Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=1>ClCCl>[F:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:2]([Cl:1])(=[O:5])=[O:3])=[CH:9][CH:8]=1
Reactant: Fc1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccccc1Oc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
16.1 g (0.138 mol) of chlorosulfonic acid are slowly added dropwise to a solution of 13.05 g of 4-fluorophenoxybenzene (0.069 mol) cooled to 0° C. After the addition is complete, the mixture is stirred at room temperature for a further 4 hours. For work up, 50 ml of dichloromethane are added, and the mixture is washed once with H2O. The aqueous phase is separated off and extracted twice more with 50 ml of dichloromethane each time. The combined organic phases are dried with MgSO4 and concentrated, resulting in the title compound as a colorless solid. Yield: 11.03 g; 60%.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[C:11]([C:15]3[N:20]=[CH:19][C:18](/[CH:21]=[CH:22]\[CH2:23][NH:24]C(=O)OC(C)(C)C)=[CH:17][N:16]=3)[CH:12]=[CH:13][CH:14]=2)[N:6]=[C:5]([C:32]2[CH:37]=[C:36]([F:38])[C:35]([F:39])=[C:34]([F:40])[CH:33]=2)[CH:4]=[CH:3]1.FC(F)(F)C(O)=O>ClCCl>[NH2:24][CH2:23]/[CH:22]=[CH:21]/[C:18]1[CH:17]=[N:16][C:15]([C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[CH2:8][N:7]2[C:2](=[O:1])[CH:3]=[CH:4][C:5]([C:32]3[CH:37]=[C:36]([F:38])[C:35]([F:39])=[C:34]([F:40])[CH:33]=3)=[N:6]2)=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC/C=C\c1cnc(-c2cccc(Cn3nc(-c4cc(F)c(F)c(F)c4)ccc3=O)c2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC/C=C/c1cnc(-c2cccc(Cn3nc(-c4cc(F)c(F)c(F)c4)ccc3=O)c2)nc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
48.3 28 mg (0.051 mmol) of tert-butyl [(Z)-3-(2-{3-[6-oxo-3-(3,4,5-trifluorophenyl)-6H-pyridazin-1-ylmethyl]phenyl}pyrimidin-5-yl) allyl]carbamate are dissolved in 4 ml of dichloromethane, and 79 μl (1.02 mmol) of trifluoroacetic acid are added. The reaction mixture is stirred at room temperature for 15 h and evaporated. The residue is purified by means of preparative HPLC; yield: 11 mg of “A284” trifluoroacetate; HPLC: Rt=2.64 min (method C); LC-MS: 450 (M+H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:6]=1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>>[N+:1]([C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:6]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:5][C:9]=2[CH:10]=1)([O-:4])=[O:2]
Reactant: CCOC(=O)Cc1nc2ccccc2[nH]1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(=O)Cc1nc2ccc([N+](=O)[O-])cc2[nH]1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92 %

Procedure:
Concentrated nitric acid (5 mL) was added to concentrated sulfonic acid (5 mL) at 0° C., and the solution was cooled thoroughly for an additional 10-15 minutes. Ethyl benzimidazole-2-acetate (Buchi, J.; Zwicky, H.; Aebi, A., Archiv. Der Pharmazie 1960, 293, 758; 1.09 g, 5.34 mmol, 1 equiv.) was added portionwise over several minutes The resulting yellow solution was stirred at 0° C. for 20 minutes then was poured carefully onto cracked ice (100 g). The pH was adjusted to 5 with cold 20% sodium carbonate (50-75 mL) and the mixture was extracted with ethyl acetate (3×50 mL). Drying (sodium sulfate), concentration, and silica gel chromatography (3:2 ethyl acetate/toluene) gave ethyl 5-nitrobenzimidazole-2-acetate (1.23 g, 92%) as a yellow solid. TLC (3:2 ethyl acetate/toluene) Rf 0.44; 1H NMR (400 MHz, CDCl3) δ 8.54 (br s, 1H), 8.21 (dd, J=8.9, 2.1 Hz, 1H), 7.58-7.70 (m, 1H), 4.31 (q, J=7.1 Hz, 2 H), 4.14 (s, 2 H), 1.35 (t, J=7.1 Hz, 3 H); IR (chloroform) 3390, 1727, 1523, 1345, 1309 cm-1 ; MS (ESMS) 250.0 (M+H)+.
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:25](Br)=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([F:27])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:28][O:29][CH2:30]/[CH:31]=[CH:32]/B(O)O.C(=O)(O)[O-].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]12([CH2:11][O:12][C:13]3[C:25](/[CH:32]=[CH:31]/[CH2:30][O:29][CH3:28])=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:15]([F:27])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: CC(C)(C)OC(=O)c1cc(Br)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Reactant: COC/C=C/B(O)O
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: [Na+]
Solvent: C1COCCO1
Product: COC/C=C/c1cc(C(=O)OC(C)(C)C)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 150 °C

