Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18](O)=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:22][CH2:23][CH3:24])([C:10]2=[O:21])[CH2:8][CH2:7][C:6](=[O:25])[CH:5]=1.[NH3:26]>O1CCCC1>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([O:16][CH2:17][C:18]([NH2:26])=[O:19])[CH:12]=[C:11]2[C:3]=1[C:4]1[C:9]([CH2:22][CH2:23][CH3:24])([C:10]2=[O:21])[CH2:8][CH2:7][C:6](=[O:25])[CH:5]=1
Reactant: N
Reactant: CCCC12CCC(=O)C=C1c1c(cc(OCC(=O)O)c(Cl)c1Cl)C2=O
Solvent: C1CCOC1
Product: CCCC12CCC(=O)C=C1c1c(cc(OCC(N)=O)c(Cl)c1Cl)C2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
[(5,6-Dichloro-3,9-dioxo-9a-propyl-2,3,9,9a-tetrahydro-1H-fluoren-7-yl)oxy]acetic acid (3.82 g, 10 mMole) is dissolved in tetrahydrofuran (30 ml) and 1,1-carbonyldiimidazole (1.78 g, 11 mMole) and the mixture stirred at ambient temperature for 30 minutes. The solution is saturated with ammonia gas and then stirred at ambient temperature for 24 hours and at 50° for 16 hours. Evaporation of the solvent and addition of water yields [(5,6-dichloro-3,9-dioxo-9a-propyl-2,3,9,9a-tetrahydro-1H-fluoren-7-yl)oxy]acetamide which is separated by filtration, washed with water, and dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]([CH3:8])=[N:6][CH:7]=1.[Se](=O)=[O:15]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:5]([CH:8]=[O:15])=[N:6][CH:7]=1
Reactant: O=[Se]=O
Reactant: CCOC(=O)c1cc(Br)cnc1C
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(Br)cnc1C=O
Temperature: 180 °C

Procedure:
To each of 106 separate 20-mL microwave vials, add: ethyl 5-bromo-2-methylpyridine-3-carboxylate (5 g, 20.48 mmol, 1.0 equiv), selenium dioxide (2.98 g, 26.63 mmol, 1.3 equiv), and 1,4-dioxane (13 mL). Heat the vessels to 180° C. for 20 min with microwave irradiation. Combine the contents of the reaction vessels; filter through a pad of silica gel (2 kg); and rinse the pad with DCM (3 L). Concentrate the combined filtrates under reduced pressure. Split the material into two equally-sized batches, and pass each through a pad of silica gel (2 kg) eluting with DCM. Concentrate the filtrate under reduced pressure to furnish the title compound as a yellow or pale orange solid (473 g, 93.2% yield). MS (m/z) (79Br/81Br) 258/260 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:9][CH:10]([OH:14])[CH2:11][CH:12]=[CH2:13].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[Br:8][C:6]1[CH:7]=[C:2](/[CH:13]=[CH:12]/[CH2:11][CH:10]([OH:14])[CH3:9])[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: C=CCC(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CC(O)C/C=C/c1cncc(Br)c1
Temperature: 140 °C
Yield: 33.5 %

Procedure:
A mixture of 3,5-dibromopyridine (23.60 g, 100.0 mmol), 4-penten-2-ol (10.8 g, 125.0 mmol), palladium(II) acetate (230 mg, 1.02 mmol), tri-o-tolylphosphine (1.20 g, 3.94.mmol), triethylamine (29.7 mL, 213.45 mmol), and acetonitrile (40 mL) was heated in a sealed glass tube at 140° C. for 14 h. The reaction mixture was cooled to ambient temperature, diluted with water, and extracted with chloroform (3×200 mL). The combined chloroform extracts were dried over sodium sulfate and filtered. Removal of solvent by rotary evaporation, followed by column chromatography over silica gel eluting with acetone-chloroform (1:9, v/v) furnished 8.10 g (34.0%) of a pale-yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[I:15]N1C(=O)CCC1=O.C(OC(C)C)(C)C>CN(C)C=O>[I:15][C:14]1[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[N:11][NH:12][CH:13]=1
Reactant: O=[N+]([O-])c1cccc(-c2cc[nH]n2)c1
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: CC(C)OC(C)C
Product: O=[N+]([O-])c1cccc(-c2n[nH]cc2I)c1
Temperature: 70 °C
Reaction time: 5 h
Yield: 75 %

