Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([OH:26])[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2].[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([O:26][C:38]4[CH:39]=[CH:40][C:35]([O:34][CH2:27][C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:36][CH:37]=4)[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(O)ccc(F)c32)cc1
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(Oc4ccc(OCc5ccccc5)cc4)ccc(F)c32)cc1
Yield: 83 %

Procedure:
(1S,2S)-2-[4-((R)-7-Fluoro-4-hydroxy-indan-1-yloxy)-phenyl]-cyclopropanecarboxylic acid ethyl ester (Intermediate 5, 0.6 g, 1.7 mmol), 4-benzyloxyphenylboronic acid (1.53 g, 6.7 mmol), copper (II) acetate (306 mg, 1.7 mmol), triethylamine (1.83 mL, 13.1 mmol), 4-dimethylaminopyridine (21 mg, 0.17 mmol) and 4 Å molecular sieves (3 g) are suspended in dichloromethane and stirred under an oxygen atmosphere over a weekend. The mixture is filtered through a plug of CELITE filter aid, washing the filter cake with dichloromethane. The organic phases are washed with 1 M aqueous HCl solution, dried and the solvent removed. The residue is purified by flash chromatography (0-40% ethyl acetate in cyclohexane) to give the title compound (Yield 0.76 g). LC (METHOD 6): tR=1.04 min; Mass spectrum (ES+): m/z=539 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:39])[C:6]=1[C:7]1[CH:8]=[C:9]([C:12]([NH:14][C@@H:15]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([F:38])([F:37])[F:36])[CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)=[O:13])[S:10][CH:11]=1.NN>C1COCC1.CO>[NH2:17][CH2:16][C@@H:15]([NH:14][C:12]([C:9]1[S:10][CH:11]=[C:7]([C:6]2[N:5]([CH3:39])[N:4]=[CH:3][C:2]=2[Cl:1])[CH:8]=1)=[O:13])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([F:38])([F:37])[F:36]
Reactant: Cn1ncc(Cl)c1-c1csc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: CO
Solvent: C1CCOC1
Product: Cn1ncc(Cl)c1-c1csc(C(=O)N[C@H](CN)Cc2ccccc2C(F)(F)F)c1
Reaction time: 12 h

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-2-thiophenecarboxamide (150 mg, 0.262 mmol) in THF-MeOH (1:1, 2 mL) was added hydrazine (123 uL, 2.62 mmol). After 12 h, the solution was filtered and the filtrate was concentrated, dry loaded onto silica and purified via column chromatography (2% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH2:12][CH2:13][NH2:14])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1COCC1>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH2:12][CH2:13][NH:14][C:23](=[O:24])[O:25][CH2:26][CH3:27])=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2cc(CCN)oc12
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)NCCc1cc2cccc(OC)c2o1
Temperature: 25 °C
Reaction time: 5 h
Yield: 21.8 %

Procedure:
2-(7-methoxy-1-benzofuran-2-yl)ethanamine (from step 5) (100 mg, 0.523 mmol) was dissolved in THF (4 ml). To this solution triethylamine (0.211 g, 2.09 mmol) and ethyl chloroformate (0.085 g, 0.784 mmol) was added at 0° C. and then stirred at room temperature for 5 h. THF was evaporated and the residue was purified by column chromatography using 100-200 mesh silica gel and eluted in 5% ethyl acetate-petroleum ether to obtain 30 mg of yellow thick liquid.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[F:6][C:7]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:8]=1[C:9](Cl)=[O:10]>>[CH2:1]([N:3]([CH2:4][CH3:5])[C:9](=[O:10])[C:8]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:7]=1[F:6])[CH3:2]
Reactant: O=C(Cl)c1cc(F)ccc1F
Reactant: CCNCC
Product: CCN(CC)C(=O)c1cc(F)ccc1F
Yield: 93.8 %

Procedure:
Diethyl amine (15.4 g, 210 mmol) and 2,5-difluorobenzoyl chloride (17.6 g, 100 mmol) were reacted using General Method E1 to afford 20.0 g of N,N-diethyl-2,5-difluorobenzamide as a clear oil, a 94% yield.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]O)=[CH:10][CH:9]=1.C(Br)(Br)(Br)[Br:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:3][C:4]1[CH:5]=[C:6]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][Br:21])=[CH:10][CH:9]=1
Reactant: OCc1ccc(Oc2cc(Cl)cc(Cl)c2)cc1
Reactant: BrC(Br)(Br)Br
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1cc(Cl)cc(Oc2ccc(CBr)cc2)c1
Temperature: 0 °C