Procedure:
To a mixture of tert-butyl 4-(adamantan-1-ylmethoxy)-5-bromo-2-fluorobenzoate (1.00 g, 2.28 mmol) in dioxane (15 mL) was added tetrakis(triphenylphosphine)palladium (0.263 g, 0.23 mmol), (E)-3-methoxy-1-propen-1-ylboronic acid, pinacol ester (1.36 g, 6.80 mmol), and 2 M sodium bicarbonate solution (4.5 mL, 9.00 mmol). The reaction mixture was thoroughly degassed by passing argon through it and then heated in a microwave at 150° C. for 30 minutes. After cooling to ambient temperature, the mixture was diluted with ethyl acetate (100 mL) and filtered over anhydrous sodium sulfate. Removal of all volatiles under reduced pressure gave a residue which was purified by silica gel column chromatography using 0-50% ethyl acetate in hexanes as eluent to afford tert-butyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-((E)-3-methoxyprop-1-en-1-yl)benzoate (1.17 g, quant.) as a colorless oil.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:31]=[CH:30][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19](O)=[O:20])=[O:14])=[CH:10][CH:9]=1)[CH:2]=[CH2:3].[C:41]([S:60][CH2:61][C@@H:62]([C:64]([NH:66][CH2:67][C:68]([NH2:70])=[O:69])=[O:65])[NH2:63])([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH2:1]([O:4][C:5](=[O:40])[C@@H:6]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]([NH:15][CH2:16][CH2:17][C@H:18]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:19]([NH:63][C@H:62]([C:64]([NH:66][CH2:67][C:68]([NH2:70])=[O:69])=[O:65])[CH2:61][S:60][C:41]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)=[O:20])=[O:14])=[CH:30][CH:31]=1)[CH:2]=[CH2:3]
Reactant: NC(=O)CNC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)NCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)NCC(N)=O)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
173 mg (0.31 mmol) of the compound from example 2A was dissolved in 10 ml dichloromethane. 128 mg (0.31 mmol) S-Trityl-L-cysteinylglycinamide, 53 μl (0.31 mmol) N,N-diisopropylethyl-amine and 116 mg (0.31 mmol) HATU were added. The reaction mixture was heated for 30 min in a sealed tube at 60° C. in a microwave synthesizer. From the reaction mixture the solvent was removed under reduced pressure. The raw product was purified by preparative RP-HPLC on a C18 column with a water methanol gradient from 9/1 to 1/9. The product-containing fractions were combined and concentrated to dryness under reduced pressure. This gave 57 mg (0.02 mmol, 18% of theory) of the desired product.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[OH:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[OH:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:24][CH:23]=1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: OB(O)c1ccc(O)cc1
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(O)cc3)ccn2c1=O

Procedure:
Methyl 8-(4-hydroxy-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (500 mg, 1.71 mmol) and 4-hydroxy-phenyl-boronic acid (283 mg, 2.06 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (610 mg, 100%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:10]O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:17]>C(Cl)Cl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH2:10][Cl:17])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cl
Reactant: COc1ccc(CO)cc1OC1CCCC1
Solvent: ClCCl
Product: COc1ccc(CCl)cc1OC1CCCC1
Yield: 98.9 %

