Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[O:9])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:18][CH:19]=1
Reactant: NCc1ccncc1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Product: COc1ccc(C(=O)NCc2ccncc2)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and 4-(aminomethyl)pyridine in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][NH:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)=O.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:1][CH2:2][C:3]1[O:15][C:7]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)=[N:6][N:5]=1
Reactant: Cc1ccc(C(=O)NNC(=O)CCl)cc1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(-c2nnc(CCl)o2)cc1
Yield: 72.4 %

Procedure:
To a mixture of 4-methylbenzohydrazide 14 (10 g, 66.59 mmol) and K2CO3 (16.57 g, 119.86 mmol) in acetonitrile (100 mL) was added 2-chloroacetyl chloride (9.02 g, 79.9 mmol) dropwise at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 hours. The solid was collected, washed with H2O and ether, and dried to afford N′-(2-chloroacetyl)-4-methylbenzohydrazide 15 (13 g, 82%) which was used for the next step without further purification. A mixture of N′-(2-chloroacetyl)-4-methylbenzohydrazide 15 (6.0 g, 26.47 mmol) and phosphorous oxychloride (5.0 g, 32.84 mmol) in acetonitrile (20 mL) was stirred under reflux for 16 hours and concentrated. The residue was subjected to flush column chromatography eluting with 10-25% acetone/hexanes to give compound 16 (4 g). Yield: 72%.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.O[N:44]=[C:45]([C:51](=[O:53])[CH3:52])[C:46]([O:48][CH2:49][CH3:50])=[O:47]>O1CCCC1>[CH3:1][C@H:2]1[CH2:7][C@H:6]([O:8]/[N:44]=[C:45](/[C:51](=[O:53])[CH3:52])\[C:46]([O:48][CH2:49][CH3:50])=[O:47])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1
Reactant: CCOC(=O)C(=NO)C(C)=O
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)/C(=N\O[C@H]1C[C@H](C)CC[C@H]1C(C)C)C(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(1R, 2S, 5R-)-(-)-Menthol (7.3 g, 45 mmol) and triphenylphosphine (8.65 g, 33 mmol) in dry tetrahydrofuran under argon were cooled in an ice bath and diethyl azodicarboxylate (5.2 ml, 5.7 g, 33 mmol) in dry tetrahydrofuran (30 ml) was added dropwise over 15 minutes. The ice bath was removed and ethyl 2-hydroxyimino-3-oxobutyrate (4.77 g, 33 mmol) in dry tetrahydrofuran (30 ml) was added dropwise over 20 min. The mixture was stirred at room temperature for 18 h and then warmed at 50° C. for 1.5 h. The mixture was cooled and the tetrahydrofuran was removed by evaporation in vacuo. Toluene was added to the residue and evaporated in vacuo. The residual yellow oil was chromatographed on silica gel, eluting with carbon tetrachloride, followed by hexane, followed by hexane/ethyl acetate mixtures. After evaporation of relevant fractions the title compound was obtained as an oil, νmax (CH2Cl2) 2945, 2920, 2860, 1740, 1685, 1365, 1315, 1235, 1070 and 1005 cm-1 ; δ (250 MHz, CDCl3) 0.87 (3H, d, J 7.3 Hz), 0.90 (3H, d, J 6.8 Hz), 0.92 (3H, d, J 6.3 Hz), 0.95-1.14 (2H, m), 1.14-1.35 (1H, m), 1.32 (3H, t, J 7.2 Hz), 1.49-1.63 (2H, m), 1.63-1.80 (2H, m), 2.13 (1H, m), 2.40 (3H, s), 4.34 (2H, q, J 7.1 Hz), 4.70 (1H, broad s).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:21])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([OH:20])=[CH:12][CH:11]=1)([CH3:6])([CH3:5])[CH3:4].Cl[C:23]1[CH:28]=[CH:27][O:26][C:25](=[O:29])[CH:24]=1>C1COCC1>[C:3]([O:7][C:8](=[O:21])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([O:20][C:23]2[CH:28]=[CH:27][O:26][C:25](=[O:29])[CH:24]=2)=[CH:12][CH:11]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: O=c1cc(Cl)cco1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(Oc2ccoc(=O)c2)c2ccccc12
Reaction time: 0.33 h

