Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[CH3:28][O:29][CH2:30][CH2:31][NH:32][C:33]1[CH:38]=[N:37][C:36]([NH2:39])=[CH:35][N:34]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:39][C:36]2[CH:35]=[N:34][C:33]([NH:32][CH2:31][CH2:30][O:29][CH3:28])=[CH:38][N:37]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: COCCNc1cnc(N)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: COCCNc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 185.8 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 325 mg, 0.33 mmol) in methylene chloride (15 mL) cooled to 0° C. was treated with a 2.0M solution of oxalyl chloride in methylene chloride (565 μL, 1.13 mmol) and N,N-dimethylformamide (1 drop). The reaction mixture was stirred at 0° C. for 30 min, concentrated in vacuo, and azeotroped with methylene chloride (2 mL) two times. The resulting oil was dissolved in tetrahydrofuran (5 mL) at 25° C. and then treated dropwise with a solution of N-(2-methoxy-ethyl)-pyrazine-2,5-diamine (182 mg, 1.08 mmol) and 2,6-lutidine (137 μL, 1.18 mmol) in tetrahydrofuran (6 mL) via an addition funnel. The resulting cloudy solution was then stirred overnight for 16 h at 25° C. After this time, the reaction was diluted with water (10 mL) and then extracted with methylene chloride (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 2/3 to 1/4 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-methoxy-ethylamino)-pyrazin-2-yl]-propionamide (295 mg, 62%) as a white foam: (ES)+-HRMS m/e calcd for C22H29ClN4O4S (M+H)+ 481.1671, found 481.1678.
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[C:10](=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:20]1([CH2:26][CH2:27]O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:27][CH2:26][N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:14][CH:13]=2)[C:10](=[O:19])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1nc2ccccc2c(=O)n1-c1ccc(O)cc1
Reactant: OCCN1CCCCC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1nc2ccccc2c(=O)n1-c1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 0.86 %

Procedure:
2-methyl-3-(4-hydroxyphenyl)-4-(3H)quinazolinone synthesized according to Example 1-(1) and -(2) (100 mg, 0.40 mmol), 2-(1-piperidinyl)ethanol (89 mg, 0.50 mmol) and triphenylphosphine (125 mg, 0.50 mmol) were dissolved in dry tetrahydrofuran (2 mL) and cooled on an ice bath. Diethylazodicarboxylate (75 uL, 0.50 mmol) was dripped in at 0° C. and stirred at room temperature for 48 hours. The solvent was distilled off under reduced pressure, ether was added, the solid precipitate was filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol=30/1) and the title compound (124 mg, 0.86%) was obtained as a light brown oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][N:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C:19]2([C:41](O)=[O:42])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:44]([C:51]1([S:54]([NH2:57])(=[O:56])=[O:55])[CH2:53][CH2:52]1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=[CH:32][N:31]=3)[CH2:25]2)[C:21](=[O:40])[NH:20][C:19]2([C:41]([NH:57][S:54]([C:51]3([CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH2:53][CH2:52]3)(=[O:55])=[O:56])=[O:42])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NS(=O)(=O)C1(Cc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)NS(=O)(=O)C2(Cc3ccccc3)CC2)NC(=O)C2CC(Oc3nccc4ccccc34)CN2C1=O

Procedure:
Prepared from 14-tert-butoxycarbonylamino-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]-nonadec-7-ene-4-carboxylic acid (50 mg, 0.075 mmol) and 1-benzyl-cyclopropanesulfonic acid amide (21 mg, 0.098 mmol, prepared as described above) to give [4-(1-benzyl-cyclopropanesulfonylaminocarbonyl)-18-(isoquinolin-1-yloxy)-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-en-14-yl]-carbamic acid tert-butyl ester as a white powder: 1H NMR (500 MHz, CD3Cl3) δ 1.23 (s, 9H), 1.04–1.92 (m, 14H), 1.96 (m, 1H), 2.32 (dd, J=17.7 Hz, 9.5 Hz, 1H), 2.59 (m, 1H), 2.70 (m, 2H), 3.20 (d, J=13.4 Hz, 1H), 3.41 (d, J=13.7 Hz, 1H), 4.02 (m, 1H), 4.29(m, 1H), 4.61 (m, 2H), 5.01 (d, J=7.6 Hz, 1H), 5.15 (m, 1H), 5.78 (m, 1H), 5.92 (s, 1H), 6.65 (s, 1H), 7.08 (d, J=8.2 Hz, 2H), 7.26 (m, 4H), 7.46 (t, J=7.3 Hz, 1H), 7.64 (t, J=7.3 Hz, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.97 (d, J=5.8 Hz, 1H), 8.17 (d, J=8.9 Hz, 1H), 10.05 (s, 1H). LC-MS (Method A, retention time: 3.87 min), MS m/z 786 (M++1).
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:9][C:10]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:11]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20])=[O:13].CO.C1C=CC=CC=1>C(Cl)Cl>[NH2:1][C:2]1[C:3]([NH:9][C:10]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[O:13])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccnc1Cl
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Solvent: CO
Solvent: c1ccccc1
Solvent: ClCCl
Product: Nc1cccnc1Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Temperature: 190 °C
Reaction time: 8 h
Yield: 5.4 %

