Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:7][C:8]1[CH:9]=[C:10]([CH:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][NH2:16])[CH:11]=[CH:12][CH:13]=1)[CH2:4][CH2:5][CH3:6].Cl[CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27].O>CN(C=O)C>[CH2:3]([O:7][C:8]1[CH:9]=[C:10]([CH:14]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:15][NH:16][CH2:25][C:26]([N:28]([CH3:30])[CH3:29])=[O:27])[CH:11]=[CH:12][CH:13]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOc1cccc(C(CN)C(=O)OC(C)(C)C)c1
Reactant: CN(C)C(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1cccc(C(CNCC(=O)N(C)C)C(=O)OC(C)(C)C)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a suspension of NaH (60%, 2.0 g, 51 mmol) in dry DMF (125 ml) cooled at 0° C., a solution of 2-(3-butoxyphenyl)-(tert-butoxycarbonyl)ethylamine (7.5 g, 25.5 mmol) in dry DMF (125 ml) was added dropwise. After 1 h at room temperature, 2-chloro-N,N-dimethylacetamide (5.2 ml, 51 mmol) was added and the mixture was stirred for 16 h at room temperature. H2O (10 ml) was added and the solvent was evaporated under reduced pressure. The residue was dissolved in H2O (150 ml) and extracted with CH2Cl2 (2×150 ml). The collected organic phases were dried over Na2SO4, filtered and evaporated. The crude was purified by flash chromatography (petroleum ether/EtOAc 4:6) affording the title compound (7.2 g, 75%) as light yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]2[C:8]([CH3:10])(C)[CH:5]([CH2:6]2)[CH2:4][CH:3]=1.[C:11]1(O)C=CC=CC=1.C1(=O)OC(=O)C=C1.C=O>>[CH2:10]1[CH:8]2[CH:5]3[CH:4]=[CH:3][CH:2]([CH:7]2[CH:6]=[CH:11]1)[CH2:1]3
Reactant: Oc1ccccc1
Reactant: CC1=CCC2CC1C2(C)C
Agent: C=O
Agent: O=C1C=CC(=O)O1
Product: C1=CC2C3C=CC(C3)C2C1
Temperature: 120 °C
Yield: 2044.7 %

Procedure:
1350 g of dicyclopentadiene are polymerized in the presence of 150 g of α-pinene at 230° C under a pressure of 4 atmospheres. A semisolid, yellow paste is obtained. 100 g of this product and 47 g of phenol are heated to 120° C. Simultaneously 15 g of maleic anhydride and 4 g of paraformaldehyde are added. After maintaining the mixture for 30 minutes at 120° C heating takes place for 6 hours to 220° C, the pressure being reduced for the last 30 minutes of the reaction. 145 g (=87.5%) of a yellow resin having a melting point of 76° to 78° C and a viscosity of 70 cP are obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:14](Cl)(=O)C(Cl)=O.CN(C=O)C.C(N(CC)CC)C>ClCCl.CN(C1C=CN=CC=1)C.O.CO>[CH3:14][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=[C:2]([I:1])[CH:3]=1
Reactant: O=C(O)c1cc(I)cc([N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(I)cc([N+](=O)[O-])c1
Reaction time: 2 h
Yield: 98 %

Procedure:
