Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[C@@H:6]([OH:19])[CH2:5]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C(C)=CC(C)=CC=1C.[C:53]([O:57][C:58]([N:60]1[C:64]([CH3:66])([CH3:65])[CH2:63][CH2:62][C@H:61]1[C@H:67]([C:71]1[CH:76]=[CH:75][C:74]([Cl:77])=[CH:73][C:72]=1[F:78])[C:68](O)=[O:69])=[O:59])([CH3:56])([CH3:55])[CH3:54]>C(Cl)Cl>[Cl:77][C:74]1[CH:75]=[CH:76][C:71]([C@@H:67]([C@H:61]2[N:60]([C:58]([O:57][C:53]([CH3:55])([CH3:54])[CH3:56])=[O:59])[C:64]([CH3:66])([CH3:65])[CH2:63][CH2:62]2)[C:68]([N:16]2[CH2:15][CH2:14][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][C@@H:6]([OH:19])[C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:18][CH2:17]2)=[O:69])=[C:72]([F:78])[CH:73]=1
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2ccc(Cl)cc2F)CCC1(C)C
Reactant: C[C@@H]1C[C@H](O)c2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Cl)cc4F)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
(5R,7R)-5-Methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (0.109 g, 0.356 mmol; see Example 3, Step 12), HATU (0.123 g, 0.324 mmol), and collidine (0.171 mL, 1.30 mmol) were added to a solution of (S)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)-2-(4-chloro-2-fluorophenyl)acetic acid (0.125 g, 0.324 mmol; prepared analogously to that described in Example B) in DCM (25 mL). The reaction was stirred overnight at room temperature. The reaction was partitioned between water (20 mL) and DCM (50 mL), and the layers were separated. The organics were washed with water (2×10 mL). The aqueous portion was back extracted with DCM (25 mL), dried (MgSO4) and concentrated to an oil that was purified by flash chromatography (5% MeOH/DCM) to give (S)-tert-butyl 5-((S)-1-(4-chloro-2-fluorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (0.116 g, 0.193 mmol, 59.5% yield). LC/MS=3.79 minutes, (APCI+) m/z=602 [M+H]+.
Reaction SMILES: [CH3:1]C1(C)[C@@H](/C=C\C(Cl)=O)[C@H]1C(O[C@H](C#N)C1C=CC=C(OC2C=CC=CC=2)C=1)=O.S(Cl)(Cl)=O.[CH3:34][C:35]1([CH3:62])[C@@H:37](/[CH:38]=[CH:39]\[C:40]([OH:42])=[O:41])[C@H:36]1[C:43]([O:45][C@H:46]([C:60]#[N:61])[C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([O:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:48]=1)=[O:44].[CH3:63][C:64]([C:67]([F:70])([F:69])[F:68])([OH:66])C>C(Cl)Cl>[CH3:34][C:35]1([CH3:62])[C@@H:37](/[CH:38]=[CH:39]\[C:40](=[O:42])[O:41][C:64]([O:66][CH3:1])([C:67]([F:70])([F:69])[F:68])[CH3:63])[C@H:36]1[C:43]([O:45][C@H:46]([C:60]#[N:61])[C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([O:53][C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:48]=1)=[O:44]
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Reactant: CC(C)(O)C(F)(F)F
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COC(C)(OC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C)C(F)(F)F

Procedure:
Under inert atmosphere, a mixture of 1.02 g of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[(Z)3-chloro-3-oxo-1-propenyl)-cyclopropane-carboxylate prepared by reaction of thionyl chloride and (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[(Z)3-hydroxy-3-oxo-1-propenyl]-cyclopropane-carboxylate and 9 ml of methylene chloride were stirred and 1.12 g of 1-methyl-1-trifluoromethyl-ethanol were added thereto. The mixture was stirred for 48 hours at room temperature and was then evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with a 8--2 mixture of hexane-ethyl ether to obtain 250 mg of (S)α-cyano-3-phenoxy-benzyl(1R,cis)2,2-dimethyl-3-[(Z)3-oxo-3-(1-methoxy-1-trifluoromethylethoxy)-1-propenyl]-cyclopropane-carboxylate with a melting point of 59° C. and a specific rotation of [α]D20 =+57°±2° (c=0.4% in benzene).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:24])[NH:11][C:12]2[S:13][CH:14]=[C:15]([C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=2)[CH:6]=[CH:7][CH:8]=1.[S:25]1[CH2:31][C:29](=[O:30])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:26]1=[S:27].[Cl-].[NH4+].N>C(O)C>[OH2:2].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:24])[NH:11][C:12]2[S:13][CH:14]=[C:15]([C:17](=[C:31]3[S:25][C:26](=[S:27])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:29]3=[O:30])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)Nc2cccc(OC)c2)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2cccc(OC)c2)n1
Product: O

