Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Br[C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)[CH:17]=1)=[O:14].[N:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13]([C:8]2[C:9]3[C:4](=[C:3]([C:34]4[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=4)[CH:12]=[CH:11][CH:10]=3)[CH:5]=[CH:6][CH:7]=2)=[O:14])=[CH:17][C:18]=1[N:24]1[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]1
Reactant: OB(O)c1ccncc1
Reactant: COc1ccc(NC(=O)c2cccc3c(Br)cccc23)cc1N1CCN(C)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(NC(=O)c2cccc3c(-c4ccncc4)cccc23)cc1N1CCN(C)CC1
Yield: 17.1 %

Procedure:
A stirred suspension of 5-bromo-N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]naphth-1-yl carboxamide hydrochloride salt (E2, 0.35 g, 0.71 mmole) and 4-pyridylboronic acid (85 mg, 0.71 mmole) in 1,2-dimethoxyethane (30 ml) and water (30 ml) containing sodium carbonate (0.38 g, 3.5 mmole) was de-gassed by bubbling argon through for 15 minutes. Tetrakis (triphenylphosphine)palladium (0) (80 mg) was added and the mixture heated at reflux for 30 h. The mixture was concentrated in vacuo to approx. 30 ml volume, then diluted with water (50 ml) and extracted with dichloromethane. The organic extract was dried (Na2SO4) and concentrated in vacuo to a dark solid. Purification by column chromatography on silica gel eluting with 0-20% methanol/dichloromethane afforded the title compound as a pale yellow oil (55 mg, 17%). This was converted to its hydrochloride salt and solidified from acetone.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]1[N:16]=[C:15]([Cl:17])[N:14]=[C:13]([NH:18][C:19]2[NH:23][N:22]=[C:21]([CH:24]3[CH2:26][CH2:25]3)[CH:20]=2)[N:12]=1.[F:27][C:28]1[N:33]=[CH:32][C:31]([NH:34][C:35]([C@:37]2([CH3:42])[CH2:41][CH2:40][CH2:39][NH:38]2)=[O:36])=[CH:30][CH:29]=1>C1COCC1>[Cl:17][C:15]1[N:14]=[C:13]([NH:18][C:19]2[NH:23][N:22]=[C:21]([CH:24]3[CH2:26][CH2:25]3)[CH:20]=2)[N:12]=[C:11]([N:38]2[CH2:39][CH2:40][CH2:41][C@@:37]2([CH3:42])[C:35]([NH:34][C:31]2[CH:32]=[N:33][C:28]([F:27])=[CH:29][CH:30]=2)=[O:36])[N:16]=1
Reactant: C[C@@]1(C(=O)Nc2ccc(F)nc2)CCCN1
Reactant: Clc1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@@]1(C(=O)Nc2ccc(F)nc2)CCCN1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
Diisopropylethylamine (0.77 mL, 4.42 mmol) was added to a mixture of 4,6-dichloro-N-(3-cyclopropyl-1H-pyrazol-5-yl)-1,3,5-triazin-2-amine (800 mg, 2.95 mmol) and (S)—N-(6-fluoropyridin-3-yl)-2-methylpyrrolidine-2-carboxamide (625 mg, 2.8 mmol) in THF (20 mL). The reaction mixture was stirred at room temperature overnight and the product was separated by preparative HPLC. Removal of the solvents furnished 1C (860 mg, 64%) as a TFA salt. LC/MS [M+H]+: 458; Ret time (Method F): 2.70 min.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([NH:10][C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[F:18])[N:5]=[C:4]([S:19][CH3:20])[N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[C:24]([CH3:31])[CH:23]=1>>[F:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[NH:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][C:24]=2[CH3:31])[N:3]=[C:4]([S:19][CH3:20])[N:5]=1
Reactant: CSc1nc(Cl)c(C=O)c(Nc2c(F)cccc2F)n1
Reactant: Cc1cc(F)ccc1B(O)O
Product: CSc1nc(Nc2c(F)cccc2F)c(C=O)c(-c2ccc(F)cc2C)n1

