Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]([OH:11])[C:8]([OH:10])=O)=[CH:3][CH:2]=1.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[C:30]([C:32]1[CH:33]=[CH:34][C:35]2[O:40][C:39]([CH3:42])([CH3:41])[CH2:38][CH:37]([NH:43]C(NC3C=CC=CC=3)=O)[C:36]=2[CH:53]=1)#[N:31].CN(C)CCCCCN=C=N.Cl>>[C:30]([C:32]1[CH:33]=[CH:34][C:35]2[O:40][C:39]([CH3:42])([CH3:41])[CH2:38][CH:37]([NH:43][C:8](=[O:10])[CH:7]([OH:11])[C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=3)[C:36]=2[CH:53]=1)#[N:31]
Reactant: CC1(C)CC(NC(=O)Nc2ccccc2)c2cc(C#N)ccc2O1
Reactant: O=C(O)[C@H](O)c1ccccc1
Agent: CN(C)CCCCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Product: CC1(C)CC(NC(=O)C(O)c2ccccc2)c2cc(C#N)ccc2O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 110.4 %

Procedure:
To a solution of R-(-)-mandelic acid (22.1 g, 0.14 mole) and 1-hydroxybenzotriazole hydrate (19.6 g, 0.14 mole) cooled to 0° C. was added successively N-methylmorpholine (16.2 g, 0.16 mole), 4-amino-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (29.4 g, 0.14 mole, Example 8, part D) and 1-(3-dimethylaminopropyl)-2-ethylcarbodiimide.HCl (27.9 g, 0.14 mole). The reaction mixture was stirred 0.5 hours at 0° C. and two hours at room temperature. The solvent was recovered under vacuum and the residue was partitioned between 5% aqueous HCl and ethyl acetate. The organic fraction was washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried over magnesium sulfate and evaporated in vacuo to obtain 52 g of yellow gum. The crude diastereomer mixture was chromatographed on silica eluting with 1:1 hexane/ethyl acetate to obtain 23.2 g (47.7%) of Isomer A. m.p.=120°-121° C., [a]D25 =-39.5°. 1H NMR (CDCl3) δ7.43-7.34 (m, 7H), 6.81 (d, J=8.20 Hz, 2H), 5.23 (m, 1H), 5.13 (d, J=3.52 Hz, 1H), 4.27 (m, 1H), 2.08 (dd, J=5.86 and 13.78 Hz, 1H), 1.71 (d, J=12.31 Hz, 1H), 1.42 (s, 3H), 1.36 (s, 3H). 13C NMR (CDCl3) δ173.26, 158.09, 139.60, 133.30, 132.46, 129.27, 129.18, 126.88, 123.39, 119.62, 118.99, 103.64, 77.00, 74.50, 42.33, 39.59, 29.77, 25.05. MS: (M+H)+ @337.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][C@@H:33]([CH3:36])[C:34]#[N:35].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:34]([C@@H:33]([NH:32][C:3](=[O:4])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[CH3:36])#[N:35]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: C[C@H](N)C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@@H](C#N)NC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 26.7 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 37 mg, 0.086 mmol), (S)-2-aminopropanenitrile (Int-XI, 9.0 mg, 0.13 mmol) [see also, McLaughlin, M. et al., J. Org. Chem., 68:50-54 (2003)], 4-methylmorpholine (34.7 mg, 0.343 mmol), and HATU (42.4 mg, 0.112 mmol) were dissolved in DMF (1 mL). After stirring 1 h, the reaction mixture was purified by prep HPLC (PHENOMENEX® 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 38 min, 25 mL/min, 220 nM, product retention=29.3 min) to provide single enantiomer N—((S)-1-cyanoethyl)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (12 mg, 0.023 mmol, 27.3% yield): [M+H]+=484.2; 1H NMR (400 MHz, methanol-d4) δ ppm 8.13-8.25 (2 H, m), 7.54-7.77 (7 H, m), 5.19 (1 H, s), 4.87 (1 H, q), 1.54 (3 H, d, J=7.04 Hz); HPLC peak RT=11.1 min (Method A).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=1)[C:8]([OH:10])=O)[CH3:3].C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[S:33][N:32]=[C:31]([CH3:34])[N:30]=1.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]=1)[C:8]([NH:28][C:29]1[S:33][N:32]=[C:31]([CH3:34])[N:30]=1)=[O:10])[CH3:1]
Reactant: Cc1nsc(N)n1
Reactant: CC(C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nsc(NC(=O)c2cc(OCc3ccccc3)cc(OC(C)C)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.6 %

