Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[O:11][C:12]([F:15])([F:14])[F:13].C([Li])CCC.C([O:24][B:25](OC(C)C)[O:26]C(C)C)(C)C>O1CCCC1>[CH2:9]([O:8][C:6]1[CH:5]=[CH:4][C:3]([O:11][C:12]([F:15])([F:14])[F:13])=[C:2]([B:25]([OH:26])[OH:24])[CH:7]=1)[CH3:10]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCOc1ccc(OC(F)(F)F)c(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1ccc(OC(F)(F)F)c(B(O)O)c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
To a stirred solution of the 2-bromo-4-ethoxy-1-trifluoromethoxy-benzene (Preparation 85, 884 mg, 3.10 mmol) in anhydrous tetrahydrofuran (10 ml) was added n butyl lithium (2M solution in cyclohexanes, 2.33 ml, 4.65 mmol) while maintaining the temperature below −70° C. under an atmosphere of nitrogen. The solution was stirred at this temperature for 1 hour then tri-isopropylborate (875 mg, 4.65 mmol) was added, and the reaction maintained at −70° C. for a further 2 hours. The reaction mixture was then quenched by the addition of ammonium chloride (aqueous solution) (5 ml), followed by acidification with hydrochloric acid (2N aqueous solution) (10 ml). The layers were separated and the organic layer was dried over anhydrous MgSO4 (s), filtered and evaporated in vacuo to afford crude title compound as a white solid (552 mg, 71%). Material was taken on without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CCCCCC.CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:25]([NH:24][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:26])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: O=C=Nc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(Nc1ccccc1)N1CCN(c2ccnc3cc(Cl)ccc23)CC1

Procedure:
7-Chloro-4-(piperazin-1-yl)quinoline (62 mg, 0.25 mmol) and phenyl isocyanate (33 μL, 0.30 mmol) in THF (10 mL) are reacted according to method C yielding the title product as colorless needles after column chromatography with hexane-EtOAc.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13].[NH:30]1[CH:34]=[CH:33][CH:32]=[N:31]1.C(=O)([O-])[O-].[K+].[K+].N[C@@H]1CCCC[C@H]1N>[Cu]I.O1CCOCC1>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:30]2[CH:34]=[CH:33][CH:32]=[N:31]2)=[C:3]([C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-n2cccn2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Temperature: 120 °C
Yield: 20.9 %

Procedure:
In a tube were added successively (2-Iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound CK, 0.1 g, 0.19 mmol), pyrazole (15 mg, 0.223 mmol), potassium carbonate (51 mg, 0.37 mmol), CuI (7 mg, 0.037 mmol), Trans-1,2-diaminocyclohexane (9 ul, 0.07 mmol) and dioxane (0.4 ml). The mixture was heated under argon at 120° C. for 24 hours. The reaction mixture was cooled to room temperature and quenched with water/dichloromethane. The aqueous layer was extracted twice with dichloromethane. The organic layers were combined, dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude oil was chromatographed over silicagel: eluent: heptane/ethylacetate: 0-5% to provide the title compound as a light grey powder (19 mg, 21%), MS (m/e): 479.1 (M+H, 100%)
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29]>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:29]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(Cl)c2)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-Chloro-benzoic acid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][CH:11]3[CH2:16][CH2:15][CH:14]([C:17]([O:19]CC)=[O:18])[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[Li+]>CO.O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][CH:11]3[CH2:12][CH2:13][CH:14]([C:17]([OH:19])=[O:18])[CH2:15][CH2:16]3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CCOC(=O)C1CCC(Oc2ccc3[nH]ncc3c2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CCC(Oc2ccc3[nH]ncc3c2)CC1
Reaction time: 2 h
Yield: 57.9 %