Procedure:
Prepared as described above in Example 11 starting from 4-chloro-6-(2,6-difluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 4-fluoro-2-methyl-phenylboronic acid to give the title compound 4-(2,6-difluoro-phenylamino)-6-(4-fluoro-2-methyl-phenyl)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 2.21 (s, 3H), 2.25 (s, 3H), 6.95 (m, 4H), 7.18 (m, 4H), 9.54 (s, 1H), 10.29 (br s, 1H). LC MS (m/e)=390 (MH+).
Reaction SMILES: C(O)(=O)C.Br.C(OC([NH:16][C@H:17]([C:24]([N:26]1[CH2:39][CH2:38][CH2:37][C@H:27]1[C:28]([NH:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:29])=[O:25])[CH2:18][C:19]1[N:23]=[CH:22][NH:21][CH:20]=1)=O)C1C=CC=CC=1>CCOCC>[NH2:16][C@H:17]([C:24]([N:26]1[CH2:39][CH2:38][CH2:37][C@H:27]1[C:28]([NH:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1)=[O:29])=[O:25])[CH2:18][C:19]1[N:23]=[CH:22][NH:21][CH:20]=1
Reactant: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)NC1CCCCC1)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: N[C@@H](Cc1c[nH]cn1)C(=O)N1CCC[C@H]1C(=O)NC1CCCCC1
Temperature: 25 °C
Yield: 188.2 %

Procedure:
To 15 ml of ice-cooled acetic acid solution of 25% hydrobromic acid was added 1.14 g of compound (37) and the reaction was maintained for 3 hours at room temperature. The reaction mixture thus obtained was added to 150 ml of desiccated ether, the precipitates thus formed were quickly collected by filtration and dried overnight in a desiccator at reduced pressure to provide 1.53 g of L-histidyl-N-cyclohexyl-L-prolinamide.2-hydrobromide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8].[C:22]([Si:26]([O:39][CH2:40][CH2:41]I)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:25])([CH3:24])[CH3:23].O>CN(C=O)C>[C:22]([Si:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[O:39][CH2:40][CH2:41][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][OH:1])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)[Si](OCCI)(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(NCCCCO)c1ccc(-c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](OCCN(CCCCO)S(=O)(=O)c1ccc(-c2ccccc2)cc1)(c1ccccc1)c1ccccc1

Procedure:
Biphenyl-4-sulfonic acid-(4-hydroxybutyl)-amide (1 g) and tert-butyl-(2-iodo-ethoxy) diphenyl silane (2 g) were heated in DMF (30 mL) for 3 hours at 60° C. The resultant mixture was poured into water and extracted with dichloromethane. Evaporation and column chromatography (petrol/ethyl acetate) gave the title compound as an amorphous solid. δC (CDCl3, 62.9 MHz): 19.2, 25.1, 26.8, 29.5, 49.3, 49.8, 62.4, 62.9, 127.3, 127.6, 127.7, 127.8, 128.5, 129.1, 129.9, 133.2, 135.6, 138.4, 139.4 and 145.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18](Cl)=[O:19])[C:15]([F:21])=[C:14]([F:22])[C:12]=2[N:13]=1.[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[NH2:33].CCN(C(C)C)C(C)C>C1COCC1>[N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:24]=1[NH:33][C:18]([C:16]1[C:15]([F:21])=[C:14]([F:22])[C:12]2[N:13]=[C:9]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])[NH:10][C:11]=2[CH:17]=1)=[O:19]
Reactant: O=C(Cl)c1cc2[nH]c(-c3c(Cl)cccc3Cl)nc2c(F)c1F
Reactant: Nc1ccc2ccccc2n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc2ccccc2n1)c1cc2[nH]c(-c3c(Cl)cccc3Cl)nc2c(F)c1F
Temperature: 60 °C

Procedure:
To a stirred suspension of 2-(2,6-dichlorophenyl)-6,7-difluoro-3H-benzoimidazole-5-carbonyl chloride (150 mg, 0.38 mmol) and quinolin-2-ylamine (55 mg, 0.38 mmol) in THF (10 mL) was added DIPEA (0.2 ml, 1.14 mmol) and the solution was heated at 60° C. for 4 days. The reaction was quenched with water and aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried with MgSO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using a gradient of heptane/EtOAc (4:1 to 100% EtOAc) to give 2-(2,6-dichlorophenyl)-6,7-difluoro-3H-benzoimidazole-5-carboxylic acid quinolin-2-ylamide as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ 13.67 (s, 1H), 11.26 (s, 1H), 8.47 (d, 1H), 8.41 (d, 1H), 7.98 (d, 1H), 7.87 (d, 1H), 7.81 (d, 1H), 7.77 (m, 4H), 7.56 (m, 1H). MS (m/z) 469.1 (M+1); Retention time: 1.51 min (Method 10).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6]>S(Cl)(Cl)=O>[Cl:2][C:3]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([Cl:1])=[O:6]
Reactant: Cl
Reactant: COc1ccc(C(=O)O)c(Cl)n1
Solvent: O=S(Cl)Cl
Product: COc1ccc(C(=O)Cl)c(Cl)n1
Temperature: 80 °C
Reaction time: 5 h
Yield: 85.7 %

