Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH2:6].C(N(CC)CC)C.S=[C:20]1[CH2:24][S:23][C:22](=[O:25])[NH:21]1>C(O)C>[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH:6][C:20]1[CH2:24][S:23][C:22](=[O:25])[N:21]=1
Reactant: C[C@@H](O)[C@H](N)C(=O)N(C)C
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C[C@@H](O)[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the crude product (12.0 g) containing N,N-dimethyl-L-threoninamide hydrochloride obtained in B) and triethylamine (20.0 g) in ethanol (150 mL) was added 4-thioxothiazolidin-2-one (8.8 g) at room temperature. The reaction mixture was stirred at room temperature for 4 hr. The solvent was evaporated under reduced pressure, the obtained solid was suspended in THF, and the suspension was filtered through celite pad and silica gel pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/petroleum ether) to give the title compound (3.0 g).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:26](/[CH:27]=[CH:28]/[C:29](=O)[CH3:30])=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1.C1(C)C=CC(S([NH:41][NH2:42])(=O)=O)=CC=1.CCO.C[O-].[Na+]>C(O)=O>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:26]([C:27]3[NH:42][N:41]=[C:29]([CH3:30])[CH:28]=3)=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:18][CH:19]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1
Reactant: CC(=O)/C=C/c1cc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cnc1N1CC[C@@H](O)C1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CCO
Product: Cc1cc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)[nH]n1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
(R,E)-6-(3-Hydroxypyrrolidin-1-yl)-5-(3-oxobut-1-en-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 3.1, 50 mg, 0.091 mmol) and toluene-4-sulfonic acid hydrazide (34.5 mg, 0.181 mmol) and EtOH (302 μL) were added to a MW vial, which was sealed and stirred at 80° C. for 1.5 h. The mixture was cooled to RT, NaOMe (17.15 mg, 0.318 mmol) was added and the RM was stirred at 80° C. for 48 h. Aq. The RM was acidified with aq. formic acid, filtered through a 0.2 μM PTFE membrane filter and purified by preparative HPLC (Condition 9, from 20% to 50% in 18 min) to yield the title compound as a white solid. UPLC-MS (Condition 1) tR=2.08 min, m/z=448.0 [M+H]+, m/z=446.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.68-1.79 (m, 1H) 1.78-1.90 (m, 1H) 2.29 (br. s, 3H) 2.98 (d, J=11.74 Hz, 1H) 3.25-3.37 (m, 2H) 3.40-3.53 (m, 1H) 4.21 (br. s, 1H) 4.83 (br. s, 1H) 6.13 (s, 1H) 7.33 (d, J=8.31 Hz, 2H) 7.86 (d, 2H) 8.01 (br. s, 1H) 8.71 (br. s, 1H) 10.15 (s, 1H) 12.57 (br. s, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][NH2:11])[CH:6]=[CH:7][C:8]=1[Cl:9].C([O-])(=O)C.[Na+].CN([CH:20]=[C:21]1[C:26](=[O:27])[CH2:25][CH2:24][CH2:23][C:22]1=O)C>CCCCO.C(O)(=O)C>[Cl:2][C:3]1[CH:4]=[C:5]([N:10]2[C:22]3[CH2:23][CH2:24][CH2:25][C:26](=[O:27])[C:21]=3[CH:20]=[N:11]2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: NNc1ccc(Cl)c(Cl)c1
Reactant: CN(C)C=C1C(=O)CCCC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCCCO
Product: O=C1CCCc2c1cnn2-c1ccc(Cl)c(Cl)c1
Yield: 55.9 %

