Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[Si:2]([Cl:16])([Cl:15])[CH2:3][CH:4]([CH3:14])[CH2:5][C:6]([CH3:13])([CH3:12])[CH2:7][C:8]([CH3:11])([CH3:10])[CH3:9].[CH:17]([Mg]Cl)([CH3:19])[CH3:18]>C1(C)C=CC=CC=1.C1COCC1>[Cl:16][Si:2]([Cl:15])([CH2:3][CH:4]([CH3:14])[CH2:5][C:6]([CH3:12])([CH3:13])[CH2:7][C:8]([CH3:9])([CH3:10])[CH3:11])[CH:17]([CH3:19])[CH3:18]
Reactant: CC(CC(C)(C)CC(C)(C)C)C[Si](Cl)(Cl)Cl
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(CC(C)(C)CC(C)(C)C)C[Si](Cl)(Cl)C(C)C
Temperature: 100 °C
Reaction time: 20 h

Procedure:
137.8 g trichloro(2,4,4,6,6-pentamethylheptyl)silane, prepared according to example 7, were dissolved in toluene and heated to 100° C. under argon. By means of a dropping funnel were added 220 ml isopropylmagnesium chloride as a 2 molar solution in THF were added to this solution within 1 h. Subsequently the THF was distilled off by means of a column and the reaction mixture was stirred at 100° C. for 20 h. Filtration was carried out for separating the precipitated solid and the product was isolated by vacuum distillation.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([F:15])([F:14])[CH2:11][CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH2:1]([O:8][CH2:9][C:10]([F:14])([F:15])[CH2:11][CH2:12][O:13][S:23]([CH3:22])(=[O:25])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCC(F)(F)COCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCC(F)(F)COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzyloxy-2,2-difluoro-4-hydroxybutane (50 g, 0.231 moles) and dry pyridine (100 mL) in dichloromethane cooled in an ice bath, methanesulfonyl chloride (26.52 g, 0.232 moles) in dichloromethane (100 mL) is slowly added. After stirring at room temperature overnight, the mixture is washed with 2N HCl (2×1 L) and twice with water. Drying and subsequent evaporation of the solvent yields 1-benzyloxy-2,2-difluoro-4-methanesulfonyloxybutane as a yellow oil: 63.44 g (93%).
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH3:5].C([Li])CCC.[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]([C:1]#[C:2][CH2:3][CH2:4][CH3:5])([OH:24])[CH2:20][CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C#CCCC
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC#CC1(O)CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 17 h
Yield: 77.6 %

