Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH:9]1[CH:21]=[CH:22][C:23](OCC)=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].B(F)(F)F.CCOCC.CC(C[AlH]CC(C)C)C.CCOC(C)=O>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][Si:14]([C:17]([CH3:19])([CH3:18])[CH3:20])([CH3:16])[CH3:15])[CH:9]1[CH:21]=[CH:22][CH2:23][OH:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C=CC1C(O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(O[Si](C)(C)C(C)(C)C)C1C=CCO
Temperature: -78 °C
Reaction time: 1 h
Yield: 108.1 %

Procedure:
A solution containing 42 (8.6 g, 22 mmol) in DCM (80 ml) was cooled to −78° C. To this solution was slowly added boron trifluoride etherate (2.8 mL, 22 mmol) followed by the addition of 1M DIBALH in DCM (60 mL). The solution was stirred at −78° C. for 1 h. The reaction mixture was then treated with EtOAc and stirred for 30 min. The reaction mixture was allowed to warm to −5° C. The reaction was quenched by the dropwise addition of 1M HCl. The mixture was diluted with DCM and H2O and the layers were separated. The aqueous layer was extracted with DCM. The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated to afford 8.5 g of 43 as a light yellow oil which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ5.70 (m, 1H), 5.59-5.55 (m, 1H), 4.16-4.13 (m, 2H), 4.05 (m, 2H), 3.72-3.35 (m, 4H), 1.95-1.88 (m, 2H), 1.77-1.67 (m, 2H), 1.48-1.44 (m, 9H), 0.88 (s, 9H), 0.08-0.03 (m, 6H) ppm.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:19]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:9]2[NH:27][C:26]([C:25]3[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:29][CH:28]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(=NO)C(=O)c1cccc(OC)c1
Product: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1cccc(OC)c1
Yield: 31.6 %

Procedure:
Ethyl 2-hydroxyimino-3-(3-methoxyphenyl)-3-oxopropionate (84.5 g) and 4-nitrobenzylamine (61.4 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(3-methoxyphenyl)-2-(4-nitrophenyl)imidazole-4-carboxylate (39.0 g), melting point 194-196° C.
Reaction SMILES: I[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27]([C:29]3[CH:60]=[CH:59][C:32]([CH2:33][O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[CH2:41][CH2:42][NH:43][CH:44]4[CH2:53][CH2:52][CH2:51][C:50]5[N:49]=[C:48]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH:47]=[CH:46][C:45]4=5)=[CH:31][CH:30]=3)=[N:26][C:25]=2[CH:61]=1>C(#N)C>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[O:28][C:27]([C:29]3[CH:60]=[CH:59][C:32]([CH2:33][O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[CH2:41][CH2:42][N:43]([CH2:2][CH2:3][C:4]4[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=4)[CH:44]4[CH2:53][CH2:52][CH2:51][C:50]5[N:49]=[C:48]([C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH:47]=[CH:46][C:45]4=5)=[CH:31][CH:30]=3)=[N:26][C:25]=2[CH:61]=1
Reactant: COC(=O)c1ccc(CCI)cc1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1ccccc1OCc1ccc(-c2nc3cc(Cl)ccc3o2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccc(C(=O)OC)cc1)CCc1ccccc1OCc1ccc(-c2nc3cc(Cl)ccc3o2)cc1

Procedure:
112 mg (0.39 mmol) of methyl 4-(2-iodoethyl)benzoate and 41 mg (0.39 mmol) of anhydrous sodium carbonate were added to a solution of 149 mg (0.26 mmol) of ethyl 5-{[2-(2-{[4-(5-chloro-1,3-benzoxazol-2-yl)benzyl]oxy}phenyl)ethyl]amino}-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 1, Example 61A) in 10 ml of dry acetonitrile, and the mixture was heated under reflux overnight. A further 112 mg of methyl 4-(2-iodoethyl)benzoate were then added, and the mixture was once more heated under reflux overnight. The reaction was then evaporated to dryness, the residue was taken up in water and ethyl acetate and the phases were separated. The organic phase was evaporated to dryness and the residue obtained was purified by preparative HPLC. This gave 72 mg (0.10 mmol, 38% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[S:6][C@@H:5]2[C:7]([Br:11])([Br:10])[C:8](=[O:9])[N:4]2[C@H:3]1[C:12]([OH:14])=[O:13].C(N(CC)CC)C.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C(=O)C>[CH3:1][C:2]1([CH3:15])[S:6][C@@H:5]2[C:7]([Br:11])([Br:10])[C:8](=[O:9])[N:4]2[C@H:3]1[C:12]([O:14][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:13]
Reactant: BrCc1ccccc1
Reactant: CC1(C)S[C@H]2N(C(=O)C2(Br)Br)[C@H]1C(=O)O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC1(C)S[C@H]2N(C(=O)C2(Br)Br)[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 95 %

