Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[CH:10]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mn]([O-])(=O)(=O)=[O:37].[K+]>C1COCC1.O>[CH2:1]([O:8][C:9]([CH:10]([NH:27][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([OH:37])=[O:26])=[CH:23][CH:24]=2)=[CH:14][CH:13]=1)=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(C=O)cc2)cc1)C(=O)OCc1ccccc1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Oc2ccc(C(=O)O)cc2)cc1)C(=O)OCc1ccccc1
Temperature: 70 °C
Yield: 94.4 %

Procedure:
Benzyl ester 3 (4.6 g, 9.7 mmol) was dissolved in THF (100 mL) and the solution stirred at 70° C. Potassium permanganate (7.7 g, 48.5 mmol) dissolved in water (125 mL) was added slowly through a dropping funnel over a period of 2 hours. After addition was complete, reaction mixture was stirred at 70° C. for 30 min and cooled to room temperature. The brown precipitate was filtered over a Celite® bed and the filtrate was concentrated under reduced pressure. The residual oil was taken up in EtOAc (100 mL) and acidified with 2.0 M HCl. The organic layer was separated and washed with water (1×100 mL) and brine (1×100 mL), dried, and concentrated under reduced pressure to yield the desired acid compound 4 (4.5 g, 94%). 1H NMR (DMSO-d6): 12.7 (br, 1H), 7.91 (d, J=8.8 Hz, 2H), 7.42 (d, J=8.4 Hz), 7.30-7.37 (m, 7H), 7.03 (d, J=8.8 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 5.12 (s, 2H), 4.24-4.28 (m, 1H), 3.04 (dd, J=13.6 and 5.2 Hz, 1H), 2.91 (dd, J=13.6 and 9.6 Hz, 1H), 1.33 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[C:8]1([C:14]2[O:18][N:17]=[CH:16][C:15]=2[CH2:19][CH2:20][C:21](O)=[O:22])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[NH:1][C:21](=[O:22])[CH2:20][CH2:19][C:15]1[CH:16]=[N:17][O:18][C:14]=1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Reactant: Nc1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1cnoc1-c1ccccc1)Nc1cnccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.5 %

Procedure:
A mixture of 2-aminopyrazine (0.26 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (0.58 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.46 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.60 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(2-pyrazinyl)-3-(5-phenyl-4-isoxazolyl)propionamide (0.46 g, yield 58%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 163–164° C.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.Cl.[CH:13]1([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][C:24]([S:26]([C:29]([CH3:34])([CH3:33])[C:30](Cl)=[O:31])(=[O:28])=[O:27])=[CH:25][C:20]=3[N:19]=[C:18]2[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:15][CH2:14]1>ClCCl>[CH:13]1([CH2:16][N:17]2[C:21]3[CH:22]=[CH:23][C:24]([S:26]([C:29]([CH3:33])([CH3:34])[C:30]([NH:4][CH2:3][CH2:1][OH:2])=[O:31])(=[O:28])=[O:27])=[CH:25][C:20]=3[N:19]=[C:18]2[CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:14][CH2:15]1
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)Cl)ccc2n1CC1CC1
Reactant: NCCO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)C(=O)NCCO)ccc2n1CC1CC1
Reaction time: 1 h
Yield: 54.4 %

Procedure:
To a mixture of ethanolamine (54 mg, 0.886 mmol), triethylamine (0.184 mL, 1.32 mmol) and dichloromethane (3 mL) was added a solution of 2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropanoyl chloride hydrochloride (Step A of Example 7, 198 mg, 0.443 mmol) in dichloromethane (2 mL) at room temperature. After stirring at the same temperature for 1 h, the mixture was concentrated under reduced pressure. The residue was purified by HPLC (ODS, gradient elution with acetonitrile/0.01% aq. NH3=4:96 to 96:4, by volume; flow rate 40 mL/min) to afford the title compound (105 mg, 55%) as an amorphous.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]N=C2CCCCC2=O)=[C:4]([F:17])[CH:3]=1.OS(O)(=O)=O.[C:23]([O-:26])(O)=O.[Na+]>CC#N>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[C:4]([F:17])[CH:3]=1)[NH:8][C:7]1[C:23](=[O:26])[CH2:5][CH2:4][CH2:3][C:2]2=1
Reactant: O=C([O-])O
Reactant: O=C1CCCCC1=NNc1ccc(Cl)cc1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Product: O=C1CCCc2c1[nH]c1c(F)cc(Cl)cc21
Temperature: 80 °C
Yield: 25 %