To a solution of 3-iodo-5-nitro-benzoic acid (5.88 g, 20.07 mmol) in dichloromethane (60 mL) at room temperature under nitrogen was added oxalyl chloride (1.92 mL, 24.28 mmol) and a drop of DMF. The mixture was stirred for 1 h. methanol (20 mL), DMAP (0.245 g, 2.00 mmol), and triethylamine (3.08 mL, 24.28 mmol) were added and the mixture was stirred for an additional 2 h. Water was added and the product was extracted, washed with water, then brine, dried over magnesium sulfate and concentrated to dryness. Purification by chromatography gave 6.04 g of 3-iodo-5-nitro-benzoic acid methyl ester, as a yellow solid.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[CH3:5][CH:6]([CH3:12])[C:7](OCC)=[O:8].NCC(N)(C)C>C(OCC)(=O)C>[CH3:5][CH:6]([CH3:12])[C:7]([NH:3][CH2:2][CH2:1][NH2:4])=[O:8]
Reactant: NCCN
Reactant: CCOC(=O)C(C)C
Agent: CC(C)(N)CN
Solvent: CCOC(C)=O
Product: CC(C)C(=O)NCCN

Procedure:
The procedure of Example IX was repeated in all essential details to produce the above compound, except that equivalent amounts of ethylenediamine and ethyl 2,2-dimethylacetate were substituted for 1,2-diamino-2-methylpropane and ethyl acetate, respectively. The product, which was identified by NMR and IR spectroscopy, was recovered as an oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:31]([Cl:34])=[CH:32][N:33]=1)[C:5]([NH:7][C:8]1[CH:30]=[CH:29][C:11]2[CH2:12][CH2:13][C:14]3[C:15]([C:26]([NH2:28])=[O:27])=[N:16][N:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[C:18]=3[C:10]=2[CH:9]=1)=[O:6].[CH3:35][N:36]1[CH2:42][CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:34][C:31]1[C:4]([C:5]([NH:7][C:8]2[CH:30]=[CH:29][C:11]3[CH2:12][CH2:13][C:14]4[C:15]([C:26]([NH2:28])=[O:27])=[N:16][N:17]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=5)[C:18]=4[C:10]=3[CH:9]=2)=[O:6])=[CH:3][C:2]([N:39]2[CH2:40][CH2:41][CH2:42][N:36]([CH3:35])[CH2:37][CH2:38]2)=[N:33][CH:32]=1
Reactant: CN1CCCNCC1
Reactant: NC(=O)c1nn(-c2ccc(F)cc2)c2c1CCc1ccc(NC(=O)c3cc(Cl)ncc3Cl)cc1-2
Product: CN1CCCN(c2cc(C(=O)Nc3ccc4c(c3)-c3c(c(C(N)=O)nn3-c3ccc(F)cc3)CC4)c(Cl)cn2)CC1
Reaction time: 24 h
Yield: 78.3 %

Procedure:
The title compound was synthesized by the same procedure as in Example 214 starting with the title compound of Example 248 (1 g, 0.0020 mol) and 1-methylhomopiperazine (4.6 g, 0.040 mol). The reaction was run at 95° C. for 24 h. After allowing the reaction mixture to cool, the volatiles were removed under vacuum. The residue was triturated with H2O to yield 0.899 g of the title compound as a tetrahydrate (yield: 71%). 1H NMR (300 MHz, d6-DMSO): δ 1.81-1.83 (m, 2H), 2.21 (s, 3H), 2.41 (t, 2H, J=5.5 Hz), 2.53 (t, 2H, J=4.56 Hz), 2.87-2.93 (m, 4H), 3.53 (t, 2H, J=5.5 Hz), 3.63-3.67 (m, 2H), 6.62 (s, 1H), 7.19 (d, 1H, J=1.9 Hz), 7.27-7.38 (m, 4H), 7.42-7.45 (dd, 1H, J=8.12 Hz, 1.88 Hz), 7.53-7.58 (m, 3H), 8.07 (s, 1H), 10.31 (s, 1H). M+1=575.
