Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][CH2:7][C:8]3[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=3[CH:10]([C:11](O)=[O:12])[C:4]=2[CH:3]=1.[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:22]=1[NH2:23]>>[Cl:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:22]=1[NH:23][C:11]([CH:10]1[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[CH2:7][O:6][C:5]2[CH:18]=[CH:19][C:2]([CH3:1])=[CH:3][C:4]1=2)=[O:12]
Reactant: Cc1cccc(Cl)c1N
Reactant: Cc1ccc2c(c1)C(C(=O)O)c1ccccc1CO2
Product: Cc1ccc2c(c1)C(C(=O)Nc1c(C)cccc1Cl)c1ccccc1CO2
Yield: 80.2 %

Procedure:
The similar procedures as in Example 1 were repeated except using 1.40 g of Compound A and 0.72 g of 2-chloro-6-methylaniline in place of aniline to obtain 1.54 g of Compound 8.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8]([CH:11]([C:17]([CH3:19])=O)[C:12](OCC)=[O:13])([CH3:10])[CH3:9].C(Cl)(Cl)Cl.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[OH:13][C:12]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:1]=[C:17]([CH3:19])[C:11]=1[CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)C(C(C)=O)C(C)C
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1nc2ccccc2c(O)c1C(C)C
Yield: 21 %

Procedure:
4.56 ml (50 mmol) of aniline and 10.7 ml (60 mmol) of ethyl 2-isopropylacetoacetate were mixed with 50 ml of chloroform. 0.48 g (2.5 mmol) of para-toluenesulfonic acid was added, and the reaction mixture was refluxed with continuous removal of the water produced in the reaction. After 2 d chloroform was removed in vacuum, and the residue was refluxed in 10 ml of phenyl ether. After cooling, the precipitate was filtered and washed with diethyl ether to give 4-hydroxy-3-isopropyl-2-methylquinoline (21%). Following the procedure of Step 3 in Example 1, but substituting 4-hydroxy-3-isopropyl-2-methylquinoline for 9-(10H)acridone, 4-chloro-3-isopropyl-2-methylquinoline (100%) was obtained, which was reacted with 4-(4-methylpiperazin-1-yl)aniline (following the procedure of Step 4 in Example 1), to afford the title compound with 61% yield (overall yield 13%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:7]=1.[CH2:18]([OH:21])[C:19]#[CH:20].C(N(CC)CC)C>O1CCOCC1.CCOC(C)=O.[Cu]I>[CH3:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:7]=[C:2]([C:20]#[C:19][CH2:18][OH:21])[CH:3]=[CH:4][C:5]=2[N+:15]([O-:17])=[O:16])[CH2:9][CH2:10]1
Reactant: C#CCO
Reactant: CC1CCN(c2cc(Br)ccc2[N+](=O)[O-])CC1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC1CCN(c2cc(C#CCO)ccc2[N+](=O)[O-])CC1
Temperature: 80 °C
Yield: 76.7 %

