Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=3)=[C:7]([CH:14]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:15]([O:17]C)=[O:16])[N:8]([CH3:13])[C:9]2=[O:12])=[CH:4][CH:3]=1.[CH3:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1.FC(F)(F)C([O-])=O>>[CH3:22][C:20]([O:19][CH:14]([C:7]1[N:8]([CH3:13])[C:9](=[O:12])[C:10]2[C:5]([C:6]=1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=1)=[CH:4][CH:3]=[C:2]([C:36]1[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=1)[CH:11]=2)[C:15]([OH:17])=[O:16])([CH3:21])[CH3:23]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(Br)cc2c(=O)n1C
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])C(F)(F)F
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3cc(-c4cnn(C)c4)ccc23)cc1C

Procedure:
The title compound was prepared in two steps in a manner similar to that described in Example 191 from methyl [7-bromo-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetate and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and was isolated as a pale yellow solid (20 mg, 57%) after reverse phase chromatography as the trifluoroacetate salt: 1H NMR (400 MHz, CHLOROFORM-d) δ=8.59 (s, 1 H), 7.91 (s, 1 H), 7.82 (s, 1 H), 7.70-7.53 (m, 1 H), 7.45-7.31 (m, 1 H), 7.32-7.22 (m, 1 H), 7.17 (dd, J=8.5, 12.4 Hz, 1 H), 7.12-7.03 (m, 1 H), 5.36 (d, J=1.0 Hz, 1 H), 4.00 (s, 3 H), 3.73 (s, 3 H), 2.38 (s, 3 H), 2.33 (d, J=2.5 Hz, 3 H), 1.07 (d, 9 H); LC/MS (m/z) ES+=474 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][O:22][CH2:23][CH2:24][NH:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[OH:28][CH2:27][C:26]([N:25]([CH2:24][CH2:23][O:22][CH3:21])[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:30])[CH3:29]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: COCCNC(C)(C)CO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)CO

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 2-(2-methoxyethylamino)-2-methylpropan-1-ol (CAN 1156380-97-0) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=414.4 [MH+].
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:19]=[CH:18][C:10]2[N:11]([CH2:14][CH:15]3[CH2:17][CH2:16]3)[N:12]=[N:13][C:9]=2[C:8]=1[C:20]([F:23])([F:22])[F:21])(=O)=O.[Cl:26][C:27]1[N:32]=[C:31]([F:33])[C:30](B(O)O)=[CH:29][CH:28]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[Cl:26][C:27]1[N:32]=[C:31]([F:33])[C:30]([C:7]2[CH:19]=[CH:18][C:10]3[N:11]([CH2:14][CH:15]4[CH2:16][CH2:17]4)[N:12]=[N:13][C:9]=3[C:8]=2[C:20]([F:21])([F:22])[F:23])=[CH:29][CH:28]=1
Reactant: OB(O)c1ccc(Cl)nc1F
Reactant: O=S(=O)(Oc1ccc2c(nnn2CC2CC2)c1C(F)(F)F)C(F)(F)F
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Fc1nc(Cl)ccc1-c1ccc2c(nnn2CC2CC2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(Cyclopropylmethyl)-4-(trifluoromethyl)-1H-benzotriazol-5-yl trifluoromethanesulfonate (221 mg, 0.568 mmol) and (6-chloro-2-fluoropyridin-3-yl)boronic acid (130 mg, 0.738 mmol, 1.3 equiv) were dissolved in degassed dioxane (5.6 mL) and treated with potassium phosphate (0.37 mL, 2 M aqueous, 0.74 mmol, 1.3 equiv) and palladium tetrakis(triphenylphosphine) (98 mg, 0.085 mmol, 0.15 equiv). The mixture was placed into a preheated oil bath at 90° C. for 3 hours, cooled to ambient temperature, diluted with ethyl acetate (40 mL) and washed with sodium bicarbonate (2×30 mL, aqueous saturated). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 70:30; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[CH2:13][CH:14]=[CH2:15]>CCOC(C)=O.[Pt]>[CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[CH2:13][CH2:14][CH3:15]
Reactant: C=CCc1cc(Cl)ccc1OCC(=O)OC
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CCCc1cc(Cl)ccc1OCC(=O)OC
Reaction time: 1 h
Yield: 98.6 %

