Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[CH:9]=[O:10]>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:1][C:7]1[S:6][C:5]([CH:9]=[O:10])=[C:4]([CH3:3])[CH:8]=1
Reactant: Cc1ccsc1C=O
Reactant: BrBr
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1cc(Br)sc1C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
Following the preparation as described in U.S. Publication No. 2006/0199836, Br2 (3.67 mL, 71.3 mmol) was added to a solution of 3-methylthiophene-2-carbaldehyde (8.55 mL, 71.3 mmol) in chloroform (59.4 mL) dropwise at 0° C. over a period of 20 min. The reaction was allowed to slowly warm to room temperature and stir for 2 h. The brown/red solution was diluted with 150 mL of CH2Cl2 and washed with water, 1.5 M K2HPO4 and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography (silica gel, hexanes:EtOAc, 100:0 to 50:50) to afford 13.9 g (72% yield) of the title compound as a brown solid: 1H NMR (400 MHz, CDCl3) δ 9.91 (s, 1H), 6.97 (s, 1H), 2.54 (s, 3H); HPLC retention time: 2.718 min., LCMS (ES): m/z 207 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(=O)([O-])O.[Na+].P(Cl)(Cl)([Cl:18])=O>>[C:8]([C:7]1[C:2]([Cl:1])=[CH:3][N:4]=[C:5]([Cl:18])[CH:6]=1)#[N:9].[C:8]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([Cl:18])[C:2]=1[Cl:1])#[N:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cc[n+]([O-])cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: N#Cc1cc(Cl)ncc1Cl
Product: N#Cc1ccnc(Cl)c1Cl

Procedure:
9.6 g of 3-chloro-4-cyanopyridine was dissolved in 70 ml of dichloromethane. Then, 23.2 g of a 31% hydrogen peroxide aqueous solution and 16.0 g of trifluoroacetic acid were added thereto, and the mixture was stirred overnight at room temperature. After completion of the reaction, the reaction solution was extracted with dichloromethane. The organic layer was washed sequentially with an aqueous sodium hydrogen carbonate solution and an aqueous sodium hydrogen sulfite solution and the dried over anhydrous magnesium sulfate. Then, dichloromethane was distilled off under reduced pressure. The obtained residue was washed with isopropyl ether to obtain 7.2 g of 3-chloro-4-cyanopyridine N-oxide as a white powder (melting point: 172° to 174° C.). Then, 20 ml of phosphorus oxychloride was added to this 3-chloro-4-cyanopyridine N-oxide, and the mixture was refluxed under heating for 5 hours. After cooling, the reaction solution was gradually poured into an aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate) to obtain 3.2 g of 4-cyano-2,5-dichloropyridine (melting point: 55° to 58° C.) and 2.5 g of 4-cyano-2,3-dichloropyridine (melting point: 65° to 69° C.).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]([NH2:8])[CH3:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([F:19])=[CH:14][N:13]=1>>[Cl:11][C:12]1[N:17]=[C:16]([NH:8][CH:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[CH3:7])[C:15]([F:19])=[CH:14][N:13]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC(N)c1ccc(F)cc1
Product: CC(Nc1nc(Cl)ncc1F)c1ccc(F)cc1

Procedure:
In like manner to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro 4-pyrimidineamine, 4-fluoro-α-methylbenzylamine and 2,4-dichloro-5-fluoropyrimidine were reacted to produce (±)-N-(2-chloro-5-fluoropyrimidinyl)-1-(4-fluorophenyl)ethylamine. 1H NMR (CDCl3): δ 7.87 (d, 1H, J=2.3 Hz), 7.37-7.33 (dd, 2H, J=5.4 and 8.4 Hz), 7.04 (t, 2H, J=8.4 Hz), 5.35-5.31 (m, 2H), 1.60 (d, 3H, J=6.4 Hz); LCMS: ret. time: 32.90 min.; purity: 98%; MS (m/e): 270 (MH|).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:13]2[O:12][C:11]([CH2:14][OH:15])=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.I[CH3:17]>O1CCCC1>[CH3:3][O:4][C:5]1[C:13]2[O:12][C:11]([CH2:14][O:15][CH3:17])=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc2cc(CO)oc12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cc2cccc(OC)c2o1
Reaction time: 8 h

