Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[CH2:30]([O:32][C:33]1[CH:47]=[CH:46][C:36]([O:37][CH2:38][CH:39]2[CH2:44][CH2:43][C:42](=O)[CH2:41][CH2:40]2)=[C:35]([F:48])[C:34]=1[F:49])[CH3:31].O>C1COCC1>[CH2:30]([O:32][C:33]1[CH:47]=[CH:46][C:36]([O:37][CH2:38][CH:39]2[CH2:44][CH2:43][C:42](=[CH:2][O:3][CH3:4])[CH2:41][CH2:40]2)=[C:35]([F:48])[C:34]=1[F:49])[CH3:31]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1ccc(OCC2CCC(=O)CC2)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc(OCC2CCC(=COC)CC2)c(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
In a reactor under nitrogen atmosphere, 50 mL of THF was added to 14.7 g of methoxymethyltriphenylphosphonium chloride, and the mixture was cooled to −20° C., to which 4.8 g of t-BuOK was added, followed by stirring for 1 hour. A solution containing 8.1 g of 4-(4-ethoxy-2,3-difluorophenoxymethyl)cyclohexanone obtained in the fifth step dissolved in 100 mL of THF was added dropwise thereto, followed by stirring for 1 hour. The temperature of the reaction mixture was increased to room temperature, and 200 mL of water was added to the reaction mixture, which was extracted three times with 300 mL of toluene. The resulting organic layer was washed with water, dried over anhydrous magnesium sulfate, and the solvent was concentrated to about 200 mL under reduced pressure, and the concentrated solution was placed in 1,000 mL of n-hexane, followed by removing the deposited solid matters. The solvent was distilled off from the resulting solution under reduced pressure, and the residue was purified by silica gel column chromatography to provide 8.3 g of 1-ethoxy-2,3-difluoro-4-(4-methoxymethylenecyclohexylmethoxy)benzene.
Reaction SMILES: [CH:1](=[O:3])[CH3:2].Cl.O1[CH2:9][CH2:8][CH2:7][CH2:6]1>O>[C:1]1(=[O:3])[C:9]2[C:8](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:7]=[CH:6][CH2:2]1
Reactant: C1CCOC1
Reactant: CC=O
Agent: Cl
Solvent: O
Product: O=C1CC=Cc2ccccc21
Yield: 52.1 %

Procedure:
The acetaldehyde intermediate (4) (2.1 g, 10 mmol) was taken up in tetrahydrofuran (200 mL), and water (0.5 mL) and concentrated hydrochloric acid (1.0 mL) were added. The solution was heated at reflux for 5 hrs., then diluted with water (20 mL) and evaporated at reduced pressure to remove most of the tetrahydrofuran. The residual aqueous solution was extracted with ether (3×200 mL), and the combined ether extracts were successively washed with saturated sodium bicarbonate solution (20 mL), brine (50 mL), then dried and concentrated to give a semisolid. Recrystallization from benzene hexane provided 1.0 g (52.1%) of compound (5). mp 86°-91° C., 1H NMR (CDCl3) δ7.04-6.78 (m, 1H), 6.12-5.84 (m, 1H), 2.60-1.0 (m, 11H), 2.16 (s, 3H); mass spectrum, m/z 192 (M+).
Reaction SMILES: [C:1]([NH:5][C:6]1[N:15]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[C:14](=[O:23])[C:13]2[C:8](=[C:9](I)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:25][C@@H:26]1[C:30]2[NH:31][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:33][C:29]=2[C:28](=[O:43])[NH:27]1>>[C:1]([NH:5][C:6]1[N:15]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH3:22])[C:14](=[O:23])[C:13]2[C:8](=[C:9]([C:32]3[NH:31][C:30]4[C@@H:26]([CH3:25])[NH:27][C:28](=[O:43])[C:29]=4[CH:33]=3)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Reactant: COCCOCCn1c(NC(C)(C)C)nc2c(I)cccc2c1=O
Product: COCCOCCn1c(NC(C)(C)C)nc2c(-c3cc4c([nH]3)[C@@H](C)NC4=O)cccc2c1=O
Yield: 40.2 %

