Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][N:9]=[C:10]2[CH2:19][CH2:18][CH:17]([O:20][C:21](=[O:26])[CH:22]([CH3:25])[CH2:23][CH3:24])[CH:16]3[C:11]2=[CH:12][C:13](=[O:39])[CH:14]([CH3:38])[CH:15]3[CH2:27][CH2:28][C:29](=[O:37])[CH2:30][CH:31]([OH:36])[CH2:32][C:33]([OH:35])=[O:34])=[C:5]([CH3:40])[O:4][N:3]=1.[OH-].[Na+:42]>O1CCOCC1.O>[CH3:1][C:2]1[C:6]([CH2:7][O:8][N:9]=[C:10]2[CH2:19][CH2:18][CH:17]([O:20][C:21](=[O:26])[CH:22]([CH3:25])[CH2:23][CH3:24])[CH:16]3[C:11]2=[CH:12][C:13](=[O:39])[CH:14]([CH3:38])[CH:15]3[CH2:27][CH2:28][C:29](=[O:37])[CH2:30][CH:31]([OH:36])[CH2:32][C:33]([O-:35])=[O:34])=[C:5]([CH3:40])[O:4][N:3]=1.[Na+:42]
Reactant: CCC(C)C(=O)OC1CCC(=NOCc2c(C)noc2C)C2=CC(=O)C(C)C(CCC(=O)CC(O)CC(=O)O)C21
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCC(C)C(=O)OC1CCC(=NOCc2c(C)noc2C)C2=CC(=O)C(C)C(CCC(=O)CC(O)CC(=O)[O-])C21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
139 mg of 7-[5-(3,5-dimethylisoxazol-4-yl)methoxyimino-2-methyl-8-(2-methylbutyryloxy)-3-oxo-1,2,3,5,6,7,8,8a-octahydro-1-naphthyl]-3-hydroxy-5-oxoheptanoic acid (prepared as described in Example 11b) were dissolved in 2.7 ml of a 1:1 by volume mixture of dioxane and water. 2.35 ml of a 0.1N aqueous solution of sodium hydroxide were added dropwise over a period of minutes at 0° C. to the solution, which was then stirred for 1 hour at room temperature. At the end of this time, the solution was freeze-dried, to obtain 140 mg of the title compound as a colorless moisture sensitive powder.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][CH2:9][C:10]([OH:12])=[O:11])=O.[F:13][C:14]1[C:19]([CH:20]=O)=[CH:18][CH:17]=[CH:16][N:15]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[F:13][C:14]1[C:19]([CH:20]=[C:9]2[C:10](=[O:11])[O:12][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[N:8]2)=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: O=Cc1cccnc1F
Reactant: O=C(O)CNC(=O)c1cccs1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C1OC(c2cccs2)=NC1=Cc1cccnc1F
Temperature: 90 °C
Yield: 64.4 %

Procedure:
To a screw-capped test tube, N-(2-thienylcarbonyl)glycine (56 mg, 0.3 mmol), 2-fluoropyridin-3-carboxaldehyde (41 mg, 0.3 mmol), sodium acetate (25 mg, 0.3 mmol) and acetic anhydride (0.3 mL) were added. The test tube was sealed, and it was then stirred at an external temperature of 90° C. Three hours later, the temperature of the reaction solution was returned to room temperature, and water (1.5 mL) was then added thereto. The obtained mixture was stirred at the same temperature as described above for 1.5 hours. Thereafter, the precipitated crystal was collected by filtration, and it was washed with water (5 mL) and was then dried under reduced pressure, so as to obtain 53 mg of the above-captioned compound.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N:14]=[C:15]=[S:16])[C:11]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][C:15]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)=[S:16])[C:11]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CCNCC1
Reactant: CN1CCN(c2cc3nc(C(C)(C)C)sc3cc2N=C=S)CC1
Product: CN1CCN(c2cc3nc(C(C)(C)C)sc3cc2NC(=S)N2CCCCC2)CC1

