Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=O)[CH:9]=1)=[O:4].F[C:18](F)(F)C(O)=O.C([SiH](CC)CC)C>>[CH2:1]([O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([CH2:10][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:9]=1)=[O:4])[CH3:18]
Reactant: COC(=O)c1cc(C(=O)C2CCCC2)c[nH]1
Reactant: O=C(O)C(F)(F)F
Agent: CC[SiH](CC)CC
Product: CCOC(=O)c1cc(CC2CCCC2)c[nH]1
Temperature: 2.5 °C
Reaction time: 20 h

Procedure:
To a mixture of 4-cyclopentanecarbonyl-1H-pyrrole-2-carboxylic acid methyl ester (A1-I) and trifluoroacetic acid was added triethylsilylhydride drop wise under stirring at 0-5° C. Stirring was further continued for 20 hours at 0-25° C. Trifluoroacetic acid was removed under reduced pressure and the residue was diluted with diethyl ether, ether layer was separated and washed with 1N NaOH followed by brine, organic layer was dried over anhydrous sodium sulfate and was evaporated to yield 4-cyclopentylmethyl-1-H-pyrrole-2-carboxylic acid ethyl ester (A1-II).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[Cl:18][C:19]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:22]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccc(Cl)cc4Cl)nc23)CC1
Yield: 72.6 %

Procedure:
Beginning with 0.085 gm (0.369 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.108 mL (0.776 mMol) 2,4-dichlorobenzoyl chloride, 0.108 gm (72.7%) of the title compound was recovered as an amorphous solid by the procedure described in Example 16.
Reaction SMILES: [CH2:1]([N:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[CH2:1]([N:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN1CCCCCC1=O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CCCCCCCCCCCCN1CCCCCC1
Reaction time: 5 h
Yield: 93.5 %

Procedure:
56.2 g (0.2 mol) of 1-dodecylazacycloheptan-2-one in 100 ml diethyl ether was added dropwise to a suspension of 7.6 g (0.2 mol) lithium aluminum hydride in 100 ml diethyl ether under argon at room temperature. After 5 hours of stirring, 20 ml saturated sodium sulfate was added dropwise. The mixture was filtered and the filtrate was dried with magnesium sulfate, filtered and concentrated. The resulting oil was distilled (130°/.03 mm) to yield 50.03 g (93.5%) of 1-n-dodecylazacycloheptane.
Reaction SMILES: C([N:8]1[C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22]CC2C=CC=CC=2)=[O:14])=[N:11][N:10]=[N:9]1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[OH:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:13]([C:12]1[NH:11][N:10]=[N:9][N:8]=1)=[O:14]
Reactant: O=C(Nc1ccccc1OCc1ccccc1)c1nnnn1Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(Nc1ccccc1O)c1nnn[nH]1
Reaction time: 18.5 h
Yield: 42.3 %

Procedure:
A solution of 1-benzyl-2'-benzyloxy-1H-tetrazole-5-carboxanilide (2.0 g) in glacial acetic acid (100 ml) was hydrogenated at 53° C. and 4.1 kg/cm2 for 18.5 hours, using a catalyst of palladium on charcoal (5% w/w). The mixture was filtered and the filtrate was evaporated at 40° C. in vacuo. The resulting solid was dissolved in a minimum volume of aqueous ammonia solution (2 N). The solution was filtered and then acidified with dilute hydrochloric acid (2 N). The resulting solid was filtered off, dried and recrystallised from aqueous dimethylformamide to give 2'-hydroxytetrazole-5-carboxanilide (0.45 g), m.p. 220°-223° C.