Procedure:
Add 5% Pt/C sulfided (250 mg) to a stirred solution of (2-allyl-4-chloro-phenoxy)-acetic acid methyl ester (587 mg, 2.44 mmol) in EtOAc (10 mL) at ambient temperature under nitrogen. The mixture is flushed with hydrogen for 1 minute then stirred vigorously under hydrogen (balloon) for 1 hour. After filtration and concentration, 584 mg (100% yield) of the title compound is obtained as oil. EIMS: m/z 242 (M+, 35Cl), 244(M+, 37Cl). Analysis for C12H15ClO3: calcd: C, 59.39; H, 6.23; found: C, 59.01; H, 6.14.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[C:13]=2[CH:14]=1.[H-].[Na+].I[CH2:18][CH3:19].CCOC(C)=O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:18][CH3:19])[C:7]3[CH2:8][CH2:9][CH2:10][CH2:11][C:12]=3[C:13]=2[CH:14]=1
Reactant: CCI
Reactant: Brc1ccc2[nH]c3c(c2c1)CCCC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c2c(c3cc(Br)ccc31)CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.5 %

Procedure:
A 500-mL round-bottomed flask was charged with 3-bromo-6,7,8,9-tetrahydro-5H-carbazole (5 g, 20.08 mmol, 1.00 equiv) in N,N-dimethylformamide (270 mL). To this solution was added sodium hydride (1.2 g, 30.00 mmol, 1.50 equiv, 60%) in several batches at −10° C., followed by addition of iodoethane (6.26 g, 40.13 mmol, 2.00 equiv) as a solution in N,N-dimethylformamide (30 mL) drop wise −10° C. The resulting mixture was stirred at room temperature for 30 minutes. The reaction progress was monitored by TLC (EtOAc:PE=1:1). Upon completion, the reaction was then quenched by the addition of water/ice (120 mL). Then, the mixture was extracted with ethyl acetate (4×80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered off and concentrated on a rotary evaporator. The residue was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1/20) affording 3-bromo-9-ethyl-6,7,8,9-tetrahydro-5H-carbazole as brown oil (5 g, 90%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[S:10][C:11]([CH3:16])=[C:12]([CH2:13][CH2:14]Cl)[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:24][O:25][C:21]=2[CH:20]=1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[S:10][C:11]([CH3:16])=[C:12]([CH2:13][CH2:14][N:29]3[CH2:28][CH2:27][CH:26]([C:23]4[C:22]5[CH:32]=[CH:33][C:19]([F:18])=[CH:20][C:21]=5[O:25][N:24]=4)[CH2:31][CH2:30]3)[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)N1CCc2sc(C)c(CCCl)c2C1
Agent: Cl
Product: CC(=O)N1CCc2sc(C)c(CCN3CCC(c4noc5cc(F)ccc45)CC3)c2C1
Yield: 14.5 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 2.0 g of 5-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno[3,2-c]pyridine and 1.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.25 g of 5-acetyl-3-(2-(4 -(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[3,2-c]pyridine as an oil.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][NH:10][CH2:11][C:12]=3[CH:13]=[C:4]2[O:3][CH2:2]1.[CH:14]([O:17][C:18]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:19]=1[C:20](O)=[O:21])([CH3:16])[CH3:15]>>[O:1]1[C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][N:10]([C:20]([C:19]4[CH:23]=[C:24]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=[CH:26][C:18]=4[O:17][CH:14]([CH3:16])[CH3:15])=[O:21])[CH2:11][C:12]=3[CH:13]=[C:4]2[O:3][CH2:2]1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: c1c2c(cc3c1OCO3)CNCC2
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2cc3c(cc2C1)OCO3

Procedure:
Prepared in analogy to example 1.1 from 5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline (CA [94143-83-6]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 418.4 (M+H+).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([Cl:13])=[CH:5][C:3]=1[NH2:4].[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16].C(N(CC)CC)C>C(OCC)C>[Cl:13][C:6]1[C:7]([C:9]([F:12])([F:11])[F:10])=[CH:8][C:2]([C:19]#[C:18][Si:15]([CH3:17])([CH3:16])[CH3:14])=[C:3]([CH:5]=1)[NH2:4]
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1Br
Reactant: C#C[Si](C)(C)C
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cc(C(F)(F)F)c(Cl)cc1N
Temperature: 60 °C
Reaction time: 9 h
Yield: 92 %

