Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[S:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1.Cl>CCOC(C)=O>[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[C:14]2[C:15](=[O:18])[CH2:16][CH2:17][S:12][CH2:13]2)=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: O=C1CCSCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C1CCSCC1=Cc1ccc(F)cc1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
Aqueous KOH (0.3 g in 250 mL water) was added to 4-fluoro-benzaldehyde Compound 12a (4.82 g, 38.9 mmol) and tetrahydro-4H-thiopyran-4-one Compound 1a (4.5 g, 38.8 mmol), and the mixture was heated to about 65° C. for 24 hrs, then cooled to r.t. and stirred for 2 hrs. The mixture was acidified to pH 7 with 1.0N HCl (2 mL) and diluted with EtOAc (200 mL). The organic layer was separated, washed with brine and dried with anhydrous Na2SO4, then filtered and concentrated to provide a crude product, which was purified by silica gel column (eluted with 8% EtOAc in hexane) to give 3-(4-fluoro-benzylidene)-tetrahydro-4H-thiopyran-4-one Compound 12b (4.8 g, 48.5%) as a white solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].C[CH2:21][N:22](C(C)C)[CH:23](C)C.CS(Cl)(=O)=O.CNC.C1COCC1>C(Cl)Cl>[CH3:21][N:22]([CH2:2][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])[CH3:23]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(CO)c1
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccccc2C)c(CN(C)C)c1
Reaction time: 0.42 h
Yield: 86.6 %

Procedure:
To a solution of methyl 2-(hydroxymethyl)-2′-methylbiphenyl-4-carboxylate (2.12 g, 8.27 mmol) in DCM (65 mL) was added DIEA (7.03 mL, 41.4 mmol) and methanesulfonyl chloride (768 μL, 9.93 mmol) at 0° C. and stirred for 25 min. After this time, a 2M solution of dimethylamine in THF (12.4 mL, 24.8 mmol) was added and the resulting mixture was stirred at RT for 16 hours. The reaction mixture was partitioned between DCM and a 5N aqueous solution of NaOH. The organic layer was dried (MgSO4) and concentrated under vacuum. A purification by chromatography (silica, DCM/MeOH) gave the title compound as a light yellow solid (2.03 g, 86%). 1H NMR (DMSO-d6) δ 8.27 (d, J=1.4 Hz, 1H), 7.95 (dd, J=7.8, 1.9 Hz, 1H), 7.32-7.18 (m, 4H), 7.06 (d, J=7.3 Hz, 1H), 3.94 (s, 3H), 3.24-3.10 (m, 2H), 2.11 (s, 6H), 2.01 (s, 3H). HPLC (Method A) Rt 2.90 min (Purity 100.0%). LC/MS (Method B): 284.1 (M−H)−.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[SH2:6]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Cl:2][CH2:1][CH:3]([OH:5])[CH2:4][S:6][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2]
Reactant: ClCC1CO1
Reactant: S
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Product: OC(CCl)CSCC(O)CCl
Temperature: 22.5 °C
Yield: 96 %

Procedure:
185 g (2.0 mol) of epichlorohydrin, 10 ml of toluene and 0.97 g of tetra-n-butylammonium bromide were mixed together, and 35 g (1.0 mol) of hydrogen sulfide was blown into the mixture with stirring with the temperature of the solution being maintained at 20 to 25° C. After that, extraction was carried out using toluene to distil away the solvent, thereby obtaining 210 g (0.96 mol, yield: 96%) of bis(3-chloro-2-hydroxypropyl)sulfide (the compound represented by formula (1) above).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([O:17][CH3:18])[C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:5]=2[N:4]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH3:8][N:7]1[C:6]2[CH:9]=[C:10]([O:17][CH3:18])[C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:5]=2[N:4]=[C:3]1[CH2:2][N:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:3]2[N:7]([CH3:8])[C:6]3[CH:9]=[C:10]([O:17][CH3:18])[C:11]([O:15][CH3:16])=[C:12]([O:13][CH3:14])[C:5]=3[N:4]=2)[CH2:21][CH2:20]1
Reactant: C1CNCCN1
Reactant: COc1cc2c(nc(CCl)n2C)c(OC)c1OC
Product: COc1cc2c(nc(CN3CCN(Cc4nc5c(OC)c(OC)c(OC)cc5n4C)CC3)n2C)c(OC)c1OC