Procedure:
This compound (102 mg, 40% yield) as a tan amorphous solid was prepared according to the procedure described for Example 448, using 2-(tert-butylamino)-8-iodo-3-(2-(2-methoxyethoxyl)ethyl)quinazolin-4(3H)-one (716) (250 mg, 0.56 mmol) and (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705) (178 mg, 0.68 mmol) as the starting materials. 1H NMR (400 MHz, MeOH-d4) δ ppm 7.99 (2H, dd, J=7.6, 1.8 Hz), 7.23 (1H, t, J=7.7 Hz), 6.75 (1H, s), 4.69 (1H, q, J=6.8 Hz), 4.27-4.38 (2H, m), 3.90 (2H, t, J=4.3 Hz), 3.67-3.74 (2H, m), 3.55-3.63 (2H, m), 1.60 (9H, s), 1.52 (3H, d, J=6.8 Hz), 1.22 (6H, s). m/z (ESI, +ve) 454.0 (M+H)+.
Reaction SMILES: C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[Cl:15][CH2:16][C:17]([NH:19][CH:20]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:22][CH2:21]1)=[O:18].O.Cl>O1CCCC1>[Cl:15][CH2:16][C:17]([NH:19][C@H:20]1[C@@H:29]([OH:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:22][CH2:21]1)=[O:18]
Reactant: O=C(CCl)NC1COc2ccccc2C1=O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCl)N[C@@H]1COc2ccccc2[C@@H]1O
Yield: 0.1 %

Procedure:
Lithium tri-sec-butylborohydride (1.0 M solution in tetrahydrofuran, 190 ml, 190 mmol) was added to a solution of 2-chloro-N-(4-oxo-chroman-3-yl)-acetamide (22.6 g, 94.3 mol) in tetrahydrofuran (1000 ml). When the reaction was complete (checked by thin layer chromatography), excess reagent was decomposed by the addition of water and pH was adjusted to 5-6 with 3N aqueous hydrochloric acid. The solution was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford 2-chloro-N-((3RS,4SR)-cis-4-hydroxychroman-3-yl)-acetamide (19 g, 78.6 mmol, 83%) as white crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[CH3:13]S(C)=O.CI.C(=O)([O-])[O-].[K+].[K+]>O>[Br:1][C:2]1[C:3]([F:12])=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH3:13])[C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Br)c(F)cc2o1
Reactant: CS(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: Cn1c(=O)oc2cc(F)c(Br)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask was charged with 5-bromo-6-fluorobenzo[d]oxazol-2(3H)-one (3.6 g, 14.74 mmol) and DMSO (150 mL), and MeI (4.18 g, 29.5 mmol) and potassium carbonate (5.09 g, 36.9 mmol) were added. The mixture was stirred at room temperature overnight. The mixture was poured to water (1.2 L) and the precipitate was filtered, washed with water and dried under high vacuum at 60° C. for 1 h to give 5-bromo-6-fluoro-3-methylbenzo[d]oxazol-2(3H)-one. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.32 (s, 3H) 7.62 (d, J=8.34 Hz, 1H) 7.70 (d, J=6.06 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1OS(C(F)(F)F)(=O)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.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]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:10]=[CH:11][C:12]=1[C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[F:21]
Reactant: CCOC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(Cl)c1
Reactant: COc1ccc(F)c(B(O)O)c1
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: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cc(OC)ccc2F)c(Cl)c1
Temperature: 100 °C

Procedure:
A reaction mixture of ethyl 3-chloro-4-(trifluoromethylsulfonyloxy)benzoate (T1.5) (3.00 g, 9.02 mmol), 2-fluoro-5-methoxyphenylboronic acid (commercially available from Aldrich) (1.84 g, 10.8 mmol), tetrakis(triphenylphosphine)palladium (0.521 g, 0.451 mmol) and potassium carbonate (2.49 g, 18.0 mmol) in DMF (20 mL), was purged with N2 three times and then heated at 100° C. for 4 hours. The reaction was cooled to room temperature, and EtOAc (130 mL) was added. The mixture was then washed with brine (30×4 mL). The organic layer was dried over MgSO4. The residue was purified by CombiFlash® silica gel column (eluting with hexane/EtOAc; 85/15) to give T1.6. 1H NMR (400 MHz, CDCl3) δ ppm 8.08 (d, 1H), 7.90 (d, 1H), 7.33 (dd, 1H), 6.96-7.02 (m, 1H), 6.82-6.85 (m, 1H), 6.74 (d, 1H), 4.33 (q, 2H), 4.31 (s, 3H), 1.34 (t, 3H). MS ESI (pos.) m/e: 309.1 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[CH:28]=[CH:27][O:26][CH:25]=2)=[O:23])=[CH:17][C:16]=1B1OC(C)(C)C(C)(C)O1>CC(O)C>[CH3:14][C:15]1[C:16]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)=[CH:4][CH:3]=2)=[CH:17][C:18]([NH:21][C:22]([C:24]2[CH:28]=[CH:27][O:26][CH:25]=2)=[O:23])=[CH:19][CH:20]=1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nnc(-c2ccc(I)cc2)o1
Solvent: CC(C)O
Product: Cc1nnc(-c2ccc(-c3cc(NC(=O)c4ccoc4)ccc3C)cc2)o1

