Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1([CH3:18])[C@@H:9]([CH:10]=[C:11](Br)Br)[C@H:8]1[C:14]([O:16][CH3:17])=[O:15].P(O)(O)([O-])=O.[Na+]>C1CCCCC1>[CH3:6][C:7]1([CH3:18])[C@@H:9]([C:10]#[CH:11])[C@H:8]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)[C@@H]1[C@H](C=C(Br)Br)C1(C)C
Agent: O=P([O-])(O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCCCC1
Product: C#C[C@H]1[C@@H](C(=O)OC)C1(C)C
Temperature: -60 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
100 ml of a solution of 1.85M of butyllithium in cyclohexane were slowly added at -100° C. to a cyclohexane solution containing 58.34 g of methyl (1R,cis) 2,2-dimethyl-3-(2,2-dibromovinyl)-cyclopropane-carboxylate and the mixture was stirred at -100° C. for 30 minutes, at -60° C. for one hour and was then poured into an iced aqueous monosodium phosphate solution. The mixture was extracted with benzene and the organic phase was evaporated to dryness under reduced pressure. The residue was rectified to obtain 14.5 g of methyl (1R,cis) 2,2-dimethyl-3-ethynyl-cyclopropane-carboxylate with a boiling point of 40° C. at 0.5 mm Hg.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[N:6][CH:7]=1.CN(C=O)C.C([O-])([O-])=O.[Cs+].[Cs+].[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1>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.[Fe+2].Cl[Cu]>[N:6]1[C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:4][CH:3]=[C:2]([C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cn1
Reactant: OB(O)c1cccnc1
Agent: Cl[Cu]
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(-c2cccnc2)cn1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Into a solution of tert-butyl 5-bromopicolinate (3.5 g, 13.56 mmol) in DMF (40 ml) Pd(OAc)2 (0.152 g, 0.68 mmol), dppf (0.753 g, 1.37 mmol), CuCl (1.4 g, 13.57 mmol), Cs2CO3 (8.9 g, 27.13 mmol) and pyridin-3-yl boronic acid (3.4 g, 27.13 mmol) were added under inert atmosphere. The reaction mixture was stirred at 110° C. overnight and diluted with H2O. The mixture was filtered through a celite bed, and the filtrate was extracted with EtOAc. The organic layer was concentrated. Yield 1.75 g. 1H-NMR (400 MHz; CDCl3): δ 1.67 (s, 9H), 7.43-7.47 (m, 1H), 7.91 (d, J=8.0 Hz, 1H), 8.01 (dd, 1H), 8.17 (d, 1H), 8.70 (dd, 1H), 8.88 (d, 1H), 8.97 (d, 1H).
Reaction SMILES: [O:1]=[C:2]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[CH3:19])[CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N+:6]=1[O-:11].C1C=C(Cl)C=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[O:1]=[C:2]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[CH3:19])[CH2:3][S:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N+:6]=1[O-:11])=[O:28]
Reactant: Cc1ccc(C)c(C(=O)CSc2cccc[n+]2[O-])c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(C)c(C(=O)CS(=O)c2cccc[n+]2[O-])c1

Procedure:
The procedure employed is identical to that of Example 68 using 8.2 gm (0.03 mol) 2-(2-oxo-2-[2,5-dimethylphenyl]ethylthio)pyridine N-oxide in 50 ml chloroform with 6 gm (0.03 mol) MCPBA (85%) in 100 ml chloroform.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:2]1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([C:2]1[S:1][CH:5]=[CH:4][C:3]=1[C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:18])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cccc(-c2ccsc2)c1
Product: COC(=O)c1cccc(-c2ccsc2C(C)=O)c1
Temperature: 75 °C
Reaction time: 2 h
Yield: 60.4 %