Procedure:
DMF (2 drops) was added to a solution of 3-[(1-methylethyl)oxy]-5-[(phenylmethyl)oxy]benzoic acid (29.6 g, 0.103 mol) and oxalyl chloride (10.78 mL, 0.12 mol) in DCM (500 mL) The mixture was stirred at ambient temperature for 4 hours and the DCM and excess oxalyl chloride removed in vacuo. The residual acid chloride was dissolved in DCM (220 mL) and added dropwise to 5-amino-3-methyl-1,2,4-thiadiazole (12.43 g, 0.108 mol) and triethylamine (30.34 mL, 0.216 mol) in DCM (220 mL), at 0° C. The reaction was allowed to warm and stirred at ambient temperature for 72 hours. The DCM was removed in vacuo, and the residue partitioned between ethyl acetate (400 mL) and 1N hydrochloric acid (200 mL). The ethyl acetate layer was washed sequentially with saturated aqueous sodium hydrogen carbonate (200 mL) and brine (100 mL), dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silica, eluting with a gradient of 20% ethyl acetate in isohexane, to give the desired compound (33 g).
Reaction SMILES: [C:1]([CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5])#[N:2].[CH3:15]S(OCCCCOS(C)(=O)=O)(=O)=O>CO>[C:1]([CH:3]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[C:4]([O:6][CH3:15])=[O:5])#[N:2]
Reactant: N#CC(Cc1ccc(O)cc1)C(=O)O
Reactant: CS(=O)(=O)OCCCCOS(C)(=O)=O
Solvent: CO
Product: COC(=O)C(C#N)Cc1ccc(O)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
To a 25 mL RB flask fitted with magnetic stirrer was charged 10 mL of methanol. To the stirred solvent was added 2-cyano-3-(4-hydroxy-phenyl)-propanoic acid (0.5 g, 2.62 mmol), followed by methanesulfonic aid (0.5 mL, 7.69 mmol). After addition, the RM was refluxed at 65° C. for 1 h. After 1 h, the solvent was evaporated, water (20 mL) was added and the organic layer was extracted with ethyl acetate (15 mL×2). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as brown liquid. (0.3 g, yield: 55.8%): MS (ESI, 120 eV): m/z=204.1 (M−H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH2:6].[CH3:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:15](O)=[O:16].CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([C@@H:7]([CH3:9])[OH:8])[NH:6][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:12]([CH3:11])[CH:13]=1
Reactant: COC(=O)[C@@H](N)[C@@H](C)O
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H](NC(=O)c1ccc([N+](=O)[O-])c(C)c1)[C@@H](C)O
Yield: 900.1 %

Procedure:
The same operation as in Example (102a) was performed using threonine methyl ester hydrochloride (6.73 g, 39.6 mmol), 3-methyl-4-nitrobenzoic acid (7.18 g, 3.96 mmol), WSC hydrochloride (8.05 g, 42 mmol), DMAP (0.18 g, 1.5 mmol), N,N-diisopropylethylamine (5.42 g, 42 mmol) and dichloromethane (100 mL). The resulting residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane=1/3, 2/3, 3/2, 3/1) to obtain 10.56 g of the title compound as a light yellow amorphous solid (90%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]([NH:12][C:13](=[NH:22])[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)=[O:11].[CH3:23]N(C(OC)OC)C>CC#N>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH:23]=[N:22][C:13]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:12][C:10]1=[O:11]
Reactant: Cc1cccc(C)c1NC(=O)NC(=N)NCc1ccccn1
Reactant: COC(OC)N(C)C
Solvent: CC#N
Product: Cc1cccc(C)c1-n1cnc(NCc2ccccn2)nc1=O