Procedure:
To a round bottom flask containing 1-(5-bromo-2-nitro-phenyl)-4-methyl-piperidine (as prepared above, 400 mg, 1.33 mmol) in 8 mL of dioxane was added propargyl alcohol (155 μL, 2.64 mmol), bis-dichloro(triphenylphosphinyl) palladium (II) (56.3 mg, 0.0798 mmol), copper (I) iodide (5.0 mg, 0.02 mmol) and triethylamine (741 μL, 5.32 mmol). The result was heated at 80° C. for 16 h. The reaction was then diluted with EtOAc (50 mL), washed with water (2×50 mL), dried (Na2SO4), and concentrated in vacuo. Purification of the crude material by preparative thin layer chromatography (75% EtOAc-hexanes) afforded 280 mg (77%) of the title compound as a reddish oil. 1H-NMR (CDCl3; 400 MHz): δ 7.73 (d, 1H, J=8.6 Hz), 7.17 (d, 1H, J=1.6 Hz), 6.98 (dd, 1H, J=8.6, 1.6 Hz), 3.23-3.26 (m, 2H), 4.53 (s, 2H), 1.73-1.42 (m, 5H), 2.86-2.79 (m, 2H), 1.00 (d, 3H, J=6.4 Hz).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=O)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=2.[NH3:17].Cl>C1COCC1>[OH:3][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=2)[CH:11]=[C:2]([CH3:1])[N:17]=1
Reactant: N
Reactant: COC(=O)c1ccc2cc(C)oc(=O)c2c1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc(C)nc(O)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 3-methyl-1-oxo-1H-isochromene-7-carboxylate (1.0 g), 29% aqueous ammonia solution (30 mL) and THF (30 mL) was stirred at room temperature for 8 hours. The reaction mixture was neutralized with hydrochloric acid, and the precipitate was collected by filtration to obtain methyl 1-hydroxy-3-methylisoquinoline-7-carboxylate (390 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:15])([CH3:14])[C:10]([O:12]C)=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:16][C:17]1[CH:25]=[C:24]([O:26][CH2:27][C@@H:28]2[CH2:33][N:32]([CH3:34])[C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[O:29]2)[C:23]([CH3:39])=[CH:22][C:18]=1[C:19](Cl)=[O:20].OC1C(C)=CC(C(OC)=O)=C(C)C=1>>[CH3:16][C:17]1[CH:25]=[C:24]([O:26][CH2:27][C@@H:28]2[CH2:33][N:32]([CH3:34])[C:31]3[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=3[O:29]2)[C:23]([CH3:39])=[CH:22][C:18]=1[C:19]([NH:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:15])([CH3:14])[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8])=[O:20]
Reactant: COC(=O)C(C)(C)c1ccc(C)c(N)c1
Reactant: Cc1cc(C(=O)Cl)c(C)cc1OC[C@@H]1CN(C)c2ccccc2O1
Agent: COC(=O)c1cc(C)c(O)cc1C
Product: Cc1ccc(C(C)(C)C(=O)O)cc1NC(=O)c1cc(C)c(OC[C@@H]2CN(C)c3ccccc3O2)cc1C
Yield: 66.2 %

Procedure:
By the same procedures as a series of Example 18 and Example 19 using methyl 2-(3-amino-4-methylphenyl)-2-methylpropanoate (132 mg)(the compound prepared by the same procedures as Example 16) and 2,5-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoylchloride (210 mg)(the compound prepared by the same procedures as a series of Example 8→Example 9→Example 10 using methyl 4-hydroxy-2,5-dimethylbenzoate.), the title compound (202 mg) having the following physical data was obtained.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Br:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29]O)=[N:27][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCCOC)=O)=NC(OCCOC)=O>C1COCC1.O>[Br:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:29][O:20][C:17]2[CH:18]=[CH:19][N:14]([C:11]3[CH:12]=[CH:13][C:6]4[N:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[N:8]([CH3:9])[C:7]=4[CH:10]=3)[C:15](=[O:21])[CH:16]=2)=[N:27][CH:28]=1
Reactant: OCc1ccc(Br)cn1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(Br)cn4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.4 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (50 mg), (5-bromopyridin-2-yl)methanol (66.8 mg) and triphenylphosphine (140 mg) in THF (6 ml) was added bis(2-methoxyethyl) azodicarboxylate (125 mg), and the mixture was stirred at room temperature for 3 h. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by silica gel column chromatography (hexane/EtOAc to EtOAc/MeOH). The resulting solid was recrystallized from EtOH-water to give the title compound (25.2 mg) as a white solid.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1.[H][H]>C(O)(C)(C)C.CO.[Ir]>[CH3:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][CH:24]=3)[CH2:12][CH2:13]2)[CH2:4][CH2:3]1.[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][CH:24]=3)[CH2:12][CH2:13]2)[CH2:4][CH2:3]1
Reactant: C=C1CCC(N2CCN(c3ccc(C(=O)OCC)cc3)CC2)CC1
Reactant: [H][H]
Agent: [Ir]
Solvent: CO
Solvent: CC(C)(C)O
Product: CCOC(=O)c1ccc(N2CCN([C@H]3CC[C@@H](C)CC3)CC2)cc1
Product: CCOC(=O)c1ccc(N2CCN([C@H]3CC[C@H](C)CC3)CC2)cc1