Procedure:
The ethyl 4-(1H-indazol-5-yloxy)cyclo-hexanecarboxylate (728.4 mg, 2.53 mmol) obtained in Example 367 was dissolved in a mixture of methanol (2.5 ml) and tetrahydrofuran (2.5 ml), and a 2M-aqueous lithium hydroxide solution (2.53 ml, 5.05 mmol) was added dropwise thereto. After 2 hours, the reaction mixture was concentrated under reduced pressure and the resulting residue was dissolved in water (5 ml). The resulting aqueous solution was adjusted to pH 4 with a 0.5M-aqueous potassium hydrogensulfate solution. The crystals formed were filtered under reduced pressure and then dried to obtain 4-(1H-indazol-5-yloxy)cyclohexanecarboxylic acid (381 mg, 58%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:29]=[N+:30]=[N-:31].[Na+]>>[N:29]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)[C:15]=2[O:14]1)=[N+:30]=[N-:31]
Reactant: Cc1ccc(-c2cccc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: Cc1ccc(-c2cccc3c2OC(CN=[N+]=[N-])C3)cc1

Procedure:
Treatment of (±)-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (1.01 g, 2.56 mmol) with sodium azide (0.664 g, 10.24 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.03 g, 10 wt. %) generally according to the procedure described for Example 1 provided 0.528 g (75%) of (±)-1-[7-(4-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp 231-232° C.; Anal. calcd. for C16H17NOHCl: C, 69.69; H, 6.58; N, 5.08. Found: C, 66.26; H, 7.0; N, 4.73.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:27]([O:26][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)CCCCCBr
Reactant: COC(=O)c1cccc(-c2cccc(O)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2cccc(OCCCCCC(=O)OC(C)(C)C)c2)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
To a solution of methyl 6-(3′-hydroxyphenyl)-pyridine-2-carboxylate (7) (600 mg, 2.6 mmol, 1 eq.) and t-butyl 6-bromohexanoate (980 mg, 3.9 mmol, 1.5 eq.) in DMF (7 mL) was added K2CO3 (1.08 g, 7.8 mmol, 3 eq.). The mixture was stirred vigorously overnight at 60° C. and then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with NaH2PO4 buffer (pH 5, 1M) and brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica using ethyl acetate:hexanes eluant to provide 730 mg of 8. Yield 73%. MS m/z 400 [M+H]+
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]3[C:19]([CH3:20])=[C:18]([C:21]([O:23]C)=O)[S:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[C:6]([O:25][CH2:26][CH3:27])[CH:5]=1)(=[O:3])[NH2:2].[Cl-].[NH4+:29]>N.CO>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]3[C:19]([CH3:20])=[C:18]([C:21]([NH2:29])=[O:23])[S:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[C:6]([O:25][CH2:26][CH3:27])[CH:5]=1)(=[O:3])[NH2:2]
Reactant: [NH4+]
Reactant: CCOc1cc(C(N)=O)ccc1Nc1ncnc2sc(C(=O)OC)c(C)c12
Agent: N
Agent: [Cl-]
Solvent: CO
Product: CCOc1cc(C(N)=O)ccc1Nc1ncnc2sc(C(N)=O)c(C)c12
Yield: 67.3 %

Procedure:
Methyl 4-(4-carbamoyl-2-ethoxyphenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.025 g, 0.06 mmol) and ammonium chloride (0.250 g, 4.67 mmol) in 7N ammonia/MeOH (3.5 mL) were heated at 100° C. in a sealed-tube for 14 days. The solution was cooled and the residue filtered. The precipitate was washed with water to yield white solid (0.015 g, 63%).
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([C@@H:10]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[C:26]1([C:32]2[CH:33]=[CH:34][C:35]([C:38](O)=[O:39])=[N:36][CH:37]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl.O>[CH3:13][C:11]([CH3:12])([CH3:14])[C@H:10]([NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:8]([N:2]1[CH2:3][C@@H:4]2[CH2:7][C@H:1]1[CH2:6][N:5]2[C:38]([C:35]1[CH:34]=[CH:33][C:32]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:37][N:36]=1)=[O:39])=[O:9]
Reactant: O=C(O)c1ccc(-c2ccccc2)cn1
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1C[C@@H]2C[C@H]1CN2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1ccc(-c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.3 %