Procedure:
A stirred mixture of 20.0 g (0.156 mole) of 3-amino-2-chloropyridine and 37.3 g (0.14 mole) of 2-amino-2',5-dichlorobenzophenone was heated at 190° C. under nitrogen atmosphere for 5.5 hr. Thin layer chromatography (5% methyl alcohol-benzene on silica gel) indicated reaction had not substantially occurred. The mixture was stirred overnight at 190° C., cooled somewhat, and 100 ml methylene chloride was added cautiously. The suspension was stirred for two hr and the black solid which formed was separated by filtration. The solid was suspended in 500 ml of methylene chloride and 300 ml of dilute sodium hydroxide was added. An emulsion formed and the mixture was filtered which allowed separation of layers. The methylene chloride layer was washed with two 250 ml portions of water by extraction, dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in benzene and filtered through a 300 g column of florisil to remove low Rf material. All fractions were combined and evaporated under reduced pressure. Thin layer chromatography showed presence of two major components with lower Rf spot predominating. The residue was dissolved in benzene and chromatographed on a 600 g column of florisil packed in benzene. The higher Rf material was eluted with 1% acetone-benzene. On evaporation, the residue was triturated in benzene and recrystallized from benzene-isooctane to give 2.7 g product; m.p. 162°-4° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]2([CH3:16])[CH3:15])#[CH:2].[CH3:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][C:21]=1[F:27].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[O:9][C:8]([CH3:14])([CH3:13])[CH2:7][C:6]3([CH3:16])[CH3:15])=[CH:22][C:21]=1[F:27]
Reactant: C#Cc1ccc2c(c1)C(C)(C)CC(C)(C)O2
Reactant: COC(=O)c1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC(C)(C)O3)cc1F

Procedure:
Following general procedure F and using 6-ethynyl-2,2,4,4-tetramethylchroman (0.11 g, 0.51 mmol), methyl-2-fluoro-4-iodo-benzoate (Reagent G, 0.14 g, 0.51 mmol), triethyl amine (5 mL), tetrahydrofiran(10 mL), copper(I)iodide(0.030 g, 0.16 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.110 g, 0.16 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-10% ethyl acetate in hexane as the eluent, the title compound was obtained (0.14 g, 79%).
Reaction SMILES: [NH2:1][C:2]([S:37][CH3:38])=[C:3]([N:9]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([N:32]=[CH:33][N:34]([CH3:36])[CH3:35])(=[O:31])=[O:30])=[CH:19][CH:18]=1)[C:10](=O)[CH2:11][CH2:12][CH2:13][CH3:14])[C:4]([O:6][CH2:7][CH3:8])=[O:5]>C1(C)C=CC=CC=1>[CH2:11]([C:10]1[N:9]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29]([N:32]=[CH:33][N:34]([CH3:36])[CH3:35])(=[O:31])=[O:30])=[CH:21][CH:22]=2)[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([S:37][CH3:38])[N:1]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2S(=O)(=O)N=CN(C)C)cc1)C(C(=O)OCC)=C(N)SC
Solvent: Cc1ccccc1
Product: CCCCc1nc(SC)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2S(=O)(=O)N=CN(C)C)cc1
Yield: 413.3 %