Procedure:
Reaction of 2-tert-butyl-6-isothiocyanato-5-(4-methyl-piperazin-1-yl)benzothiazole described in Example 2 with piperidine under conditions described in Example 1 gives 2-tert-butyl-6-[(piperidin-1-yl)thiocarbonylamino]-5-(4-methyl-piperazin-1-yl)benzothiazole, melting at 202°-206°.
Reaction SMILES: [F:1][C:2]1[C:3]([F:26])=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][NH:18][C@@H:17]([CH2:21][CH2:22][O:23][CH3:24])[CH2:16]3)[C:12]3[CH:11]=[CH:10][S:9][C:8]=3[NH:7][C:6]=2[CH:25]=1.C=O.[C:29](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[C:3]([F:26])=[CH:4][C:5]2[N:14]=[C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH3:29])[C@@H:17]([CH2:21][CH2:22][O:23][CH3:24])[CH2:16]3)[C:12]3[CH:11]=[CH:10][S:9][C:8]=3[NH:7][C:6]=2[CH:25]=1
Reactant: COCC[C@H]1CN(C2=Nc3cc(F)c(F)cc3Nc3sccc32)CCN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: COCC[C@H]1CN(C2=Nc3cc(F)c(F)cc3Nc3sccc32)CCN1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.6 %

Procedure:
Combine (S)-6,7-difluoro-10-[3-(2-methoxy-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene (207.2 mg, 0.55 mmol), formaldehyde (48.9 μL, 0.60 mmol, 37% in water), and dichloromethane (8.0 ml). Stir the mixture at ambient temperature for 5 minutes and then add sodium triacetoxyborohydride (174.0 mg, 0.82 mmol). After stirring for 30 minutes at ambient temperature, quench the reaction with saturated sodium bicarbonate. Remove the organic portion and wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Purify the residue on silica gel using a gradient of dichloromethane to dichloromethane/methanol (90:10) to give 176.2 mg (82%) of the title compound: mass spectrum (ion spray): m/z=393.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[CH:3]=1.[Cl:12][S:13](O)(=[O:15])=[O:14]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[S:13]([Cl:12])(=[O:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccc2c(c1)CCCC2
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1S(=O)(=O)Cl)CCCC2
Yield: 95.4 %

Procedure:
A solution of 20 g (0.137 mol) 2-methyl-5,6,7,8-tetrahydro-naphthalene in 200 mL CHCl3 was added to 48 g (0.412 mol) chlorosulfonic acid at 0° C. After 2 hrs at room temperature the solution was slowly poured onto ice. The organic phase was washed, dried and concentrated to give 32 g 2-methyl-5,6,7,8-tetrahydro-naphthalene-sulfonic acid chloride used directly for the subsequent reaction.
Reaction SMILES: [OH:1][CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:13]2)=[O:11])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37].O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:36]([O:1][CH:2]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]([CH:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH2:13]2)=[O:11])=[CH:7][CH:8]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:38])[CH3:37]
Reactant: O=C(Nc1ccc(C(O)c2ccccc2)cc1)C1CC(c2cccnc2)=NO1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Temperature: 25 °C
Yield: 91.7 %

Procedure:
) A suspension of compound (50) (0.021 mol), N,N-dimethyl-4-pyridinamine (0.042 mol) and triethylamine (catalytic quantity) in CH2Cl2 (100 ml) was stirred at RT. Acetic acid anhydride (0.042 mol) was added and the resulting reaction mixture was stirred and refluxed until a clear solution was obtained. The mixture was stirred and refluxed for an extra 30 minutes, then cooled to RT. Water was added. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure, yielding 8.0 g of (±)-[4-[[[4,5-dihydro-3-(3-pyridinyl)-5-isoxazolyl]-carbonyl]amino]phenyl]phenylmethyl acetate (compound 414).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[C:9]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31](=[O:36])C(Cl)(Cl)Cl)=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:11][CH:10]=1.O>O1CCOCC1>[C:9]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:10]=[CH:11][C:12]([C:15]([N:17]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[CH2:21][N:20]3[C:28]([C:31]([NH:1][CH2:2][C:3]4[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=4)=[O:36])=[CH:29][CH:30]=[C:19]3[CH2:18]2)=[O:16])=[CH:13][CH:14]=1
Reactant: O=C(c1ccc(-c2ccccc2)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Reactant: NCc1cccnc1
Solvent: O
Solvent: C1COCCO1
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(-c3ccccc3)cc1)C2
Yield: 10.6 %