Procedure:
To a solution of 5.47 g (80.3 mmol) of 1-pentyne in 65 mL THF at −78° C. was added 32.1 ml n-butyl lithium (80.3 mmol; 2.5M in hexanes). After the addition was complete the reaction mixture was warmed to 0° C. and a solution of 8.44 g (44.6 mmol) of 1-benzyl-4-piperidone and 40 mL of THF was added dropwise. The cooling bath was removed and the reaction mixture was stirred at ambient temperature. After 17 h, the reaction was quenched by addition of saturated ammonium chloride and diluted with EtOAc. The aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated to afford a reddish-gold oil. The crude product was purified by flash chromatography on silica gel (EtOAc/hexane 1:1→65:35). The light gold oil was dried over sodium sulfate to afford 8.91 g (78%) of 1-benzyl-4-pentynyl-4-piperidinol: ms (EST) [M+H]+=258.
Reaction SMILES: [NH:1]([CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)[NH2:2].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[C:22](=[O:29])N(CCO)N=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19]2[C@H:28]3[C@H:23]([CH2:24][CH:25]=[CH:26][CH2:27]3)[C:22](=[O:29])[N:1]([CH:3]3[CH2:8][CH2:7][O:6][CH2:5][CH2:4]3)[N:2]=2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(C2=NN(CCO)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Reactant: NNC1CCOCC1
Product: COc1ccc(C2=NN(C3CCOCC3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound C and 4-hydrazinotetrahydropyran as described for compound 35. Crystallized from methanol. M.p. 175°-177° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[C:1]([O:5][C:6]([N:7]([CH3:8])[C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:13][CH2:14]1)=[O:20])([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCCCO)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCCCOS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred, ice-cooled solution of 1.37 g (4.8 mmol) of trans-[4-(4-Hydroxy-butyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester and 0.95 ml NEt3 in 15 ml CH2Cl2 was added 0.5 ml (6.8 mmol) methanesulfonyl chloride. After stirring at RT for 2 h, the reaction mixture was partitioned between Et2O, 1M HCl and water. The ether-layer was concentrated in vacuo to give 1.745 g of clean trans-Methanesulfonic acid 4-[4-(tert-butoxycarbonyl-methyl-amino)-cyclohexyl]-butyl ester, that was treated in 5 ml CH2Cl2 with 5 ml of trifluoro acetic acid. After stirring the solution for 30 min at RT, the solution was evaporated under reduced pressure to dryness to give 2.25 g (quant.) trans-Methanesulfonic acid 4-(4-methylamino-cyclohexyl)-butyl ester.trifluoro-acetic acid.
Reaction SMILES: Br.[CH3:2][O:3][CH:4]([O:24][CH3:25])[CH2:5][NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.[CH2:33]([O:40][C:41](ON1C(=O)CCC1=O)=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC(C)=O>[CH2:33]([O:40][C:41]([N:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5][CH:4]([O:3][CH3:2])[O:24][CH3:25])=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: COC(CNCCCCCCOCCCCc1ccccc1)OC
Agent: Br
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COC(CN(CCCCCCOCCCCc1ccccc1)C(=O)OCc1ccccc1)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a solution of 4.15 g (9.93 mmol) N-dimethoxyethyl-6-(4-phenylbutoxy)hexylamine hydrobromide in 40 ml acetone is added 1.4 ml triethylamine and 2.41 g (10.71 mmol) N-(benzyloxycarbonyloxy)succinimide. After allowing the mixture to stir for 2 hr at room temperature, acetone is evaporated of f and 40 ml Et2O is added thereto. The resulting mixture is washed three times with 40 ml H2O. Once separated, the ether phase is dried on anhydrous Na2SO4 and evaporated to dryness, to yield 4.46 g (95.3%) N-benzyloxycarbonyl-N-dimethoxyethyl-6-(4-phenylbutoxy)hexylamine as an oil.
Reaction SMILES: [O:1]([CH2:8][CH2:9][NH:10][C:11]1[O:12][CH2:13][C:14]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=2[N:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:22][CH2:23][C:24](Cl)=[O:25]>>[Cl:22][CH2:23][C:24]([NH:21][C:19]1[CH:18]=[CH:17][C:15]2[N:16]=[C:11]([NH:10][CH2:9][CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[O:12][CH2:13][C:14]=2[CH:20]=1)=[O:25]
Reactant: Nc1ccc2c(c1)COC(NCCOc1ccccc1)=N2
Reactant: O=C(Cl)CCl
Product: O=C(CCl)Nc1ccc2c(c1)COC(NCCOc1ccccc1)=N2
Yield: 81.3 %

Procedure:
Prepared from N2-(2-phenoxy-ethyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 87) (591 mg, 2.0 mmol) and chloroacetyl chloride (167 ul, 2.1 mmol) according to the procedure described for Example 3 step A. Obtained the title compound as an off-white solid (585 mg, 81%), MS (ISP) m/e=360.1 [(M+H)+] and 362 [(M+2+H)+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])=[CH:8][CH:7]=1)[CH3:2].Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[C:13](=[O:21])[C:14]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:20][C:24]2=[O:26])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2ccccc2N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [4-(2-amino-benzoylamino)-phenyl]-acetic acid ethyl ester (14.2 g, 47 mmol) and triphosgene (0.5 eq, 7.03 g, 23.5 mmol) in DCM (200 ml) is treated with DIPEA (2 eq, 16.5 ml, 94 mmol) dropwise via dropping funnel while stirring at RT. After 1 hour, the reaction mixture is diluted with DCM and washed with saturated aqueous NaHCO3. The separated organic layer is washed with distilled water (2×), dried over MgSO4, filtered and the solvent removed in vacuo. The title compound is obtained as pure white solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9]([CH3:14])=[CH:10][C:11](Cl)=[O:12]>C1COCC1>[CH3:8][C:9]([CH3:14])=[CH:10][C:11]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:12]
Reactant: Oc1ccccc1
Reactant: CC(C)=CC(=O)Cl
Solvent: C1CCOC1
Product: CC(C)=CC(=O)Oc1ccccc1
Reaction time: 5 h

