Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1COc1cc(F)cc(F)c1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2cc(F)cc(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(3,5-difluorophenoxy)methyl]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:24])[N:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=[C:12]([C:14]([O:16][CH3:17])=O)[CH:13]=1.Br[C:26]1[C:27](=O)[N:28](C2C=CC=CC=2)[CH:29]=[C:30](C(OC)=O)[CH:31]=1.ClC1C=CC=CC=1B(O)O.C(Cl)(=O)C(Cl)=O>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:24])[N:10]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:11]=[C:12]([C:14]2[O:16][C:17]3[CH:29]=[CH:30][CH:31]=[CH:26][C:27]=3[N:28]=2)[CH:13]=1
Reactant: COC(=O)c1cc(Br)c(=O)n(-c2ccccc2)c1
Reactant: COC(=O)c1cc(-c2ccccc2Cl)c(=O)n(-c2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Agent: OB(O)c1ccccc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=c1c(-c2ccccc2Cl)cc(-c2nc3ccccc3o2)cn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
19 mg of carboxylate obtained by hydrolyzing the ester group of 3-(2-chlorophenyl)-5-(methoxycarbonyl)-1-phenyl-1,2-dihydropyridin-2-one (synthesized from 3-bromo-5-(methoxycarbonyl)-1-phenyl-1,2-dihydropyridin-2-one and 2-chlorophenylboronic acid in accordance with the method of Referential Example 3) was dissolved in 20 ml of dichloromethane. Under ice-cooling, a solution of 11 mg of oxalyl chloride in dichloromethane was added dropwise thereinto and a catalytic amount of dimethylformamide was added thereto, followed by stirring at room temperature in nitrogen atmosphere for 1 hour. The reaction solution was evaporated, and the residue was dissolved in dichloromethane. The solution was added dropwise into a solution of 19 mg of 2-aminophenol in dichloromethane under ice-cooling. After heating to room temperature, dichlotomethane was evaporated. To the residue was added 1 ml of polyphosphoric acid, followed by stirring at 180° C. overnight. After cooling to room temperature, the reaction mixture was neutralized with 1N aqueous solution of sodium hydroxide and saturated aqueous solution of sodium hydrogen carbonate under ice-cooling. The mixture was extracted with ethyl acetate, and the resulting organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethylacetate system), to give 3 mg of the title compound as white crystals.
Reaction SMILES: [C:1]([OH:11])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl-].[NH4+].[C:36]([O:39][CH2:40][CH3:41])(=[O:38])[CH3:37]>O1CCCC1>[CH2:40]([O:39][C:36](=[O:38])[CH2:37][C:1](=[O:11])/[CH:2]=[CH:3]/[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:41]
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: CCOC(C)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
Trans-cinnamic acid (5 mmol, manufactured by Fluka), 1,1′-carbonyl diimidazole (892 mg, 5.5 mmol, manufactured by Aldrich) and tetrahydrofuran (10 mL) were charged in a 25 mL round-bottom flask, followed by stirring at room temperature for 1 hour. 1M lithium bis(trimethylsilyl)amide (10 mL, 10 mmol, manufactured by Aldrich), ethyl acetate (977 μL, 10 mmol), and tetrahydrofuran (10 mL) were added to thereto, followed by stirring at −78° C. for 1 hour. Two solutions were mixed, gradually warmed and stirred at room temperature for 1 hour. A saturated ammonium chloride aqueous solution (50 mL) and ethyl acetate (50 mL) were added thereto, followed by separation of layers into two layers and washing with distilled water and saline. The organic layer was dried over anhydrous sodium sulfate and separated by column chromatography (n-Hex/EtOAc=15/1 (v/v)) to afford Compound 8a.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]3[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH2:23])[N:17]=3)[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.CCO.[Cl:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=[CH:32][CH:31]=1.Cl>O>[ClH:29].[NH2:23][C:18]1[N:17]=[C:16]([NH:15][C:11]2[CH:10]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:24]=[CH:25][C:2]([NH:1][C:30]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=[CH:32][CH:31]=4)=[CH:3][CH:4]=3)[CH:14]=[CH:13][CH:12]=2)[CH:21]=[C:20]([CH3:22])[N:19]=1
Reactant: Cc1cc(Nc2cccc(NC(=O)c3ccc(N)cc3)c2)nc(N)n1
Reactant: Clc1ccnc2ccccc12
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(Nc2cccc(NC(=O)c3ccc(Nc4ccnc5ccccc45)cc3)c2)nc(N)n1