Procedure:
A mixture of 2-bromo-5-chloro-4-(trifluoromethyl)aniline (17.1 g), trimethylsilylacetylene (14.8 ml), bistriphenylphosphinepalladium dichloride (816 mg) and triethylamine (115 ml) was stirred at 60° C. for 9 hr. The reaction mixture was ice-cooled, diethyl ether was added and the mixture was filtered through a celite (trademark) filter. The filtrate was evaporated under reduced pressure to give a brown oil. The oil was purified by silica gel column chromatography (elution solvent:ethyl acetate-hexane (1:20-1:10)) to give 5-chloro-4-(trifluoromethyl)-2-[(trimethylsilyl)ethynyl]aniline (16.5 g, yield 92%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([NH2:9])=[N:6][C:7]=1Cl.C(N(CC)CC)C.[NH2:20][CH2:21][CH2:22][OH:23]>C(O)(C)C>[NH2:9][C:5]1[N:6]=[C:7]([NH:20][CH2:21][CH2:22][OH:23])[C:2]([Cl:1])=[N:3][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: NCCO
Reactant: Nc1nc(Cl)c(Cl)nc1[N+](=O)[O-]
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Nc1nc(NCCO)c(Cl)nc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
To 1.0 g of 5,6-dichloro-3-nitropyrazinamine in 20 ml isopropanol is added 0.5 ml triethylamine and then 0.3 ml 2-aminoethanol. The reaction mixture is stirred for 3 hours and then concentrated in vacuo to solids. The solids are triturated with hot chloroform and recrystallized from acetonitrile to afford 0.6 g of 2[(6-Amino-3-chloro-5-nitropyrazin-2-yl)amino]ethanol, m.p. 196°-197° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:23][C:24]#[N:25].C(Cl)Cl.CCOC(C)=O>C(#N)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:23][C:24]#[N:25])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: N#CCCl
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: N#CCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 25 °C
Yield: 89.1 %

Procedure:
To a stirred suspension of 4-(6-fluoro-1H-indazol-3-yl)piperidine (4.95 g, 22.6 mmol) and NaHCO3 (2.1 g, 24.9 mmol) in dry acetonitrile (110 ml) was added chloroacetonitrile (1.6 ml, 24.9 mmol) at room temperature, under nitrogen. The suspension was warmed to reflux for 22.5 hours, cooled to room temperature, and subsequently filtered. The remaining solids were washed with DCM and the combined filtrates were concentrated. The resulting brown oil was dissolved into EtOAc and washed with water. The organic phase was dried (MgSO4), filtered and concentrated to give a brown solid which was re-dissolved into DCM/EtOAc and flushed through alumina with DCM. The eluent was concentrated to give 5.2 g of the desired product as a solid, m.p. 149°-151° C.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[CH2:13]Br)=[O:6])#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[F:21][C:22]1[CH:23]=[C:24]([SH:29])[CH:25]=[CH:26][C:27]=1[F:28].C(OCC)(=O)C>CC(C)=O>[C:1]([CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[CH2:13][S:29][C:24]1[CH:25]=[CH:26][C:27]([F:28])=[C:22]([F:21])[CH:23]=1)=[O:6])#[N:2]
Reactant: N#CCNC(=O)C1CCCCC1CBr
Reactant: Fc1ccc(S)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: N#CCNC(=O)C1CCCCC1CSc1ccc(F)c(F)c1
Reaction time: 16 h

