Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C2C=CC(F)=CC=2)=[C:4]([C:18](=[O:26])[C:19]2[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=2)[CH:3]=1.NC1C=CC(Cl)=CC=1[C:35](C1C=CC=C(OC)C=1)=[O:36].[OH-].[Na+]>CO>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:18]([C:19]1[CH:20]=[CH:21][C:22]([O:36][CH3:35])=[CH:23][CH:24]=1)=[O:26]
Reactant: O=C(Nc1ccc(Cl)cc1C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Reactant: COc1cccc(C(=O)c2cc(Cl)ccc2N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(=O)c2cc(Cl)ccc2N)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of N-[4-chloro-2-(4-fluoro-benzoyl)-phenyl]-4-fluoro-benzamide (6.0 g, 16 mmol), prepared as described above for compound 1s, in MeOH (400 mL) was added 5N NaOH (50 mL) and the resulting solution was allowed to reflux for 16 h. The solution was cooled to room temperature and concentrated in vacuo. The aqueous portion was extracted with CH2Cl2 (2×100 mL). The combined organic portions were washed with H2O (3×50 mL), dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by column chromatography (silica gel, 5 to 25% EtOAc/hexanes) and recrystallized from MeOH to provide 1u (3.5 g, 83%) as a light yellow powder MS m/z=262 (M+H).
Reaction SMILES: [NH:1]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:2]([C:11]([N:13]1[CH2:25][CH2:24][CH2:23][C@H:14]1[C:15]([NH:17][C@@H:18]([C:20]([NH2:22])=[O:21])[CH3:19])=[O:16])=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][CH:8]([CH3:10])[CH3:9].[C:33](Cl)([O:35][CH2:36][CH:37]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:43]2[C:38]1=[CH:39][CH:40]=[CH:41][CH:42]=2)=[O:34]>C1COCC1.CCOC(C)=O>[NH:1]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:2]([C:11]([N:13]1[CH2:25][CH2:24][CH2:23][C@H:14]1[C:15]([NH:17][C@@H:18]([C:20]([NH2:22])=[O:21])[CH3:19])=[O:16])=[O:12])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]([C:33]([O:35][CH2:36][CH:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:44]2[C:49]1=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:34])[CH:8]([CH3:10])[CH3:9]
Reactant: CC(C)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C)C(N)=O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)N(CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@H](C)C(N)=O)C(=O)OCC1c2ccccc2-c2ccccc21
Yield: 79.3 %

Procedure:
A solution of Boc-Lys(iPr)-Pro-D-Ala-NH2 (9.11 gm) in 10% Na2 CO3 (25 mL) and THF (30 mL) was cooled to 0° C. and treated with a solution of Fmoc-Cl (6.46 gm) in THF. After 1 hour at 0° C. the mixture was partitioned between EtOAc (200 mL) and water (100 mL) and the layers were separated. The organic layer was washed with water (100 mL), 10% citric acid (2×100 mL) and water (100 mL), then dried over Na2SO4 and evaporated to dryness to yield an oil. The residue was dissolved in EtOAc and precipitated from heptane to yield 11.66 gm of crude product. This material was dissolved in a small in EtOAc and loaded onto a silica gel (200 gm) column which was eluted with an EtOAc/heptane mixture (2/1), followed by EtOAc and finally by ethanol. The product-containing fractions were combined and evaporated in vacuo to dryness to yield an oil. The residue was dissolved in a small amount of EtOAc and precipitated from heptane to yield 10.75 gm of Boc-Lys(iPr,Fmoc)-Pro-D-Ala-NH2. HPLC: 98.1%, MS: (M+H)+ =678, (M+NH4)+ =695, [a]D=-12.2 (c=1, HOAc)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[O:6][CH:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8](OCC)=O)[CH3:2].[CH2:24]([NH2:27])[CH2:25][NH2:26].C[Al](C)C.O>C1(C)C=CC=CC=1.CO>[CH2:1]([O:3][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[O:6][CH:7]([C:8]1[NH:26][CH2:25][CH2:24][N:27]=1)[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccccc1)Oc1ccccc1OCC
Reactant: NCCN
Agent: C[Al](C)C
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOc1ccccc1OC(Cc1ccccc1)C1=NCCN1
Temperature: 25 °C