Procedure:
To a solution of amine E4 (0.26 g, 0.63 mmol) in 1:2 EtOH:H2O (30 mL) were sequentially added 4-chloroquinoline (0.62 g, 3.78 mmol) and c.HCl (0.17 mL, 5.67 mmol), and the resulting mixture refluxed for 3 h (reaction progress followed by TLC, eluting with the top phase of a 5:4:1 mixture of n-BuOH:H2O:acetic acid; product Rf=0.43, yellow spot after staining with KMnO4). After this time, solvent was removed under reduced pressure, and the residue dried via three MeOH-azeotrope cycles. The residue was re-precipitated from MeOH:EtOAc to give Cpd. II as an amorphous lemon-yellow solid (0.27 g, 79%); mp 251-255° C. (powder-glue); 1H NMR (400 MHz, DMSO): δ 14.78 (v br s, 1H, quinolinyl-N+—H), 12.79 (v br s, 1H, pyrimidinyl-N+—H), 11.14 (s, 1H, ArNHAr), 10.64 (br s, 1H, ArC(O)NHAr), 10.52 (s, 1H, ArNHAr), 8.87 (d, J=8.44 Hz, 1H, ArH), 8.61 (d, J=6.94 Hz, 1H, ArH), 8.30-7.45 (m, 12H, ArH & ArNH2), 7.38 (t, J=8.07 Hz, 1H, ArH), 7.00 (d, J=6.94 Hz, 1H, ArH), 6.22 (s, 1H ArH), 2.29 (s, 3H, ArCH3); LCMS (APCI+): 463 (100%); HPLC: 95.4%.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([C:9]#[N:10])[C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[CH3:19].[N-:20]=[N+:21]=[N-:22].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([C:9]2[NH:22][N:21]=[N:20][N:10]=2)[C:3]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=1[CH3:19]
Reactant: Cc1cc(I)ccc1Nc1c(C#N)ccc(F)c1F
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(I)ccc1Nc1c(-c2nnn[nH]2)ccc(F)c1F
Temperature: 100 °C
Reaction time: 12 h
Yield: 50 %

Procedure:
[2,3-Difluoro-6-cyano-phenyl]-(4-iodo-2-methyl-phenyl)-amine (1.11 g, 3 mmol) and Sodium azide(0.255 g, 3.9 mmol) and triethylamine hydrochloride (0. 537 g, 3.9 mmol) were all suspended in 10 ml toluene and stirred at 100° C. for 12 hours. The mixture was concentrated and the residue purified by column chromatography with ethyl acetate/methanol (10/1) to give the product as a foam-like solid. The yield: ˜50% m.p: 83.4-88.7° C. 1H NMR(CDCl3, 400 Hz): δ/ppm 7.69(1H, m, Phenyl-H); 7.42(1H, s, Phenyl-H); 7.27(1H, m, Phenyl-H); 6.91(1H, dd, J=16.2 Hz, 8.3 Hz, Phenyl-H); 6.40(1H, dd, Phenyl-H); 2.28(3H, s, CH3)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Li])CCC.[O:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]2([OH:20])[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: O=C1CCOCC1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: OC1(c2ccc(Br)cn2)CCOCC1
Temperature: 25 °C
Yield: 33.3 %