Reaction SMILES: [F:1][C:2]1[C:7]2[O:8][C:9]3[C:14]([C:15]4([CH2:20][C:19](=[O:21])[N:18]([CH3:22])[C:17]([NH:23]C(=O)OC(C)(C)C)=[N:16]4)[C:6]=2[CH:5]=[C:4]([C:38]2[C:39]([F:44])=[N:40][CH:41]=[CH:42][CH:43]=2)[N:3]=1)=[CH:13][C:12]([C:31]1[C:32]([F:37])=[N:33][CH:34]=[CH:35][CH:36]=1)=[CH:11][CH:10]=3.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:23][C:17]1[N:18]([CH3:22])[C:19](=[O:21])[CH2:20][C:15]2([C:6]3[CH:5]=[C:4]([C:38]4[C:39]([F:44])=[N:40][CH:41]=[CH:42][CH:43]=4)[N:3]=[C:2]([F:1])[C:7]=3[O:8][C:9]3[C:14]2=[CH:13][C:12]([C:31]2[C:32]([F:37])=[N:33][CH:34]=[CH:35][CH:36]=2)=[CH:11][CH:10]=3)[N:16]=1
Reactant: CN1C(=O)CC2(N=C1NC(=O)OC(C)(C)C)c1cc(-c3cccnc3F)ccc1Oc1c2cc(-c2cccnc2F)nc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)CC2(N=C1N)c1cc(-c3cccnc3F)ccc1Oc1c2cc(-c2cccnc2F)nc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
Tert-butyl 1-fluoro-3,7-bis(2-fluoropyridin-3-yl)-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamate was obtained as a side product in the synthesis of Example 12. To a solution of tert-butyl 1-fluoro-3,7-bis(2-fluoropyridin-3-yl)-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamate (32 mg, 0.053 mmol) in DCM (2.5 mL) was added TFA (500 μL, 6.49 mmol). The reaction was allowed to stir at RT overnight. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in MeOH and loaded onto a Varian Bond Elut SCX column. The column was washed with MeOH and subsequently eluted with a 2 M solution of ammonia in MeOH to obtain 22.6 mg 2′-amino-1-fluoro-3,7-bis(2-fluoropyridin-3-yl)-1′-methyl-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidin]-6′(5′H)-one as a white solid.
Reaction SMILES: C[O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][O:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)[CH2:12][CH2:13][C:7]=2[C:6]([O:27]C)=[C:5]([O:29][CH3:30])[C:4]=1[O:31][CH3:32].N1C(C(O)=O)=CC=CC=1C(O)=O.C1COCC1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(=O)(O)[O-].[Na+].O>[CH3:32][O:31][C:4]1[C:3](=[O:2])[C:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][O:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)[CH2:12][CH2:13][C:7]=2[C:6](=[O:27])[C:5]=1[O:29][CH3:30]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCOc1ccc3ccccc3n1)CC2
Agent: O=C(O)c1cccc(C(=O)O)n1
Agent: O=C([O-])O
Agent: O=[N+]([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: COC1=C(OC)C(=O)C2=C(CCC(CCOc3ccc4ccccc4n3)CC2)C1=O
Reaction time: 0.25 h
Yield: 64.8 %

Procedure:
To a mixture of 2-[2-(1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-yl)ethoxy]quinoline (580 mg), pyridine-2,6-dicarboxylic acid (667 mg), THF (18 ml), and water (6 ml) was added an water (6 ml) solution of CAN (2.92 g) with cooling with ice. After being stirred for 15 min, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo and the residue was recrystallized from ethyl acetate to obtain the entitled compound (350 mg).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:51])[C:19]([C:26]3[N:27]=[C:28]([NH:31]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:29][CH:30]=3)=[N:20][O:21][CH2:22][C:23]([NH2:25])=[S:24])[C:15](=[O:52])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].FC(F)(F)C(O)=O>>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:51])[C:19]([C:26]3[N:27]=[C:28]([NH2:31])[S:29][CH:30]=3)=[N:20][O:21][CH2:22][C:23]([NH2:25])=[S:24])[C:15](=[O:52])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(N)=S)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(N)=S)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of the product of Step B and 12 ml of trifluoroacetic acid was stirred for 30 minutes at room temperature and part of the acid was evaporated under reduced pressure. 120 ml of isopropyl ether were added thereto. Efflorescence occured and the mixture was occur filtered. The product was rinsed with isopropyl ether and dried to obtain the syn isomer of 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-(2-amino-2-thioxoethoxyimino)-acetamido]-ceph-3-eme-4-carboxylic acid identical to the product of Example 16.