Procedure:
A solution of ethyl 4-[4-(4-methylenecyclohexyl)-1-piperazinyl]benzoate (100 mg) and Iridium black (30 mg) in a mixture of t-butanol (1 ml) and methanol (2 ml) was stirred under atmospheric pressure of hydrogen for 4 hours. The catalyst was filtrated off and the filtrates were evaporated in vacuo. Ethyl 4-[cis-4-(4-methylcyclohexyl)-1-piperazinyl]benzoate and ethyl 4-[trans-4-(4-methylcyclohexyl)-1-piperazinyl]benzoate were obtained in the ratio 5:1-6:1 by thin-layer chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.C[O:20][CH2:21][CH2:22][NH2:23]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:23][CH2:22][CH2:21][OH:20])=[O:14]
Reactant: COCCN
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NCCO)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-(2-Fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethyl)-isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.45 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.60 mmol of 2-methoxy-ethylamine. LC/MS [3.42 min; 402 (M+1)]
Reaction SMILES: [F:1][S:2]([O:5][CH3:6])(=[O:4])=[O:3].[CH3:7][O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][S:14][C@@H:15]2[CH2:23][N:22]3[C@H:17]([C:18](=[O:25])[N:19]([CH3:24])[CH2:20][CH2:21]3)[CH2:16]2)=[CH:11][CH:10]=1>C(Cl)Cl.C(OCC)C>[F:1][S:2]([O-:5])(=[O:4])=[O:3].[CH3:6][N+:22]12[CH2:23][C@@H:15]([S:14][CH2:13][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:27][CH:26]=3)[CH2:16][C@H:17]1[C:18](=[O:25])[N:19]([CH3:24])[CH2:20][CH2:21]2
Reactant: COS(=O)(=O)F
Reactant: COc1ccc(CS[C@H]2C[C@H]3C(=O)N(C)CCN3C2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(CS[C@H]2C[C@H]3C(=O)N(C)CC[N+]3(C)C2)cc1
Product: O=S(=O)([O-])F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
461 μl of methyl fluorosulfonate was added, whilst ice-cooling, to a solution of 1.71 g of (6S, 8S)-8-(4-methoxybenzylthio)-4-methyl-5-oxo-1,4-diazabicyclo-[4.3.0]nonane dissolved in 60 ml of methylene chloride, and the mixture was stirred at room temperature for 2 hours. At the end of this time, the mixture was diluted with diethyl ether, and the resulting crystals were collected by filtration and dried under reduced pressure, to afford 2.09 g of the title compound as colorless crystals, melting at 208°-210° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[C:6]([CH:9]=1)[C:7]#[N:8].[H-].[Na+].[F:18][C:19]([F:49])([F:48])[C:20]1[CH:25]=[CH:24][C:23]([C@@H:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:29][CH2:28][N:27]2[C:36](OC2C=CC([N+]([O-])=O)=CC=2)=[O:37])=[CH:22][CH:21]=1.O>C1COCC1.CO>[C:7]([C:6]1[CH:9]=[C:2]([NH:1][C:36]([N:27]2[CH2:28][CH2:29][C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@H:26]2[C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:48])([F:18])[F:49])=[CH:21][CH:22]=2)=[O:37])[CH:3]=[N:4][C:5]=1[O:10][CH2:11][C:12]([F:15])([F:13])[F:14])#[N:8]
Reactant: N#Cc1cc(N)cnc1OCC(F)(F)F
