Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([I:9])=[CH:7][C:6]([C:10](=[O:17])[CH2:11][NH:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)=[CH:5][C:4]=1[F:18]>>[NH2:2][C:3]1[C:8]([I:9])=[CH:7][C:6]([CH:10]([OH:17])[CH2:11][NH:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)=[CH:5][C:4]=1[F:18]
Reactant: Nc1c(F)cc(C(=O)CNC2CCC2)cc1I
Agent: Cl
Product: Nc1c(F)cc(C(O)CNC2CCC2)cc1I

Procedure:
m.p. of the hydrochloride: 197°-199° C. (decomp.), was prepared from 4'-amino-2-cyclobutylamino-3'-fluoro-5'-iodo-acetophenone analogous to Example 49.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:31])C=1>C(Cl)Cl>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([S:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:31])=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cccc(Sc3ccccc3)c2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cccc(S(=O)c3ccccc3)c2s1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 38.6 %

Procedure:
To a suspension of N-ethyl-N′-[7-(phenylsulfanyl)-1,3-benzothiazol-2-yl]urea (107 mg, 0.32 mmol) in CH2Cl2 (5 mL) was added MCPBA (60 mg, 0.24 mmol, 70%). The reaction mixture was stirred at about 20° C. for about 1.5 hrs. The reaction mixture was then concentrated in vacuo. The crude reaction mixture was purified by flash chromatography on SiO2 (EtOAc/CH2Cl2 10/90). 32 mg (29%) of pure product was isolated. LC/MS 346 (MH+); RP-HPLC RT 12.96 min.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.[CH2:14]([O:16][C:17](=[O:36])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]2[C:30]([NH2:31])=[CH:29][C:28]([C:32]([CH3:35])([CH3:34])[CH3:33])=[N:27]2)[CH:21]=1)[CH3:15]>O=S(Cl)Cl.C(Cl)Cl>[CH2:14]([O:16][C:17](=[O:36])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]2[C:30]([NH:31][C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[O:13])=[CH:29][C:28]([C:32]([CH3:35])([CH3:34])[CH3:33])=[N:27]2)[CH:21]=1)[CH3:15]
Reactant: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2N)c1
Reactant: O=C(O)c1ccc2ccccc2c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)CCc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)c2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
A solution of naphthalene-2-carboxylic acid (344 mg, 2.0 mmol) in SOCl2 (10 mL) was heated to reflux for 2 h. After concentration under reduced pressure, the residue was dissolved into CH2Cl2 (5 mL) and was dropped into a solution of Example Z (315 mg, 1.0 mmol) in CH2Cl2 (10 mL) at 0° C., and was then stirred at RT overnight. After quenching with water (50 mL), the reaction mixture was extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed with brine, dried (NaSO4), filtered and concentrated under reduced pressure to yield a residue which was purified by flash chromatography to afford 3-(3-{3-t-butyl-5-[(naphthalene-2-carbonyl)-amino]-pyrazol-1-yl}-phenyl)-propionic acid ethyl ester (180 mg, 38%). 1H-NMR (CDCL3): 8.24 (s, 1H), 8.21 (s, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.88 (d, J=8.4 Hz, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.63-7.49 (m, 3H), 7.45-7.26 (m, 3H), 6.94 (s, 1H), 4.02 (q, J=7.2 Hz, 2H), 3.04 (t, J=7.6 Hz, 2H), 2.67 (t, J=7.6 Hz, 2H), 1.43 (s, 9H), 1.17 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 470 (M+H+).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)[CH:9]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[C:23]([C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][O:14][C:10]2[CH:9]=[C:8]([NH:7][S:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[Cl:25])(=[O:34])=[O:33])[CH:13]=[CH:12][CH:11]=2)=[CH:22][CH:21]=1)#[N:24]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: N#Cc1ccc(CCOc2cccc(N)c2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(CCOc2cccc(NS(=O)(=O)c3ccccc3Cl)c2)cc1
Yield: 36.6 %

