Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.BrC1C=CC(OC2C=CC=CC=2)=C(Cl)C=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:4]([F:9])[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Oc1ccc(Br)cc1F
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Agent: Clc1cc(Br)ccc1Oc1ccccc1
Solvent: CC#N
Product: Fc1cc(Br)ccc1Oc1ccccc1
Yield: 33 %

Procedure:
The title compound was prepared in a 33% yield from 4-bromo-2-fluorophenol and phenyl boronic acid in a manner similar to that described for the preparation of 4-bromo-2-chloro-1-phenoxybenzene: 1H NMR (DMSO-d6, 400 MHz) δ 7.75(dd, 1H), 7.40(m, 3H), 7.15(m, 2H), 7.01(dd, 2H); MS MH+267.2; RP-HPLC (Hypersil HS, 5 μm, 100 A 4.6×250 mm; 25%-100% acetonitrile—0.05 M ammonium acetate over 10 min, 1 ml/min) tr 13.57 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([C:15](=[N:16][O:17][CH3:18])[CH2:14][N:13](CC3C=CC=CC=3)[CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([C:15](=[N:16][O:17][CH3:18])[CH2:14][NH:13][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CON=C1CN(Cc2ccccc2)CC12CN(C(=O)OC(C)(C)C)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CON=C1CNCC12CN(C(=O)OC(C)(C)C)C2
Yield: 44 %

Procedure:
4.0 g of t-butyl-6-benzyl-8-(methoxyimino)-2,6-diazaspiro[3,4]octane-2-carboxylate was dissolved in 40 ml of methanol and thereto 4.0 g of 10% Pd-C was added. The resulting mixture was stirred for 2 hours under the pressure of hydrogen at 5° C. filtered and concentrated under the reduce pressure to give 1.3 g of the titled compound(yield: 87.9%).
Reaction SMILES: C([C:3]1[CH:22]=[CH:21][C:6]([O:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)=O.[C:23](O)(=O)[CH2:24][C:25]([OH:27])=[O:26].N1CCCCC1>N1C=CC=CC=1>[C:17]([O:16][C:14]([N:11]1[CH2:12][CH2:13][CH:8]([O:7][C:6]2[CH:21]=[CH:22][C:3]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])=[CH:4][CH:5]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:19])([CH3:18])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=O)cc2)CC1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=CC(=O)O)cc2)CC1

Procedure:
A solution of t-Butyl 4-(4-formyl phenoxy)piperidine-1-carboxylate (50.2 grams, 0.164 moles, obtained in above step), malonic acid (50.6 grams, 0.486 moles) and piperidine (12.5 mL) in pyridine (250 mL) was stirred for 8 hours at 110° C. under nitrogen atmosphere.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:34][CH:35]([OH:37])[CH3:36].[I-].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:34][CH:35]([OH:37])[CH3:36])[CH2:18][CH2:17]3)[N:12]3[N:22]=[CH:23][C:24]([CH:25]=[C:26]4[NH:30][C:29](=[O:31])[NH:28][C:27]4=[O:32])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CCNCC4)cc(Nc4cccc(Cl)c4)nc23)N1
Reactant: CC(O)CCl
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(O)CN1CCC(Nc2cc(Nc3cccc(Cl)c3)nc3c(C=C4NC(=O)NC4=O)cnn23)CC1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To 5-((5-(3-chlorophenylamino)-7-(piperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (30 mg, 0.066 mmol) in DMF was added 1-chloro2-propanol (7 μL, 0.13 mmol) and potassium iodide (11.0 mg, 0.066 mmol). The mixture was heated to 120° C. and stirred for overnight. The reaction mixture was concentrated, diluted with MeOH, and purified by prep HPLC to yield 5-((5-(3-chlorophenylamino)-7-(1-(2-hydroxypropyl)piperidin-4-ylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=511)
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)=[O:15].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:18][CH:17]=1)(=[O:15])[CH3:13]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2C#N)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.1 %

