Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10](O)=[O:11])=[C:7]([CH3:13])[C:6]=2[C:14]=1[O:15][CH:16]([CH3:18])[CH3:17].B.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[C:7]([CH3:13])[C:6]=2[C:14]=1[O:15][CH:16]([CH3:18])[CH3:17]
Reactant: Cc1c(C(=O)O)oc2ccc(Br)c(OC(C)C)c12
Agent: B
Solvent: C1CCOC1
Product: Cc1c(CO)oc2ccc(Br)c(OC(C)C)c12
Reaction time: 24 h
Yield: 80.5 %

Procedure:
A solution of 5-bromo-4-isopropoxy-3-methyl-1-benzofuran-2-carboxylic acid (0.43 g 1.37 mmole) in 25 mL of THF under nitrogen was placed in a water bath. To this solution was added 2 mL of BH3.THF (1.0M in THF, 2.06 mmole, 1.4 eq) dropwise. After 24 hours, The mixture was quenched with water, the solvent was concentrated in vacuo, and the residue was extracted with ethyl acetate. The organic layer washed with water, saturated sodium carbonate and brine, dried over sodium sulfate, filtered, and concentrated to provide 0.33 g of (5-bromo-4-isopropoxy-3-methyl-1-benzofuran-2-yl) methanol. Yield 80.5%; EA: Theory C: 52.15: H, 5.05. Found C: 52.26; H: 4.80.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:13]=[CH:12][C:11]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:23][N:15]([CH2:14][C:11]1[CH:12]=[N:13][C:8]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:9][CH:10]=1)[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:19])[CH3:20]
Reactant: CN(Cc1ccc(Cl)nc1)C(=O)OC(C)(C)C
Reactant: Nc1nccs1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CN(Cc1ccc(Nc2nccs2)nc1)C(=O)OC(C)(C)C
Temperature: 130 °C
Yield: 60.4 %

Procedure:
A suspension of 2-aminothiazole (0.556 g, 5.55 mmol, 1.15 eq), tert-butyl (6-chloropyridin-3-yl)methyl(methyl)carbamate (1.24 g, 4.83 mmol), sodium carbonate (0.717 g, 6.76 mol, 1.4 eq) and XANTPHOS (0.034 g, 0.058 mmol, 0.012 eq) in THF (12 mL, bubbled with argon for 5 minutes) was bubbled again with argon for 5 additional minutes. Tris(dibenzylideneacetone)dipalladium (0) (0.018 g, 0.019 mmol, 0.004 eq) was then added to the suspension which was heated at 130° C. for 18 hours. Tris(dibenzylideneacetone)dipalladium (0) (0.018 g, 0.019 mmol, 0.004 eq) and XANTPHOS (0.034 g, 0.058 mmol, 0.012 eq) were added again and the reaction was stirred for 18 more hours. The same was repeated a second time. The mixture was cooled down to RT and filtered. The THF filtrate was evaporated and the residue (1.72 g) was purified on Biotage silica gel chromatography (hexane/ethyl acetate 1:1 to 0:1) to give the title material (0.934 g, 60%). 1H NMR (400 MHz, CDCl3) δ ppm: 1.52 (9H, s), 2.84 (3H, s), 4.40 (2H, s), 6.86 (1H, d, J=3.54 Hz), 6.92 (1H, d, J=8.59 Hz), 7.44 (1H, d, J=3.79 Hz), 7.57 (1H, d, J=19.45 Hz) 8.27 (1H, s).
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH3:16])[CH:15]=[N:10][C:8](=[S:9])[NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=S)Nc1ccccc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=NC(=S)Nc1ccccc1