Procedure:
To a solution of 54 g. (0.165 mole) of 6,6-dibromopenicillanic acid in 350 ml. of N,N-dimethylacetamide was added 22.9 ml. (0.165 mole) of triethylamine and the solution was stirred for 40 minutes. Benzyl bromide (19.6 ml., 0.165 mole) was added and the resulting mixture was stirred at room temperature for 48 hours. The precipitated triethylamine hydrobromide was filtered off, and the filtrate was added to 1,500 ml. of ice-water, adjusted to pH 2. The mixture was extracted with ether, and the extracts were washed successively with saturated sodium bicarbonate, water and brine. The dried (MgSO4) ether solution was evaporated in vacuo to give an off-white solid, which was recrystallized from isopropanol. This afforded 70.0 g. (95% yield) of the title compound m.p. 75°-76° C. The IR spectrum (KBr disc) showed absorptions at 1795 and 1740 cm-1. The NMR spectrum (CDCl3) showed absorptions at 1.53 (s, 3H), 1.58 (s, 3H), 4.50 (s, 1H), 5.13 (s, 2H), 5.72 (s, 1H) and 7.37 (s, 5H) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[Br:24])[C:18]([OH:20])=[O:19])[CH2:12][CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CC#N>[CH2:31]([O:19][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][C:23]([Br:24])=[C:15]([CH2:14][N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH2:12][CH3:13])[CH:16]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCN(Cc1cc(C(=O)O)ccc1Br)C(=O)OCc1ccccc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCN(Cc1cc(C(=O)OCc2ccccc2)ccc1Br)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3-[(N-benzyloxycarbonyl-N-ethyl-amino)-methyl]-4-bromo-benzoic acid (8.9 g, 22.6 mmol) in MeCN (400 mL) was added cesium carbonate (18.4 g, 56.5 mmol), followed by benzyl bromide (2.95 mL, 24.9 mmol), and the reaction was stirred at room temperature overnight. The mixture was filtered and extracted with EtOAc and washed with H2O. The organic layer was dried and concentrated, and the residue was purified by silica gel chromatography (0-25% EtOAc in hexanes) to give 3-[(N-benzyloxycarbonyl-N-ethyl-amino)-methyl]-4-bromo-benzoic acid benzyl ester.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[C:9]([CH2:13][CH:14]([CH3:16])[CH3:15])=[CH:8][N:7]=1)=[O:5])C.[ClH:17]>>[ClH:17].[CH2:13]([C:9]1[C:10]([CH3:12])=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[N:7][CH:8]=1)[CH:14]([CH3:16])[CH3:15]
Reactant: CCOC(=O)c1cc(C)c(CC(C)C)cn1
Agent: Cl
Product: Cc1cc(C(=O)O)ncc1CC(C)C