Procedure:
To a suspension of NaH (0.070 g of 60% oil dispersion) in 5 mL of anhydrous THF at 0° C. was added (4-hydroxy-naphthalen-1-yl)-carbamic acid tert-butyl ester (0.414 g) (Example 5). The mixture was stirred 20 min, then 4-chloro-2H-pyran-2-one (Helvitica Chemica. Acta, 1990, 73, 883) (0.208 g) was added and the reaction stirred 5 h at 0° C. Removal of the volatiles in vacuo provided a residue which was purified by flash chromatography on silica gel eluting with 33% EtOAc in hexanes. Concentration of the product rich fractions provided [4-(2-oxo-2H-pyran-4-yloxy)-naphthalen-1-yl]-carbamic acid tert-butyl ester.
Reaction SMILES: [N:1]1([C:7](=[O:24])[CH2:8][CH:9]([CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:15])[C:10]([OH:12])=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:39][C@@H:40]([CH2:52][CH3:53])[CH:41]([C:43]1[O:44][C:45]2[CH:51]=[CH:50][CH:49]=[CH:48][C:46]=2[N:47]=1)[OH:42].CN1CCOCC1.[O-]S([O-])=O.[Na+].[Na+]>C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[O:44]1[C:45]2[CH:51]=[CH:50][CH:49]=[CH:48][C:46]=2[N:47]=[C:43]1[C:41]([C@@H:40]([NH:39][C:10](=[O:12])[CH:9]([CH2:13][S:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH2:8][C:7]([N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1)=[O:24])[CH2:52][CH3:53])=[O:42]
Reactant: O=C(O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1
Reactant: CC[C@H](N)C(O)c1nc2ccccc2o1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CC[C@H](NC(=O)C(CC(=O)N1CCOCC1)CS(=O)(=O)Cc1ccccc1)C(=O)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.9 %

Procedure:
A mixture comprised of 4-Morpholin-4-yl-4-oxo-2-(benzyl-sulfonylmethyl)-butyric acid (300 mg, 0.84 mmol), EDC (250 mg, 1.3 mmol), HOBt (250 mg, 1.6 mmol) and (2S)-2-amino-1-benzooxazol-2-yl-butan-1-ol (250 mg, 1.2 mmol) was treated with dichloromethyl (4 mL) followed by 4-methylmorpholine (0.5 mL). The mixture was stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (150 mL), the solution was washed with 1N aqueous HCl, water, saturated aqueous NaHCO3 solution and brine, dried with magnesium sulfate and evaporated under vacuum. The crude product was dissolved in dry dichloromethyl (10 mL) and 1,1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane) (500 mg, 1.2 mmol) was added. After stirring at ambient temperature for 1 hour, the mixture was diluted with ethyl acetate (150 mL) and treated with 0.26M Na2SO3 solution in saturated aqueous NaHCO3. The organic phase was washed with saturated aqueous NaHCO3 and brine, dried with magnesium sulfate and evaporated to yield N-[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide (377 mg) as mixture of diastereomers. The product was purified by flash chromatography on silica gel (hexane/ethyl acetate ratio of 1:2 to 1:4); 1H NMR: (DMSO), 8.85 (d, J=6.2 Hz), 8.77 (d, J=6.2 Hz), 1H],, 8.00 (d, J=7.7 Hz), 7.99 (d, J=7.7 Hz), 1H],, 7.90 (d, J=8.2 Hz), 7.89 (d, J=8.2 Hz), 1H], 7.64 (t, J=7.9 Hz, 1H), 7.54 (t, J=7.4 Hz, 1H), 7.42–7.34 (m, 5H), 5.25–5.12 (m, 1H), 4.55–4.38 (m, 2H), 3.60–3.28 (m, 10H), 3.12–3.02 (m, 1H), 2.64–2.50 (m, 2H), 2.08–1.91 (m, 1H), 1.82–1.65 (m, 1H), 0.98 (t, J=7.4 Hz, 3H); MS: (M++1) 542;
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)O1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CCOC(C)=O>[OH:30][C:27]1[CH:28]=[CH:29][C:24]([C:2]2[CH:11]=[C:10]3[C:5]([C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccnc2cc(Br)ccc12
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1ccnc2cc(-c3ccc(O)cc3)ccc12
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 54.9 %

