Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH3:10])[N:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.ClCCl>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH:9]([O:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:3]=1)[CH3:10]
Reactant: COc1ccccc1C(C)Oc1cncc(Cl)n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccccc1C(C)Oc1cncc(N2CCNCC2)n1
Temperature: 90 °C
Yield: 67 %

Procedure:
A mixture of the product from step 1 above (0.93 g, 3.53 mmol) piperazine (0.88 g, 10.2 mmol) and K2CO3 (0.49 g, 3.53 mmol) in acetonitrile (7 mL) was heated in a sealed pyrex flask at 90° C. for 6.5 h. The reaction mixture was diluted with dichloromethane, filtered and concentrated in vacuo. The semi-solid residue was purified by silica gel chromatography (13×4 cm) using CHCl3/MeOH (9:1) as eluent. Solvents were evaporated off and the remaining oil was redissolved in CHCl3, filtered through a short plug of alumina, covered with K2CO3, using CHCl3 as eluent. Solvent removal in vacuo gave 0.74 g (67%) of the title compound as a beige oil. HRMS m/z calcd for C17H22N4O2 (M)+ 314.1743, found 314.1733. Anal. (C17H22N4O2.0.5H2O) C, H, N.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][CH2:14]O)([O-:3])=[O:2].C1(C)C=CC=CC=1.N1C=CC=CC=1.[Cl-:29]>C(Cl)Cl>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[CH2:13][CH2:14][Cl:29])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CCO)c([N+](=O)[O-])c1
Reactant: [Cl-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccc(CCCl)c([N+](=O)[O-])c1
Yield: 98.9 %

Procedure:
20 g 2-(2,4-dinitrophenyl)ethanol (94 mmol) are dissolved in 120 ml abs. toluene and 4 ml pyridine. 34 g thidnyl chloride (21 ml, 282 mmol) in 20 ml abs. toluene are quickly added in a drop-wise manner. After 2 h under reflux, this is cooled and poured onto ice. This is mixed with 100 ml CH2Cl2 and the aqueous phase is extracted 2× each with 50 ml CH2Cl2. The combined organic phases are dried over Na2SO4, filtered and rotary evaporated. 21.51 g (93 mmol, 98%) 2-(2,4-dinitrophenyl)ethyl chloride are obtained as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)([C:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][CH:15]=2)O)=[CH:4][CH:3]=1.[ClH:30].[O:31]1CCCC1>>[ClH:30].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[C:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][CH:15]2[OH:31])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: OC(C1=CCN(Cc2ccccc2)CC1)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cl
Product: OC1CN(Cc2ccccc2)CCC1=C(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 10 °C
Reaction time: 7 h
Yield: 58.7 %

Procedure:
To a stirred solution of 50.9 parts of α,α-bis(4-fluorophenyl)-1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinemethanol in 270 parts of tetrahydrofuran were added 750 parts of a hydrochloric acid solution 1N. The whole was stirred first for 7 hours at reflux temperature and then for 8 hours at room temperature. The precipitated product was filtered off and set aside. The filtrate was evaporated till all traces of tetrahydrofuran were removed. After cooling, the solid precipitated product was filtered off and suspended, together with the precipitated product which was set aside (see above), in 80 parts of acetonitrile. The product was filtered off and stirred in 40 parts of acetonitrile while heating. After cooling to 10° C., the product was filtered off and dried, yielding 32.6 parts (58.7%) of 4-[bis(4-fluorophenyl)-methylene]-1-(phenylmethyl)-3-piperidinol hydrochloride; mp. 266° C. (intermediate 23).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:40])[CH:10]=[CH:11][CH:12]([OH:39])[CH2:13][O:14][C:15](=[O:38])[C@H:16]([CH:35]([CH3:37])[CH3:36])[NH:17][C:18]([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:47](Cl)(=[O:65])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64].C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:8][C:9](=[O:40])[CH:10]=[CH:11][CH:12]([O:39][C:47](=[O:65])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[CH2:13][O:14][C:15](=[O:38])[C@H:16]([CH:35]([CH3:37])[CH3:36])[NH:17][C:18]([O:20][CH2:21][CH:22]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]2[C:23]1=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCC(O)C=CC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCC(=O)OC(C=CC(=O)OCc1ccccc1)COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reaction time: 8 h