Procedure:
A solution containing 3-cyclopentyloxy-4-methoxybenzyl alcohol (112 grams, 0.50 mol), prepared as described in step a), in 1 liter of methylene chloride was stirred at room temperature with concentrated HCl (110 milliliters, 1.2 mol) for 3 hours, at which time the reaction was done by TLC. The layers were separated and the methylene chloride solution was washed twice with water and evaporated under reduced pressure to give 3-cyclopentyloxy-4-methoxybenzyl chloride (119 grams, 100%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([NH2:28])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.[H-].[Na+].BrC[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>C1COCC1>[C:37]([O:36][C:34](=[O:35])[CH2:33][NH:28][C:25]1[CH:26]=[CH:27][C:20]2[O:19][CH2:18][CH2:17][C:16]3[CH:15]=[C:14]([C:13]4[N:9]([C:3]5[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=5[F:1])[N:10]=[CH:11][N:12]=4)[S:23][C:22]=3[C:21]=2[N:24]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: Nc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CNc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 0 °C
Yield: 88 %

Procedure:
Compound 134 (800 mg, 2.0 mmol) was dissolved in THF (20 mL). It was stirred at 0° C. and NaH (58 mg, 2.4 mmol) was added. Then the mixture was warmed to r.t. and stirred for further 0.5 h. The mixture was cooled to 0° C. and tert-butyl 3-bromopropanoate (502 mg, 2.4 mmol) was added. Later, it was warmed to 80° C. for 2 h. The reaction mixture was filtered to gather the solution. Then water was added into the solution. It was extracted by DCM (20 mL×3). The combined organics were dried over Na2SO4, concentrated in vacuo, and separated by prep TLC (DCM) to give {2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-ylamino}-acetic acid tert-butyl ester (900 mg, yield: 90%) 1HNMR (CDCl3, 400 MHz): δ 8.04 (s, 1 H), 7.45-7.52 (m, 1 H), 7.42 (s, 1H), 7.06-6.93 (m, 4H). 4.25-4.15 (m, 2H), 4.08-3.99 (m, 2H), 3.06 (s, 2H), 1.38 (s, 9H). LC-MS (ESI): m/z=512 [M+H]+
Reaction SMILES: FC1(F)CCN(C(C2NC3C(C=2)=CC(O[CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=CC=3)=O)CC1.[CH2:30]([O:32][C:33]([C:35]1[NH:36][C:37]2[C:42]([CH:43]=1)=[CH:41][C:40]([OH:44])=[C:39]([Br:45])[CH:38]=2)=[O:34])[CH3:31]>>[CH2:30]([O:32][C:33]([C:35]1[NH:36][C:37]2[C:42]([CH:43]=1)=[CH:41][C:40]([O:44][CH:20]1[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]1)=[C:39]([Br:45])[CH:38]=2)=[O:34])[CH3:31]
Reactant: CCOC(=O)c1cc2cc(O)c(Br)cc2[nH]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: CCOC(=O)c1cc2cc(OC3CCN(C(C)C)CC3)c(Br)cc2[nH]1

Procedure:
In analogy to the procedure described for the synthesis of intermediate 1, step 2, the title compound was synthesized from 6-bromo-5-hydroxy-1H-indole-2-carboxylic acid ethyl ester (example 41, step 3). The title compound was obtained in 56% yield as light yellow solid. MS (m/e): 409.0 (MH+, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([N+:13]([O-:15])=[O:14])=[C:8]2[C:3]=1[C:4](=O)[NH:5][CH:6]=[N:7]2.O=P(Cl)(Cl)[Cl:19]>>[Br:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([N+:13]([O-:15])=[O:14])=[C:8]2[C:3]=1[C:4]([Cl:19])=[N:5][CH:6]=[N:7]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(Br)c2c(=O)[nH]cnc2c1[N+](=O)[O-]
Product: Cc1cc(Br)c2c(Cl)ncnc2c1[N+](=O)[O-]

