Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9]C1C=CNC(=O)N=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C@@H]1O[C@H](COC(=O)C)[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@H]1NC(=O)C(F)(F)F)(=O)C.Cl[Sn](Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>O>[C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1cc[nH]c(=O)n1)c1ccccc1
Agent: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](NC(=O)C(F)(F)F)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: O
Product: NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of N-benzoylcytosine (29.11 g, 135.40 mmol) in 250 mL of distilled CICH2CH2Cl was added 66.80 ml (270.82 mmol) of BSA. This suspension was heated to a gentle reflux for 40 min during which time a clear solution was effected. At this time, the solution was cooled to room temperature and 20 g (45.15 mmol) of 2-deoxy-2-[(trifluoro-acetyl)amino]-β-D-glucopyranose-1,3,4,6-tetraacetate was add followed by a solution of 100 mL of CICH2CH2Cl containing freshly distilled SnCl4 (15.17 mL, 135.42 mmol). This resulting slightly yellow solution was refluxed for 2 h. At this time, the reaction was cooled to room temperature and 57 g of NaHCO3 was added and stirred before the addition of 22 mL of H2O. The mixture was stirred for an additional 20 min at room temperature. The suspension was filtered and washed through a pad of celite with CHCl3. The filtrate was washed with saturated, aqueous NaHCO3 and brine. The organic layer was further treated with charcoal before filtration through a pad of celite. The filtrate was dried over Na2SO4, filtered and concentrated in vacuo to a yellowish foam. This residue was chromatographed on silica gel eluted with CH2Cl2 and 1 to 3.5% CH3OH/CH2Cl2. The product was further purified by recrystallization from CH3OH/H2O. As a single crop of white crystals the desired glycosylation product, N- [1,2-dihydro-2-oxo- 1-[3,4,6-tri-O-acetyl-2-deoxy-2-[(trifluoroacetyl)amino]-β-D-glucopyranosyl]]-4-pyrimidinyl]benzamide was obtained (9.22 g, 34%). 1H NMR: (CDCl3): δ anomeric H-1 6.21 (d, 1H), acetyl ester 2.06 (s, 3H), acetyl ester 1.82 (s, 3H). FAB-MS: m/z 599 for (M+1)+, 1197 for (2M+1)+. Microanalysis: calculated for C25H25N4 O10C 50.17, H 4.21, N 9.36; found: C 50.01, H 4.00, N 9.16.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[C:23]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][NH2:39])=[CH:34][CH:33]=1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].O>CN(C=O)C>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:39][CH2:38][C:35]2[CH:36]=[CH:37][C:32]([CH2:31][NH:30][C:23](=[O:24])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[CH:33][CH:34]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(CN)cc1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(CNc2c([N+](=O)[O-])c(Cl)nc3ccccc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
A solution of 2,4-dichloro-3-nitroquinoline (11.4 g, 47.1 mmol) in DMF (200 mL) was cooled to 0° C. Triethylamine (19.6 mL, 0.141 mol) and 1-(N-Boc-aminomethyl)-4-(aminomethyl)benzene (13.3 g, 56.5 mmol) were sequentially added, and the reaction was stirred for one hour and cooled again to 0° C. Water (300 mL) was added, and the mixture was stirred for 30 minutes at 0° C. and then extracted with dichloromethane. The dichloromethane fraction was concentrated under reduced pressure to provide 20 g of tert-butyl 4-{[(2-chloro-3-nitroquinolin-4-yl)amino]methyl}benzylcarbamate as a red oil.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]([CH3:15])[CH3:14])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[NH2:18][C:19]1[C:27]2[C:23](=[N:24][S:25][N:26]=2)[CH:22]=[CH:21][CH:20]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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].CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.C1C=CC([C]2[C](C3C=CC=CC=3)[C](C3C=CC=CC=3)[C](C3C=CC=CC=3)[C]2C2C=CC=CC=2)=CC=1.[Fe]>[CH3:14][N:13]([CH3:15])[CH:10]1[CH2:11][CH2:12][N:8]([C:6]([C:5]2[CH:16]=[CH:17][C:2]([NH:18][C:19]3[C:27]4[C:23](=[N:24][S:25][N:26]=4)[CH:22]=[CH:21][CH:20]=3)=[CH:3][CH:4]=2)=[O:7])[CH2:9]1
Reactant: Nc1cccc2nsnc12
Reactant: CN(C)C1CCN(C(=O)c2ccc(Br)cc2)C1
Agent: [Fe]
Agent: [Pd]
Agent: CC(C)(C)P([C]1[CH][CH][CH][CH]1)C(C)(C)C
Product: CN(C)C1CCN(C(=O)c2ccc(Nc3cccc4nsnc34)cc2)C1
Temperature: 80 °C
Yield: 23 %

