Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.O.[CH:18]1[CH:23]=CC=C[CH:19]=1>C(O)(C)C>[CH:18]([O:6][C:5](=[O:7])[C:4]1[CH:3]=[C:2]([Br:1])[CH:10]=[C:9]([Br:11])[CH:8]=1)([CH3:23])[CH3:19]
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Reactant: c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(Br)cc(Br)c1

Procedure:
A solution of 3,5-dibromobenzoic acid (Aldrich, 2.4 g, 8.6 mmol) in benzene (150 mL) and isopropanol (50 mL) was treated with concentrated sulfuric acid (2 mL) and heated to reflux overnight using a Dean-Stark water trap. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether. The organic phase was washed with water and saturated, aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a clear oil that was used as such for the next step (2.7 g, ˜100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:25])=[CH2:24])=[CH:19][CH:18]=2)[N:3]=1.[H][H]>C(O)C.O1CCOCC1.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=2)[N:3]=1
Reactant: C=C(C)c1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)c1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1
Yield: 1 %

Procedure:
A solution of 200 mg (0.60 mmol) 2-amino-4-furan-2-yl-6-(4-isopropenyl-benzylamino)-pyrimidine-5-carbonitrile in 15 ml ethanol and 15 ml dioxane was stirred with a spatula end of 10% palladium on charcoal under 1 atm of hydrogen for 16 h at room temperature. After filtration to remove the catalyst, the reaction mixture was concentrated in vacuo. HPLC afforded 2 mg (1%) 2-amino-4-furan-2-yl-6-(4-isopropyl-benzylamino)-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 334 (M+H+, 100).
Reaction SMILES: [CH:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C(=O)N([Br:20])C(=O)C1.O>CN(C=O)C>[Br:20][C:11]1[CH:12]=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:7]=[CH:8][C:9]=1[NH2:10]
Reactant: Nc1ccc(C2CCCC2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccc(C2CCCC2)cc1Br
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 80.4 %

Procedure:
4-Cyclopentylaniline (210 mg, 1.30 mmol) was dissolved in cold (0° C.) DMF (8 mL) and treated with NBS (232 mg, 1.30 mmol). The reaction was stirred at 0° C. for 5 min and then warmed to room temperature for 1 h. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts dried over MgSO4, filtered and concentrated in vacuo. Purification by silica gel chromatography (0-50% ethyl acetate/hexanes) yielded 2-bromo-4-cyclopentylaniline (251 mg, 80% yield). LC/MS m/z 242.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([C:9]([CH2:12]Br)=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[S:16]([O-:19])([O-:18])=[O:17].[Na+:20].[Na+]>C(O)C.O>[Na+:20].[Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][S:16]([O-:19])(=[O:18])=[O:17])=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[O:14][CH3:15]
Reactant: O=S([O-])[O-]
Reactant: COC(=O)c1c(CBr)ccc(Br)c1OC
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COC(=O)c1c(CS(=O)(=O)[O-])ccc(Br)c1OC
Yield: 100.1 %