Procedure:
To an ice bath cooled solution of 1.29 g (54 mmol) of NaH (obtained from a 60% suspension in mineral oil by 3×10 ml hexane wash) in 20 ml of dry THF was added slowly under oxygen a solution of 5 g (53 mmol) of phenol in 50 ml of dry THF. The mixture was then treated with a solution of 7 g (59 mmol) of dimethylacryloyl chloride in 30 ml of dry THF. The cooling bath was then removed and the mixture was stirred for a further 2 5 h. The reaction mixture was then poured into 150 ml of water containing 1 ml of glacial acetic acid. The mixture was extracted with 150 ml ether and the ether extract washed with saturated NaCl solution and then dried (MgSO4) The solvent was removed in vacuo and the residue purified by flash chromatography (silica; 5% ether in hexanes) to give the title compound as a yellow oil. PMR (CDCl3)): & 1.99 (3H, s), 2.24 (3H, s), 5.93 (1H, broad s), 7.10 (2H, d, J~7.8 Hz) 7.22 (1H, t, J~7.8 Hz), 7.38 (2H, t, J~7.8 Hz).
Reaction SMILES: [C:1](Cl)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:15][CH:14]=1>>[C:1]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:18]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCC(=O)Cl
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: CCCCCCCCC(=O)Nc1ccc(C(=O)CCC(=O)O)cc1
Yield: 66 %

Procedure:
In a manner similar to that described in Example 3, nonanoyl chloride (0.055 g, 0.00031 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.055 g of 4-[4-(nonanoylamino)-phenyl]-4-oxo-butyric acid as an off-white solid; MS-(AP+) MH+334.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13]Cl)[CH2:7][CH2:6][CH2:5]2.[I-].[K+].[CH3:18][NH:19][CH2:20][CH3:21]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:15])[CH2:13][N:19]([CH2:20][CH3:21])[CH3:18])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C(CCl)N1CCCc2cc(Br)ccc21
Reactant: CCNC
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(C)CC(=O)N1CCCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
A suspension of 1-(6-bromo-3,4-dihydroquinolin-1(2H)-yl)-2-chloroethanone (1 g, 3.47 mmol) and potassium iodide (0.115 g, 0.693 mmol) in 10 mL THF was treated with N-methylethanamine (1.786 mL, 20.79 mmol). The mixture was stirred at room temperature for 2 hours then heated at 65° C. for 1 hour. The mixture was concentrated and partitioned between CH2Cl2 (100 mL) and saturated sodium bicarbonate (25 mL). After extraction, the organic layer was separated, dried over Na2SO4, filtered and concentrated to give a light brown residue. This residue was subjected to flash chromatography on silica gel using 5% 2M NH3 in methanol/95% CH2Cl2 to give a light brown residue (1.06 g, 98%). 1H-NMR (CDCl3) δ 7.52-7.40 (br s, 1H), 7.30-7.27 (m, 2H), 3.80 (t, J=6.0 Hz, 2H), 3.28 (s, 2H), 2.72 (t, J=6.9 Hz, 2H), 2.50 (quart, J=7.2 Hz, 2H), 2.30 (s, 3H), 1.96 (quint, J=6.6 Hz, 2H), 1.03 (t, J=7.2 Hz, 3H). MS (ESI): 311.1 and 313.1 (M+1, 100%).
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1.[OH:28][C@@H:29]([C:40]1[CH:45]=[CH:44][CH:43]=[C:42](O)[CH:41]=1)[CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36]>>[O:20]=[S:16]1(=[O:19])[CH2:15][CH2:14][CH:13]([CH2:12][O:11][C:42]2[CH:41]=[C:40]([C@H:29]([OH:28])[CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:38])[CH3:37])[CH:45]=[CH:44][CH:43]=2)[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCS(=O)(=O)CC2)cc1
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OCC2CCS(=O)(=O)CC2)c1