Procedure:
To a solution of 2-(2-(4-chloro-2-fluorophenyl)hydrazono)cyclohexanone (0.5 g, 1.9 mmol) in MeCN (5 mL), H2SO4 (0.31 mL, 5.9 mmol, 1.8M solution) was added slowly and the resulting mixture was heated to 80° C. for 12 h. The reaction mixture was cooled to room temperature, basified with saturated NaHCO3 (pH-8) and extracted with EtOAc (2×30 mL). The combined organic extracts were dried over sodium Na2SO4 and concentrated in vacuo to give the crude compound which was purified by silica gel chromatography [EtOAc-hexane (1:9) as eluant] to provide the title compound (120 mg, 25%). 1H NMR (200 MHz, CDCl3, δ in ppm): 8.96 (bs, 1H), 7.43 (d, J=1.0 Hz, 1H), 7.12 (dd, 1H, J=10.2, 1.60 Hz, 1H), 2.99 (t, J=5.8 Hz, 2H), 2.71 (t, J=6.0 Hz, 2H), 2.34-2.21 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:5].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:29]([O:28][C:26]([CH2:25][O:1][C:2]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:5])=[O:27])[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: O=C(NCc1ccccn1)c1cc(OCC(F)(F)F)ccc1O
Product: CCOC(=O)COc1ccc(OCC(F)(F)F)cc1C(=O)NCc1ccccn1

Procedure:
Using the general method of Example I Part A, 9.8 g (0.03 mole) of 2-hydroxy-N-(2-pyridylmethyl)-5-(2,2,2-trifluoroethoxy)benzamide was reacted with 7.0 g (0.042 mole) of ethyl bromoacetate to give 7.6 g of ivory powdery -(ethoxycarbonylmethoxy)-N-(2-pyridylmethyl)-5-(2,2,2-trifluoroethoxy)benzamide, m.p. 109°-111° C.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](Cl)=[O:9])(=O)C.NC1C=C(S(O)(=O)=O)C2C=CC=C(S(O)(=O)=[O:27])C=2C=1>O>[OH:4][C:5]1[C:6]([CH3:14])=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:9])=[O:27]
Reactant: CC(=O)Oc1cccc(C(=O)Cl)c1C
Reactant: Nc1cc(S(=O)(=O)O)c2cccc(S(=O)(=O)O)c2c1
Solvent: O
Product: Cc1c(O)cccc1C(=O)O

Procedure:
The present invention relates to a process for the preparation of 3-acetoxy-2-methylbenzoyl chloride by reacting an alkali metal salt of 3-aminonaph-thalene-1,5-disulfonic acid with alkali metal hydroxide and water in the weight ratio 1:(1 to 1.6):(1 to 1.6) at 220 to 320° C. to give the dialkali metal salt of the 3-hydroxy-2-methylbenzoic acid, separating off insoluble constituents from the reaction mixture, then adjusting the reaction mixture to a pH of 11.5 to 13.5 by addition of acid and reacting with acetic anhydride at -5 to +25° C., precipitating the 3-acetoxy-2-methylbenzoic acid by addition of acid, separating off the 3-acetoxy-2-methylbenzoic acid and reacting it with an inorganic acid chloride to give 3-acetoxy-2-methylbenzoyl chloride.
Reaction SMILES: [CH2:1]=[C:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][C:6](=[O:14])[CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[H][H]>[Pd].C(O)C>[CH3:1][CH:2]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][C:6](=[O:14])[CH2:5][C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2
Reactant: [H][H]
Reactant: C=C1c2ccccc2CC(=O)Cc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CC1c2ccccc2CC(=O)Cc2ccccc21

