Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:13](=O)[CH2:12][CH2:11][CH2:10][C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]1=2.O.[OH-].[Na+]>O1CCCC1>[NH:7]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2[CH:15]=[CH:16][CH:17]=[CH:18][C:8]1=2
Reactant: O=C1CCCc2ccccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCCCN2
Temperature: 0 °C
Yield: 84.9 %

Procedure:
Add 80 mL of lithium aluminum hydride (1 M solution in tetrahydrofuran) to a solution of 1,3,4,5-tetrahydrobenzo-[b]azepin-2-one (12.9 g, 80.0 mmol) in 720 mL of tetrahydro-furan. Stir the reaction mixture at reflux for 3 hours and cool to 0° C. Quench the reaction by the sequential addition of 3 mL of water, 3 mL of 15% sodium hydroxide, and 9 mL of water. Filter the resulting suspension through Celite and rinse the filter cake with ethyl acetate. Concentrate the filtrate under reduced pressure to provide the desired compound as an orange solid (10.0 g, 85%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5]([CH3:21])=[C:6]([NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=[CH:8][C:9]=1[O:10]COC.O.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>CO.N1C=CC=CC=1>[CH3:23][S:24]([O:10][C:9]1[CH:8]=[CH:7][C:6]([NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[C:5]([CH3:21])[C:4]=1[O:3][CH3:2])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: COCOc1ccc(NC(=O)C(C)(C)C)c(C)c1OC
Agent: Cl
Solvent: O
Solvent: CO
Solvent: c1ccncc1
Product: COc1c(OS(C)(=O)=O)ccc(NC(=O)C(C)(C)C)c1C
Temperature: 60 °C
Reaction time: 18 h
Yield: 100.2 %

Procedure:
A 6N aqueous hydrochloric acid solution (0.355 ml, 2.13 mmol) was added dropwise to a solution of N-[3-methoxy-4-(methoxymethoxy)-2-methylphenyl]-2,2-dimethylpropanamide (300 mg, 1.07 mmol) in methanol (3 ml) at room temperature. After 18 hours, the reaction solution was poured into water (30 ml) and extracted with ethyl acetate (30 ml×2), and the ethyl acetate layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The ethyl acetate layer dried was concentrated under reduced pressure, and to a solution of the resulting residue in pyridine (3 ml) was added methanesulfonyl chloride (0.091 ml, 1.17 mmol) at 0° C. The resulting mixture was heated to 60° C. After 2.5 hours, the reaction solution was concentrated under reduced pressure and the resulting residue was poured into water (50 ml) and extracted with ethyl acetate (30 ml×2). The extract solution was dried over anhydrous magnesium sulfate. The extract solution dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 4-[(2,2-dimethylpropanoyl)amino]-2-methoxy-3-methylphenyl methanesulfonate (338 mg, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:29]([CH3:30])[C:28]4[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=4[N:26]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]3[N:29]([CH3:30])[C:28]4[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=4[N:26]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc4ccccc4n3C)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccc(OCc3nc4ccccc4n3C)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[4-(1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (700 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (520 mg, yield: 79%). This was recrystallized from ethanol-water. Melting point: 177–178° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:16]([O:18][C:19](=[O:37])[CH:20](Br)[C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[CH3:17]>C(#N)C.O>[CH2:16]([O:18][C:19](=[O:37])[CH:20]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:21]1[CH:22]=[CH:23][C:24]([S:27]([N:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)(=[O:28])=[O:29])=[CH:25][CH:26]=1)[CH3:17]
Reactant: Oc1ccc(F)cc1F
Reactant: CCOC(=O)C(Br)c1ccc(S(=O)(=O)N2CCCCC2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C(Oc1ccc(F)cc1F)c1ccc(S(=O)(=O)N2CCCCC2)cc1
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
2,4-Difluorophenol (0.38 ml, 3.89 mmol) and cesium carbonate (0.76 gm, 2.33 mmol) were taken in acetonitrile (30 ml) under argon atmosphere and was stirred for 30 minutes. Bromo-[4-(piperidine-1-sulfonyl)-phenyl]-acetic acid ethyl ester (1.4 gm, 3.86 mmol) in acetonitrile (15 ml) was added to the mixture and stirred at 25° C. for 3 hour. Reaction mixture was diluted with water (30 ml), extracted with ethyl acetate (3×20 ml), organic layer was washed with brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a gummy mass which was purified by flash column chromatography using over silica gel using 40-60% ethyl acetate in hexane as eluent to give (2,4-difluoro-phenoxy)-[4-(piperidine-1-sulfonyl)-phenyl]-acetic acid ethyl ester (1.31 gm).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][C@H:17]4[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18]4)[C:14]([CH2:24][O:25][CH2:26][CH3:27])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.B1([C:34]2[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=2)OCCCO1>>[CH3:22][C:19]1([CH3:23])[O:18][C@@H:17]([CH2:16][N:15]2[C:6]3[C:5]4[CH:4]=[CH:3][C:2]([C:34]5[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=5)=[CH:11][C:10]=4[N:9]=[C:8]([NH2:12])[C:7]=3[N:13]=[C:14]2[CH2:24][O:25][CH2:26][CH3:27])[CH2:21][O:20]1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1C[C@H]1COC(C)(C)O1
Reactant: c1cncc(B2OCCCO2)c1
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1C[C@H]1COC(C)(C)O1
Yield: 54.2 %