Procedure:
A mixture of phenylmethyl {(1S)-1-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-2,2-dimethylpropyl}carbamate (826 mg, 2.39 mmol), 5-phenyl-2-pyridinecarboxylic acid (500 mg, 2.5 mmol), EDC (550 mg, 2.87 mmol), HOBt (65 mg, 0.48 mmol), NMM (736 mg, 7.17 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 18 h. The reaction was diluted with water and CH2Cl2. The two layers were separated; the organic dried over anhydrous Na2SO4 and concentrated to give the title compound (1.3 g) as a pale brown oil. LCMS (m/z): 527.3 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14]2)=[O:12])=[CH:6][C:5]=1[CH3:41].[OH-].[Na+]>CO>[Cl:24][C:20]1[C:19]([F:25])=[C:18]([C@@H:17]2[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:38])([CH3:39])[CH3:40])[NH:14][C@H:13]2[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:42])=[O:2])=[C:5]([CH3:41])[CH:6]=2)=[O:12])[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)ccc1C(=O)O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
rac 4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-2-methyl-benzoic acid methyl ester (82 mg) was dissolved in MeOH (10 mL) with help of slight heating. To the stirred solution was added NaOH (1N, 2 mL) and the mixture was stirred for 3 hrs at 50° C. The solvent was removed and the residue was treated with 1 N HCl to make the mixture acidic. The white suspension was extracted with EtOAc (3×10 mL) and the extracts combined and dried with sodium sulfate. The solvent was removed and the residue was freeze dried to give a white powder. 67 mg.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH2:11][CH2:10][CH2:9]1)(=[O:7])=[O:6].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=2)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][N:36]([CH2:2][CH2:3][CH2:4][S:5]([N:8]4[C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=5[O:12][CH2:11][CH2:10][CH2:9]4)(=[O:7])=[O:6])[CH2:37][CH2:38]3)=[CH:29][CH:28]=2)=[CH:24][CH:25]=1
Reactant: Fc1ccc(Cc2ccc(N3CCNCC3)cc2)cc1
Reactant: O=S(=O)(CCCCl)N1CCCOc2ccccc21
Product: O=S(=O)(CCCN1CCN(c2ccc(Cc3ccc(F)cc3)cc2)CC1)N1CCCOc2ccccc21

Procedure:
The compound (17) synthesized in Reference Example 17 and the compound (5) synthesized in Reference Example 5 were used to produce the above compound in the same way as Example 1.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]([CH2:18][NH:19][C:20]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]2[C:21]=1[CH:22]=[N:23][N:24]2[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36]C)[CH:31]=1)([OH:17])[CH2:4][C:5]([C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])([CH3:7])[CH3:6].C(=O)=O.CC(C)=O.B(Br)(Br)Br>ClCCl>[F:14][C:12]1[CH:11]=[CH:10][C:9]([O:15][CH3:16])=[C:8]([C:5]([CH3:7])([CH3:6])[CH2:4][C:3]([OH:17])([C:2]([F:1])([F:39])[F:38])[CH2:18][NH:19][C:20]2[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]3[C:21]=2[CH:22]=[N:23][N:24]3[C:30]2[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=2)[CH:13]=1
Reactant: COc1cccc(-n2ncc3c(NCC(O)(CC(C)(C)c4cc(F)ccc4OC)C(F)(F)F)cc(C)cc32)c1
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cc(C)cc2c1cnn2-c1cccc(O)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 19.9 %

