Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=O.[F:3][C:4]1[CH:5]=[C:6]([S:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21]([NH2:23])=[O:22])=[CH:16][CH2:15][CH2:14]3)[CH:7]=[CH:8][CH:9]=1.[H][H]>CO>[F:3][C:4]1[CH:5]=[C:6]([S:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C@H:17]([C:21]([NH2:23])=[O:22])[CH2:16][CH2:15][CH2:14]3)[CH:7]=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: NC(=O)C1=CCCc2cc(Sc3cccc(F)c3)ccc21
Agent: O=O
Solvent: CO
Product: NC(=O)[C@@H]1CCCc2cc(Sc3cccc(F)c3)ccc21
Temperature: 25 °C

Procedure:
In a glove box (O2 content≦2 ppm) a 6 ml autoclave equipped with a glass insert and a magnetic stirring bar was charged with 50 mg (0.167 mmol) of 6-(3-fluoro-phenylsulfanyl)-3,4-dihydro-naphthalene-1-carboxylic acid amide, 6.45 mg (0.00668 mmol) of [Ru(trifluoroacetate)2((S)-pTol-MeOBIPHEP)] (S/C 25) and 1 ml of methanol. The asymmetric hydrogenation was run for 19.5 hours at 40° C. under 40 bar of hydrogen. After cooling to room temperature the pressure was released from the autoclave, the methanol solution was filtered through a silicagel pad and evaporated in vacuo to give (R)-6-(3-fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalene-1-carboxylic acid amide in quantitative yield and with an enantiomeric ratio of 99:1. The conversion was >=99.9%.
Reaction SMILES: C1COCC1.[S:6]1[CH:10]=[CH:9][C:8]2[C:11]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]4[N:29]([CH3:30])[N:28]=[C:27]([CH2:31][O:32][Si](C(C)(C)C)(C)C)[CH:26]=4)[CH2:17][CH2:16]3)=[CH:12][CH:13]=[CH:14][C:7]1=2.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(OCC)(=O)C>[S:6]1[CH:10]=[CH:9][C:8]2[C:11]([N:15]3[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]4[N:29]([CH3:30])[N:28]=[C:27]([CH2:31][OH:32])[CH:26]=4)[CH2:19][CH2:20]3)=[CH:12][CH:13]=[CH:14][C:7]1=2
Reactant: Cn1nc(CO[Si](C)(C)C(C)(C)C)cc1OCCCN1CCN(c2cccc3sccc23)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1nc(CO)cc1OCCCN1CCN(c2cccc3sccc23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.3 %

Procedure:
A THF solution (8 ml) of 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-3-(tert-butyl-dimethylsilanyloxymethyl)-1-methyl-1H-pyrazole (0.75 g, 1.5 mmol) was cooled on ice and a 1M THF solution of tetrabutyl ammonium fluoride (1.7 ml) was added thereto. The mixture was stirred at room temperature for 16 hours. Ethyl acetate was added to the reaction solution, which was washed with water. The organic layer was dried over anhydrous magnesium sulfate and thereafter concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol=1:0→30:1→15:1). The purified product was concentrated under reduced pressure and the residue was recrystallized from a solvent mixture of ethyl acetate and diisopropyl ether to obtain 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-propoxy]-3-hydroxymethyl-1-methyl-1H-pyrazole (0.46 g, 79% yield) as white powder.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]2[N:29]=[C:30]([CH3:33])[S:31][CH:32]=2)[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:34]>CO>[ClH:34].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:25][O:26][CH2:27][C:28]2[N:29]=[C:30]([CH3:33])[S:31][CH:32]=2)[C:10]([NH:12][CH:13]2[C:23](=[O:24])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: Cc1nc(CON=C(C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)c2csc(NC=O)n2)cs1
Agent: Cl
Solvent: CO
Product: Cc1nc(CON=C(C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)c2csc(N)n2)cs1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 96.7 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(2-methylthiazol-4-ylmethoxyimino)acetamido]-3-cephem-4-carboxylic acid (syn isomer, 240 mg.) and conc. hydrochloric acid (71 mg.) in methanol (2.5 ml.) was stirred at room temperature for 6.5 hours. After removing the solvent from the resultant solution in vacuo, the residue was triturated with diisopropyl ether. The precipitates were collected by filtration and washed with diisopropyl ether to give colorless crystals of 7-[2-(2-aminothiazol-4-yl)-2-(2-methylthiazol-4-ylmethoxyimino)acetamido]-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 236 mg.)
Reaction SMILES: [F:1][C@H:2]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18]CC3C=CC=CC=3)=[CH:14][CH:13]=2)=[N:10][CH:11]=1.CO.[H][H]>O1CCCC1>[F:1][C@H:2]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[N:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[N:8][CH:7]=1
Reactant: CCCC[C@@H](F)CCOc1cnc(-c2ccc(OCc3ccccc3)cc2)nc1
Reactant: [H][H]
Solvent: CO
Solvent: C1CCOC1
Product: CCCC[C@@H](F)CCOc1cnc(-c2ccc(O)cc2)nc1
Reaction time: 6 h
Yield: 102 %