Procedure:
(S)-7-Bromo-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (2.65 g, 6.09 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (1.19 g, 7.30 mmol) were coupled according to the method described in Examples 118-121. The work-up procedure described in Part F of Examples 125-135 was followed. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) followed by recrystallization from acetonitriled to provide 1.43 g of (S)-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 157-158° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([CH:10]=[O:11])=[CH:8][CH:7]=[CH:6][N:5]2[CH:12]=1.[BH4-].[Na+]>C(O)(C)C>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([CH2:10][OH:11])=[CH:8][CH:7]=[CH:6][N:5]2[CH:12]=1
Reactant: Cc1cn2cccc(C=O)c2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1cn2cccc(CO)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 56.8 g (0.36 mol) 2-methyl-8-formylimidazo[1,2-a]pyridine in 400 ml isopropanol at 0°is added in portions 8 g (0.21 mol) sodium borohydride. The reaction mixture is stirred at room temperature for an additional 2 hours. The excess sodium borohydride is decomposed by the addition of distilled waterand the solution concentrated under reduced pressure at 50° C. The residue is dissolved in water and extracted with chloroform. The chloroform extracts are combined and dried over anhydrous sodium sulfate. Following filtration, the chloroform is removed under reduced pressure to give 2-methyl-8-hydroxymethylimidazo[1,2-a]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][NH:17][CH2:16][CH:15]([C:19]([O:21][CH3:22])=[O:20])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.Cl[C:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([N+:40]([O-:42])=[O:41])=[CH:36][CH:35]=1)=[O:32]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][N:17]([C:31]([O:33][C:34]3[CH:35]=[CH:36][C:37]([N+:40]([O-:42])=[O:41])=[CH:38][CH:39]=3)=[O:32])[CH2:16][CH:15]([C:19]([O:21][CH3:22])=[O:20])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]([F:12])([F:10])[F:11]
Reactant: COC(=O)C1CNCC(c2ccc(CC(F)(F)F)c(F)c2)C1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CC(c2ccc(CC(F)(F)F)c(F)c2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4.00 g (9.52 mmol, purity 76%) of the compound from Example 76A in dichloromethane (111 ml) was admixed with 4.65 ml (3.37 g, 33.3 mmol) of triethylamine and then, at 0° C., admixed with 1.92 g (9.52 mmol) of 4-nitrophenyl chloroformate. The mixture was warmed to RT and stirred for 2 h. The reaction solution was washed with saturated aqueous sodium hydrogencarbonate solution and water, and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 5.42 g (94% of theory, purity 80%)
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH:13]=[CH2:14])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])(=O)C.CO.[OH-].[Na+]>O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH:13]=[CH2:14])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16]
Reactant: C=CCSc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CCSc1ccc(N)c([N+](=O)[O-])c1