Procedure:
1,1,1-Trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-[({6-methyl-1-[3-(methyloxy)phenyl]-1H-indazol-4-yl}amino)methyl]-2-pentanol (Example 22, 46 mg, 0.085 mmol) was dissolved in anhydrous dichloromethane (4 ml) and cooled to −70° C. (cardice/acetone bath). Boron tribromide (1.0M in dichloromethane, 0.15 ml, 0.15 mmol) was added and the mixture allowed to warm to room temperature over 2 hours and then stirred for a further 20 hours. The mixture was cooled to −70° C. and more boron tribromide (1.0M in dichloromethane, 0.1 ml, 0.1 mmol) was added and the mixture was allowed to warm to room temperature and stirred for a further 20 hours. The mixture was cooled again to −70° C. and more boron tribromide (1.0M in dichloromethane, 0.1 ml, 0.1 mmol) was added and the mixture was allowed to warm to room temperature and stirred for a further 32 hours. The mixture was then diluted with dichloromethane (15 mL), cooled in ice and quenched with methanol (3 mL). After a further 15 min the mixture was partitioned between dichloromethane (35 mL) and aqueous sodium bicarbonate (35 mL). The organic phase was washed again with aqueous sodium bicarbonate (35 mL), passed through a hydrophobic frit and evaporated under reduced pressure to yield crude material. This crude product was purified by mass-directed autopreparation to give the title compound (9 mg).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[C:15]([C:20](O)=[O:21])[CH:14]=2)=[CH:9][CH:8]=1)=[O:5].[CH2:28]([O:30][CH:31]([O:34][CH2:35][CH3:36])[CH2:32][NH2:33])[CH3:29].CN(C)CCCN=C=NCC>CN(C=O)C.O>[CH2:28]([O:30][CH:31]([O:34][CH2:35][CH3:36])[CH2:32][NH:33][C:20]([C:15]1[CH:14]=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([NH:6][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:26][CH:25]=[CH:24][C:23]=3[F:27])=[CH:8][CH:9]=2)[C:18]([CH3:19])=[CH:17][CH:16]=1)=[O:21])[CH3:29]
Reactant: Cc1ccc(C(=O)O)cc1-c1ccc(NC(=O)c2c(F)cccc2F)cc1
Reactant: CCOC(CN)OCC
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(CNC(=O)c1ccc(C)c(-c2ccc(NC(=O)c3c(F)cccc3F)cc2)c1)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Compound 1 was hydrolyzed by heating it in a solution of LiOH to yield 4′-(2,6-difluoro-benzoylamino)-6-methyl-biphenyl-3-carboxylic acid. A mixture of 4′-(2,6-difluoro-benzoylamino)-6-methyl-biphenyl-3-carboxylic acid (800 mg, 2.2 mmol), 2,2-diethoxy-ethylamine (0.32 mL, 2.2. mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) (5 mmol) in dry DMF (5 mL) was stirred at room temperature for 24 h. The mixture was diluted with water (20 mL) and extracted with ethyl acetate (EtOAc) (2×20 mL). The organic extract was washed with water and dried. The oil obtained on concentration of the organic layer was purified by flash chromatograghed on silica gel to give 4′-(2,6-difluoro-benzoylamino)-6-methyl-biphenyl-3-carboxylic acid (2,2-diethoxy-ethyl)-amide as colorless oil (0.68 g).
Reaction SMILES: Cl.[N:2]1([C:8]2[N:9]=[CH:10][CH:11]=[C:12]3[CH:16]=[CH:15][S:14][C:13]=23)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.O=[CH:27][CH2:28][C@H:29]1[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:38])[CH3:37])[CH2:31][CH2:30]1>C1COCC1>[S:14]1[C:13]2=[C:8]([N:2]3[CH2:3][CH2:4][N:5]([CH2:27][CH2:28][C@H:29]4[CH2:34][CH2:33][C@H:32]([NH:35][C:36](=[O:38])[CH3:37])[CH2:31][CH2:30]4)[CH2:6][CH2:7]3)[N:9]=[CH:10][CH:11]=[C:12]2[CH:16]=[CH:15]1
Reactant: CC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: c1cc2ccsc2c(N2CCNCC2)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4ccsc34)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution under Ar of commercially available 7-piperazine-1-yl-thieno[2,3-c]pyridine hydrochloride [CAS-No. 850734-85-9] (150 mg, 0.59 mmol) in THF (14 ml) were added subsequently iPr2NEt (0.1 ml, 0.59 mmol), trans-N-[4-(2-oxo-ethyl)-cyclohexyl]-acetamide [CAS-No. 946599-01-5, WO 2007/093540] (118 mg, 0.64 mmol) and Na(AcO)3BH (373 mg, 1.76 mmol). After stirring 18 h at room temperature the reaction mixture was partitioned between sat. aq. NaHCO3 sol. and EtOAc. The aqueous layer was extracted one more time with EtOAc. The combined organic layers were washed with H2O and brine and dried over MgSO4. After evaporation of the solvent, the crude product was purified by flash chromatography on silica gel (heptane to EtOAc) to yield the title compound as an off-white solid (82 mg, 36%), MS (ISP) m/z=387.2 [(M+H)+].
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([C:27](=[O:29])[CH3:28])[C@@H:10]([CH3:30])[CH2:9]1)=[O:7].[N:31]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1.[F-].[Cs+]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:36]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:37])[CH:16]=2)[N:11]([C:27](=[O:29])[CH3:28])[C@@H:10]([CH3:30])[CH2:9]1)=[O:7]
Reactant: O=C(Cl)N1CCCC1
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2N(C(=O)c2ccco2)C[C@@H]1C
Agent: [Cs+]
Agent: [F-]
Product: CC(=O)N1c2ccc(C(=O)N3CCCC3)cc2N(C(=O)c2ccco2)C[C@@H]1C
Temperature: 80 °C
Yield: 7.9 %