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 1.75 g of ethyl 2-(3-m-methoxyphenylureido)thiazol-4-ylglyoxylate, 0.95 g of rhodanine-3-acetic acid, 0.5 g of ammonium chloride, 0.5 ml of 28% v/v aqueous ammonia and 20 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9](=[O:11])[CH3:10])[C:5]([O:7][CH3:8])=[O:6].[I-].[Na+].C(N(CC)CC)C.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22]>C(#N)C>[Si:25]([O:11][C:9](=[CH2:10])[C:4](=[N:3][O:2][CH3:1])[C:5]([O:7][CH3:8])=[O:6])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27]
Reactant: CON=C(C(C)=O)C(=O)OC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(O[Si](C)(C)C(C)(C)C)C(=NOC)C(=O)OC

Procedure:
In 20 ml of acetonitrile were dissolved 795 mg of methyl 2-methoxyimino-3-oxobutyrate and 2.25 g of sodium iodide, followed by addition of 2.1 ml of triethylamine. Then, a solution of 1.13 g tert-butyldimethylchlorosilane in 10 ml acetonitrile was added dropwise and the mixture was refluxed for 6.5 hours. The reaction mixture was concentrated under reduced pressure and 20 ml of hexane and 20 ml of water were added to dissolve the residue. The organic layer was separated, washed with 20 ml of 5% aqueous sodium hydrogen carbonate solution, 20 ml of 1N hydrochloric acid and 20 ml of water in the order mentioned, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column and elution was carried out with 100 ml of hexane-ether (5:1, v/v). The eluate was concentrated under reduced pressure to give methyl 3-tert-butyldimethylsilyloxy-2-methoxyimino-3-butenoate as oil.
Reaction SMILES: [CH3:1][S@:2](=[O:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:11]#[C:12][Si](C)(C)C)[CH:8]=[N:7][CH:6]=1.Br[C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])[C:29]2=[O:36]>>[O:35]=[C:30]1[C:29](=[O:36])[C:28]2[C:32](=[CH:33][CH:34]=[C:26]([C:12]#[C:11][C:9]3[CH:8]=[N:7][CH:6]=[C:5]([CH:10]=3)[C:4]([N:3]=[S@@:2]([CH3:1])(=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:17])[CH:27]=2)[NH:31]1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: C[Si](C)(C)C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc3c(c2)C(=O)C(=O)N3)c1)c1ccccc1
Yield: 22.2 %

Procedure:
In a manner similar to that described in Example 443, (S)—N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide (150 mg, 0.42 mmol) and 5-bromoisatin (116 mg, 0.46 mmol) were reacted to give the title compound as a reddish oil (40 mg).
Reaction SMILES: P(=O)([O-])[O-].[CH3:5][C:6]([O-])(C)[CH3:7].[K+].[CH3:11][C:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH3:19])([CH3:18])[C:13]=1/[CH:20]=[CH:21]/[C:22]([CH3:24])=O.[CH2:25]1[CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:11][C:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH3:19])([CH3:18])[C:13]=1/[CH:20]=[CH:21]/[C:22](/[CH3:24])=[CH:7]/[CH:6]=[CH:5]/[C:26](/[CH3:27])=[CH:25]/[CH:29]=[O:28]
Reactant: C1CCOC1
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)/C=C/C1=C(C)CCCC1(C)C
Agent: O=[PH]([O-])[O-]
Agent: [K+]
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=O)C(C)(C)CCC1
Reaction time: 1.5 h

Procedure:
Phosphonate (I) (0.5 g, 1.72 mmol) in solution in THF (10 ml) was introduced under argon into a 25-ml two-necked flask. Potassium tert-butylate (0.275 g, 2.22 mmol) was added in small portions at -70° C. Stirring was continued at -70° C. for 90 minutes. β-ionone (0.34 g, 1.8 mmol) in solution in THF (1 ml) was then added. The solution was kept at -70° C. for 15 minutes and then at -20° C. for 1 hour.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH3:24]O.B(F)(F)F>O>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([O:16][CH3:24])=[O:15])=[CH:10][CH:9]=2)=[CH:20][CH:21]=1
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Reactant: CO
Agent: FB(F)F
Solvent: O
Product: COC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Yield: 71.9 %

