Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:14]([O-])([O-:16])=[O:15].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]=1[OH:13])([O-:16])=[O:15]
Reactant: Oc1ccccc1-c1ccccc1
Reactant: O=[N+]([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(-c2ccccc2)c1O
Reaction time: 24 h
Yield: 23.8 %

Procedure:
2-phenylphenol (3.00 g, 17.6 mmol) was dissolved in methylene chloride (40 ml) followed by the addition of sodium nitrate (1.65 g, 19.4 mmol). The addition of sulfuric acid (25 ml/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hrs, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2CH2) gave the desired product (900 mg, 24%). 1H NMR (CD3COCD3): d 8.19 (d, 1H), 7.79 (d, 1H), 7.64 (d, 2H), 7.50 (t, 2H), 7.45 (t, 1H), 7.22 (t, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:16]([O:17][CH3:18])=[CH:15][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@H:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.CS([C:22]1[N:27]=[CH:26][C:25]2=[CH:28][CH:29]=[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[O:37][CH3:38])[N:24]2[N:23]=1)=O.C(O)(C(F)(F)F)=O>>[CH3:18][O:17][C:16]1[C:2]([NH:1][C:22]2[N:27]=[CH:26][C:25]3=[CH:28][CH:29]=[C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[O:37][CH3:38])[N:24]3[N:23]=2)=[CH:3][C:4]2[CH2:10][CH2:9][N:8]([CH2:11][C@H:12]([OH:14])[CH3:13])[CH2:7][CH2:6][C:5]=2[CH:15]=1
Reactant: COc1cc2c(cc1N)CCN(C[C@@H](C)O)CC2
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1Nc1ncc3ccc(-c4ccccc4OC)n3n1)CCN(C[C@@H](C)O)CC2

Procedure:
Following a procedure analogous to 251c, (R)-1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol (0.139 g, 0.557 mmol) and 2-methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (64 mg, 0.22 mol) were converted to the title compounds (22.66 mgs) as a TFA salt. H-NMR (CDCl3) δ 9.30 (broad s, 1H, TFA), 8.96 (s, 1H), 7.97 (s, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.61 (s, 1H), 7.50-7.45 (m, 1H), 7.26-7.21 (m, 1H), 7.14-7.09 (m, 1H), 6.99-6.93 (m, 2H), 6.93 (s, 1H), 4.22-4.12 (m, 1H), 3.86 (s, 3H), 3.78 (s, 3H), 3.69-3.60 (m, 2H), 3.29-2.93 (complex series of m, 8H), 1.16 (d, J=6.0 Hz, 3H); LC/MS (ESI+): 474.6 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[N:3]=1.[NH2:25][CH3:26]>C1COCC1>[Cl:24][C:18]1[CH:19]=[C:20]([Cl:23])[CH:21]=[CH:22][C:17]=1[C:4]1[N:3]=[C:2]([NH:25][CH3:26])[C:7]([C:8]#[N:9])=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1
Reactant: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)nc1Cl
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)cc1C#N
Temperature: 67 °C

Procedure:
To 2-chloro-6-(2,4-dichlorophenyl)-5-(4-chlorophenyl)pyridine-3-carbonitrile (2.03 g) in THF (14 mL) was added H2NCH3 (13 mL, 2 M solution in THF). The reaction was heated to 67° C. in a closed vessel for 9 hours before concentrating. The product was dissolved in EtOAc and washed with saturated aqueous NaHCO3 solution. The solution was concentrated and purified via flash chromatography on silica gel with a gradient elution of 0% to 10% EtOAc in hexane affording the title compound. HPLC/MS: 387.8(M+1), 389.8 (M+3); Rt=4.26 min.
Reaction SMILES: [C:1]([O:8]C)(=O)[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH3:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]>>[CH2:14]([NH:15][C:1](=[O:8])[CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: COC(=O)CC(=O)OC
Reactant: CCCCCN
Product: CCCCCNC(=O)CC(=O)OC
Reaction time: 1 h
Yield: 43.8 %

