Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][CH:8]([OH:10])[CH:7]([CH2:11][NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:6]1)=[O:4].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:33]=[CH:32][N:31]=[CH:30][C:29]2=[O:34])=[CH:24][C:23]=1[F:35]>>[F:35][C:23]1[CH:24]=[C:25]([N:28]2[CH:33]=[CH:32][N:31]=[CH:30][C:29]2=[O:34])[CH:26]=[CH:27][C:22]=1[NH:21][C:3]([CH:5]1[CH2:6][CH:7]([CH2:11][NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH:8]([OH:10])[CH2:9]1)=[O:4]
Reactant: Nc1ccc(-n2ccncc2=O)cc1F
Reactant: COC(=O)C1CC(O)C(CNC(=O)c2ccc(Cl)s2)C1
Product: O=C(NCC1CC(C(=O)Nc2ccc(-n3ccncc3=O)cc2F)CC1O)c1ccc(Cl)s1

Procedure:
In analogy to example 21C, (1SR,3RS,4SR)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-hydroxy-cyclopentanecarboxylic acid methyl ester was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyrazin-2-one (prepared from 2-fluoro-4-iodoaniline by reaction with 1H-pyrazin-2-one, Cu(I)I, N,N′-dimethylethylenediamine and cesium carbonate in dioxane at 120° C.) to give 5-chloro-thiophene-2-carboxylic acid {(1RS,2SR,4SR)-4-[2-fluoro-4-(2-oxo-2H-pyrazin-1-yl)-phenylcarbamoyl]-2-hydroxy-cyclopentylmethyl}-amide. Orange solid. MS: 491.3. ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:23]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)([C:14]([NH2:23])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccn2)CC1
Reactant: N
Product: CC(C)(C)OC(=O)N1CCC(C(N)=O)(c2ccccn2)CC1

Procedure:
Prepare by the method of example 20.8 using 1-tert-butoxycarbonyl-4-(pyridin-2-yl)-piperidine-4-carboxylic acid (4 mmol) and NH3 (gas). Purify to give the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.[NH2:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1>C(#N)C>[NH:30]1[C:29]([NH:28][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:8])=[N:33][N:32]=[N:31]1
Reactant: O=C(O)c1ccco1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1nnn[nH]1)c1ccco1
Yield: 61.5 %

Procedure:
Following the procedure described in Example 120, 2-furancarboxylic acid (5.00 g, 44.46 mmol) is treated with 1,1'-carbonyl diimidazole (8.31 g, 51.25 mmol, 1.15 equiv), triethylamine (10.9 g, 107.6 mmol, 2.4 equiv) and 5-aminotetrazole (4.51 g, 53.02 mmol, 1.19 equiv) in refluxing (17 hours) acetonitrile (250 mL) to give the crude carbamoyl product. Recrystallization from N,N-dimethyl formamide/water afforded 4.90 g (7.96 g theo., 62%) of N-1H-tetrazol-5-yl-2-furancarboxamide as a white solid; mp 280°-283° C. (dec).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=2[CH:19]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CC(C)([O-])C.[Na+].O1CCOCC1>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].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.O>[N:20]1([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7][C:6]=3[CH:19]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(Br)cc2C1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(N3CCOCC3)cc2C1
Yield: 88.4 %

