Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20].C([O-])([O-])=O.[Na+].[Na+].OO>CCO.C1C=CC=CC=1.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OO
Solvent: CCO
Solvent: c1ccccc1
Product: COc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 104 %

Procedure:
A solution of 4-methoxyphenylboronic acid (11.0 g, 72 mmol) in 95% EtOH (100 mL) was added to a solution of (Ph3P)4Pd (2.25 g, 2.0 mmol) and 1-bromo-2-nitrobenzene (13.0 g, 65 mmol) in benzene (300 mL). A solution of Na2CO3 (2M, 150 mL, 300 mmol) was added, and the resulting mixture was refluxed with vigorous stirring overnight. The reaction mixture was then cooled, 30% H2O2 (20 mL) was added, and stirring was continued for 1 h. The resulting mixture was extracted with Et2O, the organic extract was rinsed with brine, dried (Na2SO4), and the solvent was removed in vacuo. The residue was taken up in CH2Cl2 :hexane 1:3, filtered through silica gel, and the biphenyl was eluted with CH2Cl2 :Hexane 1:1. The solvent was removed in vacuo to afford a yellow solid (15.5 g, quantitative yield): mp 48°-50° C.; [Jones, B.; Chapman, F., J. Chem. Soc. 1829-1832 (1952)]1H NMR (CDCl3) δ7.78 (d, 1H, J=8.4 Hz), 7.57 (t, 1H, J=7.8 Hz), 7.42 (m, 2H), 7.24 (d, 2H, J=9.0 Hz 6.94 (d, 2H, J=9.0 Hz), 3.83 (s, 3H); 13C NMR (CDCl3) δ159.70, 149.42, 135.85, 132.13, 131.92, 129.49, 129.12, 127.72, 123.99, 114.22, 55.31. Anal. Calcd for C13H11NO3 : C, 68.11; H, 4.84; N, 6.11. Found: C, 68.42; H, 4.79; N, 5.83.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][OH:11].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][S:2]([O:11][CH2:10][C:9]([CH3:13])([CH3:12])[CH2:8][O:7][CH3:6])(=[O:4])=[O:3]
Reactant: COCC(C)(C)CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(C)(C)COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Methanesulfonyl chloride (330 mL) is added dropwise to a solution of 3-methoxy-2,2-dimethylpropan-1-ol (250 mg) and N,N-diisopropylethylamine (1.1 mL) in dichloromethane (3 mL) chilled in an ice bath. The mixture is stirred at room temperature for 12 hours and partitioned between saturated aqueous NaHCO3 solution and dichloromethane. The organic phase is washed with twice with 1 N hydrochloric acid, saturated aqueous NaHCO3 solution and brine. Then the organic phase is dried (MgSO4) and concentrated to give the title compound. Yield: 407 mg; TLC: rf=0.75 (silicagel, cyclohexane/ethyl acetate 3:1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Br[CH:10]([CH3:15])[C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH3:15])=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)nc1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cnc(Cl)nc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 60.3 %

Procedure:
A mixture of 0.17 g of 2-chloro-5-hydroxypyrimidine, 0.22 g of methyl 2-bromopropionate, 0.20 g of anhydrous potassium carbonate and 2.6 ml of N,N-dimethylformamide was stirred at 60° C. for 1 hour. The reaction solution was cooled to room temperature, then, poured into water, and extracted with t-butyl methyl ether. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.17 g of 2-chloro-5-[1-(methoxycarbonyl)ethoxy]pyrimidine.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.Br[C:27]1[S:31][C:30]([C:32]2[CH:33]=[N:34][N:35]([CH3:41])[C:36]=2[C:37]([O:39][CH3:40])=[O:38])=[N:29][C:28]=1[CH:42]([F:44])[F:43].C(=O)([O-])O.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1.O>[CH:1]1([C:27]2[S:31][C:30]([C:32]3[CH:33]=[N:34][N:35]([CH3:41])[C:36]=3[C:37]([O:39][CH3:40])=[O:38])=[N:29][C:28]=2[CH:42]([F:43])[F:44])[CH2:3][CH2:2]1
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1c(-c2nc(C(F)F)c(Br)s2)cnn1C
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(-c2nc(C(F)F)c(C3CC3)s2)cnn1C
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
