Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:22]([C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[CH:21][C:20]([O:31][CH:32]([CH3:34])[CH3:33])=[C:19]([Cl:35])[C:18]=3[C:17]2=[O:36])=[C:13]([CH3:37])[CH:12]=[C:11]([CH3:38])[N:10]=1)C1C=CC=CC=1.C(O)(C(F)(F)F)=O>>[Cl:35][C:19]1[C:18]2[C:17](=[O:36])[N:16]([CH2:15][C:14]3[C:9](=[O:8])[NH:10][C:11]([CH3:38])=[CH:12][C:13]=3[CH3:37])[CH2:25][CH2:24][C:23]=2[C:22]([C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[CH:21][C:20]=1[O:31][CH:32]([CH3:34])[CH3:33]
Reactant: Cc1cc(C)c(CN2CCc3c(C(=O)N(C)C)cc(OC(C)C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(CN2CCc3c(C(=O)N(C)C)cc(OC(C)C)c(Cl)c3C2=O)c(=O)[nH]1
Yield: 82.6 %

Procedure:
A solution of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-8-chloro-N,N-dimethyl-1-oxo-7-(propan-2-yloxy)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide (90b, 16 mg, 89% yield) and TFA (1.5 mL) was stirred at room temperature for 24 hours. The volatiles were removed under vacuum and the residue was purified by preparative HPLC to give the title compound (Example 90, 11 mg, 85% yield) as a white solid. 1H NMR (700 MHz, DMSO-d6) δ 7.15 (s, 1H) 5.90 (s, 1H) 4.65-4.71 (m, 1H) 4.56 (br. s., 2H) 2.98 (s, 3H) 2.76 (s, 3H) 2.57 (br. s, 2H) 2.17 (s, 3H) 2.13 (s, 3H) 1.28 (s, 3H) 1.28 (s, 3H); MS: 446.1 [M+1].
Reaction SMILES: [Mg].[CH3:2]I.[CH3:4][N:5]1[C:11]2[CH:12]=[CH:13][C:14]([CH:16]=[O:17])=[CH:15][C:10]=2[CH2:9][CH2:8][CH2:7][CH2:6]1.[Cl-].[NH4+]>CCOCC>[CH3:2][CH:16]([C:14]1[CH:13]=[CH:12][C:11]2[N:5]([CH3:4])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:15]=1)[OH:17]
Reactant: CN1CCCCc2cc(C=O)ccc21
Reactant: CI
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(O)c1ccc2c(c1)CCCCN2C
Reaction time: 2 h

Procedure:
The Grignard reagent was prepared from 1.04 g of magnesium shavings and 2.30 ml of methyl iodide under argon in 40 ml of absolute ether. To this Grignard solution was slowly added dropwise at room temperature a solution of 4.38 g of 2,3,4,5-tetrahydro-1-methyl-1H-1-benzazepine-7-carboxaldehyde in 10 ml of ether. The reaction mixture was stirred for 2 hours. Thereafter, the mixture was hydrolyzed with saturated ammonium chloride solution, extracted with ether, washed with water and dried. After evaporation, there were obtained 4.47 g of 2,3,4,5-tetrahydro-α-methyl-1-methyl-1H-1-benzazepine-7-methanol as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1.[CH3:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>O>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:22]3[CH:23]=[CH:24][C:19]([CH3:18])=[CH:20][CH:21]=3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[O:4][N:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cc1cc(NS(=O)(=O)c2ccc(Br)cc2)on1
Solvent: O
Product: Cc1ccc(-c2ccc(S(=O)(=O)Nc3cc(C)no3)cc2)cc1
Reaction time: 24 h
Yield: 101.5 %

Procedure:
Nitrogen was bubbled through a biphasic mixture of ethanol (15 ml), toluene (15 ml) and 2M sodium carbonate solution (15 ml). N-(3-methyl-5-isoxazolyl)-4-bromobenzene sulfonamide (0.951 g, 3 mmol), 4-methylbenzeneboronic acid (0.56 g, 4 mmol) and tetrakistriphenylphosphine palladium (0) (300 mg) were added. The reaction mixture was kept at 80° C., under a N2 atmosphere for 24 h, with stirring, and was then diluted with water (50 ml) and extracted with ether (50 ml) to remove neutral impurities and excess 4-methylbenzeneboronic acid. The aqueous phase was neutralized to pH 2 using concentrated hydrochloric acid and the resultant solid was filtered. This was dried under vacuum and recrystallized using hexane/ethyl acetate giving N-(3-methyl-5-isoxazolyl)-4-(4-methylphenyl)benzenesulfonamide (1.0 g, 100% yield, m.p. 194-198° C.).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:19]([NH:21][C@H:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O>CO>[NH2:1][C@H:2]([C:19]([NH:21][C@H:22]([C:27]([O:29][CH3:30])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:8][CH:9]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccc(CNC(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1ccc(CNC(=O)OC(C)(C)C)cc1
Yield: 103.2 %

