Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC(C2C=[N:10][NH:9][C:8]=2C2C=CC(CCC3C=CC4C(=CC=CC=4)N=3)=CC=2)=CC=1.[Cl:30][C:31]1[CH:36]=[C:35]([CH2:37][C:38]([C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]3[CH:57]=[CH:56][C:55]4[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=4)[N:49]=3)=[CH:42][CH:41]=2)=O)[CH:34]=[CH:33][N:32]=1>>[Cl:30][C:31]1[CH:36]=[C:35]([C:37]2[C:38]([C:40]3[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]4[CH:57]=[CH:56][C:55]5[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=5)[N:49]=4)=[CH:42][CH:41]=3)=[N:10][NH:9][CH:8]=2)[CH:34]=[CH:33][N:32]=1
Reactant: c1ccc2nc(CCc3ccc(-c4[nH]ncc4-c4ccncc4)cc3)ccc2c1
Reactant: O=C(Cc1ccnc(Cl)c1)c1ccc(OCc2ccc3ccccc3n2)cc1
Product: Clc1cc(-c2c[nH]nc2-c2ccc(OCc3ccc4ccccc4n3)cc2)ccn1

Procedure:
Following the procedure for the preparation of 2-{2-[4-(4-Pyridin4-yl-2H-pyrazol-3-yl)-phenyl]-ethyl}-quinoline but substituting 2-(2-Chloro-pyridin-4-yl)-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.23 (m, 2 H), 8.08 (d, J=8.7 Hz, 1 H), 7.83 (d, J=8.3 Hz, 1 H), 7.80 (s, 1H), 7.75 (t, J=7.1 Hz, 1 H), 7.67 (d, J=8.3 Hz, 1H), 7.57 (t, J=7.1 Hz, 1 H), 7.33 (d, J=9.1 Hz, 2H), 7.05 (m, 4H), 5.40 (s, 2H); MS: (M+H m/z=413.1).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([O:18][CH2:19][O:20][CH3:21])=[CH:11][C:10]=2[O:22][CH2:23][O:24][CH3:25])=[N:7][NH:6][C:5]1=[S:26])([CH3:3])[CH3:2].[C:27](=O)([O-])[O-].[K+].[K+].CI>C(O)C>[CH:1]([N:4]1[C:5]([S:26][CH3:27])=[N:6][N:7]=[C:8]1[C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([O:18][CH2:19][O:20][CH3:21])=[CH:11][C:10]=1[O:22][CH2:23][O:24][CH3:25])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=S)n1C(C)C
Agent: [K+]
Solvent: CCO
Solvent: CI
Product: COCOc1cc(OCOC)c(C(C)C)cc1-c1nnc(SC)n1C(C)C
Temperature: 80 °C
Yield: 94.9 %