Reaction SMILES: [NH2:1][C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][C:4]1[CH:11]=[C:9]([I:10])[C:8]([O:12][C:13]2[CH:20]=[C:18]([I:19])[C:17]([OH:21])=[C:15]([I:16])[CH:14]=2)=[C:6]([I:7])[CH:5]=1.[CH3:25][C:26](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:27].O>C1COCC1.CN(C)C1C=CN=CC=1>[C:26]([O:23][C:22](=[O:24])[C@H:2]([CH2:3][C:4]1[CH:5]=[C:6]([I:7])[C:8]([O:12][C:13]2[CH:14]=[C:15]([I:16])[C:17]([OH:21])=[C:18]([I:19])[CH:20]=2)=[C:9]([I:10])[CH:11]=1)[NH2:1])(=[O:27])[CH3:25]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)OC(=O)[C@@H](N)Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1
Reaction time: 0.75 h
Yield: 115.5 %

Procedure:
The N-FMOC protected L-Thyroxine (26.3 g, 23.2 mmol) was dissolved in 150 mL THF, 3.28 mL (34.8 mmol) of acetic arthydride added, 283 mg (2.32 mmol) of 4-dimethylaminopyridine added, and reaction stirred under N2 for 45 minutes, then poured into 400 mL H2O and extracted with CHCl3 (3×400 mL). The CHCl3 extracts were combined, dried over Na2SO4, and solvent removed in vacuo. The residue was then purified by silica gel column chromatography, eluting with CH2 Cl2/MeOH/HOAc (90/10/0.4, v/v), to yield 21.95 g (91%) of the desired O-acetyl thyroxine as a beige solid; 1H NMR (300 MHz, DMSO-D6) d 7.12-7.91 (m, 12H), 4.07-4.31 (m, 4H), 3.07-3.19 (m, 1H), 2.82 (t, 1H), 2.29-2.40 (m, 3H); mass spec (FAB) (M+H)+1042.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N:15]1[O:16][N:17]=[C:18]2[CH:23]=[C:22]([C:24](Cl)=[O:25])[CH:21]=[CH:20][C:19]=12>ClCCl>[CH:1]1([NH:7][C:24]([C:22]2[CH:21]=[CH:20][C:19]3=[N:15][O:16][N:17]=[C:18]3[CH:23]=2)=[O:25])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: O=C(Cl)c1ccc2nonc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)c1ccc2nonc2c1
Reaction time: 1 h
Yield: 27 %

Procedure:
To a solution of cyclohexylamine (1 ml) and triethylamine (1.7 ml) in dichloromethane (20 ml) was added a solution of [2,1,3]-benzoxadiazole-5-carbonylchloride (730 mg, 4 mmol) in dichloromethane (10 ml). After stirring the mixture for 1 hour, the organic phase was washed with 1N HCl and conc. NaHCO3 solution, dried over magnesium sulfate, and concentrated under vacuum. The residue was triturated with ether to give a white solid (265 mg, yield=27%). Mp=172-173° C., 1H NMR (300 MHz, CDCl3) δ 8.15 (s, 1H), 7.90 (d, 1H, J=9.0 Hz); 7.82 (d, J=9.0 Hz, 1H); 6.09 (“s”, NH, 1H), 4.05-3.97 (m, 1H) and 2.09-1.18 ppm (m, 10H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:13][C@H:12]([N:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH:23][C@@H:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26][CH2:25]4)[C:17]=3[CH:16]=[CH:15]2)[CH2:11][C@H:10]1[CH2:33][N:34]([CH3:39])[S:35]([NH2:38])(=[O:37])=[O:36])(C(C)(C)C)(C)C.C(O)C.Cl>O1CCCC1.O>[C@@H:24]1([NH:23][C:22]2[C:17]3[CH:16]=[CH:15][N:14]([C@@H:12]4[CH2:11][C@@H:10]([CH2:33][N:34]([CH3:39])[S:35]([NH2:38])(=[O:37])=[O:36])[C@@H:9]([OH:8])[CH2:13]4)[C:18]=3[N:19]=[CH:20][N:21]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1
Reactant: CN(C[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O[Si](C)(C)C(C)(C)C)S(N)(=O)=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CN(C[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[((1S,2S,4R)-2-[tert-Butyl(dimethyl)silyl]oxy-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)methyl]-N-methylsulfamide (25.0 mg, 0.0000438 mol) was dissolved in tetrahydrofuran (2.0 mL), ethanol (2.0 mL) and 1.00 M of hydrochloric acid in water (2.0 mL). The mixture was stirred overnight at room temperature. The solution was evaporated to dryness, and the residue was dissolved in methanol and treated with a 7.00 M solution of ammonia in methanol (0.1 mL). Solvents were again evaporated, and the residue was purified by silica gel chromatography, eluting with 2 to 10% methanol in dichloromethane to yield the product, 9.8 mg (49%). 