Procedure:
Cbz-Phe (4-CH2NHBoc)-Leu-OMe 79 (282 mg, 508 μmol) was dissolved in MeOH. TFA (45 μl, 607 μmol, 1.2 equiv.) was added and the mixture was bubbled through with Ar for 20 minutes. 10% Pd/C was added (50 mg) and the flask was filled with an H2 atmosphere for 3 hours. The mixture was filtered over CELITE and concentrated. The residue was dissolved in DCM and sat. aq. NaHCO3 and the aqueous layer was extracted with DCM (3×). The organic layers were dried over Na2SO4 and concentrated to yield the title compound (221 mg, quant.), which was used without further purification. 1H NMR (400 MHz, CDCl3): δ ppm 7.67 (d, J=8.6 Hz, 1H), 7.22 (d, J=8.0 Hz, 2H), 7.17 (d, J=8.1 Hz, 2H), 5.11 (s, 1H), 4.61 (td, J=8.9, 5.0 Hz, 1H), 4.28 (d, J=5.6 Hz, 2H), 3.72 (s, 3H), 3.61 (dd, J=9.0, 4.0 Hz, 1H), 3.19 (dd, J=13.7, 3.9 Hz, 1H), 2.72 (dd, J=13.7, 9.0 Hz, 1H), 1.70-1.48 (m, 3H), 1.45 (s, 9H), 1.03-0.89 (m, 6H). 13C NMR (101 MHz, CDCl3): δ ppm 173.91, 173.25, 155.77, 137.47, 136.49, 129.35, 127.56, 79.21, 56.06, 52.03, 50.13, 44.07, 41.22, 40.26, 28.23, 24.64, 22.69, 21.68.
Reaction SMILES: CO[C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:7](F)(F)F)[C:4](O)=O.[CH2:17]1OC(=O)[C:19](O)=[C:18]1O.C(O)(C(O)=O)C(O)[C:27](O)=[O:28]>>[C:11]1([C:3]2[CH:4]=[CH:19][CH:18]=[CH:17][CH:7]=2)[CH:12]=[CH:13][C:14]([CH:27]=[O:28])=[CH:15][CH:16]=1
Reactant: COC(C(=O)O)(c1ccccc1)C(F)(F)F
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: O=C1OCC(O)=C1O
Product: O=Cc1ccc(-c2ccccc2)cc1

