Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[N:2]1.[C:13](=O)([O-])[O-].[Na+].[Na+].IC.C(=O)(O)[O-].[Na+]>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc2cn[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of 1H-indazole-6-carboxylic acid (3.00 g, 18.5 mmol) in N,N-dimethylformamide (46 mL) was added sodium carbonate (2.06 g, 19.4 mmol), followed by iodomethane (2.75 g, 1.21 mL, 19.4 mmol) dropwise. The mixture was stirred at room temperature overnight. The mixture was poured into half saturated sodium bicarbonate and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown oil. This residue was purified by flash column chromatography (12-100% ethyl acetate/heptanes) to afford methyl 1H-indazole-6-carboxylate as a yellow solid (2.95 g, 90%). 1H NMR (400 MHz, CDCl3, δ): 10.40 (br. s., 1H), 8.26 (s, 1H), 8.13 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 3.96 (s, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5]C.C(O)CO.[Na].ClC1[N:18]=[CH:17][N:16]=[C:15]([NH:19][S:20]([CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:22])=[O:21])[C:14]=1[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=1>CN(C=O)C>[OH:5][CH2:4][CH2:3][O:2][C:1]1[N:18]=[CH:17][N:16]=[C:15]([NH:19][S:20]([CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:22])=[O:21])[C:14]=1[C:31]1[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=1
Reactant: COCCOC
Reactant: Cc1ccc(-c2c(Cl)ncnc2NS(=O)(=O)C=Cc2ccccc2)cc1
Agent: [Na]
Solvent: OCCO
Solvent: CN(C)C=O
Product: Cc1ccc(-c2c(NS(=O)(=O)C=Cc3ccccc3)ncnc2OCCO)cc1
Reaction time: 96 h

Procedure:
To a mixture of 1,2-dimethoxyethan (15 ml) and ethyleneglycol (40 ml) was added sodium (298 mg) in small portions. The mixture was stirred until the sodium was completely dissolved. Then DMF (15 ml), followed by 2-phenyl-ethenesulfonic acid(6-chloro-5-p-tolyl-pyrimidin-4-yl)-amide (1.0 g) was added. Stirring was continued for 4 days at 100° C. The mixture was evaporated and water (150 ml) was added to the residue followed by addition of acetic acid (1.0 ml). The precipitate was filtered off, washed with water and dried. The crude material was purified by chromatography over silicagel with EtOAc/methanol/aqueous ammonia (25%)=4/1/0.5 to give 2-phenyl-ethenesulfonic acid[6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (500 mg). tR=4.54 (LC); M+=412.38 (ES+).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[NH2:23][CH2:24][C:25]1([OH:31])[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>ClCCl>[Cl:8][C:9]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17]([NH:23][CH2:24][C:25]2([OH:31])[CH2:30][CH2:29][S:28][CH2:27][CH2:26]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: NCC1(O)CCSCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCC1(O)CCSCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
Under a nitrogen atmosphere triethylamine (3.91 mL, 28.0 mmol) was added to a chilled (0° C.) solution of 2,4-dichloro-3-nitroquinoline (7.22 g, 26.7 mmol) in dichloromethane (100 mL). A solution of 4-(aminomethyl)tetrahydro-2H-thiopyran-4-ol (4.12 g, 28.0 mmol) in dichloromethane (30 mL) was added dropwise. The reaction mixture was stirred at ambient temperature overnight and then concentrated under reduced pressure. The orange residue was combined with saturated aqueous sodium bicarbonate (50 mL) and ethyl acetate (40 mL), sonicated for 10 minutes, and then filtered. The isolated solid was washed extensively with water and then dried to provide 5.63 g of 4-{[(2-chloro-3-nitroquinolin-4-yl)amino]methyl}tetrahydro-2H-thiopyran-4-ol as a yellow solid.
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(O[CH2:22][CH2:23][CH2:24][CH2:25][O:26][CH3:27])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:27][O:26][CH2:25][CH2:24][CH2:23][CH2:22][N:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][CH:9]=[C:10]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: COCCCCOS(C)(=O)=O
Reactant: CCOC(=O)c1ccc(-c2ccccc2)[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccccc2)n1CCCCOC
Temperature: 60 °C
Reaction time: 12 h
Yield: 76.8 %

