Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[CH:19]=[CH:20][CH:21]=[CH:22][C:11]=3[C:10]3[CH:23]=[CH:24][CH:25]=[CH:26][C:9]2=3)=[CH:4][CH:3]=1.C([Li])CCC.[B:32]([O:37]C)(OC)[O:33]C.S(=O)(=O)(O)O>O1CCCC1.CCCCCC>[CH:19]1[C:12]2[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:8]([C:5]3[CH:4]=[CH:3][C:2]([B:32]([OH:37])[OH:33])=[CH:7][CH:6]=3)[C:9]3[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=3[C:11]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Ic1ccc(N2c3ccccc3-c3ccccc3-c3ccccc32)cc1
Reactant: COB(OC)OC
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(N2c3ccccc3-c3ccccc3-c3ccccc32)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
Ten point zero (10.0) grams (22.5 mmol) of 9-(4-iodophenyl)tribenz[b,d,f]azepin was dissolved in 50 ml of tetrahydrofuran, and the solution was cooled to −78° C. Fourteen point one (14.1) ml (22.5 mmol) of a 1.6 M hexane solution containing n-butyl lithium was dropwise added thereinto. After completion of the addition, the solution was stirred for 30 minutes, and then a tetrahydrofuran solution containing 2.8 g (22.5 mmol) of trimethyl borate was dropwise added thereto over about one hour. After completion of the addition, the solution was stirred for 1 hour, then the temperature was gradually raised to room temperature, and the solution was allowed to react for further two hours. Subsequently, a dilute sulfuric acid (3 ml of sulfuric acid and 50 ml of water) was added at 0° C. and hydrolysis was performed. The reaction solution was extracted with ethyl acetate, concentrated under reduced pressure, the obtained solid of boronic acid was recrystallized with toluene and purified, thereby 6.1 g of 4-(tribenz[b,d,f]azepin-9-yl)phenyl boronic acid was obtained (yield: 75%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][NH:8][C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=2)[C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][C:19](=[O:23])[NH:20]3)=[CH:16][CH:15]=2)=[O:13])=[CH:5][C:4]([CH3:27])=[N:3]1.[CH:28](OCC)=[O:29].[O-]CC.[Na+].Cl>C(O)C>[CH3:1][N:2]1[C:6]([CH2:7][NH:8][C:9]2[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=2)[C:12]([C:14]2[CH:22]=[C:21]3[C:17]([C:18](=[CH:28][OH:29])[C:19](=[O:23])[NH:20]3)=[CH:16][CH:15]=2)=[O:13])=[CH:5][C:4]([CH3:27])=[N:3]1
Reactant: CCOC=O
Reactant: Cc1cc(CNc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)n(C)n1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(CNc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)n(C)n1
Temperature: 78 °C
Yield: 42 %

Procedure:
6-{3-[(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-amino]-benzoyl}-1,3-dihydro-indol-2-one (0.100 g, 0.278 mmol) and ethyl formate (0.066 mL, 0.834 mmol) were dissolved in anhydrous ethanol (0.600 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (0.519 mL, 1.39 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. The reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a tan precipitate. The suspension was filtered yielding 6-{3-[(2,5-Dimethyl-2H-pyrazol-3-ylmethyl)-amino]-benzoyl}-3-hydroxymethylene-1,3-dihydro-indol-2-one as an orange solid in 42% yield (0.045 g, 0.117 mmol).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:11])[CH2:7][CH2:8][CH2:9][CH2:10][C:2]1=2.[H-].[Na+].[CH3:14][O:15][C:16](=O)[O:17]C>>[O:11]=[C:6]1[C:3]2[CH:4]=[CH:5][O:1][C:2]=2[CH2:10][CH2:9][CH2:8][CH:7]1[C:16]([O:15][CH3:14])=[O:17]
Reactant: COC(=O)OC
Reactant: O=C1CCCCc2occc21
Agent: [H-]
Agent: [Na+]
Product: COC(=O)C1CCCc2occc2C1=O