Procedure:
A solution of 0.216 g (0.002 mol) of 3-aminomethylpyridine and 0.508 g (0.001 mol) of 1-[10-(1,1′-biphenyl-4-ylcarbonyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]-2,2,2-trichloroethanone of Step B in 25 mL of 1,4-dioxane was heated overnight under reflux with stirring. The cooled reaction mixture was poured into 200 mL of water. The solid was collected and dried to provide the title compound (0.053 g).
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11].[CH:14]([Mg]Br)=[CH2:15].[Cl-].[NH4+]>C1COCC1>[OH:1][CH:2]([CH:14]=[CH2:15])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: C=C[Mg]Br
Reactant: COC(=O)CCCCCCCC=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)CCCCCCCC(=O)OC
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
To a solution of methyl 9-oxononanate (5.26 g) in THF (60 ml) was dropwise added 0.95M vinyl magnesium bromide (31.1 ml) at −30° C. and then stirred for 30 minutes at −25° C. The reaction mixture was poured into saturated ammonium chloride aqueous solution and then extracted with diethyl ether. The organic layer was washed with saturated brine, dried over magnesium sulfate anhydride, and then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to give methyl 9-hydroxy-10-undecenate (3.41 g, 56.3%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:12])[CH:8]=2)[N:3]=1.[OH:13][C:14]1[CH:27]=[CH:26][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:16][CH:15]=1.N1C2C(=CC=CC=2)C=CC=1>>[F:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([O:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:26][CH:27]=1)[CH:11]=[CH:10]2
Reactant: CCOC(=O)C(C)Oc1ccc(O)cc1
Reactant: Fc1ccc2nc(Cl)ccc2c1
Solvent: c1ccc2ncccc2c1
Product: CCOC(=O)C(C)Oc1ccc(Oc2ccc3cc(F)ccc3n2)cc1

