Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[C:13]([C:14](OCC)=[O:15])=[C:12]([CH3:19])[CH:11]=[CH:10][N:9]=1>C1COCC1>[CH3:7][C:8]1[C:13]([CH2:14][OH:15])=[C:12]([CH3:19])[CH:11]=[CH:10][N:9]=1
Reactant: CCOC(=O)c1c(C)ccnc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccnc(C)c1CO
Reaction time: 0.5 h

Procedure:
To the suspension of LAH (0.95 g, 25 mmol) in THF (100 mL), ethyl 2,4-dimethylpyridine-3-carboxylate (1.5 g, 8.4 mmol) was added dropwise as a solution in THF (10 mL) at 0° C. After 30 minutes, the reaction was quenched by addition of acetone/water and then more water (100 mL) was added. The mixture was extracted with DCM (3×100 mL), dried over magnesium sulfate, and evaporated to provide (2,4-dimethylpyridin-3-yl)methanol, which was used in the next step without any further purification.
Reaction SMILES: [Br-].[CH:2]1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CC(C)([O-])C.[K+].[N+:33]([C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH:38]=O)([O-:35])=[O:34]>C1COCC1>[C:2]1(=[CH:38][C:37]2[CH:40]=[CH:41][CH:42]=[CH:43][C:36]=2[N+:33]([O-:35])=[O:34])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CCCCC2)cc1
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1C=C1CCCCC1
Reaction time: 0.5 h

Procedure:
To a slurry of cyclohexyl triphenylphosphonium bromide (16.6 g) in THF (100 mL) at 24° C. was added potassium t-butoxide (4.38 g). The mixture was stirred for 30 min. o-Nitrobenzaldehyde (3.93 g) in THF (50 mL) was added dropwise below 30° C. and stirred for 30 min. The mixture was then partitioned between EtOAc and ice water. The EtOAc layer was washed well with water, dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica gel with 5% EtOAc/hexanes to give 1-(cyclohexylidenemethyl)-2-nitrobenzene.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=3)[CH:10]=2)[CH2:4][CH2:3]1.[N:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:28][C:29](N)=[O:30])=[O:27])=[CH:22][CH:21]=1.N1C=CC=CC=1.C>O.C(Cl)(Cl)Cl>[F:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][C:29]([NH:28][C:26]([C:23]3[CH:22]=[CH:21][N:20]=[CH:25][CH:24]=3)=[O:27])=[O:30])[CH2:3][CH2:4]1)[CH:18]=[CH:17]2
Reactant: NC(=O)NC(=O)c1ccncc1
Reactant: NC1CCN(Cc2ccc3cc(F)ccc3c2)CC1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(NC(=O)c1ccncc1)NC1CCN(Cc2ccc3cc(F)ccc3c2)CC1

Procedure:
A mixture of 4-amino-1-[(6-fluoro-2-naphthalenyl)methyl]piperidine (1.3 g, 5 mmol), 4-pyridoylurea (0.9 g, 5 mmol) and pyridine (6 ml) was stirred at reflux for 16 hours. The solution was diluted with water (8 ml) and the precipitated dark brown product collected by filtration to give 1.5 g. The crude product was dissolved in chloroform (25 ml), shaken with decolourising charcoal, filtered and evaporated. The residue was suspended in hot ethanol (20 ml) and succinic acid (0.44 g) added to give a clear solution which crystallised on standing. The product crystals were collected by filtration and washed with ethanol to give the succinate salt of the title compound. m.p. 187°-188° C.
Reaction SMILES: C(OC1C(=O)N=C(CC2(C3C=CC=CC=3)CCCC2)N2CCN(C3CC3)C(=O)C=12)C1C=CC=CC=1.[CH3:36][C:37]([CH3:73])([CH3:72])[CH2:38][N:39]([CH2:69][CH2:70]O)[C:40]([C:42]1[C:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[C:46]([OH:56])[N:45]=[C:44]([CH2:57][C:58]2([C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[CH2:62][CH2:61][CH2:60][CH2:59]2)[N:43]=1)=[O:41]>>[CH2:49]([O:48][C:47]1[C:46](=[O:56])[N:45]=[C:44]([CH2:57][C:58]2([C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[CH2:62][CH2:61][CH2:60][CH2:59]2)[N:43]2[CH2:70][CH2:69][N:39]([CH2:38][C:37]([CH3:36])([CH3:73])[CH3:72])[C:40](=[O:41])[C:42]=12)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: CC(C)(C)CN(CCO)C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1CC1
Product: CC(C)(C)CN1CCn2c(CC3(c4ccccc4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O

