Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]#[N:20])[CH:18]=[C:13]3[C:12]([C:21]3[CH:22]=[C:23]([CH:44]=[CH:45][CH:46]=3)[CH2:24][NH:25][C:26]([C:28]3[C:29](=[O:43])[N:30]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=4)[CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:11]2)(=O)=O)C=CC=CC=1.[N-:47]=[N+:48]=[N-:49].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH:47]1[C:19]([C:17]2[CH:18]=[C:13]3[C:12]([C:21]4[CH:22]=[C:23]([CH:44]=[CH:45][CH:46]=4)[CH2:24][NH:25][C:26]([C:28]4[C:29](=[O:43])[N:30]([CH2:34][C:35]5[CH:40]=[CH:39][C:38]([F:41])=[C:37]([F:42])[CH:36]=5)[CH:31]=[CH:32][CH:33]=4)=[O:27])=[CH:11][NH:10][C:14]3=[N:15][CH:16]=2)=[N:20][N:49]=[N:48]1
Reactant: N#Cc1cnc2c(c1)c(-c1cccc(CNC(=O)c3cccn(Cc4ccc(F)c(F)c4)c3=O)c1)cn2S(=O)(=O)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCc1cccc(-c2c[nH]c3ncc(-c4nnn[nH]4)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Temperature: 110 °C
Reaction time: 4 h

Procedure:
1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(1-benzenesulfonyl-5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide (64 mg, 0.00010 mol) was dissolved in N,N-dimethylformamide (1.0 mL, Acros) and sodium azide (11 mg, 0.00017 mol; Aldrich) and then ammonium chloride (5 mg, 0.00009 mol; Aldrich) was added. The mixture was heated at 110° C. for 1.5 hours under an atmosphere of Argon. Additional sodium azide (29 mg, 0.00045 mol; Aldrich) and ammonium chloride (19 mg, 0.00036 mol; Aldrich) were added and the reaction was heated at 110° C. under an atmosphere of Argon. After 4 h (total), the reaction was diluted with N,N-dimethylformamide, filtered and purified by preparative HPLC to yield the product in 2.0 mg yield (3%). MS m/z=539.07 M+H.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:4][C:5]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH:8]=[CH:7]2>CCO.[Pd]>[CH3:1][C:2]1[C:3]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:4][C:5]([C:13]2[CH:14]=[N:15][N:16]([CH3:18])[CH:17]=2)=[C:6]2[C:11]=1[C:10](=[O:12])[NH:9][CH2:8][CH2:7]2
Reactant: Cc1c(OC(C)C)cc(-c2cnn(C)c2)c2cc[nH]c(=O)c12
Agent: [Pd]
Solvent: CCO
Product: Cc1c(OC(C)C)cc(-c2cnn(C)c2)c2c1C(=O)NCC2
Reaction time: 48 h
Yield: 78.2 %

Procedure:
A mixture of 8-methyl-5-(1-methyl-1H-pyrazol-4-yl)-7-(propan-2-yloxy)isoquinolin-1(2H)-one (108i, 0.14 g, 0.47 mmol) and 10% Pd/C (0.3 g) in EtOH (20 mL) was hydrogenated under H2 (1.6 MPa) at 80° C. for 48 hours in a 50 mL autoclave. The reaction mixture was filtered and the solids were washed with EtOH (2×10 mL). The filtrate was concentrated under vacuum to give 8-methyl-5-(1-methyl-1H-pyrazol-4-yl)-7-(propan-2-yloxy)-3,4-dihydroisoquinolin-1(2H)-one (108j, 0.11 g, 78.7%) as a white solid.
Reaction SMILES: C([N:8](C(C1C=CC=CC=1)C)[CH:9]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH2:10][C:11]([NH:13][CH2:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:12])C1C=CC=CC=1.CO.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:8][CH:9]([CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1)[CH2:10][C:11]([NH:13][CH2:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:12]
Reactant: [H][H]
Reactant: CC(c1ccccc1)N(Cc1ccccc1)C(CC(=O)NCCC(C)(C)C)C1CCCCC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCO
Product: CC(C)(C)CCNC(=O)CC(N)C1CCCCC1
Reaction time: 3 h