Procedure:
To a solution of benzyl-5-(N-FMOC-L-valyloxy)-4-hydroxy-2-pentenoate (6.5 g, 12 mmol) and pyridine (2.0 g, 25 mmole) in 100 ml dichloromethane at 10° C. was added dropwise a solution of stearoylchloride (4.55 g, 15 mmol) in 25 ml dichloromethane. The mixture was stirred overnight. 100 ml of 5% sodium hydrogencarbonate solution was added and the mixture was stirred for 30 minutes. The organic phase was seperated and the water phase was extracted two times with dichloromethane. The combined organic phases were dried with sodium sulfate and concentrated in vacuo. The product was isolated by silica gel column chromatography Yield: 7.8 g=80%
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[CH3:8].[CH3:9][O-:10].[Na+].ClCCl.O>CO>[CH3:9][O:10][C:2]1[S:6][C:5]([NH2:7])=[N:4][C:3]=1[CH3:8]
Reactant: Cc1nc(N)sc1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COc1sc(N)nc1C

Procedure:
5-Bromo-4-methyl-thiazol-2-ylamine (0.5 g, 2.59 mmol) was dissolved in methanol abs. (10 mL). The solution was cooled with an ice-bath, then under stirring was added portionwise sodium methoxide (140 mg, 2.59 mmol) The black reaction mixture was stirred for 30 min. at rt then poured into a mixture of dichloromethane/water. The aqueous layer was extracted with two portions of dichloromethane. The combined, organic extracts were dried over magnesium sulfate, filtered and evaporated under reduced pressure to obtain the crude product which was used without further purification. MS (EI): m/e 144.1.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:46]([O:48][C:49]([C:51]1([NH2:60])[CH2:59][C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52]1)=[O:50])[CH3:47]>CO.C(Cl)Cl.C(Cl)Cl>[CH2:46]([O:48][C:49]([C:51]1([NH:60][C:6]([C:4]2[C:3]3[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=3[S:1][CH:5]=2)=[O:8])[CH2:59][C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH2:52]1)=[O:50])[CH3:47]
Reactant: O=C(O)c1csc2ccccc12
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2csc3ccccc23)Cc2ccccc2C1
Yield: 77.4 %