Procedure:
In a 250 ml single-neck flask equipped with a magnetic stirrer and a reflux condenser fitted with a nitrogen bubbler were placed 9.13 g (0.05 moles) of 2-chloro-5-nitrobenzonitrile, 7.01 g (0.0515 moles) of 4-hydroxyacetophenone, 7.10 g (0.0515 moles) of anhydrous K2CO3, and 75 ml of acetonitrile. The mixture was heated to reflux and held there for 3 hrs. The reaction mixture was then cooled to room temperature and diluted with 150 ml of water. The product separated as a solid. The solid was filtered off, washed thoroughly with water, and air-dried. The air-dried solid was recrystallized twice from 300 ml of absolute ethanol to give 4.95 g (35% yield) of purified 2-(4-acetylphenoxy)-5-nitrobenzonitrile, mp 135°-136.5° C.
Reaction SMILES: [CH2:1]([Si:5]([C:18]1([CH2:24][CH:25]([CH3:27])[CH3:26])SCCCS1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH:3]=[CH2:4].[OH2:28]>CC#N.Cl[Hg]Cl>[CH2:1]([Si:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:18](=[O:28])[CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:2][CH:3]=[CH2:4]
Reactant: O
Reactant: C=CCC[Si](c1ccccc1)(c1ccccc1)C1(CC(C)C)SCCCS1
Agent: Cl[Hg]Cl
Solvent: CC#N
Product: C=CCC[Si](C(=O)CC(C)C)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 26 (4.64 g 11.2 mmol) in CH3CN (300 nmL) was added water (10 mL) and HgCl2 (15.26 g, 56.21 mmol). After stirring overnight at rt, the mixture was concentrated and partitioned between water (100 mL) and hexane (200 mL). The organic layer was isolated and the aqueous layer extracted with hexane (50 mL). The combined organic extracts were washed with saturated aqueous NaCl and dried over Na2SO4. Concentration to dryness in vacuo at rt gave crude ketone 33 as a yellow oil (3.2 g, 88%): R.function. =0.80 (1/9 EtOAc:hexane); 1H NMR (300 MHz, CDCl3) δ7.58 (d, J=6.4 Hz, 4H), 7.44 (m, 6H), 5.88 (m, IH), 4.99 (dd, J=17.1, 1.6 Hz, 1H), 4.91 (dd, J=10.2, 1.6 Hz, 1H), 2.50 (d, J=6.6 Hz, 2H), 2.14 (m, 2H), 1.36 (m, 2H), 0.95 (m, 1H), 0.76 (d, J=6.7 Hz, 6H); IR (neat) 3068 (m), 3046(m), 2956(s), 2925 (m), 2864 (m), 1956 (w), 1886 (w), 1826(w), 1641 (s), 1471 (m), 1431(s), 1113 (s), 1000 (m), 910 (m), 743 (s), 702 (s) cm31 1 ; MS (FAB) m/e (rel. intensity) 323 (MH+, 15), 322 (24), 321 (89), 267, (17), 236 (36), 198 (20), 182 (63), 169 (100), 167 (15), 159 (31); HRMS (FAB) calcd forC21H25OSi: 321.1675 (MH+ -2), found: 321.1670.
Reaction SMILES: CCC([N:5]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:14][CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=O.C(N1CCCCC1=[O:40])CC1C=CC=CC=1.NC1C=CC=CC=1>>[NH:5]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14](=[O:40])[CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCC(=O)N(c1ccccc1)C1CCN(CCc2ccccc2)CC1
Reactant: O=C1CCCCN1CCc1ccccc1
Solvent: Nc1ccccc1
Product: O=C1CC(Nc2ccccc2)CCN1CCc1ccccc1
Yield: 50 %

Procedure:
Fentanyl was first synthesized in 1960 by Paul Janssen founder of Janssen Pharmaceutica involving reacting N-phenethylpiperidone with aniline to produce 4-anilino-N-phenethylpiperidone with yield of about 50-80% using sodium borohydride at room temperature followed by reacting with propionyl chloride in presence of pyridine wherein the reaction is exothermic and thus requires stringent process conditions. The fentanyl thus obtained with a yield over 90% is further purified by crystallization.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH2:10])[CH2:7][N:6]1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:4].[OH:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:29]([C:20]2[CH:21]=[CH:22][C:23]3[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:19]=2[OH:18])=[O:30])[CH2:7][N:6]1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](N)CN1CC1CCCCC1
Reactant: O=C(O)c1ccc2ccccc2c1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1
Reaction time: 24 h

