Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(OOS([O-])(=O)=O)([O-])(=O)=[O:2].[K+].[K+].[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[O:27][C:20]3([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:19][C:18]=2[CH:28]=1>C(#N)C.O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[O:27][C:20]3([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:19](=[O:2])[C:18]=2[CH:28]=1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Reactant: Brc1ccc2c(c1)CC1(CCCCCC1)O2
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1c2cc(Br)ccc2OC12CCCCCC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred mixture of 17.57 g of potassium persulfate, 5.19 g of cupric sulfate and 100 ml of distilled water was added a solution of 9.13 g of 5-bromo-spiro[benzofuran-2(3H),1'-cycloheptane] in 100 ml of acetonitrile. The mixture was stirred and heated to reflux; after 1.5 hours, GC showed only 6% unreacted starting material. Another 3.51 g of potassium persulfate was added and the mixture was refluxed for another hour and thereafter cooled to room temperature. The mixture was diluted with water (1.0 liter) and extracted with ether (1×500 ml, 2×250 ml). The combined ether extracts were washed with water (250 ml) and saturated sodium chloride solution (250 ml), dried overnight over anhydrous sodium sulfate, filtered and concentrated in vacuo to a gum weighing 7.63 g. This material was taken up in 100 ml of hexane and gravity-filtered to remove insoluble material, and the flask, filter paper and insoluble material were rinsed with another 100 ml of hexane. The hexane filtrate was concentrated in vacuo to an oil weighing 5.84 g. Vacuum distillation of this material afforded 2.76 g of viscous distillate, b.p. 135°-140° C. @ 0.15 mm.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][C:9](OS(C(F)(F)F)(=O)=O)=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1.[CH3:21][C:22]([OH:26])([C:24]#[CH:25])[CH3:23].C(N(CC)CC)C>CN(C)C=O.[Cu]I>[CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:25]#[C:24][C:22]([OH:26])([CH3:23])[CH3:21])=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: CSc1ncnc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Reactant: C#CC(C)(C)O
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1ncnc2cc(C#CC(C)(C)O)ccc12
Yield: 174.2 %

Procedure:
4-(Methylthio)-7-(trifluoromethanesulphonyloxy)quinazoline (592 mg, 1.82 mmol) in dimethylformamide (20 ml) was reacted with 2-methyl-3-butyn-2-ol (0.53 ml, 0.54 mmol) in the presence of bis dichloro(triphenylphosphine)palladium (64 mg, 0.091 mmol), copper (I) iodide (20 mg) and triethylamine (1.1 ml, 0.8 mmol), at 90° C. for 2.5 hours. The solvent was removed in vacuo, aqueous hydrochloric acid (2N) was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate and the solvents were evaporated in vacuo. Purification by flash chromatography on silica gel, eluting with isohexane/ethyl acetate (55:45), yielded, 4-(methylthio)-7-(3-hydroxy-3-methylbut-1-ynyl)quinazoline (243 mg, 51% yield):
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[CH3:12][C:13]([CH3:17])([CH3:16])[C:14]#[CH:15]>C(N(CC)CC)C.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:15]#[C:14][C:13]([CH3:17])([CH3:16])[CH3:12])[CH:5]=[CH:6][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: C#CC(C)(C)C
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)C#Cc1ccc(C(=O)O)c(Cl)n1
Yield: 5 %

Procedure:
2,6-dichloropyridine-3-carboxylic acid (2.0 g, 10.42 mmol), 3,3-dimethylbut-1-yne (1.4 mL, 11.46 mmol), copper(I) iodide (0.198 g, 1.04 mmol) and bis(triphenylphosphine) palladium(II) chloride (1.46 g, 2.08 mmol) were stirred in 40 mL triethylamine at room temperature for 24 h. The solvent was removed in vacuo and the residue was purified by column chromatography using 10-50% MeOH/EtOAc to furnish 125 mg (5%) of the title compound as an orange solid. m/z=236 (M−1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2/[CH:11]=[C:12]1\[S:13][C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[NH:16][C:17]\1=[O:18].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.O[CH2:55][CH2:56][N:57]1[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1>O1CCCC1>[N:57]1([CH2:56][CH2:55][O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3/[CH:11]=[C:12]2\[S:13][C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=3[NH:16][C:17]\2=[O:18])[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1
Reactant: O=C1Nc2ccccc2S/C1=C\c1c[nH]c2ccc(O)cc12
Reactant: OCCN1CCCCC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: O=C1Nc2ccccc2S/C1=C\c1c[nH]c2ccc(OCCN3CCCCC3)cc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 14.7 %

