Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)=[O:9])([CH3:4])[CH3:3].[H][H]>C(O)C.ClCCl.[Pd]>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)=[O:9])([CH3:1])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(C(=O)Nc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)c1cc(C(=O)Nc2ccc(N)cc2)cc(C(C)(C)C)c1O
Yield: 49.3 %

Procedure:
In a 250 ml Parr flask, 2.4 g (6.5 mmoles) of 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-nitrophenyl)-benzamide is dissolved in 50 ml of an absolute ethanol/dichloromethane mixture (1/1) in the presence of 10% Pd/C. The mixture is agitated under 20 PSI of hydrogen, at 30° C., for one hour. After filtration on celite, the filtrate is concentrated under vacuum. The evaporation residue is taken up in 25 ml of a 1M HCl solution. The precipitate formed is filtered and rinsed with 50 ml of diethyl ether followed by 50 ml of ethyl acetate. The amine is released from its salt by agitation in a mixture of 50 ml of ethyl acetate and 50 ml of 1M NaOH. After decanting, the organic phase is washed with 25 ml of 1M NaOH and 25 ml of brine. The organic solution is dried over sodium sulphate, filtered, rinsed and concentrated to dryness under reduced pressure to produce 1.09 g (49%) of a white powder. Melting point: 220-221° C.
Reaction SMILES: N1C=CC=CC=1.S(Cl)([Cl:9])=O.[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21]O)([O-:13])=[O:12].C1(C)C=CC=CC=1>C(Cl)(Cl)Cl>[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][Cl:9])([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccccc1CCO
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccccc1CCCl
Temperature: 0 °C
Yield: 83.3 %

Procedure:
2.1 ml abs. pyridine and 21.62 g thionyl chloride (13.3 ml,. 0.18 mol) is added to 10.13 9 2-(2-nitrophenyl)ethanol (60 mmol) in 36 ml abs. toluene. After 2 h reflux, this is cooled and poured onto ice. The ice water is mixed with 50 ml chloroform and extracted 2× each with 50 ml chloroform. The combined organic phases are neutralized 2× each with 100 ml saturated bicarbonate solution. After drying with Na2SO4, this is filtered and rotary evaporated. After distillation under high-vacuum, 9.7 9 (50 mmol,. 87%) 2-(2-nitrophenyl)ethyl chloride is obtained as a yellow oil with a boiling point of 66 to 67° C. (0.001 mbar).
Reaction SMILES: CS(C)=O.[OH-].[K+].[CH2:7]([NH:14][C:15](=[O:39])[C@@H:16]([CH2:37][OH:38])[NH:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:40]I>C1(C)C=CC=CC=1.O>[CH2:7]([NH:14][C:15](=[O:39])[C@@H:16]([CH2:37][O:38][CH3:40])[NH:17][C:18]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CI
Reactant: O=C(NCc1ccccc1)[C@@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of DMSO (8 g) and pulverized KOH (0.308 g), Example 5 product (i.e., N-benzyl-N2-trityl-D-serinamide, 2 g) was added in one lot. It was stirred for 3 hours at ambient temperature. Methyl iodide (0.97 g) was slowly added to the mixture for 15 minutes at ambient temperature and stirred for 30 minutes. The reaction mixture was cooled to 0° C., water was added to it and the product was isolated with toluene. Oily product was recovered under vacuum at 35-40° C. from the organic layer. Hexane (100 ml) was added to the oily product and the solution formed is stirred for 15 minutes, filtered and dried to get the titled product of Formula Va. Yield=1 gm.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:18][CH:19]([C:21]1[N:25]=[C:24]([CH3:26])[O:23][N:22]=1)[NH2:20].CO>CCCCCCC>[CH3:26][C:24]1[O:23][N:22]=[C:21]([CH:19]([NH:20][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[CH3:18])[N:25]=1
Reactant: Cc1nc(C(C)N)no1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Solvent: CCCCCCC
Solvent: CO
Product: Cc1nc(C(C)NC(=O)c2ccc(C3CC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and α,5-dimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153834-40-2) as starting materials. The product was isolated by chiral chromatography on Chiralpak AD using heptane/20% ethanol as eluent. The (−)-enantiomer was isolated. LC-MS (UV peak area/ESI) 98.1%, 343.1767 (M+H)+, αD20 (MeOH)=−28.2°.