Procedure:
To a 40 mL vial containing a stirring bar, benzo[b]thiophene-3-carboxylic acid ([5381-25-9], 434 g, 2.44 mmol) is charged with dry DCM (7 mL). Stirring is initiated. HBTU (922 mg, 2.43 mmol) and DIPEA (0.95 mL, 8.0 mmol) are added. The 2-aminoindane-2-carboxylic acid ethyl ester (500 mg, 2.44 mmol) is added. The reaction is allowed to stir for 20 h. Analysis by tlc of the reaction mixture (silica, 10% MeOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are diluted with EtOAc (50 mL) and transferred to a reparatory funnel. This is washed consecutively with dilute aqueous NaHCO3 (25 mL) and brine (25 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 1.64 g of off white solid. This material is purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 20% EtOAc in heptanes over 3 column volumes followed by a linear gradient to 50% over 8 column volumes and then 90% EtOAc for 2 column volumes with a ramp of 1 column volume. 25 mL fractions are collected. Fractions 4 through 16 are combined and evaporated in vacuo. Pumping to a constant weight gives amorphous white solid 0.69 g.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][C:10]2[N:11]=[N:12][NH:13][N:14]=2)=[O:8])=[CH:5][CH:4]=1)=O.[C:17]([CH:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1)([CH3:20])([CH3:19])[CH3:18].C(O)(=O)C.C([BH3-])#N.[Na+]>CN1C(=O)CCC1.COC(OC)OC.CO>[C:17]([CH:21]1[CH2:22][CH2:23][CH:24]([NH:27][CH2:1][C:3]2[CH:16]=[CH:15][C:6]([C:7]([NH:9][C:10]3[N:11]=[N:12][NH:13][N:14]=3)=[O:8])=[CH:5][CH:4]=2)[CH2:25][CH2:26]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: O=Cc1ccc(C(=O)Nc2nn[nH]n2)cc1
Reactant: CC(C)(C)C1CCC(N)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CN1CCCC1=O
Product: CC(C)(C)C1CCC(NCc2ccc(C(=O)Nc3nn[nH]n3)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The above resin bound 4-formyl-N-(2H-tetrazol-5-yl)benzamide (50 mg) was treated with a 0.5 M solution of 4-tert-butylcyclohexylamine (0.25 mmol, 38.75 mg) in a mixture of NMP and trimethylorthoformate (1:1, 0.5 mL) and glacial acetic acid (50 μL) for 1 hour at 25° C. followed by sodium cyanoborohydride (250 μmol, 16 mg) dissolved in a mixture of NMP and methanol (1:1, 0.25 mL). Shaking at 25° C. for 4 hours followed by filtration and washing with a mixture of NMP and methanol (1:1, 2×1 mL), NMP (3×1 mL) and a mixture of 1,2-dichloropropane (DCP) and diisopropylethylamine (7:1, 2×1 mL) afforded the desired product.
Reaction SMILES: [C:1]([Si:5]([CH3:28])([CH3:27])[O:6][C:7]1[CH:26]=[CH:25][C:10]2[C:11]3[CH:20]([OH:21])[O:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]=3[CH2:22][CH2:23][O:24][C:9]=2[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].I[C:30]1[CH:44]=[CH:43][C:33]([O:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:32][CH:31]=1>>[C:1]([Si:5]([CH3:27])([CH3:28])[O:6][C:7]1[CH:26]=[CH:25][C:10]2[C:11]([CH:20]([OH:21])[C:30]3[CH:31]=[CH:32][C:33]([O:34][CH2:35][CH2:36][N:37]4[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]4)=[CH:43][CH:44]=3)=[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[OH:19])[CH2:22][CH2:23][O:24][C:9]=2[CH:8]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Ic1ccc(OCCN2CCCCC2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OCCC1=C2C(O)Oc2ccccc21
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OCCC(c1ccccc1O)=C2C(O)c1ccc(OCCN2CCCCC2)cc1

Procedure:
Following the procedure described in Examples 76, 2-(tert-Butyl-dimethyl-silyloxy)-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-5-ol, the compound prepared as in Example 105 above, was reacted with 1-[2-(4-Iodo-phenoxy)-ethyl]-piperidine to yield 2-(8-(tert-Butyl-dimethyl-silyloxy)-5-{hydroxy-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-2,3-dihydro-benzo[b]oxepin-4-yl)-phenol as a crude oil. The crude 2-(8-(tert-Butyl-dimethyl-silyloxy)-5-{hydroxy-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-2,3-dihydro-benzo[b]oxepin-4-yl)-phenol was then further treated with HCl (12N, 4 eq., 0.67 mL) in toluene (100 mL) to generate yield 1-(2-{4-[2-(tert-Butyl-dimethyl-silyloxy)-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-5-yl]-phenoxy}-ethyl)-piperidine as a crude oil. The crude 1-(2-{4-[2-(tert-Butyl-dimethyl-silyloxy)-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-5-yl]-phenoxy}-ethyl)-piperidine was then further treated with HF•Pyridine (70% HF, 30% Pyridine, 0.5 mL) in CH3CN (20 mL) at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate:THF (1:1) and then washed with 5% NaHCO3 and brine. The reaction mixture was dried, concentrated and purified by flash chromatograph eluted with 5% MeOH in DCM to yield the title compound as a slightly yellow solid.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1.Br[CH2:16][CH2:17]Br.[Cl-].[NH4+]>CN(C)C=O>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:11]([O:13][CH3:14])=[O:12])[CH2:17][CH2:16]2)=[CH:8][CH:9]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: BrCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)C1(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.6 %

