Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH3:37])[C@@H:3]([C:27]1[CH:28]=[CH:29][C:30]2[CH2:35][O:34][CH2:33][O:32][C:31]=2[CH:36]=1)[O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=1)[C:17]([O:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[O:18])[N:9]=[CH:8]2.[F:38][C:39]([F:44])([CH3:43])[C:40](O)=[O:41].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>ClCCl.O>[O:32]1[C:31]2[CH:36]=[C:27]([C@@H:3]([O:4][C:5]3[CH:6]=[C:7]4[C:11](=[CH:12][CH:13]=3)[N:10]([C:14]3[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=3)[C:17]([O:19][CH2:20][CH:21]([CH3:22])[CH3:23])=[O:18])[N:9]=[CH:8]4)[C@@H:2]([NH:1][C:40](=[O:41])[C:39]([F:44])([F:38])[CH3:43])[CH3:37])[CH:28]=[CH:29][C:30]=2[CH2:35][O:34][CH2:33]1
Reactant: CC(C)COC(=O)c1cccc(-n2ncc3cc(O[C@H](c4ccc5c(c4)OCOC5)[C@H](C)N)ccc32)c1
Reactant: CC(F)(F)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)COC(=O)c1cccc(-n2ncc3cc(O[C@H](c4ccc5c(c4)OCOC5)[C@H](C)NC(=O)C(C)(F)F)ccc32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
A mixture of isobutyl 3-(5-((1R,2S)-2-amino-1-(4H-benzo[d][1,3]dioxin-7-yl)propoxy)-1H-indazol-1-yl)benzoate (420 mg, 0.84 mmol) (I5b), 2,2-difluoropropanoic acid (213 mg, 1.94 mmol) and HBTU (420 mg, 1.11 mmol) were suspended in dichloromethane (10 mL). N-ethyl-N-isopropylpropan-2-amine (0.85 mL, 5.13 mmol) was added and the mixture was stirred at room temperature overnight. Water (ca 10 mL) was added to the solution. After stirring for some minutes the mixture was added to a phase separator. The water phase was stirred with dichloromethane (5 mL) and added to the phase separator. The combined organic phases were concentrated to a brown oil. Purification by flash chromatography on silica (dichloromethane/ethyl acetate 10/1) gave the title compound as a white foam (400 mg, 80%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][C:6]1[C:7](=[O:27])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:9][CH:10]=1.[NH2:29][O:30][K].C(O)(=O)C>CO.CO.C(Cl)(Cl)Cl>[OH:30][NH:29][C:3]([CH2:4][CH2:5][C:6]1[C:7](=[O:27])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:14][CH:13]=2)[CH2:9][CH:10]=1)=[O:2]
Reactant: NO[K]
Reactant: COC(=O)CCC1=CCN(Cc2ccc(NC(=O)c3ccccc3)cc2)C1=O
Solvent: CC(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(CCC1=CCN(Cc2ccc(NC(=O)c3ccccc3)cc2)C1=O)NO
Temperature: 0 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
7 mg of compound (i) prepared by the above Step 2 was dissolved in methanol solution (0.02 mM) and then 1.7 M methanolic suspension solution containing NH2OK (0.4 ml, 0.68 mM) was added thereto at 0° C. and the resulting mixture was stirred for 8 hrs at room temperature. The resulting mixture was neutralized with 0.01 ml of acetic acid, diluted with 10% methanol/chloroform solution, filtered and concentrated in vacuo. The resulting compound was purified by Silica gel column chromatography with a solvent mixture mixed with methanol and chloroform (1:9) as an eluant to give 3.2 mg of N-{4-[3-(2-hydroxycarbamoyl-ethyl)-2-oxo-2,5-dihydro-pyrrole-1-yl-methyl]-phenyl}-benzamide (j) (yield: 46%).