Procedure:
In a Parr bottle 10% Pd/C (0.8 g) was cooled to −78° C., followed by addition of a solution of 3-[benzyl-(1-phenyl-ethyl)-amino]-3-cyclohexyl-N-(3,3-dimethyl-butyl)-propionamide (0.8 g, 1.78 mmol) in ethyl acetate (10 mL), ethanol (100 mL), and methanol (20 mL). The resulting mixture was subjected to hydrogen atmosphere and shaken for 3 h. The hydrogen was purged with nitrogen, the reaction mixture was filtered (glass fiber filter paper) and the solvent was evaporated under reduced pressure to yield a residue.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](Br)=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:28]2[CH:29]=[C:30]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=2)O1.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>COCCOC.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>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[C:13]([Cl:18])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34](=[O:36])(=[O:35])[NH2:37])[CH:29]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)c2scc(-c3ccc(F)c(Cl)c3)c12
Reactant: CC1(C)OB(c2cccc(S(N)(=O)=O)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: Nc1ncc(-c2cccc(S(N)(=O)=O)c2)c2scc(-c3ccc(F)c(Cl)c3)c12
Temperature: 80 °C
Reaction time: 14 h
Yield: 20.2 %

Procedure:
The mixture of 4-amino-7-bromo-3-(3-chloro-4-fluoro-phenyl)thieno[3,2-c]pyridine (40 mg, 0.112 mmol), Pd(PPh3)4 (19 mg, 10 mol %), 3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonamide (36.8 mg, 0.224 mmol) and 2M Na2CO3 aqueous solution (0.28 ml, 0.56 mmol) in 2 ml of DME was stirred for 14 hours at 80° C. As starting material remained, same amount of reagents described above and DMF (2 ml) were added and stirred for 5 hours at 100° C. The resultant mixture was directly applied to SCX (Varian, 5 g) and eluted with 1N NH3 in CHCl3 and MeOH was collected, and the eluant was concentrated in vacuo. The residue was purified by chromatography on a silica gel column to afford the titled compound (9.8 mg) 1H NMR (400 MHz, DMSO-d6) ppm 8.12 (dd, J=1.8 Hz, 1H), 8.0 s, 1H), 7.91 (ddd, J=1.5, 1.5, 7.6 Hz, 1H), 7.85 (ddd, J=1.4, 1.4, 7.1 Hz, 1H), 7.75 (dd, J=7.8 Hz, 1H), 7.67 (s, 1H), 7.57 (dd, J=9.0 Hz, 1H), 7.51 (ddd, J=2.2, 4.9, 8.5 Hz, 1H), 7.45 (s, 2H), 5.66 (s, 2H). MS: m/z 434 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:19]=[C:18]2[C:9]([O:10][CH2:11][CH2:12][N:13]3[C:17]2=[N:16][C:15]([C:20]2[N:24]([CH:25]([CH3:27])[CH3:26])[N:23]=[C:22]([CH3:28])[N:21]=2)=[CH:14]3)=[CH:8][C:7]=1[O:29][CH3:30])=[CH2:5])C.CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:30][O:29][C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][C:6]=1[C:4](=[O:3])[CH3:5])[C:17]1[N:13]([CH:14]=[C:15]([C:20]3[N:24]([CH:25]([CH3:26])[CH3:27])[N:23]=[C:22]([CH3:28])[N:21]=3)[N:16]=1)[CH2:12][CH2:11][O:10]2
Reactant: C=C(OCC)c1cc2c(cc1OC)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: COc1cc2c(cc1C(C)=O)-c1nc(-c3nc(C)nn3C(C)C)cn1CCO2
Temperature: 60 °C
Reaction time: 1.25 h
Yield: 61.2 %

