Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=4[O:27][CH3:28])[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(OC)c1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: ClCc1ccncc1
Product: COc1cccc(OC)c1C1CCN(C(=O)c2cn(Cc3ccncc3)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,6-dimethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with commercially available 4-chloromethyl-pyridine gave the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH2:32]OCC)=[CH:26][C:25]=2[O:36][CH3:37])=[CH:20][CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:59]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:38])[C@H:5]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([O:30][CH3:31])=[CH:28][C:27]([CH2:32][Br:59])=[CH:26][C:25]=2[O:36][CH3:37])=[CH:20][CH:19]=1)[NH:6][C:7](=[O:16])[C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CCOCc1cc(OC)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)OCC)cc2)c(OC)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(OC)cc(CBr)cc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the product obtained in Example 1 -(5) or Reference Example 3-(3) (3.0 g) in CH2Cl2 (80 ml) containing PPh3 (1.77 g) was added CBr4 (2.8 g) at 0° C. The mixture was stirred at room temperature for 3 hours and evaporated. The residue was purified by: column chromatography (silica gel; eluent:AcOEt/n-hexane 1:1) to yield N-(2,6-dichlorobenzoyl)-4-(2,6-dimethoxy-4-bromomethylphenyl)-L-phenylalanine ethyl ester (3.15 g). IR (Nujol) 1731, 1654 cm−1; MS (APCI) m/z 59.6 (M+H).
Reaction SMILES: [OH:1][C:2]([C:5]1[O:6][CH:7]=[C:8]([C:10]([OH:12])=O)[N:9]=1)([CH3:4])[CH3:3].[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1>>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:8]3[N:9]=[C:5]([C:2]([OH:1])([CH3:3])[CH3:4])[O:6][CH:7]=3)=[O:12])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: CC(C)(O)c1nc(C(=O)O)co1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1coc(C(C)(C)O)n1
Yield: 79 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 2-(2-hydroxypropan-2-yl)oxazole-4-carboxylic acid (184 mg, 1.076 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (250 mg, 0.897 mmol). The product was purified by flash chromatography. Yield 79%. 1H-NMR (400 MHz; DMSO-d6): δ 1.13 (d, 3H), 1.52 (s, 6H), 4.31 (dd, 1H), 4.41 (dd, 1H), 4.44-4.52 (m, 1H), 5.64 (s, 1H), 7.02 (d, 1H), 7.84-7.88 (m, 2H), 7.97-7.98 (m, 1H), 8.10 (d, 1H), 8.48 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:18]/[O:19][C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)/[C:15](O)=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.Cl.[C:47]1([CH:53]([O:60][C:61]([C:63]2[N:68]3[C:69](=[O:72])[C@@H:70]([NH2:71])[C@H:67]3[S:66][CH2:65][C:64]=2[O:73][S:74]([CH3:77])(=[O:76])=[O:75])=[O:62])[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.O>[C:47]1([CH:53]([O:60][C:61]([C:63]2[N:68]3[C:69](=[O:72])[C@@H:70]([NH:71][C:15](=[O:16])/[C:14](/[C:12]4[N:13]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[S:10][CH:11]=4)=[N:18]\[O:19][C:20]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C@H:67]3[S:66][CH2:65][C:64]=2[O:73][S:74]([CH3:77])(=[O:76])=[O:75])=[O:62])[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(OS(C)(=O)=O)CS[C@H]23)cs1
Reaction time: 0.83 h
Yield: 0.6 %

Procedure:
To a suspension of (Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetic acid (41.7 g : 78.8 mMol.) in dichloromethane (600 ml) is added at -30° C. N-methylmorpholine (7.575 g : 75 mMol.), and the mixture is stirred for 10 minutes, mixed with 7β-amino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride (37.27 g : 75 mMol.), is stirred at the same temperature for 50 minutes, mixed with 1-ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride (14.38 g : 75 mMol.), stirred under ice cooling for 3 hours, diluted with water, and extracted with ethyl acetate. The extract is washed with water, dried, and concentrated under reduced pressure. The residue is purified by silica gel chromatography (toluene containing 0.5% acetic acid : ethyl acetate=10:1) and the eluate is treated with etherhexane to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)- 2-trityloxyiminoacetamido]-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester (57 .42 g). Colorless powder. Yield: 79%. This product contains ca. 5% of the 2-cephem isomer.