Procedure:
4-isopropyl-5-(5-isopropyl-2,4-bis-methoxymethoxy-phenyl)-2,4-dihydro-[1,2,4]triazol-3-thione (F63-03, 1.96 g, 5.14 mmol) and potassium carbonate (710.4 mg, 5.14 mmol) were weighed and placed in a reaction vessel, and ethanol (30 mL) was added and then methyl iodide (0.32 mL, 5.14 mmol) was added. After heating at 80° C. for 1 hour while stirring, the mixture was returned to room temperature, and the solvent was distilled off under reduced pressure. After adding water, the reaction system was extracted with ethyl acetate, and the extract was washed with saturated sodium chloride solution. After drying the extract over anhydrous sodium, sodium sulfate was removed by filtration and the solvent was distilled off under reduced pressure to obtain yellow syrup. After purification by silica gel column chromatography (chloroform, methanol), 4-isopropyl-3-(5-isopropyl-2,4-bis-methoxy methoxyphenyl)-5-methylsulfanyl-4H-[1,2,4]triazole (F63-04, pale yellow syrup, 1.93 g, 95%) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:18]3[N:17]=[C:16]([C:19]4[C:24]([Br:25])=[CH:23][CH:22]=[CH:21][C:20]=4[Br:26])[NH:15][C:14]=3[C:13]3[C:8](=[CH:9][C:10]([Br:27])=[CH:11][CH:12]=3)[C:6]=2[CH:7]=1.[H-].[Na+].[CH3:30][Si:31]([CH2:34][CH2:35][O:36][CH2:37]Cl)([CH3:33])[CH3:32].O>C1COCC1>[Br:27][C:10]1[CH:11]=[CH:12][C:13]2[C:14]3[N:15]=[C:16]([C:19]4[C:24]([Br:25])=[CH:23][CH:22]=[CH:21][C:20]=4[Br:26])[N:17]([CH2:37][O:36][CH2:35][CH2:34][Si:31]([CH3:33])([CH3:32])[CH3:30])[C:18]=3[C:5]3[C:6](=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[C:8]=2[CH:9]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1ccc2c(c1)c1cc(Br)ccc1c1[nH]c(-c3c(Br)cccc3Br)nc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(-c2c(Br)cccc2Br)nc2c3ccc(Br)cc3c3cc(Br)ccc3c21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
To a suspension of 6,9-dibromo-2-(2,6-dibromophenyl)-1H-phenanthro[9,10-d]imidazole from Step 1 (61.8 g, 0.1 mol) in THF (980 mL) at 0° C., was added sodium hydride (60% dispersion in mineral oil, 10 g, 0.25 mol). The suspension was stirred at 0° C. for 15 minutes, followed by addition of SEMCl (45 mL, 0.25 mol). The mixture was warmed to room temperature and stirred for 3 h, after which it was poured into water. The aqueous phase was extracted with ethyl acetate, the organic layer washed once with brine, dried over Na2SO4, filtered and concentrated. The crude material was swished in hexanes/diethyl ether for 4 h, then filtered to obtain 6,9-dibromo-2-(2,6-dibromophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-phenanthro[9,10-d]imidazole as a beige powder (71.5 g, 95%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[NH:17][CH2:16][CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)=[N:3][CH:2]=1.[Cl:18]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:18][C:12]1[C:11](=[O:13])[N:10]2[CH2:14][CH2:15][CH2:16][NH:17][C:9]2=[N:8][C:7]=1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=c1cc(-c2ccncn2)nc2n1CCCN2
Solvent: CC(=O)O
Product: O=c1c(Cl)c(-c2ccncn2)nc2n1CCCN2
Temperature: 90 °C

Procedure:
A suspension of 3.0 g (13.09 mmol) of 2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 60 ml of acetic acid was treated with 1.75 g (15.7 mmol) of N-chlorosuccinimide. The reaction mixture was heated at 90° C. during 18 h.
Reaction SMILES: C(S[CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:38])[CH2:6]1)C=C.[Cl:39]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:39][CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:38])[CH2:6]1
Reactant: ClCl
Reactant: C=CCSC1CC(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccc(F)cc1)C(=O)C(C)(C)C
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)C(Oc1ccc(F)cc1)=C(C(=S)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1Cl
Temperature: 25 °C
Yield: 68.5 %