Reaction SMILES: Cl[C:2](Cl)=[N:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[NH2:17][CH2:18][CH2:19][CH2:20][NH2:21].C(N(CC)CC)C>C(#N)C>[CH:10]1([C:7]2[CH:8]=[CH:9][C:4]([N:3]=[C:2]3[NH:21][CH2:20][CH2:19][CH2:18][NH:17]3)=[CH:5][CH:6]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClC(Cl)=Nc1ccc(C2CCCCC2)cc1
Reactant: NCCCN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: c1cc(C2CCCCC2)ccc1N=C1NCCCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.6 g of N-dichloromethylene 4-cyclohexylaniline in 40 ml of acetonitrile is added dropwise to a solution of 1 ml of 1,3-diaminopropane in 20 ml of acetonitrile in 15 minutes at room temperature. After the addition of 1 ml of triethylamine, the solution is stirred for 1 hour at room temperature, after which the reaction mixture is filtered while warm. After distilling off the solvent the residue is taken up in ether and successively washed with 2 N sodium hydroxide solution and water. The ether layer is dried and evaporated, after which the residue is recrystallised from acetonitrile. The resulting 2-(4-cyclohexylphenyl)imino-hexahydropyrimidine has a melting point of 180°-182° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:22])=[C:7]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][N:14]([CH3:20])[C:13]3=[O:21])[CH:8]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:34]([C:35](O)=[O:36])=[CH:33][C:32]([S:38][CH3:39])=[N:31]2)=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:34]([C:35]([NH:2][C:3]3[CH:4]=[CH:5][C:6]([CH3:22])=[C:7]([NH:9][C:10]4[CH:11]=[C:12]5[C:17](=[CH:18][CH:19]=4)[N:16]=[CH:15][N:14]([CH3:20])[C:13]5=[O:21])[CH:8]=3)=[O:36])=[CH:33][C:32]([S:38][CH3:39])=[N:31]2)=[CH:26][CH:25]=1
Reactant: Cc1ccc(N)cc1Nc1ccc2ncn(C)c(=O)c2c1
Reactant: CSc1cc(C(=O)O)n(-c2ccc(F)cc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CSc1cc(C(=O)Nc2ccc(C)c(Nc3ccc4ncn(C)c(=O)c4c3)c2)n(-c2ccc(F)cc2)n1
Reaction time: 20 h
Yield: 55.5 %

Procedure:
6-(5-amino-2-methyl-phenylamino)-3-methyl-3H-quinazolin-4-one HCl salt (110 mg, 0.28 mmol) was dissolved in DMF (5 mL) with 2-(4-fluoro-phenyl)-5-methylthio-2H-pyrazole-3-carboxylic acid (125 mg, 0.5 mmol) at RT. HATU (150 mg, 0.39 mmol) was added, followed by DIEA (0.5 mL, 2.87 mmol). The mixture was stirred for 20 h. Water (20 mL) was added and the mixture was extracted with EtOAc (30 mL). The organic layer was concentrated and the residue was dissolved in minimum amount of DMSO and purified by prep HPLC. 80 mg of title compound was obtained after lyophilization of pure fractions. LC-MS [M+H] 514.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@H:8]([NH2:11])[C@@H:7]1[C:12]([O:14][CH3:15])=[O:13].C(N(CC)CC)C.[O:29]([CH2:36][C:37](Cl)=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl.CCOCC>[CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[CH2:5][N:6]1[C:9](=[O:10])[C@H:8]([NH:11][C:37](=[O:38])[CH2:36][O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:7]1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=C(Cl)COc1ccccc1
Reactant: COC(=O)[C@H]1[C@@H](N)C(=O)N1Cc1ccc(OC)cc1OC
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1[C@@H](NC(=O)COc2ccccc2)C(=O)N1Cc1ccc(OC)cc1OC
Reaction time: 1 h
Yield: 84 %

Procedure:
The crude amine prepared in Example 2 from 10 g of the azido precursor is taken up in 100 ml of anhydrous methylene dichloride and is cooled to 0° in an ice bath. To this solution is added 4.32 ml (0.0312 mol) of triethylamine followed by the slow addition of a solution of 5.32 g (0.0312 mol) of phenoxyacetyl chloride in 40 ml of methylene dichloride. The mixture is stirred at 0° for 1 hr. then poured into a separatory funnel and extracted successively with water, aqueous HCl, aqueous NaHCO3, brine and is dried over anhydrous magnesium sulfate. After filtration the solvent is removed in vacuo to give a yellow solid. This material is partially dissolved in ether, cooled to -25° , and filtered to afford 11.2 g (84%) of the title product as a white solid which is one spot on tlc: benzene-ethyl acetate (1:1), silica gel, Rf 0.38. An analytical sample, mp 115.5°-116.0°, is obtained by recrystallization from ethyl acetate-hexane.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][C@:10]2([O:32][C@H:31]([CH2:33][O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@@H:22]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@@H:13]2[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C(O)(=O)C.[PH:53](=[O:60])([O:57][CH2:58][CH3:59])[O:54][CH2:55][CH3:56]>CCOCC>[CH2:55]([O:54][P:53]([O:57][CH2:58][CH3:59])([CH:11]([OH:12])[C@:10]1([CH2:9][O:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:32][C@H:31]([CH2:33][O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C@@H:22]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:13]1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:60])[CH3:56]
Reactant: CCO[PH](=O)OCC
Reactant: O=C[C@]1(COCc2ccccc2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOP(=O)(OCC)C(O)[C@]1(COCc2ccccc2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
A 7.20 g portion of 2,5-anhydro-2-C-[(phenylmethoxy)methyl]-3,4,6-tris-O-(phenylmethyl)-D-glucose was dissolved in 6.7 ml of phosphonic acid, diethyl ester and treated with 620 μl of triethylamine under argon. After 4.5 hours 800 μl of acetic acid was added, the resulting yellow oil taken up in ether, washed with water, saturated with hexane, rewashed with water, then twice with brine, dried and evaporated. The residual oil was flash chromatographed, eluting 75 ml fractions with ether:toluene (2:1).
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[S:15]([OH:18])(=O)=[O:16].S(Cl)(Cl)(=O)=O.[OH-].[NH4+:25]>C1(C)C=CC=CC=1.O1CCCC1.CN(C)C=O>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[S:15]([NH2:25])(=[O:18])=[O:16]
Reactant: [NH4+]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)O)c1
Agent: [OH-]
Solvent: O=S(=O)(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 2 h
Yield: 42.4 %

Procedure:
To a solution of thionyl chloride (11 mL) and 2-chloro-5-nitro-benzenesulfonic acid (4.78 g, 20.1 mmol) was added N,N-dimethylformamide (0.92 μL) and the reaction mixture was heated at reflux for 4 h. The reaction mixture was then carefully quenched by pouring it into water and the product was isolated by vacuum filtration. The sulfonyl chloride was dissolved in a minimal amount of toluene and then added to a mixture of concentrated aqueous ammonium hydroxide solution (25 mL) and tetrahydrofuran (25 mL) at −10° C. After stirring for 2 h the reaction was quenched by adding a 6.0 M aqueous hydrochloric acid solution until pH 4 was reached. The layers were separated and the organic layer was concentrated in vacuo to a slurry. Pentane was added and the product was isolated by vacuum filtration to afford 2-chloro-5-nitrobenzenesulfonamide (2.0 g, 8.48 mmol, 42.4%), as a solid. 1H NMR (400 MHz, DMSO-d6) δ: 7.94 (d, 1H, J=8.8 Hz), 7.97 (bs, 2H), 8.40 (dd, 1H, J1=8.6 Hz, J2=3.1 Hz), 8.64 (d, 1H, J=3.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9](Br)[CH:10]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:50][C:51]1[CH:52]=[C:53]([C:67]([C:72]2[CH:77]=[CH:76][C:75](/[CH:78]=[CH:79]/[C:80]([CH2:84][CH3:85])([OH:83])[CH2:81][CH3:82])=[C:74]([CH3:86])[CH:73]=2)([CH2:70][CH3:71])[CH2:68][CH3:69])[CH:54]=[C:55]([CH3:66])[C:56]=1B1OC(C)(C)C(C)(C)O1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([C:56]2[C:55]([CH3:66])=[CH:54][C:53]([C:67]([CH2:68][CH3:69])([C:72]3[CH:77]=[CH:76][C:75](/[CH:78]=[CH:79]/[C:80]([CH2:84][CH3:85])([OH:83])[CH2:81][CH3:82])=[C:74]([CH3:86])[CH:73]=3)[CH2:70][CH3:71])=[CH:52][C:51]=2[CH3:50])[CH:10]=1