Procedure:
A solution of 5-bromo-7-methyl-8-nitroquinazolin-4(3H)-one (200 mg, 0.71 mmol) in POCl3 (4 mL) was heated at reflux for 4 h. Then the reaction mixture was concentrated and the residue was co-evaporated with toluene and dried to afford 5-bromo-4-chloro-7-methyl-8-nitroquinazoline which was dissolved in THF (5 mL). Then the solution was treated with 3-(trifluoromethyl)aniline (457 mg, 2.84 mmol) and DIPEA (458 mg, 3.55 mmol) at 0° C. and the reaction mixture was stirred at rt for 12 h before it was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered, concentrated and purified by column chromatography to afford 215 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.36 (s, 1H), 9.15 (s, 1H), 8.72 (s, 1H), 8.29 (s, 1H), 8.23 (d, J=8.4 Hz, 1H), 7.67 (t, J=7.8 Hz, 1H), 7.53 (d, J=7.8 Hz, 1H), 2.47 (s, 3H); MS (m/z): 427.17 (M)+.
Reaction SMILES: O=S(Cl)Cl.[Cl:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([CH2:13][C@@H:14]([OH:18])[C:15]([OH:17])=[O:16])=[CH:8][C:7]=1[CH3:19].[CH3:20]O>>[Cl:5][C:6]1[C:7]([CH3:19])=[CH:8][C:9]([CH2:13][C@@H:14]([OH:18])[C:15]([O:17][CH3:20])=[O:16])=[CH:10][C:11]=1[CH3:12]
Reactant: CO
Reactant: Cc1cc(C[C@@H](O)C(=O)O)cc(C)c1Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H](O)Cc1cc(C)c(Cl)c(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4.4 mL (59.9 mmol) SOCl2 were added dropwise to a solution of 12.45 g (54.4 mmol) of (R)-3-(4-chloro-3,5-dimethyl-phenyl)-2-hydroxy-propionic acid in 300 mL MeOH cooled to 0° C. and the reaction mixture was stirred for 1 h at RT. The reaction solution was evaporated down i. vac. and the residue was purified by chromatography (silica gel, cyc/EtOAc 4:1).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[C:6]([O:9][CH3:10])=[CH:5][N:4]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[N:19]=[CH:18][CH:17]=[CH:16]3)[N:3]=1.[C:21]1([N:27]2[C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=[N:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC([O-])=O.[K+]>C(O)CCC.O>[CH3:10][O:9][C:6]1[C:7](=[O:8])[C:2]([C:31]2[N:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:28]=[CH:29][CH:30]=2)=[N:3][N:4]([C:11]2[CH:12]=[CH:13][CH:14]=[C:15]3[C:20]=2[N:19]=[CH:18][CH:17]=[CH:16]3)[CH:5]=1
Reactant: CC1(C)OB(c2ccnn2-c2ccccc2)OC1(C)C
Reactant: COc1cn(-c2cccc3cccnc23)nc(Br)c1=O
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: COc1cn(-c2cccc3cccnc23)nc(-c2ccnn2-c2ccccc2)c1=O
Yield: 81.5 %

Procedure:
A mixture of 3-bromo-5-methoxy-1-quinolin-8-ylpyridazin-4(1H)-one (70 mg, 0.217 mmol), 1-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (88.1 mg, 0.326 mmol), KOAc (42.6 mg, 0.434 mmol) and PdCl2{P(t-Bu)2(Ph-p-NMe2)}2 (7.7 mg, 0.0109 mmol) in BuOH (1.1 mL) and water (0.1 mL) was heated to reflux for 16 h under Ar atmosphere. The mixture was diluted with water, extracted with AcOEt, washed with saturated NaHCO3 aqueous solution, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/AcOEt=50/50 to 0/100 and AcOEt/MeOH=100/0 to 70/30) and recrystallized with AcOEt/hexane to yield the title compound (69.9 mg, 81% yield) as a white solid: mp 189-192° C. 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.76 (3H, s), 6.98 (1H, s), 7.31-7.49 (6H, m), 7.58-7.73 (2H, m), 7.78 (1H, d, J=1.9 Hz), 8.14 (1H, d, J=8.3 Hz), 8.54 (1H, d, J=7.9 Hz), 8.67 (1H, s), 8.99 (1H, d, J=4.1 Hz). Anal. Calcd for C23H17N5O2: C, 69.86; H, 4.33; N, 17.71. Found: C, 69.61; H, 4.37; N, 17.57.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)(=O)=O.[O-:26][CH2:27][CH2:28][CH3:29].[Na+]>>[CH2:27]([O:26][C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)[CH2:28][CH3:29]
Reactant: CCC[O-]
Reactant: CCCOc1ccccc1-c1nc2nc(S(C)(=O)=O)ncc2c(=O)[nH]1
Agent: [Na+]
Product: CCCOc1ncc2c(=O)[nH]c(-c3ccccc3OCCC)nc2n1