Procedure:
A mixture of 1.41 g of 5-[3-(R)-fluoroheptyloxy]-2-(4-benzyloxyphenyl)pyrimidine, 0.22 g of 10palladium-on-carbon, 14 ml of methanol, and 14 ml of tetrahydrofuran (THF) was kept at 30° C., and hydrogen gas was blown thereinto over 6 hours with stirring. The catalyst was removed by filtration, and the solvent was removed by distillation to obtain 1.11 g of 5-[3-(R)-fluoroheptyloxy]-2-(4-hydroxyphenyl)pyrimidine.
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[CH3:14][C:15]([CH3:20])([CH3:19])[C:16](Cl)=[O:17].C(N(CC)CC)C>C(Cl)Cl>[CH3:14][C:15]([CH3:20])([CH3:19])[C:16]([N:2]1[CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:1]1)=[O:17]
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)N1CCc2c([nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
To a solution of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (2 g, 11.6 mmol) dissolved in methylene chloride (20 mL) is added 2,2-dimethyl-propionyl chloride (1.42 mL, 11.6 mmol) followed by the addition of triethylamine (1.61 mL, 11.6 mmol). The reaction mixture is stirred at room temperature for 30 minutes. The reaction is quenched with water and extracted with methylene chloride three times. The combined organic extracts are washed with saturated sodium bicarbonate, a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo to give 2.8 g (94%) of the title compound as a grey solid.
Reaction SMILES: [C:1]([N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1)(=[O:3])[CH3:2].Cl[CH2:10][CH2:11][CH2:12][C:13]1[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=1.[I-:24].[Na+]>C(#N)C>[I-:24].[C:1]([N+:4]1[CH:8]=[CH:7][N:6]([CH2:10][CH2:11][CH2:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][CH:14]=2)[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(CCCCl)cc1
Reactant: CC(=O)n1ccnc1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc(CCCn2cc[n+](C(C)=O)c2)cc1
Temperature: 140 °C
Yield: 93.5 %

Procedure:
To 10 ml of dry acetonitrile were added 1.1 g of 1-acetylimidazole, 2.26 g of ethyl 4-(3-chloropropyl)benzoate and 1.5 g of sodium iodide, and the mixture was heated in a sealed tube for 18 hours at 140° C. under stirring. After cooling, the reaction mixture was filtrated to remove insoluble materials and the filtrate was concentrated under reduced pressure. To the residue was added an adequate amount of dry diethyl ether and the resulting powder was collected by filtration to obtain 3.99 g of 1-acetyl-3-[3-(4-ethoxycarbonylphenyl)propyl]imidazolium iodide. (pale yellow hygroscopic amorphous).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]([CH:15]([CH2:21][CH3:22])[CH:16]([CH3:20])[C:17](O)=[O:18])=O)=[CH:11][C:10]=1[OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:27][NH2:28]>C(O)(=O)C>[CH2:1]([NH:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]2[CH:15]([CH2:21][CH3:22])[CH:16]([CH3:20])[C:17](=[O:18])[NH:27][N:28]=2)=[CH:11][C:10]=1[OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCC(C(=O)c1ccc(NCc2ccccc2)c(O)c1)C(C)C(=O)O
Solvent: CC(=O)O
Solvent: O
Product: CCC1C(c2ccc(NCc3ccccc3)c(O)c2)=NNC(=O)C1C