Procedure:
To a solution of (Z)-2[(5-hydroxyindol-3-yl)methylene]-2H-1,4-benzothiazin-3(4H)-one (1.00 g, 3.24 mmol) and 1,1′-(azodicarbonyl)dipiperidine (1.23 g, 4.87 mmol) in dry tetrahydrofurane-(40 ml), tributylphosphine (0.98 g, 4.87 mmol) was added under nitrogen atmosphere keeping the mixture at 0–5° C. After 5 min N-(2-hydroxyethyl)piperidine (0.63 g, 4.88 mmol) was added at the same temperature. The cooling bath was removed and the mixture stirred at room temperature for 48 h. Then the solvent was removed under reduced pressure and the residue chromatographed (silica gel, eluent, ethyl acetate:ethanol (90:10) to (80:20)) to yield 0.2 g (22%) of the entitled product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17](B4OC(C)(C)C(C)(C)O4)=[CH:16][C:15]=3[O:29][CH3:30])=[O:12])[N:8]([CH3:31])[C:5]2=[N:6][CH:7]=1.Br[C:33]1[N:34]=[C:35]([C@H:43]2[CH2:48][CH2:47][C@H:46]([N:49]3[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]3)[CH2:45][CH2:44]2)[N:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[C:37]=12>>[Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([C:33]4[N:34]=[C:35]([C@H:43]5[CH2:44][CH2:45][C@H:46]([N:49]6[CH2:50][CH2:51][N:52]([CH3:55])[CH2:53][CH2:54]6)[CH2:47][CH2:48]5)[N:36]5[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[C:37]=45)=[CH:16][C:15]=3[O:29][CH3:30])=[O:12])[N:8]([CH3:31])[C:5]2=[N:6][CH:7]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2cc(Cl)cnc2n1C
Reactant: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1
Product: COc1cc(-c2nc([C@H]3CC[C@H](N4CCN(C)CC4)CC3)n3ccnc(C)c23)ccc1NC(=O)c1cc2cc(Cl)cnc2n1C

Procedure:
5-Chloro-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (34 mg) and 1-bromo-8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (30 mg) were reacted according to the procedure described in example 4 step 4c and purified by column chromatography (silica gel; dichloromethane with gradient 0 to 20% of methanol (containing 0.1% ammonium hydroxide)) to give 5-chloro-N-(2-methoxy-4-(8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazin-1-yl)phenyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (27 mg).
Reaction SMILES: [C:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:13]=2)[C:8](=[O:20])[C:7]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:26]N1C(C)(C)C(=O)N(Br)C1=O.S(=O)(O)[O-].[Na+]>ClCCl>[Br:26][C:11]1[CH:10]=[C:9]2[C:14](=[N:13][C:12]=1[N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=[C:7]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:8]2=[O:20]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CCCC3)ccc2c1=O
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CCCC3)c(Br)cc2c1=O

Procedure:
A solution of Example 74A (343.42 mg) and 1,3-dibromo-5,5-dimethylhydantoin (171.5 mg) in dichloromethane (15 mL) was stirred for 15 minutes, treated with 10% sodium bisulfite, and extracted with dichloromethane (50 mL). The extract was washed with water and brine, dried (MgSO4), filtered, and concentrated; and the concentrate was crystallized from dichloromethane/diethyl ether.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10]([CH3:12])([CH3:11])[S:9][CH2:8][CH2:7][N:6]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].[O:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]1[O:29][CH2:30][CH2:31][CH2:32][C:33]#[C:34][CH2:35]O>>[CH3:1][O:2][C:3]([CH:5]1[C:10]([CH3:12])([CH3:11])[S:9][CH2:8][CH2:7][N:6]1[S:13]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:35][C:34]#[C:33][CH2:32][CH2:31][CH2:30][O:29][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][O:23]2)=[CH:20][CH:21]=1)(=[O:15])=[O:14])=[O:4]
Reactant: OCC#CCCCOC1CCCCO1
Reactant: COC(=O)C1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Product: COC(=O)C1N(S(=O)(=O)c2ccc(OCC#CCCCOC3CCCCO3)cc2)CCSC1(C)C
Yield: 64.4 %