Procedure:
A mixture of methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89, 1.0 g) and sodium sulphite (0.445 g) in ethanol (1 ml) and water (10 ml) was stirred and heated at reflux for 2 hours. After cooling, the mixture was evaporated to dryness to give (4-bromo-3-methoxy-2-methoxycarbonylphenyl)-methanesulphonic acid sodium salt (1.07 g) as a white solid which was used without further characterization.
Reaction SMILES: [F:1][C:2]1[C:3](Br)=[C:4](Br)[CH:5]=[CH:6][C:7]=1[F:8].[O:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1.[Li]CCCC>CCOCC>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[F:8])[CH:15]1[O:11][CH:12]2[CH:13]=[CH:14]1
Reactant: c1ccoc1
Reactant: Fc1ccc(Br)c(Br)c1F
Agent: [Li]CCCC
Solvent: CCOCC
Product: Fc1cc2c(cc1F)C1C=CC2O1
Temperature: -78 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To 3,4-difluoro-1,2-dibromo-benzene (0.75 g, 2.78 mmol) and furan (1 mL, 14.7 mmol) in Et2O (15 mL) at −78° C. was added BuLi (1.1 mL, 2.5M in hexanes, 2.75 mmol) dropwise. The reaction was stirred for two hours at −78° C. and then was allowed to warm to room temperature. After 2 hours, the reaction mixture was quenched with water dropwise and then was poured into water. The organic layer was separated and the aqueous layer was extracted three times with Et2O. The combined organic layers were washed with brine, dried over MgSO4, concentrated and chromatographed (25% ethyl acetate:hexanes) on silica gel to give 24 (350 mg, 70%) as a colourless oil. Rf=0.21 on silica gel (20% ethyl acetate:hexanes); bp 40° C. @ 0.5 mmHg]; IR (neat, cm−1), 3017 (M), 1624 (s), 1465 (s), 1365 (s), 1253 (s), 1190 (m), 1040 (s), 857 (s). 1H NMR (400 MHz, CDCl3) δ7.06 (2H, dd, JH-F=7.7, 7.7 Hz), 7.01 (2H, s), 5.67 (2H, s); 13C NMR (400 MHz, CDCl3) δ147.2 (dd, JC-F=247.9, 14.5 Hz), 145.1 (dd, JC-F=4.3, 4.3 Hz), 143.1, 110.8 (m), 82.1. HRMS calcd for C10H6O (M+): 180.0387. Found: 180.0394.
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([O:19]C(=O)CC)(=[O:18])[CH2:16][CH3:17]>>[CH3:17]/[C:16](=[CH:11]\[C:10]1[CH:13]=[CH:14][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][CH:9]=1)/[C:15]([OH:19])=[O:18]
Reactant: CCC(=O)OC(=O)CC
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Product: C/C(=C\c1ccc(-c2ccccc2)cc1)C(=O)O
Yield: 49 %

Procedure:
The procedure is performed in an analogous manner to that described in Example 17 (step A), starting from 4-phenylbenzaldehyde and using 6 equivalents of propionic anhydride. Yield: 49% m.p. 178° C. IR (nujol): 1670 cm-1 1H NMR (CDCl3 /TMS): 11.50 to 11.20 (broad s, 1H); 7.70 (s, 1H); 7.60 to 7.20 (m, 9H); 2.15 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13]2)[C:9](O)=[O:10])=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:27])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13]2)[C:9]([Cl:27])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C(c1ccc(Cl)cc1)C1CCC(F)(F)C1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C(c1ccc(Cl)cc1)C1CCC(F)(F)C1
Reaction time: 1 h

Procedure:
470 mg (1.71 mmol) of (4-chlorophenyl)(3,3-difluorocyclopentyl)acetic acid were dissolved in 8 ml of dichloromethane, and a drop of DMF was added. At 0° C., 1.7 ml (3.42 mmol) of oxalyl chloride were then slowly added dropwise, and the mixture was stirred at this temperature for 1 h. After the reaction had gone to completion, the reaction solution was evaporated under reduced pressure and the residue obtained was taken up in 50 ml of dichloromethane and then once more evaporated to dryness. This gave 500 mg (99% of theory) of the title compound as a colourlees oil. The product obtained in this manner was used without further purification and without further spectroscopic characterization in subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.II.C(N(CC)CC)C.[F:21]F>S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[F:21][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: Clc1ccc2ncccc2c1
Reactant: FF
Agent: II
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Fc1ccc2cc(Cl)ccc2n1
Yield: 74 %