Procedure:
Pyridine (0.255 mL; 3.15 mmol) was added to a stirred solution of amino-3-[2-(4-cyanophenyl)ethoxy]benzene (0.15 g; 0.629 mmol; from step (ii) above) and 2-chlorobenzenesulfonyl chloride (0.173 mL; 0.818 mmol) in CH2Cl2 (4 mL). After 45 minutes at room temperature the solvent was removed in vacuo. To remove traces of pyridine, EtOH was added and evaporated. The residue was partitioned between water and EtOAc. The organic layer was washed with 0.1M aqueous HCl and brine, dried (Na2SO4) and the solvent removed in vacuo. Purification by flash chromatography (SiO2; toluene:EtOAc (1:0 to 9:1)) afforded 0.095 g (35%) of the sub-title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([C:12]#[C:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15]2)=[CH:4][N:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([F:35])[CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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].O1CCOCC1>[F:35][C:31]1[CH:30]=[C:29]([NH:28][C:2]2[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[C:5]([C:12]#[C:13][C@@H:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15]3)=[CH:4][N:3]=2)[CH:34]=[CH:33][N:32]=1
Reactant: Nc1ccnc(F)c1
Reactant: CCCNc1nc(Cl)ncc1C#C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCCNc1nc(Nc2ccnc(F)c2)ncc1C#C[C@@H]1CCC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To tert-butyl ((1S,3R)-3-((2-chloro-4-(propylamino)pyrimidin-5-yl)ethynyl)cyclohexyl)carbamate (P1, 155 mg), 4-amino-2-fluoropyridine (89 mg), tris(dibenzylideneacetone)dipalladium(0) (36 mg), 4,5′-bis(diphenylphosphino)-9,9′-dimethylxanthene (45 mg) and cesium carbonate (381 mg), 1,4-dioxane (5 mL) was added at room temperature, the reaction vessel was sealed, and then the mixture was stirred at 150° C. for 1 hour by using a microwave reaction system. The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 88 to 30% hexane in ethyl acetate) to obtain tert-butyl ((1S,3R)-3-((2-((2-fluoropyridin-4-yl)amino)-4-(propylamino)pyrimidin-5-yl)ethynyl)cyclohexyl)carbamate (P2).
Reaction SMILES: [C:1]([C:5]1[CH:43]=[CH:42][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[CH:21]=[CH:20][C:19]([N:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=3)[C@@H:14]([C:25]3[CH:30]=[N:29][CH:28]=[CH:27][N:26]=3)[CH2:13][C@@:12]2([CH2:38][CH:39]([CH3:41])[CH3:40])[C:31]([O:33]C(C)(C)C)=[O:32])=[O:10])=[CH:7][C:6]=1[O:44][CH3:45])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([C:5]1[CH:43]=[CH:42][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[CH:17]=[CH:18][C:19]([N:22]([CH3:23])[CH3:24])=[CH:20][CH:21]=3)[C@@H:14]([C:25]3[CH:30]=[N:29][CH:28]=[CH:27][N:26]=3)[CH2:13][C@@:12]2([CH2:38][CH:39]([CH3:40])[CH3:41])[C:31]([OH:33])=[O:32])=[O:10])=[CH:7][C:6]=1[O:44][CH3:45])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1cc(C(=O)N2[C@@H](c3ccc(N(C)C)cc3)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)OC(C)(C)C)ccc1C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N2[C@@H](c3ccc(N(C)C)cc3)[C@@H](c3cnccn3)C[C@@]2(CC(C)C)C(=O)O)ccc1C(C)(C)C