Procedure:
A solution of tert-butyl 7-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (200 mg, 0.609 mmol), morpholine (0.159 ml, 1.83 mmol), X-phos (17.4 mg, 0.0365 mmol), tris(dibenzylideneacetone)dipalladium(0) (11.0 mg, 0.0120 mmol), sodium tert-butoxide (87.5 mg, 0.912 mmol) and dioxane (4 ml) was stirred under an argon atmosphere for 2 hr at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (180 mg, 88.4%) as an oil.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[O:11]1[C:15]([C:16]2[N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][N:13]=[CH:12]1.[Cl:32]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:32][C:12]1[O:11][C:15]([C:16]2[N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][N:13]=1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)n1c(-c2cnco2)cc2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1c(-c2cnc(Cl)o2)cc2ccccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
LiHMDS (1.06 M in THF, 9.54 mL, 10.00 mmol) was added to a solution of tert-butyl 2-(oxazol-5-yl)-1H-indole-1-carboxylate 20 (2.37 g, 8.34 mmol) in THF (20 mL) at −78° C., and the mixture was stirred at −78° C. for 1 h. A solution of hexachloroethane (2.96 g, 12.50 mmol) in THF (5 mL) was added at −78° C., and the mixture was stirred at −78° C. for 2 h and allowed to warm to room temperature and stirred for 14 h. The reaction was quenched by adding EtOAC:H2O (50 mL:15 mL), and then extracted with Ethyl acetate. The extracts were washed with brine, dried (Na2SO4) and concentrated. The product was purified by column chromatography (Acetone/hexane as an eluent) to provide tert-butyl 2-(2-chlorooxazol-5-yl)-1H-indole-1-carboxylate 21 (2.64 g, 99% yield) as white solid. MS (ES) m/z 319 (M+H+).
Reaction SMILES: C([C@@:3]1([C:22]([OH:24])=[O:23])[CH2:8][CH2:7][CH2:6][CH2:5][C@H:4]1[O:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)C.[OH-].[Na+]>CCO>[CH3:21][O:20][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[O:18][CH3:19])[CH2:11][CH2:10][O:9][C@@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:3]1[C:22]([OH:24])=[O:23]
Reactant: CC[C@@]1(C(=O)O)CCCC[C@H]1OCCc1ccc(OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(CCO[C@@H]2CCCC[C@H]2C(=O)O)cc1OC
Yield: 74.3 %

Procedure:
A solution of crude (1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexane-1-carboxylic acid (167) (3.71 g, 10 mmol) and 4M NaOH aq (10 mL, 40 mmol) in EtOH (25 mL) was stirred at room temperature for 18 hrs. The reaction mixture was then concentrated in vacuo, the residue was re-dissolved in water (25 mL) and the resultant basic aqueous solution was extracted with diethyl ether (2×25 mL). The aqueous layer was collected, acidified to pH1 with 6M HCl aq and extracted with dichloromethane (2×25 mL). The combined organic extracts were dried over anhydrous MgSO4 and concentrated in vacuo to give 2.29 g of (1R,2R)-2-(3,4-dimethoxyphenethoxy)cyclohexane-1-carboxylic acid (168) (74% yield; Rt: 13.48 min (HPLC-method A); 1H-NMR (300 MHz, CDCl3) δ: 7.95 (br s, 1H, CO2H), 6.78-6.69 (m, 3H, Ar), 3.84 (s, 3H, CH3O), 3.82 (s, 3H, CH3O), 3.81 (overlapped dt, J 14 Hz & 7 Hz, 1H, CH2aO), 3.57 (dt, J 14 Hz & 7 Hz, 1H, CH2bO), 3.52-3.42 (m, 1H, CHO), 2.79 (t, J 7 Hz, 2H, CH2), 2.34 (dt, J 14 Hz & 6 Hz, 1H, CHN), 2.13-1.09 (m, 8H, Aliph); MS (ES+) 307.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[NH:12][CH:13]=1.Cl[C:21]1[N:26]=[CH:25][N:24]=[C:23]2[NH:27][N:28]=[CH:29][C:22]=12.CCN(CC)CC.CC(O)C>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:10][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:21]3[N:26]=[CH:25][N:24]=[C:23]4[NH:27][N:28]=[CH:29][C:22]=34)[CH2:16][CH2:15]2)=[N:12][CH:13]=1
Reactant: Clc1ncnc2[nH]ncc12
Reactant: Clc1ccc(-c2c[nH]c(C3CCNCC3)n2)c(Cl)c1
Solvent: O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Clc1ccc(-c2cnc(C3CCN(c4ncnc5[nH]ncc45)CC3)[nH]2)c(Cl)c1
Temperature: 25 °C
Yield: 80.6 %

