Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@:9]1([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:10](=O)[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C([BH3-])#N.[Na+]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:30]([NH:37][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C@@:9]1([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH2:15][C@H:14]2[C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(c3ccccc3)C(=O)CC[C@@H]1N2Cc1ccccc1
Reactant: NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](NCc3ccccc3)CC[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
(1R*,5S*,6R*)-8-Benzyl-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octan-2-one (Description 17; 5.0 g, 12.8 mmol), p-toluenesulfonic acid monohydrate (25 mg) and benzylamine (2.1 g, 20 mmol) in toluene (50mL) was heated at reflux under Dean Stark conditions for 24 hours, then cooled and the solvent removed in vacuo. The residue was dissolved in methanol (100 mL) and sodium cyanoborohydride (900 mg, 14 mmol) added. The solution formed was stirred at room temperature for 2 hours then concentrated to approximately ¼ volume. Water (500 mL) was added and the suspension formed was extracted with ethyl acetate (2×500 mL). The extracts were dried (MgSO4) and concentrated, before the residue was purified by silica chromatography to give the title compound (3.87 g, 8 mmol) as a gum.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>CN(C=O)C>[CH:14]1([N:4]2[CH:3]=[C:2]([I:1])[CH:6]=[N:5]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Ic1cn[nH]c1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Ic1cnn(C2CCCC2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.5 %

Procedure:
To a solution of 4-iodo-1H-pyrazole (5 g, 25.78 mmol, 1.0 eq.) in DMF (25 ml) were added K2CO3 (8.908 g, 64.45 mmol, 2.5 eq.) and bromocyclopentane (4.96 g, 33.51 mmol, 1.3 eq.). The mixture was stirred at RT for 12 h. The mixture was quenched and extracted as in Intermediate Example 5(a). The solvent was distilled off to give the product in 89.5% yield. 1H NMR (300 MHz, CDCl3): δ 7.49 (s, 1H), 7.45 (s, 1H), 4.66-4.62 (m, 1H), 2.17-2.02 (m, 1H), 2.00-1.96 (m, 2H), 1.93-1.78 (m, 2H), 1.73-1.67 (m, 2H). LC-MS (ESI): Calculated mass: 262; Observed mass: 263 [M+H]+ (rt: 1.57 min).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[Cl:6][CH2:7][C:8]([NH2:10])=[O:9]>>[Cl:6][CH2:7][C:8]([NH:10][CH:2]([OH:3])[C:1]([OH:5])=[O:4])=[O:9]
Reactant: NC(=O)CCl
Reactant: O=CC(=O)O
Product: O=C(CCl)NC(O)C(=O)O
Temperature: 50 °C
Yield: 56.7 %

Procedure:
740 g of an aqueous solution with 50% of glyoxylic acid (5 moles) are mixed with 514 g of chloracetamide (5.5 moles). The mixture is heated to 50° C, then the greater part of the water is removed under vacuum, 1200 g of acetic acid are added and it is cooled on ice. After filtration and drying, 475 g of product are obtained. The product concentrated under vacuum gives 112 g of a second crop, namely a total yield of 69%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH:13]=[C:12]([Br:14])[C:11]([CH3:15])=[C:10]([N+:16]([O-])=O)[C:9]2=[O:19])=[CH:5][CH:4]=1.C([O-])(O)=O.[Na+]>C(O)(=O)C.Cl.O>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH:13]=[C:12]([Br:14])[C:11]([CH3:15])=[C:10]([NH2:16])[C:9]2=[O:19])=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2cc(Br)c(C)c([N+](=O)[O-])c2=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(Cn2cc(Br)c(C)c(N)c2=O)cc1
Reaction time: 3.5 h
Yield: 61.5 %

