Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C@@H:14]([C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]([C:64]2[CH:69]=[CH:68][C:67]([NH:70][C:71](=[O:94])[C@H:72]([CH2:81][CH2:82][NH:83][C:84]([O:86][CH2:87][C:88]3[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=3)=[O:85])[NH:73]C(OC(C)(C)C)=O)=[CH:66][CH:65]=2)[C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:40](=[O:63])[C@H:41]([CH2:50][CH2:51][NH:52][C:53]([O:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[O:54])[NH:42]C(OC(C)(C)C)=O)=[CH:35][CH:34]=2)=[CH:28][CH:27]=1)=[O:24])[NH:15]C(OC(C)(C)C)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:95].O1CCOCC1>O1CCCC1>[ClH:95].[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C@@H:14]([C:23]([NH:25][C:26]1[CH:27]=[CH:28][C:29]([CH:32]([C:64]2[CH:69]=[CH:68][C:67]([NH:70][C:71](=[O:94])[C@H:72]([CH2:81][CH2:82][NH:83][C:84]([O:86][CH2:87][C:88]3[CH:89]=[CH:90][CH:91]=[CH:92][CH:93]=3)=[O:85])[NH2:73])=[CH:66][CH:65]=2)[C:33]2[CH:38]=[CH:37][C:36]([NH:39][C:40](=[O:63])[C@H:41]([CH2:50][CH2:51][NH:52][C:53]([O:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)=[O:54])[NH2:42])=[CH:35][CH:34]=2)=[CH:30][CH:31]=1)=[O:24])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCNC(=O)OCc1ccccc1)C(=O)Nc1ccc(C(c2ccc(NC(=O)[C@H](CCNC(=O)OCc3ccccc3)NC(=O)OC(C)(C)C)cc2)c2ccc(NC(=O)[C@H](CCNC(=O)OCc3ccccc3)NC(=O)OC(C)(C)C)cc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: N[C@@H](CCNC(=O)OCc1ccccc1)C(=O)Nc1ccc(C(c2ccc(NC(=O)[C@@H](N)CCNC(=O)OCc3ccccc3)cc2)c2ccc(NC(=O)[C@@H](N)CCNC(=O)OCc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The tris[4-(β-benzyloxycarbonylaminomethyl-N-t-butoxycarbonyl-L-alanyl)aminophenyl]methane (the total amount obtained in the previous reaction) was dissolved in tetrahydrofuran (4 mL), and a hydrochloric acid/dioxane solution (2 N, 4 mL) was added while cooling on ice. The mixture was raised to room temperature and stirred for 4 hours, and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:16]([CH2:17][O:18]CC[Si](C)(C)C)[C:5]2[N:6]=[CH:7][N:8]=[C:9]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:4]=2[C:3]=1[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29]>FC(F)(F)C(O)=O>[OH:18][CH2:17][N:16]1[C:5]2[N:6]=[CH:7][N:8]=[C:9]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[C:4]=2[C:3]([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[C:28]#[N:29])=[C:2]1[CH3:1]
Reactant: Cc1c(-c2cccc(C#N)c2)c2c(N3CCOCC3)ncnc2n1COCC[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2cccc(C#N)c2)c2c(N3CCOCC3)ncnc2n1CO
Yield: 128.7 %