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1)=[C:9]2[CH2:23][CH2:24][N:25]([C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:32][CH:31]=1)=[O:5])C.[OH-].[K+].O>CO>[CH2:44]([O:43][C:41]([N:25]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])=[CH:32][CH:31]=1)[CH2:24][CH2:23][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:11][C:10]=1[C:15]1[CH:16]=[C:17]([CH3:22])[CH:18]=[C:19]([CH3:21])[CH:20]=1)=[O:42])[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CCOC(=O)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccc(NS(C)(=O)=O)cc3)C(=O)OCc3ccccc3)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(C)cc(-c2[nH]c3ccc(C(=O)O)cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)C(=O)OCc2ccccc2)c1
Reaction time: 10 h

Procedure:
A solution of 600 mg (0.862 mmol) of 3-(2-{benzyloxycarbonyl-[4-(4-methanesulfonylaminophenyl)butyl]amino}ethyl)-2-(3,5-dimethylphenyl)-1H-indole-5-carboxylic acid ethyl ester in 18 mL (9 mmol) of 0.50N potassium hydroxide in methanol was stirred at about 60° C. as 2.0 mL of water was added gradually. Stirring was continued at 60°-65° C. under nitrogen for 10 hours. The cooled mixture, which contained a white precipitate, was concentrated to small volume in vacuo. The residual suspension was partitioned between 25 mL of ethyl acetate and 25 mL of 0.5N hydrochloric acid. After the aqueous layer was separated, precipitation began in the ethyl acetate phase. Dilution with 25 mL of tetrahydrofuran redissolved the precipitate. The aqueous phase was back-extracted with 10 mL of ethyl acetate+10 mL of tetrahydrofuran. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated in vacuo. The residual solid was triturated with diethyl ether, collected on a filter, and washed with some additional ether to give (after drying) 573 mg (100%) of a powder, mp 211.5°-213° C.; virtually homogeneous by TLC(92.5:7.5 CH2Cl2 --MeOH). 500 MHz 1H NMR (DMSO-d6) was consistent with the assigned structure. Mass spectrum (ESI): m/e=668 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C.O1CCOCC1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11](=[O:13])(=[O:12])[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(=O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)c1ccc(Cl)c(S(=O)(=O)Nc2ccccc2)c1
Temperature: 60 °C

Procedure:
12.6 g of 4'-chloro-3'-chlorosulfonylacetophenone were introduced, while stirring, in a mixture of 5.6 g of aniline, 7.5 g of triethyl amine and 100 ml of dioxane. The mixture was allowed to dwell over night at 20° C., it was heated to 60° C. during 30 minutes while stirring and the separated triethylamine-hydrochloride was separated. The filtrate was concentrated under reduced pressure and the residue was crystallized under water. Colorless crystals (from isopropanol/active charcoal), melting point: 142° C.
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][C:18](=[O:20])[CH3:19])=O)C1C=CC=CC=1.[N:21]1[C:30]2[C:25](=[N:26][C:27]([CH:31]=O)=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.N1CCCCC1>CC(O)C>[N:26]1[C:25]2[C:30](=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:29]=[CH:28][C:27]=1[CH:31]=[C:15]1[NH:11][C:12]([NH:17][C:18](=[O:20])[CH3:19])=[N:13][C:14]1=[O:16]
Reactant: O=Cc1ccc2ncccc2n1
Reactant: CC(=O)NC1=NC(=O)CN1C(=O)OCc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: CC(=O)NC1=NC(=O)C(=Cc2ccc3ncccc3n2)N1
Temperature: 25 °C

Procedure:
To a mixture of 2-acetylamino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (47.1 mg, 0.17 mmol), 1,5-naphthyridine-6-carboxaldehyde (31.6 mg, 0.2 mmol) and iPrOH (5.0 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 3 hrs to give a suspension. The reaction mixture was cooled to r.t. and the solid was collected by filtration to give N-(5-[1, 5]-naphthyridin-2-ylmethylene-4-oxo-4,5-dihydro-1H-imidazol-2-yl)-acetamide as a yellow solid, 15.3 mg (31.8%). HR-ES (+) m/e calcd. for C14H11N5O2: (M+H)+ 282.0986. Found: 282.0985.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:13](=[O:14])[C:12]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]3[C:10]2=[O:15])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1F