Procedure:
6.1 G. PHENYLTHIOUREA AND 4.3 G. DIMETHYL FORMAMIDE DIMETHYLACETAL WERE SUSPENDED IN 100 ML. OF BENZENE WITH ~ 100 MG OF P-TOLUENE SULFURIC ACID AND THE MIXTURE DISTILLED THROUGH A 6 PLATE DISTILLING COLUMN. The methanol-benzene azeotrope, bp 57°C, came off rapidly. After the bp rose to 80°C, the mixture was cooled and the product crystallized from the benzene. The yield was 6.3 g of solid m.p. 131°-138°C which was triturated with ether to give 6 g m.p. 139°-143°C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[CH3:13]C(C)([O-])C.[K+].CI.Cl>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[N:9]2[CH3:13])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: O=C1CCc2ccc(F)cc2N1
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)CCc2ccc(F)cc21
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To an ice cold solution of 7-fluoro-3,4-dihydro-1H-quinolin-2-one (16.5 g, 0.1 mol) in DMF (200 mL) was added potassium tert-butoxide (22.4 g, 0.2 mol) in 2 portions. The reaction mixture was stirred at 0° C. for 30 min before MeI (25.4 g, 0.18 mol) was added. After the addition, the reaction mixture was allowed to warm up to room temperature slowly and stirred at room temperature over night. The reaction mixture was diluted with EtOAc (500 mL), then poured into 200 mL of 1 N aq. HCl. After extraction with EtOAc (200 mL, 3×), the combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give crude title compounds as oil (16.0 g, 89% yield). It was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:35]=[CH:34][C:33]4[C:32]5[C:27](=[CH:28][C:29](Br)=[CH:30][CH:31]=5)[C:26]([F:38])([F:37])[C:25]=4[CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:40]([O:44][C:45]([N:47]1[CH:52]([C:53]2[NH:57][C:56]3[CH:58]=[C:59](B4OC(C)(C)C(C)(C)O4)[CH:60]=[CH:61][C:55]=3[N:54]=2)[CH:51]2[CH2:71][CH:48]1[CH2:49][CH2:50]2)=[O:46])([CH3:43])([CH3:42])[CH3:41].C([O-])([O-])=O.[K+].[K+]>COCCOC.O.CCOC(C)=O.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:40]([O:44][C:45]([N:47]1[CH:52]([C:53]2[NH:57][C:56]3[CH:58]=[C:59]([C:29]4[CH:30]=[CH:31][C:32]5[C:33]6[C:25](=[CH:24][C:23]([C:20]7[NH:19][C:18]([CH:17]8[CH2:16][C:13]9([CH2:15][CH2:14]9)[CH2:12][N:11]8[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:39])[CH:6]([CH3:8])[CH3:7])=[N:22][CH:21]=7)=[CH:35][CH:34]=6)[C:26]([F:38])([F:37])[C:27]=5[CH:28]=4)[CH:60]=[CH:61][C:55]=3[N:54]=2)[CH:51]2[CH2:71][CH:48]1[CH2:49][CH2:50]2)=[O:46])([CH3:43])([CH3:41])[CH3:42]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(Br)ccc2-3)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc3c(c2)C(F)(F)c2cc(-c4ccc5nc(C6C7CCC(C7)N6C(=O)OC(C)(C)C)[nH]c5c4)ccc2-3)[nH]1)C(C)C
Temperature: 87.5 °C
Reaction time: 3 h
Yield: 75.4 %

Procedure:
(1-{6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (840 mg, 1.4 mmol), 3-[6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-benzoimidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (615 mg, 1.4 mmol), Pd(PPh3)4 (161 mg, 0.14 mmol), K2CO3 (579 mg, 4.2 mmol), were dissolved in DME (15 mL)/water (3 mL) under an argon atmosphere. The mixture was heated for 120 minutes at 85-90° C. (oil bath). After 120 minutes additional boronate ester (61 mg, 0.14 mmol) was added and heating was continued. After 3 hours, the reaction was cooled to room temperature. Most of the DME was removed in vacuo and the crude reaction mixture was diluted with EtOAc. The mixture was washed with brine and was dried over sodium sulfate. Filtration and evaporation of solvents gave the crude reaction product, which was purified via silica gel chromatography (eluent: EtOAc/hexanes) to yield the product 3-[6-(9,9-Difluoro-7-{2-[5-(2-methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-9H-fluoren-2-yl)-1H-benzoimidazol-2-yl]-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (878 mg). LCMS-ESI+: calc'd for C47H51F2N7O5: 831.9 (M+); Found: 832.7 (M+H+).
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].C(O[C:8](=[O:18])[CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C>>[CH2:11]([N:10]1[CH2:9][C:8](=[O:18])[NH:3][C:2]1=[S:1])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: N#C[S-]
Reactant: CCOC(=O)CNCc1ccccc1
Agent: [NH4+]
Product: O=C1CN(Cc2ccccc2)C(=S)N1
Temperature: 25 °C
Yield: 57.9 %