Procedure:
To a solution of 7.2 g of 4-nitrobenzyl 2-(4-allylthioazetidin-2-on-1-yl)-3-(4-fluorophenoxy)-3-trimethylacetylthio-propenate (prepared as described in Example 25) in dichloromethane at -20°, was added a solution of 25 mmol of chlorine in carbon tetrachloride. After 30 minutes the mixture was warmed to room temperature, evaporated in vacuo, and the residual oil was chromatographed over silica gel. Elution with hexane-ethyl acetate mixtures afforded 4.6 g of the title compound as a pale yellow foam (67% of the theoretical yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Br-].[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Zn+])#[N:14].O>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2[C:15]([C:13]#[N:14])=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:3][C:4]=1[N+:9]([O-:11])=[O:10]
Reactant: N#Cc1ccccc1[Zn+]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccccc1-c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A mixture of 4-bromo-1-fluoro-2-nitrobenzene (9.68 g, 44 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.53 g, 1.3 mmol) was treated with 2-cyanophenylzinc bromide (100 ml of a 0.5M solution in tetrahydrofuran, 50 mmol) then heated under reflux for 8 h. After cooling to ambient temperature the reaction mixture was poured into water (1000 ml). After stirring for 30 min the resulting solid was collected by filtration and dried under vacuum over phosphorus pentoxide to afford 4′-fluoro-3′-nitrobiphenyl-2-carbonitrile as a tan solid (10.7 g, 100%) which was used without further purification.
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH:14]([C:16]([OH:18])=O)[CH2:13][CH2:12][C:11]=3[CH:19]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:20]([NH2:23])[CH:21]=[CH2:22]>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:15][CH:14]([C:16]([NH:23][CH2:20][CH:21]=[CH2:22])=[O:18])[CH2:13][CH2:12][C:11]=3[CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C=CCN
Reactant: O=C(O)C1CCc2cc(C3CCCCC3)ccc2O1
Product: C=CCNC(=O)C1CCc2cc(C3CCCCC3)ccc2O1

Procedure:
5 Also was prepared, as white crystals, mp: 93°-94° C., by the procedure described in the last paragraph of Example 2, from the ethyl ester of 6-cyclohexyl-3,4-dihydro-2H-1-benzopyran-2-carboxylic acid (Witiak et al. (1975)) and 2-propenamine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[N:19]([CH3:20])[CH:18]=[N:17][CH:16]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.CC(O)C>CCCCCC>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:15]2[N:19]([CH3:20])[CH:18]=[N:17][CH:16]=2)[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(c1ccc(O)cc1)c1cncn1C
Solvent: CCCCCC
Solvent: CC(C)O
Product: CCOC(=O)C[C@@H](c1ccc(O)cc1)c1cncn1C
Yield: 44 %

Procedure:
Racemic compound 74.4 (680 mg, 2.5 mmol) was separated on a semi-preparatory chiral CHIRALCEL OJ-H column (30×250 mm), using 15% i-PrOH in hexane as eluant. Eluant containing the peak with less retention time was concentrated and compound 74.5 (300 mg, 1.1 mmol) was obtained as off-white solid. The absolute configuration was assigned by analogy to other GPR40 agonist compounds. MS ESI (pos.) m/e 275.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:6]([CH2:17]Cl)=[C:5]2[O:19][CH2:20][CH2:21][CH2:22][CH3:23].[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.[K].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:6]([CH2:17][N:28]1[C:24](=[O:34])[C:25]3[C:26](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:27]1=[O:29])=[C:5]2[O:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCOc1c(CCl)n(CC2CC2)c(=O)c2ccc(Br)cc12
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOc1c(CN2C(=O)c3ccccc3C2=O)n(CC2CC2)c(=O)c2ccc(Br)cc12
Yield: 92.1 %

Procedure:
A solution of 6-bromo-4-butoxy-3-chloromethyl-2-cyclopropylmethyl-1(2H)-isoquinolinone (5.58 g, 14 mmol) and potassium phthalimide (3.89 g, 21 mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 5 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from tetrahydrofuran-n-hexane to give 2-[(6-bromo-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl]-1H-isoindole-1,3(2H)-dione (6.57 g, 94.7%) as crystals.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].[C:10]([CH2:12][O:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[N:22]=[CH:21][CH:20]=[CH:19]2)#[N:11]>O.C(O)C>[N:22]1[C:23]2[C:18](=[CH:17][CH:16]=[CH:15][C:14]=2[O:13][CH2:12][C:10](=[N:2][OH:3])[NH2:11])[CH:19]=[CH:20][CH:21]=1
Reactant: NO
Reactant: N#CCOc1cccc2cccnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NC(COc1cccc2cccnc12)=NO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 6.4 g of hydroxylamine hydrochloride in 10 ml of water and 6.4 g of potassium carbonate in 10 ml of water is added dropwise at room temperature, within 15 minutes, to 15.8 g of 8-(cyanomethoxy)-quinoline in 100 ml of ethanol, in the course of which the reaction mixture warms up to 30° C. After 3 hours' stirring at room temperature, the reaction mixture is diluted with 250 ml of water; it is subsequently filtered, and the residue is washed with water and dried. There is thus obtained 2-(8-quinolinoxy)-acetamide oxime in the form of light-brown powder, m.p. 201°-204° C. (decomposition).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]([CH3:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][CH:6]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.O>[CH3:3][N:4]([CH3:16])[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:13])([F:14])[F:15])=[CH:7][C:6]=1[Br:1]
Reactant: CN(C)c1ccc(OC(F)(F)F)cc1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CN(C)c1ccc(OC(F)(F)F)cc1Br
Reaction time: 1 h