Procedure:
Using 3,5-dichlorophenol and 4-fluorobenzaldehyde, the reaction was carried out in the same manner as in Reference Example 1 to obtain 4-(3,5-dichlorophenoxy)benzaldehyde. Subsequently, the same procedure as in Reference Example 189 was followed using sodium borohydride in place of the lithium aluminum hydride. This gave 4-(3,5-dichlorophenoxy)benzyl alcohol. The resulting alcohol (2.03 g), along with carbon tetrabromide (2.75 g), was dissolved in methylene chloride (30 mL). While this solution was stirred at 0° C., triphenyl phosphine (2.17 g) was added. The mixture was stirred at 0° C. for 1 hour and at room temperature for the subsequent 30 min. The solvent was removed under reduced pressure and the residue was purified on a silica gel column chromatography (hexane:ethyl acetate=20:1) to give the desired product as a colorless oil (3.12 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[C:31]([CH2:32]Cl)=[CH:30][C:26]2[O:27][CH2:28][O:29][C:25]=2[CH:24]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:32][C:31]2[C:23]([Cl:22])=[CH:24][C:25]3[O:29][CH2:28][O:27][C:26]=3[CH:30]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Reactant: ClCc1cc2c(cc1Cl)OCO2
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2cc3c(cc2Cl)OCO3)cc1
Yield: 34.6 %

Procedure:
Followed the same procedure as that of step 2 in Example 91 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.5 mmol) and 5-chloro-6-chloromethyl-benzo[1,3]dioxole (125 mg, 0.6 mmol) to afford the title product (80 mg, 40% yield).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[H-].[Na+].[Cl:18][C:19]1[CH:20]=[C:21]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1F>CN(C)C=O>[Cl:18][C:19]1[CH:20]=[C:21]([S:26](=[O:28])(=[O:27])[NH2:29])[CH:22]=[CH:23][C:24]=1[O:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1
Reactant: NS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOC(COc2ccc(S(N)(=O)=O)cc2Cl)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (0.478 g) in anhydrous N,N-dimethylformamide (5 mL) was added sodium hydride (0.280 g). The mixture was stirred at room temperature for 30 minutes, followed by addition of 3-chloro-4-fluorobenzenesulfonamide (0.419 g). The mixture was stirred at 40° C. overnight. The reaction was quenched with water (10 mL), and the mixture was adjusted to pH 7 and extracted with ethyl acetate. The crude product was purified on a silica gel column eluting with 60% ethyl acetate in hexane to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:17])[CH:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22][NH2:23]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22][NH:23][C:2]1[C:11]2[C:6](=[C:7]([O:12][C:13]([F:16])([F:15])[F:14])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:17])[CH:3]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(Cl)c2cccc(OC(F)(F)F)c2n1
Product: Cc1cc(NCc2ccc(Cl)c(Cl)c2)c2cccc(OC(F)(F)F)c2n1

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4-chloro-2-methyl-8-trifluoromethoxyquinoline and 3,4-dichlorobenzylamine.
Reaction SMILES: [C:1]1([S:11]([NH:14][NH2:15])(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CO>[CH:16](=[N:15][NH:14][S:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)(=[O:12])=[O:13])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1ccccc1
Reactant: NNS(=O)(=O)c1cccc2ccccc12
Solvent: CO
Product: O=S(=O)(NN=Cc1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A four neck flask (1 liter) equipped with a thermometer, a reflux condenser and a stirrer was charged with 111 g (0.5 mol) of 1-naphthalenesulfonohydrazide and 700 ml of methanol, and 63.6 g (0.6 mol) of benzaldehyde was dropwise added thereto in one hour while stirring at room temperature and heated under reflux for about 5 hours. The reaction liquid was cooled down to 20° C. or lower, and then crystal was filtered off and dried under reduced pressure, whereby white crystal was obtained.
Reaction SMILES: [NH2:1][C:2](=[S:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl[CH2:10][C:11](=O)[CH3:12]>C(O)C>[CH3:12][C:11]1[N:1]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[S:8][CH:10]=1
Reactant: CC(=O)CCl
Reactant: CCOC(=O)C(N)=S
Solvent: CCO
Product: CCOC(=O)c1nc(C)cs1
Temperature: 25 °C