Procedure:
A mixture of 1-(3,4-dichlorophenyl)hydrazine hydrochloride (6.78 g, 31.8 mmol) and anhydrous sodium acetate (2.60 g, 31.8 mmol) in n-BuOH (20 mL) is slowly added to a solution of 2-((dimethylamino)methylene)cyclohexane-1,3-dione (5.32 g, 31.8 mmol) in n-BuOH (100 mL) and acetic acid (5 mL). The resulting mixture is heated to reflux during 2 hours, effecting follow-up of the reaction by TLC. The solvent is evaporated at reduced pressure, the residue is diluted in AcOEt and washed with H2O. The solvent is next evaporated, and the crude is purified by silica-gel chromatography, to obtain 1-(3,4-dichlorophenyl)-1,5,6,7-tetrahydro-4H-indazol-4-one (5.0 g, 17.79 mmol, 56%, orange solid).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[N:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH:26]([CH2:36]O)[C:12]2=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]2[C:22]([O:24][CH3:25])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:58]>C(#N)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[N:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH:26]([CH2:36][Cl:58])[C:12]2=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]2[C:22]([O:24][CH3:25])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: COC(=O)c1c(C(F)(F)F)[nH]c2c(OCc3ccccc3)cc3c(c12)C(CO)CN3C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: COC(=O)c1c(C(F)(F)F)[nH]c2c(OCc3ccccc3)cc3c(c12)C(CCl)CN3C(=O)OC(C)(C)C
Reaction time: 5 h

Procedure:
104.1 Milligrams (0.2 mmol) of methyl 5-benzyloxy-3-t-butoxycarbonyl-1-hydroxymethyl-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-8-carboxylate, and 104.9 mg (0.4 mmol) of triphenylphosphine were suspended in 1 ml of anhydrous acetonitrile. Thereto 115.3 μl (1.2 mmol) of carbon tetrachloride was added dropwise. The mixture was stirred for 5 hours under atmosphere of argon. After removal of the solvent, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain methyl 5-benzyloxy-3-t-butoxycarbonyl-1-chloromethyl-7-trifluoromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-8-carboxylate in a yield of 106.7 mg (99%).
Reaction SMILES: [Br:1][C:2]1[C:3](I)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH2:6][CH2:5]2.F[C:15](OB([O-])[O-])(F)F.[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].C1COCC1>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.O>[Br:1][C:2]1[C:3]([CH3:15])=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH2:6][CH2:5]2
Reactant: O=C1OCCc2c1ccc(Br)c2I
Reactant: [O-]B([O-])OC(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Cc1c(Br)ccc2c1CCOC2=O
Temperature: 140 °C

Procedure:
To a 20 mL microwave tube was added 6-Bromo-5-iodo-3,4-dihydro-1H-isochromen-1-one (300 mg, 0.85 mmol), Potassium Trifluoromethylborate (114 mg, 0.94 mmol), PdCl2(dppf)-CH2Cl2 Adduct (69 mg, 0.085 mmol), cesium carbonate (830 mg, 2.6 mmol), and a stir bar. The mixture was sealed and THF (10 mL) and water (1 mL) were added with a syringe. The mixture was purged three times with nitrogen, and then heated to 140° C. for 30 minutes. TLC showed formation of the desired product. The reaction was diluted with EtOAc, washed with water and brine, dried over sodium sulfate, adsorbed onto silica gel, and purified by MPLC (Hex/EtOAc gradient) to furnish the product. LC-MS (IE, m/z): 241 [M+1]+;
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[N:9]([S:18]([C:21]3[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[CH:11][C:3]=12.[CH3:28][N:29](C)C=O>O.C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[Cl:8][C:7]1[CH:6]=[N:5][C:4]2[N:9]([S:18]([C:21]3[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=3)(=[O:20])=[O:19])[C:10]([C:12]3[CH:13]=[N:14][N:15]([CH3:17])[CH:16]=3)=[CH:11][C:3]=2[C:2]=1[C:28]#[N:29]
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(Cl)c(Cl)cnc32)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(-c3cnn(C)c3)cc3c(C#N)c(Cl)cnc32)cc1
Temperature: 160 °C