Procedure:
2.1 g (11 mmol) of 3-(3-nitrophenyl)-1H-pyrazole were dissolved in 25 ml of dry dimethylformamide and 2.63 g (11.7 mmol) of N-iodosuccinimide were added. After 5 hours under stirring at 70° C. the most part of solvent was removed in vacuo and an aqueous solution of sodium thiosulphate was added and the product extracted several times with dichloromethane. The organic phase was then dried over sodium sulphate and evaporated to give, after trituration with diisopropylether, 2.6 g (74%) of the title compound.
Reaction SMILES: O[C:2]1([C:18]2[C:19]([O:29]C(C)(C)C)=[N:20][C:21]([O:24]C(C)(C)C)=[N:22][CH:23]=2)[C:11]2[O:10][C:9]([CH3:12])=[N:8][C:7]=2[CH2:6][CH2:5][C:4]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:3]1=2>C(O)(=O)C>[CH3:12][C:9]1[O:10][C:11]2[CH:2]([C:18]3[C:19](=[O:29])[NH:20][C:21](=[O:24])[NH:22][CH:23]=3)[C:3]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:4]=3[CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: Cc1ccc2c(c1)CCc1nc(C)oc1C2(O)c1cnc(OC(C)(C)C)nc1OC(C)(C)C
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C=Cc1nc(C)oc1C2c1c[nH]c(=O)[nH]c1=O
Temperature: 100 °C

Procedure:
A solution of the product from step (vi) (5.7 g) in acetic acid (20 ml) was added dropwise over 5 min to acetic acid heated at 100° C. The mixture was heated for a further 3 hours at 100° C., the solvent removed under reduced pressure and azeotroped with toluene. Purification was by chromatography eluting with 5% methanol in dichloromethane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8](=[O:22])(=[O:21])[N:9]=[C:10]([N:14]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH:16]=[N:15]2)[NH:11][CH2:12][CH3:13])[CH:5]=[CH:4][C:3]=1[NH:23]C(=O)C.Cl.[OH-].[Na+]>CO>[NH2:23][C:3]1[CH:4]=[CH:5][C:6]([S:8]([N:9]=[C:10]([N:14]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH:16]=[N:15]2)[NH:11][CH2:12][CH3:13])(=[O:22])=[O:21])=[CH:7][C:2]=1[Cl:1]
Reactant: CCNC(=NS(=O)(=O)c1ccc(NC(C)=O)c(Cl)c1)N1CC(C)(C)C=N1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCNC(=NS(=O)(=O)c1ccc(N)c(Cl)c1)N1CC(C)(C)C=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.4 %

Procedure:
680 mg N-(2-Chloro-4-{[(4,4-dimethyl-4,5-dihydro-pyrazol-1-yl)-ethylamino-methylene]-sulfamoyl}-phenyl)-acetamide was dissolved in 5 mL MeOH, and 5 mL of concentrated HCl was added. The mixture was stirred overnight at room temperature. The mixture was basified with 2M NaOH, and extracted twice with DCM. The combined organic layers were dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography (DCM/MeOH 99:1) to give 240 mg (40%) of 4-Amino-3-chloro-N-[(4,4-dimethyl-4,5-dihydro-pyrazol-1-yl)-ethylamino-methylene]-benzenesulfonamide as an orange oil. 1H NMR (400 MHz, CDCl3) δ 1.17 (t, J=7 Hz, 3H), 1.21 (s, 6H), 3.43-3.52 (m, 2H), 3.75 (br.s., 2H), 4.37 (br.s., 2H), 6.73 (s, 1H), 6.76 (d, J=8 Hz, 1H), 6.86 (br.s., 1H), 7.62 (dd, J=2 and 8 Hz, 1H), 7.83 (d, J=2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13](S(C)=O)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[NH2:25][C:26]1[CH:38]=[CH:37][C:29]([C:30]([O:32]C(C)(C)C)=[O:31])=[CH:28][CH:27]=1.[ClH:39]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13]([NH:25][C:26]3[CH:38]=[CH:37][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=3)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[ClH:39]
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: Cl
Product: O=C(O)c1ccc(Nc2ncc3c(=O)n(-c4ccccc4Cl)c4nccn4c3n2)cc1