Procedure:
50 mg of the product of Stage E, 500 ml of toluene, and a catalytic quantity of amberlyst 15 were mixed together and the mixture was refluxed for 20 hours. The amberlyst was filtered off, followed by washing. The solvents were eliminated under reduced pressure to obtain 0.20 g of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[S:6][C:7]([C:9]3[C:18]([N:19]4[CH2:23][CH2:22][CH2:21][C@@H:20]4[CH3:24])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:25]([O:27]C)=[O:26])[CH:15]=4)[N:10]=3)=[CH:8][C:4]=2[CH:3]=1.[OH-].[Na+]>CO.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[S:6][C:7]([C:9]3[C:18]([N:19]4[CH2:23][CH2:22][CH2:21][C@@H:20]4[CH3:24])=[N:17][C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:25]([OH:27])=[O:26])[CH:15]=4)[N:10]=3)=[CH:8][C:4]=2[CH:3]=1
Reactant: COC(=O)c1ccc2nc(-c3cc4cc(F)ccc4s3)c(N3CCC[C@@H]3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C[C@H]1CCCN1c1nc2cc(C(=O)O)ccc2nc1-c1cc2cc(F)ccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
To a solution of (S)-methyl 2-(5-fluorobenzo[b]thiophen-2-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylate (89 mg, 0.21 mmol) in methanol (25 mL) and chloroform (5 mL) was added sodium hydroxide (25.2 mg, 0.63 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated in vacuo, dissolved in water (15 mL), adjusted pH to 5 with HCl (3 N) to give the precipitate, which was collected by filtration to afford (S)-2-(5-fluorobenzo[b]thiophen-2-yl)-3-(2-methylpyrrolidin-1-yl)quinoxaline-6-carboxylic acid (56 mg, 65%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[O:12][C:13]([CH3:16])=[CH:14][N:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[CH2:48][CH2:47][N:46]3[C:39](=[CH:40][C:41]4[CH2:42][C:43]([CH3:50])([CH3:49])[CH2:44][C:45]=43)[C:38]2=[O:51])=[N:24][CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1)(=[O:19])[CH3:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>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(#N)C.O>[C:17]([O:20][CH2:21][C:22]1[C:23]([N:37]2[CH2:48][CH2:47][N:46]3[C:39](=[CH:40][C:41]4[CH2:42][C:43]([CH3:50])([CH3:49])[CH2:44][C:45]=43)[C:38]2=[O:51])=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[O:12][C:13]([CH3:16])=[CH:14][N:15]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cc1cnc(Nc2cc(Br)cn(C)c2=O)o1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ncc(C)o3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 90 °C
Yield: 33.9 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 262a (150 mg, 0.53 mmol), {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (421 mg, 1.06 mmol), Pd(dppf)Cl2 (37 mg, 0.050 mmol), K3PO4 (225 mg, 1.06 mmol), sodium acetate (87 mg, 1.06 mmol), water (0.5 mL), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at 90° C. for 1 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (50:1 to 30:1) to afford 262b as yellow solid (100 mg, 34%). MS-ESI: [M+H]+ 556.9.
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:17]3[CH:26]4[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25]4)[CH2:20][CH2:19][CH2:18]3)=[O:16])=[CH:14][C:9]=2[N:8]=[CH:7]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:17]3[CH:26]4[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25]4)[CH2:20][CH2:19][CH2:18]3)=[O:16])=[CH:14][C:9]=2[N:8]=[CH:7]1
Reactant: [N-]=[N+]=NCCn1cnc2cc(C(=O)N3CCCC4CCCCC43)ccc21
Agent: [Pd]
Solvent: CO
Product: NCCn1cnc2cc(C(=O)N3CCCC4CCCCC43)ccc21
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of [1-(2-azidoethyl)-1H-benzimidazol-5-yl]-(octahydroquinolin-1-yl)methanone (1.8 g, 0.0051 mol) in methanol (10 mL) was added 10% Pd/C (0.2 g). The reaction mixture was hydrogenated at 3 kg pressure for 2 h. The catalyst was filtered over celite and the filtrate was concentrated to give [1-(2-aminoethyl)-1H-benzimidazol-5-yl]-(octahydroquinolin-1-yl)methanone (1.5 g, 90%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:22])[CH:3]=1.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:22][C:4]1[CH:3]=[C:2]([C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([O:25][C:24]([F:23])([F:35])[F:36])[CH:27]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10]
Reactant: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cccc(OC(F)(F)F)c2)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
To a degassed solution of 0.130 g (0.35 mmol) of (4-bromo-2,6-dimethyl-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (intermediate 1) and 0.147 g (0.70 mmol) of 3-trifluoromethoxy-phenyl boronic acid in 5 ml of DMF was added 2.50 ml of tribasic potassium phosphate solution (2M in water) drop by drop, followed by 0.022 g (0.019 mmol) of tetrakis-(triphenylphosphine)-palladium. This reaction mixture was stirred at 80° C. for two hours and subsequently cooled down to RT, then poured into crashed ice and extracted three times with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 95:5) to give 0.12 g (77%) of the title compound as light yellow amorphous solid. MS: 447.2 (MH+).
Reaction SMILES: BrC1C=CC(C2C3C=CC(O)=CC=3OC=2)=CC=1.BrCCCCCCBr.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:49]=[CH:48][C:37]2[C:38]([C:41]3[CH:46]=[CH:45][C:44]([Br:47])=[CH:43][CH:42]=3)=[CH:39][O:40][C:36]=2[CH:35]=1.[CH2:50]([NH:53][CH3:54])[CH:51]=[CH2:52]>>[CH2:50]([N:53]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][C:34]1[CH:49]=[CH:48][C:37]2[C:38]([C:41]3[CH:46]=[CH:45][C:44]([Br:47])=[CH:43][CH:42]=3)=[CH:39][O:40][C:36]=2[CH:35]=1)[CH3:54])[CH:51]=[CH2:52]
Reactant: BrCCCCCCOc1ccc2c(-c3ccc(Br)cc3)coc2c1
Reactant: C=CCNC
Agent: BrCCCCCCBr
Agent: Oc1ccc2c(-c3ccc(Br)cc3)coc2c1
Product: C=CCN(C)CCCCCCOc1ccc2c(-c3ccc(Br)cc3)coc2c1