Procedure:
After sodium hydride (55% oily) (2.40 g, 55.0 mmol) was added to a solution of methyl (4-bromophenyl)acetate (5.73 g, 25.0 mmol) obtained in Example (3-1) in N,N-dimethylformamide (50 ml) at 0° C., the mixture was stirred at room temperature for 10 minutes. After the reaction mixture was cooled to 0° C. and 1,2-dibromoethane (2.37 ml, 27.5 mmol) was added thereto, the mixture was further stirred at room temperature for 15 hours. After a saturated aqueous ammonium chloride solution was poured into the reaction mixture and the mixture was extracted with ethyl acetate, the organic layer was successively washed with water (twice) and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=9/1) to give methyl 1-(4-bromophenyl)cyclopropanecarboxylate as an oil (2.97 g, yield: 47%).
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Cl:27][C:28]1[N:35]=[CH:34][CH:33]=[CH:32][C:29]=1[C:30]#[N:31].Cl.C(OCC)(=O)C>C(OCC)C>[ClH:27].[C:30]([C:29]1[C:28]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:26])[S:12][CH:13]=2)=[N:35][CH:34]=[CH:33][CH:32]=1)#[N:31]
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Reactant: N#Cc1cccnc1Cl
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncccc1C#N

Procedure:
A compound obtained using 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester synthesized in Example 303-2 and 2-chloronicotinonitrile as starting materials and by operations similar to those of Example 303-3 and 303-4 was dissolved in diethyl ether, and reacted with 4 mol/L hydrochloric acid-ethyl acetate to give the title compound.
Reaction SMILES: [CH:1]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1B(O)O.[Br:22][C:23]1[CH:24]=[C:25](I)[CH:26]=[CH:27][CH:28]=1.COC.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[Br:22][C:23]1[CH:24]=[C:25]([C:14]2[CH:15]=[CH:16][C:17]3[C:18]4[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=4)[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:12]=3[CH:13]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: OB(O)c1ccc2c3ccccc3c3ccccc3c2c1
Reactant: Brc1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: COC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2ccc3c4ccccc4c4ccccc4c3c2)c1
Temperature: 25 °C

Procedure:
Under an argon atmosphere, triphenylene-2-boronic acid (32.6 g), 3-bromoiodobenzene (28.1 g), tetrakistriphenylphosphinepalladium(0) (2.31 g), toluene (200 mL), DME (dimethylether) (200 mL) and an aqueous solution of 2M sodium carbonate (200 mL) were put in a flask and heated to reflux for 24 hours. After the reaction solution was cooled down to the room temperature, the reaction solution was extracted with toluene. After an aqueous phase was removed, an organic layer was washed with saturated saline. After the organic phase was drided with magnesium sulfate and concentrated, the obtained residue was refined by silica-gel column chromatography, so that 2-(3-bromophenyl)triphenylene (27.5 g) was obtained.
Reaction SMILES: [Mg].[H-].C([Al+]CC(C)C)C(C)C.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1.[CH3:23][C:24]([S@@:27](/[N:29]=[CH:30]/[C:31]1[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][N:32]=1)=[O:28])([CH3:26])[CH3:25]>C1COCC1.CCOCC>[CH3:26][C:24]([S@@:27]([NH:29][C@H:30]([C:31]1[C:36]([CH3:37])=[CH:35][CH:34]=[CH:33][N:32]=1)[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)=[O:28])([CH3:23])[CH3:25]
Reactant: Cc1cccnc1/C=N/[S@@](=O)C(C)(C)C
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccnc1[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A 250 mL round-bottomed flask containing magnesium turnings (0.685 g, 28.2 mmol) and Et2O (25 mL) was added diisobutylaluminum hydride 1.0 M solution in hexanes (0.18 mL, 0.180 mmol) followed by dropwise addition of 4-bromobenzotrifluoride (2.0 mL, 14.28 mmol). The solution was stirred for 1.5 hours during which it turned from turbid to dark brown in color. The reaction mixture was cooled to −78° C. in a dry ice/acetone bath and then a solution of (S,E)-2-methyl-N-((3-methylpyridin-2-yl)methylene)propane-2-sulfinamide (2.15 g, 7.67 mmol) in THF (15 mL) was added dropwise over 5 minutes. The reaction was stirred for 5 hours during which it warmed to rt. The reaction was quenched with saturated aqueous NH4Cl (50 mL) and H2O (25 mL). The reaction mixture was extracted with EtOAc (2×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to yield the initial product which was purified by silica gel flash column chromatography (using a 80G ISCO cartridge) and eluted using hexanes/EtOAc gradient to yield the desired product
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:18]([NH:20][CH3:21])=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28](=[O:39])[NH:29][C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([CH3:32])[CH3:31])[CH:23]=1.[C:40](Cl)(=[O:42])[CH3:41]>N1C=CC=CC=1>[C:40]([NH:1][C:2]1[C:7]2[C:8]([C:18]([NH:20][CH3:21])=[O:19])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28](=[O:39])[NH:29][C:30]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([CH3:32])[CH3:31])[CH:23]=1)(=[O:42])[CH3:41]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)c(N)c12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)c(NC(C)=O)c12
Reaction time: 2 h
Yield: 34 %