Procedure:
2-Chloromethyl-1-methyl-4,5,6-trimethoxy-benzimidazole (75 mg) and piperazine (10 mg) were reacted in the same manner as in Example 1 to obtain the title compound as a free base.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:18]([O:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)[CH2:19][CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH2:18]([O:23][C:24]1[CH:25]=[CH:26][C:27]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)=[CH:28][CH:29]=1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: COC(=O)c1ccc(-c2ccc(I)cc2)cc1
Reactant: CCCCCOc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCOc1ccc(-c2ccc(-c3ccc(C(=O)OC)cc3)cc2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
33.8 g (0.1 mol) of methyl 4′-iodobiphenyl-4-carboxylate are introduced together with 29.3 g (0.125 mol) of glycol ester of 4-n-pentoxyphenylboronic acid, 70 mg of bis(triphenylphosphine)palladium dichloride and 15.9 g (0.15 mol) of sodium carbonate into 300 ml of DMF and stirred at 80° C. for 12 hours. After filtration and washing with water, the dried residue is recrystallized from DMF. This affords 20.5 g (45%) of methyl 4″-n-pentoxy-[1,1′:4′,1″]-terphenyl-4-carboxylate of melting point 248° C.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:4][C:3]1=2.C[Si]([C:22]#[N:23])(C)C>B(F)(F)F.Cl>[C:22]([C:2]1[C:3]2[CH:4]=[CH:5][C:6]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:8]=2[CH2:9][CH2:10][CH:11]=1)#[N:23]
Reactant: C[Si](C)(C)C#N
Reactant: COC(=O)COc1ccc2c(c1)CCCC2=O
Agent: Cl
Agent: FB(F)F
Product: COC(=O)COc1ccc2c(c1)CCC=C2C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2 to 3 drops of BF3 -etherate solution are added to 0.1 mol of methyl 5-oxo-5,6,7,8-tetrahydro-naphth-2-yl-oxyacetate and 0.15 mol of trimethylsilyl cyanide, and the mixture is stirred at room temperature for 30 minutes and then at 50° C. for 1 hour. 250 ml of a saturated methanolic hydrogen chloride solution are added to this solution at room temperature and the mixture is stirred for 1 hour. Some of the product precipitates out and is filtered off. A further batch is obtained by evaporating the mother liquor, taking up the residue in CH2Cl2, extracting the mixture twice by shaking with 0.5N NaOH, drying the extract over Na2SO4 and evaporating it and recrystallizing the residue from a little methanol or diisopropyl ether.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1.[H][H]>ClCCl.[Pd]>[F:1][C:2]([F:14])([F:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(OCC(F)(F)F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Product: Nc1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 94.5 %

Procedure:
To a solution of the crude 4-(2,2,2-trifluoroethoxy)nitrobenzene (1.6 g, 7.2 mmol, 1.0 equiv) in 40 mL of dichloromethane was added 0.4 g of a 5% palladium on activated carbon (0.19 mmol, 0.026 equiv). Hydrogen gas was introduced using a balloon while the mixture was stirred vigorously for 48 h at room temperature. After all starting material had been consumed, the mixture was filtered through a pad of Celite to remove the palladium catalyst. The filtrate was evaporated in vacuo to give a crude product as a brown liquid. This crude product was purified by distillation at reduced pressure to give 1.3 g of pure 4-(2,2,2-trifluoroethoxy)aniline as a colorless liquid, which solidified upon cooling to 0° C. b.p. 81–83° C. at 0.5 torr;. 1H NMR (DMSO-d6) δ 4.53 (q, J=9.1 Hz, 2H), 4.76 (br s, 2H), 6.52 (d, J=7.6 Hz, 2H), 6.76 (d, J=7.6 Hz, 2H) ppm.
Reaction SMILES: O[N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[N+:13]([C:16]1[C:25](Cl)=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2)([O-:15])=[O:14]>>[N+:13]([C:16]1[C:25]([C:5]23[CH:8]=[CH:9][CH:10]=[CH:11][CH:4]2[C:3]([NH:2][C:6]3=[O:7])=[O:12])=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][CH:20]=[N:21]2)([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1c(Cl)ccc2ncccc12
Reactant: O=C1c2ccccc2C(=O)N1O
Product: O=C1NC(=O)C2(c3ccc4ncccc4c3[N+](=O)[O-])C=CC=CC12