Procedure:
A mixture of Example 1E (200.0 mg, 0.556 mmol), tert-butyl 4-aminobenzoate (129 mg, 0.667 mmol), and concentrated HCl (0.08 mL, 2.63 mmol) was heated at 160° C. for 30 minutes in a Biotage microwave reactor. The solvent was decanted. The remaining residue was treated with water, sonicated, filtered, washed with water, and oven-dried to provide the title compound as an HCl salt.
Reaction SMILES: [Cl:1][C:2]1[C:7](OC2C=CC=CC=2)=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=[CH:4][C:3]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH2:32]>O1CCOCC1>[Cl:1][C:2]1[C:3]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:4][CH:5]=[C:6]([N+:15]([O-:17])=[O:16])[C:7]=1[NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH2:32]
Reactant: NCCCCCCN
Reactant: O=[N+]([O-])c1ccc(Oc2ccccc2)c(Cl)c1Oc1ccccc1
Solvent: C1COCCO1
Product: NCCCCCCNc1c([N+](=O)[O-])ccc(Oc2ccccc2)c1Cl
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 17.5 gm of 2-chloro-4-nitro-1,3-diphenoxy-benzene, 30 ml of dioxane and 9 gm of 1,6-diaminohexane was stirred for 4 hours at 50° C. Thereafter, the dioxane was distilled off, the residue was taken up in chloroform, the resulting solution was washed first with dilute sodium hydroxide and then with dilute hydrochloric acid, dried with sodium sulfate, and the chloroform was distilled off. The residue was dissolved in diethyl ether, gaseous hydrogen chloride was passed through the resulting solution, the precipitate formed thereby was collected by suction filtration, and the semi-solid filter cake was stirred with a mixture of chloroform and an aqueous sodium carbonate solution. The organic phase was separated, dried with sodium sulfate, and the chloroform was distilled off, leaving 12.5 gm (69% of theory) of the title compound as a viscous yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][C:17]([CH3:20])=[C:18](I)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].CC1(C)C(C)(C)OB([C:29]2[CH:30]=[C:31]([C:36]([F:39])([F:38])[F:37])[C:32]([NH2:35])=[N:33][CH:34]=2)O1.C(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.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]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][C:17]([CH3:20])=[C:18]([C:29]4[CH:30]=[C:31]([C:36]([F:39])([F:38])[F:37])[C:32]([NH2:35])=[N:33][CH:34]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Reactant: COc1ccc(-c2nn3c(I)c(C)nc3s2)cc1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Solvent: O
Product: COc1ccc(-c2nn3c(-c4cnc(N)c(C(F)(F)F)c4)c(C)nc3s2)cc1OC
Temperature: 25 °C
Yield: 51.5 %

Procedure:
A mixture of 2-(3,4-dimethoxy-phenyl)-5-iodo-6-methyl-imidazo[2,1-b][1,3,4]thiadiazole (0.125 g, 0.312 mmol, 1 eq), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (0.119 g, 0.414 mmol, 1.33 eq), Pd(dppf)Cl2.DCM (0.008 g, 0.009 mmol, 0.03 eq) and cesium carbonate (0.305 g, 0.935 mmol, 3 eq) in DME (4 mL) and water (0.1 mL) was heated in the microwave oven (45 min, 130° C.), cooled to RT, diluted with water, extracted with EtOAc and washed with brine. The organic layers were dried (MgSO4), filtered and concentrated, and the residue was purified by silica gel chromatography (0-100% EtOAc in hexane). Product fractions were concentrated and triturated with Et2O, the solid was filtered off and dried to give the desired product (solid, 0.070 g, 52%). HPLC-MS: (50-100% B in 8 min, 0.8 mL/min): tR=1.11 min, [M+H]+ m/z 436.0. 1H NMR (300 MHz, CDCl3) δ/ppm 8.62 (d, J=1.6, 1H), 8.22 (d, J=1.6, 0H), 7.44 (d, J=2.2, 1H), 7.39 (dd, J=8.2, 2.2, 1H), 6.96 (d, J=8.5, 1H), 5.11 (s, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 2.53 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][C:7](=O)[N:8]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=1[N+:19]([O-])=O)[CH3:9].[ClH:24]>[Pd].CO>[ClH:24].[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][C:7]1[N:8]([CH3:9])[C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=2[N:19]=1
Reactant: COC(=O)CCCC(=O)N(C)c1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)CCCc1nc2cc(N)ccc2n1C
Reaction time: 6.5 h
Yield: 99 %