Procedure:
A mixture of 6.28 g (0.02 m) of ethyl 2-(2-ethoxy-phenoxy)-3-phenylpropionate, 1.93 g (0.033 m) ethylenediamine and 150 ml of dry toluene was stirred at room temperature and 17 ml of a 2 m solution of trimethylaluminum in toluene was added dropwise. After stirring 10 minutes, the mixture was heated at reflux for 3 hours, then cooled in an ice bath. Water (10 ml) was added followed by 20 ml methanol and the mixture heated on a steam bath for 0.5 hours. Solids were filtered and the solvent evaporated. The solid residue was recrystallized from cyclohexane to give 3.53 g, melting point 95-97° C. Anal., Calcd. for C19H22N2O2 : C=73.52; H=7.14; N=9.0,
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])=[N:4][CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[NH2:37][OH:38].O>CO.O>[CH3:20][C:19]1[C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][CH:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]2[CH2:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]([NH:37][OH:38])=[NH:26])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: NO
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1cccc(C#N)c1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1cccc(C(=N)NO)c1
Yield: 87.7 %

Procedure:
To a solution of 3-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzonitrile (0.117 g, 0.31 mmol) in MeOH (3.0 mL)was added Et3N (0.14 mL, 1.00 mmol) followed by NH2OH.H2O (0.070 g, 1.01 mmol). The resultant mixture was stirred at room temperature overnight. The mixture was diluted with water (5 mL) and extracted with CH2Cl2 (5×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2—CH3OH—NH4OH) provided 113 mg (88%) of COMPOUND 71 as a white solid. 1H NMR (CDCl3) δ 1.50-1.72 (m, 3H), 1.94-2.19 (m, 3H), 2.40 (s, 6H), 3.40 (s, 2H), 3.97 (d, 2H, J=9.3 Hz), 5.75 (br s, 2H), 6.37 (d, 1H, J=7.5 Hz), 6.71 (dd, 1H, J=7.5, 7.5 Hz), 6.89 (dd, 2H, J=7.5, 4.8 Hz), 7.19 (d, 1H, J=8.1 Hz), 7.26-7.29 (m, 2H), 7.42 (s, 1H), 8.30 (d, 2H, J=3.9 Hz); ES-MS m/z 416 (M+H).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH2:6][C:7](=O)[CH2:8][CH2:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1>CCO>[NH2:1][C:2]1[S:3][CH:6]=[C:7]([CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][CH:20]=2)[N:4]=1
Reactant: CCOC(=O)c1ccc(CCC(=O)CBr)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: CCOC(=O)c1ccc(CCc2csc(N)n2)cc1

Procedure:
Thiourea (374 mg, 4.9 mmol) and 21-2 (1.4 g, 4.7 mmol) were combined in 24 mL EtOH and heated to reflux for 1 h. Concentration and flash chromatography (silica, 80% EtOAc/hexane then 10% MeOH/EtOAc) provided 21-3 as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([OH:15])=O.[OH:16][C:17]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]([N:20]1[CH2:19][CH2:18][C:17]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([OH:16])[CH2:22][CH2:21]1)=[O:15]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1C(=O)N1CCC(O)(c2ccccc2)CC1
Temperature: 25 °C

Procedure:
5-Methyl-3-phenylisooxazole-4-carboxylic acid (40 mg, 0.197 mmol), 4-hydroxy-4-phenylpiperidine (28.8 mg, 0.151 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (37.7 mg, 0.197 mmol) and triethylamine (59.8 mg, 0.591 mmol) were mixed in dichloromethane (2 mL) and stirred at room temperature over night. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C22H22N2O3: 362.1630, found 362.1627.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH2:14](I)[CH3:15]>>[CH2:14]([S:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)[CH3:15]
Reactant: CCOC(=O)Cc1ccc(S)cc1
Reactant: CCI
Product: CCOC(=O)Cc1ccc(SCC)cc1