Procedure:
According to the procedure of Step 4 of Example 243, Mitsunobu coupling of 3.4 g (9.842 mmol) of 4-(4-hydroxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid methyl ester and 2.34 g (11.81 mmol) of 6-(tetrahydro-2H-pyran-2-yloxy)-2-hexyn-1-ol provided 3.33 g (64%) of methyl-2,2-dimethyl-4-[(4-{[6-(tetrahydro-2H-pyran-2-yloxy)-2-hexynyl]oxy}phenyl)sulfonyl]-3-thiomorpholine carboxylate as a colorless oil. Electrospray Mass Spec: 526.3 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].N1C=CC=CC=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:7][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:8]=1
Reactant: Cc1ccc([N+](=O)[O-])c(N)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc([N+](=O)[O-])c(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5-methyl-2-nitroaniline (4 mmol) and pyridine (8 mmol) in dry dichloromethane (15 mL) was added dropwise benzoyl chloride (8 mmol). The reaction mixture was stirred at room temperature for 8 h. The solvent was evaporated in vacuum, and the residue was subjected to flash chromatography on silica gel using a mixture of hexanes and CH2Cl2 (7:3) as eluent to afford N-(5-methyl-2-nitrophenyl)benzamide as a solid.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([O:12]CC)=O)[C:3]1=[O:15].[NH2:16][C:17]1[S:21][N:20]=[C:19]([CH2:22][CH3:23])[N:18]=1.BrC1C=CC=CC=1>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([NH:16][C:17]2[S:21][N:20]=[C:19]([CH2:22][CH3:23])[N:18]=2)=[O:12])[C:3]1=[O:15]
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Reactant: CCc1nsc(N)n1
Solvent: Brc1ccccc1
Product: CCc1nsc(NC(=O)c2c(O)cc(C)n(C)c2=O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.5 %

Procedure:
213 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxyl ate and 120 mg of 5-amino-3-ethyl-1,2,4-thiadiazole were added to 2.5 ml of bromobenzene, then, the mixture was stirred for 4 hours under heat refluxing condition. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration, and washed with a mixed solvent of t-butyl methyl ether and hexane and dried to obtain 231 mg of 1,6-dimethyl-N-(3-ethyl-1,2,4-thiadiazol-5-yl)-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 19) represented by the formula:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1[O:11][CH2:12][CH2:13][N:14]=1>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:13][NH:14][C:10](=[O:11])[CH3:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(O)cc1
Reactant: CC1=NCCO1
Solvent: ClCCl
Product: CC(=O)NCCOc1ccc(C)cc1

Procedure:
Combine 5.0 g (0.046 mol) 4-methylphenol and 3.9 g (0.46 mol) 2-methyl-2-oxazoline under a nitrogen atmosphere and heat to 175° C. for 18 hours. After this time, cool the reaction mixture and add 50 mL of methylene chloride. Wash the organics with 3×10 mL of 10% potassium hydroxide, dry over sodium sulfate and remove the solvents to obtain the title compound.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH:9]=[C:10]4[C@:15]3([CH3:16])[CH:14]=[CH:13][C@H:12]([OH:20])[CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[OH:21].[CH2:22](COC)OC.C(I)I>CCOCC.[Cu].[Zn]>[CH2:22]1[C@@H:13]2[C@H:12]([OH:20])[CH2:11][C:10]3[C@:15]([CH3:16])([C@H:14]12)[C@@H:17]1[C@H:7]([C@H:6]2[C@@:2]([CH2:19][CH2:18]1)([CH3:1])[C@@H:3]([OH:21])[CH2:4][CH2:5]2)[CH2:8][CH:9]=3
Reactant: COCCOC
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)C=C[C@@]43C)[C@@H]1CC[C@@H]2O
Agent: [Cu]
Agent: [Zn]
Solvent: ICI
Solvent: CCOCC
Product: C[C@]12CC[C@H]3[C@@H](CC=C4C[C@@H](O)[C@H]5C[C@H]5[C@@]43C)[C@@H]1CC[C@@H]2O
Temperature: 25 °C