Procedure:
A solution in a microwave vial of 4,5-dichloro-2-(1-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (Example 113C) (300 mg, 0.712 mmol) in anhydrous N,N-dimethylformamide (4 mL) was degassed by nitrogen sparge for about 20 minutes. The solution was treated with zinc cyanide (167 mg, 1.424 mmol) and tetrakis(triphenylphosphine)palladium (82 mg, 0.071 mmol). The reaction was degassed and back-filled with nitrogen, and heated in a Biotage Initiator microwave for 60 minutes at 160° C. The reaction was treated with additional zinc cyanide (83 mg, 0.712 mmol) and tetrakis(triphenylphosphine)palladium (41 mg, 0.035 mmol), and heated to 160° C. for 30 minutes by microwave irradiation. The reaction was diluted with water and ethyl acetate, and the layers were separated. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 25 to 40% ethyl acetate in hexanes, to provide the title compound. MS ESI(+) m/z 412.4 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][N:5]1[C:21](=[O:22])[C:20]2[C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:23][CH3:24])[CH:17]=4)[NH:12][C:11]=3[CH:10]=[CH:9][C:8]=2[C:6]1=[O:7].[H-].[Na+].S(OC)(O[CH3:32])(=O)=O>CN(C)C=O>[CH3:1][N:2]([CH3:25])[CH2:3][CH2:4][N:5]1[C:21](=[O:22])[C:20]2[C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:23][CH3:24])[CH:17]=4)[N:12]([CH3:32])[C:11]=3[CH:10]=[CH:9][C:8]=2[C:6]1=[O:7]
Reactant: COc1ccc2[nH]c3ccc4c(c3c2c1)C(=O)N(CCN(C)C)C4=O
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c1c3c(ccc1n2C)C(=O)N(CCN(C)C)C3=O
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 51.3 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 380 mg of N-(2-dimethylaminoethyl)-6-methoxycarbazole-3,4-dicarboximide. Thereto was added 45 mg of 60% sodium hydride. The mixture was stirred at 40° C. for 20 minutes and then cooled to 20° C. Thereto was added 140 mg of dimethyl sulfate, and the resulting mixture was stirred at the same temperature for 2 hours. The solvent was removed by distillation under reduced pressure. The residue was mixed with 50 ml of ethyl acetate and 25 ml of water to dissolve the residue. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from n-propanol to obtain 200 mg (yield: 50%) of N-(2-dimethylaminoethyl)-6-methoxy-9-methylcarbazole-3,4-dicarboximide as yellow crystals.
Reaction SMILES: [C:1]([N:4]1[C@H:12]([C:13]([O-])=[O:14])[CH2:11][C:10](=[O:16])[C:9]2[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=2[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:6](=[O:30])[C@H:5]1[CH2:31][C:32]12[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:40][CH:34]([CH2:35]3)[CH2:33]1)[CH2:39]2)(=[O:3])[CH3:2].C([N:45]1[C@H:53]([C:54]([O-:56])=[O:55])CC(=O)C2C=CC=CC=2N(CC2C=CC=CC=2)C(=O)[C@H]1CC12CC3CC(CC(C3)C1)C2)(=O)C>>[C:1]([N:4]1[C@H:12]([C:13]([NH:45][CH2:53][C:54]([OH:56])=[O:55])=[O:14])[CH2:11][C:10](=[O:16])[C:9]2[CH:17]=[CH:18][CH:19]=[CH:20][C:8]=2[N:7]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[C:6](=[O:30])[C@H:5]1[CH2:31][C:32]12[CH2:39][CH:38]3[CH2:40][CH:34]([CH2:35][CH:36]([CH2:37]3)[CH2:41]1)[CH2:33]2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1[C@H](CC23CC4CC(CC(C4)C2)C3)C(=O)N(Cc2ccccc2)c2ccccc2C(=O)C[C@H]1C(=O)[O-]
Reactant: COc1ccc(CN2C(=O)[C@@H](CC34CC5CC(CC(C5)C3)C4)N(C(C)=O)[C@H](C(=O)[O-])CC(=O)c3ccccc32)cc1
Product: COc1ccc(CN2C(=O)[C@@H](CC34CC5CC(CC(C5)C3)C4)N(C(C)=O)[C@H](C(=O)NCC(=O)O)CC(=O)c3ccccc32)cc1

Procedure:
The compound was prepared by an identical route to that used to prepare example 22 except that (3R,5S)-4-acetyl-3-(1-adamantyl)methyl-1-(4-methoxybenzyl)-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine-5-carboxylate was used in step a in place of (3R,5S)-4-acetyl-3-(1-adamantyl)methyl-1-benzyl-2,7-dioxo-2,3,4,5,6,7-hexahydro-1H-1,4-benzodiazonine-5-carboxylate
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([Br:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[CH3:14][S:15]([O-:17])=[O:16].[Na+]>CN(C=O)C>[Br:13][C:11]1[CH:12]=[C:3]([CH2:2][S:15]([CH3:14])(=[O:17])=[O:16])[CH:4]=[C:5]2[C:10]=1[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: BrCc1cc(Br)c2ncccc2c1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1cc(Br)c2ncccc2c1
Temperature: 21 °C
Reaction time: 8 h