Procedure:
Dimethyl malonate (3.2 g, 24 mmol) and n-amylamine (2.1 g, 24 mmol) were mixed at room temperature. After stirring one hour solid began to precipitate. Diisopropyl ether (10 ml) was added and the mixture was left overnight at room temperature. The reaction mixture was concentrated in vacuo. The residue was chromatographed on silica gel (100 g, Baker for flash chromatography), eluting with CH2Cl2 and 2% MeOH in CH2Cl2 to give the title compound as an oil (1.97 g, 44%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH2:9])[CH2:5][CH2:4]1.[OH:12][CH2:13][CH2:14][O:15][C:16]1[N:24]=[C:23]([NH2:25])[C:22]([N+:26]([O-:28])=[O:27])=[CH:21][C:17]=1[C:18](O)=[O:19].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[F:1][C:2]([F:10])([F:11])[C@H:3]1[CH2:4][CH2:5][C@H:6]([NH:9][C:18](=[O:19])[C:17]2[CH:21]=[C:22]([N+:26]([O-:28])=[O:27])[C:23]([NH2:25])=[N:24][C:16]=2[O:15][CH2:14][CH2:13][OH:12])[CH2:7][CH2:8]1
Reactant: Nc1nc(OCCO)c(C(=O)O)cc1[N+](=O)[O-]
Reactant: N[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: Nc1nc(OCCO)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Reaction time: 1.5 h

Procedure:
trans-4-Trifluoromethyl-cyclohexylamine (285 mg, 1.40 mmol) and TEA (410 μl) are added successively to a mixture of 2-(2-hydroxy-ethoxy)-6-amino-5-nitro-nicotinic acid (360 mg, 1.33 mmol), TBTU (285 mg, 1.33 mmol) and TEA (195 μl) and it is stirred for 1.5 h. The mixture is concentrated filtered and purified via chromatography.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3OC)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([F:32])=[CH:4][N:3]=1.[CH3:33][O:34][C:35]1[C:40](B(O)O)=[CH:39][CH:38]=[CH:37][N:36]=1>>[F:32][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])[CH:7]=2)[C:2]([C:40]2[C:35]([O:34][CH3:33])=[N:36][CH:37]=[CH:38][CH:39]=2)=[N:3][CH:4]=1
Reactant: COc1ncccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)c(OC)c1
Product: COc1ncccc1-c1ncc(F)c2cc(S(=O)(=O)Nc3nccs3)ccc12