Procedure:
was prepared from 2-chloro-6-fluoroquinoline and ethyl 2-(4-hydroxyphenoxy)propionate following essentially the same procedure as that described in Example 1. The compound was isolated as a pale yellow oil. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 8.1-6.8 (9H, m, quinoline and phenyl protons); 4.8 (1H, q, CH-CH3); 4.3 (2H, q, OCH2 -CH3); 1.6 (3H, d, CH-CH3); 1.2 (3H, t, OCH2 -CH3).
Reaction SMILES: [C:1]([CH2:5][C:6]([OH:8])=O)([CH3:4])([CH3:3])C.O.O[C:11]1SC2C=CC=CC=2N=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:35][C:36]([CH3:58])([CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:51][CH:50]=1)[C:37]([NH:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:38]>C(OCC)(=O)C>[CH3:11][CH:5]([CH:1]([CH3:3])[CH3:4])[C:6]([NH:35][C:36]([CH3:58])([CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:51][CH:50]=1)[C:37]([NH:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:38])=[O:8]
Reactant: CC(C)(C)CC(=O)O
Reactant: Oc1nc2ccccc2s1
Reactant: CC(N)(Cc1c[nH]c2ccccc12)C(=O)NCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C(C)C(=O)NC(C)(Cc1c[nH]c2ccccc12)C(=O)NCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
A solution of 0.14 g (1.2 mmol) of tert-butylacetic acid in 5 ml of ethyl acetate was treated with 0.367 g (2.4 mmol) of hydroxybenzothiazole hydrate, and 0.247 g (1.2 mmol) of dicyclohexylcarbodiimide. After stirring at room temperature for one hour, the product of Example 12 (0.321 g, 1 mmol) was added, together with a few additional milliliters of ethyl acetate. This mixture was stirred overnight at room temperature, and the crude product isolated. Following purification by column chromatography on silica gel, there was obtained 0.095 g of (±)-α-[(2,3-dimethyl-1-oxobutyl)-amino ]-α-methyl-N-(2-phenylethyl)-1H-indole-3-propanamide, mp 104°-109° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([C:13]3[S:14][C:15](SC)=[CH:16][CH:17]=3)=[CH:11][N:12]=2)=[CH:4][CH:3]=1.Cl[C:21]1C=CC=C(C(OO)=O)C=1.[S:31]([O-:35])([O-])(=O)=[O:32].[Na+].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C:13]3[S:14][C:15]([S:31]([CH3:21])(=[O:35])=[O:32])=[CH:16][CH:17]=3)=[CH:11][N:12]=2)=[CH:6][CH:7]=1
Reactant: O=S(=O)([O-])[O-]
Reactant: CSc1ccc(-c2cnc(-c3ccc(F)cc3)s2)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2cnc(-c3ccc(F)cc3)s2)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 2-(4-fluorophenyl)-5-(5-methylthiothien-2-yl)thiazole (1.07 g, 0.0035 mole) in methylene chloride (50 mL) was added dropwise a solution of m-chloroperbenzoic acid (1.7 g, 0.0084 mole) in methylene chloride (25 mL). After complete addition the mixture was stirred at room temperature for approximately 18 hours. Approximately 100 mL of an aqueous 10% sodium sulfate solution was added, and the mixture was stirred for about 15 minutes. The mixture was washed in succession with an aqueous, saturated, sodium bicarbonate solution, water, and an aqueous, saturated, sodium chloride solution. A thin layer chromatograph of the organic phase indicated that starting material remained. Thus the washed organic phase was diluted with methylene chloride, and an additional 1.7 grams of m-chloroperoxybenzoic acid was added. This mixture was stirred and heated at reflux until only one spot was seen by thin layer chromatography. Approximately 100 mL of an aqueous 10% sodium sulfate solution was added, and the mixture was stirred for about 15 minutes. This mixture was washed in succession with an aqueous, saturated sodium bicarbonate solution, water, and an aqueous, saturated, sodium chloride solution. The washed organic phase was evaporated under reduced pressure, leaving a solid residue. This residue was purified by column chromatography on silica gel, elution with methylene chloride:ethyl acetate (19:1), to yield 0.59 g of 2-(4-fluorophenyl)-5(5-methylsulfonylthien-2-yl)thiazole as a solid, mp 183°-184° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Br:19][C:20]1[C:21]([CH:27]=[O:28])=[N:22][CH:23]=[CH:24][C:25]=1[CH3:26].[F:29][C:30]([Si](C)(C)C)([F:32])[F:31]>C1COCC1.C(OCC)(=O)C>[Br:19][C:20]1[C:21]([CH:27]([OH:28])[C:30]([F:32])([F:31])[F:29])=[N:22][CH:23]=[CH:24][C:25]=1[CH3:26]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1ccnc(C=O)c1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccnc(C(O)C(F)(F)F)c1Br
Temperature: -15 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
Tetrabutylammonium fluoride (1.0 mol/L) in THF (1.2 mL, 1.20 mmol) was added dropwise to a solution of 3-bromo-4-methyl-pyridine-2-carbaldehyde (150 mg, 0.75 mmol), and (trifluoromethyl)trimethylsilane (2.0 mol/L) in THF (0.49 mL, 0.975 mmol) in THF (10 mL) cooled at −15° C. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (25 mL). The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo to provide a residue that was purified by flash chromatography (12 g, Silica, 0-30% ethyl acetate in heptane). Desired fractions were combined and evaporated in vacuo to afford the title compound as a white solid (90 mg, 44%), which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Cl:14][C:15]1[CH:16]=[C:17]([N:22]=[C:23]=[O:24])[CH:18]=[CH:19][C:20]=1[Cl:21]>CN(C)C=O>[Cl:14][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:24])[NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7](=[O:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: CCOC(=O)C(=O)c1csc(N)n1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccc(Cl)c(Cl)c2)n1

Procedure:
Following a procedure similar to that described in Preparation 1, the desired compound was prepared from 10 g of ethyl 2-aminothiazol-4-ylglyoxylate, 10 g of 3,4-dichlorophenyl isocyanate and 100 ml of dimethylformamide. The resulting product was a pale yellow powder having the following physical properties.
Reaction SMILES: [CH:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])OCC.[O:11]=[C:12]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[O:27][C:14]2([CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH2:13]1.C(N(C(C)C)C(C)C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:9]([O:8][CH:1]([O:5][CH2:6][CH3:7])[CH:13]1[C:14]2([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]2)[O:27][C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:12]1=[O:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1ccccc1O2
Reactant: CCOC(OCC)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(OCC)C1C(=O)c2ccccc2OC12CCN(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 101 %