Procedure:
10 g of α-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid was reacted with 80 g of methanol in the presence of 5 g of boron trifluoride at 55° to 60° C. for 3 hours. The reaction product was poured into water, and extracted with chloroform. The extract was washed with dilute alkali (i.e., 2-3% NaOH aqueous solution) and water, and dried. Then, the chloroform was evaporated off. The residue was distilled at reduced pressure to afford 7.5 g of the final product having a boiling point of 165° to 167° C./3 mmHg. The yield was 74%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH2:17][CH3:18])=[O:6]
Reactant: O=C(O)c1ccc(O)c(F)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(O)c(F)c1

Procedure:
A mixture of 3-fluoro-4-hydroxybenzoic acid (1.2 g), ethanol (20 ml) and concentrated sulfuric acid (1 ml) was refluxed for 13 hours, then concentrated and extracted with chloroform. The extract was washed with aqueous sodium hydrogen carbonate solution, dried and the solvent was distilled off, whereby crystals of ethyl 3-fluoro-4-hydroxybenzoate (1.3 g) was obtained. m.p. 79°-80° C.
Reaction SMILES: [Cl-].[NH4+].[Br:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([N+:13]([O-])=O)[CH:5]=1>C(O)C.O.[Fe]>[NH2:13][C:6]1[CH:5]=[C:4]([Br:3])[CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc(Br)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Iron powder (4.15 g, 74.38 mmol) and ammonium chloride (3.32 g, 62.0 mmol) were added to a solution of 4-bromo-2-nitrobenzoic acid [J. Am. Chem. Soc. 1952, 74, 5621] (3.05 g, 12.4 mmol) in ethanol (50 mL) and water (25 mL) and the mixture was heated at reflux. After 6 h, the reaction was filtered, washed with ethanol, and concentrated in vacuo. The crude material was dissolved in water (150 mL) and concentrated HCl (30 mL) and stirred at ambient temperature for 16 h. The mixture was extracted with ethyl acetate (2×200 mL) and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. MS: m/z=216 (M+1).
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:4]([OH:6])=[O:5].[C:14]([O-])(O)=O.[Na+]>CO>[CH3:14][O:5][C:4](=[O:6])[CH:3]([OH:2])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)C(O)Cc1ccccc1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Hydrogen chloride was bubbled for 15 minutes into a solution of 2-hydroxy-3-phenyl-propionic acid (10.0 g, 60 mmol) in 100 mL of methanol at room temperature. The vessel was sealed and then stirred overnight at room temperature. The reaction was made basic by the addition of 5% NaHCO3 and then concentrated under reduced pressure to remove the methanol. The residue was diluted with water and extracted with ethyl acetate. The organic layer was extracted with saturated NaCl, dried (MgSO4) and the solvent removed under reduced pressure to give 2-hydroxy-3-phenyl-propionic acid methyl ester (9.7 g, 90%) as a yellow oil, MS m/z 180 [M]+. Elemental Analysis for C10H12O3. Calc'd: C, 66.65; H, 6.71; N, 0.00. Found: C, 66.52; H, 6.86; N, 0.29
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=O.C([O:21][C:22](=O)[C:23](=[O:30])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])C>C(O)C>[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]1[N:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[C:22](=[O:21])[C:23]([OH:30])=[C:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCC(=O)C(=O)OCC
Reactant: O=Cc1ccccc1F
Reactant: NCCCn1ccnc1
Solvent: CCO
Product: CCCCCC1=C(O)C(=O)N(CCCn2ccnc2)C1c1ccccc1F
Temperature: 50 °C
Reaction time: 24 h

Procedure:
3-Imidazol-1-yl-propylamine (1 mmol) and 2-Fluoro-benzaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 2-Oxo-octanoic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: C([O:5][C:6](=[O:50])[CH:7]([NH:12][C:13](=[O:49])[C:14]1[CH:19]=[C:18]([NH:20][CH2:21][CH3:22])[CH:17]=[CH:16][C:15]=1[S:23][S:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][CH3:33])=[CH:27][C:26]=1[C:34](=[O:48])[NH:35][CH:36]([C:41]([O:43]C(C)(C)C)=[O:42])[CH:37]([CH3:40])[CH2:38][CH3:39])[CH:8]([CH3:11])[CH2:9][CH3:10])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:21]([NH:20][C:18]1[CH:17]=[CH:16][C:15]([S:23][S:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][CH2:32][CH3:33])=[CH:27][C:26]=2[C:34]([NH:35][C@H:36]([C:41]([OH:43])=[O:42])[C@H:37]([CH2:38][CH3:39])[CH3:40])=[O:48])=[C:14]([C:13]([NH:12][C@H:7]([C:6]([OH:50])=[O:5])[C@H:8]([CH2:9][CH3:10])[CH3:11])=[O:49])[CH:19]=1)[CH3:22]
Reactant: CCNc1ccc(SSc2ccc(NCC)cc2C(=O)NC(C(=O)OC(C)(C)C)C(C)CC)c(C(=O)NC(C(=O)OC(C)(C)C)C(C)CC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNc1ccc(SSc2ccc(NCC)cc2C(=O)N[C@H](C(=O)O)[C@@H](C)CC)c(C(=O)N[C@H](C(=O)O)[C@@H](C)CC)c1