Procedure:
A mixture of 2-chloro-6-methoxy-nicotinic acid hydrochloride salt (360 g, 1925 mmol) in thionyl chloride (500 mL) was stirred at 80° C. for 5 h. The solvent was evaporated in vacuo to yield 2-chloro-6-methoxy-nicotinoyl chloride (340 g, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:4].I[CH2:33][CH:34]([F:36])[F:35].[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)=[CH:8][C:9]=1[N:10]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:33][CH:34]([F:36])[F:35])[CH2:13][CH2:12]1)[C:17]([C@H:19]1[CH2:24][CH2:23][C@H:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])=[O:4]
Reactant: FC(F)CI
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCNCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(CC(F)F)CC1
Temperature: 60 °C
Reaction time: 7 h

Procedure:
To a solution of 5-cyclohex-1-enyl-3-[(trans-4-methyl-cyclohexanecarbonyl)-piperidin-4-yl-amino]-thiophene-2-carboxylic acid methyl ester (100 mg, 0.23 mmol) and 2-iodo-1,1-difluoroethane (53 mg, 0.45 mmol) in DMF (2 mL) was added NaH (18 mg, 0.45 mmol, 60%) at 0° C. under N2 atmosphere. The reaction mixture was stirred at 60° C. for 7 h. Excess of NaH was quenched by adding water and the mixture was partitioned between water and ethyl acetate. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by HPLC to obtain 5-cyclohex-1-enyl-3-[[1-(2,2-difluoro-ethyl)-piperidin-4-yl]-(trans-4-methylcyclohexanecarbonyl)amino]-thiophene-2-carboxylic acid methyl ester (43 mg, 38%) as a white solid.
Reaction SMILES: [C:1]1([CH3:9])[C:2]([CH:7]=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH3:10][N:11]([CH3:13])[NH2:12]>C1(C)C=CC=CC=1>[CH3:10][N:11]([CH3:13])[N:12]=[CH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:9]
Reactant: CN(C)N
Reactant: Cc1ccccc1C=O
Solvent: Cc1ccccc1
Product: Cc1ccccc1C=NN(C)C
Yield: 93.9 %

Procedure:
A stirred solution of o-tolualdehyde (25.0 g, 0.21 mol), and 1,1-dimethyl hydrazine (25.2 g, 0.42 mol) was refluxed in toluene (200 mL) for 24 h. The solution was concentrated in vacuo and the residual oil was vacuum distilled (51°-60° C., 0.2 mm Hg) to afford the tided product (31.98 g, 94%): IR (neat) 2950, 2850, 1580, 1550, 1455, 1025, 745 cm-1; 1H NMR (CDCl3, 400 MHz) δ 7.8-7.6 (m, 1H), 7.4-7.3 (m, 1H), 7.1-6.9 (m, 3H), 2.9 (s, 6H), 2.4 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([N+:10]([O-])=O)=[C:6]([CH:9]=1)[NH:7][CH3:8]>C1COCC1.CO.[Ni]>[Br:1][C:2]1[CH:9]=[C:6]([NH:7][CH3:8])[C:5]([NH2:10])=[C:4]([CH3:13])[CH:3]=1
Reactant: CNc1cc(Br)cc(C)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: CNc1cc(Br)cc(C)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.8 %