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(N2C(=O)c3ccccc3C2=O)cc1F
Yield: 73.3 %

Procedure:
A mixture of 3-fluoro-4-methylaniline (12.5 g), phthalic anhydride (17.8 g), triethylamine (27.9 ml) and chloroform (100 ml) was heated under reflux for 6 days and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 2 N HCl and a saturated aqueous sodium chloride solution; the organic layer was then dried with anhydrous sodium sulfate and concentrated under reduced pressure. Subsequently, chloroform was added to the resulting residue and the insoluble matter was filtered off whereas the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform methanol=98:2) to give 18.7 g of the titled compound (yield, 73%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:12]2[N:15]=[CH:16][CH:17]=[N:18][C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2-:19].[Na+]>CN(C)C1C=CC=CC=1>[NH2:19][C:16]1[CH:17]=[N:18][C:11]2[CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:14][CH2:13][C:12]=2[N:15]=1
Reactant: c1ccc(CN2CCc3nccnc3CC2)cc1
Reactant: [NH2-]
Agent: [Na+]
Solvent: CN(C)c1ccccc1
Product: Nc1cnc2c(n1)CCN(Cc1ccccc1)CC2
Temperature: 170 °C

Procedure:
2.4 gm (0.01 mol) of 7-benzyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine were dissolved in 20 ml of dimethylaniline, 3.9 gm (0.1 mol) of sodium amide were added, and the mixture was heated for four hours at 170° C. Thereafter, the dimethylaniline was distilled off in a high vacuum, the residue was taken up in 4N sodium hydroxide, and the solution was extracted with chloroform. The chloroform extract solution was dried and column-chromatograpically purified on silicagel with methanol/methylene chloride (3:1) as the mobile phase.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Cl[C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:23])[C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:11][N:10]=1>CN(C)C=O>[Cl:22][C:19]1[CH:18]=[CH:17][C:16]([C:15]([C:12]2[CH:13]=[CH:14][C:9]([N:3]3[CH:7]=[CH:6][N:5]=[CH:4]3)=[N:10][CH:11]=2)=[O:23])=[CH:21][CH:20]=1
Reactant: c1c[nH]cn1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)c1ccc(-n2ccnc2)nc1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
To a suspension of 13 g of sodium hydride (60% dispersion in mineral oil) in 240 ml of dimethylformamide is added 20 g of imidazole over a 15 minute period under occasional ice cooling. After the mixture is stirred at room temperature for an hour, 60 g of 2-chloro-5-(4-chlorobenzoyl)pyridine is added. The whole mixture is heated to 35° C. and an exothermic reaction starts. When the temperature rises at 60° C., the mixture is ice-cooled and then stirred at room temperature for an hour. The reaction mixture is poured into ice-cold water, the crystals precipitated are filtered off and recrystallized from ethanol to give 58 g of 5-(4-chlorobenzoyl)-2-(1-imidazolyl)pyridine as white crystals, melting at 155°-156° C.
Reaction SMILES: ClC(OC(C)C)=O.FC(F)(F)C(O)=O.FC1C(OC2N=CN=C3N(C4CCNCC4)N=CC=23)=C(C=CC=1F)C#N.[C:41]([O:45][C:46]([N:48]1[CH2:53][CH2:52][CH:51]([N:54]2[C:58]3=[N:59][CH:60]=[N:61][C:62]([O:63][C:64]4[C:69]([C:70]#[N:71])=[CH:68][CH:67]=[C:66]([F:72])[C:65]=4[F:73])=[C:57]3[CH:56]=[N:55]2)[CH2:50][CH2:49]1)=[O:47])(C)([CH3:43])[CH3:42].FC(F)(F)C(O)=O.C(OC1C=CC(OC2N=CN=C3N(C4CCNCC4)N=CC=23)=C(F)C=1)C.C(N(C(C)C)CC)(C)C>ClCCl.O>[CH:41]([O:45][C:46]([N:48]1[CH2:49][CH2:50][CH:51]([N:54]2[C:58]3=[N:59][CH:60]=[N:61][C:62]([O:63][C:64]4[C:69]([C:70]#[N:71])=[CH:68][CH:67]=[C:66]([F:72])[C:65]=4[F:73])=[C:57]3[CH:56]=[N:55]2)[CH2:52][CH2:53]1)=[O:47])([CH3:43])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4c(C#N)ccc(F)c4F)ncnc32)CC1
Agent: CC(C)OC(=O)Cl