Procedure:
Alkylation of ethyl (4-mercaptophenyl)acetate (20 g, 102 mmol) with EtI (9.8 mL, 122 mmol), using a similar procedure to that described in Preparation 39, furnished ethyl (4-ethylsulfanylphenyl)acetate: m/z (ES+)=225.2 [M+H]+. Oxidation of this compound (22.6 g, 101 mmol) with mCPBA (222 mmol), employing a protocol similar to that described in Preparation 22, provided the title compound: m/z (ES+)=298.2 [M+MeCN+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[F:34][C:35]([F:39])([F:38])[CH2:36][NH2:37].C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20]([NH:37][CH2:36][C:35]([F:39])([F:38])[F:34])(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: NCC(F)(F)F
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)NCC(F)(F)F)c3)n2)n1
Yield: 41.9 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.465 g, 0.951 mmol) by treatment with commercially available 2,2,2-trifluorethylamine [CAS-no. 753-90-2] (0.15 ml, 1.9 mmol) and triethylamine (1.33 ml, 9.51 mmol) in THF (5 ml) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.220 g, 46%) as an off-white solid. MS (ISP) 552.2 [(M+H)+]; mp 198° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12]([C:22](OC2C=CC=CC=2)=[O:23])C(=O)OC2C=CC=CC=2)[CH:7]=1.[CH3:50][N:51]([CH3:62])[CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][CH:57]([NH:60][CH3:61])[CH2:56][CH2:55]1>CN(C)C=O>[CH3:50][N:51]([CH3:62])[CH2:52][CH2:53][N:54]1[CH2:55][CH2:56][CH:57]([N:60]([CH3:61])[C:22]([NH:12][C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:31]=[CH:32][C:33]([NH:34][C:35]([C:37]4([C:40]([NH:41][C:42]5[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=5)=[O:49])[CH2:38][CH2:39]4)=[O:36])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)=[O:23])[CH2:58][CH2:59]1
Reactant: CNC1CCN(CCN(C)C)CC1
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Solvent: CN(C)C=O
Product: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)c(F)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 65.7 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (2.0 ml) was added N-[1-(2-dimethylaminoethyl)piperidin-4-yl]-N-methylamine (69.5 mg), followed by stirring at room temperature for 22 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:3, and the precipitate was collected by filtration. This was washed with hexane and dried under aeration to provide the titled compound as white powder (31.4 mg, 65.9%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[F:30])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Br:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:22]([F:30])[CH:23]=1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Reactant: COc1cc(Br)c2cn[nH]c2c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(Br)c2cnn(-c3ccc(OCc4ccccc4)c(F)c3)c2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 46.8 %

Procedure:
To a solution of 4-bromo-6-(methyloxy)-1H-indazole (200 mg, 0.88 mmol) in dichloromethane (10 mL) was added 4-benzyloxy-3-fluorobenzeneboronic acid (433 mg, 1.76 mmol), pyridine (0.14 mL, 1.73 mmol), copper acetate (239 mg, 1.32 mmol) and powdered 4A molecular sieves (500 mg). The reaction mixture was stirred at room temperature in the presence of air for 3 days. Celite was added to the mixture then the mixture was filtered through a pad of celite and then the filtrate concentrated in vacuo. The product was purified by silica gel chromatography eluting with 5-80% dichloromethane in hexane to yield the title compound (D3) (176 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[C:9](OC)=[O:10].[NH3:21]>CO>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]([NH2:21])=[O:10])=[CH:15][CH:16]=1
Reactant: COC(=O)C(Oc1ccc(C)cc1)c1ccccc1Cl
Reactant: N
Solvent: CO
Product: Cc1ccc(OC(C(N)=O)c2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of 0.700 g (2.41 mmol) of methyl 2-(2-chlorophenyl)-2-(4-methylphenoxy)acetate (Example 4, Step B) in 10 mL of methanol, stirred at 0° C. (ice-bath) was added anhydrous NH3 for 45 minutes. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was then concentrated in vacuo and afforded 0.658 g (99%) of title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4C=CC=[CH:24][N:23]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:4][N:3]=1.OC[C:30]1N=C[N:32](C)[N:31]=1>>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[N:11]3[N:12]=[C:13]([O:20][CH2:21][C:22]4[N:23]=[CH:24][N:31]([CH3:30])[N:32]=4)[C:14]4[C:19]([C:10]3=[N:9][N:8]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:4][N:3]=1
Reactant: Cn1cnc(CO)n1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccccn4)nn23)on1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ncn(C)n4)nn23)on1