Reaction SMILES: [NH2:1]Cl.[NH4+].[Cl-].[NH4+].[OH-].[O-]Cl.[Na+].[C:10]([C:14]1[CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:17][CH:18]=1)([CH3:13])([CH3:12])[CH3:11].[H-].[Na+]>CCOCC.CN(C=O)C>[C:10]([C:14]1[CH:15]=[C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:17]([NH2:1])[CH:18]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CCOC(=O)c1cc(C(C)(C)C)c[nH]1
Reactant: NCl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C(C)(C)C)cn1N
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
Preparation of Monochloramine by the Method of Hynes, Jr., J. et al., J. Org. Chem., 69:1368 (2004): NH4Cl (3 g, 56 mmol, was mixed in ether (110 mL) and cooled to −5° C. Concentrated NH4OH (4.7 mL) was then added followed by dropwise addition of bleach (Chlorox, 72 mL) over 15 minutes. The mixture was stirred for 15 minutes, the layers separated and the organic layer washed with brine. The organic layer was dried over powdered CaCl2 in the freezer for 1 h and used for the subsequent step immediately. Ethyl 4-tert-butyl-1H-pyrrole-2-carboxylate (1.67 g, 8.6 mmol, 1 eq) was dissolved in DMF. Sodium hydride (60% suspension in oil) (0.41 g, 10 mmol, 1.2 eq) was then added thereto cautiously and stirred for 45 minutes at RT under nitrogen. Monochloramine was then added (0.15M in ether, 68.4 mL, 10 mmol, 1.2 eq). The next morning, the reaction is quenched with saturated aqueous Na2S2O3, diluted with water and extracted into ether. The ether layer is dried, filtered and stripped to yield 3.19 g of ethyl 3-tert-butyl-1-aminopyrrole-5-carboxylate as a yellow oil which eventually crystallized as long needles. MS found: (M+H)+=211.34.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:9][C:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([N:18]2[C:22]([C:23]([F:26])([F:25])[F:24])=[C:21]([C:27]([OH:29])=O)[CH:20]=[N:19]2)[CH2:14][C:13]1([CH3:31])[CH3:30])=[O:11])[CH3:8].[Cl:32][C:33]1[CH:34]=[N:35][CH:36]=[C:37]([Cl:55])[C:38]=1[CH:39]([O:47][Si](CC)(CC)CC)[CH2:40][NH:41][CH2:42][C:43]([CH3:46])([CH3:45])[CH3:44].CCN(C(C)C)C(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>CN(C=O)C.C1COCC1.C(Cl)Cl>[Cl:32][C:33]1[CH:34]=[N:35][CH:36]=[C:37]([Cl:55])[C:38]=1[C:39](=[O:47])[CH2:40][N:41]([CH2:42][C:43]([CH3:44])([CH3:46])[CH3:45])[C:27]([C:21]1[CH:20]=[N:19][N:18]([C@H:15]2[CH2:16][CH2:17][C@H:12]([C:10]([O:9][CH2:7][CH3:8])=[O:11])[C:13]([CH3:30])([CH3:31])[CH2:14]2)[C:22]=1[C:23]([F:24])([F:25])[F:26])=[O:29]
Reactant: CC[Si](CC)(CC)OC(CNCC(C)(C)C)c1c(Cl)cncc1Cl
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)O)c2C(F)(F)F)CC1(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(C(=O)N(CC(=O)c3c(Cl)cncc3Cl)CC(C)(C)C)c2C(F)(F)F)CC1(C)C
Reaction time: 2 h
Yield: 79.2 %

Procedure:
Oxalyl chloride (64 μL, 0.72 mmol) and DMF (1 drop) were added sequentially to a stirring solution of trans-1-(4-(ethoxycarbonyl)-3,3-dimethylcyclohexyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (0.20 g, 0.55 mmol; racemic mixture) and DCM (5.5 mL). After stirring for 2 h, the reaction mixture was concentrated under reduced pressure. The residue was dissolved with THF (4.5 mL), and then a solution of N-(2-(3,5-dichloropyridin-4-yl)-2-((triethylsilyl)oxy)ethyl)-2,2-dimethylpropan-1-amine (0.22 