Procedure:
A solution of 2,5-dibromopyridine (1 g, 4.22 mmol) in anhydrous toluene (15 mL) was cooled to −78° C. with stirring under nitrogen. n-Butyllithium (2.5M solution in hexanes, 1.7 mL) was added dropwise over 10 minutes. The reaction mixture was stirred at −78° C. for 1 h, then tetrahydro-4H-pyran-4-one (0.43 mL, 4.66 mmol) was added slowly. The reaction mixture was allowed to warm to ambient temperature, then stirred for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (20 mL) and extracted into ethyl acetate (2×20 mL). The combined organic phases were dried over sodium sulfate and concentrated under vacuum. The resulting pale brown oil (983 mg) was purified by chromatography on silica (Biotage, 25 g cartridge), eluting with 0-60% ethyl acetate in heptanes. The resulting yellow solid (578 mg) was re-purified by chromatography on silica (Biotage, 10 g cartridge), eluting with 0-50% ethyl acetate in heptanes, to afford the title compound (363 mg, 32.3%) as a yellow solid. δH (500 MHz, DMSO-d6) 8.60 (d, J 2.2 Hz, 1H), 7.86 (dd, J 8.4, 2.3 Hz, 1H), 7.31 (d, J 8.4 Hz, 1H), 4.67 (s, 1H), 3.98 (td, J 11.7, 1.8 Hz, 2H), 3.94-3.89 (m, 2H), 2.11 (td, J 12.7, 5.5 Hz, 2H), 1.56 (d, J 12.2 Hz, 2H). Method B HPLC-MS: MH+ m/z 258/260, RT 1.44 minutes.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17](Br)[O:16][C:12]=2[N:13]=[CH:14][N:15]=1.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[C:31]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[C:11]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[C:17]([C:31]3[C:32]([O:36][CH3:37])=[CH:33][CH:34]=[CH:35][C:30]=3[F:29])[O:16][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: COC(=O)CCCCCNc1ncnc2oc(Br)c(-c3ccc(OC)cc3)c12
Reactant: COc1cccc(F)c1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)CCCCCNc1ncnc2oc(-c3c(F)cccc3OC)c(-c3ccc(OC)cc3)c12
Temperature: 80 °C
Reaction time: 15 h

Procedure:
Dissolve 150 mg (0.34 mmol) 6-{[6-bromo-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]amino}hexanoic acid methyl ester and 142 mg (0.84 mmol) (2-fluoro-6-methoxyphenyl)boronic acid in 2.0 ml 1,2-dimethoxyethane and add 0.34 ml of 2 M aqueous sodium carbonate solution and 24 mg (0.03 mmol) 1,1′-bis(diphenylphosphano)ferrocene palladium(II) chloride. Next, stir for 15 h at 80° C. Purify the reaction mixture directly by preparative RP-HPLC (gradient: water/acetonitrile). 56 mg (34% of theor.) of the desired product is obtained.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]1[C:26]2[C:21](=[CH:22][C:23]([O:27]C)=[CH:24][CH:25]=2)[S:20][CH2:19][C:18]1([C:30]1[CH:35]=[CH:34][C:33]([O:36]C)=[CH:32][CH:31]=1)[CH3:29])#[N:2].OC1C=C2C(C(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(C3C=CC(O)=CC=3)(C)CS2)=CC=1>>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]1[C:26]2[C:21](=[CH:22][C:23]([OH:27])=[CH:24][CH:25]=2)[S:20][CH2:19][C:18]1([C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[CH3:29])#[N:2]
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCCCCSCCCCC#N)cc1
Agent: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCCSCCCC(F)(F)C(F)(F)F
Product: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCCSCCCCC#N

Procedure:
The title compound was prepared from 4-[9-(4-cyanobutylthio)nonyl]-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman according to the same method for the synthesis of (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylthio)nonyl]thiochroman described in International Patent Appln. No. PCT/KR97/00265.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[CH:17]=[N:16][NH:15][C:14]=12.[H-].[Na+].S(OC)(O[CH3:24])(=O)=O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]2=[N:15][N:16]([CH3:24])[CH:17]=[C:13]2[CH:12]=[CH:11][N:10]=1
Reactant: COS(=O)(=O)OC
Reactant: Clc1ccc(-c2nccc3cn[nH]c23)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc2ccnc(-c3ccc(Cl)cc3Cl)c2n1
Reaction time: 3 h