Procedure:
To triethyl orthoformate (85 mL, 510 mmol) in dry dichloromethane (460 mL) under nitrogen at −10° C. was added dropwise BF3OEt2 (65 mL, 510 mmol). The solution was allowed to warm to 0° C. and was stirred for 10 minutes. The solution was cooled to −78° C. prior to the slow dropwise addition of tert-butyl 4-oxospiro[chromane-2,4′-piperidine]-1′-carboxylate (55 g, 170 mmol) in dichloromethane (25 mL). N-ethyl-N-isopropylpropan-2-amine (100 mL, 600 mmol) was added over a 30 minutes period, and the mixture was slowly warmed to 25° C. and was stirred at this temperature overnight. The reaction mixture was diluted with dichloromethane (500 mL) followed by saturated aqueous sodium bicarbonate solution (500 mL). The layers were separated, and the organic layer was washed with additional sodium bicarbonate (500 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (0-25% ethyl acetate in hexane) to provide tert-butyl 3-(diethoxymethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-1′-carboxylate (72 g, 91%) as an orange oil. ESI-MS m/z calc. 419.5, found 420.3 (M+1)+; Retention time: 2.50 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([I:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O=S(Cl)Cl.[CH3:19]O>>[CH3:19][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([I:14])[CH:9]=[C:10]([N+:11]([O-:13])=[O:12])[C:2]=1[F:1]
Reactant: CO
Reactant: O=C(O)c1cc(I)cc([N+](=O)[O-])c1F
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(I)cc([N+](=O)[O-])c1F
Temperature: 25 °C
Yield: 96 %

Procedure:
2-Fluoro-5-iodo-3-nitro-benzoic acid (2.0 g, 6.43 mmol) and SOCl2 (918 mg, 7.72 mmol) were added to 20 mL MeOH, and the mixture was refluxed for two hours and then cooled to room temperature. Solvent was evaporated under reduced pressure and the residue was dissolved in EtOAa. The EtOAc slolution was washed with brine, dried over NasSO4, filtered and concentrated under reduced pressure to give 2.0 g (96%) of 2-fluoro-5-iodo-3-nitro-benzoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[C:14]([C:15]3[C:16]([CH3:22])=[N:17][O:18][C:19]=3[CH2:20][OH:21])=[CH:13][N:12]([CH3:23])[N:11]=2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:31][S:32]([O:21][CH2:20][C:19]1[O:18][N:17]=[C:16]([CH3:22])[C:15]=1[CH:14]1[CH2:13][N:12]([CH3:23])[N:11]=[C:10]1[C:8](=[O:9])[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:34])=[O:33]
Reactant: Cc1noc(CO)c1-c1cn(C)nc1C(=O)c1ccc(Cl)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1noc(COS(C)(=O)=O)c1C1CN(C)N=C1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
To a solution of (4-chlorophenyl)(4-(5-(hydroxymethyl)-3-methylisoxazol-4-yl)-1-methyl-1H-pyrazol-3-yl)methanone (0.05 g, 0.15 mmol) in DCM (10 mL), was added triethylamine (0.1 mL) and methane sulfonyl chloride (0.05 mL) at room temperature. The mixture was stirred for 2 h at room temperature. DCM (50 mL) and saturated sodium bicarbonate solution (20 mL) were added. The combined organic layers were dried over anhydrous sodium sulfate and concentrated to afford the titled product as yellow oil (0.035 g, 56%). LC/MS m/z 409 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>>[NH3:10].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([N:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]1)=[O:7]
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccnc(Cl)c1
Product: CN1CCN(C(=O)c2ccnc(Cl)c2)CC1
Product: N