Procedure:
To a stirred solution consisting of 1,5-androstadiene-3β,17β-diol in a mixture of dry ether and glyme is added zinc-copper couple and methylene iodide. This mixture is refluxed for approximately 4 hours, cooled to room temperature, diluted with ether and filtered. The filtrate is washed with aqueous sodium chloride, water and dried over anhydrous magnesium sulfate. The ether is removed under reduced pressure and the residue is crystallized from an acetone-hexane solution to yield 1β,2β-methylene-5-androstene-3β,17β-diol.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][C:15]=2[OH:22])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.CN(C)C=O.Cl[CH:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31]>C1(C)C=CC=CC=1>[N:7]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][C:15]=2[O:22][CH:29]([CH3:34])[C:30]([O:32][CH3:33])=[O:31])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: CCc1ccc(CN2CCOCC2)c(O)c1
Reactant: COC(=O)C(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCc1ccc(CN2CCOCC2)c(OC(C)C(=O)OC)c1
Temperature: 110 °C
Reaction time: 48 h
Yield: 84.5 %

Procedure:
To a one liter round bottom flask equipped with a mechanical stirrer and a thermometer was added 157.13 grams (1.14 moles--1.3 equiv.) of potassium carbonate, followed by 215.27 grams (0.875 mole--1.0 equiv.) of 89.9% pure 2-(morpholin-4-ylmethyl)-5-ethylphenol, and 230 mL (%Wt/Vol. Phenol to Solvent--93.6%) of N,N-dimethylformamide. The mixture was vigorously stirred and heated to 110° C., and then 139.3 grams (1.14 moles--1.3 equiv.) of methyl 2-chloropropanoate was added during a one hour period. Upon completion of addition, the reaction mixture was analyzed by GC, which indicated the reaction was incomplete. The reaction mixture was heated at 110° C. for seven hours. After this time, the reaction mixture was again analyzed by GC, which indicated the reaction was complete. The reaction mixture was filtered, and the orange filtrate was kept under a nitrogen atmosphere for about 48 hours. After this time, the filtrate was concentrated under vacuum at 90° C. and 10 mm of mercury to yield a red, brown liquid. The liquid was taken up in 200 mL of toluene, and the resulting solution was washed with two 500 mL portions of an aqueous saturated sodium chloride solution. The organic layer was separated from the aqueous layer, dried with magnesium sulfate, and filtered. The filtrate was concentrated under vacuum at 90° C. and 10 mm of mercury, yielding 252.7 grams of 83.6% pure methyl 2-[2-(morpholin-4-ylmethyl)-5-ethylphenoxy]propanoate (78.6% yield). The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].Cl[CH2:19][C:20]1[C:21]([CH2:37][O:38][CH3:39])=[N:22][C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[N:24][C:25]=1[CH3:26]>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:19][C:20]2[C:21]([CH2:37][O:38][CH3:39])=[N:22][C:23]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=3)=[N:24][C:25]=2[CH3:26])=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: COCc1nc(-c2cccc(C(F)(F)F)c2)nc(C)c1CCl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(C)nc(-c3cccc(C(F)(F)F)c3)nc2COC)cc1C

Procedure:
In analogy to the procedure described in example 113A], 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) was reacted with 5-chloromethyl-4-methoxymethyl-6-methyl-2-(3-trifluoromethyl-phenyl)-pyrimidine (example 148D]) to give the title compound as light yellow viscous oil.
Reaction SMILES: [SH:1][CH:2]([CH3:6])[C:3](=[O:5])[CH3:4].N1CCOCC1.[CH2:13]([NH:16][C:17](=[O:24])[C:18]#[C:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH2:15]>C(OCOCC)C>[CH2:13]([NH:16][C:17]([CH:18]1[C:3]([OH:5])([CH3:4])[CH:2]([CH3:6])[S:1][CH:19]1[Si:20]([CH3:21])([CH3:22])[CH3:23])=[O:24])[CH:14]=[CH2:15]
Reactant: C=CCNC(=O)C#C[Si](C)(C)C
Reactant: CC(=O)C(C)S
Solvent: CCOCOCC
Solvent: C1COCCN1
Product: C=CCNC(=O)C1C([Si](C)(C)C)SC(C)C1(C)O
Reaction time: 4 h
Yield: 81.8 %