Procedure:
To a stirred solution of 1-(4-methoxybenzyl)-5-bromo-4-methyl-3-nitro-2-pyridone (0.23 g, 0.65 mmol) in glacial acetic acid (3 mL) was added a solution of stannous chloride dihydrate (1.0 g) in concentrated HCl (2 mL). After 3.5 hours, the reaction mixture was diluted with water, neutralized with NaHCO3, and extracted with methylene chloride. The organic phase was dried, filtered, and evaporated to give 1-(4-methoxybenzyl)-5-bromo-4-methyl-3-amino-2-pyridone (0.13 g, 0.40 mmol, 61%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[NH2:11])([O-:3])=[O:2].C([O-])(O)=O.[Na+].Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].O>C(#N)C.ClCCl>[CH2:21]([O:20][C:18](=[O:19])[NH:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([NH2:11])[CH:6]=1)[CH3:22]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc([N+](=O)[O-])c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)Nc1ccc([N+](=O)[O-])c(N)c1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a solution of 4-nitro-benzene-1,3-diamine (1.6 g) in acetonitrile (20 mL) was added NaHCO3 (1 g) and ethyl chloroformate (1.0 mL). The mixture was heated at 75° C. with stirring overnight. Cooled to ambient temperature, the mixture was diluted by water and extracted twice with ethyl acetate. Combined organics were dried over Na2SO4, filtered, and concentrated to give crude yellow solid. Trituration from dichloromethane afforded (3-amino-4-nitro-phenyl)-carbamic acid ethyl ester: 1H NMR (400 MHz, CD3OD) 7.9 (d, 1H), 7.3 (s, 1H), 6.5 (d, 1H), 4.2 (q, 2H), 1.3 (t, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CN1C(=O)CCC1.C(N(CC)CC)C.F[C:23]1[CH:24]=[CH:25][C:26]([N+:30]([O-:32])=[O:31])=[C:27]([NH2:29])[CH:28]=1>O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:23]2[CH:24]=[CH:25][C:26]([N+:30]([O-:32])=[O:31])=[C:27]([NH2:29])[CH:28]=2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of N-methylpiperazine (1.0 eq), NMP, triethylamine (3.0 eq) and 5-fluoro-2-nitrophenylamine (1.0 eq) were heated at 90° C. for 1 hours. The reaction was allowed to cool to room temperature and then poured into water and let stand for 12 hours. The resulting solid was collected and dried and utilized without further purification. MH+=237.3.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[N:8]([C:16](=[O:27])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24](O)=[O:25])[CH:19]=1)[CH2:7][CH2:6]2.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH2:41][CH:42]1[CH2:46][CH2:45][N:44]([CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:43]1>ClCCl.C1COCC1.CN(C=O)C>[CH2:47]([N:44]1[CH2:45][CH2:46][CH:42]([NH:41][C:24]([C:20]2[CH:19]=[C:18]([NH:17][C:16]([N:8]3[C:9]4[C:5](=[CH:4][C:3]([S:2][CH3:1])=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=4)[CH2:6][CH2:7]3)=[O:27])[CH:23]=[CH:22][CH:21]=2)=[O:25])[CH2:43]1)[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: CSc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cccc(C(=O)O)c1)CC2
Reactant: NC1CCN(Cc2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1cc2c(cc1C(F)(F)F)N(C(=O)Nc1cccc(C(=O)NC3CCN(Cc4ccccc4)C3)c1)CC2
Reaction time: 1 h
Yield: 89.4 %

Procedure:
The carboxylic acid from Example 12 (0.5 g, 1.25 mmol) in dichloromethane (10 ml) was treated with oxalyl chloride (0.3 ml, 3.4 mmol) and DMF (catalytic). The solution was stirred for 1 hour and evaporated to dryness. The residue in dry THF (3 ml) was added to a stirred solution of triethylamine (0.3ml, 4 mmol) and 3-amino-N-benzyl pyrrolidine (0.79 g, 4.5 mmol) in dry THF (10 ml). Following 3 hours at room temperature the solution was partitioned (H2O/EtOAc). Drying and removal of solvent followed by rexst (EtOAc/60°-80° C. petrol) afforded the title compound (0.62 g, 89%) as a white powder. M.pt. 174°-175° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14](OCC)=[O:15])[C:9](OCC)=[O:10])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:14][OH:15])[CH2:9][OH:10])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(Br)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: CCOCC
Solvent: CCCCCC
Product: OCC(CO)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 37.4 %

