Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17]([NH2:24])=[CH:16][C:15]=2[NH2:25])[C:9](=[O:13])OCC)=[CH:4][CH:3]=1.[H-].[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[NH2:24][C:17]1[CH:18]=[C:19]([C:20]([F:21])([F:22])[F:23])[C:14]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:9](=[O:13])[NH:25][C:15]=2[CH:16]=1
Reactant: CCOC(=O)N(c1ccc(Cl)cc1)c1c(N)cc(N)cc1C(F)(F)F
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: Nc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1ccc(Cl)cc1
Yield: 70.3 %

Procedure:
Ethyl 4-chlorophenyl[2,4-diamino-6-(trifluoromethyl)phenyl]carbamate (1.2053 g) was dissolved in ethanol (20 ml), and to the solution was added sodium hydride (129.0 mg). The reaction mixture was heated at reflux for 9 hours. After allowing to cool, to the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by silica gel column (60 g, CHCl3:methanol=10:1→5:1) to give the title compound (0.7431 g, 70%).
Reaction SMILES: C([O:5][C:6](=[O:39])[C@H:7]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:8][N:9]([C:11](=[O:28])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:14][CH:13]=1)[NH2:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:23]1[CH:24]=[CH:25][CH:26]=[N:27][C:22]=1[NH:21][CH2:20][CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([N:9]([NH2:10])[CH2:8][C@H:7]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[C:6]([OH:39])=[O:5])=[O:28])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)[C@@H](CN(N)C(=O)c1ccc(OCCNc2ncccn2)cc1)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NN(C[C@@H](C(=O)O)C(=O)OCc1ccccc1)C(=O)c1ccc(OCCNc2ncccn2)cc1
Reaction time: 4 h

Procedure:
A solution of 25-1 (840 mg, 1.6 mmol) and CH2Cl2 (10 ml) at ambient temperature was treated with TFA (10 ml). After stirring for 4.0 h, the reaction mixture was concentrated and the residual TFA removed azeotropically with toluene. Trituration of the resulting waxy solid with ether provided 25-2 as a white solid.
Reaction SMILES: C(Cl)Cl.Br[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=1[CH2:14]Br.[O:16]=[C:17]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].[Cl-].[NH4+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+].O>[CH2:28]([O:27][C:25]([CH:24]1[C:17](=[O:16])[CH:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:14][C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[CH2:5]1)=[O:26])[CH3:29]
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Reactant: COc1ccc(CBr)c(CBr)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1Cc2ccc(OC)cc2CC(C(=O)OCC)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
From an adapted procedure in Helvetic Chimica Acta, 2001, 84, 2051-2063, to a stirred solution of Tetra-n-butylammonium iodide (12.1 g, 0.0326 mol) in 0.6 M of Sodium bicarbonate in Water (300 mL) and Methylene chloride (130 mL, 2.1 mol) was added a solution of 1,2-Bis-bromomethyl-4-methoxy-benzene (16.00 g, 0.05442 mol) and 3-Oxopentanedioic acid, diethyl ester (14.31 g, 0.07075 mol) in Methylene chloride (40 mL, 0.6 mol). The solution was stirred vigorously at room temperature for 20 h. Saturated ammonium chloride solution was added to the reaction mixture. The product was extracted with ethyl acetate (3×100 mL). The ethyl acetate extracts were washed with water and brine, then dried over magnesium sulfate, filtered and concentrated in vacuo to a yellow oil. The oil was triturated with ether and a precipitate crashed out of solution and was removed by filtration (tetrabutylammonium salts). The filtrate was concentrated to an oil (20.0 grams, 100%) that was carried on to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:17])[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[O:24]1[CH2:29][CH2:28][O:27][C:26]2[CH:30]=[C:31]([C:34](O)=[O:35])[CH:32]=[CH:33][C:25]1=2>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:17][C:34]([C:31]2[CH:32]=[CH:33][C:25]3[O:24][CH2:29][CH2:28][O:27][C:26]=3[CH:30]=2)=[O:35])[CH2:15][CH3:16])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@@H](N)CC)c2c1N
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](CC)NC(=O)c3ccc4c(c3)OCCO4)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminobutoxy)-2-methylquinoline-3-carboxylate (Example 97b) and 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid as brown solid (46%). MS 480 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH:10]([OH:14])[C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:19]([CH2:26][CH2:27][NH2:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N)C>>[CH3:4][C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[CH:10]([OH:14])[C:11](=[O:13])[NH:28][CH2:27][CH2:26][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:2])[CH3:3]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(O)C(=O)O
Reactant: NCCOc1ccccc1
Agent: CCN
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(O)C(=O)NCCOc1ccccc1