Procedure:
To a suspension of 10.2 g. (28.0 mmol) of 1-(2',6'-dimethylphenyl)-3-[(2-pyridyl)methyl]amidinourea in CH3CN (100 ml) is added 10.0 g. (84.0 mmol) of DMF-DMA and the reaction mixture heated at reflux for two hours. The solvent is removed under vacuum and the residue diluted with H2O and made basic with 10% aqueous NaOH (pH10). The aqueous layer is extracted with CHCl3 (2×100 ml.) and the extracts dried (MgSO4) and concentrated under vacuum to an orange oil, which by NMR looks to be a mixture of starting material and product. The oil is layered out with H2O and Et2O. The oil solidifies. This solid is filtered and washed with H2O and Et2O and air dried. The solid is then crystallized (2×) from EtoAc to give 3.2 g. (37%) of a tan crystalline solid, melting point 165°-6° C.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:11]([C:13]1[NH:14][C:15](=[O:23])[NH:16][C:17](=[O:22])[C:18]=1[CH:19]([CH3:21])[CH3:20])=[O:12].C(=O)([O-])[O-].[K+].[K+].I[CH2:31][CH3:32]>CN(C=O)C>[Cl:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:11]([C:13]1[N:14]([CH2:31][CH3:32])[C:15](=[O:23])[NH:16][C:17](=[O:22])[C:18]=1[CH:19]([CH3:20])[CH3:21])=[O:12]
Reactant: Cc1cc(C#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(C(=O)c2cc(C#N)cc(C)c2Cl)c(C(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of Compound 98 (0.067 g, 0.202 mmol) and potassium carbonate (0.0279 g, 0.202 mmol) in DMF (1.0 mL) was added iodoethane (14 μL, 0.168 mmol) and reaction mixture was stirred overnight at room temperature. The reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate, dried (MgSO4) and concentrated. The resulting residue was purified by reverse phase HPLC (Phenomenex Synergi® column, 5 to 100% acetonitrile/H2O) to give a white powder after lyophilization (20.5 mg, 28%). 1H NMR (300 MHz, CD3CN): 9.15 (s, 1H), 8.16 (s, 1H), 7.96 (s, 1H), 3.52 (br s, 2H), 2.47 (s, 3H), 2.3-2.2 (m, 1H), 1.1-1.0 (s, 9H); Mass Spectrum: 360.2, 362.2 (M+H).
Reaction SMILES: O[CH2:2][CH:3]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4]1.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH2:2][CH:3]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[S:4]1
Reactant: O=S(Cl)Cl
Reactant: O=C1Nc2ccccc2SC1CO
Solvent: ClC(Cl)Cl
Product: O=C1Nc2ccccc2SC1CCl
Yield: 58.7 %

Procedure:
To a solution of 1.0 g of 2-hydroxymethyl-2H-1,4-benzothiazin-3(4H)-one in 20 ml of chloroform was added 0.9 ml of thionyl chloride, and the mixture was heated for 2 hours under reflux. The mixture was concentrated under reduced pressure and the residue was extracted with ether. The extract was washed with water, dried (MgSO4), and concentrated. The crude product was subjected to a column chromatography on silica-gel (40 g). From the eluate with hexane-ethyl acetate (4:1, v/v) was obtained 640 mg (58.7%) of 2-chloromethyl-2H-1,4-benzothiazin-3(4H)-one as crystals. Recrystallization from ethyl acetate and n-hexane gave needles, m.p. 152°-153° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][C:27]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:28]=1[C:29](O)=[O:30]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:29]([C:28]4[CH:32]=[C:33]([CH3:36])[CH:34]=[CH:35][C:27]=4[CH3:26])=[O:30])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: Cc1ccc(C)c(C(=O)O)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(C)ccc4C)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP3 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 2,5-dimethylbenzoic acid as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:9][F:10])([CH2:7][CH3:8])[CH2:4][CH:5]=C.O.I([O-])(=O)(=O)=[O:13].[K+]>CC(C)=O.C(OCC)C.[Os](=O)(=O)(=O)=O>[F:1][CH2:2][C:3]([CH2:9][F:10])([CH2:7][CH3:8])[CH2:4][CH:5]=[O:13]
Reactant: C=CCC(CC)(CF)CF
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CC(C)=O
Product: CCC(CF)(CF)CC=O
Reaction time: 15 h