Procedure:
N-hydroxy-phthalimide and 5-nitro-6-chloro-quinoline were reacted to form 0-(5-nitro-6-quinolyl)-phthalimide melting at 185° C. which was reacted to obtain 0-(5-nitro-6-quinolyl)hydroxylamine melting at 165° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([S:23](OC1C(F)=C(F)C(F)=C(F)C=1F)(=[O:25])=[O:24])=[CH:18]2.[S:38]1[CH:42]=[CH:41][N:40]=[C:39]1[NH2:43].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([S:23]([NH:43][C:39]1[S:38][CH:42]=[CH:41][N:40]=1)(=[O:25])=[O:24])=[CH:18]2
Reactant: COc1cc(C(F)(F)F)ccc1-c1cccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Reactant: Nc1nccs1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)ccc1-c1cccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Reaction time: 0.08 h

Procedure:
A vial was charged with perfluorophenyl 5-(2-methoxy-4-(trifluoromethyl)phenyl)naphthalene-2-sulfonate (77.62 mg, 0.142 mmol), THF (1415 μl), and thiazol-2-amine (21.26 mg, 0.212 mmol). The vial was cooled in an ice bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (354 μl, 0.354 mmol) was added dropwise over 1 min. LC/MS after 5 min showed mostly the desired product. After a total of 20 min, the reaction was quenched by the addition of acetic acid (0.1 mL). The resulting mixture was warmed to room temperature and concentrated. The product was purified by chromatography on silica gel (0 to 5% MeOH/DCM) to give 5-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide (59.52 mg, 0.128 mmol) as an off-white foam. 1H NMR (400 MHz, DMSO-d6) δ ppm=12.79 (br. s., 1H), 8.51 (d, J=1.9 Hz, 1H), 8.21 (d, J=8.3 Hz, 1H), 7.81-7.65 (m, 2H), 7.57-7.41 (m, 5H), 7.26 (d, J=4.6 Hz, 1H), 6.84 (d, J=4.6 Hz, 1H), 3.73 (s, 3H); m/z (ESI) 465.0 (M+H)+.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][C:10]#[N:11])(=[O:6])[CH2:2][C:3]([CH3:5])=O.C([O-])(=O)C.[NH4+:16]>>[NH2:16]/[C:3](/[CH3:5])=[CH:2]\[C:1]([O:7][CH2:8][CH2:9][C:10]#[N:11])=[O:6]
Reactant: [NH4+]
Reactant: CC(=O)CC(=O)OCCC#N
Agent: CC(=O)[O-]
Product: C/C(N)=C/C(=O)OCCC#N

Procedure:
Namely, 2-cyanoethyl acetoacetate (11) is reacted with an amine or ammonium acetate to obtain 2-cyanoethyl 3-aminocrotonate (35).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[C:9]1([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:3]1([CH3:8])[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccccc1Cl
Reactant: c1ccc(Nc2ccccc2)cc1
Product: Cc1ccccc1N(c1ccccc1)c1ccccc1
Reaction time: 21 h
Yield: 103.3 %