Procedure:
This compound was prepared following the same method as described for 9-benzyloxy-2-cyclopropyl-6-(1-phenyl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (286) from 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2,2-dimethyl-propyl)-(2-hydroxyethyl)-amide (301) (140 mg, 0.27 mmol). Off-white sticky solid (120 mg, 88.8%).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][N:11]=[C:10]3[NH:15][CH:16]=[CH:17][C:9]=23)[C:5]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)=[N:4]1)[CH3:2].[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>>[CH2:25]([NH:27][C:28]([NH:22][C:21]1[CH:23]=[CH:24][C:18]([C:5]2[C:6]([C:8]3[C:13]([F:14])=[CH:12][N:11]=[C:10]4[NH:15][CH:16]=[CH:17][C:9]=34)=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=2)=[CH:19][CH:20]=1)=[O:29])[CH3:26]
Reactant: CCn1cc(-c2c(F)cnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Reactant: CCN=C=O
Product: CCNC(=O)Nc1ccc(-c2nn(CC)cc2-c2c(F)cnc3[nH]ccc23)cc1

Procedure:
Following the procedure described in Example 1 using 4-[1-ethyl-4-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and ethyl isocyanate afforded the title compound. ESMS [M+H]+: 393.4
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH:12]([CH3:14])[CH3:13])[C:6]=1[C:7](OCC)=[O:8].[CH:15]([NH2:17])=O>>[OH:8][C:7]1[C:6]2[C:5]([CH:12]([CH3:14])[CH3:13])=[CH:4][S:3][C:2]=2[N:1]=[CH:15][N:17]=1
Reactant: NC=O
Reactant: CCOC(=O)c1c(C(C)C)csc1N
Product: CC(C)c1csc2ncnc(O)c12

Procedure:
Using ethyl 2-amino-4-isopropylthiophene-3-carboxylate (800 mg, 3.8 mmol) and formamide (5 ml), a similar procedure to a) in Example 19 was carried out to obtain 4-hydroxy-5-isopropylthieno[2,3-d]pyrimidine (330 mg, 1.7 mmol) having the following physical properties:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][N:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][N:3]1[C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25][C:21]=3[NH:22][C:23]=2[CH:24]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:48].Cl>>[ClH:48].[ClH:48].[CH2:8]([N:6]1[CH2:5][CH2:4][N:3]([C:16]2[CH:17]=[CH:18][C:19]3[C:20]4[CH2:28][NH:27][CH2:26][CH2:25][C:21]=4[NH:22][C:23]=3[CH:24]=2)[C:2](=[O:1])[CH2:7]1)[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(N4CCN(CCc5ccccc5)CC4=O)ccc3c2C1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: O=C1CN(CCc2ccccc2)CCN1c1ccc2c3c([nH]c2c1)CCNC3
Yield: 73 %