g, 0.55 mmol) and THF (1.0 mL) was added followed by DIPEA (0.29 mL, 1.7 mmol). After stirring for 30 min, TBAF (1.7 mL of a 1.0 M solution with THF, 1.7 mmol) was added. After stirring for 1 h, the reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3, the layers were separated, the organic material washed sequentially with saturated aqueous NaHCO3 (2×) and brine, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved with DCM (5.5 mL) and the resulting solution was treated with Dess-Martin periodinane (0.26 g, 0.60 mmol). After stirring for 10 min, the reaction mixture was concentrated under reduced pressure, the residue was partitioned between THF-EtOAc (1:1 vol/vol) and saturated aqueous NaHCO3, the layers were separated, the organic material was washed sequentially with saturated aqueous NaHCO3 and brine, dried (Na2SO4), filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved with DCM, silica gel (1.0 g) was added to the solution, and the volatiles were removed under reduced pressure. The residue was subjected to flash chromatography on silica gel (gradient elution; 9:1 to 4:1 hexane-EtOAc) to give ethyl trans-4-(4-((2-(3,5-dichloro-4-pyridinyl)-2-oxoethyl)(2,2-dimethylpropyl)carbamoyl)-5-(trifluoromethyl)-1H-pyrazol-1-yl)-2,2-dimethylcyclohexanecarboxylate (0.27 g, 80% overall yield; racemic mixture) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4]([C:6]1[C:7]([OH:31])=[N:8][N:9]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=2[Cl:30])[C:10]=1[N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])=[O:5].[H-].[Na+].S(OCC)(O[CH2:42][CH3:43])(=O)=O.O>CS(C)=O>[Cl:1][C:2]1[CH:35]=[CH:34][CH:33]=[CH:32][C:3]=1[C:4]([C:6]1[C:7]([O:31][CH2:42][CH3:43])=[N:8][N:9]([C:22]2[C:23]([Cl:30])=[CH:24][C:25]([Cl:29])=[CH:26][C:27]=2[Cl:28])[C:10]=1[N:11]1[C:12](=[O:21])[C:13]2=[CH:20][CH:19]=[CH:18][CH:17]=[C:14]2[C:15]1=[O:16])=[O:5]
Reactant: CCOS(=O)(=O)OCC
Reactant: O=C(c1ccccc1Cl)c1c(O)nn(-c2c(Cl)cc(Cl)cc2Cl)c1N1C(=O)c2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N2C(=O)c3ccccc3C2=O)c1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A solution of 0.55 g (1.0 mmol) of the compound of Step C in 10 mL of dry dimethyl sulfoxide was treated portionwise with 36 mg (1.5 mmol) of sodium hydride and the resulting mixture was stirred for 30 minutes at room temperature. Then 0.21 mL (0.25 g, 1.61 mmol) of diethyl sulfate was added and the reaction mixture was stirred for one hour at room temperature. The reaction mixture was poured into water and the product was extracted into ethyl acetate. The extracts were washed with water and dried with brine and magnesium sulfate, and evaporated to a gum. The product was crystallized from boiling ethanol to give the product (230 mg, 40%) as fine crystals, m.p. 215°-216° C.
Reaction SMILES: Cl[C:2]1[C:3]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]2)=[N:4][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[C:21]([CH2:23][CH3:24])[CH:22]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1.C(P(C12CC3CC(CC(C3)C1)C2)[C:44]12[CH2:53]C3CC(CC(C3)[CH2:45]1)C2)CCC.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:53]1([C:2]2[C:3]([N:25]3[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:26]3)=[N:4][C:5]([N:8]3[C:16]4[CH:15]=[C:14]([C:17]5[CH:18]=[N:19][CH:20]=[C:21]([CH2:23][CH3:24])[CH:22]=5)[N:13]=[CH:12][C:11]=4[CH:10]=[N:9]3)=[CH:6][CH:7]=2)[CH2:44][CH2:45]1