Procedure:
Bromine (0.15 ml) was added dropwise to a stirred, cooled (0° C.) mixture of 1-dimethylamino-4-(trifluoromethoxy)benzene (Description 77, 600 mg) and sodium carbonate (620 mg) in chloroform (15 ml). The mixture was stirred for 1 h. and diluted with water. The organic layer was washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with hexane/EtOAc (99:1 increasing to 95:5) to give the title compound as an oil (300 mg). 1H NMR (360 MHz, CDCl3) δ2.79 (6 H, s), 7.06 (1 H, d, J 9 Hz), 7.14 (1 H, dd, J 6, 1.5 Hz), and 7.44 (1 H, d, J 2.0 Hz). m/z (ES+) m/z 270, 272 (M+1).
Reaction SMILES: [C:1]([CH:3]([NH:9][CH:10]=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[C:12](#[N:15])[CH:13]=[CH2:14].FC(F)(F)C(O)=O>ClCCCl>[NH2:2][C:1]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N:9][CH:10]=[CH:14][C:13]=1[C:12]#[N:15]
Reactant: C=CC#N
Reactant: CCOC(=O)C(C#N)NC=O
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1nccc(C#N)c1N
Yield: 20.9 %

Procedure:
A stirred solution of ethyl 2-cyano-2-(formyl-amino)acetate (J. Org. Chem., 1979, 44, 3835; 0.47 g, 0.003 mol), acrylonitrile (1.2 ml, 0.018 mol) and tri-fluoroacetic acid (0.02 ml, 0.0003 mol) in 1,2-dichloroethane (4 ml) was heated under reflux for 3 days. The solvent was removed by evaporation under vacuum, the residue dissolved in dichloromethane (30 ml) and the resulting solution washed with saturated aqueous sodium bicarbonate solution (30 ml). The aqueous phase was washed with dichloromethane (30 ml) and the organic solutions then combined, dried (MgSO4) and evaporated under vacuum. Chromatography of the residue on silica gel (12 g), eluting with dichloromethane:methanol (100:1), followed by crystallization from acetone:hexane, gave the title compound as a colourless solid (0.12 g, 21%), m.p. 114-116° C.
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[C:19]([O:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[CH2:35][OH:36])=[O:25])([CH3:22])([CH3:21])[CH3:20].C(P(CCCC)CCCC)CCC.O[C:51]1[CH:83]=[CH:82][C:54]([CH2:55][CH:56]2[S:60][C:59](=[O:61])[N:58]([C:62]([C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)([C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C:57]2=[O:81])=[CH:53][CH:52]=1>O1CCCC1.CN(C)C=O>[C:19]([O:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]1[CH2:35][O:36][C:51]1[CH:83]=[CH:82][C:54]([CH2:55][CH:56]2[S:60][C:59](=[O:61])[N:58]([C:62]([C:75]3[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=3)([C:69]3[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=3)[C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[C:57]2=[O:81])=[CH:53][CH:52]=1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CC1CO
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1c2ccccc2CC1COc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 20.4 %