Procedure:
Example 35 was prepared using 2-(4iodophenyl)-5-methyl-[1,3,4]oxadiazole (Intermediate 15) and N-[4-methyl-3-(4,4,5,5, -tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 25) with propan-2-ol as the solvent.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11].[Cl:18][C:19]1[CH:20]=[C:21](O)[CH:22]=[CH:23][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([O:9][C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:18])[CH:24]=2)[CH2:6][N:5]1[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:11]
Reactant: Oc1cccc(Cl)c1
Reactant: CCCCOC(=O)N1C[C@@H](O)C[C@H]1C(=O)OC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCOC(=O)N1C[C@H](Oc2cccc(Cl)c2)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
To a mixture of N-α-butoxycarbonyl-cis-4-hydroxy-L-proline methylester 123 mg (0.50 mmol), 3-chlorophenol 0.058 ml (0.55 mmol), triphenylphosphine 184 mg (0.70 mmol) and tetrahydrofuran 2 ml was added diisopropyl azodicarboxylate 0.150 ml (0.75 mmol) dropwise under ice-cooling and the mixture was stirred at room temperature for 16 hours. The reaction solution was concentrated and the residue was purified by a column chromatography on silica gel (eluted with a mixed solvent of ethyl acetate and hexane) to give 155 mg (0.44 mmol) of the title compound (yield: 87%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:15]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)([NH2:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.O.C([O-])([O-])=O.[K+].[K+].Cl[C:39]([O:41][C:42]([CH3:44])=[CH2:43])=[O:40]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:23][C:39](=[O:40])[O:41][C:42]([CH3:44])=[CH2:43])([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1
Reactant: N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reactant: C=C(C)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)OC(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine (48 mg, 0.11 mmol) was stirred in THF (0.5 mL) and H2O (0.05 mL) at room temperature. K2CO3 (100 mg, 0.72 mmol, 6.6 eq) was added followed by the addition of isopropenyl chloroformate (0.030 mL, 0.275 mmol, 2.5 eq). The reaction mixture was stirred at room temperature overnight. The mixture was filtered, and the filtrate concentrated to dryness to give crude (R)-prop-1-en-2-yl 1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylcarbamate as colorless film (60 mg, yield: quantative). LCMS: 4.18 min 409.27 (M-COOisopropenyl-NH3+H) (4 min gradient, MeOH/H2O 0.1% TFA).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[C:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[C:20]2[CH2:21][C:22]([CH3:29])([CH3:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH2:25]2)[C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(NC(C)=O)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
N-{4-[[4-(methyloxy)phenyl](3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}acetamide (57) (0.27 g, 0.69 mmol) was dissolved in CH2Cl2 (25 mL). The mixture was cooled to −10° C. in an ice-acetone bath. To this solution was added 1 M BBr3 in CH2Cl2 (2.1 mL, 2.07 mmol). The reaction mixture was stirred at −10° C. to 0° C. for 3 h, then poured onto ice, extracted with EtOAc (2×60 mL). The combined organic extract was washed with water, brine and dried over Na2SO4. Upon concentration and trituration with 1:1 hexanes:CH2Cl2, compound 58 was obtained as a light brown solid (0.10 g, 39%). mp 118-121° C. 1H NMR (400 MHz, DMSO-d6): δ 0.85 (s, 6H), 0.86 (s, 6H), 1.23 (s, 2H), 1.87 (s, 2H), 1.89 (s, 2H), 1.98 (s, 3H), 6.64 (d, J=8.3 Hz, 2H), 6.89 (d, J=8.5 Hz, 2H), 7.00 (d, J=8.5 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 9.24 (s, 1H), 9.84 (s, 1H); LCMS (ES): m/z 378 (M+H)+, 376 (M−H)−. Anal. Calcd for C25H31NO2.1/3H2O: C, 78.29; H, 8.32, N, 3.65; Found: C, 78.33; H, 8.26, N, 3.62.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[CH2:13]1[CH:21]2[N:16]([CH2:17][CH2:18][C:19](=O)[CH2:20]2)[CH2:15][CH2:14]1>[OH-].[K+].O>[CH2:13]1[CH:21]2[N:16]([CH2:17][CH:18]=[C:19]([C:7]3[C:6]4[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=4)[NH:9][CH:8]=3)[CH2:20]2)[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: O=C1CCN2CCCC2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1
Yield: 38.2 %