Procedure:
A mixture of 160 mg (0.60 mmol) of methyl 7-bromo-4-quinolinecarboxylate, 200 mg (0.90 mmol) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, 7 mg (0.03 mmol) of palladium(II)acetate, 16 mg (0.06 mmol) of triphenylphosphine, 450 mg (2.10 mmol) of K3PO4 and 50 uL (3.01 mmol) of H2O in 3 mL of dioxane was stirred at 60° C. for 1.5 hr. EtOAc was added then the organics were washed with H2O and brine then concentrated. The residue was suspended in cold EtOAc and the solids were collected by suction filtration, washed with cold EtOAc and dried to give 92 mg (55%) of methyl 7-(4-hydroxyphenyl)-4-quinolinecarboxylate as a tan solid. 1H NMR (400 MHz, CDCl3): δ 9.75 (s, 1H), 9.03 (s, 1H), 8.63 (d, J=9 Hz, 1H), 8.25 (d, J=2 Hz, 1H), 8.03 (dd, JA=2 Hz, JB=9 Hz, 1H), 7.87 (s, 1H), 7.72 (d, J=8 Hz, 2H), 6.90 (d, J=8 Hz, 2H), 3.98 (s, 3H). ESI-LCMS m/z 280 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9]([O:29][C@@H:30]([C@H:32]4[CH2:36][NH:35][C:34](=[O:37])[CH2:33]4)[CH3:31])=[N:10][C:11]([C:13]4[CH:18]=[CH:17][C:16](C5CCN(C6COC6)CC5)=[CH:15][CH:14]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1.CC1(C)C(C)(C)OB(C2C=CC([N:52]3[CH2:57][CH:56]4[CH2:58][CH:54]([N:55]4[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:53]3)=CC=2)O1>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([N:4]2[C:8]3[C:9]([O:29][C@@H:30]([C@@H:32]4[CH2:33][C:34](=[O:37])[NH:35][CH2:36]4)[CH3:31])=[N:10][C:11]([C:13]4[CH:14]=[CH:15][C:16]([N:52]5[CH2:53][CH:54]6[CH2:58][CH:56]([N:55]6[C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:57]5)=[CH:17][CH:18]=4)=[CH:12][C:7]=3[N:6]=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C[C@@H](Oc1nc(-c2ccc(C3CCN(C4COC4)CC3)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Reactant: CC(C)(C)OC(=O)N1C2CC1CN(c1ccc(B3OC(C)(C)C(C)(C)O3)cc1)C2
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
Product: C[C@@H](Oc1nc(-c2ccc(N3CC4CC(C3)N4C(=O)OC(C)(C)C)cc2)cc2ncn(C3CC3)c12)[C@H]1CNC(=O)C1
Temperature: 25 °C
Yield: 59 %

Procedure:
Prepared by Suzuki coupling reaction procedure, as previously described for the synthesis of (R)-4-((R)-1-((3-cyclopropyl-6-(4-(1-(oxetan-3-yl)piperidin-4-yl)phenyl)-3H-imidazo[4,5-c]pyridin-4-yl)oxy)ethyl)pyrrolidin-2-one:, using instead tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (289.4 mg, 0.72 mmol), and Pd(PPh3)4 (34.8 mg, 0.030 mmol) in DME (3 mL) and 2N Na2CO3 (2 mL). The reaction mixture was sonicated for 30 sec and degassed with nitrogen gas for 30 sec, and heated at 100 C for 1 h. Then it was cooled to room temperature, directly loaded on the pre-packed silica cartridge, and purified by flash chromatography (100% dichloromethane to 25% MeOH in dichloromethane) to give 200.0 mg (59%) of tert-butyl 3-(4-(3-cyclopropyl-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)phenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].Br[CH2:13][C:14]1[S:18][C:17]([Cl:19])=[N:16][CH:15]=1>>[Cl:19][C:17]1[S:18][C:14]([CH2:13][O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=2)=[CH:15][N:16]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: Clc1ncc(CBr)s1
Product: O=[N+]([O-])c1cc(OCc2cnc(Cl)s2)ccc1Cl