Procedure:
4-amino-2-(4-fluorophenyl)-N-methyl-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide (20 mg, 0.038 mmol) was diluted in pyridine (1 mL) and treated with excess acetyl chloride (10 μL). The reaction was allowed to stir for 2 hours. The mixture was concentrated and diluted with MeOH (1 mL). The product began to crash out, it was sonicated and filtered and washed with MeOH to afford the titled compound (8 mg, 34%). 1H NMR (500 MHz, DMSO-d6) δ ppm 9.41 (1H, s), 8.43 (1H, s), 8.31-8.38 (1H, m), 7.88-7.92 (1H, m), 7.82-7.87 (2H, m), 7.80 (1H, d, J=7.63 Hz), 7.71 (1H, d, J=8.55 Hz), 7.54-7.60 (1H, m), 7.43-7.49 (2H, m), 7.36-7.43 (5H, m), 7.28 (2H, t, J=7.78 Hz), 7.17 (1H, t, J=7.32 Hz), 2.76 (3H, d), 1.79 (3 H, s), 1.69 (6H, s). LC-MS retention time 1.42 min; m/z 564 (MH+). 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 μm, Rt=12.00 min, purity=96%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 μm, Rt=11.26 min, purity=95%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH3:18])=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[S:28])[CH:23]=[CH:24][CH:25]=1>CN(C=O)C>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:22]4[CH:23]=[CH:24][CH:25]=[C:20]([CH3:19])[CH:21]=4)=[S:28])=[CH:7][CH:6]=3)=[C:9]([CH3:18])[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: Cc1sc2ncnc(N)c2c1-c1ccc(N)cc1
Reactant: Cc1cccc(N=C=S)c1
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=S)Nc2ccc(-c3c(C)sc4ncnc(N)c34)cc2)c1
Yield: 80 %

Procedure:
A solution of Example 1E (60 mg, 0.23 mmol) and 3-methylphenyl isothiocyanate in DMF (2 mL) was stirred at room temperature, for 48 hours, quenched with water, and filtered. The filter cake was dried to provide the desired product (75 mg, 80%). MS(ESI(+)) m/e 406 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 9.96 (s, 1H); 9.84 (s, 1H); 8.27 (s, 1H); 7.65 (d, J=8.4 Hz, 2H); 7.35 (d, J=8.4 Hz, 2H); 7.30-7.18 (m, 3H); 6.97 (d, J=6.9 Hz, 1H); 2.30 (s, 6H).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:26]#[N:27])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[Cl:25])[CH:10]=2)=[O:5])C.[C:28]([O:32][C:33](=[O:39])[C:34]([CH3:38])([CH3:37])[CH2:35][NH2:36])([CH3:31])([CH3:30])[CH3:29]>CCO>[C:28]([O:32][C:33](=[O:39])[C:34]([CH3:38])([CH3:37])[CH2:35][NH:36][C:4]([C:6]1[N:7]=[C:8]([C:26]#[N:27])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[Cl:25])[CH:10]=2)=[O:5])([CH3:31])([CH3:29])[CH3:30]
Reactant: CCOC(=O)c1nc(C#N)c2cc(Oc3cc(F)ccc3Cl)ccc2c1O
Reactant: CC(C)(C)OC(=O)C(C)(C)CN
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3cc(F)ccc3Cl)ccc2c1O
Yield: 95.3 %

Procedure:
A mixture of 7-(2-chloro-5-fluoro-phenoxy)-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid ethyl ester (15 mg) and 3-amino-2,2-dimethyl-propionic acid tert-butyl ester (19 mg) in EtOH (0.7 mL) was microwaved at 150° C. for 2 h. The mixture was cooled, concentrated and the residue was column purified to give the desired product (19 mg). LC MS ESI+: 514 (M+1)+.