Procedure:
31.4 g. (0.134 mole) of 12-methylene-5,6,7,12-tetrahydrodibenzo[a,d]cycloocten-6-one and 270 mg. of 10% palladium on charcoal were combined in 225 ml. of 95% ethanol and shaken under 50 p.s.i.g. of hydrogen. When hydrogen uptake ceased at about 1 mole equivalent, the mixture was filtered and evaporated in vacuo to give 31.1 g. of white solid, m.p. 152°-155° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:3][CH2:2]1.[O:28]1[CH2:31][C:30](=O)[CH2:29]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[O:28]1[CH2:31][CH:30]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=[C:8]3[C@@H:16]([NH:18][C:19]3[N:27]=[CH:26][N:25]=[C:24]4[C:20]=3[N:21]=[CH:22][NH:23]4)[CH3:17])[CH2:3][CH2:2]2)[CH2:29]1
Reactant: O=C1COC1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCN(C2COC2)CC1
Reaction time: 4 h

Procedure:
To a mixture of (S)—N-(1-(1-(piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)ethyl)-9H-purin-6-amine from Example 113 (99 mg, 0.273 mmol) in anhydrous DCE (10 mL) was added oxetan-3-one (32 μL, 0.546 mmol) followed by AcOH (16 μL, 0.273 mmol) and 4 Å (angstrom) powdered molecular sieves (0.1 g). After stirring for 4 h, sodium triacetoxyborohydride (116 mg, 0.546 mmol) was added and stirring was continued for 48 h. The crude reaction mixture was loaded into an Isolute® SCX-2 which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) and then triturated with diethyl ether and MeOH affording 129 as a white solid (50 mg, 44%). LCMS: RT 1.61 min [M+H]+ 419.1. 1H NMR (DMSO, 400 MHz, 80° C.): δ 8.25 (1H, s), 8.05 (1H, s), 7.65-7.59 (2H, m), 7.44 (1H, bs), 7.20-7.13 (2H, m), 6.16-6.04 (1H, m), 4.63-4.39 (6H, m), 3.50-3.42 (1H, m), 2.93-2.85 (1H, bd, J=10.45 Hz), 2.76-2.69 (1H, bd, J=10.45 Hz), 2.40-2.28 (1H, m), 2.04-1.93 (1H, t, J=11.60 Hz), 1.90-1.81 (1H, m), 1.76-1.53 (6H, m)
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][N:13]=1>CO>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=2)=[N:13][CH:14]=1)([O-:20])=[O:19]
Reactant: Nc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
To a solution of sodium hydroxide (730 mg, 18.25 mmol) in methanol was added 4-aminophenol (2.00 g, 18.32 mmol). After the resulting mixture was made to dissolve, methanol was evaporated under reduced pressure. To the residue was added DMF (20 mL), and then 2-chloro-5-nitropyridine (2.91 g, 18.35 mmol). The reaction solution was stirred for 1.5 hours at 70° C., and then concentrated under reduced pressure. Water was added to the residue, and the resulting solution was extracted with ethyl acetate. The ethyl acetate layer was washed with brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, after which solvent was evaporated, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1), to thereby yield 3.37 g of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[CH3:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[N:10]=[C:9]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:17]=2[C:23]2[O:27][CH:26]=[N:25][CH:24]=2)[N:8]=1.Cl[N:29]1[N:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH3:38])[NH:30]1>CN(C=O)C>[CH3:14][O:13][C:11]1[CH:12]=[C:7]([O:6][CH3:5])[N:8]=[C:9]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][N:29]3[N:30]=[C:31]([O:37][CH3:38])[CH:32]=[C:33]([O:35][CH3:36])[NH:34]3)[C:17]=2[C:23]2[O:27][CH:26]=[N:25][CH:24]=2)[N:10]=1
Reactant: COC1=CC(OC)=NN(Cl)N1
Reactant: COc1cc(OC)nc(Oc2cccc(O)c2-c2cnco2)n1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC1=CC(OC)=NN(Oc2cccc(Oc3nc(OC)cc(OC)n3)c2-c2cnco2)N1
Temperature: 25 °C