Procedure:
The reaction was performed as in Reference Example 8 (5) by using (3S)-3-(tert-butoxycarbonylamino)-2-hydroxy-5-methyl hexanoic acid in place of (3S)-3-(tert-butoxycarbonylamino)-2-hydroxy-4-phenylbutyric acid, and by using 2-phenoxyethylamine in place of an aqueous ethylamine solution, thereby yielding ((1S)-2-hydroxy-1-(2-methylpropyl)-3-oxo-3-(2-phenoxyethyl)aminopropyl carbamic acid 1,1-dimethylethyl ester as a colorless oil.
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH2:9](B(O)O)[CH3:10]>>[CH2:9]([C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1)[CH3:10]
Reactant: CCB(O)O
Reactant: O=Cc1ccc(Br)s1
Product: CCc1ccc(C=O)s1
Yield: 50.6 %

Procedure:
The compound was synthesized as in Example 3.1 using 5-bromothiophene-2-carbaldehyde (250 mg, 1.31 mmol) in place of 5-bromo-2-formylfuran and ethylboronic acid (160 mg, 2.16 mmol) in place of hexylboronic acid to give 5-ethylthiophene-2-carbaldehyde (93 mg, 51%). Used without further characterization.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[C:6]=2[CH:19]=1.C1(C)C=CC=CC=1>C(Cl)Cl.C(C(O)=O)(F)(F)F>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:20])[C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[CH:19]=1
Reactant: Cc1cc(C)c2oc(=O)n(CC(=O)OC(C)(C)C)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cc(C)c2oc(=O)n(CC(=O)O)c2c1

Procedure:
A solution of tert-butyl (5,7-dimethyl-2-oxo-1,3-benzoxazol-3(2H)-yl)acetate from Step B in CH2Cl2 (0.7 mL) and CF3CO2H (0.3 mL) was stood at ambient temperature for 2 h. Toluene (5 mL) was added and the mixture was conc. in vacuo to give the title compound as a dark solid. MS: m/z=222 (M+1).
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].COCCO[AlH2-]OCCOC.[Na+].[H-].COCCO[Al+]OCCOC.[Na+].[H-]>C(OCC)C>[CH2:10]([SnH:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:11][CH2:12][CH3:13]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: COCCO[Al+]OCCOC
Agent: COCCO[AlH2-]OCCOC
Agent: [H-]
Solvent: CCOCC
Product: CCCC[SnH](CCCC)CCCC
Yield: 45.5 %

Procedure:
Vit et al. in Eastman Organic Chemical Bulletin, 1974, vol. 46, No. 1, page 5 discloses a dehalogenation of tributyltin chloride with VITRIDE reducing agent (sodium bis (2-methoxyethoxy) aluminum hydride) in boiling diethyl ether. After a workup procedure including water quenching, ether extraction, drying, evaporation and distillation, substantially as shown by Van der Kerk supra, for the use of lithium aluminum hydride, 45.5% yield of tributyltin hydride is obtained. Although by this method tributyltin chloride is successfully reduced to the hydride, the yield is low and it calls for the use of diethyl ether which is notoriously volatile, flammable and explosive. The yield is so low as to render impractical, by this route, many interesting processes which involve the use of the expensive organotin halides.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:8][CH3:9])[O:6][CH3:7].[CH3:12][O:13][C:14](=[O:21])/[CH:15]=[CH:16]\[C:17]([O:19][CH3:20])=[O:18]>>[CH3:12][O:13][C:14](=[O:21])[C@H:15]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[NH:1][CH2:2][CH2:3][CH2:4][Si:5]([O:10][CH3:11])([O:6][CH3:7])[O:8][CH3:9]
Reactant: COC(=O)/C=C\C(=O)OC
Reactant: CO[Si](CCCN)(OC)OC
Product: COC(=O)C[C@H](NCCC[Si](OC)(OC)OC)C(=O)OC

