Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Cl-].[K+].[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:22]=[C:21]([OH:23])[CH:20]=[C:19]([OH:24])[CH:18]=1>CN(C)C=O>[CH3:14][O:15][C:16](=[O:25])[C:17]1[CH:18]=[C:19]([O:24][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:20]=[C:21]([O:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:22]=1
Reactant: CCCCCCCCCCBr
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)cc(C(=O)OC)c1
Reaction time: 18 h
Yield: 96.5 %

Procedure:
To a 1 L round bottom flask (RBF), while stirring with a magnetic stir bar, 1-bromodecane (54.3 mL, 0.262 mol), dimethylformamide (DMF) (200 mL), and potassium chloride (49.3 g, 0.357 mol) were added. Methyl-3,5-dihydroxybenzoate (20.0 g, 0.119 mol) was dissolved in DMF (100 mL) and the solution was added to the 1 L RBF. The solution gradually changed from an opaque pale yellow to an opaque light grey. The reaction vessel was sealed with a rubber septum and was stirred overnight. After stirring for approximately 20 hours, the contents of the RBF changed to a dark grey color and solidified. The RBF was gently heated with a heat gun until the contents liquefied. After cooling to just above room temperature, the contents of the RBF were transferred into a 2 L Erlenmeyer Flask that contained 1 L of 30/70 ice/distilled H2O mixture. A white precipitate formed on contact with H2O. Vacuum filtration was used to isolate the precipitate. The white precipitate was recrystallized from absolute ethanol (800 mL) and allowed to cool slowly overnight. The contents were then vacuum filtered yielding fine bright white fibrous crystals. The filtrate was concentrated under reduced pressure to approximately 300 mL. The concentrated filtrate was warmed and then left in refrigerator for approximately 18 hours. A second crop of fine bright white fibrous crystals was isolated from the solution upon vacuum filtration. The remaining pale yellow colored filtrate was discarded. This gave a total of 51.5 g yield or a 96.5% yield of the derivative. The NMR characterization data for this derivative is as follows. 1NMR (300 MHz, CDCl3): 0.88 (t, J=6.6, 6H, CH2CH3), 1.27-1.44 (m, 28H, CH2(CH2)7), 1.80 (p, J=6.9, 4H, OCH2CH2), 3.89 (s, 3H, OCH3), 3.93 (t, J=6.6, 4H, OCH2CH2), 6.63 (t, J=2.2, 1H, ArH), 7.15 (d, J=2.5, 2H, ArH). 13C NMR (75 MHz, CDCl3): 14.22, 22.78, 26.10, 29.26, 29.42, 29.45, 29.65, 31.99, 52.27, 68.37, 77.31, 106.61, 107.65, 131.86, 160.21, 167.08.
Reaction SMILES: C(O)(=O)C(O)=O.[C:7]([O:11][C:12](=[O:43])[CH2:13][N:14]([C:24](=[O:42])[C@H:25]([CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[NH2:26])[CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16]1)([CH3:10])([CH3:9])[CH3:8].C([O-])(=O)C.[Na+].O=[C:50]([CH2:56][CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[C:51]([O:53][CH2:54][CH3:55])=[O:52].C([BH3-])#N.[Na+].P(=O)(O)(O)O>CO.C(O)(=O)C>[C:7]([O:11][C:12](=[O:43])[CH2:13][N:14]([C:24](=[O:42])[C@H:25]([CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[NH:26][C@@H:50]([C:51]([O:53][CH2:54][CH3:55])=[O:52])[CH2:56][CH2:57][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)[CH:15]1[CH2:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:23]1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)CN(C(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1)C1Cc2ccccc2C1
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: CC(=O)[O-]
Agent: O=C(O)C(=O)O
Agent: O=P(O)(O)O
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)[C@@H](CCc1ccccc1)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Reaction time: 3 h
Yield: 26.9 %