Procedure:
To DMF solution containing 0.14 g pottasium carbonate and 0.15 g 5-[2-(4,6-dimethoxypyrimidine-2-yloxy)-6-hydroxyphenyl]oxazole, was added at once DMF solution containing 0.13 g 2-chloro-4,6-dimethoxytriazine. The solution reacted was stirred for a night at room temperature. After completing the reaction, the solution reacted was poured into ice water and then extracted with ethyl acetate. The organic layer obtained was washed with water and saturated saline solution in turn and was then dried by using anhydrous magnesium sulfate. The solvent used was removed by distillation under reduced pressure, affording the objective substance in an amount of 0.22 g.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>>[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)=[O:16]
Reactant: O=C(Cl)CCCCCl
Reactant: c1ccc2c(c1)CCO2
Product: O=C(CCCCCl)c1ccc2c(c1)CCO2

Procedure:
Using 2,3-dihydro-1-benzofuran (24.5 g) and 5-chlorovaleryl chloride (34.8 g) according to the same method as that of Reference Example 1, the title compound was obtained as colorless crystals (32.4 g) having a melting point of 56 to 57° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Br:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]3[N:27]4[CH2:28][CH2:29][NH:30][CH2:31][C:26]4=[N:25][C:19]=3[C:20]([NH2:24])=[N:21]2)=[CH:16][CH:15]=1>CN(C=O)C>[Br:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18]3[N:27]4[CH2:28][CH2:29][N:30]([S:9]([CH3:8])(=[O:11])=[O:10])[CH2:31][C:26]4=[N:25][C:19]=3[C:20]([NH2:24])=[N:21]2)=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1nc2cc(Br)ccc2c2c1nc1n2CCNC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCn2c(nc3c(N)nc4cc(Br)ccc4c32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
Triethylamine (3.82 g, 37.7 mmol) and methanesulfonyl chloride (2.38 g, 20.7 mmol) were sequentially added to a solution of 3-bromo-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine (6.00 g, 18.9 mmol) in DMF (50 mL), and the mixture was stirred at ambient temperature overnight. A precipitate formed and was isolated by filtration, washed with dichloromethane, and dried to provide 600 mg of 3-bromo-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine as a white powder, mp 315-317° C.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:4][CH:3]=1.B1([C:22]2[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=2)OCCCO1.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[CH3:14][N:13]([CH2:12][CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH:10]=2)[CH:6]=[CH:7]1)[CH3:15]
Reactant: CN(C)CCn1ccc2ccc(Br)cc21
Reactant: c1cncc(B2OCCCO2)c1
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: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)CCn1ccc2ccc(-c3cccnc3)cc21
Yield: 81.5 %