1H-NMR (400 MHz, MeOD) δ 8.16 (s, 1H), 7.19 (m, 5H), 6.62 (d, 1H, J=3.6 Hz), 5.84 (t, J=7.7 Hz, 1H), 5.43 (ddd, J=4.5 Hz, 8.6 Hz, 12.8 Hz, 1H), 4.43 (t, J=3.7 Hz, 1H), 3.25 (dd, J=8.1 Hz, 13.7 Hz, 1H), 3.14 (dd, J=7.2 Hz, 13.7 Hz, 1H), 3.05 (ddd, J=3.3 Hz, 8.8 Hz, 15.8 Hz, 1H), 2.91 (m, 1H), 2.74 (m, 1H, 2.63 (m, 1H), 2.34 (ddd, J=1.1 Hz, 7.8 Hz, 13.6 Hz, 1H), 2.20 (m, 2H, 1.99 (m, 2H). LC/MS: Rt=1.51 min, ES+ 457 (AA standard).
Reaction SMILES: [OH:1][CH:2]([CH3:13])[CH2:3][NH:4][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[O:1]=[C:2]([CH3:13])[CH2:3][NH:4][C:5](=[O:12])[C:6]1[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=1
Reactant: CC(O)CNC(=O)c1ccncc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(=O)CNC(=O)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
A solution of 154 g N-(2-hydroxy-propyl)-isonicotinamide in 800 mL dichlormethane was added dropwise to a solution of 438 g Dess-Martin reagent in 1.2 L dichlormethane at 0° C. under nitrogen atmosphere. After 30 min at 0° C., the solution was stirred at RT for 4 h. The mixture was concentrated under vacuum and the resulting crude product was purified by flash chromatography (silica gel) to give 91 g of the desired product.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7](N)=[CH:6][CH:5]=1.Cl.N([O-])=O.[Na+].[I-:21].[K+]>O.OS(O)(=O)=O>[F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]([I:21])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: Nc1ccc(OC(F)(F)F)cc1C(=O)O
Reactant: [I-]
Agent: Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1cc(OC(F)(F)F)ccc1I
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The above 5-trifluoromethoxyanthranilic acid (68.8 g, 0.31 mol) is suspended in a mixture of concentrated HCl (50 mL) and water (300 mL), cooled to 0° C. and stirred. Sodium nitrite (24.2 g 0.35 mol) dissolved in water (50 mL) is slowly added taking care to maintain the temperature of the reaction mixture below 5° C. Stirring is continued at 0° C. for 30 minutes. Potassium iodide (91 g, 0.55 mol) is dissolved in a mixture of concentrated H2SO4 (19 mL) and water (130 mL) and added dropwise to the reaction mixture while keeping the temperature of the reaction mixture below 10° C. The mixture is then heated to 100° C. and stirred for 2 hours. After cooling to room temperature, the mixture is partitioned between EtOAc (1000 mL) and saturated sodium bisulfite solution (500 mL). The organic layer is washed again with saturated sodium bisulfite solution (500 mL) and then brine (500 mL), dried (MgSO4) and concentrated by rotary evaporator to give 5-trifluoromethoxy-2-iodobenzoic acid.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][NH2:9])=[CH:4][CH:3]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[N+:24]([C:27]1[CH:32]=[CH:31][C:30]([C@@H:33]2[CH2:35][O:34]2)=[CH:29][CH:28]=1)([O-:26])=[O:25]>CS(C)=O>[I:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][NH:9][CH2:35][C@@H:33]([C:30]2[CH:29]=[CH:28][C:27]([N+:24]([O-:26])=[O:25])=[CH:32][CH:31]=2)[OH:34])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc([C@@H]2CO2)cc1
