Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)Cl.[CH2:4]([OH:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]#[CH:11].Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1>C(N(CC)CC)C>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:11]#[C:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][OH:12])[CH:15]=1
Reactant: Brc1cccnc1
Reactant: C#CCCCCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCCCCCC#Cc1cccnc1
Yield: 91.1 %

Procedure:
A flame-dried, 22-L flask equipped with a mechanical stirrer, condenser, and a gas inlet tube dipping below the surface of the solvent was charged with 4.0 L of methylene chloride, 1.25 L of triethylamine, 385 g of 7-octyn-1-ol, and 285 mL (456 g) of 3-bromopyridine. The reagents were rinsed into the flask with an additional 100 mL of methylene chloride. Argon was bubbled through the reaction mixture for 30 minutes. The flask was evacuated for 3 minutes at 70 mm. The vacuum was released by bubbling in argon. This process was repeated six times and then 42 g of dichlorobis(triphenyl phosphine)palladium (II) and 4 g of cuprous iodide were added. The mixture was heated at a gentle reflux for 18 hours and cooled to 20°. To the mixture was added, with vigorous stirring, 8.0 L of ether. A small amount of yellowish-white solid was removed by filtration and washed with 2×1.5 L=3.0 L of ether. The combined filtrate was washed with 3.0 L of deionized water and 2×3.0 L=6.0 L of 1N hydrochloric acid. The combined aqueous solutions were washed with 2×2.5 L=5.0 L of ether. The organic solutions were discarded and the aqueous solution was made strongly basic by the addition of 2.50 L of 20% sodium hydroxide solution. The resulting mixture was extracted with 3×4.0 L=12.0 L of methylene chloride. The extracts were dried over sodium sulfate and filtered through Celite. Solvent removal on a rotary evaporator at 45° gave 534.2 g (91% yield) of a pale brown 8-(3-pyridinyl)-7-octyn-1-ol having a strong odor of 3-bromopyridine. No further purification of this material was undertaken.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4]([CH:7]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(=[O:6])[CH3:5].[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30])#[N:25].Cl>ClCCl.C(OCC)(=O)C.N1C=CC=CC=1>[C:4]([C:7]([C:29](=[O:30])[C:28]1[CH:32]=[CH:33][CH:34]=[C:26]([C:24]#[N:25])[CH:27]=1)([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])(=[O:6])[CH3:5]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: CCOC(=O)CCCCC(C(C)=O)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCC(C(C)=O)(C(=O)OC(C)(C)C)C(=O)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 72.9 %

Procedure:
To a suspension of magnesium chloride (1.33 g) in dichloromethane (40 mL) was added 1-tert-butyl 7-ethyl 2-acetylheptanedioate (4.0 g) at ambient temperature under N2. To this mixture was added dropwise pyridine (2.26 mL) in an ice-water bath. Then the mixture was stirred at ambient temperature for 40 minutes. To the reaction mixture was added a solution of 3-cyanobenzoyl chloride (3.01 g) in dichloromethane (6 mL) dropwise over 2 minutes. The reaction mixture was stirred at ambient temperature for 2 hours. To the mixture was added 1N hydrogen chloride and ethyl acetate in an ice-water bath. The organic layer was washed with 1N hydrogen chloride, water, and brine, dried over magnesium sulfate, and evaporated in vacuo to give a solid. The residue was purified by flash silica gel chromatography (silica gel, 300 mL) eluting with hexane-ethyl acetate=10-1, 8-1, 5-1, and 3-1 to give 1-tert-butyl 7-ethyl 2-acetyl-2-(3-cyanobenzoyl)heptanedioate (4.23 g, 72.9%) as colorless oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].C1([Mg]Cl)C=CC=CC=1.[CH:21](=[O:25])[CH:22]([CH3:24])[CH3:23]>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:21]([OH:25])[CH:22]([CH3:24])[CH3:23])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(I)c([N+](=O)[O-])c1
Reactant: CC(C)C=O
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C(O)C(C)C)c([N+](=O)[O-])c1
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 66.6 %