Reactant: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Reactant: CCc1cncc(-c2cc3c(cn2)cnn3-c2ccc(Cl)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C3CC3)c(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)c1
Temperature: 105 °C
Reaction time: 72 h
Yield: 248.6 %

Procedure:
A mixture of tert-butyl N-[(3S)-1-[3-chloro-6-[6-(5-ethyl-3-pyridyl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate (0.0801 mmol; 42.8 mg), potassium cyclopropyl trifluoroborate (0.120 mmol; 18.3 mg), butyldi-1-adamantylphosphine (0.0240 mmol; 9.07 mg), cesium carbonate (0.240 mmol; 78.3 mg) and palladium (II) acetate (0.0160 mmol; 3.60 mg) in Water (0.5 mL) and Toluene (4.5 mL) was purged with Argon for 1 minute. The reaction mixture in a pressure tube was stirred at 105° C. for 3 days. The layers were separated. The organic later was concentrated. The residue was purified on silica eluted with 0 to 5% MeOH in DCM to afford tert-butyl N-[(3S)-1-[3-cyclopropyl-6-[6-(5-ethyl-3-pyridyl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate (32.2 mg, 74%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:18]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[NH2:28])[C:19]2=[O:29])[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1.CO>C(O)C>[CH:30]1([C:33]([NH:28][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:25]=2[C:26](=[O:27])[N:18]([C@@H:12]([C:6]2[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[C:19]3=[O:29])=[O:34])[CH2:32][CH2:31]1
Reactant: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3cccc(N)c3C2=O)ccc1OC
Reactant: O=C(Cl)C1CC1
Solvent: CCO
Solvent: CO
Product: CCOc1cc([C@@H](CS(C)(=O)=O)N2C(=O)c3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Reaction time: 0.5 h
Yield: 86 %

Procedure:
A stirred mixture of 2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-4-aminoisoindoline-1,3-dione (1.3 g, 3.1 mmol) and cyclopropane carbonyl chloride (3 mL) was heated to reflux for 45 min. To the cooled mixture was added methanol (10 mL) at 0° C. and the mixture stirred for 30 min. The solvent was removed in vacuo to give an oil. The oil was stirred in ethanol (10 mL) for 2 h to give a suspension. The suspension was filtered and the solid washed with ethanol to give cyclopropyl-N-{2-[(1S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}carboxamide as a white solid (1.3 g, 86% yield); mp, 140-141° C.; 1H NMR (CDCl3) δ0.92-0.99 (m, 2H, 2CHH), 1.11-1.17 (m, 2H, 2CHH), 1.48 (t, J=6.9 Hz, 3H, CH3), 1.61-1.71 (m, 1H, CH), 2.88 (s, 3H, CH3), 3.75 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.12 (q, J=7.1 Hz, 2H, CH2), 4.57 (dd, J=10.4, 14.3 Hz, 1H, CHH), 5.89 (dd, J=4.4, 10.3 Hz, 1H, NCH), 6.84-6.88 (m, 1H, Ar), 7.11-7.15 (m, 2H, Ar), 7.48 (d, J=7.2 Hz, 1H, Ar), 7.65 (t, J=7.4 Hz, 1H, Ar), 8.76 (d, J=8.5 Hz, 1H, Ar), 9.69 (s, 1H, NH); 13C NMR (CDCl3) δ8.71, 14.62, 16.16, 41.58, 48.59, 54.60, 55.89, 64.50, 111.49, 112.44, 114.83, 117.91, 120.26, 124.99, 129.27, 130.99, 136.02, 137.77, 148.63, 149.76, 167.49, 169.52, 172.79; Anal Calcd for C24H26N2O7S: C, 59.25; H, 5.39; N, 5.76. Found: C, 58.92; H, 5.21; N, 5.56.