Procedure:
Ethyl 5-phenyl-1H-pyrrole-2-carboxylate (400 mg) and 4-methoxybutyl methanesulfonate (440 mg) were dissolved in DMF (10 ml), cesium carbonate (780 mg) was added and the mixture was stirred at 60° C. for 12 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9-1:4) was concentrated under reduced pressure to give the object product (430 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[C:14]([C:17]([CH3:19])=O)[C:15]=2[OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:20]([C:24]1[CH:33]=[C:32]([C:34]([NH:36][NH2:37])=[O:35])[CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27])[C:21]([CH3:23])=[O:22].O.S(C1C=CC(C)=CC=1)(O)(=O)=O>C(O)(C)C>[NH:20]([C:24]1[CH:33]=[C:32]([C:34]([NH:36][N:37]=[C:17]([C:14]2[C:15]([OH:16])=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[S:12][CH:13]=2)[CH3:19])=[O:35])[CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27])[C:21]([CH3:23])=[O:22]
Reactant: CC(=O)c1csc(-c2ccc(C(C)(C)C)cc2)c1O
Reactant: COC(=O)c1ccc(C(=O)NN)cc1NC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: COC(=O)c1ccc(C(=O)NN=C(C)c2csc(-c3ccc(C(C)(C)C)cc3)c2O)cc1NC(C)=O
Yield: 82.7 %

Procedure:
To a suspension of 2-(4-t-butylphenyl)-3-hydroxy-4-methylcarbonylthiophene (54.8 mg, 0.2 mmol) and methyl 2-acetamino-4-hydrazinocarbonylbenzoate (50.2 mg, 0.2 mmol) in isopropyl alcohol (2 mL), tosylic acid monohydrate (11.4 mg, 0.06 mmol) was added, and the mixture was heated with reflux for 12 hours. The precipitated solid was filtered to obtain 84 mg of the desired product as a pale yellow solid (yield 83%).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.C1(C)C=CC(S([CH2:20][N+:21]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+]>COCCOC.C(O)C.[Cl-].[Na+].O.C(OCC)(=O)C>[CH:1]1([N:4]2[CH2:9][CH2:8][CH:7]([C:20]#[N:21])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1
Reactant: O=C1CCN(C2CC2)CC1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: N#CC1CCN(C2CC2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.9 %

Procedure:
To a stirred solution of 1-cyclopropyl-4-piperidone (Alfa Aesar, 3.0 grams, 21.5 mmol) in a mixture of 1,2-dimethoxyethane (72 mL) and ethanol (2.2 mL) cooled at 0° C., was added p-toluenesulfonylmethylisocyanide (5.45 grams, 27.95 mmol). Solid potassium tertiary butoxide (5.54 grams, 49.45 mmol) was added over a period of 1 hour. The reaction mixture was stirred at this temperature for additional 1 hour and gradually warmed to room temperature. After stirring for 2 hours at this temperature, it was cooled to 0° C., diluted with brine and ethyl acetate. The organic layer was separated, dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure to obtain crude product, which was purified by slica gel column to yield 1-cyclopropyl piperidine-4-carbonitrile (1.32 grams).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Br:17])=[C:13]([CH:16]=1)[CH:14]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[OH:19][NH3+:20].C(=O)(O)[O-].[Na+]>O.C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([Br:17])=[C:13](/[CH:14]=[N:20]/[OH:19])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc(OCc2ccccc2)ccc1Br
Reactant: [NH3+]O
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O/N=C/c1cc(OCc2ccccc2)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
A mixture of 5-(benzyloxy)-2-bromobenzaldehyde (29.5 g), hydroxyl ammonium chloride (7.75 g), sodium bicarbonate (9.36 g), water (30 mL), and ethanol (270 mL) was stirred overnight at room temperature. To the reaction mixture, water (150 mL) was added, and the mixture was concentrated into half the volume under reduced pressure. Then, the residue was subjected to extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The residue was washed with hexane to obtain the title compound (27.2 g)
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[CH:23]=[CH:22][C:18]2=[N:19][S:20][N:21]=[C:17]2[CH:16]=1.[CH3:24][C:25]1[N:26]=[C:27]([N:35]2[CH2:39][CH2:38][NH:37][C:36]2=[O:40])[S:28][C:29]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[N:19]1[S:20][N:21]=[C:17]2[CH:16]=[C:15]([CH2:14][N:37]3[CH2:38][CH2:39][N:35]([C:27]4[S:28][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:25]([CH3:24])[N:26]=4)[C:36]3=[O:40])[CH:23]=[CH:22][C:18]=12
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: BrCc1ccc2nsnc2c1
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccc4nsnc4c3)C2=O)nc1C
Yield: 82 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 5-(bromomethyl)benzo[c][1,2,5]thiadiazole to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 82% yield: MS (ES+) m/z 404.1 (M+1).
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:26])[C:7]1[CH:12]=[C:11]([N:13]2[CH:17]=[N:16][N:15]=[N:14]2)[CH:10]=[C:9]([N:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]2=[O:25])[CH:8]=1>O.C1COCC1>[CH3:24][C:21]1[CH:22]=[CH:23][N:18]([C:9]2[CH:8]=[C:7]([CH:12]=[C:11]([N:13]3[CH:17]=[N:16][N:15]=[N:14]3)[CH:10]=2)[C:6]([OH:26])=[O:5])[C:19](=[O:25])[CH:20]=1
Reactant: COC(=O)c1cc(-n2cnnn2)cc(-n2ccc(C)cc2=O)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccn(-c2cc(C(=O)O)cc(-n3cnnn3)c2)c(=O)c1
Temperature: 25 °C
Yield: 94.7 %