Procedure:
2 G. of 1-acetamido-2-nitro-4-(prop-2-en-1-ylthio)-benzene is treated with 20 ml. methanol and 10 ml. 5N aqueous sodium hydroxide at 20°-25° C for one hour. The mixture is diluted with water and the crude product filtered off. Recrystallization from benzene yields 1-amino-2-nitro-4-(prop-2-en-1-ylthio)benzene. This latter compound in 200 ml. acetone is treated with 4 g. methoxy carbonyl isothiocyanate at room temperatue for several days (i.e., until no starting material is present). The mixture is concentrated and the residue triturated with methanol to yield 1-(3-methoxycarbonyl-2-thioureido)-2-nitro-4-(prop-2-en-1-ylthio)benzene.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[C:11]([Br:13])[CH:10]=[C:9]([CH3:14])[C:8]=1[N:15]=CN(C)C)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Cl-].[Zn+2].[Cl-]>[C:1]([O:5][C:6](=[O:20])[C:7]1[CH:12]=[C:11]([Br:13])[CH:10]=[C:9]([CH3:14])[C:8]=1[NH2:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(Br)cc(C(=O)OC(C)(C)C)c1N=CN(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCO
Product: Cc1cc(Br)cc(C(=O)OC(C)(C)C)c1N
Yield: 84.1 %

Procedure:
A mixture of 3.52 g (10.3 mmole) of the product of Example 234 and 6.12 g (44.94 mmol) of zinc chloride in 50 ml of absolute ethanol was heated to reflux for 18 hr. The reaction mixture was concentrated in vacuo and the residue was diluted with CH2Cl2 and washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to provide 2.48 g (84%) of the desired product as a pale brown liquid. Electrospray Mass Spec 286(M+H).
Reaction SMILES: [N+:1]([CH:4]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]2[CH2:16][CH2:17][CH:5]1[CH:6]=[CH:7]2)([O-:3])=[O:2].[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20].O1CCOCC1>C(O)(C)(C)C>[N+:1]([C:4]1([CH2:20][CH2:19][C:18]([O:22][CH3:23])=[O:21])[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]2[CH2:16][CH2:17][CH:5]1[CH:6]=[CH:7]2)([O-:3])=[O:2]
Reactant: C=CC(=O)OC
Reactant: O=[N+]([O-])C1C2C=CC(CC2)C1c1ccccc1
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Product: COC(=O)CCC1([N+](=O)[O-])C2C=CC(CC2)C1c1ccccc1

Procedure:
Variant B: 0.18 mole of 2-nitro-3-phenyl-bicyclo[2.2.2]-oct-5-ene, 0.18 mole of methyl acrylate and 3.8 ml of Triton B in 50 ml of tert.-butanol and stirred for 24 hours, a further 0.18 mole of methyl acrylate and 70 mlof dioxan are then added and the mixture is heated to the reflux temperature for 24 hours. After cooling, the reaction mixture crystallizes. A little ethanol is added, the mixture is neutralized with 2N hydrochloric acid and the crystal sludge is filtered. Recrystallization of the crystals from isopropanol with the addition of animal charcoal gives crystals of melting point 127°-131° C.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[C:60]([Cl:66])[C:61]([F:65])=[CH:62][CH:63]=2)[N:58]=[C:57]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][N:68]=2)[C:56]=1[CH3:73].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:66][C:60]1[C:61]([F:65])=[CH:62][CH:63]=[C:64]2[C:59]=1[N:58]=[C:57]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][N:68]=1)[C:56]([CH3:73])=[C:55]2[NH:47][C:46]1[C:41]([N:38]2[CH2:39][CH2:40][O:35][CH2:36][CH2:37]2)=[N:42][CH:43]=[C:44]([N:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[CH:45]=1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccccn2)nc2c(Cl)c(F)ccc2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2c(Cl)c(F)ccc2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.025 g, 0.052 mmol), 2,5-dimorpholinopyridin-3-amine (0.103 g, 0.39 mmol), 4,8-dichloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (0.1 g, 0.33 mmol), Pd2dba3 (0.012 g, 0.013 mmol) and sodium tert-butoxide (0.078 g, 0.812 mmol) in toluene (3.3 mL) at 120° C. for 3 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product 8-chloro-N-(2,5-dimorpholinopyridin-3-yl)-7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.72 (1H, d, J=1.6 Hz), 8.14 (1H, d, J=7.8 Hz), 7.94 (1H, td, J=7.7, 1.8 Hz), 7.75 (1H, br s.), 7.61 (1H, d, J=0.4 Hz), 7.42-7.39 (1H, m), 7.36 (1H, t, J=8.6 Hz), 6.80 (1H, br s.), 6.19 (1H, br. s.), 3.93 (4H, br s.), 3.74 (4H, m), 3.25 (4H, br. s.), 2.92 (4H, br. m.), 2.47 (3H, s). Mass Spectrum (ESI) m/e=535.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[CH3:16])[CH3:2].O.[Na+:19].[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([O-:31])(=[O:30])=[O:29])=O.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl.[Cl-].[Na+].O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([CH2:20][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([O-:31])(=[O:30])=[O:29])=[C:7]1[CH3:16])[CH3:2].[Na+:19]
Reactant: CCOC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1ccccc1S(=O)(=O)[O-]
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)[O-])c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.3 %