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1, to afford the title compound as a solid
Reaction SMILES: CS(C)=O.CS(O[CH2:10][CH2:11][C:12]1[CH:17]=[C:16]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:15]([Cl:27])=[C:14]([Cl:28])[CH:13]=1)(=O)=O.[C-:29]#[N:30].[K+]>CCOCC>[Cl:28][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][C:29]#[N:30])[CH:17]=[C:16]([CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[C:15]=1[Cl:27]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CCOS(C)(=O)=O)cc(Cl)c1Cl
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(CCC#N)cc(Cl)c1Cl
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a DMSO (0.4 M) solution of 2-[3,4-dichloro-5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)phenyl]ethyl methanesulfonate (1 eq.) from the previous step was added potassium cyanide (1.3 eq.). The resulting solution was stirred at 80° C. for 4 h. The reaction was then diluted with ether and quenched with water. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo to give the title compound as a pink oil.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[C:20][C:21]4[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[C:23]([F:32])[CH:22]=4)[CH:17]=3)[S:12][C:11]([CH3:34])([CH3:33])[CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+].Cl>C1COCC1.CCO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[C:20][C:21]4[CH:31]=[CH:30][C:24]([C:25]([OH:27])=[O:26])=[C:23]([F:32])[CH:22]=4)[CH:17]=3)[S:12][C:11]([CH3:33])([CH3:34])[CH:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(CC)cc2)=CC(C)(C)S3)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1ccc(C2=CC(C)(C)Sc3ccc(C#Cc4ccc(C(=O)O)c(F)c4)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
To a solution of ethyl 4-[[4-(4-ethylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl]-ethynyl]-2-fluorobenzoate (Compound 237, 125.0 mg, 0.266 mmol) in 3.0 mL THF and 3.0 mL EtOH was added NaOH (120.0 mg, 3.0 mmol, 3.0 mL of a 1M aqueous solution). The resulting solution was stirred overnight at room temperature. The reaction mixture was acidified with 10% aqueous HCl and extracted with EtOAc. The combined organic layers were washed with H2O, saturated aqueous NaCl, and dried (Na2SO4) before removing the solvent under reduced pressure. The residual solid was recrystallized from CH3CN to give 100.0 mg (86%) of the title compound as a pale-yellow solid. 1H NMR (300 MHz, d6 -acetone) δ: 7.94 (1H, d J=7.8 Hz), 7.43-7.20 (9H, m), 5.93 (1H, s), 2.68 (2H, q, J=7.6 Hz), 1.47 (6H, s), 1.24 (3H, t, J=7.6 Hz).
Reaction SMILES: [CH:1]([O:14][C:15]1[C:16](=[O:43])[N:17]=[C:18]([S:22][CH:23]2[C:28]([CH3:29])=[C:27]([C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])=[O:31])[N:26]3[C:36](=[O:40])[C@H:37]([O:38][CH3:39])[C@H:25]3[S:24]2(=[O:42])=[O:41])[N:19]([CH3:21])[N:20]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[CH2:46](N(CC)CC)C>CS(C)=O.ClCCl>[CH:1]([O:14][C:15]1[C:16](=[O:43])[N:17]=[C:18]([S:22][C:23]2([CH3:46])[C:28]([CH3:29])=[C:27]([C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])=[O:31])[N:26]3[C:36](=[O:40])[C@H:37]([O:38][CH3:39])[C@H:25]3[S:24]2(=[O:41])=[O:42])[N:19]([CH3:21])[N:20]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: CO[C@H]1C(=O)N2C(C(=O)C(C)(C)C)=C(C)C(Sc3nc(=O)c(OC(c4ccccc4)c4ccccc4)nn3C)S(=O)(=O)[C@H]12
Solvent: CS(C)=O
Solvent: CI
Solvent: ClCCl
Product: CO[C@H]1C(=O)N2C(C(=O)C(C)(C)C)=C(C)C(C)(Sc3nc(=O)c(OC(c4ccccc4)c4ccccc4)nn3C)S(=O)(=O)[C@H]12

Procedure:
A solution of 2-(6-benzhydryloxy-2-methyl-5-oxo-2,5-dihydro-1,2,4-triazin-3-yl)thio-4-tert-butylcarbonyl-7α-methoxy-3-methyl-3-cephem 1,1-dioxide (550 mg), prepared as described in PTC EP 90/02189 in dimethyl sulphoxide (4 ml) was treated with methyl iodide (0.170 ml) and triethylamine (0.147 ml). After 2 hrs the reaction was diluted with dichloromethane, washed in sequence with hydrochloric acid and brine, and dried Na2SO4. Removal of the solvent and flash chromatography of the crude residue gave the title compound (300 mg) as a yellowish solid.
Reaction SMILES: [N:1]1([C:10]2[CH:11]=[C:12]([NH:16][C:17]3[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:13]=[CH:14][CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:26](OC(=O)C)(=[O:28])[CH3:27].[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>C(Cl)Cl>[C:26]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([C:10]2[CH:11]=[C:12]([NH:16][C:17]3[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:13]=[CH:14][CH:15]=2)[CH:2]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1cccnc1Nc1cccc(-n2ccc3ccccc32)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)c1cn(-c2cccc(Nc3ncccc3[N+](=O)[O-])c2)c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 103.8 %