Procedure:
A mixture of 5-nitro-1H-indole (4.48 g, 27.6 mmol) and and 7-octahydroindolizinone (5.0 g, 35.9 mmol) in methanolic potassium hydroxide (10% potassium hydroxide in 50 mL of methanol) was heated to reflux for 3.5 hours. The reaction was diluted with water and the precipitate was collected by filtration. The filter cake was triturated with hot diethyl ether and filtered. The filter cake was recrystallized from methanol and dried to give 2.99 g of the title compound. (38.5%). Calculated for C16H17N3O2 : Theory: C, 67.83; H, 6.05; N, 14.83. Found: C, 68.07; H, 6.27; N, 14.82.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:17][C@@H:16]([NH2:18])[C:15](=[O:19])[N:14]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13][C:12]=2[C:27]=1[CH3:28])([CH3:4])([CH3:3])[CH3:2].C(N1C(=O)[C@H](N[C:46]([N:48]2[CH2:53][CH2:52][CH:51]([N:54]3[CH2:63][C:62]4[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=4)[NH:56][C:55]3=[O:64])[CH2:50][CH2:49]2)=[O:47])CC2C=C(C)C(NC(=O)OC(C)(C)C)=CC=2C1)C1C=CC=CC=1>>[CH2:20]([N:14]1[C:15](=[O:19])[C@H:16]([NH:18][C:46]([N:48]2[CH2:53][CH2:52][CH:51]([N:54]3[CH2:63][C:62]4[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=4)[NH:56][C:55]3=[O:64])[CH2:50][CH2:49]2)=[O:47])[CH2:17][C:11]2[CH:10]=[CH:9][C:8]([NH:7][C:6](=[O:29])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[C:27]([CH3:28])[C:12]=2[CH2:13]1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1c(NC(=O)OC(C)(C)C)ccc2c1CN(Cc1ccccc1)C(=O)[C@H](N)C2
Reactant: Cc1cc2c(cc1NC(=O)OC(C)(C)C)CN(Cc1ccccc1)C(=O)[C@H](NC(=O)N1CCC(N3Cc4ccccc4NC3=O)CC1)C2
Product: Cc1c(NC(=O)OC(C)(C)C)ccc2c1CN(Cc1ccccc1)C(=O)[C@H](NC(=O)N1CCC(N3Cc4ccccc4NC3=O)CC1)C2
Yield: 94 %

Procedure:
(R)-tert-Butyl-4-amino-2-benzyl-9-methyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylcarbamate was reacted in a manner analogous to the preparation of (R)-tert-butyl 2-benzyl-7-methyl-3-oxo-4-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carboxamido)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-8-ylcarbamate. Title compound was obtained as off-white solid in 94% yield.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[OH:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19]>C1COCC1>[C:18]([C:17]1[CH:16]=[C:15]([O:14][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:22]=[CH:21][CH:20]=1)#[N:19]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1cccc(C#N)c1
Temperature: 50 °C
Reaction time: 24 h
Yield: 101.6 %

Procedure:
Ethyl bromoacetate (14.7 g, 88.1 mmol) was added dropwise to a suspension of potassium carbonate (12.8 g, 92.3 mmol) and 3-hydroxybenzonitrile (10.0 g, 83.9 mmol) in THF (50 mL) at room temperature, and the mixture was stirred at 50° C. for 24 hr. The mixture was extracted with ethyl acetate and saturated aqueous ammonium chloride solution, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated to give the title compound as a pale-yellow powder (17.5 g, 99%).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:17])[C:5]=2[CH:4]=1.[Cl-].[Cl:19][CH2:20][CH:21]([OH:27])[CH2:22][N+:23]([CH3:26])([CH3:25])[CH3:24]>Cl.C(O)C>[Cl-:19].[OH:27][CH:21]([CH2:20][O:2][C:3]1[CH:16]=[CH:15][C:14]2[S:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:17])[C:5]=2[CH:4]=1)[CH2:22][N+:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: C[N+](C)(C)CC(O)CCl
Reactant: O=c1c2ccccc2sc2ccc(O)cc12
Agent: Cl
Agent: [Cl-]
Agent: [Na]
Solvent: CCO
Product: C[N+](C)(C)CC(O)COc1ccc2sc3ccccc3c(=O)c2c1