Procedure:
A mixture of 7-(2,4-dichloro-phenyl)-1H-pyrazolo[3,4-c]pyridine (31; 0.107 g; 0.405 mmol), 4 mL of THF, and 60% sodium hydride/mineral oil (0.020 g, 0.50 mmol sodium hydride) was stirred for 3 h. To the green solution was added dimethyl sulfate (0.040 mL, 0.42 mmol). The resulting yellow, cloudy solution was stirred for 30 m, then quenched with silica gel and concentrated. Column chromatography (0→50% EtOAc/hexanes) afforded of 7-(2,4-dichloro-phenyl)-2-methyl-2H-pyrazolo[3,4-c]pyridine as a white solid (32; 0.029 g; 26%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][C:5]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17](O)=[O:18])=[N:9]2)=[N:6][CH:7]=1.[NH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][OH:23]>>[OH:23][CH2:22][C:21]([NH:20][C:17]([C:10]1[C:11]2[CH2:12][C@H:13]3[CH2:16][C@H:14]3[C:15]=2[N:8]([C:5]2[CH:4]=[N:3][C:2]([Br:1])=[CH:7][N:6]=2)[N:9]=1)=[O:18])([CH3:25])[CH3:24]
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1nn(-c2cnc(Br)cn2)c2c1C[C@H]1C[C@@H]21
Product: CC(C)(CO)NC(=O)c1nn(-c2cnc(Br)cn2)c2c1C[C@H]1C[C@@H]21

Procedure:
The title compound was prepared in a manner similar to that described in Method G, using (1aR,5aR)-2-(5-bromopyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid and 2-amino-2-methylpropan-1-ol. LCMS m/z=392.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.45 (td, J=4.7 and 3.5 Hz, 1H), 1.25 (td, J=8.0 and 4.7 Hz, 1H), 1.41 (s, 3H), 1.42 (s, 3H), 2.27-2.33 (m, 1H), 2.67-2.72 (m, 1H), 2.91 (d, J=16.8 Hz, 1H), 3.00 (dd, J=16.8 and 6.2 Hz, 1H), 3.70 (s, 2H), 4.53 (s, 1H), 6.90 (s, 1H), 8.50 (d, J=1.4 Hz, 1H), 8.99 (d, J=1.4 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O>>[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: Brc1cccc(-c2ccccn2)c1
Product: Cc1ccccc1-c1cccc(-c2ccccn2)c1

Procedure:
2-(3-bromophenyl)pyridine (25.0 g, 0.107 mol) was reacted with 2-methylphenylboronic acid (17.4 g, 0.128 mol) under standard Suzuki coupling condition. The product (25 g) was collected by Kugelrohr distillation at 220° C. as a white solid.
Reaction SMILES: BrC1C=CC2C3C(CCOC=2C=1)=CN(C1N(C2C=CC(F)=CC=2F)N=CN=1)N=3.Cl[C:30]1[N:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[Cl:41])[N:33]=[CH:32][N:31]=1.[Br:42][C:43]1[CH:44]=[CH:45][C:46]2[O:55][CH2:54][CH2:53][C:52]3[C:48](=[N:49][NH:50][CH:51]=3)[C:47]=2[CH:56]=1.C(Cl)Cl>C1CCCCC1>[Br:42][C:43]1[CH:44]=[CH:45][C:46]2[O:55][CH2:54][CH2:53][C:52]3[C:48](=[N:49][N:50]([C:30]4[N:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=5[Cl:41])[N:33]=[CH:32][N:31]=4)[CH:51]=3)[C:47]=2[CH:56]=1
Reactant: Brc1ccc2c(c1)-c1n[nH]cc1CCO2
Reactant: Clc1ccccc1-n1ncnc1Cl
Agent: Fc1ccc(-n2ncnc2-n2cc3c(n2)-c2ccc(Br)cc2OCC3)c(F)c1
Solvent: C1CCCCC1
Solvent: ClCCl
Product: Clc1ccccc1-n1ncnc1-n1cc2c(n1)-c1cc(Br)ccc1OCC2
Yield: 42 %