Procedure:
The title compound was prepared in an analogous manner to that of EXAMPLE 228, except that 1-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide and 2-methoxy-3-pyridineboronic acid were used as the coupling partners. The final compound was purified via column chromatography (RediSep Gold 12 g silica gel column, gradient elution 0-10% MeOH:DCM) to afford 4-fluoro-1-(2-methoxypyridin-3-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=13.00 (br. s., 1H), 8.73 (d, J=1.3 Hz, 1H), 8.51 (d, J=1.3 Hz, 1H), 8.39 (dd, J=1.9, 4.9 Hz, 1H), 8.01 (dd, J=1.7, 8.9 Hz, 1H), 7.87-7.76 (m, 2H), 7.31 (d, J=4.6 Hz, 1H), 7.22 (dd, J=5.0, 7.2 Hz, 1H), 6.90 (d, J=4.5 Hz, 1H), 3.77 (s, 3H). m/z (ESI) 417.2 (M+H)+.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.C([N-]C(C)C)(C)C.[Li+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>O1CCCC1>[O:7]=[C:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: O=C1C=CCCC1
Reactant: CCOC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1CCC=CC1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 2-cyclohexen-1-one (20 g, 0.208 mmol) in tetrahydrofuran (250 ml) was added to a preformed lithium diisopropylamide solution (prepared from diisopropylamine (31 ml) and n-butyllithium (140 ml, 1.6M solution) at −70° C.) over 20 minutes and stirred for a further 20 minutes. Ethyl bromoacetate (25 ml, 0.228 mmol) was added dropwise and the reaction stirred for 1 hour warming to room temperature. The reaction was quenched with 6N HCl (200 ml) and the product extracted into ether (3×300 ml). Combined organic phase washed with saturated sodium chloride, dried over magnesium sulfate and evaporated to dryness. The crude oil was purified by silica chromatography eluting with hexane-ethyl acetate mixtures (10-20%), to give ethyl (2-oxo-cyclohex-3-enyl)acetate as a colourless oil, 11.8 g. 1H NMR δ (ppm) (CDCl3): 6.98-6.94 (1H, m), 6.03-6.00 (1H, m), 4.19-4.11 (2H, m), 2.92-2.82 (2H, m), 2.49-2.41 (2H, m), 2.30-2.23 (1H, m), 2.16-2.11 (1H, m), 1.87-1.77 (1H, m) and 1.28-1.24 (3H, m).
Reaction SMILES: [NH2:1][C@@H:2]([CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)[C:3]([OH:5])=[O:4].C(=O)(O)[O-].[Na+].Cl[C:18]([O:20][CH3:21])=[O:19].Cl>>[CH3:21][O:20][C:18]([NH:1][C@@H:2]([CH:6]1[CH2:7][CH2:8][O:9][CH2:10][CH2:11]1)[C:3]([OH:5])=[O:4])=[O:19]
Reactant: N[C@H](C(=O)O)C1CCOCC1
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A solution of (S)-amino-(tetrahydro-pyran-4-yl)-acetic acid (1 g, 6.28 mmol) in saturated aqueous sodium bicarbonate solution (12.32 mL, 125.6 mmol) was stirred until all solids were dissolved. Methyl chloroformate (0.97 mL, 12.56 mmol) was added dropwise, the reaction mixture was stirred for 1 h, and 1N HCl was added to adjust pH to 1. The reaction mixture was extracted with ethyl acetate (3×15 mL) and the combined organic extracts were dried over sodium sulfate, filtered, concentrated and dried overnight under vacuum to give the title intermediate (1.36 g, 99% yield) as a white, sticky solid. (m/z): [M+H]+ calcd for C9H15NO5 218.10 found 218.3.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccc(F)cc2)cc1F

Procedure:
The starting compound 2-fluoro-4-(4-fluorobenzyloxy)nitrobenzene (m.p.: 99° C.) was prepared by alkylation of 3-fluoro-4-nitrophenol with 4-fluorobenzyl chloride in DMF in the presence of potassium carbonate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:9])[C:5]([SH:8])=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:17]1[C:18](=[O:25])[N:19]([CH3:24])[C:20](=[O:23])[C:21]=1Cl.O>CN(C=O)C>[CH3:24][N:19]1[C:20](=[O:23])[C:21]2[S:9][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=3[S:8][C:17]=2[C:18]1=[O:25]
Reactant: Cc1ccc(S)c(S)c1
Reactant: CN1C(=O)C(Cl)=C(Cl)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2sc3c(=O)n(C)c(=O)c=3sc2c1
Temperature: 80 °C
Reaction time: 7 h