Procedure:
To a solution of 6-bromomethyl-8-bromoquinoline (60 g, 200 mmol, described in International Patent Publication WO 94/22852) in DMF (500 mL) was added sodium methanesulfinate (27.6 g, 270 mmol). After stirring overnight at 21° C., the mixture was quenched with H2O (2L), stirred for 1 h, isolated by filtration, and washed with Et2O to yield the 8-Bromo-6-methanesulfonylmethyl-quinoline as a white solid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C[C:7](C)=[O:8].[CH3:10][N:11]([CH3:21])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1.C([O-])(=O)C.[Na+]>CN(C)C=O>[CH3:10][N:11]([CH3:21])[C:12]1[CH:17]=[CH:16][C:15]([CH:7]=[O:8])=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: CN(C)c1cccc([N+](=O)[O-])c1
Reactant: CC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)c1ccc(C=O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
In a nitrogen atmosphere, 51 g (0.33 mol) of phosphorus oxychloride (manufactured by Wako Pure Chemical Industries, Ltd.) were added dropwise to 88 ml of cooled dimethylformaldehyde (DMF). The dropping rate was adjusted so as to keep a temperature of 2° C. to 4° C. at the time of dropping, and stirring was further continued for 30 minutes at 2° C. after the completion of dropping. To this mixture, a 70-ml dimethylformamide solution of 54.8 g (0.33 mol) of N,N-dimethyl-3-nitroaniline (manufactured by Tokyo Kasei Kogyo Co., Ltd.) was added dropwise such that the reaction temperature does not exceed 5° C.; and the mixture was stirred for 2 hours as it was. Thereafter, temperature was gradually raised, and the mixture was stirred at 60° C. for one night. After being cooled to room temperature, the reaction liquid was poured into vigorously stirred 500 ml of ice water. The pH of the mixture was adjusted to about 8 with sodium acetate being added thereto, and the precipitated crystal was filtered out and dried, whereby 50.2 g of a crude product were obtained. This product was recrystallized from acetone/normal hexane, whereby 21 g of the aimed product were obtained (yield: 33%).
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.[OH:14][CH:15]1[CH2:20][C:19]([CH3:22])([CH3:21])[N:18]([OH:23])[C:17]([CH3:25])([CH3:24])[CH2:16]1.I[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>ClC1C=CC=CC=1>[OH:14][CH:15]1[CH2:20][C:19]([CH3:21])([CH3:22])[N:18]([O:23][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:17]([CH3:25])([CH3:24])[CH2:16]1
Reactant: CCCCCCCCI
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Clc1ccccc1
Product: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C

Procedure:
The title compound is prepared by the dropwise addition of tributyltin hydride to a solution of 4-hydroxy-1-oxyl-2,2,6,6-tetramethylpiperidine and 1-iodooctane in chlorobenzene under a nitrogen atmosphere.
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[N+:13]([CH2:16][CH3:17])([O-:15])=[O:14].C(N)CCC>C(O)C>[CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[C:16]([N+:13]([O-:15])=[O:14])[CH3:17])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC[N+](=O)[O-]
Reactant: CCCCc1ccc(C=O)cc1
Solvent: CCO
Solvent: CCCCN
Product: CCCCc1ccc(C=C(C)[N+](=O)[O-])cc1