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([CH3:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:22]([O:29][CH2:30][CH3:31])(=[O:28])/[CH:23]=[CH:24]/[CH2:25][CH2:26][CH3:27].[NH4+].[Cl-]>C1COCC1>[CH2:30]([O:29][C:22](=[O:28])[CH2:23][C@@H:24]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:16])[CH2:25][CH2:26][CH3:27])[CH3:31]
Reactant: CCC/C=C/C(=O)OCC
Reactant: C[C@H](NCc1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC[C@@H](CC(=O)OCC)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
To a solution of (S)-(−)-N-benzyl-alpha-methyl-benzylamine (50 mL, 239 mmol) in THF (150 mL) at 0 C was added BuLi (2.5 M in THF) (100 mL, 250 mmol) under nitrogen atmosphere. The solution was cooled to −78 C and ethyl trans-2-hexenoate (16.6 g, 117 mmol) was added. The solution was stirred for 1 hour and Sat. NH4Cl solution was added. The solution was warmed to room temperature and was extracted with EtOAc. The combined organic layer was dried with MgSO4 and was filtered. The filtrate was concentrated and the residue was purified by CombiFlash with 5% EtOAc in Hexane as the eluent to afford the desirable product (S)-3-[Benzyl-((S)-1-phenyl-ethyl)-amino]-hexanoic acid ethyl ester (20.8 g, 50%) as a colorless oil.
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:21]1[CH2:24][CH:23]([S:25][C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)[CH2:22]1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)C>ClC(Cl)C>[ClH:1].[S:27]1[CH:28]=[CH:29][CH:30]=[C:26]1[S:25][CH:23]1[CH2:24][NH:21][CH2:22]1
Reactant: c1ccc(C(c2ccccc2)N2CC(Sc3cccs3)C2)cc1
Reactant: CC(Cl)OC(=O)Cl
Solvent: CCO
Solvent: CC(Cl)Cl
Product: Cl
Product: c1csc(SC2CNC2)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
1-Chloroethyl chloroformate (140 μL, 1.3 mmol) was added to a solution of 1-benzhydryl-3-(thiophen-2-ylthio)-azetidine (340 mg, 1.00 mmol) in dichloroethane (11 mL) at 0° C. The reaction mixture was stirred for 3 hours at room temperature and for 2 hours at 70° C. Ethanol (11 mL) was added and the reaction mixture was stirred for an additional 2 days at room temperature. After concentration to dryness, the residue was triturated in pentane (2×20 mL) to afford a brown oil (171 mg, 81%) which was used in the next step without further purification.
Reaction SMILES: [Br:1]Br.[CH3:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1)(=[O:6])=[O:5]>C(O)(=O)C.Cl>[Br:1][CH2:14][C:13]([C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH3:3])(=[O:5])=[O:6])=[CH:8][CH:9]=1)=[O:15]
Reactant: BrBr
Reactant: CC(=O)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
38.5 ml of bromine dissolved in 110 ml of acetic acid are added dropwise onto a suspension of 159 g of the product of Example 1 in 1.6 l of acetic acid and 1.6 ml of hydrochloric acid, the reaction mixture is then stirred for 3 h at ambient temperature. The precipitate obtained is filtered, rinsed with water and then dissolved in dichloromcthane and dried over magnesium sulphate. The dichloromethane is evaporated off, the residue is taken up in pentane and filtered to give 100 g of the expected product. A second batch is obtained by pouring the filtrate of the reaction mixture onto an icc/water mixture, then by filtering off and by treating the precipitate as previously. The two batches are then combined and recrystallised from acetic acid.
Reaction SMILES: C1(C(C(C2C=CC=CC=2)O)=O)C=CC=CC=1.[P]=S.[C:19]1([C:25]([CH:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[SH:28])=[S:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.S.[Ni:36](Cl)Cl>O.O1CCOCC1>[Ni:36].[C:29]1([C:27]([C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[S:26])=[S:28])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1.[C:29]1([C:27]([C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[S:26])=[S:28])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: S=C(c1ccccc1)C(S)c1ccccc1
Reactant: Cl[Ni]Cl
Agent: O=C(c1ccccc1)C(O)c1ccccc1
Agent: S
Agent: [P]=S
Solvent: O
Solvent: C1COCCO1
Product: S=C(C(=S)c1ccccc1)c1ccccc1
Product: [Ni]
Temperature: 100 °C

Procedure:
The oxidation inhibitor, bis(dithiobenzil) nickel is prepared by adding a mixture of 100 grams of benzoin, 150 grams of phosphorus sulfide and 700 ml of dioxane to a 5 liter, single necked flask equipped with heating mantle and water cooled condenser. The above-described mixture is, then, refluxed for 2 hours, during which the thiophosphoric ester of dithiobenzoin is formed and hydrogen sulfide is evolved. The reaction mixture is cooled and a solution of 50 grams of nickel chloride (hydrated) in 200 ml of water is added to the flask and heated (212° F.) for 2 hours on a steam bath. Black crystals of bis(dithiobenzil) nickel are formed and collected by filtering the cooled solution. Purification is effected by extraction with boiling toluene.