Procedure:
To a solution of 4-iodo-3-nitroanisole (2.79 g, 10.0 mmol) in anhydrous THF (20 mL) at minus 40° C. under a nitrogen atmosphere, phenylmagnesium chloride (2 M in THF, 6.0 mL, 12 mmol) was added dropwise at a rate such that the temperature would not exceed minus 35° C. Upon completion of the addition, the mixture was stirred at minus 40° C. for five min, followed by addition of isobutyraldehyde (1.8 mL, 20 mmol). The mixture was gradually warmed to room temperature, quenched with saturated NH4Cl solution (5.0 mL), diluted with CH2Cl2 (100 mL) and washed with water (100 mL). The organic phase was separated, and the aqueous phase was extracted with CH2Cl2 (50 mL) three times. The combined organic phase was washed with brine (40 mL), dried over Na2SO4, concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield (R/S)-1-(4-methoxy-2-nitrophenyl)-2-methyl-1-propanol (1.5 g, 67%) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.61 (d, 1H, J=8.8 Hz, Ph-H), 7.34 (d, 1H, J=2.8 Hz, Ph-H), 7.15 (dd, 1H, J=8.8 and 2.8 Hz, Ph-H), 4.92 (dd, 1H, J=5.6 and 3.2 Hz, Ph-CH), 2.46 (br s, 1H, OH), 2.00 (m, 1H, CH), 0.97 (d, 3H, J=6.4 Hz, CH3), 0.86 (d, 3H, J=6.8 Hz, CH3).
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([OH:21])=[N:16][CH:15]=[CH:14]2>CC#N>[I:8][C:14]1[C:13]2[C:18](=[CH:19][CH:20]=[C:11]([O:10][CH3:9])[CH:12]=2)[C:17]([OH:21])=[N:16][CH:15]=1
Reactant: COc1ccc2c(O)nccc2c1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: COc1ccc2c(O)ncc(I)c2c1
Yield: 87.3 %

Procedure:
To a solution of NIS (3.31 g, 14.73 mmol) in CH3CN (25 mL) was added 6-methoxyisoquinolin-1-ol (2.58 g, 14.73 mmol). The resulting suspension was slowly warmed to reflux and maintained refluxing for 2 h. After concentration, the residue was taken into water. The solid was collected through filter paper washing with hot water to give a crude product 4-iodo-6-methoxyisoquinolin-1-ol (3.87 g, 87% yield) which was used in the next step with out further purification. MS: MS m/z 302(M++1). 1H NMR (400 MHz, CHLOROFORM-d) δ 16.12 (br. s., 1H), 12.86 (d, J=9.0 Hz, 1H), 12.34 (d, J=5.8 Hz, 1H), 11.89 (dd, J=8.8, 2.5 Hz, 1H), 11.76 (d, J=2.3 Hz, 1H), 8.70-8.62 (m, 3H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1([CH2:13][CH2:14][CH2:15][CH2:16][C:17](O)=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.O.[OH-].[K+]>CCOCC>[CH:7]1([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C(O)CCCCC1CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: OCCCCCC1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
Under nitrogen atmosphere, at 0° C., to a stirring mixture of 2M LiAlH4 (13.04 mL, 26.08 mmol) solution in Et2O in dry Et2O (67 mL), 5-cyclohexylpentanoic acid (1.2 g, 6.52 mmol) in dry Et2O (2 mL) was added dropwise. The mixture was left to react at rt for 4 h, then upon full conversion of the starting material, at 0° C., H2O (13.04 mL), 3M KOH (13.04 mL) solution and H2O (43.65 mL) were very slowly added. The mixture was stirred for 1 h at 0° C., filtered to remove the solid residue, and the remaining organic phase dried over Na2SO4. The organic solution was again filtered and concentrated to dryness affording the title compound (0.98 g, 88%) as a colorless oil. 1H NMR (DMSO-d6): δ 0.77-0.93 (m, 2H), 1.06-1.34 (m, 10H), 1.35-1.47 (m, 2H), 1.56-1.76 (m, 5H), 3.37 (t, J=6.6 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:19]=[C:12]2[CH:13]=[N+:14]([O-:18])[CH:15]=[C:16](F)[C:11]2=[N:10]1.[CH3:20][O-:21].[K+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH:19]=[C:12]2[CH:13]=[N+:14]([O-:18])[CH:15]=[C:16]([O:21][CH3:20])[C:11]2=[N:10]1
Reactant: [O-][n+]1cc(F)c2nn(-c3c(Cl)cccc3Cl)cc2c1
Reactant: C[O-]
Agent: [K+]
Solvent: CO
Product: COc1c[n+]([O-])cc2cn(-c3c(Cl)cccc3Cl)nc12
Yield: 85.1 %