Procedure:
The title compound was prepared as described for Example 1 using 2-chloroisonicotinic acid and 1-methylpiperazine. The crude product was purified on a silica gel column using chloroform/methanolkconc. NH3(aq), (100:10:1), as the eluent to give the title compound as a colorless oil. Yield: 68%: 1H NMR (CDCl3, 400 MHz) δ 8.51 (d, J=5 Hz, 1 H), 7.57 (s, 1 H), 7.43 (dd, J=5, 1 Hz, 1 H), 3.66-3.58 (m, 2 H), 3.28-3.21 (m, 2 H), 2.41-2.34 (m, 2 H), 2.30-2.24 (m, 2 H), 2.20 (s, 3 H); MS (TSP) niz 240 (M++1).
Reaction SMILES: C([O:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][C:10]=1[CH:18]=[CH:19][C@H:20]([OH:31])[C@@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH3:22])C1C=CC=CC=1>CCOC(C)=O.[Pd]>[NH2:15][C:14]1[C:9]([OH:8])=[C:10]([CH2:18][CH2:19][C@H:20]([OH:31])[C@@H:21]([O:23][Si:24]([C:27]([CH3:29])([CH3:28])[CH3:30])([CH3:26])[CH3:25])[CH3:22])[CH:11]=[CH:12][CH:13]=1
Reactant: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O)C=Cc1cccc([N+](=O)[O-])c1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](O)CCc1cccc(N)c1O
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A mixture of (3S,4S)-1-(2-benzyloxy-3-nitrophenyl)-4-(tert-butyldimethylsilyloxy)-1-penten-3-ol (P0015; 610 mg) and 10% Pd—C (120 mg) in EtOAc (6 ml) was stirred under hydrogen atmosphere at atmospheric pressure for 1 hour. Pd—C was removed by filtration through Celite. The filtrate was filtered through silica gel (6 g) and evaporated to give (3S,4S)-1-(3-amino-2-hydroxyphenyl)-4-(tert-butyldimethylsilyloxy)pentan-3-ol (P0016; 444.9 mg) as a brown solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13](C(Br)Br)[C:12]([Br:18])=[CH:11][C:6]=1C(OC)=O)(=O)[CH3:2].[C:19](=[O:22])([O-])[O-:20].[Ca+2].[C:24](=[O:27])([O-])[O-].[K+].[K+].[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1>O1CCOCC1.O.C(OCC)(=O)C>[Br:18][C:12]1[C:13]([CH:24]=[O:27])=[CH:14][C:5]([O:4][CH2:1][C:2]2[CH:37]=[CH:38][C:31]([F:30])=[CH:32][CH:33]=2)=[C:6]([CH:11]=1)[C:19]([O:20][CH2:35][C:34]1[CH:37]=[CH:38][C:31]([F:30])=[CH:32][CH:33]=1)=[O:22]
Reactant: COC(=O)c1cc(Br)c(C(Br)Br)cc1OC(C)=O
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=Cc1cc(OCc2ccc(F)cc2)c(C(=O)OCc2ccc(F)cc2)cc1Br
Reaction time: 8 h

Procedure:
To a suspension of methyl 2-(acetyloxy)-5-bromo-4-(dibromomethyl)benzoate (may be prepared as described in Description 23; 1 g, 2.25 mmol) in 1,4-dioxane (5 ml)/water (5 ml) was added calcium carbonate (0.68 g, 6.74 mmol). The mixture was heated in a microwave for 3.5 hours, cooled and the solvent removed in vacuo. The intermediate was suspended in N,N-dimethylformamide (10 ml) and potassium carbonate (0.78 g, 5.62 mmol) and 4-fluorobenzyl bromide (0.61 ml, 4.94 mmol) were added and the mixture stirred for overnight. The solvent was removed in vacuo and the residue taken up in ethyl acetate/H2O (10 ml/10 ml). The organic layer was dried and the solvent removed in vacuo. The residue was redissolved in N,N-dimethylformamide (3 ml) and potassium carbonate (0.78 g, 5.62 mmol) and 4-fluorobenzyl bromide (0.61 ml, 4.94 mmol) added and stirred for 2 hours. Ethyl acetate (20 ml) and water (10 ml) were added, The organic layer was washed further with water (2×10 ml), dried (MgSO4) and the solvent removed in vacuo. Purification by column chromatography (SiO2, 6:1 cyclohexane/ethyl acetate) yielded the title compound as an oil. 920 mg.