Procedure:
A solution of 4-chloro-3-nitro-phenol was reacted with 5-Bromomethyl-2-chloro-thiazole (prepared according to the method of Kim, H.-J., Liu, S., Keum, Y.-S., Qing, X. J. Agric. Food Chem. 2003, 51, 1823-1830) using the conditions described in Example 10C to provide 2-Chloro-5-(4-chloro-3-nitro-phenoxymethyl)-thiazole which was treated sequentially using the procedures from Examples 10D and 10E to provide the title product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:25])[CH:3]=1.[CH3:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH2:23]([C:19]1[CH:20]=[C:21]([CH3:22])[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:29]4[CH2:30][CH2:31][N:27]([CH3:26])[C:28]4=[O:32])=[CH:3][C:4]=3[F:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=1)[CH3:24]
Reactant: CN1CCNC1=O
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCN(C)C4=O)cc3F)CC2)c(C)c1
Yield: 40.5 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (203 mg) described in Preparation Example 211 and 1-methylimidazolidin-2-one (60 mg) and by the reaction and treatment in the same manner as in Example 511, the title compound (86 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:32]=[CH:31][C:26]3[O:27][CH2:28][CH2:29][O:30][C:25]=3[CH:24]=2)[CH2:19][CH2:18]1)([O-])=O.[C:33](Cl)(=[O:35])[CH3:34]>C1COCC1>[C:33]([NH:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:32]=[CH:31][C:26]3[O:27][CH2:28][CH2:29][O:30][C:25]=3[CH:24]=2)[CH2:19][CH2:18]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc2[nH]cc(CCCCN3CCN(c4ccc5c(c4)OCCO5)CC3)c2c1
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc2[nH]cc(CCCCN3CCN(c4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 2 h

Procedure:
A solution of 4.21 g of 6-[4-(4-(5-aminoindol-3-yl)butyl)piperazino]-1,4-benzodioxane ("C") [obtainable as in Example 5] in 35 ml of THF is treated with a solution of 0.9 g of acetyl chloride in 10 ml of THF, and the mixture is stirred at 50° for 2 hours, evaporated and worked up in the conventional manner. 6-[4-(4-(5-Acetamidoindol-3-yl)butyl)piperazino]-1,4-benzodioxane is obtained.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:25])[C:10]1[CH:15]=[CH:14][C:13](B2OC(C)(C)C(C)(C)O2)=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:27]1[C:28]([NH2:33])=[N:29][CH:30]=[CH:31][N:32]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:33][C:28]1[C:27]([C:13]2[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:25])=[CH:15][CH:14]=2)=[N:32][CH:31]=[CH:30][N:29]=1
Reactant: CC1(C)OB(c2ccc(C(=O)NCc3ccccc3)cc2)OC1(C)C
Reactant: Nc1nccnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Nc1nccnc1-c1ccc(C(=O)NCc2ccccc2)cc1
Temperature: 120 °C
Yield: 59.2 %

Procedure:
To a solution of N-benzyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (150 mg, 0.445 mmol), 3-chloropyrazin-2-amine (74.9 mg, 0.578 mmol), and PdCl2(dppf)-CH2Cl2 adduct (36.3 mg, 0.044 mmol) in DME (3.3 mL) was added 2 M Na2CO3 (1.11 mL). The reaction mixture was heated at microwave synthesizer (120° C., 10 min). Diluted with EtOAc and washed with water twice. Then extracted with 1N HCl (3×15 mL). The acidic solution was washed with ether twice (2×15 mL), and then basified with Na2CO3. Followed by extracting with EtOAc (20 mL, 3 times) and then washed by sat NaHCO3, water and brine, dried over Na2SO4 and filtered off, concentrated. The crude product was purified with flash chromatography eluting with 0-100% of EtOAc(containing 10% MeOH) in heptane, then concentrated on rotavap. The residue was triturated with ether to provide 80.2 mg of desired product. LCMS (m/z): 305.2 (MH+), 0.59 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (d, J=8.22 Hz, 1H) 8.41 (s, 1H) 8.06 (dd, J=9.39, 2.74 Hz, 1H) 8.01 (d, J=8.61 Hz, 2H) 7.94 (br. s., 1H) 7.83 (d, J=8.22 Hz, 2H) 7.40-7.34 (m, 2H) 7.30 (t, J=7.63 Hz, 2H) 7.22 (d, J=7.43 Hz, 1H) 6.40 (d, J=9.39 Hz, 1H) 5.12-5.03 (m, 1H) 3.75-3.60 (m, 2H).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH:12]2[CH2:18][CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1>C(Cl)(Cl)Cl>[NH:15]1[CH2:16][CH2:17][CH2:18][CH:12]([CH2:11][NH:10][C@@H:8]2[CH2:9][C@H:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: c1ccc([C@@H]2C[C@H]2NCC2CCCNCC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.1 %