Reactant: COC(=O)Cc1cncc(Br)c1
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2cc(C)c(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2cc(C)c(-c3cncc(CC(=O)OC)c3)c(C)c2)cc1C)CC
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 23.9 %

Procedure:
(5-Bromo-pyridin-3-yl)acetic acid methyl ester (Example 24-(2); 30 mg, 0.149 mmol), palladium acetate (2.2 mg, 0.010 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (8.2 mg, 0.020 mmol), potassium phosphate (63 mg, 0.297 mmol) and water (0.2 mL) were added to a solution of (E)-1-(4-{1-[3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-3-ethyl-1-penten-3-ol (Example 38-(6); 50 mg, 0.099 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for 2.5 hours. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the target compound as a colorless oil (12.5 mg, 24%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][N:14]=1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[N:14]=[CH:15][C:16]([CH2:17][OH:18])=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccc(OCc2ccc3ccccc3n2)nc1
Agent: CCOC(=O)Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: OCc1ccc(OCc2ccc3ccccc3n2)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(2-quinolylmethoxy)nicotinic acid (4.38 g, 1.56 mmol), prepared as in step 3, and triethylamine (0.228 ml, 1.64 mmol) in THF (80 ml) at -10° C. to -5° C. was added dropwise a solution of ethyl chloroformate (1.57 ml, 1.64 mmol) in THF (5 ml), and the reaction mixture was stirred at 0° C. for 1 hour. Precipitated triethylamine hydrochloride was filtered and washed with THF. The combined filtrate and washings were placed in an addition funnel and added dropwise to a mixture of sodium borohydride (1.50g, 3.91 mmol) in water (20 ml) at 0° C. When the bubbling ceased, the mixture was allowed to warm to room temperature and stir for 2 hours. 10% Citric acid added to bring the mixture to pH 3 and the aqueous layer was extracted with ethyl acetate. The organic extract was washed with 1N NaOH, water, and brine, and dried over MgSO4. The solvent was removed in vacuo and the residue treated with ethyl acetate-hexane to precipitate the product, 3.44 g of 6-(2-quinolylmethoxy)pyrid-3-ylmethanol.
Reaction SMILES: [C:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=O.[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26](=[O:28])[NH2:27])=[CH:22][C:21]=1[NH:29][C:30](=[O:48])[CH2:31][CH:32]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][C:39]=1[O:46][CH3:47])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH3:19])([CH3:18])[CH3:17]>C(#N)C.C(OCC)(=O)C>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:26]([NH:27][C:4](=[O:6])[CH2:3][CH2:2][C:1]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[O:28])=[CH:22][C:21]=1[NH:29][C:30](=[O:48])[CH2:31][CH:32]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][C:39]=1[O:46][CH3:47])[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH3:17])([CH3:18])[CH3:19]
Reactant: CCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Reactant: O=C(O)CCC(=O)OCc1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCCC(CC(=O)Nc1cc(C(=O)NC(=O)CCC(=O)OCc2ccccc2)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15 %

Procedure:
810 mg (5.0 mmol) of N,N'-carbonyldiimidazole were added to a solution of 1.04 g (5.0 mmol) of benzyl hydrogen succinate in 10 ml of acetonitrile, and the resulting mixture was stirred for 15 minutes, after which 565 mg (1.22 mmol) of N-(2-t-butyl-5-carbamoylphenyl)-3-(2,4-dimethoxyphenyl)octanamide (prepared as described in Example 2) and 610 mg (5.0 mmol) of 4-N,N-dimethylaminopyridine were added. The mixture was then heated under reflux for 4 days, after which the reaction mixture was allowed to cool to room temperature. The reaction mixture was then diluted with ethyl acetate, and the diluted solution was washed with 2 N aqueous hydrochloric acid and with 2 a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 15 g of silica gel using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 3:1 to 1:1 by volume as the eluent, to give a crude product containing the title compound. The product was further purified by column chromatography through silica gel under the same conditions as above, to give the title compound as a viscous substance in a 15% yield.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10](Cl)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:20][C:21]1([CH3:29])[CH2:26][C:25]([CH3:28])([CH3:27])[CH2:24][NH:23][CH2:22]1.[Cl-].[NH4+]>C(#N)C>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([N:23]2[CH2:24][C:25]([CH3:28])([CH3:27])[CH2:26][C:21]([CH3:29])([CH3:20])[CH2:22]2)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC1(C)CNCC(C)(C)C1
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: CC#CCOc1cc(N2CC(C)(C)CC(C)(C)C2)ncn1
Temperature: 60 °C
Reaction time: 4 h
Yield: 73.1 %

Procedure:
Into 2 ml of acetonitrile were added 0.20 g of 4-(2-butynyloxy)-6-chloropyrimidine, 0.45 g of potassium carbonate and 0.24 g of 3,3,5,5-tetramethylpiperidine hydrochloride, and the mixture was stirred for 4 hours at 60° C. The reaction mixture was cooled to near room temperature, a saturated ammonium chloride aqueous solution was added therein, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.23 g of 4-(2-butynyloxy)-6-(3,3,5,5-tetramethylpiperidino)pyrimidine (hereinafter, referred to as Compound (38)).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][CH:12]1[CH2:17][CH:16]=[C:15]([C:18]2[N:19]=[C:20]([SH:23])[S:21][CH:22]=2)[CH2:14][N:13]1[C:24]([O:26][CH2:27][CH:28]=[CH2:29])=[O:25].O(P(OC1C=CC=CC=1)O[C:39]1[C@H:45]([CH3:46])[C@H:44]2[N:41]([C:42](=[O:54])[C@@H:43]2[C@H:47]([O:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH3:48])[C:40]=1[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])C1C=CC=CC=1.C(#N)C>C1COCC1>[CH2:27]([O:26][C:24]([N:13]1[CH:12]([CH3:11])[CH2:17][CH:16]=[C:15]([C:18]2[N:19]=[C:20]([S:23][C:39]3[C@H:45]([CH3:46])[C@H:44]4[N:41]([C:42](=[O:54])[C@@H:43]4[C@H:47]([O:49][Si:50]([CH3:51])([CH3:52])[CH3:53])[CH3:48])[C:40]=3[C:55]([O:57][CH2:58][CH:59]=[CH2:60])=[O:56])[S:21][CH:22]=2)[CH2:14]1)=[O:25])[CH:28]=[CH2:29]
Reactant: C=CCOC(=O)N1CC(c2csc(S)n2)=CCC1C
Reactant: C=CCOC(=O)C1=C(OP(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCOC1
Product: C=CCOC(=O)C1=C(Sc2nc(C3=CCC(C)N(C(=O)OCC=C)C3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C)C(=O)N12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
A solution of lithium hexamethyldisilazide in THF (1M, 1.24 ml, 1.24 mmol) was added at 0° C. to a solution of allyl 2-methyl-5-(2-mercapto-1,3-thiazol-4-yl)-3,6-dihydro-1(2 H)-pyridinecarboxylate (368 mg, 1.24 mmol) in THF (2.4 ml) and the mixture was stirred for 10 minutes. To the reaction solution was added at 0° C. a solution of allyl (4R,5R,6S)-3-[(diphenoxyphosphino)oxy]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate in acetonitrile (30%, 4.73 g, 2.5 mmol) and the solution was allowed to stand in a refrigerator for 13 hours. To the reaction solution was added ice water and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the solvent in vacuo, the residue was purified with silica gel chromatography (hexane/ethyl acetate: 4/1→3/1) to give allyl (4R,5S,6S)-3-[(4-(1-[(allyloxy)carbonyl]-6-methyl-1,2,5,6-tetrahydro-3-pyridinyl}-1,3-thiazol-2-yl)sulfanyl]-4-methyl-7-oxo-6-{(1R)-1-[(trimethylsilyl)oxy]ethyl}-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (544 mg, 71%).