Procedure:
Sodium (1.36 g) was reacted with absolute ethanol (120 mls) and 2-hydroxy-thioxanthone (11.4 g) (prepared by a method analogous to that of H. Christopher and S. Smiles. J.C.S., 1911, 99, 2050-2051) was added. To the stirred refluxing mixture (3-chloro-2-hydroxypropyl)trimethyl ammonium chloride (10.7 g) was added and the mixture refluxed overnight. After adjusting the pH to ca. 4 via the addition of a few drops of 2N isopropanolic hydrogen chloride solution, hot filtration followed by ice bath cooling of the filtrate and filtration gave the crude title compound which was washed with methanol and vacuum dried.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[NH2:34])[CH2:24][CH:23]2[OH:35])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11].C(N(CC)CC)C.Cl[C:44]([O:46][CH2:47][CH3:48])=[O:45]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][C:13]1([C:19]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[NH:34][C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:24][CH:23]2[OH:35])=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:11]
Reactant: Nc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexane carbonyl]amino]-1-(2-aminophenyl)piperidin-3-one (0.9 g) obtained in Step 2 of Example 43 in 20 ml of dichloromethane was cooled to 0° C. 0.54 ml of triethylamine and 0.37 ml of ethyl chloroformate were added to the reaction mixture, which was then stirred for about 3 hours at room temperature. 20 ml of ice water was added to the reaction mixture. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 600 mg of the titled compound.
Reaction SMILES: [CH2:1](N(CC)CC)[CH3:2].Br[C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([N:16]2[CH:26]=[C:19]3[CH:20]=[N+:21]([O-:25])[CH:22]=[C:23]([F:24])[C:18]3=[N:17]2)=[C:11]([Cl:27])[CH:10]=1.C(Cl)(Cl)Cl>C(O)CC.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]>[Cl:15][C:13]1[CH:14]=[C:9]([CH:1]=[CH2:2])[CH:10]=[C:11]([Cl:27])[C:12]=1[N:16]1[CH:26]=[C:19]2[CH:20]=[N+:21]([O-:25])[CH:22]=[C:23]([F:24])[C:18]2=[N:17]1
Reactant: CCN(CC)CC
Reactant: [O-][n+]1cc(F)c2nn(-c3c(Cl)cc(Br)cc3Cl)cc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCCO
Solvent: ClC(Cl)Cl
Product: C=Cc1cc(Cl)c(-n2cc3c[n+]([O-])cc(F)c3n2)c(Cl)c1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
Triethylamine (3.5 mL, 25 mmol) was added to a mixture of 2-(4-bromo-2,6-dichlorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine 5 oxide (1.88 g, 5.0 mmol), potassium vinyl trifluoroborate (1.0 g, 7.5 mmol) and Pd(dppf)Cl2.CHCl3 (408 mg, 0.5 mmol) in propan-1-ol (50 mL) and the reaction mixture was heated at 100° C. for 1.5 hours. The resultant mixture was allowed to cool to room temperature before being partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (4-5% methanol in DCM) to afford the title compound as a beige solid (1.0 g, 62% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.00 (d, J=2.6 Hz, 1H), 8.89 (d, J=1.4 Hz, 1H), 8.35 (dd, J=6.3, 1.5 Hz, 1H), 7.97 (s, 2H), 6.85 (dd, J=17.6, 11.0 Hz, 1H), 6.24 (d, J=17.6 Hz, 1H), 5.60 (d, J=11.0 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:11][CH2:12][C:13]#[N:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].Cl[C:19]1[C:24]([CH3:25])=[CH:23][C:22]([N+:26]([O-:28])=[O:27])=[CH:21][N:20]=1>O1CCCC1>[CH3:25][C:24]1[C:19]([C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:11][CH2:12][C:13]#[N:14])=[N:20][CH:21]=[C:22]([N+:26]([O-:28])=[O:27])[CH:23]=1
Reactant: CCOC(=O)C(CCC#N)C(=O)OCC
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC#N)(C(=O)OCC)c1ncc([N+](=O)[O-])cc1C
Yield: 48.9 %

Procedure:
2-(2-Cyanoethyl)malonic acid diethyl ester (148.3 g) was reacted with sodium hydride (15.3 g) in tetrahydrofuran at 20° C. 2-Chloro-3-methyl-5-nitropyridine (100 g) was added and the internal temperature was raised to 100° C. (some tetrahydrofuran was distilled off) over 14 hrs. The reaction mixture was partitioned between water and chloroform, the chloroform extract was dried, treated with charcoal and filtered through a silica bed and then evaporated to dryness. Crystallisation of the residue from ethanol gave 4-(3-methyl-5-nitropyrid-2-yl)-4,4-bis(carbethoxy)-butyronitrile (99 g) m.p. 64°-65.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]4[CH2:29][O:28]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:28])[CH2:29][NH:37][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C4CO4)cc3)cc2)CC1
Reactant: NCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CNCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 187, Step 2, using 1-[4′-(3-methyl-4-oxiranyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and benzyl amine.