Procedure:
The successful use of relatively unexplored LiN(Cy)2 to provide 2-hydroxytetronic acid redox compounds of high enantiomeric purity is unprecedented. Furthermore, these intramolecular Claisen condensations are applicable for construction of a wide range of optically pure 4-substituted-2-hydroxytetronic acids of known absolute configuration. Such a chiron approach becomes all the more practical since methodologies for the preparation of α-hydroxy acid precursors of known absolute configuration are available. Optically pure, but commercially unavailable α-hydroxy ester precursors, are available using Evan's chiral oxazolidinone auxiliaries, Evans et al., J. Am. Chem. Soc., 1985, 107, 4346-4348. For example, we have prepared methyl (S)-α-hydroxy-αbiphenylacetate in high optical yield (94% e.e.) from 4-biphenylacetyl chloride, Logemann, W., Hoppe-Seylers Z. Physiol. Chem., 1952, 290, 61-66, and (S)-4-isopropyloxazolidin-2-one. Treatment of the resulting oxazolidinone carboximide (76%) with LiHMDA and dibenzylperoxy dicarbonate yielded the intermediate carbonate as a single diastereomer (71%, d.e. >98%). Lithium hydroperoxide, Evans et al., Tetrahedron Lett., 1987, 28, 6141-6144, hydrolysis afforded the protected hydroxy acid (78%). Removal of the chiral auxilliary with Mg(OCH3)2, Evans et al., J. Am. Chem. Soc., supra., (0.02M; 1.1 eq) at -15° C. to -20° C. followed by deprotection via transfer hydrogenation yielded partially racemized α-hydroxy ester [(35% e.e., [α]22D +49.1° (c 1.00, MeOH)] in 61% overall yield from the oxazolidinone carboximide. Transfer hydrogenation generated the (S)-α-hydroxyacetic acid (83%), and esterification (diazomethane) yielded the methyl acetate (91%), the enantiomeric purity of which was determined by conversion to the α-methoxy-α-trifluoromethyl phenyl acetic acid (MPTA) ester with (+)-MPTA-Cl, Dale et al., J. Org. Chem., 1969, 34, 2543-2549, and observing the benzylic proton signal [1H NMR (CDCl3), 250 MHZ] at σ6.15 (s, 1H) in comparison to the ester derived from racemic hydroxy ester. The racemic methyl α-hydroxyacetate, mp 104°-105° C., was prepared by CH2N2 esterification of the racemic acid which was synthesized as follows: in situ cyanosilylation, Rasmussen et al., Organic Syntheses, 1984, 62, 196-201, [Me3SiCl, KCN, Zn(CN)2 ] of 4-biphenylcarboxaldehyde furnished trimethylsilyl cyanohydrin ether which was hydrolysed with HCl, Grunewald et al., Tetrahedron Lett., 1980, 21, 1219-1220, to the hydroxy amide (m.p. 226°-227° C.) and finally to racemic α-hydroxy acid (m.p. 201°-202° C., Lit. mp 201°-203° C.) Blicke et al., J. Am. chem. Soc., 1943, 65, 1725-1728, with KOH/MeOH in 56% overall yield.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=4)[S:15][C:8]=23)=[C:4]([F:27])[CH:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][C:37]([N:39]=[C:40]=[S:41])=[O:38]>CCO.C1(C)C=CC=CC=1>[F:27][C:4]1[CH:3]=[C:2]([NH:1][C:40]([NH:39][C:37](=[O:38])[CH2:36][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[O:29][CH3:28])=[S:41])[CH:26]=[CH:25][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[S:15][C:8]=12
Reactant: COc1cccc(Nc2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: COc1ccccc1CC(=O)N=C=S
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cccc(Nc2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5OC)cc4F)c3s2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.5 %

Procedure:
A solution of 449 (40 mg, 0.10 mmol) in 1:1 mixture of EtOH/toluene (2 mL) was treated with 2-(2-methoxyphenyl)acetyl isothiocyanate (394 mg, 2.22 mmol) and stirred at room temperature for 2 hours. The reaction mixture was then concentrated and purified by flash chromatography using the gradient 75-100% EtOAc in hexanes as an eluent, yielding 447 (15 mg, 24% yield). CDCl3 12.39 (s, 1H), 9.47 (s, 1H), 8.34 (d, J=5.7 Hz, 1H), 7.92 (dd, J=2.0, 11.8 Hz, 1H), 7.36 (m, 2H), 7.22 (m, 2H), 7.01 (m, 3H), 6.80 (s, 2H), 6.59 (d, J=7.4 Hz, 2H), 6.39 (d, J=5.6 Hz, 1H), 4.00 (s, 3H), 3.80 (s, 3H), 3.72 (s, 2H) LCMS: (M+H) 589.0
Reaction SMILES: CS([O-])(=O)=O.[CH2:6]([C@@:9]1([CH2:35][CH3:36])[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C@@H:12]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N+:11]2[C@@H:29]([CH:32]3[CH2:34][CH2:33]3)[CH2:30][O:31][C:10]1=2)[CH:7]=[CH2:8].[CH2:37]([S-:39])[CH3:38].[Na+]>>[CH2:6]([C@@:9]1([CH2:35][CH3:36])[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C@@H:12]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:11]([C@@H:29]([CH:32]2[CH2:34][CH2:33]2)[CH2:30][S:39][CH2:37][CH3:38])[C:10]1=[O:31])[CH:7]=[CH2:8]
Reactant: C=CC[C@@]1(CC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)[N+]2=C1OC[C@@H]2C1CC1
Reactant: CC[S-]
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Product: C=CC[C@@]1(CC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CSCC)C2CC2)C1=O