Procedure:
A solution of LiOH.H2O (95 mg, 2.25 mmol) in H2O (7 mL) was added dropwise to a suspension of 3-(4-methyl-2-oxo-2H-pyridin-1-yl)5-tetrazol-1-yl-benzoic acid methyl ester (500 mg, 1.61 mmol) in THF (4 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred until the reaction solution turned into clear. Solvent was removed under vacuum and the aqueous solution was acidified by addition of 10% HCl to pH=2. The resulting precipitate was collected and dried to afford 3-(4-methyl-2-oxo-2H-pyridin-1-yl)-5-tetrazol-1-yl-benzoic acid as yellow solid (453 mg, 95%). MS (M+H)=298.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[N:6][C:5]=1Cl.[CH3:14][CH:15]([SH:17])[CH3:16]>>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[N:6][C:5]=1[S:17][CH:15]([CH3:16])[CH3:14]
Reactant: COC(=O)c1ccc(OC)nc1Cl
Reactant: CC(C)S
Product: COC(=O)c1ccc(OC)nc1SC(C)C
Yield: 87 %

Procedure:
2-Chloro-6-methoxy-nicotinic acid methyl ester (52 mg, 0.26 mmol) obtained in Step B and isopropylthiol were reacted in the same manner as in Step B of Preparation Example 9 to obtain the title compound (54 mg, 87%).
Reaction SMILES: [C:1]([C:3]1[CH:49]=[CH:48][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([NH:33][S:34]([C:36]([CH3:39])([CH3:38])[CH3:37])=[O:35])([C:12]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[C:17]4[C:13]=3[CH:14]=[CH:15][N:16]4[S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH3:11])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(NS(C(C)(C)C)=O)(C3C(C)=CC(C)=C4C=3C=CN4S(C3C=CC(C)=CC=3)(=O)=O)C)N(COCC[Si](C)(C)C)C=2C=1)#N>>[C:1]([C:3]1[CH:49]=[CH:48][C:6]2[NH:7][C:8]([C:10]([NH:33][S:34]([C:36]([CH3:38])([CH3:37])[CH3:39])=[O:35])([C:12]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[C:17]4[C:13]=3[CH:14]=[CH:15][N:16]4[S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH3:11])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)(NS(=O)C(C)(C)C)c4nc5cc(C#N)ccc5n4COCC[Si](C)(C)C)c(C)cc(C)c32)cc1
Agent: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)(NS(=O)C(C)(C)C)c4nc5ccc(C#N)cc5n4COCC[Si](C)(C)C)c(C)cc(C)c32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)(NS(=O)C(C)(C)C)c4nc5cc(C#N)ccc5[nH]4)c(C)cc(C)c32)cc1