Procedure:
To a solution of diethyl 2-(4-bromophenyl)malonate (18.1 g, 57.5 mmol) in ether (285 ml) was added 0.98M-diisobutylaluminium hydride in hexane (259 ml, 254 mmol) at 0° C. under nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 4 hours. Aqueous potassium sodium tartrate (0.57M, 500 ml) was added to the reaction mixture for quenching the aluminum reagent and the mixture was stirred for 14 hours. The organic layer was extracted with ethyl acetate and dried over sodium sulfate. After concentration, the residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=40/60 to ethyl acetate only) to afford 2-(4-bromophenyl)propane-1,3-diol as white solid (4.97 g, 37%).
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([NH:14][C@@:15]([C:30]1[CH:35]=[C:34]([O:36][C:37]([F:42])([F:41])[CH:38]([F:40])[F:39])[CH:33]=[C:32]([F:43])[CH:31]=1)([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13].[C:44]([O-])([O-])=O.[K+].[K+].CI>CC#N>[F:43][C:32]1[CH:31]=[C:30]([C@:15]([NH:14][C:12]([NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]2[N:4]=[N:3][N:2]([CH3:44])[N:1]=2)=[O:13])([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:35]=[C:34]([O:36][C:37]([F:42])([F:41])[CH:38]([F:40])[F:39])[CH:33]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCCCCCc1nn[nH]n1)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: Cn1nnc(CCCCCNC(=O)N[C@](Cc2ccccc2)(c2ccc(F)cc2)c2cc(F)cc(OC(F)(F)C(F)F)c2)n1
Temperature: 80 °C
Yield: 17 %

Procedure:
To a solution of (R)-1-(5-(2H-tetrazol-5-yl)pentyl)-3-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea (12 mg, 0.019 mmol) in MeCN (115 μl) at rt was added K2CO3 (3.2 mg, 0.023 mmol) followed by MeI (1.5 μL, 0.023 mmol). The reaction mixture was heated to 80° C. overnight. The reaction mixture was quenched by addition of H2O and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were concentrated and the residue was dissolved in MeOH and purified by preparative HPLC (Phenoma Luna AXIA 10A, C18, eluting with MeCN/H2O containing 0.1% TFA, monitoring at 220 nm) to provide (R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(5-(2-methyl-2H-tetrazol-5-yl)pentyl)urea (Example 260, 2 mg, 18% yield) as white solid. 1H NMR (500 MHz, CDCl3) ppm 7.17-7.08 (m, 5H), 6.99-6.85 (m, 5H), 6.67 (d, J=5 Hz, 2 H), 5.98-5.75 (m, 1H), 4.23 (s, 3H), 3.82 (d, J=15 Hz, 1H), 3.68 (d, J=15 Hz, 1H), 3.10-3.07 (m, 2H), 2.85-2.82 (m, 2H), 1.77-1.71 (m, 2H), 1.46-1.40 (m, 2H), 1.32-1.26 (m, 2H); LC/MS: RT=3.218 min [M+H] 621.2 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeCN/H2O over 4 minutes containing 0.1% NH4OAc; 4 mL/min, monitoring at 220 nm).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][NH2:11])=[CH:2]1.Br[C:13]1[C:14]([NH2:20])=[N:15][CH:16]=[C:17]([Br:19])[N:18]=1.C(N(C(C)C)C(C)C)C>CCO>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][NH:11][C:13]2[C:14]([NH2:20])=[N:15][CH:16]=[C:17]([Br:19])[N:18]=2)=[CH:2]1
Reactant: Nc1ncc(Br)nc1Br
Reactant: NCc1c[nH]c2ncccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1ncc(Br)nc1NCc1c[nH]c2ncccc12
Temperature: 150 °C
Reaction time: 8 h
Yield: 7.3 %