Procedure:
Chloroform (50 mL) was added to a 200 mL round-bottomed flask containing tert-butyl 4-(((trans-2-phenylcyclopropyl)amino)methyl)azepane-1-carboxylate (49.4 mg, 0.143 mmol) to give a suspension. HCl/1,4-Dioxane (12 mL, 48.0 mmol) was added and the mixture stirred 18 hour at room temperature. Upon completion, the residue was adsorbed directly onto silica and purified via column chromatography on the ISCO Companion (gradient 0-100% 80:20:2 [CHCl3/MeOH/NH4OH]/CHCl3; 4 g column). Fractions were collected, solvents removed and the resulting residue was taken up in MeOH (2 mL). Excess 2M HCl in Et2O and stirred for 10 minutes. The solvent was removed to yield the 2HCl salt of the desired product (28 mg, 59% yield) as a yellow solid: LC-MS (ES) m/z=245 (M+H)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.18-1.32 (m, 1H) 1.36 (d, J=11.37 Hz, 1H) 1.54-1.79 (m, 3H) 1.80-1.96 (m, 2H) 2.06 (br. s., 2H) 2.54-2.64 (m, 1H) 2.97 (br. s., 5H) 3.06-3.27 (m, 2H) 7.14-7.26 (m, 3H) 7.27-7.35 (m, 2H) 9.03 (br. s., 2H) 9.38-9.62 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[C:15]([NH:16][NH2:17])=[CH:14][C:12](=[O:13])[N:11]([CH2:18][CH2:19][CH3:20])[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][N:22]=[C:23]=S.C(O)C>CN(C=O)C>[CH2:1]([N:8]1[C:15]2[NH:16][N:17]=[C:21]([NH:22][CH3:23])[C:14]=2[C:12](=[O:13])[N:11]([CH2:18][CH2:19][CH3:20])[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN=C=S
Reactant: CCCn1c(=O)cc(NN)n(Cc2ccccc2)c1=O
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(NC)n[nH]c2n(Cc2ccccc2)c1=O
Yield: 70 %

Procedure:
A solution of 1-benzyl-6-hydrazino-3-propyluracil (2.0 g, 7.3 mM) and methyl isothiocyanate (1.5 ml, 22 mM) in DMF (20 ml) was stirred at 120° C. for 20 hours. Ethanol (20 ml) was added to the solution, which was cooled to give crystals. Recrystallization from DMF/ethanol gave colorless needles (1.6 g, 70%), m.p. 307°-310° C.
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])[C:3]=1[C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:26][C:27]1[CH:28]=[CH:29][C:30]2[O:34][C:33](=[O:35])[NH:32][C:31]=2[CH:36]=1>CN(C=O)C>[F:19][C:13]1[CH:14]=[C:15]([I:18])[CH:16]=[CH:17][C:12]=1[NH:11][C:7]1[CH:8]=[N:9][CH:10]=[C:2]([O:26][C:27]2[CH:28]=[CH:29][C:30]3[O:34][C:33](=[O:35])[NH:32][C:31]=3[CH:36]=2)[C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1c(F)cncc1Nc1ccc(I)cc1F
Reactant: O=c1[nH]c2cc(O)ccc2o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(Nc2ccc(I)cc2F)cncc1Oc1ccc2oc(=O)[nH]c2c1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
100 mg of 3-fluoro-5-[(2-fluoro-4-iodophenyl)amino]isonicotinamide (0.251 mmol, 1. eq.) were dissolved in DMF under a nitrogen atmosphere, then 245 mg of cesium carbonate (0.752 mmol, 3 eq.) and 45 mg of 5-hydroxy-1,3-benzoxazol-2(3H)-one (0.301 mmol, 1.2 eq.) were added. The resulting mixture was stirred at 50° C. bath temperature for 3 days. Then the mixture was partitioned between aq. NH4Cl solution (30 ml) and dichloromethane (30 ml). The phases were separated and the aqueouse layer was reextracted twice with dichloromethane/isopropanole (4:1, 30 ml each).
Reaction SMILES: [CH3:1][C:2]1[NH:13][C:12]2[C:7](=[CH:8][C:9]([O:14][CH3:15])=[CH:10][CH:11]=2)[C:3]=1[CH2:4][CH2:5][NH2:6].[CH3:16][C:17](OC(C)=O)=[O:18]>C1COCC1>[CH3:1][C:2]1[NH:13][C:12]2[CH:11]=[CH:10][C:9]([O:14][CH3:15])=[CH:8][C:7]=2[C:3]=1[CH2:4][CH2:5][NH:6][C:17]([CH3:16])=[O:18]
Reactant: COc1ccc2[nH]c(C)c(CCN)c2c1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(C)c(CCNC(C)=O)c2c1
Reaction time: 8 h