Procedure:
A solution of ethyl amino(thioxo)acetate (500 mg, 3.75 mmol) in ethanol (9.387 ml) was stirred at room temperature under an atmosphere of argon. 1-Chloro-2-propanone (0.299 ml, 3.75 mmol) was added and the solution was heated to reflux for 48 hours. The solution was allowed to cool to room temperature and then it was concentrated under reduced pressure to give a yellow coloured oily solid. The residue was chromatographed [SiO2, 0-100% EtOAc in Hexane] to give a yellow coloured oil identified as product in 208 mg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)C>[CH2:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH:13]1[O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6]
Reactant: OC1Cc2ccccc2C1
Reactant: COc1ccc(C=O)cc1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C=O)cc1OC1Cc2ccccc2C1
Yield: 20.7 %

Procedure:
A solution of 3-hydroxy-4-methoxy-benzaldehyde (15.2 g, 100 mmol, 1 eq), 2-indanol (12.1 g, 90 mmol, 0.9 eq), and triphenylphosphine (26.2 g, 100 mmol, 1 eq) in dry THF (300 mL) was treated dropwise with diisopropylazodicarboxylate (19.6 mL, 100 mmol, 1 eq). The reaction mixture was stirred at reflux for 16 hours, then cooled and diluted with diethyl ether (500 mL). The solution was washed with water (2×150 mL), 1 M NAOH (4×125 mL), and saturated NaCl (sodium chloride) (2×100 mL), dried with CH2Cl2, then concentrated to provide a syrup, which solidified upon standing. The solid was suspended in diethyl ether (350 mL) and stirred overnight to break up all chunks. The solid was collected by vacuum filtration and recrystallized from ethanol/water (21.4 g). The ethereal filtrate was concentrated and purified by flash chromatography (silica gel, 7.5×36 cm Biotage KP-Sil column, eluted with 25% ethyl acetate in heptane) to yield an additional 5 g of product. 1H NMR (300 MHz, CDCl3) δ9.86 (s, 1H), 7.49-7.44 (m, 2H), 7.25-7.16 (m, 4H), 6.97 (d, J=8.7 Hz, 1H), 5.29-5.22 (m, 1H), 3.89 (s, 1H), 3.45 (dd, J=16.7, 6.6 Hz, 2H), 3.24 (dd, J=16.7, 3.6 Hz, 2H). 13C NMR (75 MHz, CDCl3) 190.9, 155.5, 147.9, 140.4, 130.0, 126.9, 126.8, 124.7, 112.1, 111.0, 78.9, 56.1, 39.7.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15](O)=[O:16])=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([N:29]3[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]3)=[O:16])=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Reactant: CN1CCNCC1
Product: Cc1cc(Nc2cc3cc(C(=O)N4CCN(C)CC4)ccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 384 was used, starting from 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid and 1-Methyl-piperazine to give [1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl]-(4-methyl-piperazin-1-yl)-methanone. LC-MS: m/e 409 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].[C:25]1([O:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCOCC1>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:13][N:12]=[C:11]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[N:10]=2)=[CH:3][C:2]=1[NH:1][C:32](=[O:33])[O:31][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cc(-c2nc(-c3ccco3)no2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(Nc1cc(-c2nc(-c3ccco3)no2)ccc1Cl)Oc1ccccc1

Procedure:
To a mixture of 5-(3-amino-4-chlorophenyl)-3-(2-furanyl)-1,2,4-oxadiazole (0.75 and 0.58 g of potassium carbonate in 30 ml of dioxane is added 0.94 g of phenylchloroformate. The resulting mixture is heated at reflux for 2 hours and concentrated to dryness. 50 ml of water is added to the residue and the mixture extracted three times with chloroform. The extracts are dried over magnesium sulfate, filtered and concentrated. The residue is recrystallized from benzene to yield 0.62 g of the title compound, melting point 177°-178°C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:11])[N:6]([CH2:8][CH2:9][OH:10])[CH:7]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O.[Pd]>[F:12][C:13]1[CH:18]=[C:17]([C:2]2[CH:3]=[CH:4][C:5](=[O:11])[N:6]([CH2:8][CH2:9][OH:10])[CH:7]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=c1ccc(Br)cn1CCO
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=c1ccc(-c2cccc(F)c2)cn1CCO
Temperature: 120 °C
Reaction time: 0.08 h