Procedure:
A mixture of 13-(1-ethoxyethenyl)-12-methoxy-4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaene (2.00 g) and 4-methylbenzenesulfonic acid (438 mg, 2.54 mmol) in acetone (20.0 mL) was stirred at 60° C. for 75 min. After removal of the solvent, the residue was purified by silica gel chromatography using 1-10% MeOH in DCM as eluant to afford the desired product (1.14 g, 80% yield for two steps). LCMS m/z [M+H]+ 382.3
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([F:35])[CH:34]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[C:31]2[CH:30]=[C:29]([F:28])[CH:34]=[C:33]([F:35])[CH:32]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Product: O=C1OC2(CCN(C(=O)c3cn(-c4cc(F)cc(F)c4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure VI as described above, the arylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16) with commercially available 3,5-difluorophenylboronic acid gave the title compound. ES-MS m/e (%): 493.1(M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1[O:43][CH3:44])[C:37](Cl)=[O:38]>N1C=CC=CC=1>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:37](=[O:38])[C:36]4[CH:40]=[CH:41][C:42]([O:43][CH3:44])=[C:34]([O:33][CH3:32])[CH:35]=4)=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Solvent: c1ccncc1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(=O)c4ccc(OC)c(OC)c4)cc3)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 8-(4-amino-benzyl)-3-butyl-1-(2-fluorobenzyl)-3,7-dihydro-purine-2,6-dione (prepared as described in example 72) in pyridine (1 mL) was added 3,4-dimethoxy-benzoyl chloride (Aldrich) (13 mg, 0.06 mmol). The reaction was stirred at room temperature for 1 h and then concentrated under reduced pressure. The residue was purified by reverse phase HPLC to afford the product. LCMS, m/z(M+H)=586.33.
Reaction SMILES: [NH:1]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@@H:2]([C:30](ON1C(=O)CCC1=O)=[O:31])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:29])[N:8]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[NH2:47][CH2:48][C:49]([OH:51])=[O:50].C([O-])(O)=O.[Na+]>O1CCOCC1.O>[NH:1]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C@@H:2]([C:30]([NH:47][CH2:48][C:49]([OH:51])=[O:50])=[O:31])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:29])[N:8]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: NCC(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=N)N(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(=N)N(C(=O)OCc1ccccc1)C(=O)OCc1ccccc1)C(=O)NCC(=O)O
Reaction time: 24 h

Procedure:
To a solution of Boc—(D)—Arg(Cbz2)—OSu (1 g, 1.6 mmol) in dioxane (10 mL) was added a solution of Gly (300 mg, 4 mmol) and NaHCO3 (400 mg, 4.76 mmol) in water (10 mL). The solution was stirred for 24 h. Solvents were evaporated and residue was dissolved in a mixture of EtOAc (20 mL) and 1 N HCl (6 mL). The separated organic layer was washed with sat. NaCl (10 mL), dried over MgSO4, filtered and evaporated to give a solid residue which was used directly without further purification. ES—MS (M+H)+=600
Reaction SMILES: N([O-])=O.[Na+].[Cl:5][C:6]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([Cl:17])[C:7]=1[NH2:8].[N-:18]=[N+:19]=[N-].[Na+].O>S(=O)(=O)(O)O.C(O)(=O)C>[N:8]([C:7]1[C:6]([Cl:5])=[CH:12][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:10][C:9]=1[Cl:17])=[N+:18]=[N-:19]
Reactant: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: [N-]=[N+]=Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C

Procedure:
A solution of sodium nitrite (3.2 g) in concentrated sulphuric acid (22 ml) was added dropwise with cooling to a solution of 2,6-dichloro-4-trifluoromethylaniline (9.3 g) in glacial acetic acid (48 ml). The mixture was stirred at room temperature for half an hour and then cooled to 0°-5°. A solution of sodium azide (2.6 g) in the minimum volume of water was added dropwise with cooling and the mixture stirred at 0°-5° for 1 hour and then at room temperature overnight. The mixture was poured into ice/water, extracted with dichloromethane and the extract worked up in conventional manner to give 1-azido-2,6-dichloro-4-trifluoromethylbenzene, as a red oil. A solution cf this oil (25.6 g) and 2-propyn-1-ol (40 ml) in xylene (80 ml) were stirred under nitrogen and heated under reflux overnight. The mixture was cooled and the solvent was evaporated under reduced pressure. Trituration of the residue with light petroleum (bp 30°-40°) gave a crude material which was purified by filtration through silica to give [1-(2,6-dichloro-4-trifluoromethylphenyl)-1H-1,2,3-triazol-4-yl]methanol, m.p.123°-125°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH3:26][C:27]([NH2:31])([CH3:30])[CH2:28][NH2:29]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:31][C:27]([CH3:30])([CH3:26])[CH2:28][NH2:29])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: CC(C)(N)CN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(C)(C)CN)c2c1