Cyclopropylboronic acid (61 mg), palladium acetate (11 mg), phosphoric acid potassium salts (203 mg), water (0.53 ml), and tricyclohexylphosphine (27 mg) were added to a toluene (6 ml) solution of the methyl 4-(5-bromo-4-(difluoromethyl)thiazol-2-yl)-1-methyl-1H-pyrazole-5-carboxylate (84 mg) obtained in (Example 1.4) <Step 1>, and the obtained mixture was then stirred in a nitrogen atmosphere at 100° C. for 1.5 hours. Thereafter, ethyl acetate (50 ml) and a saturated sodium hydrogen carbonate aqueous solution (30 ml) were added to the reaction solution. After extraction of organic layers, water layers were extracted with ethyl acetate (50 ml). The organic layers were combined. The combined organic layer was washed with a saturated saline, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (silica gel:eluent; heptane:ethyl acetate=93:7-40:60), so as to obtain the title compound (62 mg) in the form of a light brown solid.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[O:8]=[C:9]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:16]2[C:11]([C:12]([NH2:24])=[CH:13][CH:14]=[CH:15]2)=[N:10]1.N1C=CC=CC=1>O>[O:8]=[C:9]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:16]2[C:11](=[C:12]([NH:24][C:5](=[O:7])[CH3:6])[CH:13]=[CH:14][CH:15]=2)[NH:10]1
Reactant: Nc1cccc2c1=NC(=O)C=2c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1cccc2c1NC(=O)C2c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ten milliliters of acetic anhydride were added to a solution of 2-oxo-3-phenyl-7-aminoindole (0.7 g.) in 40 ml. of pyridine. The reaction mixture was stirred at ambient temperature for 18 hours. Ten milliliters of water were then added and the solvent removed in vacuo. The residue was treated with 100 ml. of 1 N aqueous hydrochloric acid. The resulting solids were separated by filtration and the filter cake washed with water. Recrystallization of the filtered material from methanol yielded N-(2-oxo-3-phenyl-7-indolinyl)acetamide formed in the above reaction melting at 258°-62° C.; yield = 490 mg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].ClCCl.O>[CH2:12]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(O)cc1C=O
Reactant: BrCc1ccccc1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(OCc2ccccc2)cc1C=O
Reaction time: 2 h

Procedure:
To a stirred suspension of 5-hydroxy-2-methoxybenzaldehyde (306.6 g, prepared by the method of Ulrich et al, J.Org.Chem., 1974, 39, 2437), benzyl bromide (355.8 g) add Adogen 464 (48.5 g) in dichloromethane (600 ml) was added a solution of sodium hydroxide (123.5 g) in water (500 ml). The mixture became warm and the suspension dissolved; additional dichloromethane (300 ml) was added to prevent crystallisation of the benzylated product. After 2 hours, the organic layer was removed, washed twice wit water, once with saturated sodium chloride solution, then dried with anhydrous magnesium sulphate. The solution was concentrated, then treated with petroleum spirit to give 5-benzyloxy-2-methoxybenzaldehyde (445.7 g, 91%, m.p. 99°-100°.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29]>>[CH3:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:29]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: Cc1cccc(C(=O)O)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)c1cccc(C)c1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 3-methyl-benzoic acid to yield (3aR,4S,7aR)-methyl 4-(3-methylbenzoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester elimination ion); RT=7.376 min; LC-MS Method II
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([NH:30][C@H:31]([CH2:35][OH:36])[CH:32]([CH3:34])[CH3:33])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.C(OCC)C>[C:26]([O:25][C:23](=[O:24])[NH:30][CH:31]([CH:35]=[O:36])[CH:32]([CH3:33])[CH3:34])([CH3:27])([CH3:29])[CH3:28]