Procedure:
A suspension of 2-(2,6-dichlorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine-5-oxide (1.5 g, 5 mmol) and potassium methoxide (525 mg, 7.5 mmol) in methanol (10 mL) was sealed in a microwave vial, purged with nitrogen and irradiated at 150° C. for 30 minutes in the microwave. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was triturated with ether to afford the title compound as a beige solid (1.32 g, 85% yield). LCMS (Method D): RT=2.31 min, m/z: 310 [M+H+].
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C:19]([N:21]1[C@H:26]([C:27]2[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=2)[CH2:25][O:24][CH2:23][C@@H:22]1[C@H:36]([OH:38])[CH3:37])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1.[Cl-].[NH4+].C(OCC)(=O)C>[CH2:11]([O:18][C:19]([N:21]1[C@H:26]([C:27]2[CH:32]=[C:31]([F:33])[C:30]([F:34])=[C:29]([F:35])[CH:28]=2)[CH2:25][O:24][CH2:23][C@@H:22]1[C:36](=[O:38])[CH3:37])=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[C@@H](O)[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1C(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)[C@H]1COC[C@@H](c2cc(F)c(F)c(F)c2)N1C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 91.4 %

Procedure:
A solution of dimethylsulfoxide (0.22 mL) in tetrahydrofuran (15 mL) was cooled to −78° C. and then oxalyl chloride (246 μL) was dropwise added thereto. The resultant solution was stirred at the same temperature for 5 minutes, and to the reaction mixture was then dropwise added a solution of (3R,5R)-3-((R)-1-hydroxyethyl)-5-(3,4,5-trifluorophenyl)morpholine-4-carboxylic acid benzyl ester (880 mg) in tetrahydrofuran (5 mL). The resultant solution was stirred at the same temperature for 1 hour, and triethylamine (1.54 mL) was then added thereto. The temperature of this solution was returned to room temperature. The solution was then stirred for 1 hour. The reaction solution was diluted with aqueous ammonium chloride and ethyl acetate, and the organic layer was partitioned. The organic layer was dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure. The resultant product was purified by silica gel column chromatography (heptane/ethyl acetate), to thereby obtain the titled compound (800 mg). The physical properties of this crude product were as follows.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]([CH2:6][S:7][C:8]2[C:18]3[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13][C:12]=3[CH:11]=[CH:10][C:9]=2[Cl:26])=[CH:4][C:3]=1[F:29].CC(C)([O-])C.[Na+].C1OCCOCCOCCOCCOCCOC1.[NH:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:22]([O:21][C:19]([N:15]1[CH2:16][CH2:17][C:18]2[C:8]([S:7][CH2:6][C:5]3[CH:27]=[CH:28][C:2]([N:54]4[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]4)=[C:3]([F:29])[CH:4]=3)=[C:9]([Cl:26])[CH:10]=[CH:11][C:12]=2[CH2:13][CH2:14]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(Br)c(F)c3)c2CC1
Agent: [Pd]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(N4CCCCC4)c(F)c3)c2CC1
Temperature: 25 °C
Yield: 53 %

Procedure:
In a sealed tube, add tris(dibenzylideneacetone)dipalladium (13 mg, 0.014 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (19 mg, 0.029 mmol) to a mixture of 6-(4-bromo-3-fluorobenzylthio)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (957 mg, 1.91 mmol), sodium tert-butoxide (367 mg, 3.83 mmol), 18-crown-6 (50 mg, 0.191 mmol) and piperidine (944 μl, 9.57 mmol) in toluene (10 mL). Flush the mixture with nitrogen and heat overnight. Cool to ambient temperature, dilute with water and extract three times with EtOAc. Dry over anhydrous Na2SO4 and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) to give 3-tert-butoxycarbonyl-7-chloro-6-(3-fluoro-4-piperidin-1-yl-benzylthio)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow oil (511 mg, 33%). Use a method similar to the General Procedure 1-4 to give the title compound as a white solid. MS (ES+) m/z: 405 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:23]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:24]([C:40]([NH:42][CH2:43][C:44](O)=[O:45])=[O:41])[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CN(C=O)C>[NH:23]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:24]([C:40]([NH:42][CH2:43][C:44]([NH:1][C@H:2]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1)=[O:45])=[O:41])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:30][CH:31]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NCC(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)NCC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)NCc1ccccc1

