Filtration and removal of solvent afforded the title compound as an oil (470 mg). Electrospray MS (positive ion): (M+H) 270.4.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18][CH2:19][CH3:20])=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:33](Br)([CH3:35])[CH3:34]>>[CH:33]([O:1][C:2]1[CH:12]=[C:11]([CH2:13][C:14]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18][CH2:19][CH3:20])=[O:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])([CH3:35])[CH3:34]
Reactant: CCCC(NC(=O)Cc1ccc(C(=O)OCC)c(O)c1)c1ccccc1N1CCCCC1
Reactant: CC(C)Br
Product: CCCC(NC(=O)Cc1ccc(C(=O)OCC)c(OC(C)C)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared from ethyl 2-hydroxy-4-[N-{1-(2-piperidino-phenyl)-1butyl}-aminocarbonylmethyl]-benzoate, using 1.5 equivalents of isopropyl bromide at 150° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][NH:11][C:12]([C:14]23[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:22][C:16]([C:24]5[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=5)([CH2:17]4)[CH2:15]2)[CH2:21]3)=[O:13])[CH:5]=[CH:6][C:7]=1[OH:8]>C(OC(=O)CCC)(=O)CCC.OS(O)(=O)=O>[C:2]([O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][CH2:10][NH:11][C:12]([C:14]23[CH2:21][CH:20]4[CH2:19][CH:18]([CH2:17][C:16]([C:24]5[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=5)([CH2:22]4)[CH2:15]2)[CH2:23]3)=[O:13])=[CH:3][C:2]=1[O:1][C:12](=[O:13])[CH2:14][CH2:15][CH3:16])(=[O:1])[CH2:7][CH2:6][CH3:5]
Reactant: O=C(NCCc1ccc(O)c(O)c1)C12CC3CC(C1)CC(c1ccc(Cl)cc1)(C3)C2
Agent: CCCC(=O)OC(=O)CCC
Agent: O=S(=O)(O)O
Product: CCCC(=O)Oc1ccc(CCNC(=O)C23CC4CC(C2)CC(c2ccc(Cl)cc2)(C4)C3)cc1OC(=O)CCC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Compound 1 was dissolved in n-butyric anhydride with a catalytic amount of 98% H2SO4 and stirred under N2 for 3 days at room temperature. The solution was then concentrated under a vacuum and filtered to give the product Compound 4, with a melting point of 78-80° C. 1H NMR (500 MHz, CDCl3) δ 1.03-1.08 (m, 6H, 2CH3), 1.74 (m, 2H, Admant-H), 1.75-1.87 (m, 12H, 2CH2, Admant-H), 1.93 (s, 2H, Admant-H), 2.26 (m, 2H, Admant-H), 2.49-2.55 (m, 4H, 2COCH2), 2.82-2.85 (t, J=7.5 Hz, 2H, CH2), 3.50-3.54 (q, 2H, NCH2), 5.69 (s, 1H, NH), 7.01-7.02 (d, J=5 Hz, 1H, Ar—H), 7.06-7.08 (d, d, 1H, H—Ar), 7.12-7.14 (d, J=10 Hz, 1H, Ar—H), 7.30 (s, 4H, Ar—H); MS m/z (relative intensity) 566.73 (MH+, 50), 567.61 (12), 568.60 (20).
Reaction SMILES: [C:1]1([O:7][C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:17]([O:15][C:12]1[CH:11]=[CH:10][C:9]([C:8]([O:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:16])=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Oc1ccccc1)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Oc1ccccc1)c1ccc(OCc2ccccc2)cc1
Yield: 93.5 %