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH:15]1([CH2:18][NH:19][C:20](=[O:37])[C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[C:23](B3OC(C)(C)C(C)(C)O3)[CH:22]=2)[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][NH:19][C:20]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[C:25]([C:2]3[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]4[CH2:12][CH2:11]4)=[O:7])=[CH:4][N:3]=3)[CH:26]=2)=[O:37])[CH2:17][CH2:16]1
Reactant: Cc1ccc(C(=O)NCC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
Product: Cc1ccc(C(=O)NCC2CC2)cc1-c1ccc(C(=O)NCC2CC2)cn1

Procedure:
6-[5-(Cyclopropylmethyl)carbamoyl-2-methyl-phenyl]-N-cyclopropylmethyl-nicotinamide was prepared from 6-chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) and N-(cyclopropylmethyl)-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 10) using General Method B. LCMS: retention time 2.87 min, MH+364. NMR: δH [2H6]-DMSO 9.10, (1H, s), 8.83, (1H, t), 8.60, (1H, t), 8.30, (1H, dd), 7.92, (1H, s), 7.84, (1H, d), 7.71, (1H, d), 7.41, (1H, d), 3.19, (2H, t), 3.13, (2H, t), 2.37, (3H, s), 1.03, (2H, m), 0.44, (4H, m), 0.23, (4H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:13]([C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[NH:14][C:15](=[O:26])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([N+:23]([O-])=O)[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].O.NN.CCOC(C)=O>[Ni].CO>[NH2:23][C:18]1[N:17]=[C:16]([C:15]([NH:14][C@@H:13]([C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([F:12])([F:10])[F:11])=[C:2]([F:1])[CH:3]=2)[C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=2)=[O:26])[CH:21]=[CH:20][C:19]=1[OH:22]
Reactant: O=C(N[C@@H](c1ccc(OC(F)(F)F)c(F)c1)c1ncccc1F)c1ccc(O)c([N+](=O)[O-])n1
Agent: [Ni]
Agent: NN
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: Nc1nc(C(=O)N[C@@H](c2ccc(OC(F)(F)F)c(F)c2)c2ncccc2F)ccc1O
Temperature: 56 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of Raney Nickel (0.2 g, Monarch, India) in MeOH (10 mL), was added (S)—N-((3-fluoro-4-(trifluoromethoxy)phenyl)(3-fluoropyridin-2-yl)methyl)-5-hydroxy-6-nitropicolinamide (200 mg, 0.0004252 mol) at room temperature. The temperature was raised to 56° C. and hydrazine hydrate (0.2 mL, Spectrochem, India) was added very slowly over 5 min (exothermic reaction). The reaction mixture was then stirred for 10 min at the same temperature. After completion of the reaction, monitored by TLC (TLC eluent: 50% EtOAc in petroleum ether, uv active), the mixture was cooled to room temperature, filtered through Celite® brand filter agent and concentrated under high vacuum to remove excess hydrazine hydrate. The resulting product was triturated with petroleum ether to give the title compound as a grey solid. 1H-NMR (400 MHz, DMSO-d6): δ 9.23 (d, J=8 Hz, 1H), 8.57 (d, J=4.4 Hz, 1H), 7.87 (t, J=8.8 Hz, 1H), 7.61-7.54 (m, 2H), 7.47 (d, J=11.6 Hz, 1H), 7.31 (d, J=8.4 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 6.86 (d, J=8 Hz, 1H), 6.57 (d, J=8 Hz, 1H), 5.53 (br. s., 2H). MS (ESI, positive ion) m/z: 441 (M+H).