Agent: CCOc1ccc(Oc2ncnc3c2cnn3C2CCNCC2)c(F)c1
Agent: N#Cc1ccc(F)c(F)c1Oc1ncnc2c1cnn2C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)OC(=O)N1CCC(n2ncc3c(Oc4c(C#N)ccc(F)c4F)ncnc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Isopropyl chloroformate (Aldrich Chemical Company, Inc., Milwaukee, Wis., USA 1M in toluene; 0.35 mL, 0.35 mmol) was added to a mixture of 3,4-difluoro-2-(1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine-4-yloxy)-benzonitrile trifluoroacetate salt (which was prepared from 4-[4-(6-cyano-2,3-difluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester [Example 49] following the procedure described for the preparation of Intermediate 29; 180 mg, 0.35 mmol), diisopropylethylamine (136 mg, 1.06 mmol) in dichloromethane (6 mL). The reaction was stirred at room temperature overnight. Water was added to quench the reaction and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried (sodium sulfate), filtered, evaporated and purified by flash chromatography on silica gel, eluting with 4% methanol/dichloromethane to give 4-[4-(6-cyano-2,3-difluoro-phenoxy)-pyrazolo-[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid isopropyl ester (147 mg, 85%) as a white solid. Mass spectrum MH+=443.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[C:10]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)=[C:10]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(-c2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3ccccc3)c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(-c2ccc(CN3CCNCC3)c(Oc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.4 %

Procedure:
A 100 mL round-bottom flask, was charged with tert-butyl 4-[[4-(3-methylphenyl)-2-phenoxyphenyl]methyl]piperazine-1-carboxylate (1.00 g, 2.18 mmol, 1.00 equiv), trifluoroacetic acid (1 mL), dichloromethane (10 mL). The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to provide 0.800 g (crude) of 1-[[4-(3-methylphenyl)-2-phenoxyphenyl]methyl]piperazine as yellow oil LCMS (ESI, m/z): 359 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7].[S:11](Cl)([CH3:14])(=[O:13])=[O:12].C(N(CC)CC)C>O1CCCC1>[CH3:14][S:11]([O:1][CH2:2][C@@H:3]1[CH2:5][C@H:4]1[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:13])=[O:12]
Reactant: CCOC(=O)[C@@H]1C[C@H]1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1C[C@H]1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A solution of trans-ethyl 2-hydroxymethyl-1-cyclopropanecarboxylate (1.136 g, 7.88 mmol) in dry tetrahydrofuran (20 ml) was cooled to 0° C. (ice bath), treated dropwise with mesyl chloride (0.675 ml, 8.66 mmol) and then treated immediately with triethylamine (1.32 ml, 9.52 mmol). This solution was stirred at 0° C. for 1.5 h (tlc indicated no substrate left). After dilution with ether (200 ml), the solution was washed with water, saturated ammonium chloride (10 ml), brine and dried over anhydrous magnesium sulfate. Evaporation of the solvent under reduced pressure gave a clear oil, 1.690 g (97%) which was used as such for the next step without purification. ir (film) νmax : 1720 cm-1 (C=O); 1Hmr (CDCl3) δ: 4.13 (2H, q, J=7, CH2 --CH3, 3.05 (2H, s, CH2 --OMs), 2.0~0.6 (4H, m, cyclopropyl), 1.27 ppm (3H, t, J=7, CH3 --CH2).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:21](OCC)=[O:22])[C:16](OCC)=[O:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([CH2:21][OH:22])[CH2:16][OH:17])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCC(CO)c1ccc(OCc2ccccc2)cc1
Temperature: 30 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
To a solution of diethyl 2-(4-(benzyloxy)phenyl)malonate (20 gm, 0.0585 mole) in ethanol (200 ml) was added sodium borohydride (17.4 gm, 0.4678 mole) in portions at 0° C. and the reaction mixture was stirred for 4 hrs at 30° C. The reaction mixture was poured into ice cold water, acidified with conc. HCl and extracted with ethyl acetate. The organic extract was successively washed with water & brine, dried over sodium sulfate and concentrated under reduced pressure to provide 14.5 gm of product as white solid.