Procedure:
Ammonium thiocyanate (47.27 g) and N-benzylglycine ethyl ester (40.0 g) were fused together at 140° C. for 4 hours. The deep red solution was allowed to cool to room temperature and the solid residue washed with ethanol/water (1:1) (200 ml). The solid was collected by filtration, washed with ethanol/water (1:1) (5×200 ml) and with diethyl ether (3×100 ml) to afford 1-benzyl-2-thiohydantoin (24.72 g), m.p. 150°-152° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH:15]2[CH2:17][CH2:16]2)[C:12]=1[O:13][CH3:14])[C:6]([O:8]C)=[O:7])#[N:2].O.[OH-].[Li+]>O1CCCC1.O>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH:15]2[CH2:16][CH2:17]2)[C:12]=1[O:13][CH3:14])[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COC(=O)c1cc(C#N)c(OC)c(C2CC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C#N)cc(C(=O)O)cc1C1CC1
Reaction time: 20 h
Yield: 85.4 %

Procedure:
Methyl 3-cyano-5-cyclopropyl-4-methoxybenzoate (491 mg) was dissolved in tetrahydrofuran (7.5 mL) and water (2.5 mL), and lithium hydroxide monohydrate (359 mg) was added to the solution, and then the mixture was stirred at mom temperature for 20 hours. The organic solvent was distilled off under reduced pressure and the aqueous layer was washed with n-hexane. To the aqueous layer, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate under acidic conditions. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (394 mg) as a pale brown crystal.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]#[CH:5].N1C=CC=CC=1.[F:12][C:13]([F:24])([F:23])[C:14]1[N:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[CH:16][CH:15]=1>ClCCl>[CH3:1][N:2]([CH2:3][C:4]#[CH:5])[C:20](=[O:21])[C:17]1[CH:16]=[CH:15][C:14]([C:13]([F:24])([F:23])[F:12])=[N:19][CH:18]=1
Reactant: C#CCNC
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C#CCN(C)C(=O)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
N-methylpropargylamine (95%, 1.0 g, 13.75 mmol) and pyridine (5 mL) in dry dichloromethane (DCM)(50 mL) were cooled with ice-water. 6-(Trifluoromethyl)pyridine-3-carbonyl chloride (97%, 2.83 g, 13.10 mmol) was added drop wise with a syringe. The ice bath was removed and the mixture was stirred at room temperature overnight. DCM (150 mL) was added and the mixture was washed with water (3×100 mL). The organic phase was dried with anhydrous MgSO4, filtered and evaporated to dryness, then purified by silica gel column chromatography, eluting with MeOH/DCM (0-2%) to give the product (1.96 g, 70.0% yield), LRMS ESI (M+H+) 243, HPLC rt=5.4 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[CH:8]=[C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([F:21])[F:20])=[CH:15][CH:16]=2)[C:11](=O)[O:10]1.C(O)(=O)C.O.[NH2:29][NH2:30]>CO>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH:19]([F:21])[F:20])=[CH:15][CH:16]=2)[C:11](=[O:10])[NH:30][N:29]=1
Reactant: NN
Reactant: O=C1OC(=Cc2c(Cl)cncc2Cl)c2ccc(OC(F)F)cc21
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]nc(Cc2c(Cl)cncc2Cl)c2ccc(OC(F)F)cc12
Yield: 85 %

Procedure:
A solution of 3-(3,5-dichloro-pyridin-4-ylmethylen)-6-difluoromethoxy-3H-isobenzofuran-1-one (14.4 g, 21 mmoles), prepared as described in example 97, in CH3OH (100 ml), under N2, was added with acetic acid (3.6 ml, 63 mmoles) and hydrazine monohydrate (3.15 ml, 63 mmoles). A precipitate formed and the mixture was refluxed for 2 hours. After 1 night to stand the mixture was cooled over ice and the solid filtered and washed with little CH3OH. After drying under vacuum at 50° C., 6.64 g of the title compound were obtained [yield: 85% from (5-difluoromethoxy-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-triphenyl-phosphonium bromide].
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:19]([C:3]1[CH:4]=[C:5]([C:8]2[S:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:11]([CH3:13])[N:12]=2)[CH:6]=[CH:7][C:2]=1[O:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: CCOC(=O)c1sc(-c2ccc(F)c([N+](=O)[O-])c2)nc1C
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(-c2ccc(Oc3ccccc3)c([N+](=O)[O-])c2)nc1C
Temperature: 100 °C
Yield: 98.8 %