Procedure:
A solution of 5-isobutyl-4-methyl-pyridine-2-carboxylic acid ethyl ester (1.27 g, 5.76 mmol) in 6 N aq. HCl (110 mL) is stirred at 65° C. for 48 h before the solvent is evaporated in vacuo. The remaining residue is suspended in DCM and filtered. The solid material is washed with additional DCM and dried under HV to give 5-isobutyl-4-methyl-pyridine-2-carboxylic acid hydrochloride (1.05 g) as a white solid; LC-MS: tR=0.59 min; [M+1]+=194.28; 1H NMR (D6-DMSO): δ 0.90 (d, J=6.3 Hz, 6H), 1.85-1.96 (m, 1H), 2.69 (d, J=7.0 Hz, 2H), 8.18 (s, 1H), 8.58 (s, 1H), 11.80 (s br, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:47])[CH2:7][N:8]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([CH:31]1[CH2:36][CH2:35][N:34](C(OCC2C=CC=CC=2)=O)[CH2:33][CH2:32]1)=[O:30])[C:9](=[O:22])[CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)=[O:13])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:47])[CH2:7][N:8]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([CH:31]1[CH2:32][CH2:33][NH:34][CH2:35][CH2:36]1)=[O:30])[C:9](=[O:22])[CH2:10][NH:11][C:12]([NH:14][C:15]1[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=1)=[O:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2C(=O)C2CCN(C(=O)OCc3ccccc3)CC2)c1
Agent: [Pd]
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2C(=O)C2CCNCC2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79 %

Procedure:
tert-Butyl((2-(N-(benzyloxycarbonyl)piperidine-4-carbonyl)phenyl)-(2-(3-tolylureido)acetyl)amino)acetate and the compound 26 g (9.7 mg, 0.015 mmol) are dissolved in ethano. To the solution is added palladium hydrooxidecarbon powder (2 mg) and stirred under a hydrogen atmosphere (1 atm) at room temperature for 24 hours. The reaction solution is filtered and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography to obtain the objective compound 60 (6.0 mg). Yield 79%.
Reaction SMILES: [O:1]([C:8]1[CH:28]=[CH:27][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH2:25][NH2:26])[CH:22]=[CH:23][CH:24]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.CN1C[CH2:39][CH2:38][C:37]1=[O:41]>ClCCl>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[C:19]2[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=2)[CH2:25][NH:26][C:37](=[O:41])[CH2:38][CH3:39])=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Reactant: CN1CCCC1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)NCc1cccc(-c2cnccc2Oc2ccc(Oc3ccccc3)cc2)c1
Yield: 58 %

Procedure:
N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)propionamide was prepared from (3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine and pyridine instead of N, N-diethylethanamine, 1-methylpyrrolidin-2-one, dichloromethane using Method G (58% yield). HPLC: 97%, RT=4.034 min. MS: m/z=425 [M+H]+, RT=3.34 min.
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[C:21](=[O:22])[C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18](=[O:27])[C:17]=2[CH3:28])[CH2:7][CH2:6]1)(=O)C>Cl.CO>[OH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[C:21](=[O:22])[C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18](=[O:27])[C:17]=2[CH3:28])[CH2:7][CH2:6]1
Reactant: COC1=C(OC)C(=O)C(CCCCC[C@H]2CC[C@H](OC(C)=O)CC2)=C(C)C1=O
Agent: Cl
Solvent: CO
Product: COC1=C(OC)C(=O)C(CCCCC[C@H]2CC[C@H](O)CC2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
trans-6-[5-(4-Acetoxycyclohexyl)pentyl]-2,3-dimethoxy-5-methyl-1,4-benzoquinone (0.415 g) is dissolved in hydrochloric acid-methanol (1.180, 10 ml), and the mixture is stirred at room temperature for 24 hours. The solvent is distilled off under reduced pressure, and the residue is dissolved in ether, washed with aqueous sodium hydrogen carbonate and then with water and dried. The ether is distilled off and the residue is subjected to silica gel column chromatography. Recrystallization of the desired fractions from ether-hexane gives trans-6-[5-(4-hydroxycyclohexyl)pentyl]-2,3-dimethoxy-5-methyl-1,4-benzoquinone as orange needles, m.p. 64°-65° C.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[CH:3]=1.[CH2:13]([Li])CCC.CI.Cl>CN(C)P(N(C)C)(N(C)C)=O.O1CCCC1.O>[CH2:1]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[CH:3]=1)[CH3:13]
Reactant: [Li]CCCC
Reactant: Cc1cc(=O)[nH]c2ccccc12
Agent: Cl
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCc1cc(=O)[nH]c2ccccc12
Temperature: -10 °C