Procedure:
A stirred solution of 4-methylbenzene-1,2-dithiol (0.5 g) in anhydrous DMF (50 ml) was treated with K2CO3 and 3,4-dichloro-1-methyl-pyrrole-2,5-dione (0.73 g) and stirred for about 7 hours at 80° C. The reaction mixture was poured into water and extracted with MTBE. The combined organic phases were washed once with water and after removal of the solvent under reduced pressure the crude product (0.85 g) was purified by flash column chromatography on silica gel (cyclohexane/ethyl acetate 9:1) to yield the compound ex. I-2 (0.25 g); m.p.: 171-176° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][CH3:9].[S:10]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11]1>CN(C)C=O.C(OCC)(=O)C>[S:10]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH2:8][CH3:9])=[O:18])=[CH:11]1
Reactant: CCI
Reactant: O=C(O)/C=C/c1ccsc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1ccsc1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
11.5 g of potassium carbonate and 6.8 ml of iodoethane are added to 11 g of (E)-3-(3-thienyl)-2-propenoic acid, obtained in step 4.1, in solution in 50 ml of dimethylformamide, and the mixture is stirred for 48 hours at 20° C. The medium is taken up in ethyl acetate and it is washed with water. The organic phase is dried over anhydrous sodium sulphate and it is concentrated to give 12.5 g of oil.
Reaction SMILES: COC1C=CC(C2(C3C=CC(OC)=CC=3)O[C:13]3[C:15]4[C:20]([C:21](O)=[C:22]([C:23](OC)=[O:24])[C:12]=3C=C2)=[CH:19][CH:18]=[CH:17][CH:16]=4)=CC=1.C(N([CH2:41][CH3:42])CC)C>C1COCC1>[CH:12]1[C:13]2[C:15]3[C:20]([CH:21]=[CH:41][C:42]=2[O:24][CH2:23][CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: CCN(CC)CC
Reactant: COC(=O)c1c2c(c3ccccc3c1O)OC(c1ccc(OC)cc1)(c1ccc(OC)cc1)C=C2
Solvent: C1CCOC1
Product: C1=Cc2c(ccc3ccccc23)OC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,2-Bis(4-methoxyphenyl)-5-(methoxycarbonyl)-6-hydroxy-[2H]-naphtho[1,2-b]pyran (U.S. Pat. No. 5,458,814) (0.225 g, 0.48 mmol) was dissolved in anhydrous THF (25 ml) under nitrogen. To this solution was added triethylamine (0.13 ml) followed by the Acid Chloride Terminated Polydimethylsiloxane (Example 1, Step 2) (0.358 g), dropwise. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through a short plug of silica gel and the solvent evaporated. The crude product (0.53 g) was then purified by column chromatography (silica gel, diethyl ether/hexane, 2:3→2:1) giving the bulk product, Naphthopyran Terminated Polydimethylsiloxane, as a viscous red oil. Analysis by 1H NMR gave an average molecular weight (Mn) of 2,297 (nPDMS=12.6). 1H NMR (200 MHz, d6-acetone) δ 8.40 (m, 2H), 7.95 (m, 2H), 7.63 (m, 4H), 7.45 (m, 8H), 6.97 (d, 2H), 6.88 (m, 8H), 6.41 (d, 2H), 4.23 (t, 4H), 3.95 (s, 6H), 3.75 (s, 12H), 3.62 (t, 4H), 3.41 (t, 4H), 3.04 (m, 4H), 2.80 (m, 4H), 1.60 (m, 4H), 0.58 (m, 4H), 0.13-0.08 (m, SiCH3).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=1)=[C:12]2[CH2:26][CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:25][C:20]1[CH:19]=[C:18]([C:13]2[NH:14][C:15]3[C:11]([C:12]=2[CH2:26][CH2:27][N:28]2[C:36](=[O:37])[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]2=[O:38])=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=3)[CH:23]=[C:22]([CH3:24])[CH:21]=1
Reactant: [H][H]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(OCc4ccccc4)cc3c2CCN2C(=O)c3ccccc3C2=O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(-c2[nH]c3ccc(O)cc3c2CCN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 2-[2-[5-benzyloxy-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl]isoindole-1,3-dione (510 mg in 20 mL dry ethyl acetate was added 197 mg of 10% palladium on carbon catalyst. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 37 hours the reaction was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo to provide the crude title compound (418 mg).
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:17]=[CH:16][C:7]2[N:8]([CH3:15])[C:9](=[O:14])[CH2:10][NH:11][C:12](=O)[C:6]=2[CH:5]=1.O=P(Cl)(Cl)[Cl:20]>C1(C)C=CC=CC=1>[Cl:20][C:12]1[C:6]2[CH:5]=[C:4]([Cl:3])[CH:17]=[CH:16][C:7]=2[N:8]([CH3:15])[C:9](=[O:14])[CH2:10][N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CN1C(=O)CNC(=O)c2cc(Cl)ccc21
Agent: N#N
Solvent: Cc1ccccc1
Product: CN1C(=O)CN=C(Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 87.1 %