Procedure:
3.00 g (8.79 mmol) 3-(4-benzylamino-3-hydroxy-benzoyl)-2-methyl-pentanoic acid, 6.31 mL (126.00 mmol) hydrazine hydrate and 25 mL glacial acetic acid are stirred for 3 h at 110° C. The reaction mixture is concentrated by rotary evaporation i. V. and the residue is separated through RP (xBridge, MeOH/H2O/TFA).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[O:9][CH:8]=[C:7]([C:15]1[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=1)[C:6]2=[O:25])[CH3:2].Cl.NO.C([N:31](CC)CC)C>CCO.O>[CH:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[C:7]1[CH:8]=[N:31][O:25][C:6]=1[C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[C:12]([O:13][CH3:14])=[CH:11][C:10]=1[OH:9]
Reactant: CCc1cc2c(=O)c(-c3ccc4ccccc4c3)coc2cc1OC
Reactant: CCN(CC)CC
Agent: Cl
Agent: NO
Solvent: CCO
Solvent: O
Product: CCc1cc(-c2oncc2-c2ccc3ccccc3c2)c(O)cc1OC
Temperature: 140 °C

Procedure:
A mixture of 6-ethyl-7-methoxy-3-naphthalen-2-yl-chromen-4-one (e, 0.36 g), hydroxylamine hydrochloride (0.6 g), triethylamine (0.5 mL) in EtOH (10 mL) was heated at 140° C. in microwave reactor for 4 h. The mixture was diluted with water (100 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic extracts were washed with water and dried using a drying agent. The oil obtained on concentration was flash chromatographed on silica gel to give 4-(naphthalen-2-yl)-5-(2-hydroxy-4-methoxy-5-ethyl-phenyl)-isoxazole as white powder (f, 0.19 g). 1H-NMR (CDCl3) δ (ppm) 8.57 (s, 1H), 7.8 (m, 4H), 7.5 (m, 3H), 7.10 (s, 1H), 6.52 (s, 2H), 3.92 (s, 3H), 2.4 (q, 2H, J=7), 1.0 (t, 3H, J=7); ESMS clcd for C22H19NO3: 345.1. Found: 346.0 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][O:8][C:9]2[C:18]3[C:17](=[O:19])[N:16]([CH3:20])[CH:15]=[N:14][C:13]=3[CH:12]=[C:11](Cl)[N:10]=2)[CH:3]=[N:2]1.[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][O:8][C:9]2[C:18]3[C:17](=[O:19])[N:16]([CH3:20])[CH:15]=[N:14][C:13]=3[CH:12]=[C:11]([C:31]3[CH:30]=[CH:29][C:28]([N:25]4[CH2:24][CH2:23][O:22][CH2:27][CH2:26]4)=[CH:33][CH:32]=3)[N:10]=2)[CH:3]=[N:2]1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)cc2)OC1(C)C
Reactant: Cn1cnc2cc(Cl)nc(OCCc3cn[nH]c3)c2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cn1cnc2cc(-c3ccc(N4CCOCC4)cc3)nc(OCCc3cn[nH]c3)c2c1=O
Temperature: 140 °C

Procedure:
To a solution of 5-(2-(1H-pyrazol-4-yl)ethoxy)-7-chloro-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (31.6 mg, 0.10 mmol) in 1,4-dioxane (1 mL) were added 4-morpholinophenylboronic acid pinacol ester (29.9 mg, 0.10 mmol), 2M aqueous Na2CO3 solution (155 μL, 0.30 mmol), and a catalytic amount of Pd(dppf)2Cl2. The reaction mixture was purged with N2 and heated at 140° C. by a microwave reactor for 15 minutes. The mixture was then cooled, quenched with H2O and extracted with EtOAc. The combined organic layer was dried over MgSO4, concentrated, and purified by silica gel chromatography (eluent: 0-10% MeOH in DCM) to provide the title compound as a yellow solid. 1H NMR (CD3OD, 400 MHz) δ 8.37 (s, 1H), 8.06 (d, J=9.2 Hz, 2H), 7.71 (s, 2H), 7.43 (s, 1H), 7.04 (d, J=9.2 Hz, 2H), 4.71 (t, J=6.4 Hz, 2H), 3.85 (t, J=4.8 Hz, 4H), 3.55 (s, 3H), 3.27 (t, J=4.8 Hz, 4H), 3.10 (t, J=6.4 Hz, 2H); ESI-MS m/z 433.1 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)(=[O:3])[NH2:2].Cl[CH2:15][C:16](=O)[CH2:17][C:18]([O:20]CC)=[O:19]>C(OCC)(=O)C>[CH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[C:1]1[O:3][CH:15]=[C:16]([CH2:17][C:18]([OH:20])=[O:19])[N:2]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NC(=O)c1ccc2ccccc2c1
Solvent: CCOC(C)=O
Product: O=C(O)Cc1coc(-c2ccc3ccccc3c2)n1
Temperature: 160 °C
Reaction time: 1 h
Yield: 14.5 %