Procedure:
To a solution of 5-bromo-N,3-dimethyl-2-nitroaniline (Step 85.1) (2.7 g, 11.02 mmol) in THF (100 mL) and MeOH (100 mL) was added Raney Nickel (189 mg, 2.203 mmol) and the resulting mixture was stirred under hydrogen atmosphere at RT for 16 hr. The reaction was filtered through a pad of Celite and the resulting filtrate was concentrated under reduced pressure to afford the title product (2.5 g, 10.56 mmol, 96% yield) as off-white solid. tR: 0.94 min (LC-MS 2); ESI-MS: 214 [M+H]+ (LC-MS 2).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH:12]1([C:15]2[C:16]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:17][CH:18]=[C:19]([CH:21]3[CH2:23][CH2:22]3)[CH:20]=2)[CH2:14][CH2:13]1>>[CH:12]1([C:15]2[C:16]([N:24]3[CH2:25][CH2:26][N:27]([C:6]([C:5]4[CH:4]=[N:3][C:2]([F:1])=[CH:10][C:9]=4[CH3:11])=[O:8])[CH2:28][CH2:29]3)=[N:17][CH:18]=[C:19]([CH:21]3[CH2:23][CH2:22]3)[CH:20]=2)[CH2:13][CH2:14]1
Reactant: Cc1cc(F)ncc1C(=O)O
Reactant: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Product: Cc1cc(F)ncc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 85.3 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 60 and using 6-fluoro-4-methylnicotinic acid (600 mg) and 1-(3,5-dicyclopropylpyridin-2-yl)piperazine (922 mg) described in Preparation Example 62, the title compound (1.23 g) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:5]=1[NH2:12].[C:14](Cl)(=[O:16])[CH3:15]>O1CCOCC1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:5]=1[NH:12][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccc(CO)cc1N
Solvent: C1COCCO1
Product: COC(=O)c1ccc(CO)cc1NC(C)=O
Temperature: 90 °C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
To a solution of 2-amino-4-hydroxymethyl-benzoic acid methyl ester (7.8 g, 43 mmol) in dioxane (150 mL) was added acetyl chloride (3.04 mL, 1 equiv) and the resulting mixture was stirred at 90° C. for 18 h. The solution was concentrated in vacuo and the resulting oil was sonicated in DCM/hexanes (2/8). The solid was filtered off, washed with hexanes and dried to afford a white solid (7.03 g, 73.2%) (ES-MS: m/z 224.2 [M+H]+, rt 3.75 min).
Reaction SMILES: [CH:1]1([C@H:7]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:9]([CH:19]=[O:20])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[CH:1]1([C@H:7]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[C@@H:9]([CH:19]=[O:20])[CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](C2CCCCC2)C[C@H]1C=O
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1C[C@H](C2CCCCC2)C[C@@H]1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
(2S,4S)-tert-butyl 4-cyclohexyl-2-formylpyrrolidine-1-carboxylate (943 mg, 3.35 mmol) was treated with THF (20 mL) and DBU (1.0 mL, 6.70 mmol) and allowed to stir at room temperature overnight. The reaction mixture was concentrated to dryness on the rotovap, treated with DCM and a saturated solution of NH4Cl and extracted, washed with brine, dried over MgSO4, filtered and concentrated affording a mixture of crude (2S,4S)-tert-butyl 4-cyclohexyl-2-formylpyrrolidine-1-carboxylate and (2R,4S)-tert-butyl 4-cyclohexyl-2-formylpyrrolidine-1-carboxylate (470 mg, 1.67 mmol, 99% yield) as a clear, colorless viscous oil. MS (ESI) 304.1 [M+Na]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][C:7](=[O:13])[CH:6]=[C:5]2[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH3:21])=[O:16].[C:32](OC(=O)C)(=[O:34])[CH3:33].N1C=CC=CC=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:32](=[O:34])[CH3:33])[O:8][C:7](=[O:13])[CH:6]=[C:5]2[CH2:14][C:15]([NH:17][CH2:18][CH2:19][N:20]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH3:21])=[O:16]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCN(C)CCNC(=O)Cc1cc(=O)oc2cc(O)c(Cl)cc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCN(C)CCNC(=O)Cc1cc(=O)oc2cc(OC(C)=O)c(Cl)cc12
Reaction time: 8 h
Yield: 74.4 %