Procedure:
5,6,7,8-Tetrahydro-cyclohepta[b]furan-4-one (J. Chem. Soc., Perkin Trans. 1, 1980, 2081-2083) (0.1 g, 0.7 mmol) in dimethylcarbonate (2 mL) was treated with a 60% dispersion of sodium hydride (0.06 g, 0.15 mmol) as described in Example 1A to yield the title product. NMR in CDCl3 indicates a 70:30 mixture of keto and enol forms: 1H NMR (300 MHz, CDCl3) δ 13.02 (s, 0.3H), 7.29 (d, J=2.03 Hz, 0.4H), 7.23 (d, J=2.03 Hz, 0.6H), 6.73 (d, J=2.03 Hz, 0.6H), 6.72 (d, J=2.03 Hz, 0.4H) 3.78 (s, 1.2H), 3.75 (s, 1.8H), 3.72 (dd, J=9.99, 3.9 Hz, 0.6H), 3.02 (m, 1.2H), 2.96 (t, J=6.6 Hz, 0.8H), 2.56 (t, 0.8H), 1.84-2.2 (m, 3.5H); MS (DCI/NH3) m/z 209 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[NH:10][C:5]2=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][CH2:23][CH2:24][CH2:25][F:26].O>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[N:10]([CH2:22][CH2:23][CH2:24][CH2:25][F:26])[C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2nc(Cl)ccc2[nH]1
Reactant: FCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc2nc(Cl)ccc2n1CCCCF
Temperature: 60 °C

Procedure:
To a solution of methyl 5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylate 11-c (2.9 g, 12.2 mmol) in DMF (50 mL) were added successively cesium carbonate (4 g, 12.2 mmol) and 1-bromo-4-fluorobutane (1.3 mL, 12.2 mmol). The resulting mixture was heated at 60° C. overnight. The reaction mixture was allowed to cool down to room temperature then poured into iced water and the product was extracted 3 times with DCM. The combined organic layers were dried over Na2SO4, filtered and evaporated to give the targeted product 11-d as a yellowish solid. The product was used as such in the next step. m/z=313 (M+H)+, Cl pattern.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][NH:9][C:8]2[N:7]=[CH:6][C:5]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[O:19])=[CH:14][CH:13]=3)=[CH:4][C:3]1=2.[Cl:27][C:28]1[CH:29]=[C:30](O)[CH:31]=[C:32]([Cl:34])[CH:33]=1>CO.C(Cl)Cl>[Cl:27][C:28]1[CH:29]=[C:30]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[O:1][CH:2]1[CH2:11][CH2:10][NH:9][C:8]2[N:7]=[CH:6][C:5]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([N:20]4[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]4)=[O:19])=[CH:16][CH:17]=3)=[CH:4][C:3]1=2
Reactant: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)C(O)CCN4)cc2)CC1
Reactant: Oc1cc(Cl)cc(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)C(Oc3cc(Cl)cc(Cl)c3)CCN4)cc2)CC1
Yield: 82 %