Procedure:
Heat a mixture of 4-(4-(2,4-dichlorophenyl)-1H-imidazol-2-yl)piperidine (270 mg, 0.91 mmol), 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (280 mg, 1.82 mmol), Et3N (0.63 mL, 4.5 mmol), and 2-propanol (10 mL) at 90° C. overnight under N2. Cool the mixture to room temperature and pour into water (100 mL). Extract the mixture with CH2Cl2 (2×200 mL), combine the organic layers, and wash with water (50 mL). Dry (Na2SO4) the organic layer, filter the mixture, and concentrate the filtrate in vacuo. Purify the residue by silica gel chromatography (25 g of SiO2, elute with CH2Cl2/CMA 4:1, 1000 mL) to provide 4-(4-(5-(2,4-dichlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine (304 mg, 80%). Add hydrochloric acid (2.0 M aqueous, 0.36 mL, 0.72 mmol) to a suspension of 4-(4-(5-(2,4-dichlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine (300 mg, 0.72 mmol) in methanol (7 mL). Concentrate the mixture in vacuo to dryness. Dissolve the residue in methanol (2 mL) and add diethyl ether (50 mL) to form a precipitate. Filter the precipitate, and wash the filter cake with Et2O. Dissolve the solid in methanol (10 mL) and remove the solvent in vacuo to dryness to provide 4-(4-(5-(2,4-dichlorophenyl)-1H-imidazol-2-yl)piperidin-1-yl)-1H-pyrazolo[3,4-d]pyrimidine hydrochloride (210 mg, 65%) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][C:11]#[N:12])=[N:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.C(OCC)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1
Reactant: Cc1cc(N)cnc1CCCC#N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(N)cnc1CCCCN
Yield: 88.4 %

Procedure:
5-Amino-2-(3-cyanopropyl)-3-methylpyridine (23.0 g) was reduced with lithium aluminium hydride (12.47 g) in a mixture of tetrahydrofuran (750 ml) and diethylether (750 ml) over 3 hours, to give 5-amino-2-(4-aminobutyl)-3-methylpyridine (20.8 g) as an amber oil. N.M.R. (CDCl3):- assignment, δ (p.p.m.) multiplicity; -- CH2CH2CH2NH2, 1.3 - 1.9, m; 3--CH3, 2.22, s; CH2 (CH 2)2CH2NH2, 2.6-2.8, m; 5-NH2, ca 3.5, broad resonance; 4-pyridyl proton, 6.77, d; 6-pyridyl proton, 7.88, d;
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:7]=1.[CH3:12][N:13]1[CH:17]=[C:16]([C:18]2[CH:19]=[N:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([CH2:28][C:29]([NH:31][NH2:32])=O)=[CH:23][CH:22]=3)[CH:15]=[N:14]1>C(O)CCC>[CH3:12][N:13]1[CH:17]=[C:16]([C:18]2[CH:19]=[N:20][C:21]3[C:26]([CH:27]=2)=[CH:25][C:24]([CH2:28][C:29]2[N:3]4[N:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]4=[N:32][N:31]=2)=[CH:23][CH:22]=3)[CH:15]=[N:14]1
Reactant: Cn1cc(-c2cnc3ccc(CC(=O)NN)cc3c2)cn1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Solvent: CCCCO
Product: Cn1cc(-c2cnc3ccc(Cc4nnc5ccc(C(F)(F)F)nn45)cc3c2)cn1
Temperature: 120 °C
Yield: 30.8 %