Procedure:
compound PSV11R. Same procedure as above with Trp-NHCH2Ph (82.43 mg, 0.281 mmol), N-Boc-Tyr(Bn)-Gly-OH (109.26 mg, 0.255 mmol), EDC (53.87 mg, 0.281 mmol) and HOBt (37.97 mg, 0.281 mmol) in CH2Cl2/DMF (2 mL/0.8 mL). The crude residue was triturated with CH2Cl2/pentane to afford a white solid (113.76, 63%). mp 183° C. 1H NMR (300 MHz, CDCl3) δ 1.38 (s, 9H, (CH3)3), 2.81 (m, 2H, CH2 Tyr), 3.26 (m, 2H), 3.72 (m, 2H, CH2 Gly), 4.30 (m, 3H, CHα and CH2Bn), 4.80 (m, 1H, CHα), 5.0 (broad s, 3H, NHBoc and CH2O), 6.72 (m, 1H, NH Gly), 6.90-7.40 (m, 20H, aromatic H and NH), 7.63 (d, 1H, J=7 Hz), 8.35 (s, 1H, NH indole). 13C NMR (75 MHz, CDCl3) δ 28.3 (CH2 Trp and (CH3)3), 37.5 (CH2 Tyr), 43.1, 43.5 (CH2 (Bn), CH2 Gly), 54.0, 55.8 (CHα Tyr, Trp), 70.0 (CH2 (Bn)), 80.4 (C(CH3)3), 110.2, 111.3, 114.9, 118.7, 119.5, 122.0, 123.4, 127.2, 127.4, 127.5, 127.7, 128.0, 128.5, 128.6, 128.7, 130.3, 136.1, 137.0, 137.9 (20 aromatic C), 155.7, 157.7 (Car-O, CO carbamate), 168.9, 171.4, 172.5 (3 CO amide). Anal. Calcd. for C41H45N5O6, 1H2O: C, 68.22; H, 6.56; N, 9.71. Found: C, 68.50; H, 6.48; N, 9.98.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([C:38](=O)[CH:39]([CH3:41])[CH3:40])=[CH:34][CH:33]=3)[CH2:27][CH2:26]2)[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([CH2:38][CH:39]([CH3:41])[CH3:40])=[CH:34][CH:33]=3)[CH2:27][CH2:26]2)[C:10]([CH:12]2[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)C(=O)c1ccc(CC2CCN(CCCN(C(=O)C3CCN(S(C)(=O)=O)CC3)c3ccc(Cl)c(Cl)c3)CC2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1ccc(CC2CCN(CCCN(C(=O)C3CCN(S(C)(=O)=O)CC3)c3ccc(Cl)c(Cl)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76 %