Procedure:
[4-(5-Hydroxy-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)phenyl]-(4-methylpiperazin-1-yl)methanone (20 mg) was reacted with 3,5-dichlorophenol (27.7 mg) as in General Procedure 12. Silica gel chromatography using a gradient of 0-15% methanol/CH2Cl2 as the eluting solvent gave the title compound as a yellow foam (82% yield). LCMS: m/z=497.12 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.02-2.13 (m, 1H), 2.24-2.35 (m, 1H), 2.33 (s, 3H), 2.35-2.60 (m, 4H), 3.40-3.66 (m, 4H), 3.70-3.92 (m, 2H), 5.30 (bs, 1H), 5.37 (t, J=3.3 Hz, 1H), 6.93 (d, J=1.6 Hz, 2H), 7.02 (dd, J=1.6 and 1.6 Hz, 1H), 7.44-7.51 (m, 4H), 7.60 (d, J=2.1 Hz, 1H), 8.31 (d, J=2.1 Hz, 1H).
Reaction SMILES: [CH3:1]N(C)CCO.[Li+].CCC[CH2-].[Si:12]([O:19][CH2:20][C@H:21]1[O:25][C:24]([CH3:27])([CH3:26])[N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:22]1[CH2:35][C:36]1[CH:41]=[CH:40][N:39]=[C:38]([Cl:42])[CH:37]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].CI>C1COCC1>[Si:12]([O:19][CH2:20][C@H:21]1[O:25][C:24]([CH3:27])([CH3:26])[N:23]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C@H:22]1[CH2:35][C:36]1[CH:41]=[C:40]([CH3:1])[N:39]=[C:38]([Cl:42])[CH:37]=1)([C:15]([CH3:16])([CH3:17])[CH3:18])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccnc(Cl)c2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: CN(C)CCO
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc(C[C@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)N2C(=O)OC(C)(C)C)cc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Dimethylethanolamine (0.128 ml, 1.27 mmol) was added to anhydrous hexanes (1.4 L) and cooled to 0° C. N-BUTYLLITHIUM (2.5 M in hexanes)(1.02 ml, 2.55 mmol) was added dropwise and stirred for 30 minutes before being cooled to −78° C. (4S,5S)-Tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-4-((2-chloropyridin-4-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (0.200 g, 0.425 mmol) in hexanes (1 mL) was added dropwise and the solution was stirred for 1 hour at −78° C. to give a dark orange solution. MeI (0.106 ml, 1.70 mmol) in THF (3.2 mL) was added dropwise and the reaction was allowed to slowly warm to 0° C. and was quenched with saturated aqueous ammonium chloride. The reaction was diluted with ethyl acetate and water and separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water, brine, dried over sodium sulfate, and concentrated to give the titled compound which was used directly for the next step without purification.
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[Cl:16][C:17]1[N:26]=[C:25]([CH3:27])[C:24]([Cl:28])=[C:23]([CH3:29])[C:18]=1/[C:19](=[N:21]/O)/[NH2:20]>CN(C)C(=O)C>[Cl:16][C:17]1[C:18]([C:19]2[N:20]=[C:5]([C:4]3[C:3]([N+:13]([O-:15])=[O:14])=[C:2]([OH:1])[C:10]([O:11][CH3:12])=[CH:9][CH:8]=3)[O:7][N:21]=2)=[C:23]([CH3:29])[C:24]([Cl:28])=[C:25]([CH3:27])[N:26]=1
Reactant: Cc1nc(Cl)c(/C(N)=N/O)c(C)c1Cl
Reactant: COc1ccc(C(=O)O)c([N+](=O)[O-])c1O
Solvent: CC(=O)N(C)C
Product: COc1ccc(-c2nc(-c3c(Cl)nc(C)c(Cl)c3C)no2)c([N+](=O)[O-])c1O
Temperature: 135 °C
Reaction time: 3 h
Yield: 18.3 %

Procedure:
To a stirred suspension of 3-hydroxy-4-methoxy-2-nitrobenzoic acid (0.900 g, 4.22 mmol) in N,N-dimethylacetamide (10.35 mL) at room temperature was added 1,1-carbonyldiimidazole (1.540 g, 9.506 mmol) in 7.65 ml of N,N-dimethylacetamide dropwise. After stirring for three hours, (Z)-2,5-dichloro-N′-hydroxy-4,6-dimethylnicotinimidamide (1.19 g, 5.107 mmol) was added in 2.7 ml of N,N-dimethylacetamide in one portion. The resulting mixture was stirred for one hour and forty five minutes then heated at 135° C. for one hour. The reaction mixture was poured onto ice/2N HCl mixture. The precipitate was filtered off, washed with water and dried under vacuum to give a yellow solid. Recrystallisation from dichloromethane/isopropanol gave 3-(3-(2,5-dichloro-4,6-dimethylpyridin-3-yl)-1,2,4-oxadiazol-5-yl)-6-methoxy-2-nitrophenol as a yellow solid (0.317 g, 18%).
Reaction SMILES: CO.[Na].[O:4]=[C:5]([CH3:29])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17](C(=O)C(C)(C)CC)[CH:16]=[N:15][C:14]=2[N:13]([CH3:28])[C:11]1=[O:12].O>CO>[O:4]=[C:5]([CH3:29])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[NH:17][CH:16]=[N:15][C:14]=2[N:13]([CH3:28])[C:11]1=[O:12]
Reactant: CCC(C)(C)C(=O)n1cnc2c1c(=O)n(CCCCC(C)=O)c(=O)n2C
Agent: [Na]
Solvent: CO
Solvent: O
Product: CC(=O)CCCCn1c(=O)c2[nH]cnc2n(C)c1=O
Reaction time: 0.25 h