Procedure:
A mixture of 1-(4-bromobenzoyl)-3-dimethylaminopyrrolidine (40 mg, 0.13 mmol), 4-amino-2,1,3-benzothiadiazole (23 mg, 0.13 mmol), potassium phosphate (27 mg, 0.13 mmol), tris(dibenzylideneacetone)dipalladium(0) (3 mg, 0.002 mmol), and CTC-Q-Phos (6 mg, 0.004 mmol) are heated to 80° C. for 16 h and concentrated in vacuo. The resultant residue is dissolved in a mixture of DMSO, methanol and water and purified by reverse-phase semi-preparative HPLC1 to give the title compound as a white powder (11 mg), identified by HPLC and mass spectral analyses. Retention Time, 1.74 min.; MS [368.6 m/e (M+H)]. 1Semi-preparative HPLC Conditions: A=0.02% TFA in water, B=0.02% TFA in acetonitrile, 10-95% B in 8 min., 34 mL/min, 50° C., 215 nm detection, Waters Xterra™ 20×50 mm column.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[C:13]([P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][S:11][C:10]=1I)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:28]1[S:29][CH:30]=[C:31]([P:41]([O:46][CH2:47][CH3:48])([O:43][CH2:44][CH3:45])=[O:42])[C:32]=1[P:33]([O:38][CH2:39][CH3:40])([O:35][CH2:36][CH3:37])=[O:34])CCC>C1COCC1.[Cu]Cl>[CH2:1]([O:3][P:4]([C:9]1[C:13]([P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][S:11][C:10]=1[C:28]1[S:29][CH:30]=[C:31]([P:41]([O:43][CH2:44][CH3:45])([O:46][CH2:47][CH3:48])=[O:42])[C:32]=1[P:33]([O:35][CH2:36][CH3:37])([O:38][CH2:39][CH3:40])=[O:34])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1scc(P(=O)(OCC)OCC)c1P(=O)(OCC)OCC
Reactant: CCOP(=O)(OCC)c1csc(I)c1P(=O)(OCC)OCC
Agent: Cl[Cu]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1csc(-c2scc(P(=O)(OCC)OCC)c2P(=O)(OCC)OCC)c1P(=O)(OCC)OCC
Temperature: 70 °C
Reaction time: 11 h
Yield: 38 %

Procedure:
In THF, 0.082 g (0.171 mmols) of the 2-iodo-3,4-bis(diethoxyphosphoryl)thiophene obtained in Example 4 and 0.009 g (0.00775 mmols) of commercially available tetrakistriphenylphosphine palladium, and 0.0014 g (0.0155 mmols) of commercially available copper(I) chloride were dissolved, to which 0.100 g (0.155 mmols) of the 2-tributylstannyl-3,4-bis(diethoxyphosphoryl)thiophene obtained in Example 5 was added at room temperature. Thereafter, the reaction mixture was heated to 70° C. and stirred for 11 hours. After the reaction, the reaction mixture was cooled down to room temperature, followed by distilling off under reduced pressure to remove the solvent, and the resulting crude product was purified with a silica gel column (ethyl acetate:methanol=15:1 to ethyl acetate:methanol=5:1) to obtain the specified substance at a yield of 0.046 g (yield: 38%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13](Cl)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].[NH2:19][C:20]1[CH:42]=[CH:41][C:23]([O:24][C:25]2[CH:40]=[CH:39][CH:38]=[CH:37][C:26]=2[O:27][C:28]([CH3:36])([CH3:35])[C:29]([NH:31][CH2:32][CH2:33][OH:34])=[O:30])=[CH:22][CH:21]=1.COC(C1C(C)=C2C(NC3C=CC(OC4C=CC=CC=4OC(C(OC(C)(C)C)=O)(C)C)=CC=3)=C(C#N)C=NN2C=1)=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:18])=[C:8]2[C:13]([NH:19][C:20]3[CH:42]=[CH:41][C:23]([O:24][C:25]4[CH:40]=[CH:39][CH:38]=[CH:37][C:26]=4[O:27][C:28]([C:29](=[O:30])[NH:31][CH2:32][CH2:33][OH:34])([CH3:35])[CH3:36])=[CH:22][CH:21]=3)=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: CC(C)(Oc1ccccc1Oc1ccc(N)cc1)C(=O)NCCO
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1C
Agent: COC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)OC(C)(C)C)cc3)c2c1C
Product: CCOC(=O)c1cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)NCCO)cc3)c2c1C
Yield: 55 %