Procedure:
Analogously to Example 18d, from 3-(4-bromo-phenyl)-benzofuran-6-ol and 1,6-dibromohexane via 6-(6-bromo-hexyloxy)-3-(4-bromo-phenyl)-benzofuran and by reaction with N-allyl-methyl-amine there is obtained allyl-[6-[3-(4-bromo-phenyl)-benzofuran-6-yloxy]-hexyl]-methyl-amine which is converted into the fumarate, MS: m/e 442 (M+H+, 1 Br).
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][C:17](=[O:20])[N:18]([CH3:19])[C:12]2=[N:11][C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])C1C=CC=CC=1>FC(F)(F)C(O)=O>[OH:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][C:17](=[O:20])[N:18]([CH3:19])[C:12]2=[N:11][C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC(=O)N2C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nc2n(c(=O)c1O)CC(=O)N2C
Yield: 83.3 %

Procedure:
Reaction of intermediate 12, ethyl 6-benzyloxy-1-methyl-2,5-dioxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate, (0.500 g, 1.46 mmol) with trifluoroacetic acid (20 ml) as described in the preparation of intermediate 5 gave 0.308 g (83% yield) of the title ester as white crystals; mp 229–230° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.49 (3H, t, J=7.1 Hz, CH3), 3.31 (3H, s, NCH3), 4.51 (2H, q, J=7.2 Hz, OCH2), 4.55 (2H, s, CH2), 10.84 (2H, s, OH). Anal. Calcd for C10H11N3O5: C, 47.43; H, 4.37; N, 16.59. Found: C, 47.22; H, 4.13; N, 16.48.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:14][N:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:20][C:21]#[N:22].Cl>C(Cl)Cl>[C:5]([C:19]1[N:15]([CH3:14])[C:16]([CH2:20][C:21]#[N:22])=[CH:17][CH:18]=1)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cn1cccc1CC#N
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cn1c(CC#N)ccc1C(=O)c1ccccc1
Temperature: 0 °C