Procedure:
5-Bromo-1-(2-hydroxyethyl)pyridin-2(1H)-one (100.7 mg, 462 μmol), 3-fluorophenylboronic acid (121.5 mg, 868 μmol), palladium fibercat catalyst (4.11%, 14.1 mg), and sodium carbonate (0.48 ml, 2.0 M in water, 960 μmol) were put in a microwave vial, and then 1,4-dioxane (0.69 ml) was added. The microwave vial was sealed and heated in the CEM microwave at 120° C. and 50 Watts for a 5 minute ramp time and then a 20-minute run time. The reaction was then cooled to room temperature, diluted with water, and extracted with 3:1 CH2Cl2/MeOH. The organic phases were combined, dried over sodium sulfate, filtered, concentrated, and dried under vacuum. The material was used for the next step. MS (ESI pos. ion) m/z (MH+): 234. Calc'd exact mass for C13H12FNO2: 233.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2=[CH:14][N:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=[C:10]2[CH2:9]1)=O)(C)(C)C.C(C(O)=O)(F)(F)F>C(Cl)Cl>[CH:14]1[N:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:16]=[C:10]2[C:11]=1[CH2:12][CH2:13][NH:8][CH2:9]2
Reactant: CCOC(=O)Cn1cc2c(c1)CN(C(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Cn1cc2c(c1)CNCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 2 ml of methylene chloride was dissolved 0.11 g (0.36 mmol) of ethyl 5-t-butoxycarbonyl-4,5,6,7-tetrahydropyrrolo[3,4-c]pyridin-2-acetate, and under ice-cooling, 0.4 ml of CF3CO2H was added to the residue and the mixture was stirred at room temperature for 2 hours.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([O-])(=[O:25])=[O:24])=[C:7]1[CH3:27])[CH3:2].[Na+].[Cl:30]S(O)(=O)=O>>[Cl:30][S:23]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:28])[C:7]=1[CH3:27])(=[O:25])=[O:24]
Reactant: O=S(=O)(O)Cl
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)[O-])c2cc(F)ccc21
Agent: [Na+]
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)Cl)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Sodium 2-((1-(2-ethoxy-2-oxoethyl)-5-fluoro-2-methyl-1H-indol-3-yl)methyl)benzenesulfonate (2.30 g, 5.38 mmol) was added portionwise to chlorosulfonic acid (10 ml) at room temperature (20° C.) over 20 min. The resulting mixture was stirred at room temperature for 2 hours, then poured onto ice/water (300 mL). The solution was next extracted with CH2Cl2, and the separated organics washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford ethyl 2-(3-(2-(chlorosulfonyl)benzyl)-5-fluoro-2-methyl-1H-indol-1-yl)acetate (2.03 g, 4.79 mmol, 89%), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][C:11]2[CH:12]=[CH:13][O:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C>C1COCC1>[CH2:1]([C:8]1[CH:16]=[CH:15][C:11]2[CH:12]=[C:13]([B:22]([OH:27])[OH:23])[O:14][C:10]=2[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: c1ccc(Cc2ccc3ccoc3c2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc2ccc(Cc3ccccc3)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a purple mixture of benzofuran-6-ol (1.85 g, 13.8 mmol) and N,N-diisopropylethylamine 99% (7.21 mL, 41.4 mmol) in 50 mL DCM was added 1,1,1-trifluoro-n-phenyl-n-((trifluoromethyl)sulfonyl)methanesulfonamide (4.93 g, 13.8 mmol). The reaction became light blue. After 2 h, the reaction was light yellow. The reaction was quenched with saturated aq. sodium bicarbonate, and the aqueous layer was extracted with DCM. The combined organics were dried over anhyd sodium sulfate, filtered, and concentrated in vacuo. The resulting material was purified by silica gel chromatography, 0-15% EtOAc/hexanes, to give benzofuran-6-yl trifluoromethanesulfonate as a semi-solid. A portion of the unpurified material was carried on as follows. A mixture of 9-benzyl-9-bora-bicyclo[3.3.1]nonane 0.5M in THF (23 mL, 11 mmol), benzofuran-6-yl trifluoromethanesulfonate (1.50 g, 5.6 mmol), potassium phosphate (3.6 g, 17 mmol), benzofuran-6-yl trifluoromethanesulfonate (1.50 g, 5.6 mmol), S-Phos (0.19 g, 0.45 mmol), Pd(OAc)2 (0.051 g, 0.23 mmol) was flushed with argon, sealed, and heated to 60° C. overnight. The green/gray reaction was cooled and filtered through celite rinsing with Et2O. The filtrate was concentrated and adsorbed onto 15 g silica gel and dried. The material was purified by silica gel chromatography, ISCO, 80 g, 0-10% EtOAc/hexanes to give 6-benzylbenzofuran. A portion of this material was processed as follows. To a solution of 6-benzylbenzofuran (0.663 g, 3.18 mmol) in 30 mL THF at −78° C. was added 1-butyllithium 2.5 M in hexanes (1.53 mL, 3.82 mmol) slowly dropwise. The reaction was allowed to stir for 25 min, at which point triisopropyl borate (1.08 mL, 4.68 mmol) was added slowly dropwise. After 0.5 h, the bath was removed and the reaction was allowed to warm to ambient temperature. After 10 min, 50 mL 2N HCl was added. The mixture was diluted with MTBE, and the organics were washed with brine, dried over anhyd. MgSO4, filtered, and concentrated in vacuo to give an oil. The oil was treated with hexanes to give a solid, and the material was filtered and rinsed with hexanes and dried in vacuo to give 6-benzylbenzofuran-2-ylboronic acid as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47 (s, 2H), 7.57 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.39 (s, 1H), 7.24-7.33 (m, 4H), 7.15-7.22 (m, 1H), 7.10 (d, J=8.0 Hz, 1H), 4.06 (s, 2H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:10][C:8](=[O:9])[NH:7][C:5]=2[CH:6]=1.[Br:11]N1C(=O)CCC1=O.O>C(O)(=O)C>[Br:11][C:2]1[CH:1]=[CH:6][C:5]2[NH:7][C:8](=[O:9])[O:10][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccccc2o1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(Br)cc2o1
Temperature: 25 °C
Reaction time: 63 h
Yield: 79.2 %