Procedure:
The title-compound was prepared from the product of Example 120 part a and 3-hydroxymethyl-1-methyl-1,2,4-triazole (prepared using the conditions of Itoh and Okongi, EP-A-421210) following the conditions described for Example 71, mp 270-271.5° C.; 1H NMR (360 MHz, CDCl3) δ 2.50 (3H, s, CH3), 3.97 (3H, s, CH3), 5.73 (2H, s, CH2), 7.31 (1H, s, Ar—H), 7.82 (1H, m, Ar—H), 7.97 (1H, m, Ar—H), 8.09 (1H, s, Ar—H), 8.31 (1H, d, J=8.6 Hz, Ar—H), 8.70 (1H, d, J=8.6 Hz, Ar—H); MS (ES30) m/e 363 [MH]+; Anal. Found. C, 55.92; H, 3.63; N, 30.16. C17H14N8O2.0.06CH2Cl2 requires C, 55.77; H, 3.87, N, 30.49%.
Reaction SMILES: C([Li])(C)(C)C.[OH:6][CH:7]([C:20]1[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:29]1([CH2:35][CH2:36][CH2:37][C:38](Cl)=[O:39])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCCCC.O1CCCC1>[C:29]1([CH2:35][CH2:36][CH2:37][C:38]([O:6][CH:7]([C:20]2[CH:21]=[C:22]([Si:25]([CH3:28])([CH3:27])[CH3:26])[O:23][CH:24]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:39])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)CCCc1ccccc1
Reactant: CCCCCCCCCCCCC(O)c1coc([Si](C)(C)C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCCCCCCCCCCCC(OC(=O)CCCc1ccccc1)c1coc([Si](C)(C)C)c1
Reaction time: 0.17 h

Procedure:
tert-Butyl lithium (a 1.7M solution in pentane; 0.47 ml, 0.79 mmol) was added dropwise to a solution of 4-(1-hydroxytridecyl)-2-trimethylsilylfuran (256.4 mg, 0.76 mmol), prepared as in Example 38, in tetrahydrofuran (5 ml) at -78° under argon. After 10 minutes, a solution of 4-phenylbutyryl chloride (145 mg, 0.79 mmol) was added. Stirring was continued at room temperature for 2 days and the mixture was quenched with water. Extraction and evaporation of the dried (magnesium sulphate) extracts gave an oil, which was purified by preparative thin-layer chromatography (20×20 cm, 1000μ silica plate; developed with 10% ethyl ether/hexane). The title ester was obtained as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[CH:8][C:9]=1[O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]
Reactant: N#Cc1cccc(O)c1
Reactant: O=Cc1ccc(F)c(F)c1
Product: N#Cc1cccc(Oc2ccc(C=O)cc2F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 3-hydroxybenzonitrile.
Reaction SMILES: Cl.Cl.[C:3]1([CH3:25])[CH:8]=[CH:7][C:6]([NH:9][CH2:10][CH:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23]C)=[C:18]([O:21]C)[CH:19]=3)[CH2:14][CH2:13][NH:12]2)=[CH:5][CH:4]=1.B(Br)(Br)[Br:27]>ClCCl>[BrH:27].[BrH:27].[C:3]1([CH3:25])[CH:4]=[CH:5][C:6]([NH:9][CH2:10][CH:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:23])=[C:18]([OH:21])[CH:19]=3)[CH2:14][CH2:13][NH:12]2)=[CH:7][CH:8]=1
Reactant: COc1cc2c(cc1OC)C(CNc1ccc(C)cc1)NCC2
Reactant: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: Br
Product: Cc1ccc(NCC2NCCc3cc(O)c(O)cc32)cc1
Reaction time: 14 h