Reactant: CC(C)[C@@H](CO)NC(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)C(C=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of Dess-Martin periodinane (3.12 g, 0.0073 mol, 1.5 eq) in dichloromethane (25 mL) was added a solution of N-Boc-L-valinol (1 g, 0.0049 mol, 1 eq) in dichloromethane (25 mL). The reaction mixture was stirred at room temperature for 3 h and was diluted with diethyl ether (50 mL). The mixture was poured into an aqueous saturated solution of sodium bicarbonate (100 mL) containing sodium thiosulfate (8.16 g, 10.5 eq). The mixture was stirred for 30 min and the layers were separated. The ether layer was washed with an aqueous saturated solution of sodium bicarbonate (50 mL), water (50 mL), dried (sodium sulfate) and filtered. The filtrate was concentrated to give the crude (1-formyl-2-methyl-propyl)-carbamic acid tert-butyl ester used for the next step without further purification.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([C@@H:14]1[CH2:19][C@H:18]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:17][CH2:16][C@@H:15]1[NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=O)[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Si:21]([O:20][C@@H:18]1[CH2:17][CH2:16][C@H:15]([NH:28][C:29](=[O:38])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:14]([C:11]([CH3:12])=[CH2:1])[CH2:19]1)([C:24]([CH3:25])([CH3:27])[CH3:26])([CH3:22])[CH3:23]
Reactant: CC(=O)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=C(C)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyltriphenylphosphonium bromide (1.2 g) was suspended in toluene (16 mL) prior to the addition of 0.5M potassium bis(trimethylsilyl)amide (5.8 mL) in toluene. After 1 h, this solution was cooled to 0° C. prior to the addition of benzyl (1S,2R,4R)-2-acetyl-4-(tert-butyldimethylsilyloxy)cyclohexylcarbamate (660 mg) in toluene (5.4 mL). After 20 min at 0° C., the reaction was quenched with saturated NH4Cl solution and extracted with EtOAc (2×). The organic extracts were combined, washed with brine, dried (MgSO4), filtered, and concentrated. The resulting residue was purified by flash chromatography to afford benzyl (1S,2S,4R)-4 -(tert-butyldimethylsilyloxy)-2-(prop-1-en-2-yl)cyclohexylcarbamate (380 mg). MS found: (M+H)+=404.2.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[CH2:20]([O:22][CH:23]([O:35][CH2:36][CH3:37])[CH2:24][O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=1[O:33][CH3:34])[CH3:21].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C.CN(C1C=CN=CC=1)C>[Cl:13][C:11]1[CH:10]=[CH:9][C:5]([C:6]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([O:25][CH2:24][CH:23]([O:35][CH2:36][CH3:37])[O:22][CH2:20][CH3:21])=[C:27]([O:33][CH3:34])[CH:28]=2)=[O:8])=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=1
Reactant: O=C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CCOC(COc1ccc(N)cc1OC)OCC
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(COc1ccc(NC(=O)c2ccc(Cl)cc2[N+](=O)[O-])cc1OC)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To a solution of 2-nitro-4-chlorobenzoic acid (5.09, 25.2 mmol) in DCM (100 mL) was added oxalyl chloride (16.8 mL, 34 mmol, 2M in DCM) and DMF (5 drops). The solution was stirred for 1 h and then concentrated by rotary evaporation. The resulting acid chloride was dissolved in DCM. To a solution of 4-(2,2-diethoxyethoxy)-3-methoxyaniline (5.36 g, 21 mmol), triethylamine (4.2 g) and DMAP (0.48 g) in DCM at 0° C. was added the acid chloride solution in 4 portions over 15 min. The reaction was stirred for 18 h and the ice was allowed to melt. The solvents were removed by rotary evaporation and the residue partitioned between water and ethyl acetate. The organic layer was washed with brine, dried and concentrated. The product was purified by by silica gel column chromatography affording the intermediate as a yellow solid (7.91 g, 86%). 1H NMR (DMSO-D6): δ 1.18 (6H, t, J=6.9 Hz), 3.57 (2H, q, J=12.1 Hz), 3.67 (2H, q, J=12.2 Hz), 3.75 (s, 3H), 3.91 (2H, d, J=5.1 Hz), 4.79 (1H, t, J=5.1 Hz), 7.00 (1H, m), 7.18 (1H, d), 7.34 (1H, s), 7.82 (1H, d), 7.95 (1H, d), 8.26 (1H, s), 10.57 (1H, d). LCMS m/z=461 (m+Na+).