Procedure:
A mixture of (1H-pyrrolo[2,3-b]pyridin-3-yl)methanamine (intermediate A) (442 mg, 3.0 mmol), 3,5-dibromopyrazin-2-amine (758 mg, 3.0 mmol) and N-ethyl-N-isopropylpropan-2-amine (1160 mg, 9.0 mmol) in EtOH (70 mL) was stirred at 150° C. overnight. After being cooled to room temperature, it was concentrated and purified by chromatography to afford the title compound (70 mg) MS (m/z): 319 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH3:12])[CH:3]=1.BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>CO.C(N(CC)CC)C.C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:39]([CH2:38][C:37]1[CH:40]=[CH:41][C:34]([F:33])=[CH:35][CH:36]=1)[CH2:12]2
Reactant: COC(=O)c1ccc(Br)cc1C
Reactant: NCc1ccc(F)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1c2ccc(Br)cc2CN1Cc1ccc(F)cc1
Yield: 34.2 %

Procedure:
A mixture of 458 mg methyl 4-bromo-2-methylbenzoate, 427 mg N-bromosuccinimide, 25 mg α,α′-azobisisobutyronitrile and 10 mL carbon tetrachloride was heated for 30 minutes under reflux. 50 mg N-bromosuccinimide was added thereto, and the mixture was further heated for 30 minutes under reflux. The reaction solution was cooled, insolubles were filtered off, and the filtrate was evaporated. 773 mg crude product of methyl 4-bromo-2-bromomethyl benzoate was obtained as a pale yellow oil. A mixture of this compound, 546 mg 4-fluorobenzyl amine, 0.34 mL triethylamine and 10 mL methanol was heated for 2 days under reflux. The reaction solution was cooled, and the precipitated crystals were collected by filtration and dried under reduced pressure with a vacuum pump, to give 219 mg of the title compound as pale brown crystals.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]3[CH2:22][CH2:21]3)[CH:18]=[N:19][C:4]=2[CH:3]=1.[CH3:23][C:24]1[S:25][C:26](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:28]=1.C([O-])([O-])=O.[Na+].[Na+].N#N>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.C(Cl)Cl.COCCOC>[CH:20]1([N:17]2[C:5]3[C:6]([O:8][C@@H:9]([C@H:11]4[CH2:15][NH:14][C:13](=[O:16])[CH2:12]4)[CH3:10])=[N:7][C:2]([C:26]4[S:25][C:24]([CH3:23])=[N:28][CH:27]=4)=[CH:3][C:4]=3[N:19]=[CH:18]2)[CH2:22][CH2:21]1
Reactant: C[C@@H](Oc1nc(Br)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: Cc1ncc(B2OC(C)(C)C(C)(C)O2)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1ncc(-c2cc3ncn(C4CC4)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)s1
Temperature: 140 °C
Yield: 14.6 %