Procedure:
Compound 433E (146 mg, 83%) was prepared from 4-chloro-3-cyano-5-methyl-pyrrolo[1,2-b]pyridazine-6-carboxylic acid ethyl ester (Example 1D) (126 mg, 0.476 mmol) and 433D (165 mg, 0.500 mmol) by a route analogous to that used for the preparation of compound 388D. It is a cream-colored crystalline solid. LCMS Found: (M+H)+=558.1
Reaction SMILES: [C:1]1([S:7][CH2:8][CH:9]([CH2:12][CH2:13][C:14]#[N:15])[C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.Cl>O1CCCC1.C(OCC)C>[C:1]1([S:7][CH2:8][CH:9]([CH2:12][CH2:13][CH2:14][NH2:15])[CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CCCC(C#N)CSc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: NCCCC(CN)CSc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2-(phenylthiomethyl)glutaronitrile (3.0 g.) in tetrahydrofuran (30 ml.) was stirred under an argon atmosphere while adding 10M borane-dimethyl sulphide complex (3 ml.), and the mixture was stirred at room temperature for 48 hours. The resulting gelatinous mass was treated with methanol (50 ml.) added over 1 hour and the mixture was stirred until a clear solution was obtained. The solution was acidified with a solution of hydrogen chloride in diethyl ether and then evaporated to dryness. The residue was partitioned between water and diethyl ether, and the aqueous phase was basified with 10N aqueous sodium hydroxide and then extracted three times with ether. The combined ether extracts were dried and then evaporated to dryness. The residue was purified by column chromatography on silica gel (150 g.) eluting with a mixture of ethyl acetate/methanol/concentrated ammonia, 6:1:0.5 (v/v) to give 2-(phenylthiomethyl)pentane-1,5-diamine characterised as the dihydrochloride, m.p. 166°-169°, after crystallisation from ethanol.
Reaction SMILES: [CH:1]([N:4]([CH:36]([CH3:38])[CH3:37])[CH2:5][CH2:6][O:7][C:8]1[CH:35]=[CH:34][C:11]([CH2:12][NH:13][C:14]2[CH:19]=[C:18]([O:20]C)[CH:17]=[CH:16][C:15]=2[CH:22]2[CH2:31][CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:32]C)[CH:28]=3)[CH2:23]2)=[CH:10][CH:9]=1)([CH3:3])[CH3:2].C(N(C(C)C)CCOC1C=CC(CNC2C=C(O)C=CC=2C2CCC3C(=CC=C(OC)C=3)C2)=CC=1)(C)C>>[CH:36]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][O:7][C:8]1[CH:35]=[CH:34][C:11]([CH2:12][NH:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[CH:22]2[CH2:31][CH2:30][C:29]3[CH:28]=[C:27]([OH:32])[CH:26]=[CH:25][C:24]=3[CH2:23]2)=[CH:10][CH:9]=1)([CH3:37])[CH3:38]
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCc1ccc(OCCN(C(C)C)C(C)C)cc1)C2
Agent: COc1ccc2c(c1)CCC(c1ccc(O)cc1NCc1ccc(OCCN(C(C)C)C(C)C)cc1)C2
Product: CC(C)N(CCOc1ccc(CNc2cc(O)ccc2C2CCc3cc(O)ccc3C2)cc1)C(C)C
Yield: 43.8 %