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4].[CH3:12][C:13]1[S:14][CH:15]=[C:16]([C:18](OCC)=[O:19])[N:17]=1.C(O)(=O)C>C1COCC1.O>[CH3:12][C:13]1[S:14][CH:15]=[C:16]([C:18](=[O:19])[CH2:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])[N:17]=1
Reactant: CC(=O)c1ccccc1
Reactant: CCOC(=O)c1csc(C)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(C(=O)CC(=O)c2ccccc2)cs1
Reaction time: 0.17 h
Yield: 88.4 %

Procedure:
To a boiling suspension of sodium hydride (60% in oil) (360 mg) in anhydrous THF (10 ml) was added dropwise a solution of acetophenone (720 mg) and ethyl 2-methylthiazol-4-carboxylate (1.20 g) in anhydrous THF (10 ml), followed by 10 minutes of heating under refluxing. After the reaction solution was cooled, a mixed solution of acetic acid (1 ml) and water (30 ml) was added thereto, and the resulting mixture was extracted with ethyl acetate. The extracted solution was washed with water and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate=4:1 (v/v)) to obtain 1-(2-methylthiazol-4-yl)-3-phenylpropan-1,3-dione (1.3 g, 88%) as yellow crystals. Hereinafter, the compounds of Reference Examples 2 to 10 were obtained similarly.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([O:8][C@H:9]2[C@@H:14]([OH:15])[CH2:13][C@H:12]([O:16][C@H:17]3[C@@H:22]([OH:23])[CH2:21][C@H:20]([O:24][C@@H:25]4[CH2:30][C@H:29]5[CH2:31][CH2:32][C@H:33]6[C@@:38]7([OH:48])[CH2:39][CH2:40][C@H:41]([C:42]8[CH2:47][O:46][C:44](=[O:45])[CH:43]=8)[C@@:37]7([CH3:49])[C@H:36]([OH:50])[CH2:35][C@@H:34]6[C@@:28]5([CH3:51])[CH2:27][CH2:26]4)[O:19][C@@H:18]3[CH3:52])[O:11][C@@H:10]2[CH3:53])[CH2:5][C@H:4]([OH:54])[C@@H:3]1[OH:55].I([O-])(=O)(=O)=O.[Na+].O>C(Cl)(Cl)Cl.CO>[CH3:52][C@H:18]1[O:19][C@@H:20]([O:24][C@@H:25]2[CH2:30][C@H:29]3[CH2:31][CH2:32][C@H:33]4[C@@:38]5([OH:48])[CH2:39][CH2:40][C@H:41]([C:42]6[CH2:47][O:46][C:44](=[O:45])[CH:43]=6)[C@@:37]5([CH3:49])[C@H:36]([OH:50])[CH2:35][C@@H:34]4[C@@:28]3([CH3:51])[CH2:27][CH2:26]2)[CH2:21][C@H:22]([OH:23])[C@@H:17]1[O:16][C@@H:12]1[O:11][C@H:10]([CH3:53])[C@@H:9]([O:8][CH:6]([O:7][CH:2]([CH:3]=[O:55])[CH3:1])[CH2:5][CH:4]=[O:54])[C@@H:14]([OH:15])[CH2:13]1
Reactant: C[C@H]1O[C@@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3[C@@H](O)C[C@H](O[C@H]4CC[C@@]5(C)[C@H](CC[C@@H]6[C@@H]5C[C@@H](O)[C@]5(C)[C@@H](C7=CC(=O)OC7)CC[C@]65O)C4)O[C@@H]3C)O[C@@H]2C)C[C@H](O)[C@@H]1O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: CC(C=O)OC(CC=O)O[C@H]1[C@@H](O)C[C@H](O[C@H]2[C@@H](O)C[C@H](O[C@H]3CC[C@@]4(C)[C@H](CC[C@@H]5[C@@H]4C[C@@H](O)[C@]4(C)[C@@H](C6=CC(=O)OC6)CC[C@]54O)C3)O[C@@H]2C)O[C@@H]1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of digoxin (2.30 g, 2.95 mmol, Sigma Chemical Co., St. Louis, Mo.) in 24 mL of chloroform:methanol (1:1) was added sodium periodate (0.699 g, 3.27 mmol, Aldrich Chemical Co.) and 1.0 mL water. The solution was stirred at room temperature for 18 hr. The sodium iodate precipitate was removed via filtration. Following solvent removal on rotary evaporator the residue was dissolved in 50 mL chloroform, washed 1×8 mL water, and dried over magnesium sulfate. The solvent was removed on a rotary evaporator and the residue was recrystalized from chloroform/hexane resulting in the formation of an oil. Crystal formation was initiated by the addition of a small amount of diethyl ether yielding 2.22 g (96.6%) amorphous, white solid. TLC: silica gel; acetonitrile/water; 1/1; Rf=0.88 after development with 2,4-dinitrophenyl hydrazine (Aldrich Chemical Co.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[N+:11]([O-])([OH:13])=[O:12]>>[OH:1][C:2]1[C:7]([N+:11]([O-:13])=[O:12])=[C:6]([OH:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: CSc1nc(O)cc(O)n1
Product: CSc1nc(O)c([N+](=O)[O-])c(O)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
Step1: 4,6-Dihydroxy-2-methylthiopyrimidine (10.0 g, 63.22 mmol) was added over 1 hr to fuming nitric acid (30 mL) at 0° C. The red solution was stirred an additional 1 hr at 0° C. and then poured onto ice to give a light brown solid which was filtered off and washed with water and diethyl ether. The solid was dried under vacuo to give 4,6-Dihydroxy-2-methylthio-5-nitropyrimidine (9.30 g, 72%) as a light brown solid. LRMS for C5H5N3O4S (M+H)+ at m/z=203. The NMR spectrum obtained on the sample is compatible with its structure.