Procedure:
A solution of 3-[6-methyl-4-(morpholin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (C8) (125 mg, 0.278 mmol) in trifluoroacetic acid (10 mL) was stirred at room temperature for 2 hours, then concentrated in vacuo to provide the product as a yellow solid (125 mg). This was used in the next step without additional purification. LCMS m/z 349.9 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.S(=O)(=O)(O)[OH:19].[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:5]([C:8]([NH2:9])=[O:19])=[N:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ncc(Br)cc1Oc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1ncc(Br)cc1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A flask was charged with 5-bromo-3-(4-fluorophenoxy)picolinonitrile (10 g, 34 mmol) and sulfuric acid (50 mL). The reaction was stirred at ambient temperature overnight. Water (500 mL) was added carefully and the mixture was adjusted to pH 5.0 using 50% sodium hydroxide. The mixture was extracted with dichloromethane and ethyl acetate, dried and concentrated to afford 5-bromo-3-(4-fluorophenoxy)picolinamide (10.6 g, 34 mmol, 100% yield) as yellow solid.
Reaction SMILES: [CH3:1][Si:2]([CH3:11])([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>C1(C)C=CC=CC=1.C1(C=CC(O)=CC=1)O>[C:19]([O:9][C:6]1[CH:7]=[CH:8][C:3]([Si:2]([CH3:11])([CH3:10])[CH3:1])=[CH:4][CH:5]=1)(=[O:22])[CH:20]=[CH2:21]
Reactant: C[Si](C)(C)c1ccc(O)cc1
Reactant: C=CC(=O)Cl
Agent: Oc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC(=O)Oc1ccc([Si](C)(C)C)cc1
Yield: 83.5 %

Procedure:
8.32 g (0.05 mole) of p-trimethylsilylphenol was dissolved in 25 ml toluene. 6.1 g (0.06 mole) triethyl amine and 0.05 g hydroquinone was added. The solution was warmed. 5.43 g (0.06 mole) of acryloyl chloride was added over a 15 minute period. After 11/2 hours, the solution was washed two times with 5 percent sodium carbonate in water and separated. After washing with brine and separating, the organic phase was dried over magnesium sulfate, filtered, and the solvent removed in a rotary evaporator under reduced pressure. Vacuum distillation yielded 9.2 g of pure p-trimethylsilylphenyl acrylate.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[NH:13][C:14](=[O:26])[C:15]3[C:21]([O:22][CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[N:18][C:16]=3[N:17]=2)=[CH:7][C:6]=1[CH3:27].[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH3:27][C:6]1[CH:7]=[C:8]([C:12]2[NH:13][C:14](=[O:26])[C:15]3[C:21]([O:22][CH3:23])=[CH:20][C:19]([O:24][CH3:25])=[N:18][C:16]=3[N:17]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[O:4][CH2:3][CH2:2][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: C1CCNC1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCBr)c(C)c3)nc2n1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCN4CCCC4)c(C)c3)nc2n1

Procedure:
A solution of 2-[4-(2-bromo-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-pyrido[2,3-d]pyrimidin-4-one (0.20 g, 0.46 mmol) in pyrrolidine (2 mL) was stirred at room temperature for 3 hours. The excess pyrrolidine was removed under reduced pressure, and the residue was purified by column chromatography (silica gel 230-400 mesh; eluting with 2% 2.0 M ammonia in methanol solution and dichloromethane) to give the title compound as a white solid. Yield: 0.17 g (87%). MP 228-230° C. 1H NMR (400 MHz, CDCl3): δ 10.06 (s, 1H), 7.83 (s, 2H), 6.22 (s, 1H), 4.12 (s, 3H), 4.00 (s, 3H), 3.95 (t, J=6.0 Hz, 2H), 2.93 (t, J=6.0 Hz, 2H), 2.64 (m, 4H), 2.37 (s, 6H), 1.80 (m, 4H). MS (ES+) m/z: 425.19 (M+1).
Reaction SMILES: CS([C:5]1[S:6][C:7]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:8]=2[N:9]=1)(=O)=O.[NH2:18][C@@H:19]1[CH2:23][CH2:22][N:21]([C:24]([C:26]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=2[O:34][CH3:35])=[O:25])[CH2:20]1>>[CH3:35][O:34][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:26]=1[C:24]([N:21]1[CH2:22][CH2:23][C@@H:19]([NH:18][C:5]2[S:6][C:7]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:8]=3[N:9]=2)[CH2:20]1)=[O:25]
Reactant: COc1cccc(OC)c1C(=O)N1CC[C@@H](N)C1
Reactant: CS(=O)(=O)c1nc2cc(C(F)(F)F)ccc2s1
Product: COc1cccc(OC)c1C(=O)N1CC[C@@H](Nc2nc3cc(C(F)(F)F)ccc3s2)C1