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc(NC(=O)N2CCc3ccccc3[C@H]2c2ccc(C(F)(F)F)cc2)cnc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-amino-2-(2,2,2-trifluoroethoxy)nicotinonitrile (49 mg, 226 μmol) in THF (1.0 mL) was added sodium hydride, 60% dispersion in mineral oil (26 mg, 678 μmol). The resulting mixture was then stirred at RT for 15 min. Then, (R)-4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 226 μmol, example 88) was added and the mixture was stirred at RT for overnight. Then, a solution of H2O and MeOH (1:1, 0.2 mL) was added and the solvents were removed. The residue was then dissolved in a solution of DMSO and MeOH (1:1, 1 mL). The solution mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired product, which was dissolved in MeOH (1.0 mL). The solution was then washed through PL-HCO3 MP resin (polymerlabs, 200 mg/6 mL tube) and the resin was washed with MeOH (2×0.5 mL). The combined washings were then concentrated and dried under vacuum to give the title compound as a light yellow solid. MS (ESI, positive ion) m/z: 521 (M+H).
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:12]=[C:13]([C:17]3[CH:21]=[C:20]([CH2:22][CH:23]([CH3:25])[CH3:24])[S:19][C:18]=3[S:26]([NH:29]C(C)(C)C)(=[O:28])=[O:27])[CH:14]=[CH:15][CH:16]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.B(Cl)(Cl)Cl.N1(C2C=CC=CN=2)CCCC1.Cl[C:50]([O:52][CH2:53][CH2:54][CH2:55][CH3:56])=[O:51].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[CH2:53]([O:52][C:50]([NH:29][S:26]([C:18]1[S:19][C:20]([CH2:22][CH:23]([CH3:24])[CH3:25])=[CH:21][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[CH:2]2)[CH:12]=1)(=[O:28])=[O:27])=[O:51])[CH2:54][CH2:55][CH3:56]
Reactant: CC(C)Cc1cc(-c2cccc(Cn3cnc4ccccc43)c2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: CCCCOC(=O)Cl
Agent: ClB(Cl)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: c1ccc(N2CCCC2)nc1
Solvent: ClCCl
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(Cn2cnc3ccccc32)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 3-(3-benzoimidazol-1-ylmethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (67.6 mg, 0.14 mmol; see step (a)) in CH2Cl2 (2 mL) was added BCl3 (0.6 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine, dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in pyridine (1.5 mL) was added pyrrolidinopyridine (41.6 mg, 0.28 mmol) and butyl chloroformate (178.4 μL, 1.40 mmol) and the reaction mixture was stirred overnight. Citric acid (3 mL, 10% aq.) was added to the reaction mixture, which was then extracted with EtOAc, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (5:95) as eluent to give the title compound in 70% yield, over two steps, (51.6 mg, 0.098 mmol).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:33])N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:34][C:35]1[CH:65]=[CH:64][C:38]([CH:39]=[CH:40][CH2:41][N:42]2[C:47](=[O:48])[C:46]([CH2:49]OS(C)(=O)=O)=[CH:45][C:44]([C:55]3[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([F:63])[CH:56]=3)=[N:43]2)=[CH:37][CH:36]=1.N1(CCO)CCNCC1>>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([CH:39]=[CH:40][CH2:41][N:42]2[C:47](=[O:48])[C:46]([CH2:49][N:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][OH:33])[CH2:10][CH2:9]3)=[CH:45][C:44]([C:55]3[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([F:63])[CH:56]=3)=[N:43]2)=[CH:64][CH:65]=1
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC=Cc3ccc(Cl)cc3)n2)cc1F
Agent: OCCN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(CCO)CC3)c(=O)n(CC=Cc3ccc(Cl)cc3)n2)cc1F
Yield: 65.1 %