Procedure:
1,2-Dihydro-4-methyl-2-oxoquinoline (79.5 g.) was dissolved in a mixture of dry hexamethylphosphoramide (530 ml.) and tetrahydrofuran (530 ml.), and the solution was cooled to -10° C. under a nitrogen atmosphere. n-Butyl-lithium (1.54 M solution in hexane; 770 ml.) was added to the stirred solution at such a rate as to keep the temperature below 0° C. When the addition was completed, the deep red solution was cooled to -50° C. and methyl iodide (50 ml.) was rapidly added. The resulting pale yellow solution was immediately poured into water (2000 ml.) and acidified to pH 1 with concentrated hydrochloric acid. The resulting mixture was filtered and the solid residue washed with water and then dried in vacuo over phosphorus pentoxide. Crystallisation from ethanol gave 4-ethyl-1,2-dihydro-2-oxoquinoline, m.p. 197° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:31].[NH2:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](O)=O>>[NH2:32][C:33]1[CH:34]=[C:35]([C:36]2[O:31][C:3]3[CH:4]=[CH:5][C:6]4[NH:7][C:8]([C:14]5[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]6[C:22]([C:23]=5[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=6)=[N:9][S:10](=[O:12])(=[O:13])[C:11]=4[C:2]=3[N:1]=2)[CH:39]=[CH:40][CH:41]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3c(ccc(O)c3N)N2)c(O)c2ccccc21
Product: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3c(ccc4oc(-c5cccc(N)c5)nc34)N2)c(O)c2ccccc21
Temperature: 190 °C
Yield: 32 %

Procedure:
A mixture of the product of Example 354 (38 mg, 0.086 mmol) and 3-aminobenzoic acid (13 mg, 0.094 mmol) in polyphosphoric acid (1 mL)was heated to 190° C. for 1 hour. The solution was cooled to 25° C., triturated with water and a 10% solution of sodium carbonate. The solid was filtered, dried, and purified by flash column, eluting with 2% methanol in dichloromethane to yield the title compound (15 mg, 38%). The sodium salt was made by the procedure of Example 1D. MS (ESI−) m/z 543 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 1.04 (d, J=6.62 Hz, 6 H) 1.86 (m, 1 H) 2.56 (m, 2 H) 5.53 (s, 2 H) 5.96 (t, J=7.35 Hz, 1 H) 6.82 (ddd, J=8.09, 2.21, 1.10 Hz, 1 H) 7.08 (td, J=7.35, 1.47 Hz, 1 H) 7.27 (m, 2 H) 7.36 (dt, J=7.72, 1.29 Hz, 1 H) 7.57 (m, 3 H) 7.96 (d, J=8.82 Hz, 1 H) 8.10 (dd, J=8.09, 1.47 Hz, 1 H) 16.51 (s, 1 H).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Si:25]([O:32][CH2:33][CH:34]1[CH2:38][C:37](CO)=[CH:36][CH2:35]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>ClCCl>[Si:25]([O:32][CH2:33][CH:34]1[CH2:35][C:36]([CH2:1][Br:5])=[CH:37][CH2:38]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)[Si](C)(C)OCC1CC=C(CO)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1CC=C(CBr)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
The carbon tetrabromide (1.39 g, 4.2 mmol) and triphenylphosphine (1.37 g, 5.2 mmol) were added in dichloromethane solution of (4-t-Butyldimethylsilyloxymethylcyclopent-1-en-1-yl)methyl alcohol (0.85 g, 3.5 mmol) under ice bath and then stirred for 30 min at 0° C. The reaction mixture was stirred for overnight at room temperature, extracted with dichloromethane, dried with MgSO4, filtered, concentrated and separated by column chromatography to give a desirable product (0.53 g).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[SH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH3:8][C:6]1[CH:7]=[C:2]([S:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH:3]=[C:4]([CH3:9])[CH:5]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: Oc1ccc(S)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: Cc1cc(C)cc(Sc2ccc(O)cc2)c1
Yield: 89.9 %