Procedure:
The title compound was synthesized from a mixture of (±)-N-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide and (±)-N-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)ethyl)-2-methylpropane-2-sulfinamide as described in Example 64-B. MS (ESI+) m/z 598.47 (M+H).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[CH2:11]([O:19][CH2:20][C:21]1[N:26]=[C:25]([C:27](O)=[O:28])[CH:24]=[CH:23][CH:22]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Cl.C(N=C=NCCCN(C)C)C.O>ClCCl>[CH2:11]([O:19][CH2:20][C:21]1[N:26]=[C:25]([C:27]([N:4]2[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N+:2]([O-:1])=[N:3]2)=[O:28])[CH:24]=[CH:23][CH:22]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: On1nnc2ccccc21
Reactant: CCCCCCCCOCc1cccc(C(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCOCc1cccc(C(=O)n2n[n+]([O-])c3ccccc32)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.3 %

Procedure:
To a suspension of 1-Hydroxybenzotriazole (0.283 g) and 6-octyloxymethylpicolinic acid (0.505 g) in dichloromethane (15 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (WSCD.HCl) (0.473 g), and stirred for 3 hours at ambient temperature. The reaction mixture was poured into water. The organic layer was taken, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 1-(6-Octyloxymethylpicolinoyl)benzotriazole 3-oxide (737 mg).
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Li+].[CH3:20][CH:21]([N-]C(C)C)[CH3:22].C(Br)C=C.CCCCCC>C1COCC1>[CH2:22]([C:4]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2][N:1]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:6][CH2:5]1)[CH:21]=[CH2:20]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86.8 %

Procedure:
A solution of 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (5 g, 19.37 mmol) in THF (50 mL) was cooled to −78° C. followed by drop wise addition of LDA (1.80 M in THF, 21.67 mL, 38.74 mmol) solution and was stirred at the same temperature for 45 min followed by addition of allyl bromide (5 mL, 58.14 mmol) at −78° C. The temperature of the reaction was slowly raised to rt and left to stir for 5-6 h. The reaction was then cooled to 0° C. and quenched by drop wise addition of saturated NH4Cl solution (50 mL), extracted with EtOAc (3×100 mL) and the combined organics washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 1% EtOAc:hexane to obtain the product as an orange viscous liquid (5 g, 87% yield). MS: 298.19 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([O-])(C)[CH3:3].[K+].[C:7](=[N:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:22]1=[O:35])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Br)C#C.C1(C)C=CC=CC=1>C1COCC1>[C:7](=[N:20][C:21]1([CH2:3][C:2]#[CH:1])[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[C:22]1=[O:35])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)[O-]
Reactant: C[Si](C)(C)CCOCN1CCCC(N=C(c2ccccc2)c2ccccc2)C1=O
Agent: C#CCBr
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C#CCC1(N=C(c2ccccc2)c2ccccc2)CCCN(COCC[Si](C)(C)C)C1=O
Reaction time: 0.67 h
Yield: 32.8 %

Procedure:
KOtBu 1.7M in THF (4.32 mL, 7.34 mmol) was added dropwise to a solution of 3-(benzhydrylideneamino)-1-(2-trimethylsilylethoxymethyl)piperidin-2-one (which may be prepared as described in Description 22) (2.5 g, 6.12 mmol) and propargyl bromide 80 wt % in toluene (0.95 mL, 8.57 mmol) in THF (100 mL) at 0° C. under N2. The reaction was stirred for 40 mins. The reaction was quenched by the addition of satd. aq. NaHCO3 and then diluted with EtOAc. The phases were separated, the organic layer was dried (Na2SO4) and the solvent was evaporated to afford an oil. The material was purified by SP4, 100 g SNAP, 0 to 50% EtOAc/i-hexane to afford product: 3-(benzhydrylideneamino)-3-prop-2-ynyl-1-(2-trimethylsilylethoxymethyl)-piperidin-2-one (D23) (897 mg, 2.0082 mmol, 32.8% yield) as a pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C:10](=[CH:11][C:12]3[C:17]2=[N:16][CH:15]=[C:14]([F:22])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([BH3-])#N.[Na+]>C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][CH:15]=[C:14]([F:22])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)Cc2cc3cc(F)cnc3n21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(F)cnc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.4 %