Procedure:
Following the procedure of Example 1 (10), 2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-piperazineethanol were reacted to yield the title compound as slightly-yellow needles (yield: 65.1%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1.[I:21]I>C(OCC)(=O)C.C1COCC1>[I:21][C:20]1[C:15]([O:14][CH3:13])=[N:16][CH:17]=[CH:18][N:19]=1
Reactant: COc1cnccn1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: COc1nccnc1I
Reaction time: 0.33 h

Procedure:
To 20 ml of an anhydrous THF solution of 1.3 g of diisopropylamine was added 4.8 ml (2.5 M hexane solution) of n-butyllithium at −78° C., and the mixture was stirred at that temperature for 20 minutes. To the reaction mixture was added 10 ml of a THF solution of 1.1 of 2-methoxypyrazine, followed by stirring at −78° C. for 1 hour. To the reaction mixture was further added 10 ml of a THF solution of 4.0 g of iodine, followed by stirring for 4 hours while gradually elevating the temperature to room temperature. The reaction mixture was diluted with ethyl acetate, washed successively with a saturated sodium thiosulfate aqueous solution and a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was subjected to silica gel column chromatography using chloroform as a developing solution. The fraction containing the desired compound was concentrated to give 0.49 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:28][C:27]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])=[CH:26][C:25](=O)[O:24]1>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:20][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:36]=[CH:35][CH:34]=[C:31]([C:32]#[N:33])[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Yield: 80.8 %

Procedure:
Prepared from (3-amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G9) (250 mg, 0.88 mmol) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) (243 mg, 1.06 mmol) according to the general procedure K. Obtained as a white solid (324 mg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[C:4]([CH2:12][C:13]([OH:15])=O)[CH:3]=1.[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH2:22])[S:20][CH:21]=1>>[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH:22][C:13](=[O:15])[CH2:12][C:4]2[CH:3]=[C:2]([F:1])[CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][CH:8]=[N:9]3)[S:20][CH:21]=1
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Reactant: O=C(O)Cc1cc(F)cc2ncccc12
Product: O=C(Cc1cc(F)cc2ncccc12)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(7-fluoroquinolin-5-yl)acetic acid (0.025 g, 0.122 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-yl-amine (0.20 g, 0.083 mmol) according to protocol A. The desired product was submitted to prep HPLC for further purification. Retention time (min)=2.33, method [7], MS (ESI) 434.0 (M+H). 1H NMR (CDCl3) δ 11.79 (s, 1H), 8.94 (d, J=4.0 Hz, 1H), 8.54 (d, J=8.1 Hz, 1H) 8.38 (s, 1H broad), 7.80 (d, J=10.1 Hz, 1H), 7.70 (d, J=10.1 Hz, 1H), 7.59-7.55 (m 1H), 7.22 (s, 1H), 4.47 (s, 2H).
Reaction SMILES: [CH:1]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[CH:2][CH2:3][CH3:4].C(=O)([O-])[OH:12].[Na+].ClC1C=CC=C(C(OO)=O)C=1>ClCCl.O>[CH2:2]([CH:3]1[CH2:4][O:12]1)[CH2:1][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCC=Cc1ccccc1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: c1ccc(CCC2CO2)cc1
Reaction time: 4 h

Procedure:
To a suspension of but-3-butenylbenzene (3 ml) and sodium hydrogen carbonate (2.5 g) in a mixture of dichloromethane (200 ml) and water (60 ml) was added small portions of m-chloroperbenzoic acid (3.5 g) at room temperature, and the mixture was stirred at the same temperature for 4 hours. After separation, the organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=100:3) to give 2-phenethyloxirane (970 mg).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH3:11][O:12][C:13]([C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][OH:22])[CH2:17][CH2:16]1)=[O:14].C(N(CC)CC)C.Cl>ClCCl>[CH3:11][O:12][C:13]([C@H:15]1[CH2:20][CH2:19][C@H:18]([CH:21]=[O:22])[CH2:17][CH2:16]1)=[O:14]
Reactant: COC(=O)[C@H]1CC[C@H](CO)CC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)[C@H]1CC[C@H](C=O)CC1
Temperature: -50 °C
Reaction time: 0.08 h