Procedure:
To a solution of N-cyanomethyl 2-bromomethylcyclohexanecarboxamide (3.0 g, 11.58 mmol) in acetone (100 mL) at room temperature were added, in two portions, cesium carbonate (5.77 g, 17.5 mmol) and the crude 3,4-difluorothiophenol (2.69 g, 18.4 mmol). After 16 h, ethyl acetate (100 mL) was added. The solution was washed with 1M HCl (40 mL), brine (20 mL), evaporated, and purified on a short plug of silica gel (30% ethyl acetate/hexane to elute non-polar impurities, then 20-30% ethyl acetate/dichloromethane to give N-cyanomethyl 2-(3,4-difluorophenylsulfanylmethyl)-cyclohexanecarboxamide.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[C:21](=[O:23])[CH2:20][CH2:19][CH2:18]3)=[CH:14][C:13]([Cl:24])=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[CH:21]([OH:23])[CH2:20][CH2:19][CH2:18]3)=[CH:14][C:13]([Cl:24])=[CH:12][CH:11]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCc2nc3cc(Cl)ccc3c(NCc3ccccc3)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CCCc2nc3cc(Cl)ccc3c(NCc3ccccc3)c21
Temperature: 10 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
In 100 ml of dry THF was added 2.90 g of 9-benzylamino-6-chloro-3,4-dihydroacridin-1(2H)-one. The mechanically stirred solution was cooled with ice under nitrogen and 4.3 ml of 1M lithium aluminum hydride solution in THF was added dropwise over 10 minutes. After 1 hour of stirring at 10° C., the reaction was complete by TLC, so it was quenched with 1 ml of saturated ammonium chloride solution. The inorganic salts were filtered off and the filtrate was evaporated to a solid. The solid was recrystallized from 1:1 dichloromethane/pentane to yield 2.14 g of solid, mp 163° C.
Reaction SMILES: [CH2:1]([CH:8]1[NH:15][CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][C:35]=2[S:37](Cl)(=[O:39])=[O:38])[CH:30]=[CH:29][CH:28]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([CH:8]1[N:15]([S:37]([C:35]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:36]=2[N:27]=[CH:28][CH:29]=[CH:30]3)(=[O:38])=[O:39])[CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: c1ccc(CC2CCCc3ccccc3CN2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccc2cccnc12)N1Cc2ccccc2CCCC1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 301 (crude 1.58 mmol), Et3N (0.33 mL, 2.4 mmol) and DMAP (39 mg, 0.32 mmol) in DCM (25 mL), quinoline-8-sulfonyl chloride (538 mg, 2.37 mmol) in DCM (5 mL) was added dropwise at 0° C. After addition was complete, the solution was left to stir at rt overnight. The mixture was washed with water (2×30 mL) and brine. The organic layer was combined, dried over Na2SO4, concentrated in vacuo. MeOH (10 mL) was added to the residue and the precipitation was filtered to give the desired product (60 mg, 81% over three steps). 1H NMR (500 MHz, CDCl3) δ: 9.07 (m, 1H), 8.51 (d, 1H), 8.13 (d, 1H), 7.93 (d, 1H), 7.57 (t, 1H), 7.44 (m, 1H), 7.29 (d, 1H), 7.12 (m, 2H), 6.98 (m, 1H), 6.90 (m, 3H), 6.59 (d, 2H), 5.76 (d, 1H), 5.53 (d, 1H), 4.34 (m, 1H), 3.61 (m, 1H), 2.59 (m, 1H), 2.27 (t, 1H), 2.07 (m, 1H), 1.88 (m, 1H), 1.60 (m, 1H), 1.34 (m, 1H), 1.24 (m, 1H). MS (ESI+) m/z: 443 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([CH3:18])[C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[CH:26]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(#N)C>[CH:26]1([C:31]([O:10][C:9]2[C:8]([F:11])=[C:7]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:6]([CH3:18])=[C:3]([C:4]#[N:5])[C:2]=2[NH2:1])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Reactant: O=C(Cl)C1CCCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(C#N)c(N)c(OC(=O)C2CCCC2)c(F)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
Under nitrogen atmosphere, 2-amino-5-phenyl-4-fluoro-3-hydroxy-6-methylbenzonitrile (I-41) (200 mg, 0.83 mmol) was dissolved in acetonitrile (10 ml), and cooled at 0° C. Triethylamine (138 μl, 1.36 mmol) and cyclopentanecarbonyl chloride (138 μl, 1.36 mmol) were dropwise added to the solution, followed by stirring at room temperature for 2 hours. 10% citric acid was added to the reaction liquid, and the solvent was evaporated away under reduced pressure. Ethyl acetate was added to the resulting residue, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified by preparative TLC (ethyl acetate:n-hexane=1:3, v/v) to obtain the entitled compound (200 mg, 72%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[O:8])[N:4]=[CH:3]1.[Br:9]N1C(=O)CCC1=O.C(Cl)(Cl)Cl>C(=O)([O-])[O-].[Na+].[Na+]>[Br:9][C:6]1[N:2]([CH3:1])[CH:3]=[N:4][C:5]=1[CH:7]=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1cnc(C=O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1cnc(C=O)c1Br
Temperature: 0 °C
Yield: 43.1 %