Procedure:
Nε -Carbobenzoxy-L-lysyl-N-(indan-2-yl)glycine tert-butyl ester oxalate (3.5 g) is dissolved in 20 ml of methanol, and 1 g of sodium acetate, 1.2 g of acetic acid, 8 g of molecular sieve and 15 g of ethyl 2-oxo-4-phenylbutyrate are added. To this mixture is added dropwise with stirring a solution of 3.3 g of sodium cyanoborohydride in 30 ml of methanol over 2 hours. 3 g of sodium cyanoborohydride is further added, and the mixture is stirred for 3 hours. After addition of 200 ml of 25% aqueous phosphoric acid, the reaction mixture is extracted with two 200-ml portions of ethyl acetate. The extract is washed with 0.5N aqueous sodium hydroxide and with water, and dried over anhydrous magnesium sulfate. The ethyl acetate is distilled off under reduced pressure, and the oil thus obtained is separated and purified by silica gel column chromatography (acetone-benzene (1:12 to 1:5)). The first fraction gives 1.1 g of Nα -[1-(R)-ethoxycarbonyl-3-phenylpropyl]-Nε -carbobenzoxy-L-lysyl-N-(indan-2-yl)glycine tert-butyl ester as an oil.
Reaction SMILES: CN(C)C=O.S(Cl)([Cl:8])=O.[F:10][C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14](O)=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=1>C1(C)C=CC=CC=1>[Cl:8][C:14]1[C:15]([N+:17]([O-:19])=[O:18])=[CH:16][C:11]([F:10])=[CH:12][C:13]=1[N+:21]([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)cc([N+](=O)[O-])c1Cl
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 56.3 %

Procedure:
To a stirred solution of N,N-dimethylformamide (2.02, 26.1 mmol) in toluene (20 mL) was added thionyl chloride (2.86 mL, 39.2 mmol) at room temperature. After 10 min, 4-fluoro-2,6-dinitrophenol (5.27 g, 26.1 mmol) was added and the mixture was stirred for 7 h at 80° C. The reaction mixture was concentrated in vacuo, and the resulting solid was washed with ethanol to give the title compound as a pale yellow solid (3.24 g, 14.7 mmol, 56%).
Reaction SMILES: [C:1]1([C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][NH:3]1)=[O:2].[K].[CH3:13][C:14](C)([O-])[CH3:15].C(Br)C#C.C(O)(=O)C>CN(C)C=O.O>[CH2:15]([N:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:1]1=[O:2])[C:14]#[CH:13]
Reactant: CC(C)(C)[O-]
Reactant: O=c1[nH]ccc2ccccc12
Agent: C#CCBr
Agent: [K]
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: C#CCn1ccc2ccccc2c1=O
Reaction time: 0.5 h

Procedure:
A solution of 1 g (7 mmol) of isocarbostyril in 40 ml of dimethylformamide was treated with 0.86 g (7.7 mmol) of potassium-tert.-butoxide. After stirring under nitrogen for 30 minutes, 0.7 ml of propargyl bromide was added and stirring at room temperature was continued for 1 hour. The reaction mixture was acidified with acetic acid and diluted with water. The precipitated product was filtered off, washed with water and sucked dry. The residue was purified by chromatography over 30 g of silica gel using 5% (v/v) of ethanol in methylene chloride and crystallization from ether to give colorless crystals of 2-(2-propynyl)-1(2H)-isoquinolinone with m.p. 104°-105°. contains about. 0.125 molar amounts of H2O.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>ClCCl>[CH2:1]([O:8][C:9]1[C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:15][CH:14]=[CH:13][C:10]=1[OH:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1cccc(C=O)c1OCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)c1cccc(O)c1OCc1ccccc1
Reaction time: 8 h
Yield: 83.7 %