Procedure:
Synthesized from [4-(2-diisopropylaminoethoxy)benzyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (70 mg) according to an analogous synthetic method to Example 111, 3-[4-(2-diisopropylaminoethoxy)benzylamino]-4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenol (25 mg) and 6-{2-[4-(2-diisopropylaminoethoxy)benzylamino]-4-hydroxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-ol (29 mg) were obtained. 3-[4-(2-Diisopropylaminoethoxy)benzylamino]-4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenol:
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.[CH:24]([C@H:26]1[CH2:31][CH2:30][C@H:29]([C:32]([O:34]C)=[O:33])[CH2:28][CH2:27]1)=O.C([BH3-])#N.[Na+].O>CO>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:24][C@H:26]3[CH2:31][CH2:30][C@H:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]3)[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Reactant: COC(=O)[C@H]1CC[C@H](C=O)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)[C@H]1CC[C@H](CN2CCC(CN[C@@H]3C[C@H]3c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (250 mg, 0.766 mmol) in methanol (20 mL) was added trans-methyl 4-formylcyclohexanecarboxylate (130 mg, 0.766 mmol) and the reaction mixture was heated for 2 minutes to reflux. After cooling to room temperature, sodium cyanoborohydride (96 mg, 1.532 mmol) was added and the reaction mixture was stirred for 1 hour. Water (40 mL) was added. The reaction mixture was concentrated. 50 mL of ethyl acetate was added. The layers were separated. The organic layer was washed with water, brine, dried over MgSO4, filtered and evaporated. The oil was purified by preparatory HPLC (10 to 60% AcCN:water with 0.1% formic acid as modifier. Fractions were combined and evaporated. The resulting oil was dissolved in 10 ml of methanol and 5 mL of 1 M NaOH was added portion wise. The solution was stirred for 1 hour until no protected product was visible by LC-MS. The solution was concentrated, and injected on preparatory HPLC (2 to 20% AcCN:water with 0.1% formic acid as modifier. Fractions were combined 6 M HCl was added (12 mL) and evaporated. trans-4-((4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)methyl)cyclohexanecarboxylic acid (50 mg, 0.107 mmol, 13.98% yield) was isolated as white solid. 1H NMR (400 MHz, METHANOL-d4) δ 7.29-7.39 (m, 2H), 7.07-7.29 (m, 3H), 3.67 (d, J=12.63 Hz, 2H), 3.36 (d, J=6.82 Hz, 1H), 3.22 (d, J=6.82 Hz, 2H), 2.98-3.10 (m, 4H), 2.63 (ddd, J=3.54, 6.63, 10.29 Hz, 1H), 2.29 (tt, J=3.54, 12.25 Hz, 1H), 2.01-2.24 (m, 5H), 1.92-2.03 (m, 2H), 1.90 (dt, 1H), 1.69-1.85 (m, 2H), 1.64 (ddd, J=4.29, 6.57, 10.61 Hz, 1H), 1.51 (qd, J=3.16, 13.01 Hz, 2H), 1.33-1.45 (m, 1H), 1.03-1.25 (m, 2H); LC-MS Rt=0.50 min; MS (ESI): 371.3 [M+H]+.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]2[CH:22]=[C:21](C(C)(C)C)[C:20](O)=[C:19](C(C)(C)C)[CH:18]=2)=[O:15])[CH:6]=[C:5]([CH3:32])[CH:4]=1.[CH3:33][N:34](C)[C:35]1C=CC(N)=CC=1.C(C1C=C(N)C=C(C(C)(C)C)C=1O)(C)(C)C>>[ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([N:34]([CH3:35])[CH3:33])=[CH:21][CH:22]=2)=[O:15])[CH:6]=[C:5]([CH3:32])[CH:4]=1
Reactant: CN(C)c1ccc(N)cc1
Reactant: Cc1cc(N)nc(CCCCCC(=O)Nc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1
Agent: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Agent: Cl
Product: Cc1cc(N)nc(CCCCCC(=O)Nc2ccc(N(C)C)cc2)c1

Procedure:
The experimental protocol used is the same as that described for compound 17, N,N-dimethyl-p-phenylenediamine replacing the 2,6-di-t-butyl-4-aminophenol. Hygroscopic grey solid.
Reaction SMILES: S(O[CH:6]([CH3:35])[CH2:7][C:8]1[C:16]([C:17]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[N:18][NH:19][C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[CH:9]=1)(=O)(=O)C.[OH-].[Na+]>ClCCl.CO>[CH3:35][CH:6]1[CH2:7][C:8]2[CH:9]=[C:10]3[O:14][CH2:13][O:12][C:11]3=[CH:15][C:16]=2[C:17]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[N:18][N:19]1[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: CC(Cc1cc2c(cc1C(=NNc1ncccn1)c1ccc([N+](=O)[O-])cc1)OCO2)OS(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1c1ncccn1)OCO3
Reaction time: 1.5 h
Yield: 77.5 %