Procedure:
A 1.5 mL reaction vial was charged with (S)-1-(4-(furan-2-carbonyl)-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoxalin-1 (2H)-yl)ethanone (0.2 M in 1,4-dioxane, 150 μL, 0.03 mmol), and pyrrolidine-1-carbonyl chloride (4 mg, 0.030 mmol). Cesium fluoride was then added (5 mg, 0.030 mmol) and the reaction mixture was purged with nitrogen. Bis(triphenylphosphine)palladium(II) dichloride (1 mg, 0.0015) was then added, and the reaction was purged with nitrogen and heated overnight at 80° C. on a heater shaker. The reaction was diluted with ethyl acetate (0.5 mL) washed with brine (0.5 mL). The aqueous layer was separated and washed with ethyl acetate (1 mL) and the combined organic layers were concentrated under a stream of nitrogen. The crude product was purified by mass triggered preparatory HPLC. The product-containing fractions were combined and concentrated in a Genevac to afford (S)-1-(4-(furan-2-carbonyl)-2-methyl-6-(pyrrolidine-1-carbonyl)-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.0009 g, 8%). MS (ESI, pos. ion) m/z 382.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][C:14]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)=[CH:15][C:10]=2[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-:25].[Na+]>O1CCOCC1>[O:1]=[C:2]1[C:11]2[CH:12]=[CH:13][C:14]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([NH2:22])=[O:25])=[CH:23][CH:24]=3)=[CH:15][C:10]=2[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: [OH-]
Reactant: N#Cc1ccc(Nc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1
Agent: [Na+]
Solvent: C1COCCO1
Product: NC(=O)c1ccc(Nc2ccc3c(=O)[nH]c4ncccc4c3c2)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 4.7 %

Procedure:
4-[(6-Oxo-5,6-dihydrobenzo[c]-1,8-naphthyridin-9-yl)amino]benzonitrile (40 mg, 0.13 mmol) and NaOH (1.3 mL, 1.00 M; 1.28 mmol) were suspended in dioxane (2 mL), and stirred for 120 min at 120° C. in the microwave. The crude material was purified directly via prep-LC-MS to provide 249 (2 mg, 6% yield) as a brown solid. LC-MS (M+H=331 obsd.=331).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:18]=[C:17]([N:19]=[N:20][C:21]2[CH:26]=[C:25]([S:27](O)(=[O:29])=[O:28])[C:24]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:23][CH:22]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:10]=1[OH:41])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)=O.P(Cl)(Cl)([Cl:48])=O>CN(C)C(=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:18]=[C:17]([N:19]=[N:20][C:21]2[CH:26]=[C:25]([S:27]([Cl:48])(=[O:29])=[O:28])[C:24]([O:31][CH2:32][CH2:33][O:34][CH3:35])=[CH:23][CH:22]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:10]=1[OH:41])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCOc1ccc(N=Nc2cc(S(=O)(=O)NC(C)(C)C)c(O)c3cccc(NS(C)(=O)=O)c23)cc1S(=O)(=O)O
Solvent: CC(C)=O
Solvent: CC(=O)N(C)C
Product: COCCOc1ccc(N=Nc2cc(S(=O)(=O)NC(C)(C)C)c(O)c3cccc(NS(C)(=O)=O)c23)cc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixed solution containing 19 g of 2-(N-tert-butylsulfamoyl)-4-[4-(2-methoxyethoxy)-5-sulfophenylazo]-5-methanesulfonamido-1-naphthol prepared as described in Step (a) above, 100 ml of acetone and 20 ml of phosphorous oxychloride, 20 ml of N,N-dimethylacetamide was added dropwise at a temperature of 50° C. or below. After completion of the dropwise addition, the mixture was stirred for 1 hour and was poured gradually into 500 ml of ice water. The crystals thus-precipitated were collected by filtration, washed with 50 ml of acetonitrile and air-dried.