Procedure:
A mixture of 2-carbamoylnaphthalene (2.64 g, 15.4 mmol) and ethyl 4-chloroacetoacetate (2.06 g, 12.5 mmol) was stirred at 160° C. for 1 hr. and then diluted with ethyl acetate (200 ml) at room temperature. The solution was washed with saturated sodium bicarbonate aqueous solution and brine in turn, and then dried. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=8−4) to give ethyl ester of [2-(2-naphthyl)oxazol-4-yl]acetic acid(459 mg, 13%) as yellow crystals.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:29][C:30]1[N:31]=[C:32]([CH3:35])[S:33][CH:34]=1>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[C@H:20]([CH3:25])[CH2:21][N:22]([CH2:29][C:30]5[N:31]=[C:32]([CH3:35])[S:33][CH:34]=5)[C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(CCl)cs1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3[C@H](C)CNC2=O)CC1
Agent: [H-]
Agent: [Na+]
Product: Cc1nc(CN2C[C@@H](C)n3c(cc4cc(OC5CCN(C(C)C)CC5)ccc43)C2=O)cs1
Yield: 61 %

Procedure:
The title compound was synthesized in analogy to example 17, from (R)-8-(1-isopropyl-piperidin-4-yloxy)-4-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 8), sodium hydride (2.4 equivalents) and 4-(chloromethyl)-2-methyl-1,3-thiazole, to give the desired product as a light yellow foam (61%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:50])[N:24]([CH:25]([CH2:42][CH2:43]O)[C:26]([NH:28][CH:29]([CH2:34][CH2:35][CH2:36][CH:37]([O:40][CH3:41])[O:38][CH3:39])[C:30]([O:32][CH3:33])=[O:31])=[O:27])[C:23](=[O:45])[C:22]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:21]12.[C:51]([OH:54])(=[S:53])[CH3:52]>O1CCCC1>[C:23]1(=[O:45])[N:24]([CH:25]([CH2:42][CH2:43][S:53][C:51](=[O:54])[CH3:52])[C:26]([NH:28][CH:29]([CH2:34][CH2:35][CH2:36][CH:37]([O:38][CH3:39])[O:40][CH3:41])[C:30]([O:32][CH3:33])=[O:31])=[O:27])[C:20](=[O:50])[C:21]2=[CH:49][CH:48]=[CH:47][CH:46]=[C:22]12
Reactant: CC(O)=S
Reactant: COC(=O)C(CCCC(OC)OC)NC(=O)C(CCO)N1C(=O)c2ccccc2C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(CCCC(OC)OC)NC(=O)C(CCSC(C)=O)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A cold (0° C.) solution of triphenylphosphine (1.143 g., 4.36 mmol.) in tetrahydrofuran (20 ml.) was treated with diisopropyl azidodicarboxylate (860 μl., 883 mg., 4.37 mmol.). Within 5 minutes a white slurry developed. After 30 minutes, a solution of [S-(R*,R*)-2-[(2-phthalimido-4-hydroxy-1-oxobutyl]-amino]-6,6-dimethoxyhexanoic acid, methyl ester [prepared as described in Example 1(f), 928 mg., 2.19 mmol.] in tetrahydrofuran (8 ml.) was added followed by neat thioacetic acid (312 μl., 332 mg., 4.36 mmol.). The mixture was stirred at 0° C. for 1.25 hours, then partitioned between 50% saturated sodium bicarbonate and ethyl acetate. The ethyl acetate extract was washed with brine, dried (sodium sulfate), filtered and stripped. The residue was redissolved in ethyl acetate and treated with a small amount of hexane to precipitate triphenylphosphine oxide. The mixture was filtered and the filtrate was flash chromatographed (Merck silica gel, 65:35-ethyl acetate:hexanes) to give 894 mg. of the title product as a colorless oil. TLC (75:25-ethyl acetate:hexanes) Rf =0.43.
Reaction SMILES: [Cl:1][O-].[Na+].[C:4]([C:7]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2)(=[O:6])[CH3:5].C(O)(=O)C>CO.O>[C:4]([C:7]1[CH:16]=[C:15]([Cl:1])[C:14]([OH:17])=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2)(=[O:6])[CH3:5]
Reactant: CC(=O)c1ccc(O)c2ncccc12
Reactant: [O-]Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC(=O)c1cc(Cl)c(O)c2ncccc12