Procedure:
The title compound was prepared from (3S,5S,6R,8S)-8-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-cyclopropyl-8-ethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium methanesulfonate (Example 357, Step A) and sodium ethanethiolate by the method described in Example 339.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([NH:17][CH3:18])[C:14]([C:19]3[CH:24]=[CH:23]C(Cl)=[CH:21][CH:20]=3)=[N:13]2)=[O:11])=[CH:5][CH:4]=1.[OH-].[Na+].[N:30]#[C:31]Br.[CH2:33]([Cl:35])Cl>>[F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([N:12]2[CH2:16][CH:15]([N:17]([CH3:18])[C:31]#[N:30])[C:14]([C:19]3[CH:24]=[CH:23][C:33]([Cl:35])=[CH:21][CH:20]=3)=[N:13]2)=[O:11])=[CH:7][CH:8]=1
Reactant: ClCCl
Reactant: CNC1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Product: CN(C#N)C1CN(C(=O)Nc2ccc(C(F)(F)F)cc2)N=C1c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
To 4.0 g (10 mmole) of N-(4-trifluoromethylphenyl)-3-(4-chlorophenyl)-4-(N-methylamino)-4,5-dihydro-1H-pyrazole-1-carboxamide (Example 116) in 100 ml of methylene chloride was added 10 ml of 1.0M aqueous NaOH and 1.2 g (11.3 mmole) of cyanogen bromide dissolved in 5 ml of methylene chloride. After stirring overnight, the organic layer was separated, concentrated in vacuo, and triturated with diethyl ether to yield the title compound, a white solid, mp 216°-217° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[C:12]([OH:19])=[CH:11][C:10]2=[O:20])[CH:6]=[CH:7][CH:8]=1)#[N:2].[H-].[Na+].[H][H].[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[C:5]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[C:12]([OH:19])=[C:11]([C:32](=[O:33])[CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:10]2=[O:20])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: N#Cc1cccc(-n2c(=O)cc(O)c3cccnc32)c1
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(-n2c(=O)c(C(=O)Cc3ccccc3)c(O)c3cccnc32)c1
Temperature: 25 °C
Yield: 24.6 %

Procedure:
To a suspension of a mixture containing 1-(3-cyanophenyl)-4-hydroxy-1,8-naphthyridin-2 (1H)-one (958 mg, 3.64 mmol) in DMF (16 ml) was added sodium hydride (about 60%, 350 mg, 8.74 mmol, 2.4 eq.), and the mixture was stirred until the production of hydrogen was completed. Next, after phenylacetyl chloride (563 mg, 3.64 mmol, 1.0 eq.) was added, the mixture was stirred at room temperature, admixed with water, acidified with hydrochloric acid, filtered off to give precipitates which were washed with water. The resultant residue was purified by flash column chromatography to afford 1-(3-cyanophenyl)-4-hydroxy-3-(1-oxo-2-phenylethyl)-1,8-naphthyridin-2 (1H)-one (341 mg, 25%).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:28])[CH2:13][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)(O)[C:15]([F:18])([F:17])[F:16])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.S(Cl)(Cl)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12](=[O:28])[CH:13]=[C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)[C:15]([F:18])([F:16])[F:17])=[CH:10][CH:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2cncn2)cc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=C(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2cncn2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
After adding 6.00 g of toluene to 2.00 g (4.65 mmol) of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 1.11 g (9.30 mmol) of thionyl chloride and 0.74 g (9.30 mmol) of pyridine were added at 80° C., and stirred for 3 hours. The reaction solution was cooled to room temperature, and separated by adding 50 ml of chloroform and 20 ml of water. After washing the organic phase with an aqueous solution of 0.37 g of sodium hydroxide dissolved into 2.0 g of water, then the phase was washed with water. The solvent was distilled off under reduced pressure to obtain 1.58 g of 1-(4-(1H-1,2,4-triazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one (Yield 82.4%). Here, the target compound obtained in this Synthesis Example is a mixture of geometric isomers whose ratio determined by 1H-NMR was 4 to 1. 1H-NMR data of mainly produced geometric isomer are shown below.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:13](Cl)[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.CCOC(C)=O>[CH2:15]([O:14][CH2:13][N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc2[nH]cnc12
Reactant: ClCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc2c1ncn2COCc1ccccc1
Reaction time: 0.08 h
Yield: 24.2 %