Procedure:
A reaction mixture solution prepared by suspending 931 mg of ethyl 2-(4-fluoro-3-nitrophenyl)-4-methyl-1,3-thiazole-5-carboxylate, 339 mg of phenol and 622 mg of potassium carbonate in 15 mL of dimethylformamide was heated at 100° C. for 14 hours under a nitrogen atmosphere. The reaction mixture solution was cooled to room temperature, water was added and extraction was performed using ethyl acetate. The organic layer was washed with saline and then dried and concentrated under reduced pressure. The resulting crude product was separated and purified by silica gel column chromatography to obtain 1.14 g of ethyl 2-(3-nitro-4-phenoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate.
Reaction SMILES: [CH:1]12[N:8]([C:9]3[C:10]4[C:32]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[CH:31][S:30][C:11]=4[N:12]=[C:13]([O:15][CH:16]4[CH2:21][CH:20]5[CH2:22][CH:17]4[CH2:18][N:19]5C(OC(C)(C)C)=O)[N:14]=3)[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2>C(Cl)Cl.FC(F)(F)C(O)=O>[CH:20]12[CH2:22][CH:17]([CH:16]([O:15][C:13]3[N:14]=[C:9]([N:8]4[CH:1]5[CH2:7][CH2:6][CH:5]4[CH2:4][O:3][CH2:2]5)[C:10]4[C:32]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)=[CH:31][S:30][C:11]=4[N:12]=3)[CH2:21]1)[CH2:18][NH:19]2
Reactant: CC(C)(C)OC(=O)N1CC2CC1CC2Oc1nc(N2C3CCC2COC3)c2c(-c3ccccc3)csc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(-c2csc3nc(OC4CC5CC4CN5)nc(N4C5CCC4COC5)c23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 2.7 %