Reaction SMILES: C(C1CC2C(=CC(F)=C(OC)C=2C)C1=O)CCC.C(C(CCC)=O)=C.N12CCCN=C1CCCCC2.[CH2:37]([C:41]1([CH2:55][CH2:56][C:57](=[O:61])[CH2:58][CH2:59][CH3:60])[CH2:49][C:48]2[C:43](=[CH:44][C:45]([F:53])=[C:46]([O:51][CH3:52])[C:47]=2[CH3:50])[C:42]1=O)[CH2:38][CH2:39][CH3:40].Cl>O1CCCC1.C(O)(=O)C>[CH2:37]([C:41]12[CH2:55][CH2:56][C:57](=[O:61])[C:58]([CH2:59][CH3:60])=[C:42]1[C:43]1[C:48](=[C:47]([CH3:50])[C:46]([O:51][CH3:52])=[C:45]([F:53])[CH:44]=1)[CH2:49]2)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCC1(CCC(=O)CCC)Cc2c(cc(F)c(OC)c2C)C1=O
Agent: C=CC(=O)CCC
Agent: CCCCC1Cc2c(cc(F)c(OC)c2C)C1=O
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCC12CCC(=O)C(CC)=C1c1cc(F)c(OC)c(C)c1C2
Temperature: 50 °C
Reaction time: 64 h

Procedure:
A solution of 2-butyl-6-fluoro-5-methoxy-4-methyl-1-indanone (118 mg, 0.47 mmol) in anhydrous tetrahydrofuran (0.47 mL) was treated with propyl vinyl ketone (0.065 mL, 0.56 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.0143 mL, 0.094 mmol). The mixture was stirred and heated in an oil bath at 50° C. for 6 hours and then at room temperature for 64 hours. The solvent was evaporated under vacuum to give a residue consisting mainly of 2-butyl-6-fluoro-5-methoxy-4-methyl-2-(3-oxohexyl)-1-indanone. This material was dissolved in acetic acid (2 mL), treated with aqueous 6N HCl (1.5 mL), and stirred while heating in an 80° C. oil bath for 6 hours. After cooling, the mixture was partitioned between EtOAc (25 mL) and saturated aqueous K2CO3 (25 mL). The organic phase was washed with brine (10 mL), dried over MgSO4, filtered, and evaporated under vacuum to an oil (138 mg). The crude product was purified by preparative layer chromatography on two 0.1×20×20 cm silica gel GF plates, developing with CH2Cl2. The product bands were eluted with EtOAc and the eluent evaporated under vacuum to afford 9a-butyl-4-ethyl-6-fluoro-7-methoxy-8-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (93 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH2:18][CH3:19])=[N:11][C:12]([N+:15]([O-])=O)=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[NH4+].[Cl-]>CO.C1COCC1.[Zn]>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[N:11][C:10]=2[CH2:18][CH3:19])[CH:5]=[CH:4][N:3]=1
Reactant: CCc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1nc(N)ccc1Oc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
A suspension of Example A8 (1.3 g, 4.65 mmol) and NH4Cl (7.5 g, 140 mmol) in MeOH (24 mL) and THF (24 mL) was treated portion-wise with zinc dust (3 g, 45.9 mmol) and stirred at RT overnight. The solids were removed via filtration through diatomaceous earth and the filtrate concentrated to dryness to afford 5-((2-chloropyridin-4-yl)oxy)-6-ethylpyridin-2-amine (1.1 g, 85%). MS (ESI) m/z: 250.1 (M+H+).
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][C:14]([CH2:17][CH3:18])([CH3:16])[NH:13][C:12]([CH2:20][CH3:21])([CH3:19])[CH:11]1[CH3:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23](Br)[CH:24]=[CH2:25]>CN(C)C=O>[C:1]([O:9][CH:10]1[CH2:15][C:14]([CH2:17][CH3:18])([CH3:16])[N:13]([CH2:25][CH:24]=[CH2:23])[C:12]([CH2:20][CH3:21])([CH3:19])[CH:11]1[CH3:22])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCBr
Reactant: CCC1(C)CC(OC(=O)c2ccccc2)C(C)C(C)(CC)N1
Solvent: CN(C)C=O
Product: C=CCN1C(C)(CC)CC(OC(=O)c2ccccc2)C(C)C1(C)CC
Yield: 23.6 %

Procedure:
To a solution of 6.0 g of 2,6-diethyl-2,3,6-trimethyl-4-piperidyl benzoate (Compound 10 - prepared using the same procedure as is described in Preparation 2) in 20 ml of dimethylformamide were added 6.0 g of allyl bromide, and the mixture was heated at 110° - 115° C for 9 hours. The mixture was then concentrated by evaporation under reduced pressure and 50 ml of benzene were added. The resulting mixture was then washed, in turn, with an aqueous solution of sodium carbonate and with water and was then dried over anhydrous sodium sulphate. After removing the solvent, the residue was distilled under reduced pressure, giving 1.6 g of Compound 36 as a colourless, viscous liquid (bp 163° C/0.004 mmHg).