Procedure:
To a solution of Intermediate 171.1 (130 mg, 0.984 mmol) in 3 mL THF at rt, was added sodium hydride (60%, 43 mg, 1.1 mmol). The mixture was stirred 5 min, then BOM-Cl (80%, 0.204 mL, 1.18 mmol) was added. The mixture was stirred at rt for 2 h, then was diluted with EtOAc, washed with H2O (2×) and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 100% EtOAc/hexanes gradient) to afford 60 mg of Intermediate 171.2.
Reaction SMILES: [C:1]1([S:7][C:8]2[C:16]([OH:17])=[CH:15][C:11]3[CH2:12][CH2:13][O:14][C:10]=3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1(CSC2C(O)=CC3CCOC=3C=2)C=CC=C[CH:19]=1>>[C:5]1([CH2:6][CH2:1][S:7][C:8]2[C:16]([OH:17])=[CH:15][C:11]3[CH2:12][CH2:13][O:14][C:10]=3[CH:9]=2)[CH:4]=[CH:3][CH:2]=[CH:19][CH:18]=1
Reactant: Oc1cc2c(cc1Sc1ccccc1)OCC2
Reactant: Oc1cc2c(cc1SCc1ccccc1)OCC2
Product: Oc1cc2c(cc1SCCc1ccccc1)OCC2

Procedure:
To a solution of 17 (3.00 g, 11.6 mmol) in dry tetrahydrofuran (50 mL) at -60° was added dropwise a solution of n-butyllithium (1.56 M in hexane, 8.25 mL, 13.0 mmol) and the mixture allowed to stir for 20 minutes. To the resulting white suspension was added dropwise a solution of diphenyl disulfide (4.00 g, 18.5 mmol) in tetrahydrofuran (20 mL) and the mixture allowed to stir for 20 minutes at -60° C. then warmed to room temperature over 40 minutes. The reaction mixture was poured into water (150 mL) and extracted with ether (3×100 mL). The combined extracts were dried (Na2SO4) and concentrated. The crude product (5.0 g) was purified by preparative HPLC using 10% ethyl acetate in hexane as eluant then directly deprotected in methanol (40 mL) containing concentrated HCl (0.25 mL) at 50° C. for 3 hours. Most of the methanol was removed in vacuo and the residue partitioned between ethyl acetate (75 mL) and water (25 mL). The organic extract was washed with an additional portion of water (25 mL), dried (Na2SO4), and concentrated. Flash chromatography using 10% ethyl acetate in hexane afforded 18a. 18a: mp 80°-81° C. Recrystallization from hexane gave an analytical sample. 2,3-Dihydro-6-phenylmethylthio-5-benzofuranol (18b); 2,3-dihydro 6 (2 phenylethyl)thio-5-benzofuranol (18c) and 2.3-dihydro-6-3-phenylpropyl)thio-5 -benzofuranol (18d) can be produced from 17 in similar fashion. 18b: mp 50°-52° C.; 18c and 18d are oils.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:26])([F:25])[CH2:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[O:17][CH2:18][CH2:19][OH:20].C(N(CC)CC)C>ClCCl>[F:11][C:12]([F:25])([F:26])[CH2:13][O:14][C:15]1[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=1[O:17][CH2:18][CH:19]=[O:20]
Reactant: OCCOc1ccccc1OCC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=CCOc1ccccc1OCC(F)(F)F
Yield: 64.1 %

Procedure:
A solution of oxalyl chloride (0.73 ml, 8 mmole) in Dichloromethane (7 ml) was cooled below −70° C. Then charged DMSO (1.2 ml) below −70° C. To the reaction mixture was added, solution of 2-[2-(2,2,2-Trifluoro-ethoxy)-phenoxy]-ethanol (XIV) (1.0 g, 4 mmole) in Dichloromethane (10 ml) over a period of 10 minutes below −50° C. Triethylamine (2.3 ml, 0.016 mole) was added below −70° C. Reaction mixture was quenched in cold water and the product was extracted with Dichloromethane (10 ml). Organic layer was washed with aqueous sodium bicarbonate solution followed by washing with water. Dried the organic layer over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (5/95) as eluent to give 0.6 g of (VIII) as colourless solid, melting at 57-58° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6](O)[C@H:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH2:3]1.[CH3:12][C:13](=[CH:15][CH2:16][CH2:17][CH:18]([CH2:20][CH:21]=O)[CH3:19])[CH3:14]>>[CH3:19][CH:18]([CH2:17][CH2:16][CH:15]=[C:13]([CH3:14])[CH3:12])[CH2:20][CH:21]=[CH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1
Reactant: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: CC(C)=CCCC(C)CC=O
Product: CC(C)=CCCC(C)CC=Cc1ccc(C(C)C)cc1
Yield: 82 %