Procedure:
To a stirred solution of the title compound of example 335 (318 mg, 0.50 mmol) in trifluoroacetic acid (5 mL) was added triethylsilane (0.399 mL, 2.50 mmol),and the mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated under reduced pressure, 1N aqueous sodium hydroxide (15 mL) was added and the aqueous layer was extracted with ethyl acetate (15 mL, 2×10 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was subjected to column chromatography (silica gel 10 g, ethyl acetate/methanol=1/0 to 9/1). The fractions containing the product were collected and evaporated under reduced pressure. Diisopropyl ether was added to the residue, the resulting precipitate was collected by filtration, washed with diisopropyl ether and dried under reduced pressure to afford the title compound (236 mg, 0.38 mmol, yield 76%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][NH:5][C:6](=O)[CH2:7][CH2:8][CH3:9].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:1][O:2][C:3](=[O:11])[CH2:4][NH:5][C:6](=[S:21])[CH2:7][CH2:8][CH3:9]
Reactant: CCCC(=O)NCC(=O)OC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(=S)NCC(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of the product of Example 5A (0.774 g, 4.862 mmol) in anhydrous THF (50 mL) was treated with Lawesson reagent (1.338 g, 3.209 mmol), then heated at reflux under a nitrogen atmosphere for 30 minutes. The reaction was cooled to 0° and a saturated aqueous sodium bicarbonate solution (40 mL) was slowly added dropwise. The mixture was stirred at room temperature for 15 minutes, and then extracted with ethyl acetate (100 mL), and the organic extract washed with saturated aqueous sodium bicarbonate (50 mL), water (2×25 mL), and brine. Dried the organic phase over anhydrous sodium sulfate, filtered, and concentrated under vacuum giving the title compound. Purification by silica gel flash chromatography with 1% ethyl acetate/methylene chloride afforded the title compound as a colorless oil (0.790 g, 4.508 mmol, 93%).
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:11][C:12]([CH:15]=O)=[C:13]([CH3:14])[C:6]=2[C:5]1=[O:17].[Br:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])[CH2:29]2.N1CCCCC1>C(O)C>[Br:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])/[C:29]/2=[CH:15]\[C:12]1[NH:11][C:7]2[CH2:8][CH2:9][CH2:10][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:18][N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)[C:5](=[O:17])[C:6]=2[C:13]=1[CH3:14]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CCC2
Reactant: O=C1Cc2cc(Br)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(/C=C2\C(=O)Nc3ccc(Br)cc32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CCC2
Temperature: 45 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
(S)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexa hydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 78f (40 mg, 0.12 mmol) and 5-bromo-1,3-dihydro-indol-2-one (25 mg, 0.12 mmol) were dissolved in 1.5 ml of ethanol, and added with 6 μl of piperidine to the solution at room temperature. Upon completion of the addition, the reaction mixture was stirred at 45° C. for 16 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (1 ml×2) and dried to obtain the title compound (S,Z)-2-((5-bromo-2-oxoindolin-3-ylidene)methyl)-5-(2-hydroxy-3-morpholinoprop yl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 80 (51 mg, yield 81%) as a yellow solid.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([C@@H:15]([CH3:19])[C:16](=[O:18])[CH3:17])[N:13]([C:20](=[P:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])[C:12]1=[O:46])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[CH2:55]([O:58][C:59]([N:61]1[CH2:65][CH2:64][CH2:63][C@H:62]1[CH:66]=[O:67])=[O:60])[CH:56]=[CH2:57].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH2:55]([O:58][C:59]([N:61]1[CH2:65][CH2:64][CH2:63][C@H:62]1[CH:66]([OH:67])[CH2:17][C:16](=[O:18])[C@@H:15]([C@H:14]1[N:13]([C:20](=[P:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])[C:12](=[O:46])[C@@H:11]1[C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[CH3:10])[CH3:19])=[O:60])[CH:56]=[CH2:57]
Reactant: C=CCOC(=O)C(N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](C)C(C)=O)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CCOC(=O)N1CCC[C@H]1C=O
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)C(N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](C)C(=O)CC(O)[C@@H]1CCCN1C(=O)OCC=C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
To a solution of diisopropylamine (7.7 ml) in tetrahydrofuran (60.0 ml) was added dropwise a 1.55M solution of n-butyllithium in n-hexane (32.3 ml) at -78° C. The mixture was allowed to warm to 0° C., stirred at 0° C. for 30 minutes, and cooled to -78° C. to give ca. 0.5M lithium diisopropylamide solution. To a solution of allyl 2-[(3S,4R)-3-{(1R)-1-t-butyldimethylsilyloxyethyl}-4-{(1R)-1-methyl-2-oxopropyl}-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetate (2.50 g) in tetrahydrofuran (40 ml) was added dropwise the lithium diisopropylamide solution (9.50 ml) obtained above at -78° C. After stirring for 30 minutes at -78° C., to the mixture was added a solution of (2S)-1-allyloxycarbonyl-2-formylpyrrolidine (1.39 g) in tetrahydrofuran (10.0 ml) and the mixture was allowed to warm to -30° C. over a period of 45 minutes. To this mixture was added aqueous ammonium chloride (50 ml) and diluted with ethyl acetate (200 ml). The organic layer was separated, washed in turn with water, aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate. Evaporation of the solvent gave a residue which was chromatographed on silica gel (150 ml) eluting with a mixture of dichloromethane and acetone (9:1-8:2 V/V) to give allyl 2-[(3S,4R)-4-[(1R)-4-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-4-hydroxy-1-methyl-2-oxobutyl]-3-{ (1R)-1-t-butyldimethylsilyloxyethyl}-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetate (2.36 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[NH:36][C:37]2[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2>>[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]1[N:36]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)[C:37]2[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Reactant: c1ccc(-c2cc3ccccc3[nH]2)nc1
Product: O=S(=O)(Nc1nccnc1-c1ccc(Cn2c(-c3ccccn3)cc3ccccc32)cc1)c1ccccc1C(F)(F)F
Yield: 56 %

Procedure:
Following the general method as outlined in Example 1 (Method A), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 2-pyridine-2-yl-1H-indole, the title compound was isolated as a yellow solid in 56% yield (92% purity by HPLC).