Procedure:
A mixture of 3.13 g (6.27 mmol) of the compound obtained in Step B, 60 ml of a 1:1 mixture of dichloromethane-methanol and 0.52 ml (6.90 mmol) of 50% sodium hydroxide solution was stirred at room for 1.5 h. After filtration the reaction mixture was concentrated, the residue was treated with water and recrystallized from three fold dimethylformamide containing 10% water to yield 1.96 g (77%) of the title compound; Mp.: 261-263° C.
Reaction SMILES: [F:1]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.N12CCCN=C1CCCCC2.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([O:38][CH2:39][C@H:40](O)[CH2:41][O:42][C:43]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[C:34]([CH:37]=1)[C:35]#[N:36].[OH-].[Na+]>C1(C)C=CC=CC=1>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([O:38][CH2:39][C@@H:40]([F:1])[CH2:41][O:42][C:43]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[C:34]([CH:37]=1)[C:35]#[N:36]
Reactant: N#Cc1cc(Cl)ccc1OC[C@H](O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: N#Cc1cc(Cl)ccc1OC[C@@H](F)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 35 °C
Yield: 81 %

Procedure:
Perfluorobutanesulfonyl fluoride (594 g, 2.0 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (282 g, 1.85 mol) were added to an ice-cooled toluene (14.5 L) solution of 5-chloro-2-[[(2S)-2-hydroxy-3-(trityloxy)propyl]oxy]benzonitrile (580 g, 1.23 mol) at the same temperature in a nitrogen atmosphere, followed by stirring the reaction mixture at 35° C. Toluene (2.0 L) and a 1N sodium hydroxide aqueous solution (1.7 L) were added to the reaction mixture to separate an organic layer which was then washed 3 times each sequentially with the 1N sodium hydroxide aqueous solution (1.7 L) and water (1.1 L), followed by vacuum concentration. Methanol (3.3 L) was added to the resultant crude crystal, followed by heating the reaction mixture to 44° C. before cooling to room temperature. The precipitated crystal was filtered and then washed with methanol (0.75 L), followed by drying at 50° C. for 18 hours to obtain 470 g of the title compound (yield: 81%).
Reaction SMILES: C1(C)C=CC(S[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:13]=2)([CH3:11])[C:9]#[N:10])=CC=1.O.CCOCC>C(O)(=O)C.[Zn].S([O-])([O-])(=O)=O.[Cu+2]>[O:18]([C:14]1[CH:13]=[C:12]([CH:8]([CH3:11])[C:9]#[N:10])[CH:17]=[CH:16][CH:15]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ccc(SC(C)(C#N)c2cccc(Oc3ccccc3)c2)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Zn]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: O
Product: CC(C#N)c1cccc(Oc2ccccc2)c1
Yield: 91.6 %

Procedure:
417 mg of alpha-(p-tolylthio)-alpha-(m-phenoxyphenyl)propionitrile was dissolved in 4 ml of acetic acid. Zinc powder (370 mg) and 25 mg of anhydrous copper sulfate were added. The mixture was heated under reflux for 1 hour with stirring. After the cooling, 20 ml of water and 20 ml of ether were added. The insoluble matter was separated by filtration. Sodium carbonate (5 g) was added to the filtrate to neutralize the acetic acid, followed by extraction with ether (15 ml×4 times). The extract was washed with 30 ml of water three times, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The oily residue was purified by column chromatography (silica gel; hexane and methylene chloride) to afford 247 mg (yield 92%) of alpha-(m-phenoxyphenyl)propionitrile as an oil. A sample for elemental analysis was prepared by subjecting the oil to bulb-to-bulb distillation [149°-154° C. (bath temperature)/1 torr].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:16]([CH2:18][C:19]([OH:21])=[O:20])=[O:17])[CH3:15])=[CH:10][CH:9]=1.[CH2:22](N(CC)CC)C.COC(Cl)=O>C(Cl)(Cl)Cl>[CH3:22][O:20][C:19](=[O:21])[CH2:18][S:16]([CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][CH:10]=1)[CH3:15])=[O:17]
Reactant: CC(c1ccc(-c2ccccc2F)cc1)S(=O)CC(=O)O
Reactant: CCN(CC)CC
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)CS(=O)C(C)c1ccc(-c2ccccc2F)cc1
Reaction time: 0.5 h