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:16])([F:15])[O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)C.CC(C[AlH]CC(C)C)C.CO.O>CCOCC>[OH2:3].[F:16][C:5]([F:15])([O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1)[CH:4]=[O:3]
Reactant: CCOC(=O)C(F)(F)Oc1ccc(SC)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: CSc1ccc(OC(F)(F)C=O)cc1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
To a solution of 2,2-difluoro-2-(4-methylsulfanylphenoxy)acetic acid ethyl ester (19.8 g, 75 mmol) in dry ether (200 ml) at −70° C., a 1 M solution of DIBALH in hexanes (113 ml, 113 mmol) was added slowly. Ater stirring for 2 h at −70° C., methanol (4 ml) and water (27 ml) were dropwise added and the reaction mixture was left stirring at rt for 30 min. The heterogeneous mixture was filtered through a plug of Celite and the filtrate was diluted with ether (200 ml). The organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated to yield 2,2-difluoro-2-(4-methylsulfanylphenoxy)-acetaldehyde monohydrate which was then converted to the title compound as described in Example 1, Steps 8-12 above. Note: In step 11, both the sulfur atoms were oxidized to sulfonyl group. 1HNMR (DMSO-d6): δ 9.05 (1H, s), 7.99 (2H, m), 7.52 (2H, dd), 7.41 (2H, d), 7.25 (2H, t), 4.39 (1H, q), 3.80 (1H, m), 3.51 (2H, m), 3.36 (3H, s), 3.35 (2H, m), 3.20 (1H, m), 1.39 (2H, m), 1.13 (1H, m), 1.02 (1H, m), 0.75 (1H, m), 0.59 (2H, m), 0.31 (2H, m). LC/MS: M+1: 600.2; M−1: 598.2.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C:19]([CH3:33])([C:30](O)=[O:31])[CH2:20][C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[NH:23][CH:22]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.FC1C(O)=C(F)C(F)=C(F)C=1F.C1(N=C=NC2CCCCC2)CCCCC1.[CH:61]1[CH:66]=[CH:65][C:64]([CH2:67][CH2:68][NH2:69])=[CH:63][CH:62]=1>C(OCC)(=O)C>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH2:20][C:19]([NH:18][C:16](=[O:17])[O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)([CH3:33])[C:30](=[O:31])[NH:69][CH2:68][CH2:67][C:64]2[CH:65]=[CH:66][CH:61]=[CH:62][CH:63]=2)=[CH:22]1
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: NCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCOC(C)=O
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34.3 %

Procedure:
To a solution of N-[(9H-fluoren-9-ylmethyloxy)carbonyl]-α-methyl-DL-tryptophan (8.80 g, 20 mmol) in dry ethyl acetate (350 mL) was added pentafluorophenol (3.68 g, 20 mmol) and stirred for 10 minutes. The reaction mixture was cooled to 0° C. and a solution of dicyclohexylcarbodiimide (20 mmol) in ethyl acetate (25 mL) was added dropwise. This solution was stirred for one hour at 0° C. then at room temperature for four hours before leaving it at 4° C. overnight. The mixture was filtered and the precipitate washed with cold ethyl acetate (30 mL) and a solution of 2-phenethylamine (2.66 g, 22 mmol) in ethyl acetate (30 mL) was added dropwise to the combined filtrates. The mixture was left to stir for 48 hours at room temperature. The reaction mixture was filtered and the residue washed with cold ethyl acetate (2×30 mL) to give the title compound (3.73 g, 75%). The filtrates were combined and the solvent removed in vacuo and taken up again in ethyl acetate (5 mL) to give a second crop of 1.67 g (15%), a total of 90% yield as a white solid, mp 179°-181° C. (EtOAc); IR (film) 1708, 1652 cm-1 ; NMR (DMSO d6) δ1.30 (3H, s), 2.64 (2H, t, J 7.2 Hz), 3.2-3.3 (4H, m), 4.19 (1H, t, J 6.7 Hz), 4.25-4.40 (2H, m), 6.9-7.9 (20H, m), 10.8 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]2[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH2:16][N:6]3[C:7]=2[C:3]=1[CH:4]=[C:5]3[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH3:23][O:24][CH2:25]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[C:10]([O:11][CH2:23][O:24][CH3:25])=[CH:9][C:8]2[C:12](=[O:17])[CH2:13][CH2:14][CH2:15][CH2:16][N:6]3[C:7]=2[C:3]=1[CH:4]=[C:5]3[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1cc2c(Cl)c(O)cc3c2n1CCCCC3=O
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Cl)c(OCOC)cc3c2n1CCCCC3=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
A mixture of ethyl 5,6,7,8-tetrahydro-11-chloro-10-hydroxy-8-oxo-4H-azocino [3,2,1-hi]indole-2-carboxylate (0.95 g, 2.93 mmol), chloromethyl methyl ether (0.35 g, 4.40 mmol), potassium carbonate (1.22 g, 8.80 mmol) and N,N-dimethylformamide (25 ml) was stirred at room temperature for 1 hour. The insoluble material was filtered off and the filtrate was poured into ice water and extracted twice with ethyl acetate. The extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent:ethyl acetate/n-hexane= 2/98) to obtain 0.51 g of ethyl 5,6,7,8-tetrahydro-11-chloro-10-methoxymethyloxy-8-oxo-4H-azocino [3,2,1-hi]indole-2-carboxylate.