Procedure:
A stirred solution of 4-butylbenzaldehyde (13.5 g), nitroethane (9.0 ml) and butylamine (1.6 ml) in ethanol (20 ml) was heated under reflux for 6 hours and evaporated. The residue was distilled under vacuum to give 1-(4-butylphenyl)-2-nitropropene (bp 124°-125° C./0.15 mm).
Reaction SMILES: B(Br)(Br)Br.CC(C)(C)C([NH:9][NH:10][C:11]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][C:17]([O:25]C)=[C:18]([O:23]C)[CH:19]=2)[CH:14]=1)=[O:12])=O.O.CCOCC>ClCCl>[OH:23][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][C:17]=1[OH:25])[CH:14]=[C:13]([C:11]([NH:10][NH2:9])=[O:12])[CH:22]=[CH:21]2
Reactant: COc1cc2ccc(C(=O)NNC(=O)C(C)(C)C)cc2cc1OC
Agent: BrB(Br)Br
Solvent: CCOCC
Solvent: O
Solvent: ClCCl
Product: NNC(=O)c1ccc2cc(O)c(O)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
At -78° C., 3.5 g (14.2 mmol) of boron tribromide (0.5M in dichloromethane) was added dropwise to a solution of 1.59 g (4.7 mmol) of 6,7-dimethoxy-2-naphthalenecarboxylic acid, 2-(2,2-dimethyl-1-oxopropyl)hydrazide in 40 ml of dry dichloromethane. The solution was allowed to warm to room temperature and was stirred overnight. 30 ml of water and 115 ml of ether were added and the resulting precipitate filtered, washed and dried in vacuo to give 0.42 g of the title compound as its hydrobromide salt. The salt was dissolved in water and treated with one equivalent of sodium bicarbonate solution to give, after precipitation and collection by filtration, 0.22 g of the desired title compound.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([N:10]2[CH:14]=[N:13][N:12]=[C:11]2[S:15]([CH3:18])(=[O:17])=[O:16])[CH:7]=[CH:6][C:5]=1[O:19][CH3:20].[OH-].[Li+].O.Cl>O1CCCC1>[CH3:18][S:15]([C:11]1[N:10]([C:8]2[CH:7]=[CH:6][C:5]([O:19][CH3:20])=[C:4]([CH:9]=2)[C:3]([OH:21])=[O:2])[CH:14]=[N:13][N:12]=1)(=[O:16])=[O:17]
Reactant: COC(=O)c1cc(-n2cnnc2S(C)(=O)=O)ccc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-n2cnnc2S(C)(=O)=O)cc1C(=O)O
Yield: 83 %

Procedure:
Stir a mixture of 5-(3-methanesulfonyl-[1,2,4]triazol-4-yl)-2-methoxy-benzoic acid methyl ester (1.0 g, 3.2 mmol), lithium hydroxide (0.042 g, 3.6 mmol), and 25% water in tetrahydrofuran (30 mL) at reflux overnight. Cool and add 1N hydrochloric acid (3.6 mL) dropwise via syringe. Concentrate to remove the tetrahydrofuran and collect the precipitate by vacuum filtration. Wash the filter cake twice with water and hexane, and dry in vacuo overnight to give 0.79 g of 5-(3-methanesulfonyl-[1,2,4]triazol-4-yl)-2-methoxy-benzoic acid as a solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.IC.[C:13](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([O:9][CH3:13])=[C:4]([CH3:10])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Br)nc(C)c1O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(C)cc(Br)nc1C
Temperature: 25 °C
Yield: 84.8 %

Procedure:
A mixture of 6-bromo-2,4-dimethyl-3-hydroxypyridine (8.7 g, 43.1 mmol), iodomethane (4.0 mL, 64.6 mmol) and potassium carbonate (11.9 g, 86.1 mmol) in acetone (250 mL) was heated at reflux temperature for 3 hours. The reaction mixture was then cooled to room temperature and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography using 20% ethyl acetate in hexane to afford 7.9 g (85%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[CH:17][C:18]([F:23])=[C:19]([CH:22]=1)[C:20]#[N:21].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:23][C:18]1[CH:17]=[CH:16][C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])=[CH:22][C:19]=1[C:20]#[N:21]
Reactant: N#Cc1cc(Br)ccc1F
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc(F)c(C#N)c2)C1=O
Yield: 65.8 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 100 mg, 0.5643 mmol) was reacted with 5-bromo-2-fluoro-benzonitrile (124 mg, 0.6199 mmol), 1,4-dioxane (20 mL), copper iodide (10.7 mg, 0.056 mmol), trans-1,2-diamino cyclohexane (19.4 mg, 0.169 mmol) and potassium phosphate (300 mg, 1.413 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 110 mg of the product (65.7% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]([CH:19]([CH:21]2[CH2:23][CH2:22]2)O)=[C:17]2[C:12]([C:13](=[O:35])[C:14]([CH3:34])=[C:15]([CH:24]3[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31][CH3:32])[CH2:26][CH2:25]3)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([O:8][C:9]1[C:18]([CH2:19][CH:21]2[CH2:23][CH2:22]2)=[C:17]2[C:12]([C:13](=[O:35])[C:14]([CH3:34])=[C:15]([CH:24]3[CH2:29][CH2:28][N:27]([C:30](=[O:33])[CH2:31][CH3:32])[CH2:26][CH2:25]3)[O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(=O)N1CCC(c2oc3c(C(O)C4CC4)c(OCc4ccccc4)ccc3c(=O)c2C)CC1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N1CCC(c2oc3c(CC4CC4)c(OCc4ccccc4)ccc3c(=O)c2C)CC1
Reaction time: 0.25 h
Yield: 64.2 %