Procedure:
A mixture of 2-[3-(indol-1-yl)phenylamino]-3-nitropyridine (1.0 g), acetic anhydride (0.46 g), and aluminum chloride (1.21 g) in dry methylene chloride (10 ml) was stirred at room temperature for 3 hours. The reaction mixture was treated with 1N sodium hydroxide solution and precipitated brown crystals were collected, washed with water and dried to give 2-[3-(3-acetylindol-1-yl)phenylamino]-3-nitropyridine (1.17 g).
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:7][CH2:6][NH:5][C:4]1=[O:8].S(C1C=CC(C)=CC=1)(O[CH2:13][C@@H:14]1[CH2:28][C@H:27]2[C@@H:17]([CH2:18][C:19]3[C:29]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]2=4)[NH:21][CH:20]=3)[N:16]([CH3:30])[CH2:15]1)(=O)=O>CN(C)C=O>[CH3:30][N:16]1[C@H:17]2[C@@H:27]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:29]=3[C:19]([CH2:18]2)=[CH:20][NH:21]4)[CH2:28][C@@H:14]([CH2:13][N:5]2[CH2:6][CH2:7][O:3][C:4]2=[O:8])[CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H]3c4cccc5[nH]cc(c45)C[C@H]3N(C)C2)cc1
Reactant: O=C1NCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C[C@H](CN2CCOC2=O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reaction time: 0.5 h
Yield: 82 %

Procedure:
0.5 g of 50% sodium hydride in an oil was added in small portions to a mixture of 2.0 g of oxazolidin-2-one and 15 ml of dimethylformamide, and the resulting mixture was stirred for 30 minutes. 2.0 g of 6-methylergolin-8β-ylmethyl tosylate was added to the mixture which was then heated on a water bath for 1 hour. The solvent was distilled off under reduced pressure, and the residue (which was dissolved in dichloromethane and adsorbed on silica gel) was purified by silica gel column chromatography (eluted with ethyl acetate:isopropyl alcohol=1:1 by volume). The product was recrystallized from isopropyl alcohol to obtain 1.3 g of the titled compound as colorless needles having a melting point higher than 240° C. (with decomposition).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]([C:5]1(C)[CH:9]=[CH:8][S:7][CH2:6]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[CH2:19](OCC)C>>[CH3:1][N:2]([CH3:11])[CH2:3][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH3:19]
Reactant: CCOCC
Reactant: CN(C)C(=O)C1(C)C=CSC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: Cc1sccc1CN(C)C
Reaction time: 1 h

Procedure:
A solution of N,N,3-trimethyl-3-thiophene carboxamide (1.3 g) in dry diethylether (50 ml) was added to a slurry of lithium aluminium hydride (0.3 g) in dry diethylether (100 ml) at room temperature. The mixture was stirred for 1 hour and then water was added. The mixture was filtered and the filtrate was evaporated to give the title compound (0.75 g) as a colourless oil. The picrate salt was formed in ethanol m.p. 155°.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]([CH:16]=1)[C:12]([O:14]C)=[O:13]>[OH-].[Na+].O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:4]([CH3:32])=[C:5]([C:23]([O:30][CH3:31])=[C:24]([O:28][CH3:29])[C:25]=1[O:26][CH3:27])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:11]([CH:16]=1)[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(Cc2c(C)c(OC)c(OC)c(OC)c2OC)ccc1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1c(C)c(Cc2ccc(-c3ccccc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.7 %