Procedure:
In analogy to the procedure described for example 202, step 4, the title compound was prepared from 2-methanesulfonyl-5-trifluoromethyl-benzothiazole and ((R)-3-Amino-pyrrolidin-1-yl)-(2,6-dimethoxy-phenyl)-methanone (Intermediate 5). (M+H+) 452.2.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH:12]3[CH2:13][CH2:14][CH:8]2[CH2:9][O:10][CH2:11]3)=[N:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1.C(O)C.[NH2:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH:12]12[N:7]([C:5]3[S:6][C:2]([C:32]4[CH:33]=[CH:34][C:29]([S:26]([NH2:25])(=[O:28])=[O:27])=[CH:30][CH:31]=4)=[C:3]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=4)[N:4]=3)[CH:8]([CH2:14][CH2:13]1)[CH2:9][O:10][CH2:11]2
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Clc1ccc(-c2nc(N3C4CCC3COC4)sc2Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: NS(=O)(=O)c1ccc(-c2sc(N3C4CCC3COC4)nc2-c2ccc(Cl)cc2)cc1
Temperature: 92.5 °C
Yield: 42 %

Procedure:
To a solution of 8-(5-bromo-4-(4-chlorophenyl)thiazol-2-yl)-3-oxa-8-azabicyclo[3.2.1]octane (Step 3 of compound 56, 0.26 g, 0.67 mmol) in a mixture of toluene:ethanol (2.5 ml:7.5 ml) were added 4-aminosulfonylbenzene boronic acid (0.15 g, 0.74 mmol) and potassium carbonate (0.23 g, 1.68 mmol) at 25° C. in a tube, the nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (0.039 g. 0.034 mmol) under nitrogen and the tube was sealed. The reaction mixture was heated at 90-95° C. for 18 hr with stirring. The progress of reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and filtered through celite. The residue was washed with mixture of 10% methanol in dichloromethane (2×20 ml). The filtrate was concentrated under reduced pressure to obtain a crude product; which was purified by flash column chromatography using 2-3% methanol in DCM as an eluent to obtain the title compound (0.13 g, 41.7%). MS: m/z 462 (M+1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Cl.C(N(CC)CC)C>CN(C)C=O>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: COc1cccc(CCl)c1
Reactant: CCOC(=O)C1CCCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCCN1Cc1cccc(OC)c1

Procedure:
A solution of ethyl 2-piperidinecarboxylate (10.0 ml), 3-methoxybenzyl chloride (9.2 ml), and triethylamine (26.6 ml) in N,N-dimethylformamide (64.0 ml) was stirred at room temperature overnight and partitioned between ethyl acetate and water. The organic layer was separated, washed with water (four times) and brine, dried over MgSO4, and evaporated in vacuo. The residue was chromatographed over silica gel to afford ethyl 1-(3-methoxybenzyl)-2-piperidinecarboxylate (12.06 g) as a colorless oil. (+) APCI-MS (m/z): 278 (M+ +1) IR (Film): 1725, 1600, 1260 cm-1NMR (CDCl3, δ): 1.29 (3H, t, J=7.1 Hz), 1.50-1.85 (6H, m), 2.10-2.22 (1H, m), 2.88-3.00 (1H, m), 3.14 (1H, dd, J=6.8, 5.2 Hz), 3.40 (1H, d, J=13.4 Hz), 3.78 (1H, d, J=13.4 Hz), 3.81 (3H, s), 4.21 (2H, q, J=7.1 Hz), 6.77-6.82 (1H, m), 6.89-6.93 (2H, m), 7.17-7.27 (1H, m)
Reaction SMILES: B(Br)(Br)Br.[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18]C)[C:13]=1[O:20]C>C(Cl)Cl>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:13]=1[OH:20]
Reactant: COc1cccc(CCCCCCBr)c1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1cccc(CCCCCCBr)c1O
Yield: 95.5 %