Procedure:
A solution of 3-mercapto-2-butanone (2.1 g, 0.020 mol) and morpholine (1.5 g, 0.017 mol) in diethoxymethane (20 mL) was heated to reflux and treated with N-allyl-3-trimethylsilylpropiolic amide (3.04 g, 0.017 mol). The mixture is heated at reflux under a nitrogen atmosphere overnight. An additional portion of the 3-mercapto-2-butanone (0.7 g, 0.0067 mol) was added, and heating was continued for 4 hours more. A final portion of the 3-mercapto-2-butanone (0.7 g, 0.0067 mol) was added, heating was continued for 4 hours at reflux, then the mixture was cooled and evaporated under reduced pressure. The residue was extracted with two 40 mL portions of hot heptane, filtered, and allowed to cool (ice/salt bath). The resulting solid precipitate was collected by filtration and dried to give 4.0 g of 4-hydroxy-4,5-dimethyl-2-trimethylsilanyl-dihydrothiophene-3-carboxylic acid allylamide (84% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][N:15]([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH:5]=[CH:6][CH:7]=O.[O:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][CH2:7][N:25]2[C:26](=[O:28])[CH2:27][O:23][C:24]2=[O:29])[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][N:15]([CH3:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=C1COC(=O)N1
Reactant: CN(CCOc1ccc(C=CC=O)cc1F)c1ccccn1
Product: CN(CCOc1ccc(CCCN2C(=O)COC2=O)cc1F)c1ccccn1

Procedure:
In substantially the same manner as in Working Example 11, 3-fluoro-4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]cinnamaldehyde was condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic hydrogenation to yield 5-[3-[3-fluoro-4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]phenyl]propyl-2,4-oxazolidinedione, which was recrystallized from ethyl acetate-hexane to give colorless prisms, m.p.124-125° C.
Reaction SMILES: [OH:1][CH:2]([CH:28]1[CH2:32][O:31]C(C)(C)[O:29]1)[CH2:3][NH:4][C:5](=[O:27])[C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:26])(=[O:25])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:15]=2)=[CH:8][CH:7]=1>CO.O>[OH:1][CH:2]([CH:28]([OH:29])[CH2:32][OH:31])[CH2:3][NH:4][C:5](=[O:27])[C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:25])(=[O:26])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([C:21]([F:24])([F:22])[F:23])[CH:15]=2)=[CH:8][CH:7]=1
Reactant: CC1(C)OCC(C(O)CNC(=O)c2ccc(S(=O)(=O)Nc3ccc(F)c(C(F)(F)F)c3)cc2)O1
Solvent: O
Solvent: CO
Product: O=C(NCC(O)C(O)CO)c1ccc(S(=O)(=O)Nc2ccc(F)c(C(F)(F)F)c2)cc1

Procedure:
Analogously to Example 1l(b), 3.8 g (7.5 mmol) of 4-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]-benzoic acid-[2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamide] in methanol/water with cation exchanger is converted into the title compound. 1.74 g=83% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1([NH:8][C:9]2[C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:6]1>C(#N)C>[CH:5]1([NH:8][C:9]2[C:14]([C:15]([Cl:3])=[O:17])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH2:7][CH2:6]1
Reactant: O=C(O)c1cccnc1NC1CC1
Reactant: O=S(Cl)Cl
Solvent: CC#N
Product: O=C(Cl)c1cccnc1NC1CC1