Procedure:
The general procedure in example 39 was followed. 5-Iodo-m-Xylene (144 μL, 1.0 mmol), 4-mercaptophenol (126 mg, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-Propanol (1.0 mL) were used to obtain the 4-(3,5-dimethylphenyl)sulfanylphenol (207 mg, 90% yield) as colorless liquid. Workup procedure: ethyl acetate (approx. 5 mL) and dodecane (227 μL, GC standard) were added to the reaction mixture after the reaction was completed. The organic layer was neutralized by dilute HCl to pH 8. The aqueous layer was extracted by ethyl acetate (4×10 mL). The combined organic layers were concentrated and purified by column chromatography on silica gel using hexane/ethyl acetate=10/1 as the eluent to afford the titled product. Rf=0.3 (hexane/ethyl acetate=10/1). 1H NMR (CDCl3, 300 MHz) δ 7.33 (dt, 2 H, J=1.8 Hz, 8.4 Hz), 6.77-6.81 (m, 5 H), 4.83 (s, 1 H), 2.22 (s, 6 H). 13C NMR (CDCl3, 75 MHz) δ 155.6, 138.8, 137.7, 135.4, 128.1, 126.4, 125.3, 116.6, 21.6. IR (neat, cm−1) 3371 (broad), 3031, 2917, 2860. MS (EI) m/z (relative intensity) 230 (100), 215 (20). Anal Cald for C14H14OS, Cald. C: 73.01, H: 6.13; Found C: 73.21, H: 6.11.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)[CH:13]=1)[O:10][C:9]([C:21](O)=[O:22])=[CH:8][C:7]2=[O:24].[Cl:25][C:26]1[CH:27]=[C:28]([NH2:38])[CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[Cl:25][C:26]1[CH:27]=[C:28]([NH:38][C:21]([C:9]2[O:10][C:11]3[C:6]([C:7](=[O:24])[CH:8]=2)=[CH:5][C:4]([O:3][CH3:2])=[CH:13][C:12]=3[N:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]2)=[O:22])[CH:29]=[CH:30][C:31]=1[N:32]1[CH2:33][CH2:34][O:35][CH2:36][CH2:37]1
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)O)cc(=O)c2c1
Reactant: Nc1ccc(N2CCOCC2)c(Cl)c1
Agent: Cl
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCOCC4)c(Cl)c3)cc(=O)c2c1

Procedure:
This compound was prepared from 6-Methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid hydrochloride (Reference Example 2) and commercially available 3-chloro-4-morpholin-4-yl-phenylamine (Maybridge) as prepared in Example 12, yielding a yellow solid. (45 mg=31%) LCMS-m/z=513.5.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=2[Cl:13])[CH2:3][CH2:2]1.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17].C(N(CC)CC)C.BrC1C=CC(C2C3C(=C(Cl)C=C(Cl)C=3)CN(C)C2)=CC=1>O1CCOCC1>[CH:1]1([N:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=2[Cl:13])[CH2:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:2][CH2:3]1
Reactant: Clc1ccc(CNC2CC2)c(Cl)c1
Reactant: O=C(CBr)c1ccccc1
Agent: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(Br)cc2)C1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(CN(Cc1ccc(Cl)cc1Cl)C1CC1)c1ccccc1

Procedure:
Intermediate 1 was reacted with alpha-bromoacetophenone in the presence of triethylamine in dioxane by the method described in example 1, intermediate 3. For workup, the solvent was distilled off, and the residue was taken up in ethyl acetate. It was washed twice with H2O and twice with 2 N HCl, dried with MgSO4 and concentrated. The crude product obtained in this way was reacted further without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]([S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Cl)[CH:13]=1)(=[O:11])=[O:10])=[CH:5][O:6][CH2:7][CH3:8].COC(=O)C(S(C1C=CC(F)=C([Cl:38])C=1)(=O)=O)=COCC.COC(=O)C(S(C1C=C(Cl)C=C(Cl)C=1)(=O)=O)=COCC.COC(=O)C(S(C1C=CC(F)=CC=1)(=O)=O)=COCC.COC(=O)C(S(C1C=C(F)C=C(C#N)C=1)(=O)=O)=COCC>>[CH3:1][O:2][C:3](=[O:19])[C:4]([S:9]([C:12]1[CH:17]=[CH:16][C:15]([Cl:38])=[CH:14][CH:13]=1)(=[O:11])=[O:10])=[CH:5][O:6][CH2:7][CH3:8]
Reactant: CCOC=C(C(=O)OC)S(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: CCOC=C(C(=O)OC)S(=O)(=O)c1cccc(Cl)c1
Agent: CCOC=C(C(=O)OC)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Agent: CCOC=C(C(=O)OC)S(=O)(=O)c1cc(F)cc(C#N)c1
Agent: CCOC=C(C(=O)OC)S(=O)(=O)c1ccc(F)cc1
Product: CCOC=C(C(=O)OC)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
Applying the above procedure the following compounds were prepared: e.g. 2-(3-chloro-benzenesulfonyl)-3-ethoxy-acrylic acid methyl ester (MS (EI) M+=305.1); 2-(3-chloro-4-fluoro-benzenesulfonyl)-3-ethoxy-acrylic acid methyl ester (MS (EI) M+=323.1); 2-(3,5-dichloro-benzenesulfonyl)-3-ethoxy-acrylic acid methyl ester (MS (EI) M+=340.1); 2-(4-fluoro-benzenesulfonyl)-3-ethoxy-acrylic acid methyl ester (MS (EI) M+=289.1); 2-(3-cyano-5 fluoro-benzenesulfonyl)-3-ethoxy-acrylic acid methyl ester (MS (EI) M+=314.2).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(CN2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.2 %