Procedure:
Reaction between (1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl 4-methylbenzenesulfonate and phenol (7, Intermediate I) following the method used in Example 7 gave (R)-tert-butyl (3-(3-((1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy)phenyl)-3-hydroxypropyl)carbamate as colorless oil. Yield (58%); 1H NMR (400 MHz, DMSO-d6): δ 7.20 (t, J=8.0 Hz, 1H), 6.87 (d, J=8.0 Hz, 2H), 6.78 (d, J=4.0 Hz, 1H), 5.19 (d, J=4.4 Hz, 1H), 4.51-4.49 (bs, 1H), 3.87-3.85 (d, J=8.0 Hz, 1H), 3.22-3.15 (m, 2H), 3.08-3.05 (m, 2H), 2.96-2.94 (m, 2H), 2.15-2.11 (m, 3H), 1.79-1.74 (m, 2H), 1.67-1.65 (m, 2H), 1.36 (s, 9H).
Reaction SMILES: [CH:1]([C:4]1[O:5][C:6]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[C:7]([CH2:9][C:10]([O:12]CC)=[O:11])[N:8]=1)([CH3:3])[CH3:2].CO.[OH-].[K+]>O>[CH:1]([C:4]1[O:5][C:6]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=[C:7]([CH2:9][C:10]([OH:12])=[O:11])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1nc(C(C)C)oc1-c1ccco1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)c1nc(CC(=O)O)c(-c2ccco2)o1
Yield: 67.2 %

Procedure:
5.0 g of ethyl 2-[2-isopropyl-5-(2-furyl)-4-oxazolyl]acetate, 70 ml of methanol, 7 ml of water and 3.75 g of potassium hydroxide are treated in the same manner as described in Example 16. 3.0 g of 2-[2-isopropyl-5-(2-furyl)-4-oxazolyl]acetic acid are obtained. Yield: 67.1%
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:27])[C:14]([CH3:26])([CH2:23][CH2:24][CH3:25])[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.[OH-].[Na+:30]>O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:27])[C:14]([CH3:26])([CH2:23][CH2:24][CH3:25])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[O-:22])=[N:3]1.[Na+:30]
Reactant: CCCC1(C)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC1(C)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C([O-])c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A suspension of the product of Example 29A (0.113 g) in water (2 mL) was treated with 0.997N sodium hydroxide solution (0.286 mL, 0.285 mmol) and stirred at 25° C. for 1 hour. The solution was lyophilized to give the title compound (0.119 g, 99%). 1H NMR (300 MHz, DMSO-d6): δ ppm 0.64 (m, 4 H) 0.91 (m, 1 H) 1.40 (m, 3 H) 1.68 (m, 1 H) 2.10 (m, 1H) 7.30 (m, 3 H) 7.49 (m, 3 H) 7.64 (m, 1 H) 8.05 (m, 1 H) 15.44 (m, 1 H). MS (ESI−) m/z 395 (M−H)−.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:20]([C:22]1[O:23][CH:24]=[CH:25][C:26]=1B1OC(C)(C)C(C)(C)O1)=[O:21].C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH:20]([C:22]1[O:23][CH:24]=[CH:25][C:26]=1[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Reactant: CC1(C)OB(c2ccoc2C=O)OC1(C)C
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: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2ccoc2C=O)C1
Temperature: 85 °C
Reaction time: 12 h
Yield: 48.5 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.48 g, 4.50 mmol), 2-formylfuran-3-boronic acid pinacol ester (1.00 g, 4.50 mmol), saturated aqueous sodium carbonate solution (20 ml), and tetrakis(triphenylphosphine)palladium(0) (147 mg, 0.127 mmol) in ethylene glycol dimethyl ether (25 ml) was stirred under a nitrogen atmosphere at 85° C. for 12 hr. 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, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (750 mg, 48.4%) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[C:16]([CH2:19][CH2:20]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:18])=[O:17].[H-].[Na+]>CS(C)=O.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[CH:20][CH2:19][C:16]([OH:18])=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C(O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(=CCC(=O)O)CC1
Temperature: 0 °C
Reaction time: 20 h
Yield: 24.9 %