Procedure:
Sodium hydride (3.82 g, 60% in mineral oil) was added to a solution of 7-methoxy-benzofuran-2-ylmethanol (11.21 g) in dry tetrahydrofuran (300 ml) under an atmosphere of dry nitrogen at room temperature. After 10 minutes iodomethane (15.67 ml) was added and the reaction was left to stir overnight. The solvent was removed in vacuo and the residue partitioned between ethyl acetate (100 ml) and water (50 ml). The organic extract was washed with water (50 ml), followed by brine (50 ml), dried over magnesium sulphate, filtered and the solvent removed in vacuo to afford the title compound (13.32 g) as a yellow oil.
Reaction SMILES: Cl.O1CCOCC1.[Cl:8][C:9]1[C:10]([C:26]#[N:27])=[N:11][CH:12]=[C:13]([C:15]2[N:19](C3CCCCO3)[N:18]=[CH:17][CH:16]=2)[CH:14]=1>C(O)C>[Cl:8][C:9]1[C:10]([C:26]#[N:27])=[N:11][CH:12]=[C:13]([C:15]2[NH:19][N:18]=[CH:17][CH:16]=2)[CH:14]=1
Reactant: N#Cc1ncc(-c2ccnn2C2CCCCO2)cc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: N#Cc1ncc(-c2ccn[nH]2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.1 %

Procedure:
4 M hydrogen chloride in dioxane (1.1 ml, 4.40 mmol) was added to a solution of 3-chloro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)picolinonitrile (1.1 g, 3.81 mmol) in absolute ethanol (15 ml) and stirred at RT for 3 h. Solvents were evaporated and water was added to the residue. The mixture was neutralised with saturated NaHCO3 and extracted with EtOAc. The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to give 0.796 g of the product. 1H-NMR (400 MHz; d6-DMSO): δ 7.10 (d, 1H), 7.92 (d, 1H), 8.58 (d, 1H), 9.17 (d, 1H), 13.4 (bs, 1H).
Reaction SMILES: [CH2:1]([C:3]1[NH:12][C:11]2[C:10](=[O:13])[N:8]([CH3:9])[C:7](=[O:14])[N:6]([CH3:15])[C:5]=2[N:4]=1)[CH3:2].[H-].[Na+].[O:18]([CH2:25][CH2:26][CH2:27]Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:1]([C:3]1[N:12]([CH2:27][CH2:26][CH2:25][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11]2[C:10](=[O:13])[N:8]([CH3:9])[C:7](=[O:14])[N:6]([CH3:15])[C:5]=2[N:4]=1)[CH3:2]
Reactant: BrCCCOc1ccccc1
Reactant: CCc1nc2c([nH]1)c(=O)n(C)c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc2c(c(=O)n(C)c(=O)n2C)n1CCCOc1ccccc1
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A suspension of 8-ethyltheophylline (20.8 g; 0.1 M) in dry dimethylformamide (100 ml) was added to an oil free suspension of sodium hydride (2.4 g; 0.1 M) in dry dimethylformamide (100 ml) and the mixture was stirred for 30 minutes. 3-Phenoxypropylbromide (21.5 g; 0.1 M) was added and the mixture was stirred at room temperature for 24 hours. The resulting suspension was poured into water and the precipitate was filtered off and dried. The solid was crystallised from ethanol to give 8-ethyl-7-(3-phenoxy propyl)theophylline as white prisms 23.6 g (69%) mp 107°-8°.
Reaction SMILES: C([C:4]1[C:5](=[O:16])[O:6][C:7]2[C:12]([CH:13]=1)=[CH:11][C:10](Cl)=[C:9](O)[CH:8]=2)(O)=O.C([N:20](C(C)C)CC)(C)C.ClCOCC1C=CC=CC=1.CN(C)CCN>C1COCC1.CN(C=O)C>[O:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:4]([NH2:20])[C:5]1=[O:16]
Reactant: O=C(O)c1cc2cc(Cl)c(O)cc2oc1=O
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)CCN
Agent: ClCOCc1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Nc1cc2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 117.9 %