Procedure:
To a stirred solution of sodium (21 g, 0.9 at) in 1500 ml of absolute ethanol was added 388 g of p-isopropylbenzyltriphenylphosphonium chloride. The resulting phosphorane solution was cooled to 15°-20° C. (The light orange color fades when the temperature is lowered!) Freshly vacuum distilled citronellal (150 g, 1 mol.) was added dropwise while keeping the reaction mixture at reflux for 4 hours. The cooled reaction mixture was filtered to remove sodium chloride, most of the alcohol was distilled off in vacuo and 500 ml of hexane was added. The triphenylphosphineoxide was allowed to crystallize and filtered off. The solvents were removed from the mother liquors under vacuum and another 500 ml of hexane added. Cooling afforded another crop of triphenylphosphineoxide. The hexane was again evaporated and the residue distilled yielding, after a small forerun of isopulegol (a contaminant of citronellal), 200 g (82%) of the desired product. bp. 150°-145° C/0.1 mm. Ratio of E to Z is app. 40:60. nD25 =1.5172.
Reaction SMILES: C1(C)C=CC=CC=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C@@:15]2(O)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][C@@H:16]2[O:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:11][CH:10]=1.C([N+](CC)(CC)S(NC(=O)OC)(=O)=O)C>C(OCC)(=O)C>[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C@@H:16]([O:28][C:29](=[O:34])[C:30]([CH3:31])([CH3:32])[CH3:33])[CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@](O)(c2ccc(F)cc2)[C@@H](OC(=O)C(C)(C)C)C1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)[C@@H](OC(=O)C(C)(C)C)C1
Yield: 74.5 %

Procedure:
To a toluene solution (40 mL) of tert-butyl (3S,4S)-4-(4-fluorophenyl)-4-hydroxy-3-(pivaloyloxy)piperidine-1-carboxylate (2.07 g, 5.23 mmol) synthesized in Reference Synthesis Example 130, methyl N-(triethylammoniosulfonyl)carbamate (1.74 g, 7.32 mmol) was added and the resultant mixture was stirred at 60° C. for 3 hours. After completion of the reaction, ethyl acetate was added to the reaction solution and the resultant mixture was washed with each of saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1→3/1) to obtain the title compound (1.47 g, yield 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[O:19][C:18]4[C:13](=NC=[CH:16][CH:17]=4)[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1.BrC1N2N=C(Cl)C=CC2=[N:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[O:19][C:18]4[CH:17]=[CH:16][N:23]=[CH:22][C:13]=4[CH:12]=3)=[CH:9][N:10]=2)[N:7]=1
Reactant: Clc1ccc2ncc(-c3cc4ncccc4o3)n2n1
Reactant: Clc1ccc2ncc(Br)n2n1
Product: Clc1ccc2ncc(-c3cc4cnccc4o3)n2n1

Procedure:
6-Chloro-3-(furo[3,2-c]pyridin-2-yl)imidazo[1,2-b]pyridazine was prepared in analogy to 6-chloro-3-(furo[3,2-b]pyridin-2-yl)imidazo[1,2-b]pyridazine starting from 314 mg (1.35 mmol) of 3-bromo-6-chloroimidazo[1,2-b]pyridazine to yield 62% of a solid material.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)=[O:4].[NH2:14][C:15]1[N:29]=[CH:28][C:27](Br)=[CH:26][C:16]=1[C:17]([NH:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1)=[O:18].NC1N=CC(C2SC(CN3CCCCC3)=CC=2)=CC=1C(NC1C=CN=CC=1)=O>>[NH2:14][C:15]1[N:29]=[CH:28][C:27]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[O:4])=[CH:26][C:16]=1[C:17](=[O:18])[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: Nc1ncc(-c2ccc(CN3CCCCC3)s2)cc1C(=O)Nc1ccncc1
Product: COC(=O)c1cccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)c1

Procedure:
(3-Methoxycarbonylphenyl)boronic acid and 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide are reacted analogously to “A1” step 2 to give methyl 3-[6-amino-5-(4-pyridylcarbamoyl)-3-pyridyl]benzoate.