Procedure:
To a solution of benzoxazolinone (20 g, 0.148 mol) in 220 mL glacial acetic acid was added N-bromosuccinimide (NBS, 26.36 g, 0.148 mol), and the reaction mixture was stirred at room temperature for 63 hours before pouring into 1500 mL water. The precipitated product was washed thoroughly with water upon collection and recrystallized from EtOH to give 6-bromo-3H-benzoxazol-2-one (9) (25.09 g, 79%): Theory: C, 39.28; H, 1.88; N, 6.54; Br, 37.33. Found: C, 39.36; H, 2.02; N, 6.36; Br, 37.43. MP 192-194° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][C:15]1[C:19]2[C:20]([OH:28])=[C:21]([CH2:25][CH2:26][CH3:27])[CH:22]=[C:23]([Cl:24])[C:18]=2[O:17][CH:16]=1>C(Cl)CCl>[C:1]([C:16]1[O:17][C:18]2[C:23]([Cl:24])=[CH:22][C:21]([CH2:25][CH2:26][CH3:27])=[C:20]([O:28][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:19]=2[C:15]=1[CH3:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCc1cc(Cl)c2occ(C)c2c1O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCc1cc(Cl)c2oc(C(=O)c3ccccc3)c(C)c2c1OC(=O)c1ccccc1
Reaction time: 0.17 h
Yield: 37.9 %

Procedure:
A solution of benzoyl chloride (3.03 gm; 21.6 mmoles) in ethylene dichloride (20 mL) was added slowly to a cooled suspension of aluminium chloride (5.8 gm; 43 mmoles) in ethylenedichloride (100 mL). After stirring for a period of 10 minutes, 3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (1.62 gm; 7.2 mmoles) in dichloroethylene (20 mL) was added over a period of 2 minutes. The reaction mixture was stirred at room temperature for 1 hour. It was cooled with an ice-bath and ice was added slowly. When the vigorous reaction subsided, the organic layer was separated and the aqueous phase was extracted with methylene chloride. The organic phases were combined, dried (Na2SO4), and concentrated in vacuo. The residue was chromatographed on silica gel and eluted with 10% ethylacetate in hexane to yield 1.18 gm (63%) of 2-benzoyl-3-methyl-4-benzoyloxy-5-propyl-7-chlorobenzofuran, mp. 141°-142° C.