Procedure:
A mixture of 1-methyl-1H-imidazole-4-carbaldehyde (0.50 g), N-bromosuccinimide (0.89 g) and chloroform (7.0 mL) was heated at reflux for 2 hours. The mixture was cooled to 0° C., diluted with saturated aqueous sodium carbonate solution (10 mL) and extracted with dichloromethane. The combined organic extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and dichloromethane (0:1 to 7:10 by volume) to afford the title compound as a white solid (0.37 g).
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16].[CH3:18]O>>[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:18])=[O:11])=[CH:8][C:7]=1[N+:15]([O-:17])=[O:16]
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 100 %

Procedure:
Thionyl chloride (19.4 g, 164.85 mmol) was added to a solution of 4-amino-3-nitrobenzoic acid (20 g, 109.89 mmol) in methanol (200 mL) at 0° C. The resulting mixture was then refluxed for 12 h. The reaction mixture was allowed to cool to room temperature. The yellow solid precipitated was filtered and dried to afford the title compound (22 g, yield: 100%) as a solid. 1H-NMR (CDCl3, 300 MHz): δ 8.85 (d, 1H), 7.99 (dd, 1H), 6.83 (d, 1H), 6.40 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH2:49][O:50][CH3:51])[CH2:46][N:45]3[C:52](OC(C)(C)C)=[O:53])=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].[CH3:59][O:60][C:61]([NH:63][C@@H:64]([CH:68]([CH3:70])[CH3:69])C(O)=O)=[O:62].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>Cl.CCO.CN(C=O)C>[CH3:1][O:2][C:3](=[O:4])[NH:5][C@@H:6]([CH:7]([CH3:8])[CH3:9])[C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH2:49][O:50][CH3:51])[CH2:46][N:45]3[C:52](=[O:53])[C@@H:64]([NH:63][C:61]([O:60][CH3:59])=[O:62])[CH:68]([CH3:70])[CH3:69])=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c65)cc3-4)[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c65)cc3-4)[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Reaction time: 3 h
Yield: 82.5 %

Procedure:
Tert-butyl(2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (100 mg, 0.13 mmol) in 1.25 N HCl in EtOH (3 mL) was heated to 50° C. for 3 h and then concentrated under reduced pressure. The crude residue was treated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (34 mg, 0.20 mmol), HATU (54 mg, 0.14 mmol) and DMF (1.3 mL), then N-methylmorpholine (0.043 mL, 0.39 mmol) was added dropwise. After 3 h, the mixture was quenched with 1N HCl (0.100 mL) and then purified by HPLC to afford methyl{(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (91 mg, 82%).
Reaction SMILES: [C:1]([C:4]1[C:9]([CH3:10])=[CH:8][C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:6][C:5]=1[CH3:15])(=[O:3])[CH3:2].[Br-:16].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[Br:16][CH2:2][C:1]([C:4]1[C:5]([CH3:15])=[CH:6][C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:8][C:9]=1[CH3:10])=[O:3]
Reactant: [Br-]
Reactant: CC(=O)Nc1cc(C)c(C(C)=O)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Product: CC(=O)Nc1cc(C)c(C(=O)CBr)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101 %

Procedure:
To a solution of N-(4-acetyl-3,5-dimethylphenyl)acetamide (5.00 g, 24.4 mmol) in acetonitrile (48.7 mL) was added tetrabutylammoniumtribromide (TBABr3, 11.7 g, 24.4 mmol). The reaction was stirred at room temperature overnight. The solution was concentrated under reduced pressure, added with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give N-(4-(2-bromoacetyl)-3,5-dimethylphenyl)acetamide (7.00 g), which was used directly for the next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:9]([C:19](=[O:24])[NH:20][CH:21]2[CH2:23][CH2:22]2)=[N:10][O:11][C:12]=1C(=O)NC1CC1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:21]1([NH:20][C:19]([C:9]2[C:8]([NH2:7])=[CH:12][O:11][N:10]=2)=[O:24])[CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)Nc1c(C(=O)NC2CC2)noc1C(=O)NC1CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1conc1C(=O)NC1CC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
A mixture of (3-Cyclopropylcarbamoylcyclopropylcarbamoyl-isoxazol-4-yl)-carbamic acid tert-butyl ester (142 mg, 531 μmol), trifluoroacetic acid (614 μl, 7.97 mmol) in dichloromethane (3 ml) was stirred for 3 h at 20° C. The volatiles were evaporated in vacuo and the resulting crude product was poured into 50 ml dichloromethane and extracted with sodium bicarbonate (saturated aqueous solution). The aqueous phase was washed with dichloromethane and the organic layers were dried and evaporated to yield the product as light yellow oil (85 mg, 91%).