Procedure:
A two liter Buchi reactor was charged with 42.7 g (131.4 mmol, 1.0 equiv.) of 4-[(2,4-dinitro-phenyl)-methyl-carbamoyl]-butyric acid methyl ester, 20 g of 10% palladium on carbon (4.7% weight ratio palladium vs. starting material), and 650 mL of methanol at ambient temperature. The resulting mixture was subjected to hydrogenation at 40 psi overnight, about 18 hours. HPLC indicated that the reaction was complete in about 6-7 hours (HPLC Method B). The reaction mixture was filtered through a thin layer of Celite® 540. To the filtrate was added 11 mL of concentrated hydrochloric acid (1.0 equiv.). The resulting mixture was stirred under reflux for 3.5 hours. Approximately a half amount of solvent was removed under reduced pressure. Tert-butyl methyl ether (MTBE, 900 mL) was added with vigorous stirring. The precipitate was collected by filtration and washed with a mixture of MeOH-MTBE (1:10). The product was dried in an over at 60° C. overnight under vacuum to afford a tan solid (36.8 g, 99% yield) with a purity of 99 Area % by HPLC analysis (HPLC Method B).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([CH3:8])=[N:6][CH:7]=1.[CH2:12]([N:15]([CH3:17])[CH3:16])[C:13]#[CH:14]>C(NCC)C.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+].[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:16][N:15]([CH3:17])[CH2:12][C:13]#[C:14][C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: C#CCN(C)C
Reactant: Cc1ncc(Br)cc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCNCC
Product: Cc1ncc(C#CCN(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.9 %

Procedure:
To a mixture of 5-bromo-2-methyl-3-nitropyridine (6.50 g, 30.0 mmol), copper iodide (280 mg, 1.5 mmol) and bis(triphenylphosphine)palladium(II) chloride (520 mg, 0.75 mmol) in diethylamine (17 mL) was added propargyl(dimethylamine) (4.04 mL, 37.5 mmol). The reaction mixture was allowed to stir for 15 h at rt. The resulting mixture was diluted with EtOAc (200 mL) and 1M aqueous Na2CO3 (150 mL). After stirring for 30 min, the organic solution was separated and the aqueous solution was extracted with EtOAc (2×100 mL). The organic solutions were combined, washed with water and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give N,N-dimethyl-3-(6-methyl-5-nitropyridin-3-yl)prop-2-yn-1-amine (5.98 g, 91%) as a dark oil. LCMS (FA): Rt=0.77 min, m/z=220.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:9](=[O:28])[C@:10]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][CH2:13][C:12](=[O:23])[N:11]3[CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:5]2=[CH:4][CH:3]=1.[Li+].[CH3:38][CH:39]([N-]C(C)C)[CH3:40].C(Br)C=C>C1COCC1>[CH2:40]([C@@H:13]1[C:12](=[O:23])[N:11]([CH2:24][CH:25]2[CH2:26][CH2:27]2)[C@:10]2([C:5]3[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:8]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:9]2=[O:28])[C@@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[CH2:14]1)[CH:39]=[CH2:38]
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@@]2(c3ccc(Cl)cc31)[C@@H](c1cccc(Cl)c1)CCC(=O)N2CC1CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@]2(C(=O)N(COCC[Si](C)(C)C)c3cc(Cl)ccc32)N(CC2CC2)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of (rac) (2′S,3′R)-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)-1′-((2-(trimethylsilyl) ethoxy)methyl)spiro[indoline-3,2′-piperidine]-2,6′-dione (Example 62, Step I) (97 mg, 0.178 mmol) in THF (1 mL) at −78° C. under Ar was added freshly prepared LDA (1.0 M in THF) (178 μL, 0.178 mmol). The reaction color turned yellowish orange. The reaction was stirred at −78° C. for 30 min then distilled allyl bromide (15.39 μL, 0.178 mmol) was added. The reaction was stirred at −78° C. for 10 min then warmed to 0° C. The reaction was quenched with sat. NH4Cl and warmed to room temperature. The mixture was diluted with EtOAc and the layers were separated. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0 to 25% EtOAc in hexanes) to give the title compound.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[C:16]([O:20][C:21]1[CH:26]=[N:25][CH:24]=[C:23]([Cl:27])[N:22]=1)([CH3:19])([CH3:18])[CH3:17].CN(C)[CH:30]=[O:31]>O1CCCC1.O.C(O)(=O)C.C1(C)C=CC=CC=1>[C:16]([O:20][C:21]1[C:26]([CH:30]=[O:31])=[N:25][CH:24]=[C:23]([Cl:27])[N:22]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)Oc1cncc(Cl)n1
Reactant: CN(C)C=O
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)Oc1nc(Cl)cnc1C=O
Temperature: -30 °C
Reaction time: 0.08 h