Procedure:
A mixture of 7.53 g (37.8 mmol) of 1-t-butoxycarbonyl-piperidin-4 one and 14 g (37.8 mmol) of (3-carboxypropyl)triphenyl-phosphonium chloride (from EXAMPLE 98, Step A) were dissolved in 100 mL of 1:1 v/v DMSO/THF. The mixture was cooled to 0° C. and was then added to 2 g (83.2 mmol) of dry 95% sodium hydride powder at 0° C. over a 10 min period. After stirring this mixture at 0 ° C. for 20 h, the reaction was quenched with H2O, treated with sat'd NaCl and extracted 2× with CH2Cl2. The aqueous phase was acidified to pH 1 with 1 N HCl, and extracted 3× with CH2Cl2. The combined organic layers were washed with sat'd NaCl and H2O, dried over Na2SO4, filtered and the filtrate concentrated. The residue was purified by column chomatography on 150 g of silica using a gradient of 25-50% acetone/hexanes (v/v), to give 2.4 g (25%) of the title compound: 1H NMR (500 _MHz) δ 1.47 (s, 9H1.2.21 (d, J=5.5,44H), 3.12 (d, J=7.3,22H), 3.42 (d, J=5.7, 4H), 5.41 (t, J=7.1, 11H).
Reaction SMILES: [Cl:1][C:2]1C(C)=[N:4][O:5][C:6]=1[N:7]([CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]=1OC(=O)C)(=[O:10])=[O:9].C([SiH]([CH2:47][CH3:48])CC)C.B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[C:47]([CH3:48])=[N:4][O:5][C:6]=1[N:7]([CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][CH:30]=1)(=[O:10])=[O:9]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2ccc3ccccc3c2OC(C)=O)sc2ncccc12
Reactant: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2cccc3ccccc23)sc2ncccc12
Yield: 65 %

Procedure:
The title compound was prepared by the method of Example 5(A) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-(α-acetoxynaphthylmethyl)thieno[2,3-b]pyridine-3-sulfonamide (97 mg, 0.16 mmoles), CH2Cl2 (3 ml), triethylsilane (0.25 ml, 1.6 mmoles) and boron trifluoride etherate (0.19 ml, 1.6 mmoles). Flash chromatography (40% EtOAc/hexanes) provided 58 mg (66%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6](=[O:22])[C:7]1[CH:12]=[CH:11][C:10]([N:13]([S:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:31])=[O:30])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(NCc2ccc(Cl)cc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1ccc(N(Cc2ccc(Cl)cc2)S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Yield: 76.3 %

Procedure:
A mixture of 4-(4-chloro-benzylamino)-benzoic acid tert-butyl ester (6 g, 6.3 mmol), phenylsulfonylchloride (2.9 ml, 21 mmol) and pyridine (1.86 mL, 23 mmol) in dichloromethane (25 mL) was heated to reflux for 16 hours. The reaction mixture was cooled to room temperature, diluted with dichloromethane (25 ml) and washed with water (2×25 ml). The organics were collected, dried over magnesium sulfate and concentrated in vacuo to afford a yellow oil which was purified by flash chromatography (hexanes/ethyl acetate 9:1) to afford the title compound as a white solid (2.2 g, 76% yield). HPLC retention time 8.54 min.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([CH3:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:37]([CH3:38])=[CH:36][CH:35]=[C:34]([C:39](O)=[O:40])[C:33]2=[O:42])=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:19]1([C:17]([NH:16][C:14]2[N:15]=[C:10]3[CH:9]=[CH:8][C:7]([O:6][C:5]4[CH:22]=[CH:23][C:2]([NH:1][C:39]([C:34]5[C:33](=[O:42])[N:32]([C:29]6[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=6)[C:37]([CH3:38])=[CH:36][CH:35]=5)=[O:40])=[CH:3][C:4]=4[CH3:24])=[CH:12][N:11]3[CH:13]=2)=[O:18])[CH2:20][CH2:21]1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1
Reactant: Cc1cc(N)ccc1Oc1ccc2nc(NC(=O)C3CC3)cn2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)c2ccc(C)n(-c3ccc(F)cc3)c2=O)ccc1Oc1ccc2nc(NC(=O)C3CC3)cn2c1
Yield: 73.5 %

Procedure:
Using N-[6-(4-amino-2-methylphenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (100 mg, 0.31 mmol), 1-(4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (99.7 mg, 0.403 mmol), N,N-dimethylformamide (1 mL), N,N-diisopropylethylamine (107 μL, 0.620 mmol) and HATU (153 mg, 0.403 mmol) and in the same manner as in Example 57, the title compound (125.7 mg, 74%) was obtained as a white solid.