Procedure:
To a stirred solution of (2S,4S)-4-amino-1-cyclohexylmethyl-pyrrolidine-2-carboxylic acid methyl ester (150 mg, 0.62 mmol) and 1-hydroxy-naphthalene-2-carboxylic acid (90 mg, 0.75 mmol) in DMF (2 mL) were added HATU (285 mg, 0.75 mmol) and N,N-diisopropylethylamine (96 mg, 0.75 mmol). The mixture was stirred at room temp. for 24 h. The reaction mixture was then extracted with ethyl acetate and washed with water and brine. The organic layer was then dried over anhydrous sodium sulfate, concentrated and purified by column chromatography to give (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester. MS calcd. for C24H31N2O4 [(M+H)+] 411.0, obsd. 411.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH2:8]O)[CH:7]=1.O=S(Cl)[Cl:14]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:7]=1)[CH2:8][Cl:14]
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(F)cc1CO
Solvent: Cc1ccccc1
Product: COc1ccc(F)cc1CCl
Temperature: 25 °C
Yield: 61 %

Procedure:
Neat (5-Fluoro-2-methoxy-phenyl)-methanol (19.587 g, 1 equiv.) is added to neat SOCl2 (42.2 mL, 4.6 equiv.) at −78° C. under a nitrogen atmosphere and the solution is then allowed to warm to room temperature and stirred until evolution of gas ceases. An equivalent volume of anhydrous toluene is added to the flask and the solution heated to 60° C. On cooling, the reaction solution is poured onto ice water. The toluene layer is separated and dried (MgSO4) and the solvent removed under reduced pressure. The crude material is sublimed (60-80° C./0.05 mBarr) to give the title compound as a white solid (13.40 g, 61%). MW 174.60; C8H8ClFO; 1H NMR (CDCl3): 3.87 (s, 3H), 4.60 (s, 2H), 6.79-7.20 (m, 3H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.F[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:12]([O:11][C:9](=[O:10])[NH:8][C@H:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=2[N+:24]([O-:26])=[O:25])[CH2:3][CH2:4]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Reactant: Cc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(N[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a mixture of tert-butyl cis-4-aminocyclohexanecarbamate (1.27 g, 5.93 mmol) and 4-fluoro-3-nitrotoluene (0.92 g, 5.93 mmol) in DMF (20 mL) was added potassium carbonate (1.64 g, 11.88 mmol). The mixture was heated at 85° C. and stirred overnight. The mixture was cooled to room temperature and the solid was filtered. The filtrate was evaporated to dryness. The residue was extracted with ethyl acetate and brine. The organic layer was dried over sodium sulfate and solvents were evaporated. The resulting material was purified through flash column chromatography using hexanes and ethyl acetate (4:1) to give an orange colored solid as cis-[4-(4-methyl-2-nitro-phenylamino)-cyclohexyl]-carbamic acid tert-butyl ester (1.88 g). This material (1.80 g, 5.17 mmol) was suspended in a mixture of methanol (50 mL) and water (25 mL). To this suspension was added ammonium chloride (4.15 g, 77.6 mmol) and zinc dust (3.36 g, 51.6 mmol). The mixture was stirred at room temperature for 20 minutes and THF (20 mL) was added. The mixture was stirred an additional 1 hr during which the orange color disappeared. The mixture was filtered and rinsed with THF and ethyl acetate. The filtrate was extracted with brine and ethyl acetate. Solvents were evaporated to give cis-[4-(2-amino-4-methyl-phenylamino)-cyclohexyl]-carbamic acid tert-butyl ester (1.65 g). LC-MS showed a single peak, C18H29N3O2 (m/e) calcd 319.2260, obsd 320.3 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[C:15]=2[F:33])[C:11]([NH2:13])=[S:12])=[CH:5][CH:4]=1)#[N:2].F[B-](F)(F)F.[C:39](=O)([O-])O.[Na+].C(OCC)(=O)C>C(#N)C>[CH3:39][S:12][C:11](=[NH:13])[CH:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][Si:23]([CH:27]([CH3:29])[CH3:28])([CH:30]([CH3:32])[CH3:31])[CH:24]([CH3:26])[CH3:25])[C:15]=1[F:33]