Procedure:
A solution of 2-(benzyloxy)-3-tert-butylbenzaldehyde (20 g, 74.53 mmol) in dichloromethane (400 mL) was treated with m-chloroperbenzoic acid (70%, 20 g) in 3 portions at room temperature. Stirring was continued overnight. The reaction mixture was diluted with dichloromethane (to 1 L) and washed with saturated sodium bicarbonate (2×400 mL) and water (500 mL). The organic layer was dried over sodium sulfate and filtered. The solvent was removed in a rotary evaporator. The residue was taken in methanol (375 mL), potassium hydroxide (7.5 g) was added and this mixture was stirred at room temperature overnight. The solvent was removed in a rotary evaporator. The residue was taken in water (250 mL) and made acidic with 6N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (800 mL). The organic extract was washed with water (300 mL), dried over sodium sulfate and the solvent was removed in a rotary evaporator. The crude product was purified by chromatography on silica (350 g) with 5% ethyl acetate in heptane (4 L) to afford pure 7 (16 g, 84%).
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1.Br[CH:23]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]1[C:40](=[O:41])[C:39]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:38]2[C:37]1=[O:46])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(#N)C>C(N(CC)CC)C>[CH2:27]([O:26][C:24]([C@H:23]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:36]1[C:37](=[O:46])[C:38]2=[CH:45][CH:44]=[CH:43][CH:42]=[C:39]2[C:40]1=[O:41])=[O:25])[CH3:28]
Reactant: CCOC(=O)C(Br)CCCCCCCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)COc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)[C@@H](CCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Temperature: 80 °C
Yield: 13.4 %

Procedure:
A mixture of tert-butyl 3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5 -benzoxazepine-5-acetate (2.1 g), ethyl 2-bromo-9-phthalimidononanoate (3 g), acetonitrile (100 ml) and triethylamine (0.96 g) is heated at 80° C. for 3 days. After evaporation of the solvent, ethyl acetate (200 ml) and water (150 ml) are added to the residue. The ethyl acetate layer is separated, dried over anhydrous magnesium sulfate and evaporated in vacuo. The oily residue is chromatographed on silica gel using hexane-ethyl acetate (2:1-1:1) as an eluent. Evaporation of the first eluate gives tert-butyl 3(S)-[1(R)-ethoxycarbonyl-8-phthalimidooctyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (0.6 g) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:29])[C@:14]([CH3:28])([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>ClCCl>[OH:22][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@@:14]([CH3:28])([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:29])[C:12]=1[C:7]1[NH:6][C:5]2[CH:30]=[CH:31][C:2]([NH:1][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 64.7 %

Procedure:
To a solution of the product of Example 39-6 (310 g, 0.705 mol) and pyridine (167.6 g, 2.12 mol) in dichloromethane (1645 mL) at 18-20° C. was added methanesulfonyl chloride (121.1 g, 1.06 mol) over 45 minutes. The solution was mixed at RT for 16 h then quenched with 1 M HCl (2000 mL). The layers were separated and the organic layer was concentrated under vacuum. The product was crystallized from ethyl acetate/heptane (1/1, 8 volumes) to give the title compound (236.0 g, 65%).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:20][C@H:21]([NH:23][CH2:24][C@@H:25]([C:27]4[CH:28]=[CH:29][C:30]([O:36]CC5C=CC=CC=5)=[C:31]([NH:33][CH:34]=[O:35])[CH:32]=4)[OH:26])[CH3:22])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>[Pd]>[C:1]12([CH2:11][CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH2:20][C@H:21]([NH:23][CH2:24][C@@H:25]([C:27]4[CH:28]=[CH:29][C:30]([OH:36])=[C:31]([NH:33][CH:34]=[O:35])[CH:32]=4)[OH:26])[CH3:22])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: C[C@H](Cc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1)NC[C@H](O)c1ccc(OCc2ccccc2)c(NC=O)c1
Agent: [Pd]
Product: C[C@H](Cc1cccc(OCCC23CC4CC(CC(C4)C2)C3)c1)NC[C@H](O)c1ccc(O)c(NC=O)c1
Yield: 34.7 %