Procedure:
A mixture of 1-butanol (2 mL), 3-chloro-6-trifluoromethyl-pyridazine (0.13 mmol, 25 mg), [3-(1-methyl-1H-pyrazol-4-yl)-quinolin-6-yl]-acetic acid hydrazide (0.13 mmol, 40 mg) was heated at 120° C. for 18 hours. The solvent was then removed by blowing nitrogen, the brown residue dissolved in 1 ml of dimethylformamide and one 1 ml of methanol and purified by preparatory HPLC to return the title compound (15.8 mg, 0.04 mmol, 29%). Analytical data is presented in Table 2.
Reaction SMILES: [C:1]([CH2:4][S:5][C:6]1([CH3:11])[CH2:10][CH2:9][CH2:8][O:7]1)(O)=[O:2].O>O1CCCC1>[OH:2][CH2:1][CH2:4][S:5][C:6]1([CH3:11])[CH2:10][CH2:9][CH2:8][O:7]1
Reactant: CC1(SCC(=O)O)CCCO1
Solvent: O
Solvent: C1CCOC1
Product: CC1(SCCO)CCCO1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 2 mmol of 26 in 10 mL of anhydrous tetrahydrofuran (kept at 0° C.) 3 mL of BH3. THF complex (lM) is added slowly. The mixture is stirred for 3 hours in a nitrogen atmosphere at 0° C. Approximately 10 mL of water added slowly and the reaction is stirred for 15 min. The mixture is concentrated in vacuo at 40°-45° C. and the aqueous residue is extracted with ethyl acetate. The organic layer is washed with 10% bicarbonate. The ethyl acetate layer is dried and evaporated to give the product, 27 as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[CH3:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[CH3:30].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([C:26]2[CH:27]=[CH:28][C:29]([CH3:30])=[C:24]([CH3:23])[CH:25]=2)=[CH:17][CH:16]=1)=[O:22]
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)cc1C
Yield: 67.7 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 3,4-dimethyl phenylboronic acid (0.028 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.048 g (68%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′,4′-dimethylbiphenyl-4-carboxamide as a white solid.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=1)[CH:2]=[CH2:3].ClC1C=CC=C(C(OO)=[O:21])C=1>C(Cl)Cl>[F:12][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH3:11])[CH2:1][CH:2]1[CH2:3][O:21]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCc1ccc(OC)c(F)c1
Solvent: ClCCl
Product: COc1ccc(CC2CO2)cc1F
Temperature: 25 °C
Reaction time: 63 h
Yield: 37.3 %

Procedure:
4-Allyl-2-fluoro-1-methoxy benzene (1.2 g, 7.22 mmol) was dissolved in CH2Cl2 (35 ml) and treated successively with buffer pH=7.95 (35 ml, NaH2PO4 --Na2HPO4) and m-chloroperbenzoic acid 70% (2.2 g, 9 mmol). Reaction mixture was stirred at room temperature for 63 hours. The aqueous phase was extracted with CH2Cl2 (4×30 ml), combined organic phases were washed with sat. NaHCO3 (50 ml), dried over Na2SO4 and concentrated. The residue was chromatographed over siliga gel (hexan-ethyl acetate 9:1) to provide (RS)-2-(3-Fluoro-4-methoxy-benzyl)-oxirane (0.49 g, 37%) as a yellow oil MS: m/e=182 (M+).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[O:16][C:17]([CH3:20])=[N:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.Cl.[CH3:35][O:36][C:37]1[CH:45]=[N:44][C:43]([N:46]2[CH:50]=[C:49]([CH3:51])[N:48]=[N:47]2)=[C:42]2[C:38]=1[C:39]([C:52](=[O:56])C(O)=O)=[CH:40][NH:41]2.C(N(CC)CC)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl>[C:21]1([C:14](=[C:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:52]([C:39]3[C:38]4[C:42](=[C:43]([N:46]5[CH:50]=[C:49]([CH3:51])[N:48]=[N:47]5)[N:44]=[CH:45][C:37]=4[O:36][CH3:35])[NH:41][CH:40]=3)=[O:56])[CH2:9][CH2:10]2)[C:15]2[O:16][C:17]([CH3:20])=[N:18][N:19]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cnc(-n2cc(C)nn2)c2[nH]cc(C(=O)C(=O)O)c12
Reactant: Cc1nnc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc2)o1
Agent: CCN(CC)C(C)C
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc(-n2cc(C)nn2)c2[nH]cc(C(=O)C(=O)N3CCC(=C(c4ccccc4)c4nnc(C)o4)CC3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
To a solution of 4-[1-phenyl-1-(5-methyl-1,3,4-oxadiazol-2-yl)methylene]piperidine-1-carboxylic acid tert-butyl ester (0.0300 g, 0.084 mmol) in CH2Cl2 (1 mL) was added TFA (0.4 mL) and the reaction mixture was stirred at rt for 30 min. The solvent was subsequently removed in vacuo and the material was dissolved in CHCl3 (3 mL). To this solution was then added 4-methoxy-7-(4-methyl-1,2,3-triazol-1-yl)-6-azaindol-3-yl-oxoacetic acid hydrochloride salt (0.0250 g, 0.084 mmol) and iPrNEt2 (0.059 mL, 0.338 mmol), followed by BOP—Cl (0.0210 g, 0.084 mmol). The mixture was allowed to stir at rt for 2 h and then the solvent was removed in vacuo. The residue was diluted with H2O and extracted with EtOAc (×3). The combined organic layers were washed (H2O, brine), dried (Na2SO4) and concentrated, and the residue was purified by preparative HPLC (NH4OAc) affording the title compound (0.0174 g, 39%) as a colorless solid:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16]=3[C:17](=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:27][CH2:28][C:29]#[N:30].[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:17]([C:16]1[C:15]2[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=2[O:13][C:12]=1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([C:36]1[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=1)=[C:3]([O:27][CH2:28][C:29]#[N:30])[CH:2]=[CH:11]2)(=[O:22])[CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCCCC(=O)c1c(-c2ccc3c(Br)c(OCC#N)ccc3c2)oc2ccccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CCCCC(=O)c1c(-c2ccc3c(-c4ccc(C(F)(F)F)cc4)c(OCC#N)ccc3c2)oc2ccccc12
Temperature: 77 °C