Procedure:
According to the general procedure A, 2-bromotoluene (188 mg, 1.10 mmol) reacted with diphenylamine (169 mg, 1.00 mmol) to give the title compound (258 mg, 99%) as a white solid at room temperature for 4 h. Reaction of 2-chlorotoluene (70 mg, 0.55 mmol) with diphenylamine (85 mg, 0.50 mmol) proceeded at 80° C. for 21 h to give the title compound (134 mg, 99%). 1H-NMR (400 MHz, CDCl3): δ 7.14-7.27 (m, 8H), 7.01-6.92 (m, 6H), 2.06 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 147.46, 145.37, 136.49, 131.67, 129.61, 128.99, 127.33, 125.95, 121.50, 121.33, 18.56. GC/MS(EI): m/z 259 (M+).
Reaction SMILES: [C:1]([CH2:6][S:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])([O:3][CH2:4][CH3:5])=[O:2].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[C:1]([CH2:6][S:7]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[O:30])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CSc1c(C(=O)OCC)[nH]c2ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)CS(=O)c1c(C(=O)OCC)[nH]c2ccccc12

Procedure:
3-[(Carbethoxymethyl)thio]-2-carbethoxyindole is treated with m-chloroperbenzoic acid (1 eq.) in methylene chloride at 0° C. The reaction is followed by TLC. After starting material is consumed the reaction mixture is washed with sat. NaHCO3 and sat. NaCl. The organic layer is dried. 3-[(Carbethoxymethyl)sulfinyl]-2-carbethoxyindole may be isolated by flash column chromatography followed by recrystallization.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:27][NH:28][O:29][CH3:30].C(=O)=O.C([Mg]Cl)(C)C>C1COCC1>[CH3:30][O:29][N:28]([CH3:27])[C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCCCCCCCCCNC(=O)OCc1ccccc1
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Agent: O=C=O
Solvent: C1CCOC1
Product: CON(C)C(=O)CCCCCCCCCCNC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
A solution of 19 (2.25 g, 6.44 mmol), methyl methoxyamine hydrochloride (1.26 g, 12.88 mmol) and THF (anhydrous, 30 mL) was cooled to −15 to −20° C. with an ice/methanol bath containing a few pieces of dry ice. To this cold solution was added dropwise i-PrMgCl (3M solution in pentane, 11.27 mL, 22.54 mmol) over 15 min and temperature was then raised to −10° C. and stirring continued at the temperature for additional 2 h. After this time the reaction was quenched by the slow addition of saturated aqueous NH4Cl (50 mL). The aqueous layer was separated and washed with dichloromethane (2×50 mL). Organics were combined, dried over anhydrous Na2SO4, concentrated and further dried under high vacuum overnight to afford the desired product 20 (2.04 g, 84% yield) as a colorless, viscous oil: 1H NMR (300 MHz, CDCl3) δ 1.27 (m, 12H), 1.48 (m, 2H), 1.60 (m, 2H), 2.40 (m, 2H), 3.18 (m, 5H), 3.68 (s, 3H), 5.09 (s, 2H), 7.34 (m, 5H); m/z (ESI) 379 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:11]=[N:10]1.C([O-])([O-])=O.[K+].[K+].[CH:26]1[CH:31]=[CH:30][C:29]([CH2:32][O:33][C:34](Cl)=[O:35])=[CH:28][CH:27]=1.O>ClCCl>[CH2:32]([O:33][C:34]([NH:8][C:6]1[CH:5]=[CH:4][C:3]([N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:11]=[N:10]2)=[C:2]([F:1])[CH:7]=1)=[O:35])[C:29]1[CH:30]=[CH:31][CH:26]=[CH:27][CH:28]=1
Reactant: Nc1ccc(-n2cc(-c3ccccn3)cn2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccc(-n2cc(-c3ccccn3)cn2)c(F)c1)OCc1ccccc1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
200 mg of 2-(1-(2-fluoro-4-aminophenyl)-1H-pyrazol-4-yl)pyridine (25f) was dissolved in 5 mL dichloromethane, with addition of 194.3 mg K2CO3. Then, 990 μL Cbz-Cl was slowly dropped into the resultant mixture maintained in an ice bath. After completion of the addition, the ice bath was removed. The reaction mixture was warmed naturally to room temperature and reacted for 2 hours. TLC monitoring was performed to determine the completion of the reaction, after which water was added into the reaction solution. The mixture was extracted with dichloromethane for three times. The combined organic phase was dried and rotary evaporated. The residue obtained was repeatedly washed with petroleum ether until the excess Cbz-Cl was completely removed, thereby affording 260 mg of a light yellow solid, with a yield of 95.1%.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(CCN(C)C)C.[Li]CCCC.[P:22](Cl)([O:27][CH2:28][CH3:29])([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[CH2:25]([O:24][P:22]([C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([O:27][CH2:28][CH3:29])=[O:23])[CH3:26]
Reactant: CCOP(=O)(Cl)OCC
Reactant: C#Cc1ccccc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOP(=O)(C#Cc1ccccc1)OCC
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of phenylacetylene (1 mmole) in anhydrous THF (5 mL) was treated with TMEDA (1.2 mmole) followed by n-BuLi (1.2 mmole) at −78° C. After 30 min the reaction was treated with diethyl chlorophosphate, and the resulting solution was stirred at −78° C. for 1 h. The reaction was quenched with saturated ammonium chloride. Extraction and chromatography gave 1-diethylphosphono-2-phenylacetylene as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([NH:13][C:14](=[O:21])[CH:15]([CH3:20])[CH2:16][CH2:17][CH2:18]Br)=[CH:11][C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:37]1([C:44](=[O:46])[CH3:45])[CH2:43][CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:12]([NH:13][C:14](=[O:21])[CH:15]([CH3:20])[CH2:16][CH2:17][CH2:18][N:40]2[CH2:41][CH2:42][CH2:43][N:37]([C:44](=[O:46])[CH3:45])[CH2:38][CH2:39]2)=[CH:11][C:10]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(-c2cc(NC(=O)C(C)CCCBr)n(C(=O)OC(C)(C)C)n2)cc1
Reactant: CC(=O)N1CCCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cc(NC(=O)C(C)CCCN3CCCN(C(C)=O)CC3)n(C(=O)OC(C)(C)C)n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 57.3 %