Reactant: COc1cc(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c(C(Nc2ccc(C#N)cc2)C(N)=S)c1
Reactant: O=C([O-])O
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c(C(Nc2ccc(C#N)cc2)C(=N)SC)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of 57.96 g of 2-(4-cyanophenylamino)-2-(2-fluoro-5-methoxy-3-triisopropylsilanyloxyphenyl)thioacetamide in 200 ml of acetonitrile there was added 18.5 g of Me3O+BF4−, and the mixture was stirred at room temperature for 3 hours. After adding 2.1 g of Me3O+BF4− to the reaction mixture, it was further stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. After washing the organic layer with saturated brine, it was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give 2-(4-cyanophenylamino)-2-(2-fluoro-5-methoxy-3-triisopropylsilanyloxyphenyl)thioacetimidic acid methyl ester (crude product).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:27]=[C:28]([NH:40][C:41](=[O:43])[CH3:42])[CH:29]=[CH:30][C:31]=1[NH:32][CH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[F:44][C:45]([F:50])([CH3:49])[C:46](O)=O.CCN(C(C)C)C(C)C>CN(C=O)C>[F:44][C:45]([C:49]1[N:32]([CH2:33][CH:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)[C:31]2[CH:30]=[CH:29][C:28]([NH:40][C:41](=[O:43])[CH3:42])=[CH:27][C:26]=2[N:25]=1)([F:50])[CH3:46]
Reactant: CC(F)(F)C(=O)O
Reactant: CC(=O)Nc1ccc(NCC2CCOCC2)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc2c(c1)nc(C(C)(F)F)n2CC1CCOCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
HATU (1.58 g, 4.17 mmol) and N-{3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}acetamide (1.00 g, 3.79 mmol) were added to a solution of 2,2-difluoropropanoic acid (0.43 g, 3.98 mmol) and DIPEA (0.80 mL, 4.55 mmol) in DMF (100 mL) at ambient temperature. The reaction mixture was stirred overnight and the solvent was concentrated. The intermediate was heated to 80° C. for 3 h in glacial AcOH (100 mL), and the solvent was concentrated. The crude product was recovered in DCM (300 mL), washed with saturated NaHCO3 solution (3×100 mL), brine and dried over anhydrous MgSO4. The solvent was concentrated and the product was purified by normal-phase MPLC using MeOH 5% and Acetone 10% in DCM to provide the title compound as a white solid. Yield: 1.07 g (83%); MS (ESI) (M+H)+=338.2.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([O-:13])=[O:12].[Na+].Br[C:16]1[CH:24]=[CH:23][C:22]2[N:21]([CH3:25])[C:20]3[CH2:26][CH:27]4[NH:31][CH:30]([C:19]=3[C:18]=2[C:17]=1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28]4>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([C:16]1[CH:24]=[CH:23][C:22]2[N:21]([CH3:25])[C:20]3[CH2:26][CH:27]4[NH:31][CH:30]([C:19]=3[C:18]=2[C:17]=1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28]4)(=[O:13])=[O:12]
Reactant: O=S([O-])c1ccc2ccccc2c1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Agent: [Na+]
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4ccc5ccccc5c4)ccc31)C1CCC(C2)N1
Yield: 24 %