Reaction SMILES: [C:1](=[N:14][C:15]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[C:1](=[N:14][C:15]1[CH:22]=[C:21]([CH2:23][Br:24])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)c(N=C(c2ccccc2)c2ccccc2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)cc1N=C(c1ccccc1)c1ccccc1

Procedure:
To a solution of 2-(benzhydrylidene-amino)-4-methyl-benzonitrile (11.2 g, 37.8 mmol) in 500 mL of CCl4 is added N-bromosuccinimide (7.06 g, 39.7 mmol), and benzoyl peroxide (0.92 g, 3.8 mmol). The solution is heated to reflux for 16 hours. After this time, the solution is filtered and the organic solution is concentrated under vacuum. The residue is purified by column chromatography eluting with a gradient of 20% t-butyl ether/hexanes to 25% t-butyl ether/hexanes. The product is obtained as an oil containing a mixture of the desired monobromide, dibromide and unreacted starting material. The mixture is assayed by proton NMR and is found to have a purity between 60-75%. 1H NMR (CDCl3, 300 MHz) δ7.82 (m, 2H), 7.42 (m, 9H), 6.92 (d, 1H), 6.81 (s, 1H), 4.29 (s, 2H).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[CH:10][C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])CCC.[NH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+]>>[OH:18][C:17]1[C:16]2[C:11](=[CH:12][C:13]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9][C:8]=1[C:6]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:7]
Reactant: CCCCOC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O
Reactant: NCCCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCCCNC(=O)c1ncc2cc(Sc3ccccc3)ccc2c1O
Yield: 72.1 %

Procedure:
A mixture of 4-hydroxy-7-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (50 mg, 0.14 mmol) (prepared according to WO 2004108681), 5-aminovaleric acid (830 mg, 7.08 mmol) and NaOMe (11 mL, 5.31 mmol, 0.5 M in MeOH) was refluxed for 3 days. Solvent was evaporated, and the residue was partitioned between EtOAc and water. 1 M HCl was added with stirring until pH was ˜1. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-60% EtOAc/hexanes+2% AcOH) to give 40 mg of the title compound. MS: (+) m/z 397.11 (M+1).
Reaction SMILES: C[O:2][P:3]([CH2:17][CH:18]([C:24](=[O:35])[NH:25][C@H:26]([C:31](=[O:34])[NH:32][CH3:33])[CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:19][C:20](C)([CH3:22])[CH3:21])([CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])=[O:4]>C(O)(=O)C.Br>[CH3:21][CH:20]([CH3:22])[CH2:19][CH:18]([C:24](=[O:35])[NH:25][C@H:26]([C:31](=[O:34])[NH:32][CH3:33])[CH2:27][CH:28]([CH3:29])[CH3:30])[CH2:17][P:3]([CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])(=[O:2])[OH:4]
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)(C)C)CP(=O)(CN1C(=O)c2ccccc2C1=O)OC
Agent: Br
Solvent: CC(=O)O
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(O)CN1C(=O)c2ccccc2C1=O
Reaction time: 18 h
Yield: 99 %

Procedure:
123 mg of [(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]-4-methylpentyl](phthalimidomethyl)phosphinic acid methyl ester were dissolved in a mixture of 3 ml of acetic acid and 3 ml of 48% hydrogen bromide in acetic acid and the mixture was left to stand at room temperature for 18 hours. The solvent was removed by evaporation, the residue was dissolved in a mixture of 10 ml of toluene and 5 ml of acetone and the solution was evaporated. This procedure was repeated twice and the residue was then dissolved in a mixture of 5 ml of dichloromethane and 3 ml of acetone and the solution was evaporated. After drying under a high vacuum (0.1 mmHg), there were obtained 115 mg of [(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl](phthalimidomethyl)phosphinic acid in the form of an off-white foam.