Procedure:
350 ml of a 14% strength sodium hypochlorite solution are added dropwise to a suspension of 94 g of 5-acetyl-8-hydroxyquinoline in 1 litre of methanol and 1 litre of water at 10°-20°C, whilst stirring well. After stirring for a further hour, the mixture is acidified with 60 ml of glacial acetic acid and diluted with 1 liter of water, and the product is filtered off. The filter residue is washed with water and recrystallised, whilst still moist, from alcohol. 70 g of almost colourless 5-acetyl-7-chloro-8-hydroxyquinoline are obtained, melting point 163°-166° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].Cl.[OH-].[NH4+].[C:16](O)(=O)[CH3:17]>>[CH3:16][C:17]1[NH:1][C:2]2[C:3]([CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=2[N:8]=1
Reactant: CC(=O)O
Reactant: Cc1c([N+](=O)[O-])ccc(N)c1N
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: Cc1nc2ccc([N+](=O)[O-])c(C)c2[nH]1
Temperature: 25 °C

Procedure:
A mixture of 2,3-diamino-6-nitrotoluene (0.945 g, 5.65 mmol), conc. hydrochloric acid (5 mL) and glacial acetic acid (30 mL) is heated to reflux for 2 hours. The mixture is cooled to room temperature, then poured in a mixture of crushed ice (100 mL) and ammonium hydroxide (100 mL) and extracted with 20% methanol in chloroform (2×400 mL). The combined extracts are dried over potassium carbonate and rotary evaporated to afford 2,4-dimethyl-5-nitrobenzimidazole as a brown solid. The product is used in the following step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C:14](=[O:24])[CH2:13][CH2:12]1.Br[C:26]1[S:27][CH:28]=[C:29]([CH3:31])[N:30]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1C(=O)CCC1.Cl[Cu].C1(C)C=CC=CC=1.CCOC(C)=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:15]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][C:26]3[S:27][CH:28]=[C:29]([CH3:31])[N:30]=3)=[CH:21][CH:22]=2)[C:14](=[O:24])[CH2:13][CH2:12]1
Reactant: COc1cccc(OC)c1C1CCC(=O)N1Cc1ccc(O)cc1
Reactant: Cc1csc(Br)n1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1ccc(Oc2nc(C)cs2)cc1

Procedure:
In a microwave tube, a mixture of 5-(2,6-dimethoxyphenyl)-1-(4-hydroxybenzyl)pyrrolidin-2-one (prepared as described in example 282; 60 mg; 0.18 mmol), commercially available 2-bromo-4-methylthiazole (65 mg; 0.36 mmol), Cs2CO3 (66 mg; 0.20 mmol), CuCl (9 mg; 0.09 mmol), and commercially available 2,2,6,6-tetramethylheptane-3,5-dione (34 mg; 0.18 mmol) in anh. NMP (1 ml) was sealed and irradiated by microwave (175° C.; 10 min.). Water (1 ml), AcOEt (2 ml), and toluene (1 ml) were added, and the resulting suspension was filtered over a pad of celite. The separated organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.83 min.; [M+H]+: 424.98 g/mol.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[CH2:4][C:5]1([NH:18][CH3:19])[S:17][CH:8]2[C:9]3[N:14]([CH2:15][CH2:16][CH:7]2[CH2:6]1)[CH2:13][CH:12]=[CH:11][CH:10]=3.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>>[CH3:19][NH:18][C:5]1([CH2:4][CH2:3][NH:2][CH3:1])[S:17][CH:8]2[C:9]3[N:14]([CH2:15][CH2:16][CH:7]2[CH2:6]1)[CH2:13][CH:12]=[CH:11][CH:10]=3
Reactant: CNC(=O)CC1(NC)CC2CCN3CC=CC=C3C2S1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Product: CNCCC1(NC)CC2CCN3CC=CC=C3C2S1
Yield: 58.3 %