Procedure:
Following the procedure described in Step 1 of Example 1, 2-{[1-bromo-6-(3-pentanoyl-1-benzofuran-2-yl)-2-naphthyl]oxy}acetonitrile (0.476 g, 1.03 mmol) was coupled to 4-trifluoromethylphenylboronic acid (0.785 g, 4.13 mmol), using [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.088 g, 0.108 mmol) and potassium carbonate (0.301 g, 2.18 mmol) in dioxane (10 mL) and water (1 mL). The reaction mixture was heated at 77° C. for 16 hours. Purification by flash chromatography (Biotage apparatus) using 2-10% ethyl acetate in hexane as an eluant yielded 2-({6-(3-pentanoyl-1-benzofuran-2-yl)-1-[4-(trifluoromethyl)phenyl]-2-naphthyl}oxy)acetonitrile as a yellow wax (0.364 g); 1HNMR (300 MHz, DMSO-d6): δ8.55 (s, 1H), 8.35 (d, 1H, J=8.5 Hz), 8.05 (d, 1H, J=7.7 Hz), 7.95 (d, 2H, J=7.7 Hz), 7.75-7.85 (m, 2H), 7.75 (d, 1H, J=7.7 Hz), 7.35-7.5 (m, 3H), 5.3 (s, 2H), 2.75 (t, 2H, J=7.7 Hz), 1.5-1.6 (m, 2H), 1.1-1.25 (m, 2H), and 0.7 (t, 3H, J=7.7 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]([CH3:18])([C:15]([OH:17])=O)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5])[CH3:2].C1C=CC2N(O)N=NC=2C=1.[NH:29]1[CH2:43][CH2:42][CH2:41][C@H:30]1[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].Cl.C(N(CC)C(C)C)(C)C.CN(C)CCCN=C=NCC.Cl>CN(C)C=O>[CH2:1]([O:3][C:4]([NH:6][C:7]([CH3:18])([C:15]([N:29]1[CH2:43][CH2:42][CH2:41][C@H:30]1[C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])=[O:17])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)NC(C)(Cc1ccccc1)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)NC(C)(Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 75.1 %