Procedure:
tert-Butyl 7-(2-oxo-4-phenethylpiperazin-1-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (160 mg, 0.337 mmol) was deprotected and converted to the dihydrochloride salt according to Example 2 (step f) to provide the title compound (110 mg, 73%) as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 12.06 (s, 1H), 11.35 (s, 1H), 9.35 (s, 2H), 7.49 (d, J=8.3 Hz, 1H), 7.41-7.23 (m, 6H), 6.97-6.94 (dd, J=8.3, 1.7 Hz, 1H), 4.30 (s, 2H), 4.24-3.97 (m, 3H), 3.96-3.73 (m, 2H), 3.63-3.27 (m, 5H), 3.23-3.08 (m, 2H), 3.08-2.98 (m, 2H); ESI MS m/z 375 [M+H]+; HPLC (Method B) 98.8% (AUC), tR=11.2 min.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32](=[O:44])[C:33]([C:36]1[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][CH:37]=1)([CH3:35])[CH3:34])C>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH2:42][C:39]1[CH:38]=[CH:37][C:36]([C:33]([CH3:35])([CH3:34])[C:32]([O:31][CH3:29])=[O:44])=[CH:41][CH:40]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(CBr)cc1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COC(=O)C(C)(C)c1ccc(COc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol and 2-(4-Bromomethyl-phenyl)-2-methyl-propionic acid ethyl ester as in the procedure of Example 43. MS m/z 570;
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([NH2:15])[C:9]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[CH3:18][N:19]1[CH:23]=[C:22]([S:24](Cl)(=[O:26])=[O:25])[N:21]=[CH:20]1.N1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([NH:15][S:24]([C:22]2[N:21]=[CH:20][N:19]([CH3:18])[CH:23]=2)(=[O:26])=[O:25])[C:9]=1[F:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1c(F)ccc(N)c1F
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1cnc(S(=O)(=O)Nc2ccc(F)c(NC(=O)OC(C)(C)C)c2F)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
The tert-butyl-3-amino-2,6-difluorophenylcarbamate (50 mg, 0.20 mmol) prepared at Step 3 was added and dissolved into dichloromethane solvent. 1-methyl-1H-imidazole-4-sulfonyl chloride (44 uL, 0.25 mmol) and pyridine (50 uL, 0.61 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 74 mg of the target compound, tert-butyl-2,6-difluoro-3-(1-methyl-1H-imidazole-4-sulfonamido)phenylcarbamate (percentage yield: 95%), was obtained.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>CO>[O:12]1[CH2:13][CH2:14][N:9]([C:6]2[C:7]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:8][C:1](=[O:2])[C:3](=[O:4])[CH:5]=2)[CH2:10][CH2:11]1
Reactant: Oc1ccccc1O
Reactant: C1COCCN1
Solvent: CO
Product: O=C1C=C(N2CCOCC2)C(N2CCOCC2)=CC1=O

Procedure:
Pyrocatechol (99.0 g; 0.9 mole) was dissolved in methanol (2.5 l), then morpholine (360 ml; 4.1 mole) and cupric acetate (9.0 g) were added. Air was bubbled through the reaction solution for about 9 hours. The mixture was cooled and filtered; the solid was washed with methanol (1.5 l) and air dried. The yield was 150.3 g (60%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:15][CH:14]=1.I[CH2:30][CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCCC1.CN1CCCN(C)C1=O>[C:13]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:14]=[CH:15][C:16]([CH:19]([CH2:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:20]([OH:22])=[O:21])=[CH:17][CH:18]=1
Reactant: ICC1CCCC1
Reactant: O=C(O)Cc1ccc(-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)NC(C)C
Product: O=C(O)C(CC1CCCC1)c1ccc(-c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
A solution of diisopropylamine (6.93 mL, 49.5 mmol) in dry tetrahydrofuran (64 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (16 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (19.8 mL, 49.5 mmol). The yellow reaction mixture was stirred at −78° C. for 30 min and then treated dropwise with a solution of 4-biphenylacetic acid (5.00 g, 23.6 mmol) in a small amount of dry tetrahydrofuran. The reaction mixture turned dark in color and was allowed to stir at −78° C. for 45 min, at which time, a solution of iodomethylcyclopentane (4.96 g, 23.6 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C. over a period of 15 h. The reaction mixture was quenched with water (100 mL), and the reaction mixture was concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous layer was acidified to pH=2 with concentrated hydrochloric acid and then extracted with ethyl acetate (2×150 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded 2-biphenyl-4-yl-3-cyclopentylpropionic acid (5.13 g, 74%) as a white solid: mp 131-133° C.; FAB-HRMS m/e calcd for C20H22O2 (M+H)+ 294.1620, found 294.1626.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@@H:10]([S:25][CH2:26][C:27]1([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH2:29][CH2:28]1)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18]C2CCCCO2)[CH:12]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(N(CC)CC)C>CO>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@@H:10]([S:25][CH2:26][C:27]1([CH2:30][C:31]([O:33][CH3:34])=[O:32])[CH2:28][CH2:29]1)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=1
Reactant: COC(=O)CC1(CS[C@H](CCc2ccccc2Br)c2cccc(COC3CCCCO3)c2)CC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CC1(CS[C@H](CCc2ccccc2Br)c2cccc(CO)c2)CC1