Procedure:
A solution containing 6-chloroquinoline (1.0 g, 6.1 mmol), iodine (1.55 g, 6.1 mmol) and triethylamine (0.62 g, 6.2 mmol) in CF2ClCFCl2 (30 ml) was placed in a fluorination apparatus fitted with a drying tube filled with soda lime. Elemental fluorine (7 mmol) as a 10% mixture in dry nitrogen was then passed through the stirred solution using narrow bore PTFE tubing at ca. 15 ml/min. After the fluorine had been added the solution was poured into 10% aqueous sodium metabisulfite solution (30 ml) and extracted with dichloromethane. The organic extracts were dried and evaporated to a brown solid (1.03 g). GC/MS analysis showed a 79% conversion of starting material. Column chromatography on silica gel with dichloromethane as eluant gave 2-fluoro-6-chloroquinoline (0.82 g, 93%), RF 0.78 (CH2Cl2); δH (400 MHz CDCl3, Me4Si) 7.12 ppm (1H, d d, JH3,H4 8.8, JH3,F 2.8, H-3), 7.67 (1H, d d, JH7,H8 9.2, JH5,H7 2.4, H-7), 7.82 (1H, d, JH5,H7 2.4, H-5), 7.87 (1H, d, JH7,H8 9.0, H-8), 8.16 (1H, d d, JH3,H4 =JH4,F 8.8, H-4);δC (100 MHz, CDCl3, Me4Si) 111.1 ppm (d, 2J 42.3, C-3), 126.3 (s, C-5), 127.3 (s, C-4a), 129.6 (s, C-8), 131.4 (s, C-7), 131.9 (s, C-6) 141.0 (d,3J 9.9, C-4), 144.1 (d 3J 16.8, C-8a), 161.2 (d, 1J 243.8, C-2); δF (235 MHz, CDC13, CFCl3) -61.5 ppm (s); m/z (E1+) 181 (M+, 100%), 183 (M+, 32), 146 (34), 126 (11).
Reaction SMILES: [NH:1]1[C:5]2=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.CN(C)C=O.CS([Cl:20])(=O)=O.[OH-].[Na+]>O>[Cl:20][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]=12
Reactant: [O-][n+]1cccc2cc[nH]c21
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccnc2[nH]ccc12
Temperature: 40 °C
Yield: 135.4 %

Procedure:
To a pink solution of 1H-pyrrolo[2,3-b]pyridine 7-oxide (2.47 g, 0.0184 mol) in dimethylformamide (DMF) (13.3 mL, 0.172 mol) was added methanesulfonyl chloride (4.0 mL, 0.052 mol) at 50° C., and the pink color changed to orange. The reaction mixture was heated at 73° C. for 2h, then cooled to 40° C. Water (35 mL) was added, and the resulting suspension was cooled at 0° C. NaOH was added to adjust the pH of the mixture to about 7. The mixture was filtered and washed with water (×3) to give 3.8 g of a wet pale orange solid that was dried at 40° C. overnight to give the product (2.35 g, 82.2% yield).
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]3[N:18]=[C:19]([CH2:24][O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20](B(O)O)=[C:14]3[CH2:13]2)=[O:11])=[CH:6][CH:5]=1.OO>C1COCC1>[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]3[N:18]=[C:19]([CH2:24][O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]([OH:1])=[C:14]3[CH2:13]2)=[O:11])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)c(B(O)O)c2C1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)N1CCn2nc(COc3ccccc3)c(O)c2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 9.8 %

Procedure:
A 2M aqueous solution of sodium hydroxide (0.53 mL, 1.06 mmol) was added to a stirred solution of {5-[(4-fluorophenyl)carbonyl]-2-(phenoxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-3-yl}boronic acid (0.21 g, 0.53 mmol) and hydrogen peroxide (0.084 mL, 1.06 mmol) in THF (5.3 mL) at 0° C. The mixture was stirred at room temperature for 16 hours. Then the solvent was evaporated in vacuo and the crude product was purified by flash column chromatography (silica; 7N solution of ammonia in methanol in DCM 0/100 to 5/95). The desired fractions were collected and the solvents evaporated in vacuo to yield (4-fluoro-phenyl)-(3-hydroxy-2-phenoxymethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazin-5-yl)-methanone (19 mg, 10% yield) as a colourless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH3:2].O[CH:12]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH:12]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH:26]=[CH:27][CH:28]=2)[CH2:19][CH2:18]1)[CH3:2]
Reactant: CCOc1ccccc1O
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3ccccc3)CC2)c1
Product: CCOc1ccccc1OC(CCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure A and Scheme AN using 2-ethoxyphenol and N-(3-[1-(5-hydroxy-5-phenylpentyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 529.2 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.C(OC[O:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH2:32][CH2:33][CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[CH:27]=[CH:28][CH:29]=2)[CH:14]=[C:15]([O:17]COCC)[CH:16]=1)C>CO.C1COCC1>[OH:37][C:35]([CH3:38])([CH3:36])[CH2:34][CH2:33][CH2:32][CH:31]=[CH:30][C:26]1[CH:25]=[C:24]([CH:23]=[CH:22][C:13]2[CH:12]=[C:11]([OH:10])[CH:16]=[C:15]([OH:17])[CH:14]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOCOc1cc(C=Cc2cccc(C=CCCCC(C)(C)O)c2)cc(OCOCC)c1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(O)CCCC=Cc1cccc(C=Cc2cc(O)cc(O)c2)c1