Procedure:
A mixture of methyl 3-(thiophen-3-yl)benzoate (2 g) in acetic anhydride (2 g) was heated to 75° C. The oil bath was removed and phosphoric acid (0.063 ml) was added thereto. The reaction mixture was stirred at 140° C. for 2 hours and cooled to room temperature. The mixture was diluted with ethyl acetate and washed successively with water, an aqueous sodium carbonate solution (×2) and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of hexane:ethyl acetate (10:1) to afford methyl 3-(2-acetylthiophen-3-yl)benzoate (1.44 g).
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH:24]([C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[C:30]([F:36])[CH:29]=2)[C:23]1=[O:37].[CH3:38][O:39][C:40]1[CH:41]=[C:42](/[CH:52]=[CH:53]/[C:54](O)=[O:55])[CH:43]=[CH:44][C:45]=1[N:46]1[CH:50]=[C:49]([CH3:51])[N:48]=[CH:47]1.O.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C.C(Cl)CCl>[CH3:38][O:39][C:40]1[CH:41]=[C:42](/[CH:52]=[CH:53]/[C:54]([NH:21][N:22]2[CH2:27][CH2:26][CH2:25][CH:24]([C:28]3[CH:29]=[C:30]([F:36])[C:31]([F:35])=[C:32]([F:34])[CH:33]=3)[C:23]2=[O:37])=[O:55])[CH:43]=[CH:44][C:45]=1[N:46]1[CH:50]=[C:49]([CH3:51])[N:48]=[CH:47]1
Reactant: COc1cc(/C=C/C(=O)O)ccc1-n1cnc(C)c1
Reactant: NN1CCCC(c2cc(F)c(F)c(F)c2)C1=O
Agent: Cl
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(/C=C/C(=O)NN2CCCC(c3cc(F)c(F)c(F)c3)C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.6 %

Procedure:
IPEA (0.41 mL), HOBT (105 mg) and EDC (149 mg) were added to a solution of 1-amino-3-(3,4,5-trifluorophenyl)piperidin-2-one hydrochloride (109 mg) and (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid (100 mg) in DMF (2 mL), and the reaction solution was stirred at room temperature for three hours. Ethyl acetate and saturated sodium bicarbonate water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate->ethyl acetate:methanol=5:1) to obtain 95 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH2:10][CH2:9]2)=[O:5].Cl>S(=O)(=O)(O)O>[C:4]1(=[O:5])[C:6]2[C:14](=[CH:13][C:12]3[CH2:11][CH2:10][CH2:9][C:8]=3[CH:7]=2)[CH2:2][CH2:3]1
Reactant: O=C(CCCl)c1ccc2c(c1)CCC2
Agent: Cl
Agent: O=S(=O)(O)O
Product: O=C1CCc2cc3c(cc21)CCC3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Concentrated sulfuric acid (550 mL) was added dropwise, with stirring over a time period of 2 hours to 137 grams of 3-chloro-1-indan-5-yl-propan-1-one. The resulting thick black solution was heated to 90° C. until hydrogen chloride evolution ceased (usually 1-4 hours). The mixture was then cooled to room temperature and poured onto 5 kg of ice. The resulting slurry was stirred overnight and filtered. The solid was washed with water until the water ran clear through the filter. The tan solid was then dried in vacuo and recrystallized from hexane to afford 90 grams of the title compound, m.p. 72.4-74.8° C.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Br[C:36]1[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:37]=1[C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1)=[O:44].[CH3:50][O:51][C:52]1[CH:84]=[CH:83][C:55]([CH2:56][NH:57][C:58]2[C:67]([N:68]3[CH2:73][CH2:72][O:71][CH2:70][CH2:69]3)=[CH:66][C:65]3[C:60](=[CH:61][CH:62]=[C:63](B4OC(C)(C)C(C)(C)O4)[CH:64]=3)[N:59]=2)=[CH:54][CH:53]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[CH3:50][O:51][C:52]1[CH:53]=[CH:54][C:55]([CH2:56][NH:57][C:58]2[C:67]([N:68]3[CH2:69][CH2:70][O:71][CH2:72][CH2:73]3)=[CH:66][C:65]3[C:60](=[CH:61][CH:62]=[C:63]([C:36]4[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:37]=4[C:43]([N:45]4[CH2:49][CH2:48][CH2:47][CH2:46]4)=[O:44])[CH:64]=3)[N:59]=2)=[CH:83][CH:84]=1
Reactant: COc1ccc(CNc2nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3cc2N2CCOCC2)cc1
Reactant: Cc1cccc(C(=O)N2CCCC2)c1Br
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CNc2nc3ccc(-c4c(C)cccc4C(=O)N4CCCC4)cc3cc2N2CCOCC2)cc1
Temperature: 140 °C