Procedure:
In a similar manner to Example 63 reaction of 7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.54 g) and sodium propoxide solution (from sodium, 0.17 g, and n-propanol, 25 ml) yielded the title compound, 0.19 g, m.p. 157-8° C. (recrystallized from n-propanol).
Reaction SMILES: OC(CCC[CH2:7][C@H:8]1[C@@H:16]2[C@@H:11]([NH:12][C:13](N2)=O)CS1)=O.C1(=O)N([N:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]2[S:28][S:29]CCC([O-])=O)C(=O)CC1>[Cl-].[Na+].C(O)C>[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28][S:29][C:13]1[CH:7]=[CH:8][CH:16]=[CH:11][N:12]=1
Reactant: O=C([O-])CCSSC1C=CC=CN1N1C(=O)CCC1=O
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(SSc2ccccn2)nc1
Reaction time: 0.5 h

Procedure:
RA-NAH prepared in the item (1) above was weighed in an amount of 10.4 mg, and dissolved in 2 ml of 0.1 M sodium chloride-0.1 M phosphate buffer (pH 7.5). 80 μl of a solution of 5 mM N-succinimidyl-3-(2-pyridyldithio)propionate (hereinafter, referred to as “SPDP”, Sigma-Aldrich Co.) dissolved in ethanol was added thereto, and the PDP reaction was carried out at room temperature for 30 minutes. The solution was dialyzed against distilled water to remove excessive SPDP, followed by freeze-drying, to thereby yield 9.5 mg of a freeze-dried product of PDP-NAH.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:25](=[O:26])[C:24]3[CH:23]=[C:22]4[CH:27]=[CH:28][CH:29]=[CH:30][C:21]4=[CH:20][C:19]=3[C:18]2=[O:31])[CH2:13][C:14](O)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].Cl.[NH2:33][OH:34]>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([N:17]2[C:25](=[O:26])[C:24]3[CH:23]=[C:22]4[CH:27]=[CH:28][CH:29]=[CH:30][C:21]4=[CH:20][C:19]=3[C:18]2=[O:31])[CH2:13][C:14]([NH:33][OH:34])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: NO
Reactant: CCOc1cc(C(CC(=O)O)N2C(=O)c3cc4ccccc4cc3C2=O)ccc1OC
Agent: Cl
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(=O)NO)N2C(=O)c3cc4ccccc4cc3C2=O)ccc1OC
Yield: 77.2 %