Procedure:
To a stirred solution of [5-fluoro-2-methyl-1H-indol-1-yl]acetic acid ethyl ester (2.16 g, 9.19 mmol) at room temperature in dichloromethane (80 mL), was added 2-formylbenzenesulfonic acid sodium salt hydrate (2.01 g, 9.66 mmol) followed by triethylsilane (7.6 mL, 47.8 mmol). TFA (2.24 mL, 29.1 mmol) was then added dropwise over 30 min, and after the addition was complete, the mixture was stirred at room temperature for 72 h. Saturated aqueous NaHCO3 (100 mL) was then added to the solution plus saturated brine (10 mL) and the product extracted with ethyl acetate (200 ml). The organic layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resulting pink sticky solid was triturated with ethanol and hexanes to give sodium 2-((1-(2-ethoxy-2-oxoethyl)-5-fluoro-2-methyl-1H-indol-3-yl)methyl)benzene-sulfonate (2.33 g, 5.45 mmol, 59%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][C:7]2=[O:12].[C:13]1([CH2:19][CH2:20][CH:21]=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>CO>[C:13]1([CH2:19][CH2:20][C:21]2[N:10]3[C:11]4[C:6]([C:7](=[O:12])[CH2:8][CH2:9]3)=[CH:5][CH:4]=[CH:3][C:2]=4[N:1]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cccc2c1NCCC2=O
Reactant: O=CCCc1ccccc1
Agent: Cl
Solvent: CO
Product: O=C1CCn2c(CCc3ccccc3)nc3cccc1c32
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Fifteen grams of 8-amino-2,3-dihydro-4(1H) -quinolinone was dissolved in methanol (300 mL), and after addition of 3-phenylpropionaldehyde (14.6 mL) and 1N HCl (3 mL), the mixture was stirred at room temperature for 2 hrs, followed by addition of silica gel (60 g) to the reaction mixture, and the solvent was removed under reduced pressure. The residue was heated at 100° C. for 2 hrs and purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to yield the titled compound as yellow crystals (13.2 g).
Reaction SMILES: Cl.[CH2:2]([O:9][CH:10]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(OCC)(=O)C.C(OCC)C>[CH2:2]([O:9][CH:10]1[CH2:14][CH2:13][NH:12][CH2:11]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OCc2ccccc2)C1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: c1ccc(COC2CCNC2)cc1
Reaction time: 0.25 h
Yield: 40.4 %

Procedure:
Hydrogen chloride (4N) in ethyl acetate (1.5 ml) was added to a solution of crude 3-benzyloxy-1-(tert-butoxycarbonyl)-pyrrolidine (705 mg) in diethyl ether (3 ml) and the mixture was stirred for 15 minutes. Reaction was quenched with water, and the solution was washed with diethyl ether. After addition of aqueous sodium hydroxide to make the solution basic, the solution was extracted with diethyl ether and the organic layer was washed with brine and dried over sodium sulfate. Removal of the solvent under reduced pressure afforded 3-benzyloxy-pyrrolidine (182 mg, 37%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][OH:12])=[CH:9][C:4]=2[O:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: OCCc1ccc2c(c1)OCO2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=CCc1ccc2c(c1)OCO2
Yield: 76.1 %

Procedure:
A solution of 2-benzo[1,3]dioxol-5-yl-ethanol (Intermediate D2) (1 g, 6.0 mmol) in dichloromethane (40 mL) was treated with the Dess-Martin periodinane (commercially available from Lancaster) (2.65 g, 6.25 mmol) at rt for 2 h. Silica gel was added to the mixture and the solvent was removed under vacuum. The solids were placed onto a column of silica gel and the product was eluted with a mixture of ether: hexanes to give benzo[1,3]dioxol-5-yl-acetaldehyde (Intermediate D3) 0.75 g.
Reaction SMILES: [Cl-].[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[Te:10][CH:9]([CH3:11])[NH2+:8][C:7]=2[CH:12]=1.C(=O)(O)[O-].[Na+]>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[Te:10][C:9]([CH3:11])=[N:8][C:7]=2[CH:12]=1
Reactant: CC1[NH2+]c2cc(O)ccc2[Te]1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: Cc1nc2cc(O)ccc2[te]1