Reactant: NCCOc1ccc(I)cc1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc([C@@H](O)CNCCOc2ccc(I)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a solution of [2-(4-iodophenoxy)ethyl]amine (6.14 g) in dimethyl sulfoxide (50 ml) was added N,O-bis(trimethylsilyl)acetamide (2.88 ml) and the mixture was stirred for 1 hour. To the mixture was added a solution of (2R)-2-(4-nitrophenyl)oxirane (3.21 g) in dimethyl sulfoxide (10 ml) and the mixture was stirred for 37 hours. After cooling to room temperature, the mixture was quenched by the addition of 5% acetic acid/water (120 ml) and stirred for 30 minutes. The mixture was basified with 1N sodium hydroxide and extracted with ethyl acetate (120 ml). The extract was washed with water (120 ml×2) and brine (120 ml), and dried over magnesium sulfate. Filtration followed by evaporation gave (1R)-2-[[2-(4-iodophenoxy)ethyl]amino]-1-(4-nitrophenyl)ethanol (7.52 g) as a brown solid. The compound was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][Si:3](OC)([CH3:5])[CH3:4].C(OCC)C.[CH2:13]([Si:16]([CH2:25][CH:26]=[CH2:27])([CH2:22][CH:23]=[CH2:24])[CH2:17][CH2:18][CH2:19][Mg]Br)[CH:14]=[CH2:15].Cl>O>[CH2:13]([Si:16]([CH2:25][CH:26]=[CH2:27])([CH2:22][CH:23]=[CH2:24])[CH2:17][CH2:18][CH2:19][Si:3]([O:2][CH3:1])([CH3:5])[CH3:4])[CH:14]=[CH2:15]
Reactant: CO[Si](C)(C)OC
Reactant: C=CC[Si](CC=C)(CC=C)CCC[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: C=CC[Si](CC=C)(CC=C)CCC[Si](C)(C)OC
Temperature: 0 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
Under a nitrogen atmosphere, dimethoxydimethylsilane (31) (1.0 ml, 7.0 mmol) was added to a reaction container, cooled down to 0° C., diethyl ether solution of 0.72M 3-(triallylsilyl)propylmagnesium bromide (24) (19.44 mL, 14 mmol) was added dropwise. After the dropwise adding, stirring was continued at room temperature for 5 hours. To the reaction mixture, water was added to stop the reaction, then 10% hydrochloric acid was added until the salt was completely dissolved. The obtained organic layer was separated and the obtained water layer was extracted with diethyl ether. The collected organic layer was washed each with saturated sodium bicarbonate aqueous solution and saturated saline solution in this order, dried over anhydrous magnesium sulfate, then filtered, concentrated under reduced pressure, obtaining {3-(triallylsilyl)propyl}(methoxy)dimethylsilane (32) represented by the following chemical reaction equation (yield: 1.5 g, yield (%): 72%).
Reaction SMILES: [ClH:1].CN1CCCC(C(O)=O)C1.[CH:12]([N:15]([CH:24]([CH3:26])[CH3:25])[CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])([CH3:14])[CH3:13].Cl>>[ClH:1].[CH:24]([N:15]([CH:12]([CH3:14])[CH3:13])[CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])([CH3:26])[CH3:25]
Reactant: CCOC(=O)CCCN(C(C)C)C(C)C
Agent: CN1CCCC(C(=O)O)C1
Agent: Cl
Product: CC(C)N(CCCC(=O)O)C(C)C

Procedure:
4-Diisopropylaminobutyric acid hydrochloride may be obtained by working according to the method described in Example 4 for the preparation of 1-methyl-3-piperidinecarboxylic acid hydrochloride, but starting with ethyl 4-diisopropylaminobutyrate (9.2 g) and 6 N aqueous hydrochloric acid solution (28.5 cc) and by heating for 6 hours under reflux. 4-Diisopropylaminobutyric acid hydrochloride (8 g), m.p. 136° C., is thereby obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]#[C:10][CH2:11][O:12]C2CCCCO2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[CH3:1][O:2][C:3]1([C:9]#[C:10][CH2:11][OH:12])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: COC1(C#CCOC2CCCCO2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC1(C#CCO)CCOCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 47.6 %

Procedure:
To a solution of 4-methoxy-4-[3-(tetrahydropyran-2-yloxy)-prop-1-ynyl]tetrahydropyran (3.8 g, 14.8 mmol), prepared as in step 2, in methanol (50 mL), was added a catalytic amount of pyridinium p-toluenesulfonate (PPTS). The resulting yellow solution was stirred under nitrogen for 17 hours at ambient temperature. The volatiles were removed in vacuo and the residue was dissolved in ethyl acetate and treated with saturated aqueous NH4Cl. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. Purification by chromatography on silica gel (100 g, 30% ethyl acetate: hexanes) provided 4-methoxy-4-(3-hydroxyprop-1-ynyl)tetrahydropyran (1.2 g, 47 %) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=1I)[CH3:20]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:22]1[CH:23]=[C:24]([S:27]([CH3:30])(=[O:28])=[O:29])[CH:25]=[CH:26][C:21]=1[CH2:19][CH3:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1ccc(S(C)(=O)=O)cc1I