Procedure:
A mixture of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (47.8 mg, 0.10 mmol), (2-bromo-3-methylphenyl)(pyrrolidin-1-yl)methanone (323 mg, 1.2 mmol), N-(4-methoxybenzyl)-3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (477 mg, 1.0 mmol), Pd2(dba)3 (45.9 mg, 0.050 mmol), K3PO4 (0.25 mL, 3.0 mmol), and 1,4-dioxane (7 mL)/water (3.50 mL) was heated in a microwave at 140° C. for 12 min. The reaction mixture was filtered then concentrated in vacuo. The crude product was purified by silica flash chromatography (0-10% MeOH/DCM) to give (2-(2-(4-methoxybenzylamino)-3-morpholinoquinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone as an orange oil.
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([NH:17][CH2:18][C:19]([NH:21][C:22]2[C:27]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=2[CH:31]([CH3:33])[CH3:32])=[O:20])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=1.[OH-].[Na+]>CO>[CH3:30][CH:28]([C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:31]([CH3:32])[CH3:33])[C:22]=1[NH:21][C:19](=[O:20])[CH2:18][NH:17][CH:10]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:34])=[O:2])[CH3:29]
Reactant: COC(=O)c1cccc(C(NCC(=O)Nc2c(C(C)C)cccc2C(C)C)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)c1cccc(C(C)C)c1NC(=O)CNC(c1ccccc1)c1cccc(C(=O)O)c1

Procedure:
The title compound was prepared by the hydrolysis of the product of Example 149 by NaOH in aqueous methanol, mp 190°-191° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)#[CH:2].[NH3:10]>>[C:6]1([CH3:9])[CH:7]=[CH:8][C:3]([C:1](=[NH:10])[CH3:2])=[CH:4][CH:5]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: N
Product: CC(=N)c1ccc(C)cc1
Yield: 60 %

Procedure:
1-p-tolylethanimine was prepared by reacting 1-ethynyl-4-methylbenzene and excess ammonia in the presence of 5 mol % of catalyst E (110° C., 18 h). The yield was 60%. 1H NMR (600 MHz, C6D6) δ=2.17 (3H, s, CH3), 2.18 (3H, s, CH3), 7.07 (2H, d, J=7.9 Hz, CH), 7.72 (2H, d, J=7.9 Hz, CH); 13C NMR (150 MHz, C6D6) δ=21.3 (CH3), 25.7 (NCCH3), 127.3 (CHortho), 129.5 (CHmeta), 136.9 (Cq,ipso), 140.8 (Cq,paraCH3), 173.7 (C═NH); HRMS (ESI): 134.0968 [(MH)+, 134.0970 (C9H12N)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9](Cl)=[N:10][OH:11].[Cl:13][CH:14]([Cl:26])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1)=[O:16]>C1COCC1.C(N(CC)CC)C>[Cl:13][CH:14]([Cl:26])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[O:11][N:10]=[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[CH:25]=2)=[CH:20][CH:19]=1)=[O:16]
Reactant: ON=C(Cl)c1c(Cl)cccc1Cl
Reactant: C#Cc1ccc(NC(=O)C(Cl)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(-c2cc(-c3c(Cl)cccc3Cl)no2)cc1)C(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,6-Dichloro-N-hydroxybenzenecarboximidoyl chloride (1.01 g, 4.5 mmol) and 2,2-dichloro-N-(4-ethynylphenyl)acetamide (1.01 g, 4.42 mmol) were dissolved in anhydrous THF (40 mL) and triethylamine (1.0 mL). The mixture was stirred at room temperature for 1 h then heated at reflux for 4 h to generate the 2,6-dichlorophenyl nitrile oxide intermediate, which reacted by a 1,3-dipolar cycloaddition reaction with 2,2-dichloro-N-(4-ethynylphenyl)acetamide. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with water and brine. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was purified by column chromatography on silica gel, eluting with 8:2 hexanes-ethyl acetate. The appropriate fractions were combined to give 2,2-dichloro-N-[4-[3-(2,6-dichlorophenyl)-5-isoxazolyl]phenyl]acetamide as a tan solid.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]([NH2:26])=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13](B2OC(C)(C)C(C)(C)O2)=[CH:12][CH:11]=3)[CH2:3][CH2:2]1.C([O-])(=O)C.[K+].I[C:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][C:34]=1[C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1)=[O:41].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:26][C:8]1[C:7]([C:4]2[CH2:3][CH2:2][O:1][CH2:6][CH:5]=2)=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:33]3[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][C:34]=3[C:40]([N:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)=[O:41])[CH:14]=2)[N:9]=1
Reactant: Cc1cccc(C(=O)N2CCCC2)c1I
Reactant: CC1(C)OB(c2ccc3nc(N)c(C4=CCOCC4)cc3c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Pd]
Agent: CC(=O)[O-]
Product: Cc1cccc(C(=O)N2CCCC2)c1-c1ccc2nc(N)c(C3=CCOCC3)cc2c1
Temperature: 130 °C