Procedure:
To a microwave tube equipped with a stirring bar, (R)-4-((R)-1-((6-bromo-3-cyclopropyl-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one: (100 mg, 0.274 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (184.9 mg, 0.821 mmol), 1,2-dimethoxyethane (1.1 mL), 1 N Na2CO3 aqueous solution (0.82 mL, 0.82 mmol) were added, the mixture was bubbled N2 for 5 minutes before Pd(PPh3)4 (31.6 mg, 0.027 mmol) was added. The tube was sealed and heated in a microwave at 140° C. for 20 minutes. DCM (200 mL) was added and the resulting mixture was washed with saturated NaHCO3 aqueous solution (20 mL×4), brine (20 mL×1), dried over anhydrous Na2SO4, filtered, removed solvents in vacuo. The resulting residue was passed a ISCO silica gel column (MeOH:DCM=5:95) to give off-white solids, 15.3 mg (yield 14.6%). 1H NMR (300 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.21 (s, 1H), 7.77 (s, 1H), 7.57 (broad s, 1H), 5.41 (p, J=6.0 Hz, 1H), 3.70-3.65 (m, 1H), 3.44-3.38 (m, 1H), 3.22-3.16 (m, 1H), 2.94-2.75 (m, 1H), 2.65 (s, 3H), 2.32 (dd, J=8.6, 2.3 Hz, 2H), 1.40 (d, J=6.1 Hz, 3H), 1.20-1.11 (m, 2H), 1.10-1.02 (m, 2H) ppm; MS (ESI+) m/z 384 (M+H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:11]([NH2:13])=[O:12])[CH2:10][CH2:9]1.[C:14]([Si:16]([CH3:19])([CH3:18])[CH3:17])#[CH:15].F[B-](F)(F)F>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:17][Si:16]([C:14]#[C:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:11]([NH2:13])=[O:12])[CH2:10][CH2:9]1)([CH3:19])[CH3:18]
Reactant: NC(=O)C1(c2ccccc2I)CC1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccccc1C1(C(N)=O)CC1

Procedure:
A solution of 1-(2-iodophenyl)cyclopropanecarboxamide (I11) (1.53 g, 85.3 mmol), ethynyltrimethylsilane (1.05 mL, 7.46 mmol), PdCl2(PPh3)2 (0.037 g, 0.053 mmol), t-Bu3PH.BF4 (0.031 g, 0.11 mmol) and copper(I) iodide (0.020 g, 0.11 mmol) in DMF (10 mL) was stirred under a nitrogen atmosphere at 50° C. for 26 hours. The volatiles were evaporated in vacuo and the resulting black residue was purified using silica gel column chromatography (CombiFlash Rf, 24 g SiO2 Cartridge, 5-20% EtOAc in cyclohexane) to give the title compound I12 as a dark yellow amorphous solid (1.09 g, 79%); 1H NMR (300 MHz, CDCl3) δ 7.52 (d, J=7.1 Hz, 1H), 7.26-7.50 (m, 3H), 5.26 (brs, 2H), 1.72 (dq, J=4.1 Hz, 2H) 1.16 (dq, J=3.9 Hz, 2H), 0.26 (s, 9H). LCMS-B: rt 7.446 min; m/z 258 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:11]=2[C:12]#[N:13])=O)[CH:5]=[CH:4][N:3]=1.[CH3:19][C:20]([S:23]([NH2:25])=[O:24])([CH3:22])[CH3:21].CO>C1COCC1.C(=O)(O)[O-].[Na+].[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:11]=2[C:12]#[N:13])=[N:25][S:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)S(N)=O
Reactant: N#Cc1c(F)cccc1C(=O)c1ccnc(Br)c1
Agent: [Ti+4]
Agent: CC[O-]
Agent: O=C([O-])O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=C(c1ccnc(Br)c1)c1cccc(F)c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.5 %

Procedure:
A solution of 2-(2-bromopyridine-4-carbonyl)-6-fluorobenzonitrile (3.0 g, 9.8 mmol) in dry THF (60 mL) was added to a solution of titanium (IV) ethoxide (8.0 mL, 38.6 mmol) in dry THF (20 mL) at room temperature. 2-Methyl-2-propanesulfinamide (1.8 g, 14.7 mmol) was then added in one portion and the reaction mixture was heated at reflux temperature for 40 hours. The reaction mixture was cooled to room temperature and methanol (10 mL) was added, followed by saturated sodium bicarbonate solution (10 drops). The mixture was stirred at room temperature for 1 hour, filtered through a pad of sodium sulfate, and the solids were washed thoroughly with ethyl acetate. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (20-50% ethyl acetate in hexanes) to afford the title compound (2.7 g, 67.5%).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[CH2:5]([SnH:9]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH3:8].N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>>[CH2:14]([Sn:9]([CH2:5][CH2:6][CH2:7][CH3:8])([CH2:10][CH2:11][CH2:12][CH3:13])/[CH:3]=[CH:2]/[CH2:1][OH:4])[CH2:15][CH2:16][CH3:17]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCO
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Product: CCCC[Sn](/C=C/CO)(CCCC)CCCC
Temperature: 80 °C