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CCc1ccc(S(C)(=O)=O)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 1-ethyl-2-iodo-4-(methylsulfonyl)benzene (Intermediate 123), the title compound was obtained as an orange oil after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]([CH3:19])([CH2:15][CH2:16][C:17]#[N:18])[C:11](OC)=[O:12])=[CH:4][CH:3]=1.Cl.C([O-])([O-])=O.[K+].[K+]>CO.O=[Pt]=O>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([C:10]2([CH3:19])[CH2:15][CH2:16][CH2:17][NH:18][C:11]2=[O:12])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(CCC#N)c1ccc(Cl)nc1OC
Agent: O=[Pt]=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: COc1nc(Cl)ccc1C1(C)CCCNC1=O
Reaction time: 16 h
Yield: 775.1 %

Procedure:
To a stirred solution of methyl 2-(6-chloro-2-methoxypyridin-3-yl)-4-cyano-2-methylbutanoate (110 g, 390 mmol) and conc. HCl (60 mL) in MeOH (1 L) was added PtO2 (11 g) under N2. The suspension was degassed and refilled with H2 several times. Then the resulting mixture was stirred under 50 Psi of H2 at r.t for 16 hours. The reaction mixture was filtered and the combined filtrates were evaporated to dryness. To the above residue in MeOH (12 L) was added solid K2CO3 (2158 g, 15.6 mol) at r.t. The reaction mixture was heated at reflux for 16 hours. The reaction mixture was filtered, and the filter cake was washed with MeOH (5 L). The combined filtrates were evaporated to dryness, and the crude residue was partitioned between CH2Cl2 (10 L) and water (5 L). The aqueous layer was extracted with CH2Cl2 (5 L). The combined organic layers were washed with brine (5 L), dried over Na2SO4 and concentrated to dryness. The crude residue was triturated with MTBE to give 3-(6-chloro-2-methoxypyridin-3-yl)-3-methylpiperidin-2-one (770 g, 64%) as a white solid. 1H NMR was consistent with data described in the other synthetic route.
Reaction SMILES: [Na].[C:2]1([CH:9]=[CH:8][C:6]([OH:7])=[CH:5][CH:4]=1)[OH:3].Cl[CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14].[Cl-].[NH4+]>O.CN(C)C=O>[CH3:14][O:13][CH:12]([O:15][CH3:16])[CH2:11][O:3][C:2]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][CH:4]=1
Reactant: COC(CCl)OC
Reactant: Oc1ccc(O)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: COC(COc1ccc(O)cc1)OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The monosodium salt of hydroquinone prepared in Example 1 and dimethyl formamide (100 ml) were charged under nitrogen gas into a glass reaction vessel equipped with a mechanical stirrer, thermometer and addition funnel and were warmed to effect dissolution. The resulting solution was then allowed to warm to room temperature, and 1-chloro-2,2-dimethoxyethane was added dropwise over a period of about 20 minutes. After the addition was completed, the reaction mixture was heated at about 85° to 90° C. with stirring for a period of about 48 hours. After this time water (200 ml) was added, and the reaction mixture was neutralized with ammonium chloride. The reaction mixture was then extracted with chloroform, and the organic phase was separated from the aqueous phase. The organic phase was then stripped of solvent, leaving a red oil. This oil was distilled to yield the desired product 4-(2,2-dimethoxyethoxy)phenol as a pink oil boiling at 116° to 120° C. at 0.008 mm of Hg pressure.