Procedure:
A solution of the tetrahydropyranyl ether of Step 6 (1.552 g, 2.83 mmol) and pyridinium p-toluenesulfonate (176 mg, 0.25 equiv.) in 15 mL of MeOH was stirred at room temperature for 2 days. Triethylamine (100 μL, 1 equiv.) was then added, the solvent evaporated, and the residue purified by flash chromotography on silica with EtOAc:toluene 20:80. Yield 1.189 g, 91%.
Reaction SMILES: N#N.[CH3:3][C:4]1([C:9]2[S:10][C:11]([CH2:14][N:15]3[N:19]=[C:18]([N+:20]([O-])=O)[CH:17]=[N:16]3)=[CH:12][N:13]=2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([C:9]2[S:10][C:11]([CH2:14][N:15]3[N:19]=[C:18]([NH2:20])[CH:17]=[N:16]3)=[CH:12][N:13]=2)[O:5][CH2:6][CH2:7][O:8]1
Reactant: CC1(c2ncc(Cn3ncc([N+](=O)[O-])n3)s2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC1(c2ncc(Cn3ncc(N)n3)s2)OCCO1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 2-[2-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-5-ylmethyl]-4-nitro-2H-[1,2,3]triazole (201 mg, 0.68 mmol), iron powder (114 mg, 2.03 mmol) and NH4Cl (183 mg, 3.38 mmol) in a mixture of EtOH (3.0 mL) and water (1.5 mL) was stirred at 75° C. for 60 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (10 mL) was added followed by 1N NaOH (10 mL). The aq. layer was extracted with CH2Cl2 (2×10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil: TLC:rf (19:1 CH2Cl2-MeOH)=0.2. LC-MS-conditions 02: tR=0.68 min; [M+H]+=268.25.
Reaction SMILES: CC(C)([O-])C.[Na+].Br[C:8]1[S:12][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][CH:9]=1.[CH2:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.CO.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]>[CH2:18]([N:20]1[CH2:25][CH2:24][N:23]([C:8]2[S:12][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][CH:9]=2)[CH2:22][CH2:21]1)[CH3:19]
Reactant: CCN1CCNCC1
Reactant: CCOC(=O)c1ccc(Br)s1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N2CCN(CC)CC2)s1
Temperature: 110 °C
Reaction time: 18 h
Yield: 31.6 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (183 m,g, 0.20 mmol) followed by sodium tert-butoxide (538 mg, 5.60 mmol) was added to ethyl 5-bromothiophene-2-carboxylate (1.034 g, 4.40 mmol), 1-ethylpiperazine (0.51 ml, 4.00 mmol) and (rac)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (249 mg, 0.40 mmol) in toluene (20.00 ml) at 25° C. under nitrogen. The resulting suspension was stirred at 110° C. for 18 h. The cooled reaction mixture was diluted with methanol and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford crude product. The residue was purified by silica column chromatography, eluting with a gradient of 0 to 3% 7M NH3/MeOH in DCM. Fractions containing desired product were evaporated to dryness to give impure orange oil. The impure material was further purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford ethyl 5-(4-ethylpiperazin-1-yl)thiophene-2-carboxylate (339 mg, 32%) as a yellow oil.
Reaction SMILES: CC(C(N=NC1C=CC(Cl)=CC=1[N+]([O-])=O)C(N[C:8]1[CH:13]=[CH:12][C:11]2[NH:14][C:15]([NH:17][C:10]=2[CH:9]=1)=[O:16])=O)=O.[Br-].NC1C=C[N+](CC)=CC=1.[N+]([O-])(O)=O.N([O-])=O.[Na+]>O>[N:14]1[C:15](=[O:16])[N:17]=[C:10]2[CH:9]=[CH:8][CH:13]=[CH:12][C:11]=12
Reactant: CC(=O)C(N=Nc1ccc(Cl)cc1[N+](=O)[O-])C(=O)Nc1ccc2[nH]c(=O)[nH]c2c1
Agent: CC[n+]1ccc(N)cc1
Agent: O=N[O-]
Agent: [Br-]
Solvent: O
Solvent: O=[N+]([O-])O
Product: O=C1N=c2ccccc2=N1
Temperature: 75 °C
Reaction time: 0.08 h