Procedure:
5-(5-Bromo-2-methyl-pentanoylamino)-3-(4-methoxy-phenyl)-pyrazole-1-carboxylic acid tert-butyl ester (280.0 mg, 0.6 mmol, 1.0 eq) was dissolved in DCM (3 mL). Triethylamine (80 μL, 0.6 mmol, 1.0 eq) and 1-[1,4]-diazepan-1-yl-ethanone (158 μL, 170.0 mg, 1.2 mmol, 2.0 eq) were added and the mixture was stirred at room temperature for 24 hours, then at 50° C. for 16 hours. NaHCO3 saturated solution was added and the organic layer separated and collected. Evaporation of the solvent gave a crude product purified using SiO2 column (elution DCM, DCM:MeOH 99:1 to 96:4) obtaining the title product (181.3 mg, yield 54%).
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][CH2:5][O:6][CH3:7].[SH:8][CH2:9][C:10]([OH:12])=[O:11]>>[CH3:7][O:6][CH2:5][CH2:4][O:3][CH2:2][S:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=C(O)CS
Reactant: COCCOCCl
Product: COCCOCSCC(=O)O
Yield: 58 %

Procedure:
In a similar manner, 2-methoxyethyl chloromethyl ether (4d) was reacted with mercaptoacetic acid to give S-(methoxy-ethoxy)methylmercaptoacetic acid (5d) in 58% yield as an oil.
Reaction SMILES: [N:1]1[C:10]2[C@@H:9]([NH2:11])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:12][C:13]1[C:14]([CH:20]=O)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:12][C:13]1[C:14]([CH2:20][NH:11][C@@H:9]2[C:10]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH2:6][CH2:7][CH2:8]2)=[N:15][CH:16]=[C:17]([CH3:19])[CH:18]=1
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: N[C@H]1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN[C@H]2CCCc3cccnc32)c(C)c1