Procedure:
A sodium methanol solution (prepared by adding sodium (20 mg, 0.9 mmol) to 1 ml of methanol) was added to a solution of 1-(5-oxohexyl)-3-methyl-7(methylpivaloyl)xanthine (270 mg, 0.7 mmol) in 4 ml of methanol and stirred for 15 min. The reaction mixture was poured into water (20 ml), then extracted with 25% ethanol/dichloromethane (4×50 ml). The organic extracts were combined, dried with sodium sulfate, and evaporated to give a yellow solid. The solid was washed with ether to remove impurities and give CT1505 (1-(5-oxohexyl)-3-methylxanthine) as a white solid (120 mg, 0.45 mmol, 65% yield).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([CH3:24])[CH:18]=3)[CH2:14][CH:13]([C:25](O)=[O:26])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:29]=[C:30]([CH:32]1[CH2:34][CH2:33]1)[NH2:31]>>[CH:32]1([C:30]2[N:31]=[C:25]([CH:13]3[CH2:14][CH:15]([C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([CH3:24])[CH:18]=4)[CH2:16][N:11]([C:9]([N:6]4[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]4)=[O:10])[CH2:12]3)[O:26][N:29]=2)[CH2:34][CH2:33]1
Reactant: NC(=NO)C1CC1
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(C#N)CC3)C2)cc1C
Product: Cc1ccc(C2CC(c3nc(C4CC4)no3)CN(C(=O)N3CCC(C#N)CC3)C2)cc1C

Procedure:
80 mg (0.21 mmol) of the compound from Example 132A and 32 mg (0.32 mmol) of N′-hydroxycyclopropanimidamide were reacted according to the General Method 2. Yield: 41 mg (45% of theory)
Reaction SMILES: C([BH3-])#N.[Na+].[Br:5][C:6]1[CH:7]=[C:8]([CH:11]=O)[S:9][CH:10]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+]>C(O)C.C(O)(=O)C>[Br:5][C:6]1[CH:7]=[C:8]([CH2:11][N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[S:9][CH:10]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: C1COCCN1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: Brc1csc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
Sodium cyanoborohydride (2 g) was added portionwise to a stirred mixture of 4-bromo-2-thiophenecarbaldehyde (4.78 g), morpholine (2.1 g), glacial acetic acid (1.8 g) and ethanol (125 ml). The mixture was stirred at ambient temperature for 1 hour. The mixture was poured into a saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. The organic phase was washed with brine and evaporated. The resultant oil was partitioned between a dilute (10%) aqueous hydrochloric acid solution and methylene chloride. The aqueous phase was basified by the addition of a saturated aqueous sodium bicarbonate solution and extracted with methylene chloride. The organic extract was dried (MgSO4) and evaporated to give 4-bromo-2-morpholinomethylthiophene (3.2 g);
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:6][C:5]2[C:7]([CH3:25])=[C:8]([CH3:24])[C:9]([CH:12]3[CH2:17][C:16](=[O:18])[C:15]([C:19](=O)[CH2:20][CH3:21])=[C:14]([OH:23])[CH2:13]3)=[C:10]([CH3:11])[C:4]=2[O:3]1.C([O-])(=O)C.[Na+].Cl.[CH2:33]([O:35][NH2:36])[CH3:34]>C(O)C>[CH3:1][C:2]1([CH3:26])[CH2:6][C:5]2[C:7]([CH3:25])=[C:8]([CH3:24])[C:9]([CH:12]3[CH2:17][C:16](=[O:18])[C:15]([C:19](=[N:36][O:35][CH2:33][CH3:34])[CH2:20][CH3:21])=[C:14]([OH:23])[CH2:13]3)=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2c(C)c(C)c3c(c2C)OC(C)(C)C3)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2c(C)c(C)c3c(c2C)OC(C)(C)C3)CC1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.3 %