Procedure:
A glass microwave reaction vessel was charged with 3-(3,6-dihydro-2H-pyran-4-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.058 g, 0.165 mmol), potassium acetate (0.032 g, 0.329 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (5.83 mg, 8.23 μmol), and (2-iodo-3-methylphenyl)(pyrrolidin-1-yl)methanone (0.078 g, 0.247 mmol). The vessel was evacuated and flushed with N2 gas 3× before EtOH1 (1.6 mL) and water (0.23 mL) (each degassed by bubbling N2 gas through the solution for 10 min prior to addition) was added. The reaction mixture was stirred and heated in a microwave reactor at 130° C. for 10 min. 2-(Dicyclohexylphosphino)-2′,4′,6′,-tri-1-propyl-1,1′-biphenyl (0.012 g, 0.026 mmol), potassium phosphate tribasic (0.041 mL, 0.494 mmol), Pd2(dba)3 (7.54 mg, 8.23 μmol) were added and the reaction was degassed and heated in the Initiator microwave reactor again for 20 min at 130° C. The reaction mixture was diluted with 10:1 saturated ammonium chloride/ammonium hydroxide and extracted with EtOAc. The combined organic extracts were washed with 10:1 saturated ammonium chloride/ammonium hydroxide, water, saturated sodium chloride, and dried over sodium sulfate. The solution was filtered and concentrated in vacuo to give the crude material which was purified by silica gel chromatography by eluting with 1:20 2M NH3 in MeOH/DCM, to provide (2-(2-amino-3-(3,6-dihydro-2H-pyran-4-yl)quinolin-6-yl)-3-methylphenyl)(pyrrolidin-1-yl)methanone.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH:25]([CH2:28][OH:29])[CH2:26][OH:27])[CH:20]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.FC(F)(F)C(O)=O.ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[N:21]([CH:25]([CH2:26][OH:27])[CH2:28][OH:29])[C:20]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:19]5)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)C1Cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2N1C(CO)CO
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2n1C(CO)CO
Temperature: 100 °C