Procedure:
9-Bromo-2-[2-(2-chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene was prepared similarly to 8-bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene from 5-chloro-1-(2-chloro-phenyl)-1H-[1,2,4]triazole (2.25 g, 10.5 mmol) and 9-bromo-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (1.9 g, 7 mmol), the crude product was subjected to flash chromatography (SiO2, gradient 0 to 60% DCM (+10% ethyl acetate) in cyclohexane) to give 9-Bromo-2-[2-(2-chloro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-2H-6-oxa-1,2-diaza-benzo[e]azulene (1.3 g, 33%). LCMS RT=4.82 M+H+=442/444
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][C:35]=1[OH:43].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=3)[N:4]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=2)=[CH:36][C:35]=1[OH:43]
Reactant: O=[N+]([O-])c1ccc2c(c1)c(Br)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OB(O)c1ccc(F)c(O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc2c(c1)c(-c1ccc(F)c(O)c1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 75 °C

Procedure:
A suspension of 3-bromo-5-nitro-1-trityl-1H-indazole 1AJ (10.0 g, 20.68 mmol), 4-fluoro-3-hydroxyphenylboronic acid 6AU (3.55 g, 22.78 mmol), Pd(dppf)Cl2 (1.6 mg, 1.96 mmol) and K3PO4 (10.6 g, 4.99 mmol) in 200 mL of dioxane/H2O (4/1) was heated to 75° C. for overnight. After removal of most of the solvent, the black residue was diluted with EtOAc (250 mL) and H2O (60 mL). The resulting mixture was filtered through a pad of Celite. Additional 150 mL of EtOAc was used to wash the Celite cake. The filtrates were combined. The aqueous layer was separated and the organic layer was washed with brine, dried (MgSO4) and concentrated to give a green solid, which was recrystallized from CH2Cl2/hexane to give 3-(4-fluoro-3-hydroxyphenyl)-5-nitro-1-trityl-1H-indazole 7AU (8.1 g).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH3:11])=[CH:5][CH:4]=1.COB(OC)OC.Br[C:20]1[CH:21]=[CH:22][C:23]([OH:28])=[C:24]([CH:27]=1)[CH:25]=[O:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl>C1COCC1.O.C1(C)C=CC=CC=1>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:20]2[CH:21]=[CH:22][C:23]([OH:28])=[C:24]([CH:25]=[O:26])[CH:27]=2)=[CH:4][CH:5]=1)[CH3:11]
Reactant: CCOc1ccc(Br)cc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: COB(OC)OC
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1ccc(-c2ccc(O)c(C=O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
To a suspension of magnesium (0.5 g) in THF (7 ml), a solution of 1-bromo-4-ethoxybenzene (4.0 g) in THF (2.5 ml) was added slowly at room temperature under an argon atmosphere, and the resulting solution was stirred for 1 hour. Subsequently, a solution of trimethoxyborane (2.1 g) in THF (2.5 ml) was added dropwise at −10 to 10° C., and after further addition of THF (7 ml), the reaction mixture was stirred at the same temperature for 1 hour. The reaction mixture was allowed to warm to room temperature and tetrakistriphenylphosphine palladium (115mg), 5-bromo-2-hydroxybenzaldehyde (2.0 g) and an aqueous solution of tripotassium phosphate (11.1 g) in water (15 ml) were added, and the resulting mixture was stirred under reflux for 1 hour. After the mixture was allowed to cool to room temperature, 6N hydrochloric acid (20 ml) was added dropwise, and then toluene(20 ml) was added. After separation, the aqueous phase was further extracted with toluene (30 ml). The organic layers were combined and washed with aqueous 10% sodium chloride solutions (10 ml×3), dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (n-hexane/ethyl acetate=6/1), and the appropriate eluate was concentrated. Diisopropylether (15 ml) was added to the concentrate and the resulting mixture was heated under reflux, and then allowed to cool to room temperature. n-Hexane (15 ml) was added to the solution, and stirred at room temperature for 1 hour and at 0° C. for 0.5 hour. The precipitated crystal was collected by filtration and washed with diisopropylether/n-hexane (1/1.4 ml) which was previously cooled to 0 to 5° C. Drying under reduced pressure (room temperature, 2 hours) gave yellow crystal of the title compound (1.8 g, yield 73%).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH:3]=C.[CH3:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][CH:9]([NH:24][C:25](=[O:47])[C@H:26]([CH2:43][CH:44]([CH3:46])[CH3:45])[C@H:27]([CH2:40]C=C)[C:28]([NH:30]CC2C=C(F)C=C(F)C=2)=[O:29])[C:8]1=[O:48].C([O-])(=O)CCC([O-])=O.CN1C2C=CC=CC=2C(C2C=CC=CC=2)=NC(N)C1=O>>[CH3:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:10][C@H:9]([NH:24][C:25](=[O:47])[C@H:26]([CH2:43][CH:44]([CH3:45])[CH3:46])[C@H:27]([CH2:40][CH2:3][CH:2]=[CH2:1])[C:28]([NH2:30])=[O:29])[C:8]1=[O:48]
Reactant: C=CC[C@H](C(=O)NCc1cc(F)cc(F)c1)[C@@H](CC(C)C)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O
Reactant: C=CCCBr
Agent: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Agent: O=C([O-])CCC(=O)[O-]
Product: C=CCC[C@H](C(N)=O)[C@@H](CC(C)C)C(=O)N[C@H]1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
A procedure analogous to the preparation of Example 5 was followed. The appropriate succinate ester was prepared using the method disclosed in PCT publication WO 98/51665), using 3-butenyl bromide for R3—X in place allyl bromide (see Scheme 2). The anti-succinate half-ester was coupled to (S)-isomer benzodiazepine (30) using the procedures of Step 1. After Steps 2 and 3, the title compound was isolated. MS (M+H)+=475.3; (M+Na)+=497.3.
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[CH3:8][C:9]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1O)=[O:10].C(=O)([O-])[O-].[K+].[K+].N>CC(C)=O>[CH3:8][C:9]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[O:6][CH3:7])=[O:10]
Reactant: CC(=O)c1cc(F)ccc1O
Reactant: COS(=O)(=O)OC
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(F)cc1C(C)=O