Procedure:
Boron tribromide (266 mL, 0.266 mol, 1M in methylene chloride) was added dropwise over 1 hour to a cooled (-65°) solution of 40.0 g (0.133 mol) of 1-(6-bromohexyl)-2,3-dimethoxybenzene in 800 mL of anhydrous methylene chloride which was stirred in an argon atmosphere. The cooling bath was then removed and the reaction mixture was stirred for 1.5 hours. After cooling in an ice bath, 100 mL of water and 50 mL of 3N HCl were added and the mixture was stirred for 2 hours. The organic layer was separated, dried and concentrated under reduced pressure to an oil which was purified by HPLC using 5% methanol-chloroform to yield 34.7 g of 1-(6-bromohexyl)-2,3-dihydroxybenzene as an oil. To this was added 32 mL (0.28 mol) of benzyl chloride, 46 g (0.28 mol) of potassium iodide, 122 g (0.88 mol) of potassium carbonate and 700 mL of anhydrous acetone and the reaction mixture was stirred at reflux for 72 hours. The solid was removed by filtration and the filtrate was concentrated under reduced pressure to an oil which was purified by HPLC using 1% ethyl acetate-hexane to give 47 g (74% yield) of 1-(6-Iodohexyl)-2,3-bis-(phenylmethoxy)benzene as an oil. The nmr spectrum was consistent with the structure (CH2I at δ3.14) and the mass spectrum showed the molecular ion at m/e 500 (C26H29IO2).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=1.[Si:14]([O:21][CH2:22]/[CH:23]=[N:24]/[S@:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>C1(C)C=CC=CC=1>[Si:14]([O:21][CH2:22][C@@H:23]([NH:24][S@:25]([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[S@](=O)/N=C/CO[Si](C)(C)C(C)(C)C
Reactant: Fc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)[S@](=O)N[C@H](CO[Si](C)(C)C(C)(C)C)c1ccc(F)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
To a solution of toluene (500 mL) at −78° C. was added butyl lithium (1.6 M in hexanes, 75.6 ml, 121 mmol) at a rate such that the internal temperature did not exceed −50° C. To this solution was added 2-bromo-5-fluoropyridine (23.2 g, 132 mmol) in toluene (200 mL) at a rate such that the internal temperature did not exceed −68° C. The reaction was stirred at −78° C. for 1 hour. To the reaction was added (S,E)-N-(2-(tert-butyldimethylsilyloxy)ethylidene)-2-methylpropane-2-sulfinamide (30.5 g, 110 mmol) in toluene (200 mL) at a rate such that the internal temperature did exceed −68° C. The reaction was again stirred at −78° C. for 1 hour. To the reaction was added 200 mL of water and the layers separated. The toluene solution was washed with water (200 mL), brine (200 mL), dried over MgSO4 and concentrated in vacuo. The crude material was chromatographed using 4:1 hexanes/ethyl acetate as eluent to yield (S)—N—((S)-2-(tert-butyldimethylsilyloxy)-1-(5-fluoropyridin-2-yl)ethyl)-2-methylpropane-2-sulfinamide (20 g, 48%).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[C:9]1([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH:25]=[CH:26][C:27](Cl)=[O:28])(=[O:18])=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[OH:3][NH:2][C:27](=[O:28])[CH:26]=[CH:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[S:16](=[O:18])(=[O:17])[NH:15][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)C=Cc1ccccc1S(=O)(=O)Nc1ccccc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1S(=O)(=O)Nc1ccccc1)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
To a suspension of hydroxylamine hydrochloride (0.21 g, 3.01 mmol) in tetrahydrofuran (4.0 ml) a saturated NaHCO3 solution (2.6 ml) was added and the resultant mixture was stirred at ambient temperature for 25 min. To the reaction mixture a 3-(2-phenylsulfamoyl-phenyl)-acryloyl chloride (36a) (0.19 g, 0.59 mmol) solution in tetrahydrofuran (2.5 ml) was added and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, and the solvent was removed. The residue was washed with diethyl ether and crystallised from acetonitrile to give the title compound (0.056 g, 30%) as white crystals, m.p. 205-206.5° C. 1H NMR (DMSO-d6, HMDSO), δ: 6.37 (1H, d, J=16.0 Hz); 6.99-8.04 (10H, m); 8.23 (1H, d, J=116.0 Hz); 10.55 (1H, s); 10.83 (1H, br s). HPLC analysis on Symmetry C18 column: impurities 6.4% (column size 3.9×150 mm; mobile phase acetonitrile-0.1M phosphate buffer, pH 2.5, 30:70; sample concentration 0.2 mg/ml; flow rate 1.2 ml/min; detector UV 220 nm). Anal. Calcd for C15H14N2O4S*0.1H2O, %: C, 56.28; H, 8.75; N, 4.47. Found %: C, 55.63; H, 9.07; N, 4.36.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=4[Cl:32])=[CH:19][CH:18]=3)=[O:16])[CH2:6][C:5]=12.[C:34](OC(=O)C)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([C:3]1[N:4]2[C:5]([CH2:6][N:7]([C:15]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=4[Cl:32])=[CH:21][CH:22]=3)=[O:16])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10]2)=[CH:1][CH:2]=1)(=[O:36])[CH3:35]
Reactant: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccc(Cl)cc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(NC(=O)c3ccc(Cl)cc3Cl)cc1)C2