Procedure:
This compound was prepared according to the procedure described in Example 50 using [S-(R*,R*)] 2-{5-ethylamino-2-[4-ethylamino-2-(1-tert-butoxycarbonyl-2-methyl-butylcarbamoyl)-phenyldisulfanyl]-benzoylamino}-3-methyl-pentanoic acid tert-butyl ester (0.8 g, 1.1 mmol) from Example 45, 10 mL dichloromethane, and 10 mL trifluoroacetic acid. The product was washed with hexane/ether to afford 0.6 of the title compound, mp 97-100° C.
Reaction SMILES: [CH2:1]([Sn:5](=O)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:11](=O)(OC)[O:12]C>CO>[CH3:11][O-:12].[CH3:11][O-:12].[CH2:1]([Sn+2:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](=O)CCCC
Reactant: COC(=O)OC
Solvent: CO
Product: CCCC[Sn+2]CCCC
Product: C[O-]

Procedure:
Dibutyltin oxide is reacted with methanol and dimethyl carbonate, at a temperature in the range between about 50° to 200° C. and at a pressure in the range between about 75 to 600 psi (0.52 to 4.14 MPa) resulting in a quantitative formation of dibutyltin dimethoxide (i.e., dibutyltin dimethoxide is present in the final product in an amount between about 90 to 100 mole % (based on tin species in the catalyst product), more preferably about 95 to 100 mole %) and carbon dioxide as shown in Equation 4 below: ##STR4##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18](O)=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:60]1[C:64]([C:65]2[CH:70]=[CH:69][C:68]([NH2:71])=[CH:67][CH:66]=2)=[N:63][N:62]=[N:61]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([NH:71][C:68]3[CH:69]=[CH:70][C:65]([C:64]4[NH:60][N:61]=[N:62][N:63]=4)=[CH:66][CH:67]=3)=[O:19])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Reactant: Nc1ccc(-c2nnn[nH]2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(-c2nnn[nH]2)cc1)C(c1c2c(nn1-c1ccc(Cl)cc1)CCCC2)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid (250 mg, 0.67 mmol; example 5.1) in dry DMF (12 mL) was added dry DIPEA (0.375 ml, 2.32 mmol) followed by HATU (510 mg, 1.34 mmol) at 0° C. Then the reaction mixture was allowed to warm to rt and stirred for 45 min at that temperature. TLC shows total consumption of acid and formation of a new spot. 4-(1H-Tetrazol-5-yl)-phenylamine (162.5 mg, 1.02 mmol) was added to this reaction mixture at 0° C. Then the cooling bath was removed and the reaction mixture was stirred at room temperature for 16 h. TLC shows total consumption of [2-(4-chloro-phenyl)-4,5,6,7-tetrahydro-2H-indazol-3-yl]-cyclohexyl-acetic acid and DMF was removed in vacuo at 50° C. It was then diluted with H2O (15 ml). Aqueous layer was extracted with EtOAc (4×20 mL) and combined organic layers were washed with brine (20 ml), dried over Na2SO4 and concentrated in vacuo. Crude product (355.0 mg) was subjected to column chromatography [SiO2 (230-400 mesh), McOH:DCM 5:95] to give the title compound as brownish sticky solid. Yield (170 mg, 52%). MS: m/e=516.0 [M+H+].
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])[CH:7]=[CH:8][CH:9]=1.[CH3:15]I>C1COCC1.CCOCC>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([CH3:14])([CH3:13])[CH2:11][O:12][CH3:15])[CH:5]=1
Reactant: CI
Reactant: CC(C)(CO)c1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCC(C)(C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
To a suspension of NaH (0.22 g, 9.00 mmol, 95%) in THF (30 mL) was added dropwise at ambient temperature the solution of 2-(3-bromo-phenyl)-2-methyl-propan-1-ol (1.7 g, 7.46 mmol) in THF (10 mL). After 10 min MeI (0.8 mL, 15 mmol) was added and the mixture stirred for 3 h at ambient temperature. The mixture was diluted with ether and washed twice with water. Organic layer was separated and concentrated to obtain the desired product (1.64 g, 91%) as a clear oil. NMR (DMSO-d6): 7.52 (m, 1H), 7.40 (m, 2H), 7.26 (m, 1H), 3.38 (s, 2H), 3.20 (s, 3H), 1.12 (s, 6H). MS (DCI): 260 (M+NH4).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]3[C:38](=[CH:39][CH:40]=2)[O:37][CH2:36][C:32]2([CH2:35][O:34][CH2:33]2)[C:12]23[CH2:16][O:15][C:14]([N:17](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:13]2)[CH:6]=[CH:5][CH:4]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC#N>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]3[C:38](=[CH:39][CH:40]=2)[O:37][CH2:36][C:32]2([CH2:33][O:34][CH2:35]2)[C:12]23[CH2:16][O:15][C:14]([NH2:17])=[N:13]2)[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc(-c2ccc3c(c2)C2(COC(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=N2)C2(COC2)CO3)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC#N
Product: COc1cccc(-c2ccc3c(c2)C2(COC(N)=N2)C2(COC2)CO3)n1
Temperature: 40 °C
Reaction time: 4 h
Yield: 39.2 %