Procedure:
Intermediate 24 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude material was purified by flash column chromatography (SiO2, 8:2 hexanes/ethyl acetate) to give tert-butyl 2-(2-napthyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (113 mg, 24%) as a light-yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.58 (d, J=0.9 Hz, 1H), 8.26 (s, 1H), 7.93-8.04 (m, 1H), 7.81-7.88 (m, 2H), 7.71 (d, J=9.9 Hz, 1H), 7.52-7.63 (m, 2H), 7.42-7.51 (m, 1H), 7.29 (d, J=8.7 Hz, 1H), 5.26 (br s, 1H), 4.71 (br s, 1H), 3.59 (s, 3H), 3.39 (br s, 1H), 2.49 (d, J=16.2 Hz, 1H), 2.20-2.48 (m, 2H), 1.88-1.99 (m, 1H), 1.59-1.67 (m, 1H), 1.37 (br s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)(C)C.C(O[K])(C)(C)C.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:44])(=O)=O)=CC=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:44])([C:14](=[O:22])[C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: CC(C)(C)O[K]
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N1CCC(F)(C(=O)c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 58 %

Procedure:
4-(4-Fluoro-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester in 0.5 mL of DMF was added to a solution at 0° C. containing 0.5 mL of tBuOH, (0.109 mg, 0.651 mmol) tBuOK and 2 mL of DMF. After 20 min stirring at 0° C., N-Fluorobenzenesulfonimide (0.246 g, 0.781 mmol) was added portionwise. The reaction was stirred at 0° C. during 45 min. and (0.55 g, 0.33 mmol) of tBuOK were added at 0° C. and 10 min later (0.123 g, 0.390 mmol) of N-Fluorobenzenesulfonimide. Each 0.5 h two more additions of (0.55 g, 0.33 mmol) tBuOK and (0.123 g, 0.390 mmol) N-Fluorobenzenesulfonimide were repited. 1 h later of the last addition the reaction was quenched with 4 mL of water and the DMF was removed under vacuum. The water was extracted with ethyl acetate and the combined organic phases were purified with column chromatography on silica using n-heptane-EtOAc (3:1). The product fractions were concentrated to give 0.122 g (0.375 mmol, 58% yield) of a yellow oil. MS (m/e): 326.1 (M+H+).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.O[CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)C(=O)[N:14]1CC1SC=CC=1.C(N)C1C=CC=CC=1>>[CH2:13]([N:14]1[CH:4]([OH:6])[C:3]2[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1]1=[O:11])[C:21]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1c2ccccc2C(O)N1Cc1cccs1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: NCc1ccccc1
Product: O=C1c2ccccc2C(O)N1Cc1ccccc1

Procedure:
Compound 20 was prepared using the synthetic sequence in a manner analogous to the method described for the conversion of commercially available phthalic anhydride 1 to compound 12 using benzylamine instead of thiophene-2-methylamine in the first step.
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:23]=[CH:22][C:21]([C:24]4[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=4)[C:27]([O:29]C)=O)=[CH:20][C:14]=3[C:15]=2[C:16](=[O:19])[NH:17][CH3:18])=[CH:7][CH:6]=1.O/[N:35]=[C:36](\[NH2:40])/[CH:37]([CH3:39])[CH3:38]>CCO>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:23]=[CH:22][C:21]([C:24]4[CH:33]=[CH:32][CH:31]=[C:26]([C:27]5[O:29][N:40]=[C:36]([CH:37]([CH3:39])[CH3:38])[N:35]=5)[CH:25]=4)=[CH:20][C:14]=3[C:15]=2[C:16]([NH:17][CH3:18])=[O:19])=[CH:7][CH:6]=1
Reactant: CC(C)/C(N)=N/O
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)OC)c3)cc12
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nc(C(C)C)no4)c3)cc12
Yield: 19.5 %

Procedure:
Sodium methoxide (33 mg, 0.620 mmol) was added to a stirring slurry of methyl 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoate (50 mg, 0.124 mmol) and (Z)—N′-hydroxyisobutyrimidamide (38 mg, 0.372 mmol) in EtOH (2.5 mL) at rt. The mixture was subjected to microwave irradiation for 5 min at 160° C. The mixture was concentrated and purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (11 mg, 20%). 1H NMR (400 MHz, DMSO-d6) d ppm 8.46-8.54 (1H, m), 8.35 (1H, s), 8.11 (1H, d, J=7.78 Hz), 7.97-8.08 (3H, m), 7.92-7.97 (1 H, m), 7.73-7.84 (3H, m), 7.40 (2H, t, J=8.91 Hz), 3.12-3.23 (1H, m), 2.87 (3H, d, J=4.52 Hz), 1.36 (6H, d, J=7.03 Hz). LC-MS retention time: 1.80 min; m/z (MH+): 456. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=16.33 min, purity=99%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 mm, Rt=13.72 min, purity=99%.
Reaction SMILES: [CH3:1][CH:2]1[C:8](=[O:9])[N:7]2[CH:3]1[CH2:4][C:5]([Cl:20])=[C:6]2[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].C([N-]C(C)C)(C)C.[Li+].[CH:29](=[O:31])[CH3:30]>C1COCC1>[OH:31][CH:29]([C:2]1([CH3:1])[C:8](=[O:9])[N:7]2[CH:3]1[CH2:4][C:5]([Cl:20])=[C:6]2[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[CH3:30]
Reactant: CC=O
Reactant: CC1C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC12
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)C1(C)C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC21

Procedure:
Benzyl 6-methyl-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate is converted to its enolate derivative with lithium diisopropylamide in anhydrous THF at -78° as described in the previous example. To this solution is added 10 equivalents of acetaldehyde. Workup as described in example 16 yields benzyl 6-(1-hydroxyethyl)-6-methyl-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.