Procedure:
20 parts of abenzimidazolone orange pigment (C.I. pigment orange 36) which had been previously finely ground and 62 parts of p-amino-N-ethylpyridinium bromide were dispersed in 150 parts of water. To the mixture were then added dropwise 32 parts of nitric acid. The mixture was then stirred at a temperature of 75° C. for 5 minutes. To the mixture was then added an aqueous solution of sodium nitrite. The mixture was further stirred for 2 hours, and then repeatedly rinsed and filtered to obtain a slurry of a surface-treated benzimidazolone orange pigment having an N-ethylpyridyl group introduced therein with the interposition of phenyl group.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][N:6]([C:8]2[CH:23]=[C:13]3[C:14]4[C:19]([CH2:20][CH2:21][N:12]3[C:11](=[O:24])[CH2:10][N:9]=2)=[C:18](I)[CH:17]=[CH:16][CH:15]=4)[CH:7]=1)[CH3:2].C([Sn](CCCC)(CCCC)[C:30]1[O:31][CH2:32][CH2:33][CH:34]=1)CCC>O1CCOCC1.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>[O:31]1[CH2:32][CH2:33][CH:34]=[C:30]1[C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[CH2:20][CH2:21][N:12]1[C:11](=[O:24])[CH2:10][N:9]=[C:8]([N:6]3[CH:7]=[C:3]([CH2:1][CH3:2])[N:4]=[CH:5]3)[CH:23]=[C:13]12
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCCO1
Reactant: CCc1cn(C2=NCC(=O)N3CCc4c(I)cccc4C3=C2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCc1cn(C2=NCC(=O)N3CCc4c(C5=CCCO5)cccc4C3=C2)cn1
Temperature: 150 °C
Yield: 56.5 %