Procedure:
Obtained from Intermediate 68 (0.24 g, 0.41 mmol) and palladium on charcoal (10%, 0.04 g) by the same procedure described in Example 1 (reaction time: 2 hours). The crude was purified by column chromatography with silica gel, eluting with methylen chloride/methanol (form 98:2 to 90:10) to give the title compound as a solid (0.07 g, 38%).
Reaction SMILES: [CH3:1][C:2]([O:37]C(=O)C)([CH3:36])[C:3]([N:5]1[CH2:8][CH:7]([CH2:9][C:10]2[N:11]([CH3:35])[C:12]3[C:17]([N:18]=2)=[C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:15]=[C:14]([N:25]2[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]2[CH3:34])[N:13]=3)[CH2:6]1)=[O:4].[Li+].[OH-]>C1COCC1.CO>[OH:37][C:2]([CH3:36])([CH3:1])[C:3]([N:5]1[CH2:8][CH:7]([CH2:9][C:10]2[N:11]([CH3:35])[C:12]3[C:17]([N:18]=2)=[C:16]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:15]=[C:14]([N:25]2[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[N:27]=[C:26]2[CH3:34])[N:13]=3)[CH2:6]1)=[O:4]
Reactant: CC(=O)OC(C)(C)C(=O)N1CC(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CN(C(=O)C(C)(C)O)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
A mixture of acetic acid 1,1-dimethyl-2-{3-[9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purin-8-ylmethyl]azetidin-1-yl}-2-oxoethyl ester (125 mg, 0.23 mmol) and LiOH (114 μL, 0.46 mmol, 4M solution) in THF (3 mL) and MeOH (1 mL) was allowed to stir at r.t. for 18 h. Further LiOH (343 μL, 1.37 mmol, 4M solution) and the mixture stirred at 50° C. for 5 days. The reaction mixture was concentrated in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-10%) then dissolved in a mixture of MeCN and H2O and allowed to freeze-dry affording 855 as a white solid (88 mg, 77%). LCMS (method I): RT 2.88 min, [M+H]+ 505.3. 1H NMR (DMSO, 400 MHz): δ 8.09-8.08 (1 H, m), 7.64-7.61 (1 H, m), 7.28-7.27 (2 H, m), 5.02 (1 H, brd s), 4.57 (1 H, t, J=8.94 Hz), 4.26 (4 H, brd s), 4.17 (1 H, dd, J=10.24, 5.60 Hz), 4.03 (1 H, t, J=8.97 Hz), 3.77 (4 H, t, J=4.64 Hz), 3.74 (3 H, s), 3.67 (1 H, dd, J=9.96, 5.41 Hz), 3.21-3.20 (3 H, m), 2.85 (3 H, s), 1.28-1.21 (6 H, m)
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[N:14]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]2[S:34][CH:35]=[C:36]([CH3:38])[CH:37]=2)=[N:25][N:24]=1.CC(O)(C)C>C(OCC)C.C(=O)([O-])[O-].[Na+].[Na+]>[NH2:19][C:15]1[N:14]=[C:13]([C:12]2[C:7]([O:6][C:5]3[CH:20]=[CH:21][C:2]([NH:1][C:23]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:26]([C:33]5[S:34][CH:35]=[C:36]([CH3:38])[CH:37]=5)=[N:25][N:24]=4)=[CH:3][CH:4]=3)=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:18]=[CH:17][N:16]=1
Reactant: Cc1csc(-c2nnc(Cl)c3ccccc23)c1
Reactant: Nc1ccc(Oc2ncccc2-c2ccnc(N)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: Cc1csc(-c2nnc(Nc3ccc(Oc4ncccc4-c4ccnc(N)n4)cc3)c3ccccc23)c1
Temperature: 100 °C