Procedure:
179.0 g (1.0 mol) of 3-aminopropyl-trimethoxysilane and 144.0 g (1.0 mol) of maleic acid dimethyl ester were reacted by the same procedure used in Example 2. The viscosity of the clear, pale yellow liquid was about 30 mPa.s (23° C.). Base titration showed an amine equivalent weight of about 331 g (theory: 323 g).
Reaction SMILES: [CH2:1]([C:8]1[C:17]2[C:12](=[C:13]([I:19])[C:14](I)=[CH:15][CH:16]=2)[C:11](=[O:20])[NH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:23])[CH3:22]>>[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([C:14]2[C:13]([I:19])=[C:12]3[C:17](=[CH:16][CH:15]=2)[C:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][NH:10][C:11]3=[O:20])=[CH:27][CH:26]=1)(=[O:23])[CH3:22]
Reactant: O=c1[nH]nc(Cc2ccccc2)c2ccc(I)c(I)c12
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Product: CC(=O)Nc1ccc(-c2ccc3c(Cc4ccccc4)n[nH]c(=O)c3c2I)cc1

Procedure:
1-Benzyl-5,6-diiodo-phthalazin-4-one (Indian J. Chem. 16B, 1978, 301-304) is reacted analogously to Example 1/f. with 1 equivalent of 4-acetamidophenyl-boronic acid. The title compound is obtained in pure form by chromatography on silica gel.
Reaction SMILES: [CH3:1][O:2][O:3][CH2:4][C:5]1[N:25]=[C:8]2[N:9]([CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([O:23][CH3:24])[CH:15]=3)[CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1.[CH:26]1([NH-:31])[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:13][CH:14]1[CH2:22][CH2:21][CH:17]([N:31]([CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:18](=[O:19])[C:17]2[CH:21]=[CH:22][C:14]([CH2:13][N:9]3[CH:10]=[CH:11][CH:12]=[C:7]4[N:6]=[C:5]([CH2:4][O:3][O:2][CH3:1])[N:25]=[C:8]34)=[CH:15][C:16]=2[O:23][CH3:24])[CH2:16][CH2:15]1
Reactant: [NH-]C1CCCC1
Reactant: COOCc1nc2cccn(Cc3ccc(C(=O)O)c(OC)c3)c-2n1
Product: COOCc1nc2cccn(Cc3ccc(C(=O)N(C4CCCC4)C4CCC(C)CC4)c(OC)c3)c-2n1

Procedure:
4-[(2-(methoxyoxymethyl)-4H-imidazo[4,5-b]pyridin-4-yl)methyl]-2-methoxybenzoic acid, N-2-methylcyclohexyl, N-cyclopentyl amide;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH:11]([NH2:14])([CH3:13])[CH3:12]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:14][CH:11]([CH3:13])[CH3:12])=[O:6]
Reactant: CC(C)N
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: ClCCl
Product: CC(C)NC(=O)c1cccc(Br)c1
Reaction time: 24 h

Procedure:
A solution of 3-bromo-benzoyl chloride (0.83 g, 3.8 mmol) in DCM (40 mL) was chilled to zero degrees and treated with isopropylamine (0.96 mL, 11.32 mmol). Reaction was allowed to come to room temperature and stir for 24 h. Mixture was then poured onto water and washed once. Organic phase then washed with brine, dried over sodium sulfate, filtered and evaporated to white solids (0.6 g, 66%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]1([CH2:8][OH:9])[CH2:7][CH2:6]1.[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C.Cl>ClCCl.C(=O)=O.CC(C)=O.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]1([CH2:8][O:9][S:12]([CH3:11])(=[O:14])=[O:13])[CH2:7][CH2:6]1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)CC1(CO)CC1
Agent: Cl
Agent: O=C=O
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)CC1(COS(C)(=O)=O)CC1
Temperature: -60 °C
Yield: 104 %