Procedure:
In a 25 mL round bottom flask equipped with a stir bar was added 6-Bromo-1-(2-(N,N-dimethylamino)ethyl)-1H-indole (0.10 g; 0.37 mmol), pyridine-3-boronic acid-1,3-propanediol cyclic ester (0.12 g; 0.74 mmol), toluene (10 mL), sodium carbonate (2M) (4 mL) and tetrakis(triphenylphosphine)palladium(0) (0.02 g; 0.04 mmol). The reaction mixture was refluxed overnight, filtered through a pad of celite and the solvent evaporated in vacuo. The residue was dissolved in ethyl acetate (30 mL) and successively washed with water (2×20 mL) and brine (20 mL). The organic phase was dried (sodium sulfate), filtered and the solvent was removed in vacuo. The crude residue was purified by column chromatography on silica gel using chloroform:ammonialmethanol (2N) (98:2) to yield the title compound as yellow oil (0.08 g; 85%). 13C NMR (CDCl3): δ 148.6, 147.8, 137.9, 136.5, 134.5, 131.4, 129.3, 128.5, 123.5, 121.6, 118.9, 107.9, 101.3, 59.1, 45.8, 44.8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:10]([O-])=O)[CH:5]=[C:6]([F:9])[C:7]=1[CH3:8].Cl>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:9])[C:7]=1[CH3:8])[NH2:10]
Reactant: Cc1c(F)cc([N+](=O)[O-])cc1Br
Agent: Cl
Solvent: CCO
Product: Cc1c(F)cc(N)cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 106.2 %

Procedure:
To 3-bromo-5-fluoro-4-methylnitrobenzene (1.4 gm, 6.0 mmol) in ethanol (100%, 25 mL) was added (c) HCl (7.0 mL) and stannous chloride dihydrate (4.1 gm, 18 mmol). The solution was stirred at room temperature for 16 hr and then concentrated in vacuo. The residue was diluted with water, made basic with 2N NaOH and extracted twice with ether. The ether layers were each washed with brine, dried over sodium sulfate, combined and evaporated to give 1.3 gm of crude title compound as an oil. NMR (CDCl3): δ 2.17 (d, 3H, J=3 Hz), 6.31 (dd, 1H, J=2.2 and 11 Hz), 6.67 (dd, 1H, J=1.8 and 2.2 Hz).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15](=[O:17])[N:14]([CH3:18])[C:13]=2[CH:19]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15](=[O:17])[N:14]([CH3:18])[C:13]=2[CH:19]=1
Reactant: Cn1c(=O)oc2ccc(O[Si](C)(C)C(C)(C)C)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1c(=O)oc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.2 %

Procedure:
To a cooled (0° C.) solution of 5-{[tert-butyl(dimethyl)silyl]oxy}-3-methyl-1,3-benzoxazol-2(3H)-one (1.20 g, 4.3 mmol) in anhydrous tetrahydrofuran (15 mL) was added dropwise tetra-n-butylammonium fluoride (4.7 mL, 1 M in tetrahydrofuran, 4.7 mmol). The reaction mixture was stirred at ambient temperature for 16 h and concentrated in vacuo. To the residue was added ethyl acetate (10 mL) and a 1 M solution of hydrochloric acid (20 mL) and the resultant suspension was sonicated for 5 min. The product was collected by vacuum filtration, washed with ethyl acetate (10 mL), air-dried and dried under high vacuum to afford 5-hydroxy-3-methyl-1,3-benzoxazol-2(3H)-one (0.47 g, 67%) as a pink solid: 1H NMR (300 MHz, DMSO-d6) δ 9.52 (br s, 1H), 7.09 (d, J=8.6 Hz, 1H), 6.62 (d, J=2.4 Hz, 1H), 6.47 (dd, J=8.6, 2.4 Hz, 1H), 3.27 (s, 3H); MS (ES−) m/z 164.2 (M−1).
Reaction SMILES: C[O-].[Na+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:26](OCC)=O)=[N:12]2)=[CH:7][C:6]=1[CH3:31].C([NH2:34])=O>>[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=3)=[CH:14][C:13]([C:26]#[N:34])=[N:12]2)=[CH:7][C:6]=1[CH3:31]
Reactant: CCOC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)c(C)c2)n1
Reactant: NC=O
Agent: C[O-]
Agent: [Na+]
Product: Cc1cc(-n2nc(C#N)cc2-c2ccc(S(C)(=O)=O)cc2)ccc1F
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of sodium methoxide (169 mg) and ethyl 1-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carboxylate (420 mg) in formamide (5 ml) was warmed at 110° C. for 30 minutes. The reaction mixture was poured into ice-water (50 ml) and the precipitate was collected by filtration, and washed with water and dried in vacuo. To an ice-cooled solution of POCl3 (0.23 ml) in dimethylformamide (3 ml) was added the residue by small portions under nitrogen atmosphere. After 2 hours, the mixture was poured into water (50 ml) and stirred for 30 minutes. The resulting precipitates were collected by filtration and washed with water and dried in vacuo. The resulting residue was purified by column chromatography on silica gel using chloroform and was recrystallized from ethanol to afford 1-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carbonitrile (297 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:11]=2)[CH2:8][NH:7][CH2:6]1)=[O:4].Cl[C:30]([O:32][CH3:33])=[O:31]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOCC>[CH3:33][O:32][C:30]([N:7]1[CH2:8][C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][CH2:21][O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:11]=2)[C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1)=[O:31]
Reactant: COC(=O)C1CNCC1c1ccc(OC)c(OCCCOc2ccccc2)c1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CN(C(=O)OC)C[C@H]1c1ccc(OC)c(OCCCOc2ccccc2)c1
Reaction time: 2 h
Yield: 76.4 %