Procedure:
To 4-(2-(4-aminophenoxy)pyridin-3-yl)pyrimidin-2-amine and 1-chloro-4-(4-methyl-2-thienyl)phthalazine was added tBuOH. The resulting mixture was heated at 100° C. in a sealed tube for 16 hours. The reaction was diluted with diethyl ether and saturated sodium carbonate and vigorously shaken. The resulting solids were filtered and washed with water, diethyl ether and air dried to yield N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine as an off-white solid. MS m/z=504 [M+H]+. Calc'd for C28H21N7OS: 503.58.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[O:29][CH:28]=[N:27][C:26]=2[C:30](O)=[O:31])=[CH:21][CH:20]=1>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([NH:16][C:30]([C:26]2[N:27]=[CH:28][O:29][C:25]=2[C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)=[O:31])[CH:13]=[N:12]1
Reactant: CC1(CCCCn2cc(N)cn2)OCCO1
Reactant: COc1ccc(-c2ocnc2C(=O)O)cc1
Product: COc1ccc(-c2ocnc2C(=O)Nc2cnn(CCCCC(C)=O)c2)cc1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-4-ylamine and 5-(4-methoxy-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: FC1C=CC=CC=1C(C1N(CNC(=O)OCC)C=CC=1)=O.F[C:23]1[CH:41]=[CH:40][CH:39]=[CH:38][C:24]=1[C:25]([C:27]1[N:28]([NH:32][C:33](=O)OCC)[CH:29]=[CH:30][CH:31]=1)=[O:26].CI.[OH-].[Na+]>C(O)C>[CH3:33][N:32]1[C:23]2[CH:41]=[CH:40][CH:39]=[CH:38][C:24]=2[C:25](=[O:26])[C:27]2=[CH:31][CH:30]=[CH:29][N:28]12
Reactant: CCOC(=O)Nn1cccc1C(=O)c1ccccc1F
Agent: CCOC(=O)NCn1cccc1C(=O)c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CI
Product: Cn1c2ccccc2c(=O)c2cccn21

Procedure:
A solution containing [2-(2-fluorobenzoyl)-1H-pyrrol-1-yl]methylcarbamic acid, ethyl ester (23.5 g, prepared from [2-(2-fluorobenzoyl)-1H-pyrrol-1-yl]carbamic acid, ethyl ester and methyl iodide in substantially the same manner as in Example 4) and sodium hydroxide (12.0 g) in 140 mL of 50% aqueous ethanol was refluxed under N2 for 16 h. Evaporation of the volatiles left a bright yellow solid which was diluted with 300 ml of H2O and extracted with two 200 mL portions of dichloromethane. The organic extracts were dried (MgSO4), filtered and concentrated. The residue was recrystallized from dichloromethane to give 8.0 g of bright yellow crystals, mp 154°-156° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.C(Cl)(Cl)Cl.[CH3:16][S:17][CH:18]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:16][S:17]([CH:18]([C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)=[O:9]
Reactant: CSC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CS(=O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
A solution of 10.7 grams (0.0525 mole) of m-chloroperbenzoic acid in 150 ml. of chloroform was slowly added to a cool solution (5°-7° C.) of 14.1 grams (0.050 mole) of bis(p-chlorophenyl)methyl methyl sulfide (prepared above) in 500 ml. of chloroform, and the resulting solution stirred for two hours at a temperature of 5° C., while a white precipitate formed. The mixture after warming to ambient temperature and holding at this temperature for a two hour period was then mixed with a solution having 20 grams of potassium carbonate in 200 ml. of water. The chloroform phase was then removed and washed with 100 ml. of water, and the chloroform distilled off by vacuum distillation leaving 14.7 grams of a crude product which was recrystallized twice from 2,2,4-trimethylpentane-benzene (2:1) mixture to yield 11.7 grams (78 percent) of the white colored solid of bis(p-chlorophenyl)methyl methyl sulfoxide with a melting point of 109.5°-110.5° C.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[N:10]([C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9]1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[NH2:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH3:16])[C:12]2[CH:17]=[CH:18][CH:19]=[CH:20][C:11]=2[N:10]([C:21](=[O:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:9]1
Reactant: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CN(C(=O)c2ccccc2)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)[C@@H](N)CN(C(=O)c2ccccc2)c2ccccc21