Procedure:
The mixture of di-tert-butyl [6′-(6-methoxypyridin-2-yl)dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]imidodicarbonate (160 mg, 0.289 mmol) and TsOH.H2O (275 mg, 1.45 mmol) in MeCN (3.2 mL) was stirred for 4 hours at 40° C. After dilution with CHCl3, the organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (CHCl3:MeOH=99:1-95:5) and then the residue was washed with EtOAc to afford 6′-(6-methoxypyridin-2-yl)dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-amine (40 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].C1CCNCC1.[Br:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>C(Cl)Cl>[Br:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:27]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccccc3Br)c2)CC1
Reaction time: 0.08 h
Yield: 49.6 %

Procedure:
A mixture of 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and (piperidinomethyl)-polystyrene (100 mg, 0.260 mmol) in methylene chloride (1 mL) was allowed to stand for 5 min. To this mixture was added 2-bromobenzoyl chloride (151 mg, 0.687 mmol). The reaction mixture was mixed for 2 h at ambient temperature. The reaction mixture was filtered and the filter cake was rinsed with methanol. The filtrate solution was diluted with 10% acetic acid in methanol and poured over a Varian Mega Bond Elut™ strong cation exchange column (Siegel, M. G.; Hahn, P. J.; Dressman, B. A.; Fritz, J. E.; Grunwell, J. R.; Kaldor, S. W. Tetrahedron Lett. 1997, 38, 3357-3360). The column was rinsed with methanol to remove impurities, then treated with a 7M ammonia in methanol to elute the product from the column. The solvent was evaporated to give 45.6 mg (50%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]#[N:12])=[CH:5]2.[H-].[Na+].Cl[CH2:16][C@@H:17]([CH2:26][O:27][Si:28]([CH3:34])([CH3:33])[C:29]([CH3:32])([CH3:31])[CH3:30])[O:18][Si:19]([CH3:25])([CH3:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C.O>[Si:19]([O:18][C@H:17]([CH2:26][O:27][Si:28]([C:29]([CH3:30])([CH3:32])[CH3:31])([CH3:33])[CH3:34])[CH2:16][N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:11]#[N:12])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](CCl)O[Si](C)(C)C(C)(C)C
Reactant: Cc1ccc2[nH]c(C#N)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)cc(C#N)n2C[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 48.8 %

Procedure:
To a solution of 39 mg of 5-methyl-1H-indole-2-carbonitrile (0.25 mmol) in 0.5 mL of DMF 15 mg of NaH (60% in oil, 0.375 mmol) was added and mixture was stirred for 30 min. Then 170 mg of (R)-5-(chloromethyl)-2,2,3,3,8,8,9,9-octamethyl-4,7-dioxa-3,8-disiladecane (0.5 mmol) was added and stirring continued for 24 hs. The reaction mixture was diluted with 10 mL of water and extracted with DCM. Combined organic extracts dried over sodium sulfate, concentrated and purified using silica gel column eluting with hexane-ethyl acetate 50:1 to afford 56 mg of (S)-1-(2,3-bis((tert-butyldimethylsilyl)oxy)propyl)-5-methyl-1H-indole-2-carbonitrile. 1H NMR (600 MHz, CDCl3): δ 8.09 (d, 1H, J=8.8 Hz), 7.35 (s, 1H), 7.24 (d, 1H, J=8.8 Hz), 7.18 (s, 1H), 4.04 (m, 1H), 3.82 (m, 1H), 3.77 (m, 2H), 3.68 (m, 1H), 2.43 (s, 3H), 1.08 (m, 18H), 0.26 (m, 12H).