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(1,3-dihydroxypropan-2-yl)indolin-5-yl)cyclopropanecarboxamide (40.3 mg, 0.0711 mmol as the trifluoracetic acid salt) was dissolved in toluene (1 mL). To the resulting solution was added 2,3,5,6-tetrachlorocyclohexa-2,5-diene-1,4-dione (35 mg, 0.14 mmol). The resulting suspension was heated at 100° C. in an oil bath for 10 minutes. The crude product was then evaporated to dryness, dissolved in a 1 mL of N,N-dimethylformamide and purified by purified by preparative HPLC using a gradient of 0-99% acetonitrile in water containing 0.05% trifluoroacetic acid to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-1-(1,3-dihydroxypropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 450.2, found 451.5 (M+1)+. Retention time of 1.59 minutes.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19](I)=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[N:25]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:25]4[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:24]4=[O:23])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(NCc1cn(-c2ccc(I)cc2)cn1)c1ccc(Cl)s1
Reactant: Cc1cccc(O)n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cc1cccc(=O)n1-c1ccc(-n2cnc(CNC(=O)c3ccc(Cl)s3)c2)cc1
Temperature: 130 °C
Yield: 4.3 %

Procedure:
A mixture of 5-chloro-N-((1-(4-iodophenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide 1-6 (100 mg, 0.22 mmol), 2-hydroxy-6-methylpyridine (60 mg, 0.55 mmol), 8-hydroxyquinoline (20 mg, 0.14 mmol) and K2CO3 (140 mg, 1.01 mmol) in DMSO (3 mL) was degassed with Ar before being charged with CuI (28 mg, 0.15 mmol). The mixture in a sealed tube was heated at 130° C. overnight. The mixture was then purified by HPLC to give the titled compound (4 mg). MS 425.1 and 427.1 (M+H, Cl pattern).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:28][C:29]1[C:30]([CH3:35])=[CH:31][CH:32]=[CH:33][CH:34]=1>O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35])=[CH:13][CH:12]=[CH:11][C:10]=2[N:17]1[C:21](=[O:22])[C:20]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:19]2[C:18]1=[O:27])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(N3C(=O)c4ccccc4C3=O)cccc2c1Cl
Reactant: Cc1ccccc1N
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(N3C(=O)c4ccccc4C3=O)cccc2c1Nc1ccccc1C
Yield: 58.4 %

Procedure:
A mixture of 3-butyryl-4-chloro-8-phthalimidoquinoline (61.6 g, 0.16 moles) and o-toluidine (20 ml, 0.19 mol) was heated under reflux in 1,4-dioxan (300 ml) for 3 hours. The solvent was evaporated and the residue was dissolved in chloroform, washed with dil. ammonia solution and brine. The organic solution was dried (anhyd. MgSO4) filtered and evaporated to a dark oil which crystallized on standing to give 3-butyryl-4-(2-methylphenylamino)-8-phthalimidoquinoline (42 g, 58.3%), m.p. b 170°-2° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(C)N=NCCO)(OCC)=O.[C:32]([N:35]([CH3:41])[N:36]=[N:37][CH2:38][CH2:39]O)(=[O:34])[CH3:33].C(Cl)(Cl)(Cl)[Cl:43]>CCCCC>[C:32]([N:35]([CH3:41])[N:36]=[N:37][CH2:38][CH2:39][Cl:43])(=[O:34])[CH3:33]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(=O)N(C)N=NCCO
Agent: CCOC(=O)N(C)N=NCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Product: CC(=O)N(C)N=NCCCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of triphenylphosphine (5.89 g, 2.25×10-2 mol) and 3-carboethoxy-1-(2 hydroxyethyl)-3-methyltriazene, 5b, (2.9 g, 2.0×10 -2 mol) in 50 mL of carbon tetrachloride (dried over 3A molecular sieves) was refluxed overnight under nitrogen. The reaction mixture was cooled to room temperature and diluted with pentane (250 mL). After standing at 10° C. overnight, the reaction mixture was filtered through a pad of Celite to remove precipitated triphenylphosphine oxide. The filtrate was concentrated on a rotary evaporator at 220° C., the residue (4.2 g) was dissolved in a minimum amount of ether and chromatographed on a column of 35 g of Silica Gel 60 packed in 10% ether in pentane and eluted with 600 mL of this same solvent mixture. Evaporation of the eluent on a rotary evaporator and vacuum transfer (40° C./0.005 mm) of the residue gave 1.94 g 0.0119 mol, 59.6%) of 3-acetyl-1-(2-chloroethyl)-3-methyltriazene, 6b; IR (CCl4) 2970, 1710, 1515, 1145, 990 cm10-1 ; UV (CH3CN) λmax 238 (log ε 4.23); 1H NMR (CDCl3, Me4Si) δ 3.45 (CH3,s), 3.23 (N--CH3, s), 3.90 (Cl--CH2,t,J=5.5 Hz), 4.12 (CH2 -N,t,J=5.5 Hz); proton decoupled 13C NMR (CDCl3, Me4Si) δ 21.85 (CH3 (, 26.92 (N--C H3), 41.78 Cl--CH2), 62.68 (CH2 --N), 63.17 (0--CH2CH3), 173.0 (C=0); exact mass calcd. m/z for C5H10N3OC1 163.0512, found 163.0506 (by EI).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[CH:15][CH2:16][CH:17]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([BH3-])#N.[Na+]>CO>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:16][CH:17]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=CCC(NS(=O)(=O)c1ccccc1)c1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=S(=O)(NC(CCN1CCC(Cc2ccccc2)CC1)c1ccccc1)c1ccccc1