Procedure:
To neat propargyl alcohol (1 mL) were added tributyltin hydride (5.8 mL) followed by 1,1′-azobis(cyclohexanecarbonitrile) (213 mg). The mixture was heated for 2 h at 80° C., cooled to RT and directly purified by CC (EA/Hept 4/96 to 5/95) to afford the desired compound (2.98 g).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[C:21]3[CH:20]=[C:19]([C:22]([O:24]C)=[O:23])[NH:18][C:17]=3[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+].CO>C1COCC1>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[C:21]3[CH:20]=[C:19]([C:22]([OH:24])=[O:23])[NH:18][C:17]=3[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2c([nH]1)CCC2c1ccc(Cc2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2c([nH]1)CCC2c1ccc(Cc2ccccc2)cc1

Procedure:
The title compound was synthesized from methyl 4-(4-benzylphenyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (150 mg, 0.45 mmol) and lithium hydroxide monohydrate (108 mg, 4.5 mmol), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (10 mL) was used. The resulting product was purified by chromatography over silica gel (gradient 0 to 100% EtOAc in heptane over 20 min) to give a pure product (50 mg). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.14-2.25 (m, 1H), 2.66-2.94 (m, 3H), 3.91 (s, 2H), 4.14 (t, J=7.30 Hz, 1H), 6.51 (s, 1H), 7.09 (s, 5H), 7.12-7.19 (m, 3H), 7.21-7.28 (m, 2H). LCMS m/e 316 (M−H) and 100% pure by HPLC.
Reaction SMILES: [CH3:1][CH:2]([C:7](=[O:10])[CH2:8][CH3:9])[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[Li]CCCC.[N:18]1([C:24]2[CH:36]=[CH:35][C:27]3[CH:28]=[C:29](C(OC)=O)[O:30][C:26]=3[CH:25]=2)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[Cl-].[NH4+]>C1COCC1>[CH3:1][C:2]1[C:3](=[O:4])[O:5][C:6]([C:29]2[O:30][C:26]3[CH:25]=[C:24]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[CH:36]=[CH:35][C:27]=3[CH:28]=2)=[C:8]([CH3:9])[C:7]=1[OH:10]
Reactant: CCC(=O)C(C)C(=O)OC
Reactant: COC(=O)c1cc2ccc(N3CCOCC3)cc2o1
Agent: [Cl-]
Agent: [H-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(-c2cc3ccc(N4CCOCC4)cc3o2)oc(=O)c(C)c1O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of methyl 2-methyl-3-oxopentanoate (865 mg) in THF (30 ml) was slowly added to a suspension of NaH (240 mg) in THF (50 ml), and after stirring for 10 minutes, the mixture was cooled to −78° C. and 1.58 M n-BuLi (3.8 ml) was slowly added dropwise. After stirring the reaction solution at −78° C. for 30 minutes, a solution of methyl 6-morpholinylbenzofuran-2-carboxylate (1.3 g) in THF (15 ml) was slowly added and the mixture was stirred at −78° C. for 4 hours. A saturated ammonium chloride aqueous solution (30 ml) was added to the reaction solution, and after bringing it to room temperature, extraction was performed with AcOEt and the organic layer was dried with MgSO4 and then filtered and concentrated. The residue was dissolved in MeOH (30 ml) and THF (30 ml), a 4 N lithium hydroxide aqueous solution (10 ml) was added, and after stirring at room temperature for 4 hours, a saturated KHSO4 aqueous solution (50 ml) was slowly added. The deposited yellow precipitate was filtered off and rinsed with AcOEt to obtain 3,5-dimethyl-4-hydroxy-6-(6-morpholinylbenzofuran-2-yl)-2H-pyran-2-one.