Procedure:
In a manner similar to Example 1(j), by reacting 0.15 ml of concentrated sulphuric acid in 3 ml of methanol with 314 mg (0.67 mmol) of 7-{3-[2-(3,5-bis-ethoxymethoxyphenyl)vinyl]phenyl}-2-methylhept-6-en-2-ol in 3 ml of methanol and 3 ml of THF, after purification on a silica column (ethyl acetate 50-heptane 50), white crystals (m=206 mg; Y=91%) are obtained. m.p.=60-4° C.
Reaction SMILES: [CH3:1][N:2]([CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)[S:3]([C:6]1[CH:25]=[CH:24][C:9]2[N:10]([CH3:23])[C:11]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=3)=[N:12][C:8]=2[CH:7]=1)(=[O:5])=[O:4].[ClH:33].C(=O)([O-])[O-].[NH4+:38].[NH4+]>>[ClH:33].[CH3:1][N:2]([CH:26]1[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]1)[S:3]([C:6]1[CH:25]=[CH:24][C:9]2[N:10]([CH3:23])[C:11]([CH2:13][O:14][C:15]3[CH:16]=[CH:17][C:18]([C:21](=[NH:38])[NH2:22])=[CH:19][CH:20]=3)=[N:12][C:8]=2[CH:7]=1)(=[O:4])=[O:5]
Reactant: CN1CCC(N(C)S(=O)(=O)c2ccc3c(c2)nc(COc2ccc(C#N)cc2)n3C)CC1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Product: CN1CCC(N(C)S(=O)(=O)c2ccc3c(c2)nc(COc2ccc(C(=N)N)cc2)n3C)CC1