Reaction SMILES: [O:1]=[C:2]([CH3:8])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.[CH2:9](N)[CH3:10].CC[N:14]=C=NCCCN(C)C.Cl.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:9](/[C:4](=[CH:3]\[C:2](=[O:1])[CH3:8])/[C:5]([NH2:14])=[O:7])[CH3:10]
Reactant: CC(=O)/C=C/C(=O)O
Reactant: CCN=C=NCCCN(C)C
Reactant: CCN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC/C(=C\C(C)=O)C(N)=O
Temperature: 0 °C
Reaction time: 17 h

Procedure:
(2E)-4-Oxopent-2-enoic acid (9.41 g, 80 mmol) and EtNH2 (2 M in THF, 40 ml, 80 mmol) are dissolved in CH2Cl2 (250 ml). The solution is cooled to 0° C. Then DMAP (1.47 g, 12 mmol) and EDCl (15.34 g, 80 mmol) are added. The resulting suspension is stirred for 17 h at 0 (C. Then the reaction mixture is poured into 2 M HCl (100 ml) and extracted with CH2Cl2 (2×1 l). The organic phases are washed with 2 M HCl (50 ml), saturated NaHCO3 (50 ml) and brine (100 ml) successively. The combined organic phases are dried with Na2SO4 and evaporated under reduced pressure at 40° C. 24 (ethyl (2E)-4-oxopent-2-enamide) (5.74 g, 51%) is obtained as a brown solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH:5]=[CH:4][C@H:3]1[NH2:7].C(N(CC)CC)C.C[O:16][C:17]([C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22])=O>O1CCCC1>[OH:1][C@@H:2]1[CH2:6][CH:5]=[CH:4][C@H:3]1[N:7]1[C:17](=[O:16])[C:19]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:20]2[C:21]1=[O:22]
Reactant: COC(=O)c1ccccc1C(=O)Cl
Reactant: N[C@@H]1C=CC[C@H]1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C=CC[C@H]1O

Procedure:
A quantity of dl-trans-4-hydroxy-3-amino-cyclopentene is dissolved in 450 ml of tetrahydrofuran and 87 ml. (0.60 M) of triethylamine. The solution is cooled to 0° and treated dropwise with 59.6 g. (0.3 M) of o-methoxycarbonylbenzoylchloride over 50 min. The reaction is then allowed to warm to 25°. After 66 hours the reaction is partitioned between ethyl acetate and water. The ethyl acetate layer is dried over magnesium sulfate and distilled in vacuo to yield 62.4 g. of residual oil. This is chromatographed over 3 kg. of silica gel 60 eluted with 6 l. of (10-90), 2.5 l. of (15-85), and 11 l. of (20-80) acetonemethylene chloride. Two hundred fifty ml. fractions are collected. The product is found in fractions 38-61. These fractions crystallized on standing to yield 25.9 g. of dl-trans-4-hydroxy-3-phthalidocyclopentene.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([NH:16][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:5]=1.[CH2:28](Br)[CH:29]=[CH2:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])[CH:7]=[C:6]([N:16]([CH2:30][CH:29]=[CH2:28])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:5]=1
Reactant: COC(=O)c1cc(NC(=O)OCc2ccccc2)cc(N2CCCC2=O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN(C(=O)OCc1ccccc1)c1cc(C(=O)OC)cc(N2CCCC2=O)c1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A suspension of 3.69 g (8.1 mmol) 3-benzyloxycarbonylamino-5-(2-oxo-pyrrolidin-1-yl)-benzoic acid methyl ester, 1.37 ml (16.2 mmol) allyl bromide, 2.24 g (16.2 mmol) potassium carbonate in 8 ml DMF is stirred at 50° C. for 4 h. The mixture is diluted with water and extracted with EtOAc. The organic phase is washed with water and dried over sodium sulfate. The product is purified by chromatography on silica gel (EtOAc/hexanes 1:4, 1:2, 1:1, 2:1). The title compound is isolated as a yellow resin.