Procedure:
To a solution of dimethylsulfoxide (9.53 g, 122 mmol) in dry dichloromethane (400 ml) was slowly added oxalyl chloride (7.74 g, 61.0 mmol) at −78° C. The cooling bath was removed and the reaction mixture was stirred at −50° C. for 5 min. A solution of trans-4-hydroxymethyl-cyclohexanecarboxylic acid methyl ester (8.75 g, 50.8 mmol) in dichloromethane (108 ml) was added at −65° C. Stirring for 30 minutes was followed by addition of triethylamine (25.7 g, 254 mmol). The cooling bath was removed 15 minutes after completed addition. The reaction mixture was quenched with 1 M aqueous hydrochloric acid solution (152 ml, 152 mmol) at −10° C. The layers were separated. The organic layer was washed with two 250 ml-portions of water and one 100-ml portion of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound as yellow oil (9.3 g, quantitative), which was used in the next step without further purification. MS m/e: 170 (M+)
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH:11]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[C:2]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:12]
Reactant: N#Cc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Reactant: C1CNCCN1
Product: N#Cc1ccc(-n2c(N3CCNCC3)c(C=O)c3ccccc32)cc1

Procedure:
4-(2-chloro-3-formylindol-1-yl)-benzonitrile is reacted with piperazine as described in Step 2 of Example 29 to afford 4-[3-formyl-2-(piperazin-1-yl)-indol-1-yl]-benzonitrile as a light tan solid. ESI/MS 331 (M+H); NMR (CDCl3) 10.35 (1H, s); 8.31 (1H, d, J=9 Hz); 7.92 (2H, d); 7.60 (2H, d); 7.31 (3H, m); 6.99 (1H, d, J=9 Hz); 3.28 (4H, m); 2.79 (4H, m).
Reaction SMILES: CN(C)[CH:3]=[C:4]([CH3:12])[C:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=O.[NH2:14][C:15]([NH2:17])=[S:16].[CH3:18]C(C)([O-])C.[K+].IC>C(O)(C)C.CC(O)(C)C>[CH3:12][C:4]1[C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:14][C:15]([S:16][CH3:18])=[N:17][CH:3]=1
Reactant: NC(N)=S
Reactant: CC(=CN(C)C)C(=O)c1cccs1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)O
Solvent: CC(C)(C)O
Product: CSc1ncc(C)c(-c2cccs2)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
3-(Dimethylamino)-2-methyl-1-(thiophen-2-yl)prop-2-en-1-one (0.2 g, 1.02 mmol) was dissolved in isopropyl alcohol (2mL) at room temperature. Thiourea (0.077 g, 1.02 mmol) followed by potassium tert-butoxide (1.102 mL of a 1.0 M solution in 2-methyl-2-propanol) was added to the mixture, which was then heated to reflux overnight. The reaction was cooled down to rt and iodomethane (0.126 mL, 2.04 mmol) was added to the reaction, which was stirred for an additional 6 h. The volatiles were removed in vacuo and the residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was then dried with sodium sulfate, concentrated in vacuo and purified by flash chromatography using a gradient of 5 to 30% ethyl acetate in hexanes. The pure fractions yielded a tan solid (0.15 g). MS (M+H)+ 223.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.[CH2:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[CH3:24]>>[Cl:22][C:19]1[CH:20]=[CH:21][C:7]2[N:6]3[C:2]([N:28]4[CH2:29][CH2:30][N:25]([CH2:23][CH3:24])[CH2:26][CH2:27]4)=[N:3][N:4]=[C:5]3[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:8]=2[CH:18]=1
Reactant: CCN1CCNCC1
Reactant: Clc1ccc2c(c1)C(c1ccccn1)=NCc1nnc(Br)n1-2
Product: CCN1CCN(c2nnc3n2-c2ccc(Cl)cc2C(c2ccccn2)=NC3)CC1

Procedure:
In the manner given in Example 1, 1-bromo-8-chloro-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is heated with excess of 1-ethylpiperazine to give 8-chloro-1-(4-ethylpiperazino)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.