Reaction SMILES: BrC1C(OC)=NC2CCN(C(=O)C(F)(F)F)CC(C)C=2C=1.[Sn](C=C)(CCCC)(CCCC)CCCC.[CH3:37][O:38][C:39]1[C:40]([CH:57]=[CH2:58])=[CH:41][C:42]2[CH:48]([CH3:49])[CH2:47][N:46](C(=O)C(F)(F)F)[CH2:45][CH2:44][C:43]=2[N:56]=1.C([O-])([O-])=O.[K+].[K+]>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.O.CO.C1(C)C=CC=CC=1>[CH3:37][O:38][C:39]1[C:40]([CH:57]=[CH2:58])=[CH:41][C:42]2[CH:48]([CH3:49])[CH2:47][NH:46][CH2:45][CH2:44][C:43]=2[N:56]=1
Reactant: C=Cc1cc2c(nc1OC)CCN(C(=O)C(F)(F)F)CC2C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Agent: COc1nc2c(cc1Br)C(C)CN(C(=O)C(F)(F)F)CC2
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: C=Cc1cc2c(nc1OC)CCNCC2C
Temperature: 110 °C
Yield: 76.3 %

Procedure:
A mixture of 3-bromo-2-methoxy-5-methyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro -5H-pyrido[2,3-d]azepine (220 mg, 599 μmol), Bu3SnCH═CH2 (523 μl, 1.79 mmol), Pd(PPh3)4 (50 mg), and toluene (10 ml) was heated in a sealed tube at 110° C. for 16 h. The solvent was evaporated and the resulting residue was purified by column chromatography to render 165 mg (88%) of 2-methoxy-5-methyl-7-(trifluoroacetyl)-3-vinyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. A mixture of 2-methoxy-5-methyl-7-(trifluoroacetyl)-3-vinyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine (32 mg, 102 μmol), K2CO3 (40 mg), MeOH (5 ml) and H2O (1 ml) was heated to reflux for 10 min. The reaction mixture was concentrated in vacuo and the resulting residue was purified by column chromatography to yield 17.0 mg (77%) of 2-methoxy-5-methyl-3-vinyl-6,7,8,9-tetrahydro-5H-pyrido[2,3-d]azepine. 1H-NMR (CDCl3) δ 7.58 (s, 1H), 6.92 (dd, 1H), 5.86 (d, 1H), 5.40 (d, 1H), 4.02 (s, 3H), 3.60-3.40 (m, 4H), 3.31 (m, 1H), 3.18 (dd, 1H), 3.00 (m, 1H), 1.52 (d, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=[CH:10][N:11](C)C)=[CH:4][C:3]=1[CH2:15][NH:16][C:17](=[O:19])[CH3:18].O.[NH2:21]N>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][NH:11][N:21]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17](=[O:19])[CH3:18]
Reactant: NN
Reactant: CC(=O)NCc1cc(C(=O)C=CN(C)C)ccc1Cl
Solvent: CO
Solvent: O
Product: CC(=O)NCc1cc(-c2cc[nH]n2)ccc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of N-[[2-chloro-5-[3-(dimethylamino)-1-oxo-2-propen-1-yl]phenyl]methyl]-acetamide (i.e. the product of Step A) (10.0 g, 35.7 mmol) and hydrazine hydrate (2.6 mL, 53.6 mmol) in methanol (100 mL) was stirred at room temperature for 20 h. The reaction mixture was then cooled to −5° C. and filtered, resulting in the title product as a solid (2.0 g), which was used in the next step without purification.