Procedure:
Prepared analogously to Example 25d from 400 mg of 1-methyl-2-[(4-cyanophenyl)oxymethyl]benzimidazol-5-yl-sulfonic acid-N-methyl-N-(1-methylpiperidin-4-yl)amide with ethanolic hydrochloric acid and ammonium carbonate.
Reaction SMILES: [CH3:1][C@H:2]([C:15]([OH:17])=[O:16])[C:3]1[CH:8]=[CH:7][C:6]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:5]=2[CH:4]=1.[F:18][C:19]([F:27])([C:23]([F:26])([F:25])[F:24])[CH:20](O)[CH3:21].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:14][O:13][C:10]1[CH:9]=[C:6]2[C:5](=[CH:12][CH:11]=1)[CH:4]=[C:3]([CH:2]([CH3:1])[C:15]([O:17][C@H:20]([C:19]([F:27])([F:18])[C:23]([F:26])([F:25])[F:24])[CH3:21])=[O:16])[CH:8]=[CH:7]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: CC(O)C(F)(F)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc2cc(C(C)C(=O)O[C@@H](C)C(F)(F)C(F)(F)F)ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-naproxen (9.23 g, 40.1 mmol), racemic 3,3,4,4,4-pentafluoro-2-butanol (6.58 g, 40.1 mmol), EDC (9.20 g, 48.0 mmol) and DMAP (4.89 g, 40.0 mmol) was dissolved in CH2Cl2 (40 mL) at room temperature. After stirring for 8 h at room temperature, the mixture was diluted with CH2Cl2, then washed successively with 1 N HCl, sat. NaHCO3, and brine. After drying over Na2SO4 and concentrating, a mixture of diastereomeric naproxen esters was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[CH:10]=1)[C:5]([OH:7])=O.[CH3:18][C:19]1[N:24]=[CH:23][C:22]([C@H:25]([NH2:27])[CH3:26])=[CH:21][N:20]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][N:12]=2)[CH:10]=1)[C:5]([NH:27][C@@H:25]([C:22]1[CH:21]=[N:20][C:19]([CH3:18])=[N:24][CH:23]=1)[CH3:26])=[O:7]
Reactant: Cc1ccc(-c2cc(Br)cc(C(=O)O)c2)nc1
Reactant: Cc1ncc([C@@H](C)N)cn1
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: CN(C)C=O
Product: Cc1ccc(-c2cc(Br)cc(C(=O)N[C@H](C)c3cnc(C)nc3)c2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with 3-bromo-5-(5-methylpyridin-2-yl)benzoic acid (250 mg, 0.86 mmol), (R)-1-(2-methylpyrimidin-5-yl)ethanamine (141 mg, 1.03 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (651 mg, 1.71 mmol), N,N-diisopropylethylamine (0.60 mL, 3.42 mmol), and N,N-dimethylformamide (6 mL). The reaction mixture was stirred at room temperature overnight, and then washed with brine and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure to afford a light brown oil.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]2[C:14](=[O:15])[NH:13][C:12](=[O:16])[C:11]=2[C:17]2[C:23]3[CH:24]=[C:25]([F:41])[CH:26]=[C:27]4[CH:28](CC[O-])[CH:29]([C:30]([N:32]5[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]5)=[O:31])[N:21]([C:22]=34)[CH2:20][CH2:19][N:18]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl.[OH-:43].[Na+]>O>[OH2:15].[OH2:43].[N:1]1[CH:2]=[C:3]([C:10]2[C:14](=[O:15])[NH:13][C:12](=[O:16])[C:11]=2[C:17]2[C:23]3[CH:24]=[C:25]([F:41])[CH:26]=[C:27]4[CH2:28][CH:29]([C:30]([N:32]5[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]5)=[O:31])[N:21]([C:22]=34)[CH2:20][CH2:19][N:18]=2)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C1NC(=O)C(c2cnc3ccccn23)=C1C1=NCCN2c3c1cc(F)cc3C(CC[O-])C2C(=O)N1CCCCC1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C1NC(=O)C(c2cnc3ccccn23)=C1C1=NCCN2c3c(cc(F)cc31)CC2C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Heat a slurry of 7-(2,5-dihydro-4-imidazo[1,2-a]pyridine-3-yl-2,5-dioxo-1H-pyrrol-3-yl)-9-fluoro-1,2,3,4-tetrahydro-2-(1-piperidinyl-carbonyl)-pyrrolo[3,2,1-jk][1,4]benzodiazepine ethanolate (200.8 mg) in water (25 mL) to 75° C. for 0.67 hours. Add 0.72 mL of 1N HCl and continue to heat for 1.75 hours. Add 0.1N NaOH in 1 mL increments every 5 minutes until 7.2 mL have been added. After the last addition, allow the suspension to remain at 75° C. for 0.67 hours and then allow the suspension to cool to room temperature. Collect the solid using vacuum filtration through Whatman #1 paper, rinse with 20 mL deionized water and allow to dry loosely covered for 2 days. Powder X-ray Principal Peaks (Degrees 2 Theta, Intensity): 5.498°, 100%; 22.149°, 100%; 14.921°, 32.9%; 11.399°, 36.7%; and 11.019°, 20.5%.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19](Br)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1)#[N:24].C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([C:23]#[N:24])[CH:30]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(Br)ccc3O2)CC1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(C2Cc3cc(-c4cccc(C#N)c4)ccc3O2)CC1
Temperature: 90 °C