Procedure:
4-Benzylpiperidine (54 μL, 0.30 mmol) was added to a stirred solution of N-(3-oxo-1-phenylpropyl)benzenesulfonamide (83 mg, 0.28 mmol) (Example 3 Step 4) in MeOH (1.0 mL) under N2 and sodium cyanoborohydride (40 mg, 0.62 mmol) added. After 4 h the reaction was quenched with water, applied to an SCX-2 cartridge and washed with MeOH and then 2 M NH3 in MeOH solution. The desired fractions were concentrated under reduced pressure and further purified by reversed phase prep-HPLC system to give the title compound as a residue (10 mg, 7%), after isolating the free base. 1H NMR (400 MHz, CDCl3) δ 1.3–2.0 (9H, m), 2.25–2.40 (2H, m), 2.59 (2H, d, J 6.9 Hz), 2.91 (2H, t, J 9.4 Hz), 4.50–4.54 (1H, m), 7.08–7.22 (8H,m), 7.27–7.36 (4H, m), 7.41–7.46 (1H, m), 7.64–7.69 (2H,m). MS (ES+) C27H32N2O2S requires: 448, found: 449 (M+H+)
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:30])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@H:23]5[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]5)=[CH:17][C:9]=4[C:10]([CH3:16])([CH3:15])[C:11]=3[NH:12]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]I.[Cl-].[NH4+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:30])[C:8]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][C@H:23]5[CH2:27][O:26][C:25]([CH3:29])([CH3:28])[O:24]5)=[CH:17][C:9]=4[C:10]([CH3:15])([CH3:16])[C:11]=3[N:12]2[CH3:33])=[CH:4][CH:3]=1
Reactant: CC1(C)OC[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(Br)ccc4c2C3=O)O1
Reactant: CI
Agent: O=S([O-])([O-])=S
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: Cn1c2c(c3ccc(Br)cc31)C(=O)c1ccc(OC[C@H]3COC(C)(C)O3)cc1C2(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92.7 %

Procedure:
Under nitrogen atmosphere, to the DMF (1 mL) suspension of 3-bromo-8-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl methoxy)-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound T18-1, 112.2 mg, 0.239 mmol) and sodium hydride (60%) (19 mg, 0.477 mmol), cooled in an ice bath, methyl iodide (37 mL, 0.596 mmol) was added. The reaction mixture was stirred at room temperature for 45 min, and then added with saturated aqueous solution of ammonium chloride and saturated aqueous solution of sodium thiosulfate under ice cooling. The mixture was extracted twice with ethyl acetate/diethyl ether/hexane. The organic layer was washed with water and subsequently with aqueous solution of ammonium chloride, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography {Merck Kieselgel60, solution for elution:hexane/ethyl acetate (1:1)} to obtain the title compound (white solid, 107.3 mg, 93%).