Procedure:
To a cold solution in THF (15 mL) of the crude 2-methyl-5-methoxytryptamine, from the step above, TEA (0.7 mL) and 0.47 mL of Ac2O were added. The ice bath was removed and the solution stirred for 8 h. The solvent was evaporated in vacuo, the residue was taken up in ethyl acetate and washed with a saturated aqueous solution of NaHCO3 followed by saturated NaCl solution. The organic phase was dried (Na2SO4), concentrated under vacuum and the crude oil residue was purified by flash chromatography (silica gel; ethyl acetate-cyclohexane, 7:3) and crystallization. The overall yield of 4a was 0.541 g (44%); mp 122° C.; 1H NMR data were identical with that reported in literature (Flaugh et at., J. Med. Chem. 22, 63-67 (1979).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([NH:16][NH2:17])=[O:15])=[CH:12][C:11]=1[C:20]([F:23])([F:22])[F:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:24](#N)[CH3:25].O>>[C:5]1([CH2:4][CH2:3][CH2:2][CH2:1][O:9][C:10]2[CH:19]=[CH:18][C:13]([C:14]([NH:16][NH2:17])=[O:15])=[CH:12][C:11]=2[C:20]([F:21])([F:22])[F:23])[CH:25]=[CH:24][CH:8]=[CH:7][CH:6]=1
Reactant: CC#N
Reactant: CCCCCCCCOc1ccc(C(=O)NN)cc1C(F)(F)F
Solvent: O
Product: NNC(=O)c1ccc(OCCCCc2ccccc2)c(C(F)(F)F)c1
Yield: 95 %

Procedure:
The title compound was prepared analogously to 4-(octyloxy)-3-(trifluoromethyl)-benzo-hydrazide (12a) in >95% yield. MS (ESI): 353.11 (MH+); HPLC retention time on a C8(2) column (30×3.00 mm, 3μ) is 2.30 min with gradient 20-98% acetonitrile-H2O (0.1% TFA) in 3.5 min as mobile phase.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]([C:18]1[CH:19]=[N:20][CH:21]=[N:22][CH:23]=1)([CH:15]([CH3:17])[CH3:16])[C:9]#[C:10][Si](C)(C)C>CO>[OH:7][C:8]([C:18]1[CH:23]=[N:22][CH:21]=[N:20][CH:19]=1)([CH:15]([CH3:17])[CH3:16])[C:9]#[CH:10]
Reactant: CC(C)C(O)(C#C[Si](C)(C)C)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC(O)(c1cncnc1)C(C)C
Reaction time: 3.3 h

Procedure:
Potassium carbonate (4 g) was added to the product of stage 1 (19.5 g, 0.11 mol) in methanol (100 ml) and the mixture was stirred for 3.3 hours. The mixture was then partitioned between ether and water. The ether layer was separated, dried over sodium sulphate, and concentrated under reduced pressure to give the title compound as an almost colourless solid (11.2 g). The product was further purified by recrystallisation from hexane to give a solid of melting point 112.4° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2.Br[CH2:21][CH:22]1[CH2:24][CH2:23]1>>[CH:22]1([CH2:21][N:5]2[C:6]3[C:11](=[C:10]([C:13]([F:16])([F:14])[F:15])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=3)[CH:12]=[C:4]2[CH2:3][CH:2]([CH3:19])[CH3:1])[CH2:24][CH2:23]1
Reactant: BrCC1CC1
Reactant: CC(C)Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: CC(C)Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC1CC1

Procedure:
Synthesized as described in Example 4 using 2-(2-methylpropyl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile and (bromomethyl)cyclopropane. 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J=9.2 Hz, 1H), 7.48 (d, J=9.2 Hz, 1H), 6.56 (d, J=1.7 Hz, 1H), 4.05 (d, J=6.6 Hz, 2H), 2.67 (t, J=7.1 Hz, 2H), 2.07 (m, 1H), 1.15 (m, 1H), 1.03 (d, J=6.6 Hz, 6H), 0.58 (m, 2H), 0.35 (m, 2H); MS (ES) m/z 321 (M+1).