Procedure:
In a 1 L 2-neck RBF equipped with mechanical stir, condenser and N2 inlet, C1 (42.5 g, 0.189 mol) was suspended into 400 mL of toluene. To this was added N,N-dimethylanaline (45.5 g. 0.375 mol) followed by the addition of POCl3 (29 g, 0.189 mol) and the reaction mixture stirred for 3 minutes at room temperature (RT). Reaction flask was placed in a 90° C. oil bath and the reaction mixture stirred/heated for 7 h and then at RT for 9 h. The reaction was quenched by adding 500 mL of ice water and stirred for 15 min. Organic layer was separated and quickly washed with cold 0.5 M HCl (300 mL), cold water (300 mL), and then cold saturated NaHCO3 (300 mL). Organic layer was dried (MgSO4), filtered and concentrated on a rotary evaporator to give 40 g of yellow solid. Yield 87.5%. 1H NMR (300 MHz, DMSO-d6) δ 3.25 (s, 3H), 3.8-3.9 (s, 1H, br), 4.3-4.4 (s, 1H, br), 7.4 (d, 1H), 7.7-7.8 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH2:19])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:19][S:31]([C:27]2[S:26][CH:30]=[CH:29][CH:28]=2)(=[O:33])=[O:32])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(OCc2ccccc2)ccc1NS(=O)(=O)c1cccs1
Reaction time: 1 h

Procedure:
Methyl 5-(benzyloxy)-2-(amino)benzoate ([116027-17-9], 1.3 g, 5.06 mmol) was stirred in DCM (20 mL) and pyridine (1.2 mL) at 0° C. Thiophene-2-sulfonyl chloride (1.02 g, 5.56 mmol) was added. After one hour, the cooling bath was removed and the reaction was stirred overnight. The mixture was washed once with 10% aqueous HCl. The organics were dried and concentrated. Chromatography (20 to 40% ethyl acetate in hexanes) gave the title compound. [M+H] calc'd for C19H17NO5S2, 404; found, 404.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].CO[CH:14](OC)[N:15]([CH3:17])[CH3:16]>>[CH3:14][N:15]([CH3:17])/[CH:16]=[CH:2]/[C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])=[O:3]
Reactant: CC(=O)c1cccc(C#N)c1
Reactant: COC(OC)N(C)C
Product: CN(C)/C=C/C(=O)c1cccc(C#N)c1
Temperature: 120 °C

Procedure:
3-Acetylbenzonitrile (0.435 g, 0.00300 mol) and 1,1-dimethoxy-N,N-dimethylmethanamine (0.400 mL, 0.00301 mol) were combined and heated in sealed tube to 120° C. in the microwave for 15 min. The reaction was then allowed to cool to rt giving the 3-[(2E)-3-(dimethylamino)prop-2-enoyl]-benzonitrile as a red-orange crystalline material, LC/MS (M+H)+: 201.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1)=[O:4].[OH2:12]>C(#N)C>[OH:12][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1)=[O:4]
Reactant: Cc1cccc(C(=O)CBr)c1
Reactant: O
Solvent: CC#N
Product: Cc1cccc(C(=O)CO)c1

Procedure:
A solution of 2-bromo-1-(3-methylphenyl)ethanone (1 g) in acetonitrile (2.5 mL) and water (13 mL) is treated under microwave irradiation (125° C., 50 min). The same experiment is repeated three times. All the vials are collected, extracted with DCM, dried over magnesium sulfate and concentrated under vacuum to give the desired compound.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9](OCC)(=[O:13])[C:10]([O-])=[O:11]>>[NH:7]1[C:2]2[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:8][C:10](=[O:11])[C:9]1=[O:13]
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)C(=O)[O-]
Product: O=c1[nH]c2ccccc2[nH]c1=O

Procedure:
o-Phenylenediamine (10 grams) and ethyl oxalate (100 ml.) were mixed and the mixture was heated, with stirring, to reflux and refluxed for 30 minutes. The reaction mixture was then cooled and the resulting precipitate, the desired 2(1H), 3(4H)-quinoxalinedione, was separated by filtration. The product did not melt below 400° C. It was recrystallized from a mixture of dimethylformamide and water, yielding a purified product which did not melt below 405° C. The identity of the product was confirmed by NMR and IR. Elemental analysis showed
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][C:29]=1[CH2:38][O:39][CH2:40][CH2:41]O>C(Cl)Cl.[Al]>[Br:1][CH2:41][CH2:40][O:39][CH2:38][C:29]1[CH:30]=[CH:31][C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:28]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCOCc1ccc2ccccc2c1
Agent: [Al]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCOCc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.1 %