Procedure:
Dimethyl sulphate (30 ml) was added dropwise over 45 min to a stirred mixture of 5-fluoro-2-hydroxyacetophenone (32.43 g) and potassium carbonate (40.5 g) in acetone (500 ml) and the mixture was then heated under reflux for 8 hr. Concentrated ammonia solution was added and the inorganic solids removed by filtration. The solvent was removed under reduced pressure and the product was dissolved in ether and washed with water. After drying the ethereal solution (Na2SO4) the ether was removed under reduced pressure and the residue was distilled to give 5-fluoro-2-methoxyacetophenone (28.4 g); b.p. 58°-64 ° C./0.2 mm.
Reaction SMILES: [OH:1][C@@H:2]([CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)/[CH:3]=[CH:4]/[C@@H:5]1[C@@H:13]2[C@@H:8]([S:9][C@@H:10]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH2:12]2)[CH2:7][C@H:6]1[O:21]C1CCCCO1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:21][C@@H:6]1[CH2:7][C@@H:8]2[S:9][C@@H:10]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH2:12][C@@H:13]2[C@H:5]1/[CH:4]=[CH:3]/[C@@H:2]([OH:1])[CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)CCC[C@H]1CC[C@@H]2[C@@H](/C=C/[C@@H](O)COc3ccccc3)[C@H](OC3CCCCO3)C[C@@H]2S1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)CCC[C@H]1CC[C@@H]2[C@@H](/C=C/[C@@H](O)COc3ccccc3)[C@H](O)C[C@@H]2S1
Reaction time: 2 h
Yield: 44.7 %

Procedure:
The compound 13 (220 mg) was dissolved in methanol (1.1 mL), a p-toluenesulfonic acid monohydrate (20 mg) was added at room temperature, and the mixture was stirred for 2 hours. The residue obtained by concentration of the reaction liquid under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=2:1→1:1→ethyl acetate) to obtain a titled compound (82 mg) having the following physical property values.