Procedure:
A mixture of 0.125 g (0.43 mmol) of (2RS, 10bSR)-N-methyl-2-(2-methylamino-1,3,4,6,7,10b-hexahydrothieno[2,3-a]quinolizin-2-yl)acetamide and 0.51 ml (1.72 mmol) of 3.4 M sodium bis (2-methoxyethoxy) aluminum hydride were reacted employing the procedure substantially described in Example 27 Step B to give 0.07 g (59%) of (2RS,10bSR)-2-methylamino-2-(2-methylaminoethyl)-1,3,4,6,7,10b-hexahydrothieno[2,3-a]quinolizine as a brown oil.
Reaction SMILES: [CH:1]1[C:5]2=[CH:6][S:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[N:4]2[CH2:3][CH:2]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-]>CC#N>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C@H:6]2[C@@H:5]3[CH2:1][CH2:2][CH2:3][N:4]3[C:10](=[O:11])[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[S:7]2)[CH2:19][CH2:18]1
Reactant: O=C1c2ccccc2SC=C2C=CCN12
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CN1CCN([C@@H]2Sc3ccccc3C(=O)N3CCC[C@@H]23)CC1

Procedure:
A mixture of (+)-11-chloro-2,3,11,11a-tetrahydro-1H,5H,-pyrrolo[2,1-c][1,4]benzothiazepin-5-one (38)15 (0.6 g, 2.4 mmol), freshly distilled 1-methylpiperazine (0.34 mL, 3.1 mmol), Na2CO3(1.06 g, 10.0 mmol), NaI (0.36 g, 2.4 mmol) in dry CH3CN (30 mL) was gently refluxed for 20 hours. The solvent was evaporated and the residue was partitioned between CH2Cl2 and water. The organic phase was successively washed with a 2% solution of Na2S2O3, water and brine. The residue obtained after evaporation was chromatographed on silica gel eluting with 5% methanol in CH2Cl2. The title compound 27 was obtained as a white solid (0.55 g, 73% yield): mp 188–190° C. (2-propanol-isopropyl ether); IR (KBr) 1630 cm−1; 1H NMR (CDCl3) δ7.71 (m, 1H), 7.50 (m, 2H), 7.61 (m, 1H), 7.33 (m, 2H), 4.36 (d, 1H, J=11.2 Hz), 3.70 (m, 3H), 2.58 (m, 4H), 2.38 (m, 4H), 2.27 (s, 3H), 2.02 (m, 4H). MS m/z 317 (100, M+), 217, 180, 139, 99, 70. Anal. (C17H23N3OS)C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]=[C:9]2[CH2:18][NH:19][C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:31]I.Cl>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]2[CH2:18][N:19]([CH3:31])[C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnc(CNc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(Cc1ncc(C(=O)O)n1-c1ccc(F)cc1)c1c(F)ccc(F)c1F
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 1-(4-fluorophenyl)-2-(((2,3,6-trifluorophenyl)amino)methyl)-1H-imidazole-5-carboxylate (23) (56 mg, 0.14 mmol) in DMF (2 mL) was added sodium hydride (60% in mineral oil, 7 mg, 0.28 mmol) and stirred for 30 minutes. To the solution was added methyl iodide (18 μL, 0.28 mmol) and again stirred overnight at room temperature. Ethyl acetate was added and the reaction was acidified with 2N HCl. The ethyl acetate was separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give 1-(4-fluorophenyl)-2-((methyl(2,3,6-trifluorophenyl)amino)methyl)-1H-imidazole-5-carboxylic acid (24).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][OH:7].[Si:13](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CN=C1>CN(C=O)C>[Si:13]([O:7][CH2:6][C:5]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:3]([O:2][CH3:1])[CH:4]=1)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COc1cc(CO)cc(OC)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.9 %

Procedure:
A mixture of 3,5-dimethoxybenzyl alcohol (4.0 g), tert-butyl-diphenylsilyl chloride (6.54 g) and imidazole (3.28 g) in DMF (60 mL) was stirred at room temperature for 24 h. DMF was evaporated and the residue was purified by column chromatography (silica gel; eluent: hexane to hexane/EtOAc 20%) to yield 8.5 g of 3,5-dimethoxybenzyl tert-butyldiphenylsilyl ether. ESMS: m/z 407 (MH+).