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([CH2:8][C:9]2([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=3)[CH2:15][O:14][C:13]3=[CH:16][S:17][CH:18]=[C:12]3[O:11][CH2:10]2)=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[NH2:1][C:4]1[CH:30]=[CH:29][C:7]([CH2:8][C:9]2([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=3)[CH2:15][O:14][C:13]3=[CH:16][S:17][CH:18]=[C:12]3[O:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CC2(Cc3ccc([N+](=O)[O-])cc3)COc3cscc3OC2)cc1
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(CC2(Cc3ccc(N)cc3)COc3cscc3OC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(See Scheme, FIG. 7). To a 200 mL round bottom flask was added 0.307 g (0.722 mmol) of 3,3-Bis(4-nitrobenzyl)-3,4-dihydro-2H-thieno[3,4-b][1,4]-dioxepine, 2.1 g (9.3 mmol) of tin(II) chloride dihydrate and 50 mL of ethyl acetate. The solution was heated to reflux for overnight. After heating, the mixture was allowed to cool to room temperature. After cooling, 20 mL of a 0.25 M solution of sodium carbonate and 100 mL of dichloromethane were added. This mixture was vigorously stirred for 30 minutes. The mixture was then filtered through a celite pad and poured into a 500 mL separatory funnel. The organic layer was removed and washed twice with 50 mL of water and once with 50 mL of brine. The solution was dried with MgSO4 and the solvent was removed in vacuo to give the product, 3,3-bis(4-aminobenzyl)-3,4-dihydro-2H-thieno[3,4-b][1,4]-dioxepine, in quantitative yield. IR, 1HNMR, 13CNMR in addition to TLC were used to confirm identity of the product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:19]([C:20]5[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=5[F:27])[N:18]=[CH:17][N:16]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:28]=1.ClCCl.[I-].C(OC([N:40]1[CH2:43][CH:42]([Zn+])[CH2:41]1)=O)(C)(C)C.Cl>CN(C)C(=O)C.[Cu]I>[NH:40]1[CH2:43][CH:42]([C:2]2[CH:3]=[CH:4][C:5]3[C:11]4[S:12][C:13]([C:15]5[N:19]([C:20]6[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=6[F:27])[N:18]=[CH:17][N:16]=5)=[CH:14][C:10]=4[CH2:9][CH2:8][O:7][C:6]=3[CH:28]=2)[CH2:41]1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2ccc(Br)cc2OCC3)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CC([Zn+])C1
Agent: [Cu]I
Agent: Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2ccc(C4CNC4)cc2OCC3)c(F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 8.1 %

Procedure:
5-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-1-(2,4-difluorophenyl)-1H-1,2,4-triazole (300 mg, 0.6 mmol) was dissolved in N,N-dimethyacetamide and purged with nitrogen. Added [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (30 mg, 0.04 mmol) and copper(I)iodide (10 mg, 0.08 mmol). Bubbled in nitrogen for 10 minutes. Added (1-(tert-butoxycarbonyl)azetidin-3-yl)zinc(II) iodide (230 mg, 0.65 mmol) in 2.3 mL DMA. Heated at 80° C. overnight. Complete reaction was confirmed by LCMS. Diluted reaction mixture with 1 M HCl and extracted the t-Boc protected intermediate, tert-butyl 3-(2-(1-(2,4-difluorophenyl)-1H-1,2,4-triazol-5-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)azetidine-1-carboxylate, with ethyl acetate. Dried over magnesium sulfate and concentrated in vacuo. Purified by flash chromatography (0 to 50% ethyl acetate in hexanes). Concentrated in vacuo and re-dissolved the residue in 10 mL 1,4-dioxane. Added 5 mL 4 N HCl in dioxane and let stir for 2 hours. Complete deprotection was confirmed by LCMS. Concentrated in vacuo purified by HPLC to give 419 (21.1 mg, 7% yield, M=1 437.1).
Reaction SMILES: [ClH:1].[C:2]1([C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:9][C:10]2[CH:18]=[CH:17][C:13]([CH:14]([NH2:16])[CH3:15])=[CH:12][CH:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[CH:27]([NH2:42])[C:28]1C=[CH:32][C:31](CCC2C=CC=CC=2)=[CH:30][CH:29]=1>>[ClH:1].[C:19]1([C:8]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:9][C:10]2[CH:18]=[CH:17][C:13]([CH:14]([N:16]=[C:27]3[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][NH:42]3)[CH3:15])=[CH:12][CH:11]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(N)c1ccc(CCc2ccccc2)cc1
Reactant: CC(N)c1ccc(C=C(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Product: CC(N=C1CCCCCN1)c1ccc(C=C(c2ccccc2)c2ccccc2)cc1

Procedure:
Following essentially the same procedure described in Example IV above and substituting ρ-(2,2-diphenylvinyl)-α-methylbenzylamine hydrochloride for the α-methyl-ρ-phenethylbenzylamine hydrochloride above, results in the formation of 2-[ρ-(2,2-Diphenylvinyl)-α-methylbenzylimino hexahydroazepine hydrochloride having a M.P. of 219°-21° C.