Procedure:
5-Hydroxy-2-methylbenzotellurazolium chloride (Example 17) (7.45 g) was dissolved in warm water (300 ml) and a slurry of sodium bicarbonate (8 g) in water was added slowly. The free base product separated as a cream colored amorphous solid, which was collected by filtration, washed with water, and dried in a vacuum over Drierite® brand calcium sulfate drying agent, yield 6.3 g. The material was then recrystallized from isopropanol (50 ml) to give a recovery of ≃4.0 g, m.p. 190°-192° C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C@@H:7]2[C@@H:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8]2)=[O:6])[CH2:3][CH2:2]1.[C:17](#[N:21])[CH:18]([CH3:20])[CH3:19].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH:1]1([NH:4][C:5]([C@H:7]2[O:8][C:17]([CH:18]([CH3:20])[CH3:19])=[N:21][C@H:9]2[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: O=C(NC1CC1)[C@H]1O[C@@H]1Cc1ccccc1
Reactant: CC(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)C1=N[C@@H](Cc2ccccc2)[C@@H](C(=O)NC2CC2)O1
Temperature: 5 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
(2S,3R)-3-Benzyl-2-oxiranecarboxylic cyclopropylamide (50 mg) and isobutyronitrile (2 ml) were mixed, and the mixture was cooled to 5° C. Boron trifluoride diethyl ether complex (2.5 equivalents) was gradually added, and the mixture was stirred at 5 to 20° C. for 2 hours. A mixture solution of ethyl acetate (10 ml) and saturated aqueous solution of sodium hydrogencarbonate (5 ml) was kept cooled at 5° C., and the reaction mixture was gradually added thereinto dropwise. The aqueous layer was removed, and then the solvent was evaporated away under reduced pressure to obtain the title compound as a brown solid (63 mg, yield: 96%).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][S:16]([CH3:19])(=[O:18])=[O:17].[CH3:20][C:21]([C:23]#[CH:24])=[CH2:22]>>[C:21]([C:23]1[N:15]([S:16]([CH3:19])(=[O:18])=[O:17])[C:3]2[C:2]([CH:24]=1)=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:4]=2)([CH3:22])=[CH2:20]
Reactant: CS(=O)(=O)Nc1cc(C(F)(F)F)c([N+](=O)[O-])cc1I
Reactant: C#CC(=C)C
Product: C=C(C)c1cc2cc([N+](=O)[O-])c(C(F)(F)F)cc2n1S(C)(=O)=O

Procedure:
This compound was prepared using the general Sonagashira conditions as described in general Example C, starting from N-(2-iodo-4-nitro-5-trifluoromethyl-phenyl)-methanesulfonamide (9.0 g, 21.9 mmol) and 2-methyl-1-buten-3-yne (6.25 mL, 65.7 mmol) to yield the title compound as a reddish-brown solid.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][NH:6][C:7](=[O:26])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:18][C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][CH:20]=2)[CH2:15][CH2:16][CH3:17])=[CH:10][CH:9]=1.[C:28]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)(=[O:30])[CH3:29]>>[C:28]([C:31]1[CH:36]=[CH:35][C:34]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:27])=[O:26])=[CH:9][CH:10]=3)[CH2:15][CH2:16][CH3:17])=[CH:20][CH:21]=2)=[CH:33][CH:32]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: CCCC(Oc1ccc(Br)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Product: CCCC(Oc1ccc(-c2ccc(C(C)=O)cc2)cc1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
This compound is made in a substantially similar manner as Example 117 using isomer 1 of 3-{4-[1-(4-bromo-phenoxy)-butyl]-benzoylamino}-propionic acid methyl ester and 4-acetylphenylboronic acid as starting materials in step D. MS (ES): 458.3 [M−H]−.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([Cl:29])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][N:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[CH:28]=[C:27]([Cl:29])[S:26][C:16]=2[N:17]=1
Reactant: Clc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCCc1ccc2c(c1)OCO2
Product: Clc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.