Procedure:
A stirred solution of 0.954 g of N-[4-(5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-ylcarbonyl)phenyl]-2,4-dichlorobenzamide in 25 ml of methylene chloride and 5 ml of acetic anhydride is heated at reflux for 24 hours. The volatiles are evaporated in vacuo to a residue which is purified by column chromatography on silica gel by elution with ethyl acetatehexane (7:3) to give 0.800 g of a white solid; mass spectrum (M+H)519.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[C:13]([CH3:15])[CH:12]=[CH:11][CH:10]=1.[Se](=O)=[O:19]>O1CCOCC1>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[C:13]([CH:15]=[O:19])[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cccc(-c2ccccc2C(F)(F)F)n1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=Cc1cccc(-c2ccccc2C(F)(F)F)n1
Reaction time: 48 h

Procedure:
0.6 g of 6-(2-trifluoromethylphenyl)-2-methylpyridine was dissolved in 50 ml of 1,4-dioxane, 0.43 g of selenium dioxide (Aldrich, Gold Label) was added and the mixture was refluxed for 48 hours. A further 0.7 g, selenium dioxide and 50 ml dioxane were added and refluxing was continued for a further 48 hours. The solids were removed by filtration and the dioxane evaporated to afford crude 6-(2-trifluoromethylphenyl)-2-pyridinecarboxaldehyde.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])[CH:18]=[CH:17]3)[C:7]([CH:11]=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+]>O1CCCC1.CO>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])[CH:18]=[CH:17]3)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nc(-c3ccccc3C(=O)OC)ccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nc(-c3ccccc3C(=O)OC)ccc2c1
Yield: 83.2 %

Procedure:
440 mg (0.953 mmol) of methyl 2-{6-[(2-butyl-4-chloro-5-formyl-1H-imidazol-1-yl)methyl]quinolin-2-yl}benzoate obtained in Example 1 were dissolved in a mixed solvent of 10 ml of tetrahydrofuran and 10 ml of methanol and the mixture was stirred. 40 mg (1.0 mmol) of sodium borohydride were added thereto and allowed to react at room temperature for one hour. After the reaction mixture was concentrated under reduced pressure, dichloromethane was added to the residue and the mixture was washed with a saturated sodium chloride solution. The organic layer was dried over magnesium sulfate followed by filtration. The filtrate was concentrated under reduced pressure to obtain 368 mg of methyl 2-{6-[(2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]quinolin-2-yl}benzoate.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][C:5]2[C:10]=1[C:9](=[O:11])[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[N:6]=2.[O:18]1[CH:22]=[CH:21][CH2:20][CH2:19]1.B(F)(F)F.CCOCC>CN(C=O)C>[O:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[N:4]1[C:5]2=[N:6][C:7]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[N:8][C:9](=[O:11])[C:10]2=[C:2]([CH3:1])[NH:3]1
Reactant: C1=COCC1
Reactant: CC1=C2C(=O)N=C(c3ccncc3)N=C2N=N1
Agent: FB(F)F
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1[nH]n(C2CCCO2)c2nc(-c3ccncc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 108 h
Yield: 37 %