Procedure:
4-Hydroxy-benzoic acid phenyl ester (5 g, 23.3 mmol), benzyl bromide (5.54 mL, 46.7 mmol), K2CO3 (9.6 g, 70.0 mmol), and anhydrous acetone (200 mL) were mixed and reflux overnight. All acetone was removed. To the mixture was added water (300 mL). The solid was filtered, washed with methanol (50 mL×3), and dried to give the desired compound (6.63 g, 93%). MS (DCI) m/z 305 (M+H)+; 1H NMR (300 MHz, CDCl3) δ ppm 5.17 (s, 2H) 7.30-7.09 (m, 2H) 7.17-7.23 (m, 2H) 7.27 (m, 1H) 7.34-7.48 (m, 7H) 8.13-8.19 (m, 2H)
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[NH:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=1)=[O:4].[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O>>[C:21]([O:20][C:18]([N:6]1[CH:7]=[CH:8][C:9]([C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][CH:11]=2)=[C:5]1[CH:3]=[O:4])=[O:17])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: O=Cc1[nH]ccc1-c1ccc(I)cc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)n1ccc(-c2ccc(I)cc2)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Following a standard procedure (Tietze, L. F.; Kettschau, G.; Heitmann, K. Synthesis 1996, 851-857), sample of NaH (70 mg, 1.75 mmol, 60% dispersion in mineral oil) in a round-bottomed flask under argon was washed twice with anhydrous pentane (˜5 mL). Anhydrous THF (14 mL) was added followed by 5 (400 mg, 1.35 mmol). After stirring for 30 min at room temperature, (BOC)2O(325 mg, 1.5 mmol) was added and stirring was continued for another 2 h. The reaction was quenched with 50% satd. aq NH4Cl (50 mL). The mixture was extracted with ether, and the combined organic layers were washed with brine, dried (Na2SO4), and filtered [silica, hexanes/ethyl acetate (4:1)] to yield a viscous oil (535 mg, quantitative). 1H NMR δ 1.64 (s, 9H), 6.33 (d, J=3.0 Hz, 1H), 7.30 (d, J=8.1 Hz, 2H), 7.46 (d, J=3.0 Hz, 1H), 7.72 (d, J=8.1 Hz, 2H), 10.22 (s, 1H); 13C NMR δ 27.7, 85.8, 94.2, 113.2, 126.7, 128.5, 131.3, 132.8, 137.0, 137.4, 148.3, 181.6; FAB-MS obsd 397.0176, calcd 397.0175 (C16H16INO3).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH2:14][NH2:15])=[C:8]([N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])[C:7]=2[CH:23]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].O>ClCCl>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:12])([CH3:13])[C:9]([CH2:14][NH:15][C:33](=[O:35])[CH3:34])=[C:8]([N:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]3=[O:22])[C:7]=2[CH:23]=1
Reactant: CC(=O)Cl
Reactant: CC1(C)Oc2ccc(C(F)(F)F)cc2C(n2ccccc2=O)=C1CN
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)NCC1=C(n2ccccc2=O)c2cc(C(F)(F)F)ccc2OC1(C)C
Reaction time: 6 h
Yield: 42 %

Procedure:
To a solution containing 6-trifluoromethyl-2,2-dimethyl-3-aminomethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (0.68 g, 1.82 mmol) and triethylamine (0.3 ml, 2.18 mmol) in dichloromethane (18 ml), acetyl chloride (0.15 ml, 2.18 mmol) was added at room temperature. The solution was stirred for 6 hours and then water added. The organic layer was separated, dried and evaporated, to give crude product which was chromatographed on silica gel. Elution with dichloromethane/methanol (95/5) gave a product which was crystallized from ether to afford 0.3 g of 6-trifluoromethyl-2,2-dimethyl-3-(acetamido)methyl-4-(2-oxo-1,2-dihydropyridin-1-yl)2H-1-benzopyran, m.p. 174° C.
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[C:11]([F:19])[CH:10]=1.[CH3:20]O>C1(C)C=CC=CC=1>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([O:18][CH3:20])=[O:17])=[C:11]([F:19])[CH:10]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: CO
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc(Br)cc1F
Yield: 91 %

Procedure:
Trimethylsilyl diazomethane (11.6 mL of 2 M in toluene, 23.2 mmol) was added dropwise to a solution of 2-(4-bromo-2-fluoro-phenyl)acetic acid (4.5 g, 19.3 mmol) in a mixture of toluene (7.65 mL)/methanol (7.65 mL) under a nitrogen atmosphere at room temperature. The reaction mixture was then quenched with a few drops of acetic acid and the solvents were concentrated in vacuo. The residue was purified by silica gel column chromatography using 0-10% EtOAc-hexanes as eluent to yield methyl 2-(4-bromo-2-fluoro-phenyl)acetate (4.3 g, 91%). 1H NMR (400 MHz, CDCl3) δ 7.28-7.22 (m, 2H), 7.15 (t, J=8.0 Hz, 1H), 3.71 (s, 3H), 3.63 (d, J=1.0 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:13]([O:15]C)=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18]>[OH-].[Na+].CO.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:13]([OH:15])=[O:14])=[CH:8][N:9]2[CH3:12])=[CH:5][C:4]=1[C:17]([F:20])([F:18])[F:19]
Reactant: COC(=O)c1cn(C)c2cc(OC)c(C(F)(F)F)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc2c(cc1C(F)(F)F)c(C(=O)O)cn2C
Yield: 88 %

Procedure:
The trifluoromethylindole ester (D25, 0.67 g, 2.33 mmol) was heated under reflux in a mixture of 10% aqueous sodium hydroxide (5 ml) and methanol (10 ml) for 30 min. The mixture was then diluted with water to dissolve all solid and extracted with dichloromethane. The aqueous phase was acidified with 5M hydrochloric acid and the precipitate was filtered off and dried to give the title compound (0.56 g, 88%), mp. >247° C. (decomp.)