Reaction SMILES: CC[O:3]C(/N=N/C(OCC)=O)=O.C(OC(=O)CCCCCCCCCCCO)C1C=CC=CC=1.[C:35]1([P:41]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.ON1C(=O)C2=CC=CC=C2C1=O>C1COCC1.CCCCCC.C(OC(=O)C)C>[C:48]1([P:41](=[O:3])([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: O=C(CCCCCCCCCCCO)OCc1ccccc1
Agent: O=C1c2ccccc2C(=O)N1O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Diethylazodicarboxylate (DEAD, 16.96 ml, 107.7 mmol) was added dropwise to the mixture of 12-Hydroxydodecanoic acid benzyl ester (21 g, 71.8 mmol), triphenylphosphine (28.29 g, 107.7 mmol) and N-hydroxyphthalimide (12.88 g, 78.98 mmol) in absolute THF (250 ml) at −20°-−30° C. under stirring. The reaction mixture was stirred at this temperature for additional 2-3 h, after which time TLC (hexane-ethylacetate 3:1) indicated reaction completion. The solvent was removed in vacuo and the residue was treated ether (250 ml). Formed precipitate of triphenylphosphine oxide was filtered off, mother liquor was evaporated to dryness and the residue was dissolved in methylene chloride and purified by flash chromatography on silica gel in hexane-ethyl acetate (7:3). Appropriate fractions were pooled and evaporated to dryness to afford 26.5 g (84.4%) of compound 15.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([CH:26]=O)=[C:19]([CH:25]=1)[C:20]([N:22]([CH3:24])[CH3:23])=[O:21].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O.ClCCl>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:26][N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[C:19]([C:20](=[O:21])[N:22]([CH3:24])[CH3:23])[CH:25]=1
Reactant: CN(C)C(=O)c1cc(Br)ccc1C=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl piperazine-1-carboxylate (86.0 mg, 0.460 mmol, 1.00 equiv), 5-bromo-2-formyl-N,N-dimethylbenzamide (130 mg, 0.510 mmol, 1.10 equiv), dichloromethane (10 mL). Triethylamine (139 mg, 1.37 mmol, 3.00 equiv) was added. The mixture was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (293 mg, 1.38 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with water (15 mL), extracted with dichloromethane (3×15 mL) and the organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (50/50) to provide 170 mg (87% yield) of tert-butyl 4-[[4-bromo-2-(dimethylcarbamoyl)phenyl]methyl]piperazine-1-carboxylate as light yellow oil. LCMS (ESI, m/z): 426 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[N:12][NH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.B(O)O>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:18][C:19]1[CH:20]=[C:21]([N:13]2[C:14]3[C:10](=[C:9]([O:8][CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:17]=[CH:16][CH:15]=3)[CH:11]=[N:12]2)[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: c1ccc(COc2cccc3[nH]ncc23)cc1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: OBO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1cc(-n2ncc3c(OCc4ccccc4)cccc32)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 30.7 %

Procedure:
A mixture of 4-[(phenylmethyl)oxy]-1H-indazole (D1) (530 mg, 2.37 mmol), {3-fluoro-4-[(phenylmethyl)oxy]phenyl}boronic acid (873 mg, 3.55 mmol), copper acetate (861 mg, 4.74 mmol), triethylamine (0.660 mL, 4.74 mmol) and powdered 4A molecular sieves (2.5 g) in dichloromethane (10 mL) was stirred vigorously under an air atmosphere at ambient temperature. Further quantities of boronic acid, triethylamine and copper acetate were added after 18 hours (0.5 equivalents of each) and 22 hours (1 equivalent of each). After stirring for a further 24 hrs, the mixture was filtered through a plug of silica gel and concentrated. Chromatography (silica gel, elution with 0-20% ethyl acetate in hexane) gave the title compound (D2) as a white solid (309 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([Br:14])=[CH:9][N:10]=[CH:11]2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].[Cl-].[Na+]>C(O)C.O1CCCC1.O.[Fe]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([Br:14])=[CH:9][N:10]=[CH:11]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(Br)cncc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc2c(Br)cncc2c1
Yield: 56.9 %

Procedure:
In 1 ml of ethanol, 2 ml of tetrahydrofuran and 1 ml of water was dissolved 66 mg (0.26 mmol) of 7-nitro-4-bromoisoquinoline, and 70 mg of powdered iron and 140 mg of ammonium chloride were added thereto, followed by heating at 50 degrees for 3 hours. To the reaction mixture was added 1 N sodium chloride aqueous solution, followed by extracting with chloroform. The organic layer was dried over magnesium sulfate and concentrated. Then, the resulting residue was crystallized from isopropyl ether, to give 33 mg of the title compound.