Procedure:
Methyl 5-(3,4,5,6-tetramethoxy-2-methylbenzyl)-2-phenylbenzoate (349 mg, 0.8004 mmol) was dissolved in a mixed solution of a 1N aqueous solution of sodium hydroxide (10 ml) and 1,4-dioxane (20 ml) followed by stirring at room temperature for 16 hours. The reaction solution was diluted with water (100 ml), washed with ether, acidified with concentrated hydrochloric acid and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom to give the title compound (340 mg, 0.7819 mmol, 98%).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:20][CH2:21][CH:22]1[O:26][CH2:25][CH2:24][O:23]1>C1COCC1>[C:1]1([CH2:20][CH2:21][CH:22]2[O:26][CH2:25][CH2:24][O:23]2)[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: BrCCC1OCCO1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1ccc2c(c1)Cc1c(CCC3OCCO3)cccc1-2
Reaction time: 0.33 h
Yield: 71.1 %

Procedure:
A solution of fluorene (5.04 g; 30.32 mmol) in THF (50 mL) was cooled to 0° C. and treated with n-butyllithium (12.13 mL of a 2.5M solution in hexanes; 30.32 mL). After stirring the resulting dark red mixture for 20 minutes, a solution of 2-(2-bromoethyl)-1,3-dioxolane (6.03 g; 33.35 mmol) in 20 mL of THF was added, and the resulting mixture was stirred overnight, allowing it to come to room temperature. It was quenched by the addition of saturated ammonium chloride (50 mL) and extracted into ethyl acetate (50 mL). The organic phase was washed with brine, dried and freed of solvent. The crude residue was purified on a flash chromatography column, eluting with 20% ethyl acetate in hexane, to obtain 5.74 g (72%) of the product as an oil. 1H NMR (CDCl3): δ 1.43 (m, 2H); 2.18 (m, 2H); 3.82, 3.86 (m, 2H each); 4.15 (t, 1H); 4.77 (t, 1H); 7.31 (m, 4H); 7.51 (dd, 2H); 7.68 (dd, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([S:10][C:11]#[N:12])=[CH:6][C:3]=1[C:4]#[N:5].[H+].[B-:14]([F:18])([F:17])([F:16])[F:15].[N:19]([O-])=O.[Na+]>C(O)C.O>[F:15][B-:14]([F:18])([F:17])[F:16].[C:4]([C:3]1[CH:6]=[C:7]([S:10][C:11]#[N:12])[CH:8]=[CH:9][C:2]=1[N+:1]#[N:19])#[N:5]
Reactant: O=N[O-]
Reactant: N#CSc1ccc(N)c(C#N)c1
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#CSc1ccc([N+]#N)c(C#N)c1
Yield: 95.4 %

Procedure:
To a solution of 2-amino-5-(thiocyanato)benzonitrile (2.00 g (11.4 mmol)) and 42% borofluoric acid (7.16 g (34.2 mmol)) in ethanol (10.0 ml), a solution of sodium nitrite (0.87 g (12.6 mmol)) in water (1.2 ml), was added dropwise under cooling with ice. The mixture was stirred under cooling with ice for 2 hours and crystals separated were filtered. The solid was washed with water, methanol and then ether, successively, and dried under reduced pressure to give 2.98 g (95%) of 2-cyano-4-(thiocyanato)benzenediazonium fluoroborate as white crystals.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[C:4]1=O)[CH3:2].[CH3:11][CH:12]([NH2:16])[CH2:13][O:14][CH3:15]>C1(C)C=CC=CC=1.CCOCC.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[C:4]1=[N:16][CH:12]([CH3:11])[CH2:13][O:14][CH3:15])[CH3:2]
Reactant: CCC1CCCC(C)C1=O
Reactant: COCC(C)N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCC1CCCC(C)C1=NC(C)COC
Yield: 50.2 %