Procedure:
To a solution of 7-(benzyloxy)-8-[cyclopropyl(hydroxy)methyl]-3-methyl-2-(1-propanoylpiperidin-4-yl)-4H-chromen-4-one (100 mg, 0.21 mmol) obtained in Example 34-3 in dichloromethane (2 mL), triethylsilane (336 μL, 2.10 mmol) was added dropwise under cooling with ice. Then, trifluoroacetic acid (79 μL, 1.05 mmol) was added dropwise thereto, and the mixture was stirred for 15 minutes under cooling with ice and then at room temperature for 1 hour. Trifluoroacetic acid (79 μL, 1.05 mmol) was added dropwise to the reaction solution, and the mixture was further stirred at room temperature for 2 hours. The reaction solution was cooled with ice, and then a saturated aqueous solution of sodium bicarbonate (30 mL) was added dropwise thereto, followed by extraction with dichloromethane. The organic layer was dried over sodium sulfate. The desiccant was filtered off, and then the filtrate was concentrated under reduced pressure. The obtained residue was purified by NH silica gel column chromatography (n-hexane/ethyl acetate=98/2→0/100). The title compound (62 mg, yield: 64%) was obtained as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[OH:11])[CH3:2].Cl[CH2:13][CH2:14][CH2:15][O:16][CH3:17]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH2:13][CH2:14][CH2:15][O:16][CH3:17])[CH3:2]
Reactant: CCOc1ccc(C)cc1O
Reactant: COCCCCl
Product: CCOc1ccc(C)cc1OCCCOC

Procedure:
Analogously to Method F, 5.05 g of 2-ethoxy-5-methylphenol and 4.03 g of 1-chloro-3-methoxypropane are reacted. The title compound is obtained as a slightly orange oil. Rf=0.32 (1:4 EtOAc-heptane); Rt=4.60
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[O:33]1[CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([CH:36]3[CH2:37][CH2:38][O:33][CH2:34][CH2:35]3)[CH2:17][CH2:18]1)=[N:7]2
Reactant: O=C1CCOCC1
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: Cc1c(N2CCN(C3CCOCC3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Essentially prepared according to Procedure L using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (67.0 mg, 0.15 mmol) and dihydro-2H-pyran-4(3H)-one to give 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(4-(tetrahydro-2H-pyran-4-yl)piperazin-1-yl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 1H NMR 7.93 (1H, d, J=2.5 Hz), 7.69 (1H, d, J=2.2 Hz), 7.30 (1H, ddd, J=10.0, 2.6, 1.3 Hz), 6.87 (1H, d, J=12.7 Hz), 6.79 (1H, ddd, J=13.9, 8.7, 2.4 Hz), 6.58 (1H, t, J=2.3 Hz), 4.07 (2H, dd, J=11.2, 3.9 Hz), 3.80-3.92 (4H, m), 3.46-3.53 (4H, m), 3.41 (2H, td, J=11.7, 1.6 Hz), 3.16 (4H, dd, J=5.7, 3.9 Hz), 2.75-2.93 (4H, m), 2.06 (3H, s), 1.87 (2H, d, J=12.3 Hz), 1.61-1.78 (2H, m). Mass Spectrum (ESI) m/e=525.4 (M+1).