Procedure:
Trifluoroacetic acid (8 ml) was added to a solution of tert-butyl 4-(4-chlorobenzyl)piperazine-1-carboxylate (2.50 g, 8.05 mmol) prepared in Reference Example 178 in methylene chloride (16 ml), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. Sodium hydroxide aqueous solution was added to the residue, and the mixture was extracted with methylene chloride. The extract was dried over sodium sulfate, and then filtered. The filtrate was concentrated under reduced pressure to afford 1-(4-chlorobenzyl)piperazine (1.70 g, quantitative) as a colorless oil.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:8]([CH3:17])=[N:9][C:10]2[N:11]([N:14]=[CH:15][CH:16]=2)[C:12]=1O>>[Cl:6][C:7]1[C:8]([CH3:17])=[N:9][C:10]2[N:11]([N:14]=[CH:15][CH:16]=2)[C:12]=1[Cl:3]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc2ccnn2c(O)c1Cl
Product: Cc1nc2ccnn2c(Cl)c1Cl
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Phosphorous oxychloride (excess) is added to 6-chloro-5-methylpyrazolo[1,5-a]pyrimidin-7-ol (1.00 equivalent) and heated to 80° C. After 2 hours, the reaction mixture is concentrated under reduced pressure. The resulting residue is poured onto ice and, carefully neutralized with saturated NaHCO3 (pH 8), and diluted with EtOAc. After stirring for 17 hours, the organic layer was separated and the aqueous layer was re-extracted with EtOAc, repeatedly. The combined organic extracts are dried (MgSO4) and concentrated. The product is purified by flash chromatography as necessary.
Reaction SMILES: [H-].[Na+].C([C:5](CC)(P(O)(O)=O)[C:6]#[N:7])C.[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][C:22](=O)[CH2:23]2)=[CH:18][CH:17]=1>C(COC)OC>[CH3:14][O:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][C:22]([CH2:5][C:6]#[N:7])=[CH:23]2)=[CH:18][CH:17]=1
Reactant: CCC(C#N)(CC)P(=O)(O)O
Reactant: COc1ccc2c(c1)CC(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc2c(c1)C=C(CC#N)CC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of 7.1 g. of a 57% mineral oil dispersion of sodium hydride in 400 ml. of dry glyme under nitrogen was added dropwise 28.0 g. of diethyl phosphonoacetonitrile followed by a solution of 25.5 g. of 7-methoxy-2-tetralone in 50 ml. of glyme. After stirring four hours at room temperature the mixture was allowed to stand overnight under nitrogen. The mixture was decanted from an insoluble residue; the supernatant was concentrated in vacuo, and poured into 350 ml. of ice-water. The product was extracted with chloroform and the extracts were washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness to give 29.9 g of 3,4-dihydro-7-methoxy-2-naphthaleneacetonitrile which was converted directly to 7-methoxy-2-naphthaleneacetonitrile as described hereinabove in Example 123.