Procedure:
After dissolving 11.4 ml of 2,2,6,6-tetramethylpiperidine in 100 ml of tetrahydrofuran, the solution was cooled to −30° C. Next, 24.1 ml of n-butyllithium (2.6 M, n-hexane solution) was added dropwise under a nitrogen atmosphere. After stirring for 5 minutes, the mixture was cooled on ice and stirred for an additional 20 minutes. It was then cooled to −78° C., and a solution of 9.00 g of 2-tert-butoxy-6-chloropyrazine in tetrahydrofuran (10 ml) was added dropwise at below −70° C. The mixture was then stirred for 30 minutes, and 6 ml of N,N-dimethylformamide was added dropwise at below −65° C. After 10 minutes, 50 ml of toluene was added to the reaction solution at below −60° C., and after 2 minutes, a tetrahydrofuran solution (5 ml) containing 2 ml of water was added at below −65° C. After an additional 5 minutes, 60 ml of 50% aqueous acetic acid was added at once, and after 5 minutes, 100 ml of water was added and the temperature was raised to room temperature. The reaction solution was extracted with ethyl acetate, washed with water, a 1N sodium hydroxide solution, water and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 9.39 g of crude 3-tert-butoxy-5-chloropyrazine-2-carboxaldehyde.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:7]2.[C:16](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:16][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:7]2
Reactant: COC(=O)c1ccc2cccc(O)c2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1ccc2cccc(OC)c2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100.6 %

Procedure:
Methyl 8-hydroxyquinoline-2-carboxylate (1.6 g), acetone (15 ml), potassium carbonate (1.3 g) and iodomethane (0.6 ml) were combined and stirred at room temperature for 48 h. The solvents were removed in vacuo and the resulting white residue suspended in water (25 ml) which was extracted with ethyl acetate (3×25 ml). The combined organic layers were dried (magnesium sulphate) and the solvents removed in vacuo to give the title compound as a white solid (1.72 g).
Reaction SMILES: [O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([OH:18])=O)[C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C([N:22](C(C)C)CC)(C)C.[OH-].[NH4+]>CN(C)C=O>[O:1]=[C:2]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH2:22])=[O:18])[C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: O=C(O)c1cccc2c(=O)c3ccccc3oc12
Reactant: CCN(C(C)C)C(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)c1cccc2c(=O)c3ccccc3oc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
To a solution of 9-oxo-9H-xanthene-4-carboxylic acid 5j (1.84 g, 7.66 mmol) in dimethylformamide (20 mL) was added N,N-diisopropyl-N-ethylamine (1.74 mmol, 9.96 mmol) and O(benzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate (2.9 g, 7.66 mmol). The mixture was stirred for 30 min at rt, and ammonium hydroxide (2 mL) was added. The mixture was stirred for 3 h, poured onto ice, and the solid was collected via filtration. The solid was washed with water and air-dried to yield 1.78 g (97.2% of title compound 6j.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1.CC([O-])(C)C.[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>O1CCOCC1>[C:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([NH:1][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:7][CH2:6]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccn2)CC1
Temperature: 90 °C