Procedure:
To a stirred solution of (1-hydroxymethyl-cyclopropyl)-acetic acid methyl ester (600 mg, 4.16 mmol) in dichloromethane (10 mL) cooled in dry ice-acetone bath (−40° C.), was added methanesulfonyl chloride (483 μL, 6.24 mmol). The mixture was then cooled to −60° C. and triethylamine (928 μA, 6.66 mmol) was added. With stirring, the mixture was warmed up to 0° C. during 1 hr. After cooling the mixture to −15° C., cold 3 N HCl solution (0.6 mL), cold brine (2 mL), and dichloromethane (25 mL) were added in this order. The mixture was washed with cold brine (25 mL) twice, dried with MgSO4, filtered, and evaporated in vacuo to give 962 mg (quantitative) of crude (1-methanesulfonyloxymethyl-cyclopropyl)-acetic acid methyl ester as a colorless oil. This crude product was used directly in the next reaction without further purification. 1H-NMR (200 MHz, CDCl3) δ 0.62-0.72 (4H, m), 2.42 (2H, s), 3.02 (3H, s), 3.70 (3H, s), 4.17 (2H, s).
Reaction SMILES: [H-].[Na+].[CH:3]1([O:7][CH2:8][C@H:9]([OH:20])[C:10]([NH:12][C:13]2[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=2)=[O:11])[CH2:6][CH2:5][CH2:4]1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]2[N:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:37])[N:29]=[CH:30][C:23]=12>C1COCC1.C(OCC)(=O)C>[Cl:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[N:28]1[C:24]2=[N:25][CH:26]=[N:27][C:22]([O:20][C@@H:9]([CH2:8][O:7][CH:3]3[CH2:6][CH2:5][CH2:4]3)[C:10]([NH:12][C:13]3[CH:18]=[N:17][C:16]([CH3:19])=[CH:15][N:14]=3)=[O:11])=[C:23]2[CH:30]=[N:29]1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Reactant: Cc1cnc(NC(=O)[C@@H](O)COC2CCC2)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)[C@H](COC2CCC2)Oc2ncnc3c2cnn3-c2ccccc2Cl)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.8 %

Procedure:
Sodium hydride (44.4 mg, 1.11 mmol) was added to (S)-3-cyclobutoxy-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate R1) (186 mg, 0.74 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting mixture was stirred for 10 minutes at 0° C. and 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B1) (255 mg, 0.96 mmol) was added and the reaction was allowed to warm up to room temperature and stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate (20 mL), and washed sequentially with water (10 mL) and saturated brine (5 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0-100% ethyl acetate in isohexane to afford the product (262 mg, 73.8%). 1H NMR (400 MHz, DMSO) δ 1.39-1.52 (m, 1H), 1.56-1.67 (m, 1H), 1.77-1.91 (m, 2H), 2.13-2.24 (m, 2H), 2.44 (s, 3H), 3.88-4.02 (m, 2H), 4.06-4.15 (m, 1H), 5.89-5.94 (m, 1H), 7.56-7.70 (m, 3H), 7.73-7.78 (m, 1H), 8.31-8.33 (m, 1H), 8.54 (s, 1H), 8.63 (s, 1H), 9.10 (s, 1H), 11.17 (s, 1H). m/z (ESI+) (M+H)+=480.33; HPLC tR=2.45 min.
Reaction SMILES: CO[CH:3](OC)[CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1>ClC1C=CC=CC=1>[F:12][C:9]1[CH:8]=[CH:7][C:6]2[S:5][CH:4]=[CH:3][C:11]=2[CH:10]=1
Reactant: COC(CSc1ccc(F)cc1)OC
Solvent: Clc1ccccc1
Product: Fc1ccc2sccc2c1
Temperature: 25 °C
Yield: 55.4 %