Procedure:
241 mg 3-carboxy-6-chloro-7-hydroxy coumarin (1 mmol) dissolved in the mixture of 5 ml THF and 5 ml DMF was added 200 ul diisopropylethylamine (DIEA, 1.1 mmol) and 330 mg O-(N-succinium)-N,N,N′,N′-tetramethyl uronium tetrafluoroborate (TSTU, 1.1 mmol). After stirring at room temperature for 20 minutes under nitrogen atmosphere, the reaction mixture was added 400 ul of DIEA and 460 ul benzyl chloromethyl ether (BOM-Cl) and stirred for another 2 hours at room temperature. The resulted mixture was then pulled high vacuum for 2 hours and 1 ml THF, 480 ul 2-dimethyaminoethylamine was added into the solution afterwards. After the reaction mixture was allowed to react at room temperature for 1 hour, the crude product was pulled high vacuum again overnight and purified on a silica gel column (chloroform: methanol=95:5 as eluent). 190 mg colorless solid was obtained as product, 44% yield. 1H NMR (CDCl3, ppm): 2.32 (d, 6H), 2.56 (t, 2H), 2.16 (t, 2H), 4.76 (s, 2H), 5.46 (s, 2H), 7.33 (m, 7H), 7.68 (s, 1H), 8.76 (s, 1H). MS: C22H23O5N2Cl, 430.3 calculated; 431.2 (M+1) found.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20](Cl)[C:21]=1[C:22]1[NH:23][C:24]2[C:30]3[CH:31]=[CH:32][N:33]=[CH:34][C:29]=3[NH:28][C:27]3[N:35]=[CH:36][CH:37]=[CH:38][C:26]=3[C:25]=2[N:39]=1.[CH3:41][N:42](C)C=O>[C-]#N.[Zn+2].[C-]#N>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][CH:19]=[C:20]([C:21]=1[C:22]1[NH:23][C:24]2[C:30]3[CH:31]=[CH:32][N:33]=[CH:34][C:29]=3[NH:28][C:27]3[N:35]=[CH:36][CH:37]=[CH:38][C:26]=3[C:25]=2[N:39]=1)[C:41]#[N:42]
Reactant: Clc1cncc(Cl)c1-c1nc2c([nH]1)-c1ccncc1Nc1ncccc1-2
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cncc(Cl)c1-c1nc2c([nH]1)-c1ccncc1Nc1ncccc1-2
Temperature: 175 °C
Yield: 13 %

Procedure:
2-(3,5-Dichloropyridin-4-yl)-3,8-dihydroimidazo[4,5-d]dipyrido[2,3-b:4′,3′-f]azepine bis(trifluoroacetate) (200 mg, 0.3 mmol), zinc cyanide (231 mg, 1.97 mmol), and tetrakis-(triphenylphosphine)palladium(0) (190 mg, 0.16 mmol) were stirred in N,N-dimethylformamide and degassed for 10 minutes by bubbling with nitrogen gas. The mixture was heated in a microwave for 20 minutes at 175° C. Purification by preparative LCMS gave the desired product (25 mg, 13%). 1H NMR (DMSO-d6): δ 9.20 (d, 2H), 8.60 (m, 1H), 8.0 (m, 1H), 7.65 (m, 1H), 6.90 (m, 1H). LC/MS: 372 (M+H)+.
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12]Cl.[OH:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=[O:19]
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=C(O)c1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 70 °C