Procedure:
To a stirred solution of 4,4-bis(fluoromethyl)hex-1-ene (9.1 g, 62 mmol) in acetone (360 mL)/water (120 mL) at rt was added osmium tetroxide (155 mg, 0.62 mmol) and potassium periodate (29.7 g; 129 mmol) (the latter in portions). After stirring for 15 h, the reaction mixture was diluted with diethyl ether (180 mL). The organic layer was separated, and the aqueous layer was extracted with diethyl ether (3×180 mL). The extracts were washed with saturated sodium thiosulfate (250 mL) and brine (250 mL), dried over sodium sulfate and concentrated to give a residue. The resulting residue was distilled under vacuum to provide 3,3-bis(fluoromethyl)pentanal.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:1]([N:8]([CH2:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH3:20])[CH:23]=1)[CH2:9][CH:10]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)[OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(C=O)c1
Reactant: COc1ccc(C(O)CNCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: COc1ccc(C(O)CN(Cc2ccccc2)Cc2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
Alternatively, to a solution of 2-benzylamino-1-(4-methoxy-phenyl)-ethanol (1.20 g, 4.66 mmol, see Preparation 61) and 3-methoxybenzaldehyde (0.700 g, 5.13 mmol) in 1,2 DCE (25 ml) was added NaB(OAc)3H. The mixture was stirred at RT overnight. The reaction mixture was poured into sat. NaHCO3 (30 ml) and extracted with CH2Cl2 (3×50 ml). The combined organics were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified via flash chromatography (Biotage 15% EtOAc/hexanes) to give the title product (1.72 g, 4.56 mmol, 98% yield).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1/[CH:27]=[CH:28]/[C:29](O)=[O:30]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:21]3[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=3[Cl:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccc(F)cc1Cl
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3ccc(F)cc3Cl)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2-chloro-4-fluoro-phenyl)-acrylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].C([O-])([O-])=O.[K+].[K+].F[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 120 °C

Procedure:
The mixture of 4-chloro-3-(trifluoromethyl)phenol (2 g, 10.18 mmol), K2CO3 (2.109 g, 15.26 mmol) and 4-fluorobenzonitrile (1.232 g, 10.18 mmol) in DMF (20 ml), was heated at 120° C. overnight. It was diluted with water and extracted with EtOAc. The organic phases were collected, washed with water and brine, dried over Na2SO4 and concentrated to afford the title compound as a brown oil. LCMS: rt=3.81 min, [M+H+]=298
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].[CH2:13]([O:20][C@:21]1([CH3:44])[C@H:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:24]([CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:23][C:22]1=[O:43])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[CH2:13]([O:20][C@:21]1([CH3:44])[C@H:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:24]([CH2:34][O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[O:23][CH:22]1[OH:43])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[C@]1(OCc2ccccc2)C(=O)O[C@H](COCc2ccccc2)[C@H]1OCc1ccccc1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C[C@]1(OCc2ccccc2)C(O)O[C@H](COCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -40 °C

Procedure:
Vitride (22 L, 76.19 mole, 70% wt. in toluene, 3.46M) was diluted with toluene (18 L) and added dropwise to a solution of (3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxymethyl)-3-methyl-dihydrofuran-2(3H)-one (62.5 mole from step 1) in toluene (150 L) maintaining temperature around −40±5° C. during the addition. After the addition was over, TLC was checked to ensure completion of the reaction (if the reaction is not complete, more Vitride is added till reaction is complete). The reaction was quenched with acetone (5.5 L) maintaining temperature between −30° C. and −40° C. and 2.5 N HCl (70 L) was added at 0° C. The toluene layer was separated and the aqueous layer was extracted with ethyl acetate (30 L). The combined organic layers were washed with brine (30 L), dried over magnesium sulfate (10 Kg), filtered and the filtrate was concentrated in vacuo to dryness to furnish 32 kg of crude residue. The crude material was used as such for the next step. An analytical sample was prepared by purification of 1 g of residue by flash column chromatography (silica gel, ethyl acetate in hexane) to furnish (3R,4R,5R)-3,4-bis(benzyloxy)-5-(benzyloxymethyl)-3-methyl-tetrahydrofuran-2-ol. 1HNMR (DMSO-d6): δ 7.35-7.24 (m, 15 H), 6.68 (d, J=5 Hz, 0.6 H), 5.89 (d, J=6.8 Hz, 0.4 H), 5.00 (m, 1 H), 4.73-4.50 (m, 6 H), 4.18-4.13 (m, 0.4 H), 4.06-4.00 (m, 0.6 H), 3.79 (d, J=7.5 Hz, 0.6 H), 3.65 (d, J=6 Hz, 0.4 H), 3.61-3.48 (m, 2 H), 1.33 (s, 2 H), 1.32 (s, 1 H); MS (ES+): 457.38 (100% M+Na). Analysis: Calculated for C27H30O5: C, 74.62; H, 6.96; Found: C, 74.36; H, 7.05.
Reaction SMILES: [C:1](=[O:16])([S:3][CH2:4][CH2:5][CH2:6][N:7](C(OC(C)(C)C)=O)[CH3:8])[CH3:2].[ClH:17]>C(O)C.C1(C)C=CC=CC=1>[ClH:17].[C:1](=[O:16])([S:3][CH2:4][CH2:5][CH2:6][NH:7][CH3:8])[CH3:2]
Reactant: CC(=O)SCCCN(C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: CNCCCSC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
S-3-(tert-Butoxycarbonyl(methyl)amino)propyl ethanethioate (206 mg, 0.834 mmol) in 4 ml of EtAc was added 1.0 ml of HCl (conc.) at RT. The mixture was stirred at RT for 1 h, diluted with ethanol/toluene (6 ml, 1:1), evaporated and co-evaporated with ethanol/toluene (3×10 ml), crystallized with ethanol/EtAc/Hexane, filtered, and dried over a vacuum to afford 135 mg (88%) of the title compound. 1H NMR (CDCl3) 9.70 (br, 1H), 8.56 (br, 1H), 3.42 (m, 2H), 2.52 (m, 2H), 2.35 (s, 3H), 2.05 (s, 3H), 1.88 (m, 2H); 13C NMR 174.64, 40.57, 31.57, 27.69, 20.94, 15.62; MS m/z+ 170.0 (M+Na), 148.10 (M+H).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:20]>[Pd].C(O)(=O)C.CO.C(#N)C>[ClH:20].[C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C(c2ccccc2)c2ccncc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CC#N
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Reaction time: 96 h