Procedure:
Using General Procedure B: Reaction of (S)-5,6,7,8-tetrahydro-quinolin-8-ylamine in CH2Cl2 with 3,5-dimethyl-pyridine-2-carbaldehyde and NaBH(OAc)3 gave (S)-(3,5-dimethyl-pyridin-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine. 1H NMR (CDCl3) δ 1.75 (m, 1H), 1.91 (m, 2H), 2.26 (s+m, 4H), 2.33 (s, 3H), 2.80 (m, 2H), 3.96 (t, 1H, J=6.0 Hz), 4.02 (d, 1H, J=15.0 Hz), 4.17 (d, 1H, J=15.0 Hz), 5.41 (br s, 1H), 7.06 (dd, 1H, J=7.5, 3.0 Hz), 7.25 (s, 1H), 7.37 (d, 1H, J=9.0 Hz), 8.24 (s, 1H), 8.40 (d, 1H, J=3.0 Hz).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:12][CH:11]=1.C(=O)(O)[O-].[Na+]>CCO>[C:4]([C:3]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:13][N:12]2[C:2]=1[C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:19]=1[N:10]=[CH:11]2)([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)Cc1ncnc2ccccc12
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cn2cnc3ccccc3c2c1C(=O)OCC

Procedure:
A solution of ethyl bromopyruvate (8.0 g, 0.1041 m) and ethyl 4-quinazolylacetate prepared according to the procedure of Elderfield and Serlin, J. Org. Chem. 16, 1669 (1951) (2.32 g, 0.011 m) in dry EtOH (250 ml) was heated at reflux for 24 hr. Sodium bicarbonate was added until effervescence ceased. A solid formed and this was filtered, washed well with H2O, and dried. The crude product (1.8 g) was chromatographed on 150 g of Silicar. The desired product was eluted with 3% EtOAc/benzene. Crystallization from MeOH afforded the desired product as a white solid; m.p. 125°-126° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[NH2:5].C(N(C(C)C)CC)(C)C.[Si:24](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([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(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:11][CH:12]=1)[NH2:5]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@@H](N)Cc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Yield: 87.7 %

Procedure:
To a solution of L-tyrosine methyl ester (Sigma Chemical Company) (10.0 g, 51.3 mmol) and diisopropylethylamine (25.9 g, 200.0 mmol) in CH2Cl2 (400 mL) was added t-butyldiphenylsilyl chloride (TBDPS-Cl; 35.2 g, 128.2 mmol) at 23° C. The resultant mixture was stirred at 23° C. for 14 hours. The crude reaction mixture was dried over (MgSO4) and concentrated in vacuo. The resultant residue was purified by silica gel flash column chromatography. The polarity of the eluting solvent mixture was adjusted according to the Rf value of the product. The eluted fractions were combined, dried over MgSO4, concentrated and dried to give 19.5 g (87.8% yield) of O-(tert-butyldiphenylsilyl)-L-tyrosine methyl ester as a colorless syrup. Rf (hexanes/ethyl acetate (AcOEt)/methanol (MeOH) 20:20:1)=0.38.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[NH:28][C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23](F)[CH:22]=[C:21]([NH2:26])[C:20]=4C)[C:13]=3[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[F:30]C1C=C(B2OC(C)(C)C(C)(C)O2)C(C)=C(C=1)N>>[CH3:29][N:2]([CH3:1])[C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[NH:28][C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([F:30])=[C:21]([NH2:26])[CH:20]=4)[C:13]=3[CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: Cc1c(N)cc(F)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)N(C)C)CC3)cc12
Product: CN(C)C(=O)N1CC=C(c2cc3c(-c4ccc(F)c(N)c4)ncnc3[nH]2)CC1

Procedure:
Intermediate 10 was prepared analogue to Intermediate 6 by replacing Intermediate 5 with 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.