Procedure:
A mixture of 28.16 g (0.132 mol) of 2-quinolinylmethyl chloride HCl, 18 g (0.132 mol) of 3-hydroxybenzoic acid and 39.6 g of potassium carbonate in 110 ml of DMF is heated at 70° C. overnight. The reaction mixture is poured into water, and the precipitated product is collected, filtered and dried to give 3-(2quinolinylmethyloxy)benzoic acid.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12].[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][C:25]=1[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=1.ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:6]([F:12])=[CH:7][CH:8]=[CH:9][C:10]=3[F:11])[N:29]=2)=[CH:26][C:25]=1[O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:40])([F:41])[F:42])=[CH:35][N:34]=1
Reactant: CN(N=C(Cl)c1c(F)cccc1F)S(=O)(=O)c1ccccc1
Reactant: N#Cc1ccc(Cl)c(Oc2ccc(C(F)(F)F)cn2)c1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cn1nc(-c2c(F)cccc2F)nc1-c1ccc(Cl)c(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 24.6 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2,6-difluorobenzohydrazonoyl chloride (0.90 g), 4-chloro-3-(5-trifluoromethylpyridine-2-yloxy)benzonitrile (0.90 g), anhydrous iron (III) chloride (0.50 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexaneethyl acetate as eluent to give 0.30 g of desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[N:14]2)=[CH:8][C:4]=1[C:5](O)=[O:6].C(Cl)(=O)C([Cl:21])=O>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:17]=[CH:16][N:15]=[N:14]2)=[CH:8][C:4]=1[C:5]([Cl:21])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(Cn2ccnn2)cc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(Cn2ccnn2)cc1C(=O)Cl
Reaction time: 4 h

Procedure:
Combine 2-methoxy-5-(1H-triazol-1-ylmethyl)benzoic acid (0.22 g, 0.94 mmol) and dichloromethane (50 mL). Add dropwise oxalyl chloride (0.14 mL, 1.6 mmol) followed by dimethylformamide (5 drops). After 4 hours, evaporate in vacuo and dry to give the title compound.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][NH:16][CH2:17][C:18]=2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[F:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](Cl)=[O:45])=[CH:42][CH:41]=1>C(Cl)Cl>[C:1]([O:5][CH:6]([C:10]1[C:11]([CH:29]([CH3:31])[CH3:30])=[N:12][C:13]2[C:14]([CH3:28])([CH3:27])[CH2:15][N:16]([C:44](=[O:45])[C:43]3[CH:47]=[CH:48][C:40]([F:39])=[CH:41][CH:42]=3)[CH2:17][C:18]=2[C:19]=1[C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CNCC2(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1nc2c(c(-c3ccc(F)cc3)c1C(OC(C)(C)C)C(=O)O)CN(C(=O)c1ccc(F)cc1)CC2(C)C
Reaction time: 3 h
Yield: 78.7 %

Procedure:
To a stirred turbid mixture of 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (example 1) (0.0103 g, 0.024 mmol) and Et3N (0.017 ml, 0.120 mmol) in CH2Cl2 (2 mL) was added 4-fluorobenzoyl chloride (8.52 μl, 0.072 mmol) at room temperature. After 3 h, the reaction mixture concentrated and purified by preparative-HPLC (MeCN/H2O/NH4OAc) to afford 2-tert-butoxy-2-(6-(4-fluorobenzoyl)-4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetic acid (0.0104 g, 77% yield) as white powder. 1H NMR (500 MHz, CD3OD) δ ppm 6.98-7.59 (8H, m), 4.75-4.87 (1H, br. s.), 4.57 (0.5H, d, J=17.7 Hz), 4.40 (0.5H, d, J=17.7 Hz), 4.31 (0.5H, d, J=17.7 Hz), 4.02 (0.5H, d, J=11.6 Hz), 3.92 (0.5H, d, J=15.3 Hz), 3.73 (0.5H, d, J=12.5Hz), 3.53-3.78 (2H, m), 1.37-1.48 (3H, m), 1.19-1.35 (6H, m), 1.15 (3H, d, J=6.1 Hz), 0.96 (9H, br. s.). LCMS (M+H) calcd for C32H37FN2O4: 551.27. found: 551.4.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH2:9]Br)[CH:3]=1.[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([Cl:8])[CH:7]=1)[CH2:9][N:15]1[C:11](=[O:21])[C:12]2[C:13](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:14]1=[O:16]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Clc1cc(Br)cc(CBr)c1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cc(Cl)cc(Br)c1
Temperature: 120 °C
Yield: 85.6 %