Procedure:
Tert-butyl 5-[4-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-5-phenyl-thieno[2,3-d]pyrimidin-2-yl]oxy-2-azabicyclo[2.2.1]heptane-2-carboxylate (269 mg, 0.503 mmol) was dissolved in DCM (2 mL) and trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 2 hrs and then evaporated. The residue was dissolved in water (2 mL) and DCM (2 mL). Solid sodium bicarbonate was added to neutralize the remaining acid. The layers were separated and the aqueous was extracted with DCM (2×2 mL). The combined organic layers were evaporated to give a brown solid. This was purified by preparative HPLC (acidic method 1). Fractions containing the target compound (by LCMS) were combined and evaporated. The residue was dissolved in methanol and applied to an SCX cartridge (2 g, equilibrated with methanol). The cartridge was washed with methanol (2 column volumes) then 0.5 M ammonia in methanol (2 column volumes). The ammonia solution was evaporated to give 8-[2-(2-azabicyclo[2.2.1]heptan-5-yloxy)-5-phenyl-thieno[2,3-d]pyrimidin-4-yl]-3-oxa-8-azabicyclo[3.2.1]octane as a white solid (6 mg). LCMS RT=3.16 min. M+1=435.
Reaction SMILES: C([O:5][C:6]1[CH:14]=[CH:13][C:12]2[N:8]([C:9]([C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:10]([CH2:24][C:25]([CH3:32])([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:11]=2[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[O:16])[CH:7]=1)(C)(C)C.[Cl-].[Al+3].[Cl-].[Cl-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(Cl)Cl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]([C:11]2[C:10]([CH2:24][C:25]([CH3:31])([CH3:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:9]([C:33](=[O:38])[C:34]([CH3:36])([CH3:37])[CH3:35])[N:8]3[C:12]=2[CH:13]=[CH:14][C:6]([OH:5])=[CH:7]3)=[O:16])=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(C)(C)Cc1c(C(=O)c2ccc(Cl)cc2)c2ccc(OC(C)(C)C)cn2c1C(=O)C(C)(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Cc1c(C(=O)c2ccc(Cl)cc2)c2ccc(O)cn2c1C(=O)C(C)(C)C
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
To a solution of the ethyl 3-{6-tert-butoxy-1-[(4-chlorophenyl)carbonyl]-3-(2,2-dimethylpropanoyl)indolizin-2-yl}-2,2-dimethylpropanoate (1.23 g, 2.27 mmol) in CH2Cl2 (10 mL) is added aluminum chloride (454 mg, 3.41 mmol). The reaction is stirred for 30 min at 23° C. then treated with a saturated aqueous solution of Rochelle's salt. The mixture is partitioned between CH2Cl2 and brine, then organics are collected, dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude by flash chromatography (SiO2, hexanes to 25% EtOAc in hexanes) affords ethyl 3-{1-[(4-chlorophenyl)carbonyl]-3-(2,2-dimethylpropanoyl)-6-hydroxyindolizin-2-yl}-2,2-dimethylpropanoate (605 mg, 22%).
Reaction SMILES: C1(C[B:8]([OH:10])[OH:9])C=CC=CC=1.[C:11]12([OH:22])[CH2:19][CH:15]([C:16]1([CH3:18])[CH3:17])[CH2:14][CH2:13][C:12]2([OH:21])[CH3:20].[C:23]([O:27][C:28]([C:30]1[CH:31]=[C:32](CB(O)O)[CH:33]=[CH:34][CH:35]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C12(O)CC(C1(C)C)CCC2(O)C>>[C:11]12([OH:22])[CH2:19][CH:15]([C:16]1([CH3:18])[CH3:17])[CH2:14][CH2:13][C:12]2([OH:21])[CH3:20].[C:23]([O:27][C:28]([C:30]1[CH:31]=[C:32]([B:8]([O-:10])[O-:9])[CH:33]=[CH:34][CH:35]=1)=[O:29])([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)c1cccc(CB(O)O)c1
Reactant: OB(O)Cc1ccccc1
Agent: CC1(O)CCC2CC1(O)C2(C)C
Product: CC(C)(C)OC(=O)c1cccc(B([O-])[O-])c1
Yield: 88 %

Procedure:
Following the procedure described for the synthesis of 13a, compound 13b was recovered from 12b as a yellow oil (88% yield). [α]D+8.7 (c 1.4, CHCl3). 1H-NMR (400 MHz, CDCl3): δ 0.87 (3H, s, pinanyl CH3), 1.11 (1H, d, J 11.0, pinanyl Hendo), 1.32 (3H, s, pinanyl CH3), 1.43 (3H, s, pinanyl CH3), 1.63 (9H, s, t-Bu), 1.84-2.39 (5H, m, pinanyl protons), 2.42 (2H, s, BCH2), 4.32 (1H, dd, J 8.8, 2.0, CHOB), 7.33 (1H, t, J 7.7, H5), 7.40 (1H, d, J 7.7, H6), 7.80 (1H, d, J 7.7, H4), 7.86 (1H, s, H2). 13C-NMR (100 MHz, CDCl3): δ 19.3 (CB), 24.0, 26.5, 27.1, 28.2, 28.6, 35.4, 38.2, 39.5, 51.3, 78.0, 80.7, 86.0, 126.2, 128.1, 129.9, 132.0, 133.2, 139.0, 166.0; EI-MS: m/z 370 (M+, 18%), 314 (71), 297 (59), 135 (55), 57 (100). Anal. Calcd. for C22H31BO4: C, 71.36; H, 8.44. Found: C, 71.60; H, 8.27.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:24])[CH:21](Cl)[CH3:22])=[N:17][CH:18]=1.O>CN(C=O)C>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][C:20](=[O:24])[CH:21]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH3:22])=[N:17][CH:18]=1
Reactant: CC(Cl)C(=O)Nc1ccc(Br)cn1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C(=O)Nc1ccc(Br)cn1)N1CCCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4.01 g (29.0 mmol) K2CO3 and 1.19 mL (14.5 mmol) pyrrolidine are added successively to a solution of 3.5 g (13.3 mmol) N-(5-bromo-pyridin-2-yl)-2-chloro-propionamide in 50 mL DMF. The reaction is stirred for 3 days at RT and combined with 150 mL water. The aqueous phase is extracted twice with EtOAc and the organic phase is dried over MgSO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, gradient: PE/EtOAc 4:6 after EtOAc).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]([OH:13])=[O:12])=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][CH2:3]1.[C:14](Cl)(=O)[CH3:15]>C(O)C>[O:1]=[C:2]1[C:7]2[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: CC(=O)Cl
Reactant: O=C(O)c1coc2c1C(=O)CCC2
Solvent: CCO
Product: CCOC(=O)c1coc2c1C(=O)CCC2
Reaction time: 1 h