Procedure:
111-2. A mixture of 2-(4-ethyl-1H-imidazol-1-yl)-9-iodo-7,8-dihydro-[1,4]diazepino[7,1-a]isoquinolin-5(4H)-one (520 mg, 1.20 mmol), tributyl(4,5-dihydrofuran-2-yl)stannane (864 mg, 2.41 mmol) and Pd(PPh3)4 (70 mg, 0.06 mmol) in dioxane (10 mL) was heated to 150° C. for 1.5 h. The mixture was filtered and the filtrate concentrated in vacuo. Purification by flash chromatography (SiO2, DCM to DCM/MeOH 95:5) afforded the title compound (254 mg) as a beige solid. UPLC-MS: MS 375.3 (M+H+); UPLC rt 0.91 min.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.CN(C)[CH:26]=[O:27]>C1COCC1>[Cl:13][C:14]1[C:23]([CH:26]=[O:27])=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: CN(C)C=O
Reactant: Clc1ccc2ccccc2n1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=Cc1cc2ccccc2nc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To a solution of 0.46 mL (3.30 mmol) of diisopropylamine in 8 mL of THF at 0° C. was added 1.53 mL (3.30 mmol) of n-BuLi dropwise. After 20 min the solution was cooled to -78° C. and 2-chloroquinoline (491 mg, 3.0 mmol) was added neat. The mixture was stirred at -78° C. for 30 min, then dimethylformamide (0.39 mL, 5.04 mmol) was added dropwise and the reaction mixture was stirred an additional 30 min at this temperature. After quenching at -78° C. with glacial acetic acid (1 mL), the mixture was warmed to room temperature and diluted with ether (30 mL). The organic phase was washed with saturated NaHCO3 solution (10 mL) and brine (10 mL), and was dried over MgSO4. Concentration afforded 2-chloro-3-quinolinecarboxaldehyde (530 mg, 92%) as a light yellow solid (mp 145°-149 ° C.), which was used directly in the next step without further purification. Recrystallization from ethyl acetate afforded the pure compound as light yellow needles: mp 149°-150° C. (mp 148°-149° C. reported in Meth-Cohn, O.; Narhe, B.; Tarnowski, B. J. Chem. Soc. Perkin Trans. I 1981, 1520.). 1H NMR (300 MHZ, CDCl3) δ 10.57 (s, 1H), 8.77 (s, 1H), 8.08 (d, 1H, J=9 HZ), 8.0 (d, 1H, J=9 HZ), 7.90 (t, 1H, J=9 HZ), 7.67 (t, 1H, J=9 HZ); IR (nujol) 1685, 1575, 1045, 760, 745 cm-1.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[CH2:15][CH:16]=O.[Br:18][C:19]1[CH:24]=[C:23]([NH:25]C(=O)OC(C)(C)C)[C:22]([CH:33]=O)=[CH:21][N:20]=1.Cl>O1CCOCC1.O.C(OCC)(=O)C>[Br:18][C:19]1[CH:24]=[C:23]2[C:22]([CH:33]=[C:15]([C:9]3[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=3[Cl:7])[CH:16]=[N:25]2)=[CH:21][N:20]=1
Reactant: O=CCc1cc(F)ccc1Cl
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)ncc1C=O
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Fc1ccc(Cl)c(-c2cnc3cc(Br)ncc3c2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29.6 %

Procedure:
To a slurry of potassium tert-butoxide (94 mg, 0.8 mmol) in 1,4-dioxane (1 mL) cooled at 0° C. was added 2-(2-chloro-5-fluorophenyl)acetaldehyde (98 mg, 0.4 mmol) as a solution in 1,4-dioxane (0.6 mL). The reaction mixture was stirred for 10 minutes at this temperature, and then tert-butyl 2-bromo-5-formylpyridin-4-ylcarbamate (60 mg, 0.2 mmol) was added as a solution in dioxane (0.6 mL). The reaction mixture was allowed to warm to room temperature, and after 30 minutes a 5.0M solution of hydrogen chloride in water (0.5 mL) was added and the mixture was heated at 100° C. for 1 hour. The cooled reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (50 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 4 g, ISCO, 0-50% ethyl acetate in heptane) to afford the title compound as an off-white solid (20 mg, 30%), which was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:13][O:14][C:15]1[C:16]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][N:24]2[CH2:25][CH2:26][N:21]([C:16]3[C:15]([O:14][CH3:13])=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:22][CH2:23]2)=[CH:5]1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: COc1cccnc1N1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Solvent: CC#N
Product: COc1cccnc1N1CCN(CCc2c[nH]c3ccccc23)CC1

Procedure:
A mixture of 3-(2-bromoethyl)indole (2.00 g), 1-(3-methoxy-2-pyridinyl)piperazine (1.72 g), micropulverized K2CO3 (2.46 g) and tetrabutylammonium hydrogen sulfate (0.15 g), in acetonitrile (50 mL) was heated at reflux under N2 atmosphere for 5 h. The excess acetonitrile was removed under reduced pressure and water (10 mL) was added to the concentrate. The aqueous phase was extracted with CH2Cl2 (3×50 mL). The combined CH2Cl2 extracts were washed with sat. NaCl solution, dried with anhydrous K2CO3, and concentrated under reduced pressure. Silica gel chromatography (CH2Cl2 /MeOH; 96.4) of the residue yielded the free base of the desired Ia product (1.32 g; 44%).