Procedure:
Step G3. A mixture of 1-bromo-3-(bromomethyl)-5-chlorobenzene (6 g, ˜21 mmol) and potassium phthalimide (3.15 g, 17 mmol) in DMF (50 ml) was heated at 120° C. for 2 hours. After cooled down, a white solid precipitated. The solid was filtered and washed with ethanol, then dried in vacuum. 2-(3-Bromo-5-chlorobenzyl)isoindoline-1,3-dione (5.1 g, 85%) was obtained as white solid. 1H NMR (DMSO-d6): δ3.72 (s, 2H), 7.43 (s, 1H), 7.51 (s, 1H), 7.52 (s, 1H), 7.84,7.86 (d,2H), 8.05,8.07 (d,2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O.[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1O
Reaction time: 5 h

Procedure:
0.125 mol(16 g) of 4-chlorophenol, 25 ml of water and 35 ml of acetic acid are introduced into a 125 ml three-necked flask equipped with a stirring system and a thermometer; the mixture is brought to 40° C and 14.2 ml of nitric acid (d=1.38) are then added drop by drop; the reactants are left in contact for 5 hours. The product is separated by filtration and is crystallized in the minimum of absolute alcohol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:15]=[CH:16][C:9]=23)[CH:7]=1.C([N-]C(C)C)(C)C.[Li+].[I:36]I>O1CCCC1.O1CCCC1.CCCCCCC.C(C1C=CC=CC=1)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:26][CH3:27])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[N:14]([S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])[C:15]([I:36])=[CH:16][C:9]=23)[CH:7]=1
Reactant: II
Reactant: COc1ccc(F)cc1-c1ccnc2c1ccn2S(=O)(=O)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COc1ccc(F)cc1-c1ccnc2c1cc(I)n2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 87A (4.24 g, 11.09 mmol) in tetrahydrofuran at −78° C. was added dropwise 2M lithium diisopropylamide (8.32 mL, 16.63 mmol) in tetrahydrofuran/heptane/ethylbenzene. After 30 minutes, iodine (5.63 g, 22.18 mmol) in tetrahydrofuran (50 mL) was cannulated into the mixture. The mixture was stirred at −78° C. for 3 hours, quenched with aqueous sodium thiosulfate and extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated until a precipitate formed. The solids were filtered, washed with ethyl acetate and dried under vacuum to afford the title compound. MS (ESI+) m/z 508.9 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19].O>O1CCCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:18](=[O:19])[O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccc2[nH]cnc2c1
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1ccc2[nH]cnc2c1)OCC(Cl)(Cl)Cl

Procedure:
To a solution of 1H-benzimidazol-5-amine (1.00 g, 7.51 mmol) and pyridine (0.73 ml, 9.01 mmol) in tetrahydrofuran (25 ml) was added, under ice-cooling, 2,2,2-trichloroethyl chloroformate (1.25 ml, 9.01 mmol), and the mixture was stirred at room temperature for 1.5 hour. Water was poured to the reaction mixture, and the resulting solution was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was poured to the residue, and 1.49 g (64.4%) of the desired product as a solid was separated by filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[F:15][C:16]([F:33])([F:32])[CH:17]([OH:31])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:12]([CH3:14])[CH3:13])[C:9]([O:31][CH:17]([C:16]([F:15])([F:32])[F:33])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: OC(c1cccc(Oc2ccccc2)c1)C(F)(F)F
Reactant: CC(C)C(C(=O)Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)C(C(=O)OC(c1cccc(Oc2ccccc2)c1)C(F)(F)F)c1ccc(Cl)cc1
Yield: 98.3 %