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-N-hydroxy-3-(1,3-dioxo-2,3-dihydro-1H-benzo[f]isoindol-2-yl)propionamide was prepared by the procedure of Example 1 from 3-(3-ethoxy-4-methoxyphenyl)-3-(1,3-dioxo-2,3-dihydro-1H-benzo[f]isoindol-2-yl)propanoic acid (2.00 g, 4.77 mmol), N,N′-carbonyldiimidazole (889 mg, 5.48 mmol) and hydroxylamine hydrochloride (419 mg, 6.03 mmol) in tetrahydrofuran (8 mL) to afford 3-(3-ethoxy-4-methoxyphenyl)-N-hydroxy-3-(1,3-dioxo-2,3-dihydro-1H-benzo[f]isoindol-2-yl)propionamide as an off-white solid (1.6 g, 77% yield): mp, 197.0-199.0° C.; 1H NMR (DMSO-d6) δ1.33 (t, J=7.0 Hz, 3H, CH3), 3.11-3.28 (m, 2H, CH2), 3.73 (s, 3H, CH3), 4.00 (q, J=7.0 Hz, 2H, CH2), 5.79 (t, J=7.8 Hz, 1H, NCH), 6.87-7.09 (m, 2H, Ar), 7.10 (br s, 1H, Ar), 7.74-7.78 (m, 2H, Ar), 8.23-8.27 (m, 2H, Ar), 8.49 (br s, 1H, Ar), 8.85 (br s, 1H, OH), 10.66 (br s, 1H, NH); 13C NMR (DMSO-d6) δ14.69, 34.27, 50.42, 55.45, 63.73, 111.73, 112.45, 119.82, 124.50, 127.04, 129.28, 130.26, 131.20, 135.05, 147.69, 148.58, 166.07, 167.30; Anal Calcd for C24H22N2O6: C, 66.35; H, 5.10; N, 6.45. Found: C, 66.22; H, 5.24; N, 6.08.
Reaction SMILES: [C:1]([C:4]1([CH:11]=[C:10]([CH:12]([CH:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:13])[CH2:9][C:7]([C:21](=[O:23])[CH3:22])([OH:8])[CH:6]1[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:29]=1[C:30]([CH3:32])=[CH2:31])[OH:5])(=[O:3])[CH3:2]>[Pd].C(OCC)(=O)C>[C:1]([C:4]1([CH:11]=[C:10]([CH:12]([CH:14]([CH3:20])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:13])[CH2:9][C:7]([C:21](=[O:23])[CH3:22])([OH:8])[CH:6]1[C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:29]=1[CH:30]([CH3:31])[CH3:32])[OH:5])(=[O:3])[CH3:2]
Reactant: C=C(C)c1ccncc1C1C(O)(C(C)=O)C=C(C(C)C(C)CCCCC)CC1(O)C(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCC(C)C(C)C1=CC(O)(C(C)=O)C(c2cnccc2C(C)C)C(O)(C(C)=O)C1
Reaction time: 4 h

Procedure:
A solution of 6.0 g. of 1,3-diacetyl-2-[4-isopropenyl-3-pyridyl]-5-(3-methyl-2-octyl)resorcinol in 200 ml. of ethyl acetate with 1.2 g. of 5% palladium on carbon was hydrogenated in a Parr apparatus for 11/2 hours. The solution was filtered and 1.2 g. of 5% palladium on carbon was added and the mixture was hydrogenated for 4 hours. After removal of the catalyst, the filtrate was evaporated in vacuo to yield the pure product.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9](Br)[CH:10]=[CH2:11].C1COCC1>[NH4+].[Cl-].CCOCC.[Zn]>[C:2]1([CH:1]([OH:8])[CH2:11][CH:10]=[CH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCBr
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
39 g (0.6 mol) of zinc powder were added at 0° C., a little at a time, to a solution of 53 g (0.5 mol) of benzaldehyde and 73 g (0.6 mol) of allyl bromide in 500 ml of saturated NH4Cl solution/100 ml of THF. The mixture was stirred for 4 hours at room temperature and diluted with ether, and the solid constituents were filtered off with suction. After washing with ether, the phases were separated, and the organic phase was washed with water (2×) and saturated NaCl solution. Drying and concentrating gave 65.2 g (88% of theory) of a colorless oil which was further employed directly.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][C:12]2[C:14]([C:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH:23]=3)=[CH:15][C:16]([C:18]([F:21])([F:20])[F:19])=[CH:17][C:11]=2[N:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][C:12]2[C:14]([C:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH:23]=3)=[CH:15][C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:11]=2[N:10]=1
Reactant: COc1ccccc1-c1nc2cc(C(F)(F)F)cc(C3=CCN(C(=O)OC(C)(C)C)CC3)c2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1-c1nc2cc(C(F)(F)F)cc(C3=CCNCC3)c2[nH]1
Yield: 92 %

Procedure:
Compound 177 (47 mg, 0.099 mmol) was stirred in a solution of DCM (0.8 mL) and TFA (0.200 mL) for 1 hour. After the usual work-up 2-(2-methoxyphenyl)-7-(1,2,3,6-tetrahydropyridin-4-yl)-5-(trifluoromethyl)-1H-benzo[d]imidazole was obtained (34 mg, 0.091 mmol, 92% yield). LRMS (ESI): (calc.) 373.4 (found) 374.1 (MH)+