Procedure:
A mixture of 4-Amino-1-Boc-piperidine (2.0 g, 9.7 mmol), 2-Bromo-pyridine (1.93 mL, 19.4 mmol), NaOtBu (2.7 g, 27.1 mmol), 2-Dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (472 mg, 1.16 mmol) and Tris(dibenzylideneacetone)dipalladium Chloroforme Complex (620 mg, 0.58 mmol) in dioxane (10 mL) is heated to 90° C. After completion, the reaction mixture is quenched by H2O, DCM is added and the organic layer is washed with brine, dried over MgSO4 and evaporated in vacuo. Silica gel flash chromatography of the residue affords the title compound as a white powder; ES-MS: M+H=278.3: AtRet=4.75.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([C:5]1[CH:6]=[C:7]([CH:12]2[CH:21]([C:22]3[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=3)[C:20](=O)[C:19]3[C:18]([C:29]([O:31]CC)=O)=[CH:17][CH:16]=[CH:15][C:14]=3[NH:13]2)[CH:8]=[CH:9][C:10]=1[F:11])=[O:4].O.[NH2:36][NH2:37]>CO>[F:11][C:10]1[CH:9]=[CH:8][C:7]([CH:12]2[NH:13][C:14]3[C:19]4[C:20](=[N:36][NH:37][C:29](=[O:31])[C:18]=4[CH:17]=[CH:16][CH:15]=3)[CH:21]2[C:22]2[N:23]([CH3:27])[CH:24]=[CH:25][N:26]=2)=[CH:6][C:5]=1[C:3]([N:2]([CH3:1])[CH3:34])=[O:4]
Reactant: NN
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nccn1C)C(c1ccc(F)c(C(=O)N(C)C)c1)N2
Solvent: O
Solvent: CO
Product: CN(C)C(=O)c1cc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2nccn2C)ccc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
A mixture of compound ethyl 2-(3-(dimethylcarbamoyl)-4-fluorophenyl)-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (130 mg) in hydrazine monohydrate (85%, 2 mL) and methanol (5 mL) was stirred at room temperature for 4 h. The resulting mixture was filtered and washed with water (20 ml) and methanol (5 ml) to obtain a white solid. The solid was dried in vacuum at 50° C. to obtain the title compound (30.0 mg, yield 30%). 1H-NMR (400 MHz, DMSO-d) δ (ppm): 2.72 (s, 3H), 2.97 (s, 3H), 3.43 (s, 3H), 4.67-4.70 (d, J=10.8 Hz, 1H), 4.95-4.97 (d, J=10.8 Hz, 1H), 6.72-6.73 (d, J=1.2 Hz, 1H), 6.89-6.89 (d, J=0.8 Hz, 1H), 7.15-7.23 (m, 2H), 7.34-7.41 (m, 3H), 7.48-7.49 (m, 1H), 7.56-7.60 (t, J=8 Hz, 1H), 12.17 (s, 1H); LC-MS (ESI) m/z: 433 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:5]#[N:6].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:5]#[N:6])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(-c2ccccc2)c(O)c1
Product: N#Cc1ccc(-c2ccccc2)c(OCc2ccccc2)c1

Procedure:
The title compound was prepared in a similar manner to that described in Reference Example 20 using 3-hydroxy-4-phenylbenzonitrile instead of tert-butyl N-(3′-hydroxybiphenyl-4-ylmethyl)carbamate and benzyl bromide instead of 1-bromopropane.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]1[O:8][C@H:7]1[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]C)=O.[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28]>>[CH2:5]([CH:6]1[O:8][CH:7]1[CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH:11]=[CH:10][CH2:9][CH:7]1[CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[O:8]1)=[O:21])[CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: NCCCCN
Reactant: CCCCC[C@H]1O[C@H]1C/C=C\CCCCCCCC(=O)OC
Product: CCCCCC1OC1CC=CCCCCCCCC(=O)NCCCCNC(=O)CCCCCCCC=CCC1OC1CCCCC

Procedure:
Precursor 8 was prepared from methyl vernolate and 1,4-diaminobutane according to the procedure described in Example 1(f) and shown in Scheme 11.