Procedure:
To a chilled suspension of 9.7 g. (0.07 mole) of aluminum chloride in 45 ml. methylene chloride is added 9 ml. (0.07 mole) benzoyl chloride. The resulting solution is added dropwise to a solution of 1-methylpyrrole-2-acetonitrile in 30 ml. methylene chloride while cooling externally with an ammonium chloride ice bath (temperature below 5° C.). After the addition is complete, the reaction mixture is stirred at 0° C. for fifteen minutes and then poured into ice acidified with 3N hydrochloric acid. The acidic fraction is extracted three times with methylene chloride. The organic fractions are combined and washed consecutively with N,N-dimethyl-1,3-propanediamine and 3N hydrochloric acid. The organic solution is dried over anhydrous magnesium sulfate. The solvent is then evaporated off to yield an oily residue which is column chromatographed on neutral alumina using hexane, benzene and ethylacetate as successive solvents. The first few fractions having ultraviolet absorption in the 240-260 mμ range contain the desired product. These fractions are combined, the solvent evaporated off, and the oily residue, when triturated with methanol, yields the crystalline product, 5-benzoyl-1-methylpyrrole-2-acetonitrile, m.p. 106-108° C.
Reaction SMILES: [C:1]12([OH:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([C:22](O)=[O:23])[CH:13]=1.CN(C1C=CC=CN=1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C=O>[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([C:22]([O:11][C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]4)[CH2:2]2)[CH2:10]3)=[O:23])[CH:13]=1
Reactant: O=C(O)c1cnc2ccccc2c1
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(OC12CC3CC(CC(C3)C1)C2)c1cnc2ccccc2c1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A mixture of 1-adamantanol (152 mg, 1.0 mmol), 3-quinolinecarboxylic acid (173 mg, 1.0 mmol), and dimethylaminopyridine (122 mg, 1.0 mmol) in dichloromethane (2 mL) and N,N-dimethylformamide (2 mL) was cooled to 0° C. 1,3-Dicyclohexylcarbodiimide (227 mg, 1.1 mmol) in dichloromethane (1 mL) was added in one portion. The reaction mixture was stirred at 25° C. for 20 h. The reaction mixture was then diluted with dichloromethane (40 mL) and washed with 1 M sodium hydroxide (3×30 mL). The organic layer was dried (anhydrous magnesium sulfate), filtered through Celite, and rotary evaporated. The resulting material was purified by spinning thin-layer chromatography (3% methanol in chloroform). The purest fraction was rotary evaporated, and the resulting material was recrystallized from ethanol. This provided 42 mg (14%) of (101):
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=1.[Br:19]NC(=O)CCC(N)=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[O:3][C:4]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][Br:19])[CH:8]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: Cc1cccc(-c2c(Br)oc3ccc(Cl)cc23)c1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc2oc(Br)c(-c3cccc(CBr)c3)c2c1

Procedure:
A mixture of 22.6 g (0.07 mole) of 2-bromo-5-chloro-3-(3-methylphenyl) benzofuran, 12.5 g (0.07mole) of N-bromosuccinamide in 500 ml of carbon tetrachloride is irradiated and heated with a sun lamp for about 20 hours. The reaction mixture is filtered hot and the filtrate is allowed to cool. A solid forms which is collected, washed with carbon tetrachloride, and dried, then recrystallized from ethyl acetate to provide white product, 2-bromo-3-(3-bromomethylphenyl)-5-chlorobenzofuran, which is used directly in the next step.
Reaction SMILES: CO[C:3]1[CH:8]=[C:7]([O:9]C)[CH:6]=[C:5]([O:11]C)[C:4]=1[C:13]1[C:18]([O:19]C)=[CH:17][C:16]([O:21]C)=[CH:15][C:14]=1[O:23]C.Br.C([O-])(O)=O.[Na+]>C(O)(=O)C>[OH:11][C:5]1[C:4]2[C:13]3[C:14]([OH:23])=[CH:15][C:16]([OH:21])=[CH:17][C:18]=3[O:19][C:3]=2[CH:8]=[C:7]([OH:9])[CH:6]=1
Reactant: COc1cc(OC)c(-c2c(OC)cc(OC)cc2OC)c(OC)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1cc(O)c2c(c1)oc1cc(O)cc(O)c12
Yield: 76.8 %

Procedure:
Compound 7 (3 g, 8.97 mmol) was refluxed for 18 h in a 20 mL solution consisting of a 1:1 mixture of HBr and acetic acid. The reaction mixture was neutralized by adding saturated aqueous NaHCO3. The subsequent mixture was then extracted with ethyl acetate and the organic layer was further washed with brine, water and dried over Na2SO4. After removing the solvent in vacuo, the brown, viscous residue was purified by column chromatography (5-20% ethyl acetate/hexane) to yield 8 (1.6 g, 77%) as a yellow solid.