Procedure:
To a mixture of 4-(5-bromo-2,3-dihydro-benzofuran-2-yl)-piperidine-1-carboxylic acid isopropyl ester (37 mg) and 3-cyanophenylboronic acid (18 mg) in N,N-dimethyl-formamide (2 mL) a 2 M aqueous Na2CO3 solution (0.125 mL) is added. The mixture is sparged with argon and PdCl2[1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex (8.2 mg) is added. The resulting mixture is stirred over night at 90° C. After cooling to room temperature, the mixture is filtered through basic alumina, washed with DMF/MeOH (9:1) and concentrated. The residue is purified by preparative HPLC (eluent water (+0.1% TFA)/MeOH) to yield the desired product. HPLC (method 8): tR=1.95 min; Mass spectrum (ESI+): m/z=391 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.[Si]([O:25][CH2:26][C:27]1[NH:28][C:29](=[O:45])[N:30]([CH:32]2[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]2)[CH:31]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>ClCCl>[OH:25][CH2:26][C:27]1[NH:28][C:29](=[O:45])[N:30]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[nH]c2=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c(CO)cn1C1CCNCC1
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (5 mL) was added to a solution of tert-butyl 4-[4-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]piperidine-1-carboxylate (550 mg, 1.03 mmol) in dichloromethane (15 mL). After 30 min, the reaction was concentrated to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:13](=O)[CH2:14][CH3:15])=[C:6](OS(C)(=O)=O)[CH:7]=1.Cl.[F:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1.C([O-])(=O)C.[Na+].CCCCCC>C1(C)C=C(C)C=C(C)C=1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:13]([CH2:14][CH3:15])=[N:26][N:25]2[C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[CH:4][CH:3]=1
Reactant: CCC(=O)c1ccc(Br)cc1OS(C)(=O)=O
Reactant: NNc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCCC
Solvent: Cc1cc(C)cc(C)c1
Product: CCc1nn(-c2ccc(F)cc2)c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 13 h

Procedure:
Methanesulfonic acid 5-bromo-2-propionyl-phenyl ester, prepared as described in U.S. Ser. No. 09/308,954, now U.S. Pat. No. 6,011,159, filed May 8, 1997 as Attorney Docket No. PC9798, 30 grams (97.66 mmol) was combined with 4-fluorophenyl hydrazine hydrochloride (31.76 g, 175.33 mmol) and sodium acetate (30 g, 364 mmol) in mesitylene (400 mL). The reaction mixture was heated to reflux in a Dean-Stark apparatus for 96 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was diluted with 500 mL of diethyl ether and 600 mL of water. Organic layer was separated and aqueous layer extracted with 500 mL of ethyl acetate. Combined organic extracts were washed with water (2×600 mL), brine (1×200 mL), dried over MgSO4 and concentrated which gave a brown-red oil. Hexane (600 mL) was added to crude reaction product and the mixture boiled in a steam bath for a few minutes. This was followed by cooling still the heterogeneous mixture to room temperature and allowing to stand at room temperature for 12-14 hours. The reaction mixture was filtered, undissolved solid washed with additional hexane and filtrate which contained approximately 80% pure desired product concentrated in vacuo to give brown-yellow solid. Purification of this product on silica gel column and eluting with 15% ethyl acetate/85% hexane gave 14.1 grams of light brown-tan solid. Recrystallization from hexane gave light tan needles. mp=72-73° C.; MS (APCI) m/z 319 (base).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:24]2[CH:25]=[CH:26][NH:27][C:28]=2[CH:29]=[CH:30][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:19][CH2:20][CH2:21][O:22][C:23]4[CH:31]=[CH:30][CH:29]=[C:28]5[C:24]=4[CH:25]=[CH:26][NH:27]5)[CH2:14][CH2:13]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: ClCCCOc1cccc2[nH]ccc12
Reactant: Clc1ccc2c(C3CCNCC3)c[nH]c2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ccc2c(C3CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c2c1Cl

Procedure:
The title compound was prepared in a fashion similar to that described in Example 192 from 6,7-dichloro-3-(piperidin-4-yl)-1H-indole (0.80 g, 3.0 mmol), 1-chloro-3-(1H-indole-4-oxy)propane (0.64 g, 3.1 mmol) and potassium carbonate (0.83 g, 6.0 mmol). The product was isolated as a tan foam. Yield 278mg, 21%. mp 160-165° C. FDMS m/e=441 (M+ of free base).