Procedure:
A sample of this 2-(6-Chloro-7-hydroxycoumarin-4-yl)-N-[2-(N-decyl-N-methyl-amino)ethyl]acetamide (26 mg, 0.06 mmole) was dissolved in anhydrous dichloromethane (5 mL) and acetic anhydride (0.5 mL, 5.3 mmole) and dry pyridine (0.5 mL, 6.2 mmole) added. This mixture was allowed to stir overnight, and the resulting solution, diluted with dichloromethane (30 mL) and extracted with water (1×25 mL), saturated sodium bicarbonate solution (1×25 mL), 1N HCl (1×25 mL) and water (1×25 mL). The resulting dichloromethane layer was dried over anhydrous sodium sulfate, filtered and evaporated. Drying in vacuo provided an off-white solid (22 mg, 79%). A biocompatible solution of this substrate was prepared by dissolving 22 mg in dry DMSO (0.446 mL) for staining live cells for esterase activity.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[N:2]1.Cl[C:12]1[NH:21][C:20](=[O:22])[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=2)[N:13]=1>>[CH2:9]([O:8][C:6]([C:4]1[CH:5]=[N:1][N:2]([C:12]2[NH:21][C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=3)[N:13]=2)[CH:3]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: O=c1[nH]c(Cl)nc2ccc([N+](=O)[O-])cc12
Product: CCOC(=O)c1cnn(-c2nc3ccc([N+](=O)[O-])cc3c(=O)[nH]2)c1
Temperature: 130 °C
Reaction time: 18 h
Yield: 97.8 %

Procedure:
Ethyl pyrazole-4-carboxylate (1.83 g, 13.1 mmol) was added to a suspension of 2-chloro-6-nitro-3H-quinazolin-4-one (2.95 g, 13.1 mmol) in xylenes (52 mL). The reaction mixture was heated to 130° C. for 1 h, allowed to cool, and stirred at room temperature for 18 h. The precipitate was collected and rinsed with ether (20 mL) to yield the titled compound (4.22 g, 98%). MS (ESI/Cl): mass calcd. for C14H11N5O5, 329.1; m/z found, 330.1 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:21])/[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[C:11]([O:22][CH3:23])[C:10]([CH3:24])=[C:9]2[C:5]=1[C:6](=[O:25])[O:7][CH2:8]2)([OH:3])=[O:2].[C:26]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([C:4]1[C:12]([CH2:13]/[CH:14]=[C:15](\[CH3:21])/[CH2:16][CH2:17][C:18]([O:20][CH3:26])=[O:19])=[C:11]([O:22][CH3:23])[C:10]([CH3:24])=[C:9]2[C:5]=1[C:6](=[O:25])[O:7][CH2:8]2)([OH:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1c(C)c2c(c(C(=O)O)c1C/C=C(\C)CCC(=O)O)C(=O)OC2
Solvent: CO
Product: COC(=O)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1C(=O)O)C(=O)OC2
Yield: 930 %