Procedure:
A solution of 3-methyl-6-(4-pyridyl)-pyrazolo[3,4-d]-pyrimidin-4-one (2.3 g, 0.01 mol), DMF (50 ml) and 2,3-dihydrofuran (14.0 g, 0.20 mol) was stirred at 0° C. for 10 minutes and BF3.Et2O (1.5 ml, 0.012 mol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 108 hours. The reaction was quenched with concentrated ammonium hydroxide until pH of 7.5 and the resulting precipitate was collected by filtration. The solid residue was taken up in isopropanol (200 ml), heated to reflux and filtered to remove insoluble material. Concentration of the filtrate to 75 ml and cooling caused precipitation of the product. The product was collected by filtration and washed with ether to afford 1.1 g (37%) of 1-(2-tetrahydrofuranyl)-3-methyl-6-(4-pyridyl)-pyrazolo-[3,4-d]pyrimidin-4-one as a white powder, m.p. 268°-9° C. when dried at 70° C. in high vacuum.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:10][C:11]1[CH:16]=[C:15]([C:17]([O:19]C(C)(C)C)=[O:18])[CH:14]=[C:13]([O:24][CH2:25][CH3:26])[C:12]=1[C:27]1[CH:32]=[CH:31][C:30]([C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:28]=1)[CH3:9]>C(Cl)(Cl)Cl>[CH2:25]([O:24][C:13]1[CH:14]=[C:15]([C:17]([OH:19])=[O:18])[CH:16]=[C:11]([O:10][CH2:8][CH3:9])[C:12]=1[C:27]1[CH:28]=[CH:29][C:30]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:32]=1)[CH3:26]
Reactant: CCOc1cc(C(=O)OC(C)(C)C)cc(OCC)c1-c1ccc(C(=O)OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOc1cc(C(=O)O)cc(OCC)c1-c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TFA (4 ml) was added to a stirred solution of 4-tert-butyl 4′-methyl 2,6-diethoxybiphenyl-4,4′-dicarboxylate (850 mg, 2.12 mmol) in CHCl3 (2 ml) and the reaction mixture was stirred at room temperature overnight. After the solvents were removed under reduced pressure, CHCl3 and MeOH were added to the residue. The solvents were removed under reduced pressure again, and the residue was dried in vacuo to give the crude intended compound as a colorless solid. Thus obtained crude product was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH:12](=O)[CH3:13].CC1C=CC(S)=CC=1>C(O)C>[CH2:12]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)[CH3:13]
Reactant: CC=O
Reactant: Nc1cccc2ncccc12
Agent: Cc1ccc(S)cc1
Solvent: CCO
Product: CCNc1cccc2ncccc12
Temperature: 25 °C
Yield: 62.7 %

Procedure:
A mixture of 5-aminoquinoline (7.2 g, 0.05 mol), acetaldehyde (2.6 g, 0.06 mol) and 4-thiocresol (6.8 g, 0.055 mol) in ethanol (100 ml) was stirred at reflux for 4 h. The reaction mixture was evaporated under reduced pressure and the residue dissolved in ethanol (100 ml). Sodium borohydride (10 g) was then added to the reaction mixture in portions maintaining the temperature below 5° C. This reaction mixture was stirred at reflux for 2 h and cooled to room temperature. Water (40 ml) was then added and the mixture was stirred for a further 25 min at reflux. The pH of the mixture was then adjusted to pH8 with 2N NaOH and the product was extracted with dichloromethane (4×100 ml). The dichloromethane extracts were combined and washed with water (250 ml) before being dried over MgSO4. The solvent was then removed under reduced pressure and the residue was purified by column chromatography on silica gel eluting with ethyl acetate in hexane. The solvent in the eluent was evaporated to give 5.4 g of a yellow solid which was used without further purification.