Procedure:
A mixture of 62.69 g (0.256 mole) of 4-(diphenylmethyl)pyridine and 6.4 g of 10% palladium on carbon (0.006 mole) in 300 ml of glacial acetic acid and under an atmosphere of hydrogen (44 psi) was shaken on a Parr apparatus at 85° for 4 days. The reaction mixture was filtered, and the solvent was removed in vacuo from the filtate. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, and the solvent was removed in vacuo to give a solid. This was dissolved in a mixture of methanol-acetonitrile, and excess ethereal hydrogen chloride was added. A precipitate was collected to give 59.13 g (80.3%) of slightly impure title compound as a white, crystalline solid, mp 273°-274° C. Part of this was recrystallized from methanol-ether to give an analytically pure sample, mp 275.5°-277° C.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[Br:10][C:11]1[CH:18]=[C:17]([CH3:19])[C:14]([C:15]#N)=[C:13]([CH3:20])[CH:12]=1.C(C(C(C([O-])=O)O)O)([O-])=[O:22].[K+].[Na+]>C(Cl)Cl>[Br:10][C:11]1[CH:18]=[C:17]([CH3:19])[C:14]([CH:15]=[O:22])=[C:13]([CH3:20])[CH:12]=1
Reactant: Cc1cc(Br)cc(C)c1C#N
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: CC(C)C[AlH]CC(C)C
Agent: [K+]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(Br)cc(C)c1C=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
DIBAL-H (1.0M in hexanes; 22.0 mL, 22.0 mmol) was added to a solution of 4-bromo-2,6-dimethylbenzonitrile (3.87 g, 18 mmol) in CH2Cl2 (50 mL) at 0° C., and the resulting mixture stirred at 25° C. for 3 h. Saturated aqueous sodium potassium tartrate solution (75 mL) was then slowly added, and the resulting mixture was stirred vigorously for 30 min. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Chromatographic purification of the residue (silica gel, 0-20% EtOAc/hexanes) furnished 4-bromo-2,6-dimethylbenzaldehyde as a light brown solid.
Reaction SMILES: [C:1]([S:5]([NH2:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH:15]=O)[CH:10]=1>ClCCl.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](/[CH:15]=[N:7]/[S@:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[O:6])[CH:10]=1
Reactant: CC(C)(C)S(N)=O
Reactant: O=Cc1cc(Cl)ccn1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Liu, G. et al., J. Org. Chem., 64:1278 (1999). To a solution of S-(−)-t-butyl-sulfinamide (0.856 g, 7.06 mmol) in dichloromethane (14.13 mL) was added sequentially copper(II) sulfate (2.481 g, 15.54 mmol) and 4-chloropicolinaldehyde[1.0 g, 7.06 mmol, prepared according to a modified described by Negi etc, Synthesis, 991 (1996)]. The white suspension was stirred at rt. After 3 h, the brown suspension was filtered through CELITE®, eluting with DCM, to give a clear brown filtrate. Concentration gave a brown oil weighing 1.85 g. Purification by normal phase chromatography gave 1.31 g of 45A as a clear, yellow oil. MS (ESI) m/z: 245.0 (M+H)+.