Procedure:
This compound was prepared in the manner of Example II, using 5.3 g of 2-(4-chlorophenyl)-3-methylbutanoyl chloride, whose preparation is described in Agr. Biol. Chem., 38, 881 (1974), together with J. Kagaku To Seibutsu, 14, 427 (1976), 4.6 g of α-trifluoromethyl-3-phenoxybenzyl alcohol, and 1.5 g of pyridine in 50 ml of toluene. Volatiles were removed from the crude reaction product at 100° C./0.02 mm through a short path Kugelrohr distillation system to give as a residue 7.8 g of α-trifluoromethyl-3-phenoxybenzyl 2-(4-chlorophenyl)-3-methylbutanoate. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:35]=[CH:36][CH:37]=1)[O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:28]=[N:27][N:26]([CH2:29][C:30]([O:32]CC)=[O:31])[N:25]=2)=[CH:20][CH:19]=1.C(O)(=O)C>C(O)C.[OH-].[Na+].O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:35]=[CH:36][CH:37]=1)[O:16][CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[N:28]=[N:27][N:26]([CH2:29][C:30]([OH:32])=[O:31])[N:25]=2)=[CH:22][CH:23]=1
Reactant: CCOC(=O)Cn1nnc(-c2ccc(COc3cccc(OCc4ccc5ccccc5n4)c3)cc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)Cn1nnc(-c2ccc(COc3cccc(OCc4ccc5ccccc5n4)c3)cc2)n1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A mixture of 1 g of ethyl [5-(4-(3-(2-quinolinylmethyl-oxy)phenoxymethyl)phenyl)tetrazol-3-yl]acetate in 5 ml ethanol and 40 ml of 1N NaOH is stirred at 70° C. for 4 hours. This is cooled, diluted with water, acidified with acetic acid, filtered, washed with water, and then ethyl acetate to give 5-(4-(3-(2-quinolinylmethyloxy)phenoxymethyl)phenyl)tetrazol-3-yl acetic acid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][C:18](Br)=[N:19][CH:20]=3)[C:15]2=[O:25])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:27]([N:30]1[CH:34]=[CH:33][N:32]=C1)[C:28]#[CH:29].C([N:37](CC)CC)C>CN(C)C=O.[Cu]I.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]([O:5][C:6](=[O:26])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][C:18]([C:29]#[C:28][CH2:27][N:30]4[CH:34]=[CH:33][N:32]=[N:37]4)=[N:19][CH:20]=3)[C:15]2=[O:25])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCn1ccnc1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)c1ccc(Cn2ccc3cnc(Br)cc3c2=O)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(Cn2ccc3cnc(C#CCn4ccnn4)cc3c2=O)cc1

Procedure:
The coupling of 4-(7-bromo-1-oxo-1H-6-azaisoquinolin-2-ylmethyl)benzoic acid tert-butyl ester (0.70 g, 1.69 mmol) with 1-prop-2-ynyl-1H-imidazole (0.45 g, 4.22 mmol) using triethylamine (0.94 mL, 6.76 mmol), CuI (0.023 g, 0.12 mmol), and Pd(Ph3P)4 (0.08 g, 0.07 mmol) in dimethyl-formamide is carried out as described in Example 1, Step (2). The silica gel mesh is purified on a 3.5×18 cm silica gel column eluted with hexanes/ethyl acetate 1:1, methylene chloride/THF 7:1, then methylene chloride/THF 4:1. Evaporation and drying will afford the desired product.