Procedure:
Anhydrous chlorobenzene (1500 ml) was placed in a 3 liter 3-necked flask equipped with a condenser and a mechanical stirrer. The apparatus was flushed with nitrogen and about 495 grams of polyphosphoric acid (PPA) was added. The mixture was brought to gentle reflux and 161 g (0.74 mol) of crude (4-fluorophenylthio)- acetaldehyde dimethyl acetal was added during 2.5 hours and the solution was further refluxed for 19 hours. The reaction mixture was allowed to cool to ambient temperature and the organic phase was separated from the PPA. Residual PPA was decomposed with water and the resulting aqueous phase was extracted with toluene (2×150 ml). The combined organic phases was dried over MgSO4 and the solvents evaporated. The residue was fractionated to give 62.4 g (55%) of 5-fluorobenzothiophene which had b.p. 76°-77° C./ 4.5 mm Hg and m.p. 21°-22° C. 1H-NMR (CDCl3)δ7.00 (ddd, 1H), 7.20 (d, 1H, J =5.5Hz), 7.36 (dd,1H), 7.47 (d, 1H, J =5.5 Hz), 7.70 (dd,1H).
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26])(=[O:19])=[O:18].[CH:27]([O:40][C:41]([NH:43][C:44]1[N:52]=[CH:51][N:50]=[C:49]2[C:45]=1[N:46]=[CH:47][N:48]2[CH2:53][C:54](O)=[O:55])=[O:42])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[S:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[S:17]([N:20]1[CH2:25][CH2:24][N:23]([C:54](=[O:55])[CH2:53][N:48]2[CH:47]=[N:46][C:45]3[C:49]2=[N:50][CH:51]=[N:52][C:44]=3[NH:43][C:41]([O:40][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:42])[CH2:22][C:21]1=[O:26])(=[O:19])=[O:18]
Reactant: O=C1CNCCN1S(=O)(=O)c1nc2ccccc2s1
Reactant: O=C(O)Cn1cnc2c(NC(=O)OC(c3ccccc3)c3ccccc3)ncnc21
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ncnc2c1ncn2CC(=O)N1CCN(S(=O)(=O)c2nc3ccccc3s2)C(=O)C1)OC(c1ccccc1)c1ccccc1

Procedure:
The title compound was synthesized by the reaction of 1-(benzothiazole-2-sulfonyl)-piperazin-2-one trifluoroacetic acid salt with [6-N-(benzhydryloxycarbonyl)-adenine-9-yl]-acetic acid as per the procedure of Example 52. 1H NMR (500 MHz; DMSO-d6) δ 11.15 (brs, 1H), 8.60 (d, 1H), 8.45˜8.32 (m, 2H), 8.26 (m, 1H), 7.72 (m, 2H), 7.52 (d, 4H), 7.38 (t, 4H), 7.29 (t, 2H), 6.83 (s, 1H), 5.41 (s, 1.2H), 5.30 (s, 0.8H), 4.57 (s, 0.8H), 4.28 (s, 2.4H), 4.09 (brs, 2.0H), 3.88 (t, 0.8H).
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][CH:30]([C:33]2[N:38]=[C:37]([NH:39][C:40](=[O:44])[CH:41]([CH3:43])[CH3:42])[CH:36]=[CH:35][CH:34]=2)[CH2:29][CH2:28]1>>[CH3:42][CH:41]([CH3:43])[C:40]([NH:39][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:30]2[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][CH2:24][NH:23][C:8](=[O:9])[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:28][CH2:29]2)[N:38]=1)=[O:44]
Reactant: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)n1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)(c3ccccc3)c3ccccc3)CC2)n1

Procedure:
Example 82 was prepared from triphenyl acetic acid and N-{6-[1-(3-aminopropyl)-4-piperidinyl]-2-pyridinyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 8.05 (d, 1H, J=8.0 Hz), 7.81 (s, 1H), 7.63 (t, 1H, J=7.6 Hz), 7.30–7.24 (m, 15H), 6.84 (d, 1H, J=7.2 Hz), 6.33 (br s, 1H), 3.44 (dd, 2H, J=6.4, 12.4 Hz), 2.89 (d, 2H, J=11.6 Hz), 2.57–2.49 (m, 2H), 2.31 (t, 2H, J=6.8 Hz), 1.95 (t, 2H, J=12.0 Hz), 1.79–1.58 (m, 6H), 1.27 (d, 6H, J=6.8 Hz); ESMS m/e: 575.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[CH3:12].O.[As+3]=O.S(=O)(=O)(O)O.[OH-].[NH4+].O[CH2:24][CH:25]([CH2:27]O)O>O>[NH2:1][C:2]1[C:3]([CH3:12])=[C:4]2[C:5]([CH:24]=[CH:25][CH:27]=[N:9]2)=[C:6]([F:8])[CH:7]=1
Reactant: Cc1c(N)cc(F)cc1[N+](=O)[O-]
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: O=[As+3]
Agent: [NH4+]
Solvent: O
Product: Cc1c(N)cc(F)c2cccnc12
Temperature: 140 °C