Procedure:
306 mgm (1millimol) of [1-(2'-fluoro-4-biphenylyl)-ethylsulfinyl]-acetic acid and 0.15 ml of triethylamine were dissolved in 2 ml of chloroform, and 0.15 ml of chloroformic acid methyl ester was added to the solution at room temperature. After 30 minutes of standing, the mixture was washed with water, dried and evaporated, and the residue was recrystallized from 1 ml. of isopropanol. Yield: 200 mgm (62.5% of theory); m.p. 75°-78° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:5]=2[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C-:19]#[N:20].[K+].[I-].[K+].C(O)C>O>[Cl:18][C:16]1[CH:15]=[CH:14][C:5]2[S:6][C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[C:3]([CH2:2][C:19]#[N:20])[C:4]=2[CH:17]=1
Reactant: Clc1ccc2sc(-c3ccccc3)c(CBr)c2c1
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1c(-c2ccccc2)sc2ccc(Cl)cc12
Temperature: 52 °C
Reaction time: 0.5 h

Procedure:
13.0 Parts by weight of 3-bromomethyl-5-chloro-2-phenylbenzo[b]thiophene, 5.1 parts by weight of potassium cyanide and 1.5 parts by weight of potassium iodide are suspended in 250 parts by volume of 95% ethanol and heated at 52° C. under a nitrogen atmosphere for 22.5 hours. The reaction mixture is then diluted with 250 parts by volume of water and stirred for an additional 0.5 hour. The resulting precipitate is separated from the reaction mixture by filtration. Crystallization of this precipitate from ethyl acetate affords as a white crystalline solid 5-chloro-2-phenylbenzo[b]thiophene-3-acetonitrile, melting at 158°-160° C. This compound is represented by the following structural formula. ##STR12##
Reaction SMILES: I[C:2]1[C:3]2[N:4]([C:9]([CH2:12][CH:13]3[CH2:15][CH2:14]3)=[N:10][N:11]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:16]1([B-](F)(F)F)[CH2:18][CH2:17]1.[K+].C12(P(C34CC5CC(CC(C5)C3)C4)CCCC)CC3CC(CC(C3)C1)C2.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:16]1([C:2]2[C:3]3[N:4]([C:9]([CH2:12][CH:13]4[CH2:15][CH2:14]4)=[N:10][N:11]=3)[CH:5]=[CH:6][C:7]=2[Cl:8])[CH2:18][CH2:17]1
Reactant: Clc1ccn2c(CC3CC3)nnc2c1I
Reactant: F[B-](F)(F)C1CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Clc1ccn2c(CC3CC3)nnc2c1C1CC1
Temperature: 100 °C

Procedure:
To a mixture of D70 (0.6 g, 1.8 mmol) in toluene (14 ml) under a nitrogen atmosphere were added potassium cyclopropyltrifluoroborate (0.799 g, 5.4 mmol), bis(adamantan-1-yl)(butyl)phosphine (0.019 g, 0.054 mmol), palladium(II) acetate (8.15 mg, 0.036 mmol) and Cs2CO3 (1.758 g, 5.4 mmol). The reaction mixture was heated at 100° C. overnight. After cooling, additional potassium cyclopropyltrifluoroborate (0.7 g, 4.71 mmol), bis(adamantan-1-yl)(butyl)phosphine (0.019 g, 0.054 mmol) and palladium(II) acetate (8.15 mg, 0.036 mmol) were added to the reaction mixture, which was then heated at 100° C. for 48 h. After cooling, more potassium cyclopropyltrifluoroborate (0.35 g, 2.37 mmol) was added and heated at 100° C. for 3 days. After cooling, the reaction mixture was diluted with EtOAc and washed with water. The organic layer was separated and concentrated in vacuo. The residue was purified by column chromatography (silica gel; DCM/EtOAc from 100/0 to 60/40 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate D82 (0.217 g, 48.7%) as a yellow solid.