Procedure:
To a solution 0.3 g of the 5-(2,3-dihydro-2,2,4,5,7-pentamethylbenzofuran-6-yl)-2-propionyl-3-hydroxycyclohex-2-en-1-one in 10 ml of ethanol was added 0.14 g of sodium acetate and 0.09 g of ethoxyamine hydrochloric acid. After stirring at room temperature for 20 hours, the reaction mixture was quenched with 20 ml water and extracted with diethyl ether. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under the reduced pressure to afford a crude product. Final purification was carried by silica-gel column chromatography to afford 0.28 g of 5-(2,3-dihydro-2,2,4,5,7-pentamethylbenzofuran-6-yl)-2-[1-(ethoxyimino)propyl]-3-hydroxycyclohex-2-en-1-one as yellow oil.
Reaction SMILES: [CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]3=[O:31])=[CH:16][CH:15]=2)[C:7]([O:9]C(C)(C)C)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([CH:6]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]3=[O:31])=[CH:16][CH:15]=2)[C:7]([OH:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(Cn2cc(C(F)(F)F)ccc2=O)cc1)C1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C(c1ccc(Cn2cc(C(F)(F)F)ccc2=O)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
390 mg (0.90 mmol) of tert-butyl(+/−)-cyclopentyl(4-{[2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl]methyl}phenyl)ethanoate were initially charged in 2.7 ml of dichloromethane, and 690 μl of trifluoroacetic acid were added. The reaction mixture was stirred at RT for 2 h and then concentrated under reduced pressure, and the residue was dried under high vacuum. This gave 523 mg of product, which was used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([OH:19])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])=[C:24]([O:42][CH3:43])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]([O:19][CH2:21][C:22]2[CH:41]=[CH:40][C:25]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[O:31][C:32]=3[CH3:33])=[C:24]([O:42][CH3:43])[CH:23]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)nc1O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)c(OC)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 55.7 %

Procedure:
A mixture of ethyl (1-benzyl-3-hydroxy-1H-pyrazol-4-yl)acetate (521 mg), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole (687 mg), potassium carbonate (553 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 5 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl [1-benzyl-3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]acetate (632 mg, yield 56%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 86–87° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=1[NH:54][C:55](=[O:61])[O:56][C:57]([CH3:60])([CH3:59])[CH3:58]>CN(C=O)C>[C:57]([O:56][C:55]([NH:54][C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=1[NH:47][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:13])=[O:61])([CH3:60])([CH3:58])[CH3:59]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1N
Reactant: CCOC(=O)CCCCCC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCCCC(=O)Nc1ccccc1NC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 92.2 %

Procedure:
To a solution of 7-ethoxy-7-oxoheptanoic acid (2.0 g, 10.6 mmol) in DMF (50 mL) were added HBTU (4.4 g, 11.6 mmol), DIEA (4.1 g, 31.8 mmol) at room temperature. The resulting mixture was stirred for 10 min, then tert-butyl (2-aminophenyl)carbamate (2.43 g, 11.7 mmol) was added to the reaction solution. The reaction mixture was stirred for 12 h at room temperature. The reaction was quenched with water (200 mL). The resulting mixture was extracted by EtOAc (200 mL×2). The organic layers were combined, dried with anhydrous Na2SO4 and concentrated under reduced pressure. The resulting solid was purified by column chromatography (elute: EtOAc:PE (petroleum ether)=1:4) to afford the desired compound (3.7 g, yield 92.1%) as a light yellow oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH:26][CH:27]([CH2:32][CH:33]3[O:35]C3)[C:28]([O:30]C)=[O:29])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>>[CH3:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[CH:19][C:20]([S:23]([NH:26][CH:27]([CH2:32][CH:33]([OH:35])[CH2:1][NH:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:28]([OH:30])=[O:29])(=[O:24])=[O:25])=[CH:21][CH:22]=2)=[CH:15][CH:16]=1
Reactant: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: CNc1ccccc1
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(CC(O)CNc3ccccc3)C(=O)O)cc2)cc1