Procedure:
Thionyl chloride (25 ml, 40.8 g, 0.343 mol) was charged in a thin stream to 9.00 g, 0.048 mol, of 2-(cyclopropylamino)-3-pyridine carboxylic acid from Example 2 in acetonitrile. The mixture was heated at reflux temperature for 30 minutes. The mixture was allowed to cool and the thionyl chloride was distilled off at 40° C./23 in. Hg until the pot contents became thick. Toluene (25 ml) was added and distillation of thionyl chloride and toluene at 40° C. was continued until about one-half of the liquid was distilled. The remaining solution was allowed to cool and stirred to promote crystallization. Heptane (25 ml) was added to the mixture with stirring and the mixture filtered under a nitrogen atmosphere to obtain the title compound.
Reaction SMILES: [Na].[CH2:2]=[C:3]1[CH2:6][CH:5]([C:7](=[O:9])[CH3:8])[CH2:4]1.[O-]CC.[Na+].[C:14](OCC)(=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>CCO>[CH2:2]=[C:3]1[CH2:6][CH:5]([C:7](=[O:9])[CH2:8][C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:4]1
Reactant: C=C1CC(C(C)=O)C1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: C=C1CC(C(=O)CC(=O)C(=O)OCC)C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium (1.15 g, 49.9 mmol) was dissolved in dry EtOH (30 mL, denaturated with 5% diethylether). Compound 8a (5.5 g, 49.9 mmol, crude) was dissolved in dry EtOH (45 mL) and the above prepared sodium ethoxide solution was added. This mixture was stirred at rt for 15 min and then diethyl oxalate (6.8 mL, 49.9 mmol) was added dropwise. The reaction mixture was placed in a pre-heated (to 67° C.) oil bath and stirred at this temperature for 4.5 h. The mixture was left at rt overnight. The solvent was removed, EA (100 mL) and 1 M HCl (70 mL) were added and organic phase was separated. The aq. phase was re-extracted with EA (50 mL). The combined organic phases were washed with water, brine and dried over anh. Na2SO4. The solvent was removed under reduced pressure and the residue was purified on silica using hexanes/MTBE 9:1 as eluent giving pure product 8b. Yield: 6.29 g, 56% over two steps. 1H-NMR (CDCl3), δ (ppm): 6.36 (s, 1H), 4.85-4.80 (m, 2H), 4.34 (q, J=8.0 Hz, 2H), 3.35-3.25 (m, 1H), 3.05-2.85 (m, 4H), 1.36 (t, J=8.0 Hz, 3H).
Reaction SMILES: [CH2:1]([C@@:8]([OH:28])([C:12]([N:14]1[C@H:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:17]2[O:16][C:15]1([CH3:27])[CH3:26])=[O:13])[CH2:9][CH:10]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]([NH:33][C@H:34]([C:39]([NH:41][NH2:42])=[O:40])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:32].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[CH3:29][O:30][C:31](=[O:32])[NH:33][C@H:34]([C:39]([NH:41][NH:42][CH2:10][CH2:9][C@:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([OH:28])[C:12]([N:14]1[C@H:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:17]2[O:16][C:15]1([CH3:27])[CH3:26])=[O:13])=[O:40])[C:35]([CH3:38])([CH3:37])[CH3:36]
Reactant: COC(=O)N[C@H](C(=O)NN)C(C)(C)C
Reactant: CC1(C)O[C@@H]2Cc3ccccc3[C@@H]2N1C(=O)[C@@](O)(CC=O)Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)NNCC[C@@](O)(Cc1ccccc1)C(=O)N1[C@H]2c3ccccc3C[C@H]2OC1(C)C)C(C)(C)C
Reaction time: 8 h

Procedure:
(S)-3-Benzyl-4-((3aS,8aR)-2,2-dimethyl-8,8a-dihydro-3 aH-indeno[1,2-d]oxazol-3-yl)-3-hydroxy-4-oxo-butyraldehyde (21h) (0.082 g, 0.21 mmol) and [N-(methoxycarbony)-L-tert-leucinyl]hydrazine (0.048 g, 0.23 mmol, prepared as reported JMC, 41, 3387, 1998) in dry THF (10 mL) was stirred for 3 h and [the LCMS (ESI+) shows 565 (M+)], then Na(OAc)3BH (0.137 g, 0.64 mmol) was added and stirred overnight. The reaction mixture was quenched with water and evaporated. The residue was dissolved in dichloromethane and washed with water, brine and dried. The crude product was analysed by LCMS (ESI+) which showed 567 (M+) the title compound with a minor quantity of the compound lacking the protection group on the indanol moiety [MS (ESI+): 527 (M+)]. This mixture was alkylated by the next step without purification.