Procedure:
A solution of N-bromosuccinimide (272 mg, 1.53 mmol) in DCM (2.5 mL) was added to resin-bound triphenylphosphine (510 mg, 1.53 mEquiv, Fluka) in DCM (2.5 mL), and the reaction was stirred at rt for 10 min. A solution 2-[(2-naphthalenylmethyl)oxy]ethanol (101 mg, 0.499 mmol) in DCM (1.5 mL) was added to the reaction, and the residual alcohol was transferred with additional DCM (1.5 mL). The reaction vial was capped, wrapped in aluminum foil, and stirred at rt for 20 h. The reaction was filtered through a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and 50% EtOAc/hexanes (fraction 3) to give the title compound (57 mg, 43%). The product was characterized by 1H NMR (400 MHz) in CDCl3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13]CC2C=CC=CC=2)[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(O)cc1OC
Reaction time: 24 h
Yield: 99 %

Procedure:
To a solution of methyl 2-methoxy-4-benzyloxybenzoate (40 g, 147 mmol) from Step 2 above in EtOAc (200 mL) in a Parr shaker flask was added 2 gm of 10% Pd/C catalyst. The reaction was shaken under on a Parr hydrogenation apparatus under 55 psi of H2 for 24 hours. The catalyst was filtered off under a blanket of argon and the solvent was removed under reduced pressure. The resulting solid washed with a small volume of EtOAc and filtered and dried in vacuo for 24 hours to give methyl 2-methoxy-4-hydroxybenzoate in 99% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18](=[O:28])[C@@H:19]([NH:23][C:24](=[O:27])[O:25][CH3:26])[CH:20]([CH3:22])[CH3:21])=[N:10][CH:9]=2)=[CH:4][C:3]=1OC(F)F.Br[C:34]1[CH:39]=[CH:38]C(C2NC([C@@H]3CCCN3C(OC(C)(C)C)=O)=NC=2)=[CH:36][C:35]=1OC(F)F>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[C:8]1[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18](=[O:28])[C@@H:19]([NH:23][C:24](=[O:27])[O:25][CH3:26])[CH:20]([CH3:22])[CH3:21])=[N:10][C:9]=1[CH:36]=[C:35]2[C:34]#[C:39][CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)c(OC(F)F)c2)[nH]1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc(Br)c(OC(F)F)c2)[nH]1)C(C)C
Product: CC#Cc1cc2nc([C@@H]3CCCN3C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c2c2ccc(Br)cc12

Procedure:
Methyl (S)-1-((S)-2-(7-bromo-5-(prop-1-ynyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate was prepared according to the procedure described for the synthesis of methyl (S)-1-((S)-2-(5-(4-bromo-3-(difluoromethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate, substituting (S)-tert-butyl 2-(7-bromo-5-(prop-1-ynyl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate for (S)-tert-Butyl 2-(5-(4-bromo-3-(difluoromethoxy)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][C:8]=2[C:9]=1[C:10](O)=[O:11])[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:24])=O>>[CH2:1]([C:5]1[O:6][C:7]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][C:8]=2[C:9]=1[C:10]([Cl:24])=[O:11])[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)O
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(=O)Cl
Temperature: 22.5 °C
Reaction time: 3 h

Procedure:
7 g (22.48 mmol) of 2-butyl-5-methanesulfonamidobenzofuran-3-carboxylic acid are dissolved in 50 g of thionyl chloride and stirred for 3 hours at 20-25° C. and then refluxed for 30 minutes (79° C.). The reaction medium is then concentrated to dryness under reduced pressure and the residue (8.8 g) is taken up in 46.2 g of anhydrous DCE (total mass=55 g).