Procedure:
To a stirring suspension of 4-Oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (28.2 g. 157 mmol) in ethanol (500 mL) under Nitrogen at ambient temperature was added acetyl chloride (56 mL, 783 mmol) dropwise. After stirring 1 h, the solution was then heated at reflux for 1 h. The solution was cooled and concentrated in vacuo. The residue was taken up into dichloromethane, washed with aqueous sodium bicarbonate, washed quickly with 1N sodium hyroxide, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford Ethyl 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylate as an oil. A mixture of this ester (24.46 g, 117 mmol) and ammonium acetate (15.85 g, 206 mmol) in dimethylformamide (225 mL) was heated at 100° C. under Nitrogen for 1.25 h. The mixture was cooled, poured into ice water, and extracted two times with dichloromethane. The combined organic extracts were washed with water, dried over magnesium sulfate, filtered, concentrated in vacuo, and the residue triturated with ether to give Ethyl 4-oxo-4,5,6,7-tetrahydroindole-3-carboxylate. A mixture of this ester (11.31 g, 55 mmol) in 5N sodium hydroxide (200 mL) and ethanol (20 mL) was heated at reflux for 1 h. After cooling in an ice bath, the mixture was acididified with concentrated hydrochloric acid, the precipitate filtered, rinsed with ice water, and dried in vacuo to afford 4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid.
Reaction SMILES: N(OC(C)(C)C)=O.I[CH2:9][I:10].NC1[S:13][CH:14]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:16]=1>C(#N)C.[Cl-].[Na+].O>[CH2:20]([O:19][C:17]([C:15]1[N:16]=[C:9]([I:10])[S:13][CH:14]=1)=[O:18])[CH3:21]
Reactant: ICI
Reactant: CCOC(=O)c1csc(N)n1
Agent: CC(C)(C)ON=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1csc(I)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
A solution of 6.0 ml of t-butyl nitrite in 120 ml of acetonitrile was cooled in ice under an argon atmosphere, and 9.64 g of diiodomethane and 5.16 g of 2-amino-4-ethoxycarbonylthiazole were added to the cooled solution. The mixture was stirred at room temperature for one hr, brine was added thereto, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, were washed twice with brine, were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1 to 3:1) to give 5.58 g of 4-ethoxycarbonyl-2-iodothiazole.
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[C:5](=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>C(O)C>[CH:21]1([C:18]2[CH:17]=[CH:16][C:15]([NH:14][C:10]3[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:27])=[O:2])[C:5]=3[C:6]([OH:8])=[O:7])=[CH:20][CH:19]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: COC(=O)c1cccc(Nc2ccc(C3CCCCC3)cc2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cccc(Nc2ccc(C3CCCCC3)cc2)c1C(=O)O
Yield: 90 %

Procedure:
A mixture of 3-(4-cyclohexylphenylamino)phthalic acid dimethyl ester (0.85 g, 2.3 mmol) and 3N NaOH (50 mL) in ethanol (100 mL) was heated to reflux for 90 minutes. The mixture was cooled, and the solvent was removed under vacuum. The residue was dissolved in water (100 mL), washed with ethyl acetate (3×75 mL), acidified (HCl) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with water (3×75 mL), dried (MgSO4), and evaporated, providing 0.70 g in 90% yield: 1H NMR (DMSO-d6) δ 1.14-1.44 (s, 5H), 1.67-1.78 (m, 5H), 2.35-2.45 (m, 1H), 7.00-7.04 (m, 2H), 7.08-7.14 (m, 3H), 7.26-7.37 (m, 2H), 7.98 (s, 1H).