Procedure:
163 g of titanium tetrachloride in 800 ml of toluene were added dropwise to a solution of 229 g (1,64 mole) of 2-ethyl-6-methylcyclohexanon and 435 g (4,9 mole) of 1-methyl-2-methoxyethylamine in 1000 ml toluene and 110 ml of ether over a period of two hours with stirring and at a temperature of between 0°-10° C. After distilling off the ether the reaction mixture was refluxed for 61/2 hours. After cooling the precipitate was filtered off and the filtrate concentrated in a rotary evaporator at 50° C. Distillation of the residue under reduced pressure gave 174 g 2-ethyl-6-methyl-N-(1-methyl-2-methoxyethyl)-cyclohexylidene-amine, m.p. 109°-113° C./15 Torr.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:7]([O:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:6]([C:24]([F:27])([F:26])[F:25])=[CH:5][CH:4]=1.[CH:28]([C:30]1[CH:35]=[C:34]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:33]=[CH:32][C:31]=1[C:41]1[CH:46]=[CH:45][C:44]([OH:47])=[CH:43][CH:42]=1)=[O:29]>>[C:20]([O:19][C:17]([O:16][C:7]1[C:6]([C:24]([F:25])([F:26])[F:27])=[CH:5][CH:4]=[C:3]([CH2:2][O:47][C:44]2[CH:43]=[CH:42][C:41]([C:31]3[CH:32]=[CH:33][C:34]([CH2:36][C:37]([O:39][CH3:40])=[O:38])=[CH:35][C:30]=3[CH:28]=[O:29])=[CH:46][CH:45]=2)[C:8]=1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:18])([CH3:21])([CH3:22])[CH3:23]
Reactant: COC(=O)Cc1ccc(-c2ccc(O)cc2)c(C=O)c1
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Product: COC(=O)Cc1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(OC(=O)OC(C)(C)C)c3C(=O)OC(C)(C)C)cc2)c(C=O)c1
Yield: 61 %

Procedure:
According to a method similar to Example (2-3), from tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (3.60 g, 8.56 mmol) obtained in Example (28-5) and methyl (2-formyl-4′-hydroxy-1,1′-biphenyl-4-yl)acetate (2.10 g, 7.78 mmol) obtained in Example (45-1), tert-butyl 2-[(tert-butoxycarbonyl)oxy]-6-[({2′-formyl-4′-[(methoxycarbonyl)methyl]-1,1′-biphenyl-4-yl}oxy)methyl]-3-(trifluoromethyl)benzoate was obtained (3.06 g, yield: 61%).
Reaction SMILES: [OH-].[K+].O.[C@@H:4]1([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[C:20]([C:26]([O:28]CC)=[O:27])[C:21](=[O:25])[O:22]3)=[CH:17][CH:16]=2)[O:12][C@H:11]([CH2:13][OH:14])[C@H:9]([OH:10])[C@H:7]([OH:8])[C@H:5]1[OH:6]>CO>[C@@H:4]1([C:15]2[CH:24]=[C:23]3[C:18]([CH:19]=[C:20]([C:26]([OH:28])=[O:27])[C:21](=[O:25])[O:22]3)=[CH:17][CH:16]=2)[O:12][C@H:11]([CH2:13][OH:14])[C@H:9]([OH:10])[C@H:7]([OH:8])[C@H:5]1[OH:6]
Reactant: CCOC(=O)c1cc2ccc([C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)cc2oc1=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2ccc([C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)cc2oc1=O
Temperature: 50 °C
Reaction time: 15 h
Yield: 97.3 %

Procedure:
A mixture of 24 g of potassium hydroxide, 80 ml of water, 240 ml of methanol, and 20 g (0.035 mol) of ethyl 7-β-galactosylcoumarin-3-carboxylate [Burd et al, Clin. Chem 23:1402(1977)] was stirred at 50° C. for 15 hours. When cool, the methanol was removed under reduced pressure. The concentrated aqueous solution was acidified to pH 2.0 with concentrated hydrochloric acid. The white precipitate was collected, washed with cold water, and recrystallized from hot water. The crystals were collected, washed with acetone, and dried at 80° C. for 1 hour. This gave 12 g (54% yield) of 7-β-galactosylcoumarin-3-carboxylic acid as white crystals, mp 250°-255° C.