Procedure:
1-(p-Toluidinomethyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline dihydrochloride (260 mg) was converted into the free amine compound by conventional methods. The amine compound was dissolved in anhydrous dichloromethane (10 ml) and to the solution was dropwise added at -50° C. anhydrous dichloromethane (5 ml) containing boron tribromide (340 mg). The mixture was stirred for 14 hours at the same temperature and the reaction temperature was gradually elevated to 8° C. The reaction mixture was concentrated to dryness under reduced pressure and the residue obtained was crystallized with acetone. The crystals were further recrystallized from a mixture of isopropyl alcohol and ether to give 1-(p-toluidinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline dihydrobromide, mp 211° to 213° C. The product was identified by means of comparison with an authentic sample prepared by another process by its infrared absorption spectrum and nuclear magnetic resonance spectrum.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:9]([O:11][CH:12]([Cl:14])[CH3:13])=[O:10].[Cl-].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[C:9](=[O:10])([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:11][CH:12]([Cl:14])[CH3:13]
Reactant: OC1CCCCC1
Reactant: CC(Cl)OC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(Cl)OC(=O)OC1CCCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
9.15 g of cyclohexanol was dissolved in 150 mL of methylene chloride, to which 7.4 mL of pyridine was added followed by dropwise addition of 10 mL of 1-chloroethyl chloroformate in an ice bath, and this mixture was stirred for 2 hours at room temperature. Then, a sodium chloride solution was added to the reaction mixture and the organic phase was separated therefrom. After the resultant organic phase was dried over anhydrous magnesium sulfate, the solvent was distilled out under reduced pressure to yield 18.6 g of 1-chloroethyl cyclohexyl carbonate as colorless oil. 5.00 g of this 1-chloroethyl cyclohexyl carbonate was dissolved in 150 mL of acetonitrile, to which 16.3 g of sodium iodide was added, and this mixture was stirred for one hour at 60° C. The mixture was cooled to room temperature, followed by concentration thereof under reduced pressure, and then insoluble substances were filtered out therefrom by adding diethyl ether to the residue. The resultant filtrate was concentrated under reduced pressure to yield 5.90 g of cyclohexyl 1-iodoethyl carbonate as red oil.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C([BH3-])#N.[Na+].[O:21]1CCC[CH2:22]1>ICI.C[Li]>[O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][CH2:22][OH:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: O=Cc1ccccc1Oc1ccccc1
Agent: [BH3-]C#N
Agent: [Li]C
Agent: [Na+]
Solvent: ICI
Solvent: O
Product: OCCc1ccccc1Oc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 2-phenoxybenzaldehyde (535 mg) in tetrahydrofuran (5 ml), 0.326 ml of diiodomethane and 5.4 ml of methyllithium (1.0M diethyl ether solution) were added under ice-cooling, and the reaction solution was stirred at the same temperature for 30 minutes and then at room temperature for 1 hour. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to afford a crude product as a yellow oil. To a solution of the crude product in tetrahydrofuran (5 ml), 284 mg of sodium cyanoborohydride and 0.569 ml of trifluoroborane-diethyl ether complex were added under ice-cooling, and the reaction solution was stirred at the same temperature for 50 minutes. To the reaction solution was added a saturated saline solution, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (95:5-50/50)) to afford the title compound as a colorless oil.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][OH:8])(=[O:4])[CH:2]=[CH2:3].C(N(CC)CC)C.Cl[P:17]1(=[O:22])[O:21][CH2:20][CH2:19][O:18]1>C(OCC)C>[C:1]([O:5][CH2:6][CH2:7][O:8][P:17]1(=[O:22])[O:21][CH2:20][CH2:19][O:18]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: O=P1(Cl)OCCO1
Reactant: C=CC(=O)OCCO
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C=CC(=O)OCCOP1(=O)OCCO1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
2-Hydroxyethyl acrylate (11.5 ml, 0.1 M) and triethylamine (14.6 ml) in dry diethyl ether (250 ml) were cooled to -25° C. under nitrogen as a solution of 2-chloro-2-oxo-1,3,2-dioxaphospholane (14.3 g) in dry diethyl ether was added over 20 minutes. The mixture was stirred for a further 1 hour at -20° C. and then allowed to warm to 10° C. over a further hour. The precipitate was filtered, washed with ethyl acetate (100 ml) and the combined filtrate and washings evaporated under reduced pressue to give a pale yellow oil (21 g).