Procedure:
(S)-(5-Benzoyl-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-carbamic acid tert-butyl ester (260 mg, 0.66 mmol) was dissolved in a mixture of trifluoroacetic acid and dichloromethane (1:1, 2 ml) for 2.5 h. Upon evaporation of the volatile parts, (S)-3-amino-5-benzoyl-1-methyl-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one was obtained in sufficient purity for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].Br[CH:18]([CH3:20])[CH3:19]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH:18]([CH3:20])[CH3:19]
Reactant: FC(F)(F)c1cc(Br)c2cc[nH]c2c1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1ccc2c(Br)cc(C(F)(F)F)cc21
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
To a solution of 4-bromo-6-(trifluoromethyl)-1H-indole (1 g, 3.79 mmol) in DMF (6 mL) was added 60% sodium hydride (0.182 g, 4.54 mmol), and the mixture was stirred for 30 min. 2-bromopropane (0.533 mL, 5.68 mmol) was added and the mixture was stirred overnight. The reaction was then quenched with 10% NaHCO3 and extracted with EtOAc (3×). The extract was dried over Na2SO4 and concentrated. The residue was purified using column chromatography (Silica gel, 0 to 100% EtOAc/hexanes) to give the title compound (460 mg, 40%) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.56-1.61 (m, 6H), 4.66-4.79 (m, 1H), 6.65 (d, J=3.03 Hz, 1H), 7.27-7.31 (m, 1H), 7.45 (d, J=3.03 Hz, 1H), 7.54 (s, 1H), 7.63 (s, 1H). MS: (M+H)+=306.2.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C:18]([NH:20][C:21]3[O:25][N:24]=[C:23]([CH3:26])[CH:22]=3)=[O:19])[CH2:13][CH2:12]2)[C:5]([Cl:27])=[CH:4][N:3]=1.[CH:28](=O)[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Cl:27][C:5]1[C:6]([N:11]2[CH2:12][CH2:13][N:14]([CH2:17][C:18]([NH:20][C:21]3[O:25][N:24]=[C:23]([CH3:26])[CH:22]=3)=[O:19])[CH2:15][CH2:16]2)=[C:7]2[N:8]=[C:28]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1cc(NC(=O)CN2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)on1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(CC(=O)Nc5cc(C)no5)CC4)c(Cl)cnc3[nH]2)cc1
Temperature: 70 °C
Reaction time: 6.5 h

Procedure:
To a mixture of 2-(4-(2-amino-5-chloro-3-nitropyridin-4-yl)piperazin-1-yl)-N-(3-methylisoxazol-5-yl)acetamide (0.036 g, 0.09 mmol) and ethanol (3 ml) was added p-anisaldehyde (0.024 g, 0.18 mmol) with the aid of ethanol (1 ml) followed by a freshly prepared 1M aqueous solution of Na2S2O4 (0.36 ml, 0.36 mmol). The reaction mixture was stirred at 70° C. for 6.5 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was absorbed on silica gel, and the free-running powder was placed on a 10 g silica isolute column which was eluted with ethyl acetate/dichloromethane (v/v; 1:1), and 2% methanol in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.008 g, 18%). 1H-NMR (500 MHz, DMSO-d6) 2.19 (s, 3H, isoxazole CH3), 2.73 (s, 4H, piperazine N(CH2)2), 3.32 (s, 2H, NCH2CO), 3.73 (s, 4H, piperazine N(CH2)2), 3.83 (s, 3H, OCH3), 6.18 (s, 1H, isoxazole C—H), 7.11 (d, J=8.9 Hz, 2H) and 8.13 (d, J=8.8 Hz, 2H) (3,5-C6H4OMe and 2,6-C6H4OMe), 8.09 (s, 1H, imidazo[4,5-b]pyridine 5-H), 11.43 (br s, 1H, CONH), 13.38 (br s, 1H, imidazo[4,5-b]pyridine N—H);