Procedure:
To a stirring solution of EtOCO-D,L-Phe(αMe)-OH (10.3 g, 41 mmol), HOBT (5.5 g, 41 mmol), Pro-OBzl.HCl (9.9 g, 41 mmol) and N,N-diisopropylethylamine (15.9 g, 123 mmol) in dimethylformamide (200 mL) at 0° C., was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.HCl (8.6 g, 45 mmol). After stirring for 16 h, the solvents were removed in vacuo and the residue was dissolved in ethyl acetate (500 mL). The organic phase was washed three times with 0.1N HCl, three times with saturated aqueous NaHCO3, and once with brine. The organic phase was then dried (Na2SO4), filtered and concentrated in vacuo. The residue was chromatographed over silica gel eluting with 1:1 ethyl acetate:hexanes and the product containing fractions (as judged by TLC) were combined and concentrated in vacuo to give 13.5 g (75% yield) of a white foam.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][NH:4][CH2:3][CH2:2]1.[S:12](Cl)([Cl:15])(=[O:14])=[O:13].C(N(C(C)C)C(C)C)C.COC1C=C2C(CCN(S(Cl)(=O)=O)C2)=CC=1>>[O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][N:4]([S:12]([Cl:15])(=[O:14])=[O:13])[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)Cl
Reactant: c1ccc2c(c1)CNCCO2
Agent: COc1ccc2c(c1)CN(S(=O)(=O)Cl)CC2
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(Cl)N1CCOc2ccccc2C1

Procedure:
This compound was prepared from 1.5 g of 2,3,4,5-tetrahydro-benzo[f][1,4]oxazepine, 0.81 mL of sulfuryl chloride and 1.8 mL of ethyl diisopropyl amine using the procedure described for 63f. Yield: 0.3 g (oil), EI-MS: 247 (M+).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH:28]1[C:33]([C@H:34]([OH:37])[CH2:35][NH2:36])=[CH:32][C:31]([OH:38])=[C:30]([OH:39])[CH:29]=1>>[OH:38][C:31]1[CH:32]=[C:33]([C@@H:34]([OH:37])[CH2:35][NH:36][CH:2]2[CH2:3][CH2:4][N:5]([C:8]3[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]4[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=4)(=[O:16])=[O:17])=[CH:12][CH:13]=3)[CH2:6][CH2:7]2)[CH:28]=[CH:29][C:30]=1[OH:39]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NC[C@@H](O)c1ccc(O)c(O)c1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)c4ccc(O)c(O)c4)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and L-norepinephrine according to the procedure of Example 255 as a grey solid; 1H NMR (300 MHz, DMSO-d6) δ 1.50–1.72 (m, 2 H), 1.95–2.10 (m, 2 H), 2.06 (s, 3 H), 2.50–3.20 (m, 5 H), 3.55–3.70 (m, 2 H), 4.05–4.20 (brs, 1), 4.60–4.75 (m, 1 H), 5.75–5.90 (brs, 1 H), 6.60–6.90 (m, 7 H), 7.59 (d, J=9.0 Hz, 2 H), 7.70 (d, J=9.0 Hz, 2 H), 8.93 (brs, 1 H), 10.42 (s, 1 H); MS (ES) m/z: 541.6 (MH+); HRMS Calcd. for C27H33N4O6S (MH+): 541.2121. Found: 541.2133.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:28]1([C:31]([O:33]C)=[O:32])[CH2:30][CH2:29]1)([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:16][CH:15]=1)[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Li+].Cl>N1C=CC=CC=1.O.CCOC(C)=O>[CH2:1]([NH:8][C:9]([C:28]1([C:31]([OH:33])=[O:32])[CH2:29][CH2:30]1)([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]([F:25])([F:26])[F:27])=[CH:16][CH:15]=1)[C:10]([F:13])([F:12])[F:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1(C(NCc2ccccc2)(c2ccc(OCCCC(F)(F)F)cc2)C(F)(F)F)CC1
Agent: Cl
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)C1(C(NCc2ccccc2)(c2ccc(OCCCC(F)(F)F)cc2)C(F)(F)F)CC1
Temperature: 25 °C
Yield: 93.4 %

Procedure:
To a solution Intermediate 14D (558 mg, 1.140 mmol) in pyridine (5.7 mL) was added lithium iodide (1.53 g, 11.4 mmol). The reaction was heated to reflux overnight. The reaction was cooled to rt and diluted with water and EtOAc. The aqueous layer was made acidic with 1 N HCl and the layers were separated. The organic layer was washed with sat'd aq NaCl, dried over MgSO4, filtered and concentrated to provide Intermediate 14E (506 mg, 84%) which was used in the next step without further purification. LCMS Anal. Calc'd for C23H23F6NO3 475.42, found [M+H] 476.2.