Procedure:
A solution of 3.88 g (11.1 mmol) of (E)-6-(1,3-dihydro-4-carboxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoic acid and 0.2 g (1.0 mmol) of p-toluene sulfonic acid in methanol (60 ml) was stirred at room temperature for 8 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and this solution was washed twice with water, once with brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a solid which was recrystallized from ethyl acetate to give 3.37 g (9.3 mmol) of methyl (E)-6-(1,3-dihydro-4-carboxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate as a white solid, mp 169°-170° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:11]2[CH2:16][CH2:15][C:14]([CH2:23][C:24]3([CH3:27])[CH2:26][O:25]3)([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:13][C:12]2=[O:28])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.OO.[CH2:31]1COCC1>CC(OC)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:11]2[CH2:16][CH2:15][C:14]([CH2:23][C:24]([OH:25])([CH2:26][CH3:31])[CH3:27])([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[O:13][C:12]2=[O:28])([CH3:9])[CH3:10])=[CH:6][CH:7]=1
Reactant: CC1(CC2(c3ccccc3)CCN(C(C)(C)c3ccc(Br)cc3)C(=O)O2)CO1
Reactant: C1CCOC1
Agent: OO
Solvent: COC(C)(C)C
Product: CCC(C)(O)CC1(c2ccccc2)CCN(C(C)(C)c2ccc(Br)cc2)C(=O)O1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(2-(4-bromophenyl)propan-2-yl)-6-((2-methyloxiran-2-yl)methyl)-6-phenyl-1,3-oxazinan-2-one (57 mg, 128.4 μmol) in THF (10 mL) was added dropwise LiBEt3H (642 mL, 642 μmol) at 0° C. under nitrogen. The resulting mixture was stirred at 10° C. for 2 h. The reaction solution was cooled to 0° C. Hydrogen peroxide (10 mL) was added dropwise while maintain the temperature below 25° C. The resulting mixture was diluted with MTBE (50 mL), washed with water (50 mL) and 30 wt % aqueous sodium thiosulfate (50 mL×3). The organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by preparative HPLC to afford 3-(2-(4-bromophenyl) propan-2-yl)-6-(2-hyroxy-2-ethylpropyl)-6-phenyl-1,3-oxazinan-2-one. 1H NMR: (CDCl3) δ 7.45-7.26 (m, 7H), 6.94-6.92 (d, 2H), 3.27-3.24 (m, 1H), 2.85-2.78 (m, 1H), 2.41-2.30 (m, 2H), 2.22 (m, 3H), 1.65 (s, 3H), 1.47 (s, 3H), 1.15 (s, 3H), 1.03 (s, 3H); LC-MS Method 2 tR=1.35 min, m/z=448, 446.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.I[CH2:13][CH2:14][CH2:15][N:16]([CH2:29][CH2:30][N:31]1[CH:40]=[CH:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]1=[O:41])[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27])(=[O:19])=[O:18].[CH2:42]([N:44]1[C:50](=[O:51])[C:49]([CH3:53])([CH3:52])[C:48](=[O:54])[N:47]([CH3:55])[C:46]2[CH:56]=[C:57]([OH:60])[CH:58]=[CH:59][C:45]1=2)[CH3:43]>C(OCC)(=O)C>[CH2:42]([N:44]1[C:50](=[O:51])[C:49]([CH3:53])([CH3:52])[C:48](=[O:54])[N:47]([CH3:55])[C:46]2[CH:56]=[C:57]([O:60][CH2:13][CH2:14][CH2:15][N:16]([CH2:29][CH2:30][N:31]3[CH:40]=[CH:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:32]3=[O:41])[S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:26]([O-:28])=[O:27])(=[O:19])=[O:18])[CH:58]=[CH:59][C:45]1=2)[CH3:43]
Reactant: O=c1c2ccccc2ccn1CCN(CCCI)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(OCCCN(CCn3ccc4ccccc4c3=O)S(=O)(=O)c3ccccc3[N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
Potassium carbonate (0.22 g, 1.6 mmol) was added to a DMF solution (10 ml) of N-(3-iodopropyl)-2-nitro-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]benzenesulfonamide (0.57 g, 1.05 mmol) and 1-ethyl-7-hydroxy-3,3,5-trimethyl-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione (0.33 g, 1.26 mmol), and stirred at room temperature overnight. The reaction mixture was added to ice water, and extraction with ethyl acetate was performed. The organic layer was washed with 1N-sodium hydroxide aqueous solution and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1→0:1). The purified product was concentrated to dryness under reduced pressure to thereby obtain 0.49 g (yield: 69%) of N-[3-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-yloxy)propyl]-2-nitro-N-[2-(1-oxo-1H-isoquinolin-2-yl)ethyl]benzenesulfonamide as a white amorphous solid.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[C:16]([OH:17])=[C:15]([F:18])[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:13]([CH3:25])[C:12]=1[C:26]#[N:27].[CH3:28][O:29][CH2:30][C:31](Cl)=[O:32].[Cl-].[NH4+]>C(OCC)(=O)C>[CH3:28][O:29][CH2:30][C:31]([O:17][C:16]1[C:15]([F:18])=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]([CH3:25])=[C:12]([C:26]#[N:27])[C:11]=1[NH2:10])=[O:32]
Reactant: COCC(=O)Cl
Reactant: Cc1c(C#N)c(N)c(O)c(F)c1-c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)Oc1c(N)c(C#N)c(C)c(-c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
Diisopropylethylamine (0.64 ml, 3.7 mmol) was added to an ethyl acetate (8 ml) solution of 4-amino-3-cyano-6-fluoro-5-hydroxy-2-methylbiphenyl (I-41) (180 mg, 0.74 mmol), then with cooling with ice, methoxyacetyl chloride (0.17 ml, 1.85 mmol) was added, followed by stirring for 16 hours with gradually heating up to room temperature. Aqueous saturated ammonium chloride solution was added to the reaction liquid, followed by extraction three times with ethyl acetate, the organic layer was washed with saturated sodium bicarbonate water and saturated brine, then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column chromatography, and the eluate with n-hexane:ethyl acetate (1:1) was concentrated under reduced pressure to obtain the entitled compound (229 mg, 99%) as a yellow solid.