Procedure:
A solution of 6.6 g of 1,1'-(azodicarbonyl)dipiperidine in 10 ml of anhydrous tetrahydrofuran and 20 ml of anhydrous dimethylformamide was added dropwise to a mixture of 6.5 g of 1-t-butoxycarbonyl-2-hydroxymethylindoline (prepared as described in Preparation 3), 6.5 ml of tributylphosphine, 12.2 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione [prepared as described in European Patent Publication No. 549 365A1] and 100 ml of anhydrous tetrahydrofuran, and the resulting mixture was stirred at room temperature for about 20 hours. At the end of this time, insoluble materials were filtered off and the filtrate was concentrated by evaporation under reduced pressure. The concentrate thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.70 g of the title compound, melting at 85.4-87.2° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])[CH2:4][CH2:5]O)[CH3:2].C(N(S(F)(F)[F:26])CC)C.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH2:1]([N:3]([CH2:7][CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])[CH2:4][CH2:5][F:26])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCN(CCO)CCN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CCN(CCF)CCN1C(=O)c2ccccc2C1=O
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
To a solution of compound 3 (100 mg, 0.38 mmol) in dimethoxyethane (DME, 7 mL) was added at −50° C., under argon, (diethylamino)sulfur trifluoride (DAST, 100 μL, 0.76 mmol). The mixture was stirred at −50° C. for 10 min and then at room temperature for 1.5 h. Dichloromethane (5 mL) and a saturated aqueous sodium carbonate solution (5 mL) were then successively added. The organic layer was dried on magnesium sulfate, filtered and evaporated under vacuum. The residue was chromatographed (SiO2, AcOEt/pentane, 1/1, v/v) to give compound 21 (51 mg, 0.19 mmol) as a white solid. Yield 50%; Rf (SiO2, AcOEt/pentane, 1/1, v/v) 0.53; mp 57-59° C.; IR (KBr) ν 1023, 1403, 1715, 1769, 2700-3000 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.00 (t, 3H, J=7.1 Hz), 2.68 (q, 2H, J=7.1 Hz), 2.86 (m, 4H), 3.78 (t, 2H, J=6.6 Hz), 4.47 (td, 2H, 2JH-F=47.5 Hz, J=5.1 Hz), 7.70 (m, 2H), 7.83 (m, 2H); MS m/z 264 (M+, 1), 104 (100), 76 (38), 56 (18).
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]21[CH2:18][CH2:17][CH:16]([OH:19])[CH2:15][CH2:14]2)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>O>[CH3:26][S:27]([O:19][CH:16]1[CH2:17][CH2:18][C:6]2([CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:5]2[NH:4][C:1](=[O:3])[CH3:2])[CH2:14][CH2:15]1)(=[O:29])=[O:28]
Reactant: CC(=O)NC1c2ccccc2CC12CCC(O)CC2
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NC1c2ccccc2CC12CCC(OS(C)(=O)=O)CC2
Temperature: 0 °C

Procedure:
To an ice cold solution of 1.21 g. of 1'-acetamidospiro(cyclohexane-1,2'-indan)-4-ol (isomer B)[27] (prepared in Example 61B) in 12 ml. of pyridine, 1.2 ml. of methane sulfonyl chloride is added. After about 5 hours in the cold the mixture is poured into ice: water. The solid that precipitates is recrystallized from acetone: Skellysolve B to give 1.21 g. of 1'-acetamidospiro(cyclohexane-1,2'-indan-4-ol methanesulfonate (isomer B)[28], melting at 161° to 163° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>O.C(O)(C)C>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)c1ccc(OC(=O)c2ccccc2)cc1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
138.1 g (1.0 mol) of para-hydroxybenzoic acid were first dissolved in 400 ml of water and 600 ml of isopropanol and this solution was admixed at 0 to 5° C. with 235.7 g of KOH solution (50% strength by weight aqueous solution, 2.1 mol). The resulting pH was 14. Metered into this solution over the course of one hour, then, at 0 to 5° C., were 140.4 g (1.0 mol) of benzoyl chloride, and the batch was stirred for 30 minutes at 0 to 5° C. thereafter. At the end of the after-stirring, the pH of the reaction mixture was 9.3. The reaction mixture was subsequently adjusted to a pH of 8 at 0 to 5° C. using 25.0 g of HCl solution (32% strength by weight aqueous solution), and the complete solution was heated to 55 to 60° C. and then adjusted to a pH of 1.5 to 3 using 100 g of HCl solution (32% strength by weight aqueous solution). The reaction mixture was cooled to 20 to 25° C. and the solid was filtered off on a suction filter and washed ten times with 150 ml of water. The yield after drying under reduced pressure at 100° C. was 220.5 g (91.0% of theory). According to HPLC and NMR measurement, the product was free from benzoic acid and from unreacted para-hydroxybenzoic acid. The purity of the product is >99.9% by weight.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[CH:3]=1.C([Li])CCC.[B:18](OC)([O:21]C)[O:19]C.Cl>CCCCCC.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([B:18]([OH:21])[OH:19])[CH:6]=[CH:5]2
Reactant: Brc1ccc2cc(Br)ccc2c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc2cc(Br)ccc2c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 35 %