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2-methylpropane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J=7.83, 1.26 Hz, 1 H), 7.86 (d, J=6.82 Hz, 1 H), 7.70 (s, 1 H), 7.61 (td, J=7.45, 1.26 Hz, 1 H), 7.47-7.42 (m, 2 H), 7.29 (dd, J=8.59, 1.77 Hz, 1 H), 6.09 (s, 1 H), 5.16 (s, 2 H), 3.58 (t, J=4.80 Hz, 2 H), 3.33 (m, 2 H), 3.27 (s, 2 H), 2.43 (s, 3 H), 1.27 (s, 6 H).
Reaction SMILES: N#N.C[O:4][C:5]1[CH:10]=[C:9]([O:11]C)[CH:8]=[C:7]([O:13]C)[C:6]=1[CH2:15][C:16]([NH:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23])=[O:17].B(Br)(Br)Br>C(Cl)Cl>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:13])[C:6]=1[CH2:15][C:16]([NH:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([OH:24])=[O:23])=[O:17]
Reactant: COc1cc(OC)c(CC(=O)Nc2cccc(C(=O)O)c2)c(OC)c1
Agent: BrB(Br)Br
Agent: N#N
Solvent: ClCCl
Product: O=C(Cc1c(O)cc(O)cc1O)Nc1cccc(C(=O)O)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 24.5 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Dissolve 3-[2-(2,4,6-Trimethoxy-phenyl)-acetylamino]-benzoic acid (17) (134 mg, 0.39 mmol) in anhydrous DCM (5.3 mL), cool the solution to −78° C. and add dropwise BBr3 (240 μL, 2.55 mmol). Stir the reaction mixture for 30 min at −78° C. and after slowly warming up for additional 2 h at rt. Add dropwise ice water, separate layers and extract aqu. layer with EtOAc (3 times). Wash combined organic layer with brine and dry with Na2SO4. Purify the crude product by preparative RP HPLC (gradient, water/CH3CN 95:5 to 5:95) to obtain 3-[2-(2,4,6-Trihydroxy-phenyl)-acetylamino]-benzoic acid (18) (29 mg, 22%) as a yellowish solid. 1H NMR (400 MHz, CD3OD): 3.69 (s, 2H); 5.97 (s, 2H); 7.43 (t, 1H, J=8.0 Hz); 7.76 (br.dd, 1H, J1=7.6 Hz); 7.84 (br.dd, 1H, J1=8.1 Hz); 8.17 (t, 1H, J=1.8 Hz).
Reaction SMILES: CC(C)(C)C([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[N:17]=[CH:16][CH:15]=[N:14]2)=[CH:8][C:7]=1[Cl:18])=O.[OH-].[Na+]>C(O)C>[Cl:18][C:7]1[CH:8]=[C:9]([CH2:12][N:13]2[N:17]=[CH:16][CH:15]=[N:14]2)[CH:10]=[CH:11][C:6]=1[OH:5]
Reactant: CC(C)(C)C(=O)Oc1ccc(Cn2nccn2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Oc1ccc(Cn2nccn2)cc1Cl