Procedure:
Example 21 is prepared from N-methylaniline and 1d using the procedure described for compound 19.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([O:21][CH3:22])=[CH:10][CH:9]=2.C(N(CC)CC)C.Cl[CH2:33][CH2:34][CH2:35][C:36](Cl)=[O:37]>ClCCl>[CH3:22][O:21][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:23])[N:6]([CH3:24])[C:5]([CH2:4][CH2:3][N:2]1[CH2:33][CH2:34][CH2:35][C:36]1=[O:37])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc2c(=O)n(C)c(CCN)c(-c3ccccc3)c2c1
Reactant: O=C(Cl)CCCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(=O)n(C)c(CCN3CCCC3=O)c(-c3ccccc3)c2c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 3-(2-aminoethyl)-6-methoxy-2-methyl-4-phenylisoquinolin-1(2H)-one hydrochloride (125 mg, 0.362 mmol) in 15 mL of dichloromethane was added triethylamine (0.202 mL, 1.45 mmol), followed by 4-chlorobutanoyl chloride (0.045 mL, 0.40 mmol). After 45 minutes, the mixture was concentrated in vacuo. Tetrahydrofuran was added (15 mL), and the solution was cooled to 0° C. Sodium hydride was added (58 mg, 60% dispersion in mineral oil, 1.45 mmol). The reaction mixture was stirred at 0° C. for 30 minutes, at room temperature for 16 hours, then at 50° C. for 2 hours. The solution was partitioned between EtOAc and saturated NaHCO3 solution, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC to provide the titled product. Proton NMR for the product was consistent with the titled compound. ESI+MS: 377.27 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=[C:11]([Cl:18])[C:10]=2[Cl:19])=[C:4]([Cl:20])[CH:3]=1.CO.[Si](C=[N+]=[N-])(C)(C)[CH3:24]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([O:17][CH3:24])=[O:16])=[CH:13][N:12]=[C:11]([Cl:18])[C:10]=2[Cl:19])=[C:4]([Cl:20])[CH:3]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cnc(Cl)c(Cl)c1Nc1ccc(Br)cc1Cl
Yield: 65.9 %

Procedure:
To a suspension of 4-(4-bromo-2-chlorophenylamino)-5,6-dichloronicotinic acid (4.3975 g, 11.2 mmol) in a mixture 70 ml MeOH and 70 ml toluene was added TMS-diazomethane (10 ml, 20 mmol, 2M/hexanes) in small portions at room temperature. At the end of the addition the suspension turned into a solution, and then a precipitate was formed again. The suspension was diluted with hexanes and filtered. And the precipitate was washed with hexanes and dried in vacuo to obtain the title compound 3.03 g (66%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].C(N(CC)C(C)C)(C)C.[NH2:21][C:22]1[CH:44]=[CH:43][C:25]([C:26]([N:28]2[CH2:34][C:33]3[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=3[CH2:31][C:30]3[CH:39]=[CH:40][CH:41]=[CH:42][C:29]2=3)=[O:27])=[CH:24][CH:23]=1>C1(C)C(C)=CC=CC=1>[CH:39]1[C:30]2[CH2:31][C:32]3[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=3[CH2:34][N:28]([C:26]([C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:4](=[O:5])[C:3]4[C:2]([Cl:1])=[CH:10][CH:9]=[CH:8][C:7]=4[Cl:11])=[CH:44][CH:43]=3)=[O:27])[C:29]=2[CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1C
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1c(Cl)cccc1Cl
Temperature: 110 °C
Yield: 76 %

Procedure:
A mixture of 335 mg of 2,6-dichlorobenzoyl chloride and 258 mg of N,N-diisopropylethylamine is stirred in 2 ml of xylene while 314 mg of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine is added. The reactants are refluxed in an oil bath at 110° C. for 18 hours. The xylene is evaporated in vacuo to a residue which is partitioned between methylene chloride and water. The organic layer is separated, washed with 1N HCl, 1M NaHCO3, and brine. The organic layer is dried with Na2SO4 and passed through a pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 370 mg of the desired product as a crystalline solid, m.p. 257°-259° C.