Procedure:
First, 5.0 g of 2,6-dibromonaphthalene was placed into a 500-mL three-neck flask, and the air in the flask was replaced with nitrogen. To this compound was added 200 mL of tetrahydrofuran (THF), and this solution was stirred at −78° C. for 20 minutes. Then, 12 mL of a 1.7M hexane solution of n-butyllithium (n-BuLi) was dripped into this mixture solution, followed by stirring at −78° C. for 2 hours. After the predetermined time had elapsed, 3.5 mL of trimethyl borate was added to the mixture and this solution was stirred for 18 hours while the temperature was raised to room temperature. After the predetermined time had elapsed, 80 mL of 1.0M hydrochloric acid was poured into this solution, and the mixture was stirred for 1 hour. Then, the mixture solution was separated into an organic layer and an aqueous layer. Organic substances were extracted with ethyl acetate from the obtained aqueous layer. The solution of the extract was combined with the organic layer that had been first obtained, and the mixture was washed with saturated brine and dried by addition of anhydrous magnesium sulfate. Then, the filtrate obtained by gravity filtration was concentrated to give a white solid. The obtained white solid was washed with ethanol, whereby 6-bromonaphthalene-2-boronic acid was obtained (as a white powder in 35% yield). The synthesis scheme of Step 1 is illustrated in the following (a-4).
Reaction SMILES: [CH3:1][CH:2]([CH:6]=[CH2:7])[C:3]([OH:5])=[O:4].[Cl:8][CH2:9][CH2:10]O>C(OCC)C.CC1C=CN=C(N)C=1C>[Cl:8][CH2:9][CH2:10][O:4][C:3](=[O:5])[CH:2]([CH3:1])[CH:6]=[CH2:7]
Reactant: OCCCl
Reactant: C=CC(C)C(=O)O
Agent: Cc1ccnc(N)c1C
Solvent: CCOCC
Product: C=CC(C)C(=O)OCCCl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.1 %

Procedure:
45.1 g (0.45 mol) of 2-methyl-3-butenoic acid, 45.33 g (0.56 mol) of 2-chloroethanol and 4.1 g (34 mmol) of dimethyl-aminopyridine were placed in 450 ml of diethyl ether under argon. 102.2 g (0.495 mol) of N,N-dicyclohexylcarbodiimide were added thereto in 5 portions at 0° C. within 30 minutes, the mixture was stirred at room temperature for a further 2 hours and the separated urea was filtered off. The filtrate was washed in succession with 200 ml of 0.5N aqueous hydrochloric acid, 100 ml of saturated sodium bicarbonate solution and 100 ml of saturated sodium chloride solution. The organic solution was dried over anhydrous 2 0 sodium sulphate and, after concentration, the product was distilled on a Vigreux column (20 cm) at 80°-81° C./10 mbar. This gave 62.3 g (83% yield) of 2-methyl-but-3-enoic acid 2-chloroethyl ester as a colourless oil with a content of 97.5% according to GC.