Procedure:
A mixture of 3 g of 2-chloro-4-(2-2H-1,2,3-triazolyl)methylphenyl 2,2-dimethylpropanoate, 10 ml of 20% aqueous sodium hydroxide solution and 60 ml of ethanol was heated at reflux for 5 hours. The reaction mixture was then concentrated under reduced pressure, to which water was added, and the mixture was adjusted to pH 6.0 with concentrated hydrochloric acid. This mixture was extracted with ethyl acetate. The organic layer was washed with water, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, which afforded 2-chloro-4-(2-2H-1,2,3-triazolylmethyl)phenol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[N:9]2[C:13]3=[N:14][C:15]([CH3:19])=[CH:16][C:17]([CH3:18])=[C:12]3[C:11]([C:20]#[N:21])=[C:10]2/[CH:22]=[CH:23]/[C:24]([OH:26])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:40]([NH2:44])([CH3:43])([CH3:42])[CH3:41].C(N(CC)CC)C>C1COCC1.O.CN(C=O)C>[F:33][C:30]1[CH:29]=[CH:28][C:27]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]2[C:13]3=[N:14][C:15]([CH3:19])=[CH:16][C:17]([CH3:18])=[C:12]3[C:11]([C:20]#[N:21])=[C:10]2/[CH:22]=[CH:23]/[C:24]([NH:44][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:26])=[CH:32][CH:31]=1
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n(C(c3ccc(F)cc3)c3ccc(F)cc3)c2n1
Reactant: CC(C)(C)N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)NC(C)(C)C)n(C(c3ccc(F)cc3)c3ccc(F)cc3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{1-[bis(4-fluorophenyl)methyl]-3-cyano-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (200 mg, 0.451 mmol) in THF (2 ml) were added DMF (0.020 ml) and oxalylchloride (0.0471 ml, 0.540 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of tert-butylamine (0.0945 ml, 0.900 mmol), triethylamine (0.251 ml, 1.80 mmol) and THF (2 ml), and the mixture was stirred under ice-cooling for 2 hours and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from hexane and ethyl acetate.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.FC1C=CC=C(OCC#C)C=1F>C1COCC1.[Pd]>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(c1F)OCC=C2
Agent: [Pd]
Agent: C#CCOc1cccc(F)c1F
Solvent: C1CCOC1
Product: Fc1ccc2c(c1F)OCCC2

Procedure:
A mixture of 7,8-difluoro-2H-chromene and 1,2-difluoro-3-prop-2-ynyloxybenzene (43.2 g) is hydrogenated at 20° C. for 1 h in 430 ml of THF in the presence of Pd/C (5% Pd). The batch is concentrated to dryness, and the crude product is purified by column chromatography (SiO2, n-pentane:1-chlorobutane=4:1), giving pure 7,8-difluorochroman as a slightly yellowish liquid.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[CH:5]=[C:4](Cl)[N:3]=1.C1CCN2C(=NCCC2)CC1.[OH:28][C:29]([CH3:38])([CH3:37])[CH2:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>CS(C)=O>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[CH:5]=[C:4]([N:34]2[CH2:35][CH2:36][N:31]([CH2:30][C:29]([OH:28])([CH3:37])[CH3:38])[CH2:32][CH2:33]2)[N:3]=1
Reactant: Nc1nc(Cl)cc2nc(-c3ccco3)nn12
Reactant: CC(C)(O)CN1CCNCC1
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(O)CN1CCN(c2cc3nc(-c4ccco4)nn3c(N)n2)CC1
Temperature: 140 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
Into 7 mL of DMSO, 500 mg (2.12 mmol) of Compound E was dissolved, and then 0.95 mL (6.36 mmol) of DBU and 1.50 g (9.50 mmol) of 1-(2-hydroxy-2-methylpropyl)piperazine were added thereto, followed by stirring at 140° C. for about 2 hours. After completion of the reaction, the reaction mixture was extracted by adding chloroform and water, and the organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. After evaporation of the solvent, the resulting residue was purified by silica gel column chromatography (3% methanol-chloroform) and then recrystallized from a mixed solvent of hexane-ethyl acetate to obtain 250 mg of Compound 1 as a white solid (yield: 33%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)[C:8]([CH3:18])=[CH:7][C:5]=2[N:6]=1.[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:22]([C:21]4[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=4[Cl:19])=[O:23])=[N:15][CH:16]=3)[C:8]([CH3:18])=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(C)c(-c3ccc(N)nc3)cc2o1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc2cc(C)c(-c3ccc(NC(=O)c4ccccc4Cl)nc3)cc2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.1 %