Procedure:
To a solution of 3-methoxycarbonyl-4-[3-(3-phenoxypropoxy)-4-methoxyphenyl]pyrrolidine (720 mg, 1.87 mmol) in 5 mL of CH2Cl2 at 0° C. was added DMAP (275 mg, 2.25 mmol), followed by methyl chloroformate (213 mg, 2.25 mmol). The solution was stirred for 2 hr, diluted with ether, and washed with 1M H3PO4. The aqueous layer was extracted with ether (2×) and ethyl acetate (1×). The combined organic layers were dried over MgSO4, filtered and concentrated to a colorless oil. Silica gel chromatography (4:2:1, hexanes:ethyl acetate:CH2Cl2) provided trans-1-methoxycarbonyl-3-methoxycarbonyl-4-[3-(3-phenoxypropoxy)-4-methoxyphenyl]pyrrolidine as a colorless oil (634 mg, 77%). Anal. Calcd for C24H29NO7 : C, 64.99; H, 6.59; N, 3.16. Found: C, 64.85; H, 6.57; N, 3.15.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:5]=[C:4]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[N:3]=1.[C:34]1([C:40]2[CH:46]=[C:45]([OH:47])[CH:44]=[C:43]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:41]=2[OH:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[OH-].[Na+].Cl>O>[OH:42][C:41]1[C:40]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:46][C:45]([O:47][C:2]2[N:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:5]=[C:4]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[N:3]=2)=[CH:44][C:43]=1[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1
Reactant: Oc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Reactant: CCCCCCCCCCCCOc1nc(Cl)nc(OCCCCCCCCCCCC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCOc1nc(OCCCCCCCCCCCC)nc(Oc2cc(-c3ccccc3)c(O)c(-c3ccccc3)c2)n1
Temperature: 0 °C

Procedure:
In a 500 ml-three-necked flask 4.8 g (0.01 mole) of the 2-chloro-4,6-dilauroxy-s-triazine prepared above, were mixed with 2.6 g (0.01 mole) of 2,6-diphenyl hydroquinone. After rinsing with nitrogen, 150 ml of acetone were added, followed by adding dropwise, with vigorous stilling, 0.4 g (0.01 mole) of NaOH dissolved in 7 ml of water, at 20° C. The solution then assumed an orange-yellow color, which largely disappeared upon heating the reaction mixture for a longth of time under reflux. After completion of the reaction, the contents of the flask were poured into 100 ml of ice water containing 2 ml of hydrochloric acid. The organic layer was extracted three times with methylene chloride, after which the combined extracts were washed and dried. After concentration of the organic layer by evaporation a product was obtained which crystallized out after a length of time (melting point 18°-20° C.).