Procedure:
A mixture of 2-amino-4-fluoro-6-nitrotoluene (4.4 g), glycerin (7.5 g), arsenic(V) oxide hydrate (Aldrich, 54% in arsenic, 5.0 g), and concentrated sulfuric acid (35 mL) is heated to 140° C. for 4 hours. The reaction is allowed to cool to room temperature and diluted with water (300 mL). The mixture is basified with concentrated ammonium hydroxide to pH=10 and extracted with ethyl acetate (6×300 mL). The combined extracts are dried over sodium sulfate and rotary evaporated. The crude product is purified by flash chromatography on silica gel, eluting with 25% ethyl acetate/hexane to afford 7-amino-5-fluoro-8-methylquinoline as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[CH3:12].ClC1C=CC(O[CH2:19][C:20]#[N:21])=CC=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([CH3:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[C:7]([CH2:19][C:20]#[N:21])[CH:8]=1
Reactant: N#CCOc1ccc(Cl)cc1
Reactant: COc1ccc([N+](=O)[O-])cc1C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CC#N)c([N+](=O)[O-])cc1C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
To a solution of 1-methoxy-2-methyl-4-nitrobezene (0.4 g) and (4-chlorophenoxy)acetonitrile (0.4 g) in N,N-dimethylformamide (10 mL) was added potassium tert-butoxide (0.3 g) under ice cooling and this mixture was stirred at the same temperature for 1 hours. This mixture was poured into water and the resulting mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.2 g).
Reaction SMILES: C[Mg]I.[CH3:4]I.[Mg].[O:7]=[C:8]([CH2:33][O:34][CH2:35][CH2:36][CH3:37])[CH:9]=[CH:10][CH:11]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH:12]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][Si](C)(C)C)=[O:27].[Cl-].[NH4+]>C(OCC)C>[OH:7][C:8]([CH3:4])([CH2:33][O:34][CH2:35][CH2:36][CH3:37])[CH:9]=[CH:10][CH:11]1[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH:12]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: CCCOCC(=O)C=CC1CCC2(OCCO2)C1CCCCCCC(=O)O[Si](C)(C)C
Reactant: CI
Agent: C[Mg]I
Agent: [Cl-]
Agent: [Mg]
Solvent: CCOCC
Product: CCCOCC(C)(O)C=CC1CCC2(OCCO2)C1CCCCCCC(=O)O
Reaction time: 0.5 h
Yield: 66.4 %

Procedure:
A solution (1.66 ml.) of methyl magnesium iodide in diethyl ether [prepared in the manner well known in the art from methyl iodide (6 g.), magnesium (1.07 g.) and diethyl ether (20 ml.)] was added dropwise to a stirred solution of trimethylsilyl 7-{7-(3-oxo-4-propoxybut-1-enyl)-1,4-dioxaspiro[4,4]non-6-yl}heptanoate (0.67 g.) in diethyl ether (25 ml.) at room temperature. The mixture was stirred for 30 minutes and a further quantity of the solution of methyl magnesium iodide in diethyl ether (0.4 ml.) was then added dropwise. The mixture was stirred for a further 30 minutes and then added to saturated aqueous ammonium chloride solution (100 ml.) at 0° C. and stirred for 15 minutes. The ether layer was separated and the aqueous layer was extracted with diethyl ether. The combined ether layers were added to 10% w/v aqueous sodium carbonate solution (25 ml.) and stirred for 1 hour. The aqueous layer was separated and washed with diethyl ether, and then acidified to pH 5 by the addition of 20% w/v aqueous sodium dihydrogen phosphate solution. The aqueous layers were again extracted with diethyl ether and the resulting ether extracts dried over sodium sulphate. The solvent was removed in vacuo to give crude 7-{7-(3-hydroxy-3-methyl-4-propoxybut-1-enyl)-1,4-dioxaspiro[4,4]non-6-yl}heptanoic acid (0.39 g.).