Procedure:
To a solution of 5-(2,5-dimethylbenzoxazol-6-yl)-2-pyridylamine (49) (42 mg, 0.175 mmol) in 2 ml DCM was added 2-chlorobenzoyl chloride (44 μl, 2 eq) followed by addition of DIEA (153 μl). The resulting solution was stirred at r.t. for 3 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (350 μl) at r.t. for 4 h before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished 47.7 mg N-[5-(2,5-dimethylbenzoxazol-6-yl)(2-pyridyl)](2-chlorophenyl)carboxamide (50) as white solid. (yield: 72.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[NH:16][CH:15]=2)[CH:5]=[C:4]([Cl:27])[C:3]=1[NH:28]C(=O)C.COC1C=C2C(=CC=1)NC=C2CC(O)=O.ClC1C=C(C=C(Cl)C=1N)CN>>[NH2:28][C:3]1[C:4]([Cl:27])=[CH:5][C:6]([CH2:8][NH:9][C:10]([NH2:26])=[N:11][C:12](=[O:25])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH3:24])[CH:21]=3)[NH:16][CH:15]=2)=[CH:7][C:2]=1[Cl:1]
Reactant: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(Cl)c(NC(C)=O)c(Cl)c3)c2c1
Agent: COc1ccc2[nH]cc(CC(=O)O)c2c1
Agent: NCc1cc(Cl)c(N)c(Cl)c1
Product: COc1ccc2[nH]cc(CC(=O)N=C(N)NCc3cc(Cl)c(N)c(Cl)c3)c2c1

Procedure:
In a manner similar to that used in the preparation of the compound of example 2, but using 2-(5-methoxy-1H-indol-3-yl)acetic acid in step 7 (A) and 3,5-dichloro-4-aminobenzylamine (preparation A) in step 7 (B), the title compound was prepared. MS (ESI) (M+H)+=419.99 1H-NMR (500 MHz, CD3OD) δ 7.29 (d, J=8.85 Hz, 1 H), 7.25 (s, 1 H), 7.21 (s, 2 H), 7.03 (d, J=2.44 Hz, 1 H), 6.82 (dd, J=8.85, 2.44 Hz, 1 H), 4.33 (s, 2 H), 3.92 (s, 2 H), 3.82 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][F:6])[C:3]#[N:4].ON1C2N=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.[I:30][C:31]1[CH:32]=[N:33][C:34]2[C:39]([CH:40]=1)=[CH:38][C:37]([O:41][CH:42]([S:46][CH3:47])[C:43](O)=[O:44])=[CH:36][C:35]=2[CH3:48]>CN(C)C=O.[Cl-].[Na+].O.C(N(CC)CC)C>[C:3]([C:2]([NH:1][C:43](=[O:44])[CH:42]([O:41][C:37]1[CH:38]=[C:39]2[C:34](=[C:35]([CH3:48])[CH:36]=1)[N:33]=[CH:32][C:31]([I:30])=[CH:40]2)[S:46][CH3:47])([CH3:7])[CH2:5][F:6])#[N:4]
Reactant: CSC(Oc1cc(C)c2ncc(I)cc2c1)C(=O)O
Reactant: CC(N)(C#N)CF
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CSC(Oc1cc(C)c2ncc(I)cc2c1)C(=O)NC(C)(C#N)CF
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.1 %

Procedure:
To a solution of 2-amino-3-fluoro-2-methylpropionitrile (315 mg) in dry dimethylformamide (20 mL) were added triethylamine (0.43 mL), 1-hydroxy-7-azabenzotriazole (420 mg), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide.HCl (591 mg), then (3-iodo-8-methyl-quinolin-6-yloxy)-methylsulfanyl-acetic acid (1.2 g). The reaction mixture was stirred at room temperature for 18 hours. The mixture was poured over brine and extracted twice with ethyl acetate (thrice). The organic layer was washed with water then with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude was purified by chromatography eluting with cyclohexane/ethyl acetate (3:2 by volume), to give N-(1-cyano-2-fluoro-1-methyl-ethyl)-2-(3-iodo-8-methyl-quinolin-6-yloxy)-2-methylsulfanyl-acetamide (906 mg) as a solid.