Procedure:
T a solution of 0.907 g (R)-7-fluoro-4-methyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (0.0030 mol) in 12 mL of glacial acetic acid was added in 2 portions 0.936 g sodium cyanoborohydride (0.015 mol) with cooling. The mixture was then stirred at ambient temperature for 2 h. The solvent was evaporated and the residue was partitioned between water (adjusted to pH 10–11 by addition of aqueous sodium hydroxide solution) and dichloromethane. The organic phase was evaporated to dryness then purified by chromatography on silica gel with heptane:ethyl acetate (2:1) to yield a slightly yellow oil which solidified on standing to yield 0.852g [4R,9aR]-7-fluoro-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (94% th) slightly yellow crystals; m.p.: 56.6–58.4° C.
Reaction SMILES: [OH:1][C@:2]12[C@@H:15]3[NH:16][CH2:17][CH2:18][C@:7]1([C:8]1[CH:9]=[C:10]([O:19][CH3:20])[CH:11]=[CH:12][C:13]=1[CH2:14]3)[CH2:6][CH2:5][CH2:4][CH2:3]2.N1C=CC=CC=1.[CH:27]1([C:31](O)=[O:32])[CH2:30][CH2:29][CH2:28]1>C(Cl)Cl>[CH:27]1([C:31]([N:16]2[CH2:17][CH2:18][C@@:7]34[C:8]5[CH:9]=[C:10]([O:19][CH3:20])[CH:11]=[CH:12][C:13]=5[CH2:14][C@@H:15]2[C@:2]3([OH:1])[CH2:3][CH2:4][CH2:5][CH2:6]4)=[O:32])[CH2:30][CH2:29][CH2:28]1
Reactant: COc1ccc2c(c1)[C@@]13CCCC[C@@]1(O)[C@@H](C2)NCC3
Reactant: O=C(O)C1CCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc2c(c1)[C@@]13CCCC[C@@]1(O)[C@@H](C2)N(C(=O)C1CCC1)CC3

Procedure:
To a stirred and cooled solution of 400 mg. (0.00146 mole) of the amino alcohol XXI in 0.16 g. (0.002 mole) of dry pyridine and 5 ml. of methylene chloride, there was added, dropwise, a solution of 0.19 g. (0.0016 mole) of the acid chloride of cyclobutylcarboxylic acid in 5 ml. of methylene chloride. After stirring for ten minutes, the reaction mixture was washed successively with cold dilute aqueous hydrochlorid acid, dilute aqueous sodium hydroxide, water and finally with a saturated aqueous sodium chloride solution. After drying over Na2SO4 and evaporation of the solvent, there was obtained 400 mg. of an oil which crystallized on standing. The oil was treated with a small amount of cold ether and filtered to yield 320 mg. (61.6 %) of crystals which after recrystallization from methanol melted at 183°-85° C. The IR and NMR spectra were consistent with the structure.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([F:32])[CH:11]=1>>[CH3:30][C:29]1[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C:13]3[CH:14]=[CH:15][C:10]([N:7]4[C@@H:3]([CH2:2][OH:1])[CH2:4][CH2:5][C:6]4=[O:8])=[CH:11][C:12]=3[F:32])=[O:17])[CH2:19][CH2:20]2)=[N:25][CH:26]=[C:27]([CH3:31])[CH:28]=1
Reactant: O=C1CC[C@H](CO)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@@H]4CO)cc3F)CC2)c(C)c1
Yield: 77.4 %

Procedure:
Using (R)-5-hydroxymethylpyrrolidin-2-one (138 mg) and (4-bromo-2-fluorophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (392 mg) described in Preparation Example 114 and by the reaction and treatment in the same manner as in Example 1, (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-5-hydroxymethylpyrrolidin-2-one (330 mg) was obtained. To a mixture of the obtained (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-5-hydroxymethylpyrrolidin-2-one (330 mg) and sodium hydride (37 mg) were added tetrahydrofuran and N,N-dimethylformamide, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added methyl tosylate (117 μL), and the mixture was further stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-5-methoxymethylpyrrolidin-2-one. The obtained (R)-1-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-3-fluorophenyl}-5-methoxymethylpyrrolidin-2-one was dissolved in ethyl acetate, 4N hydrogen chloride/ethyl acetate was added and the mixture was stirred. The reaction mixture was concentrated under reduced pressure, diethyl ether was added, and the precipitate was collected by filtration to give the title compound (48 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](Cl)=[O:16])=[CH:11][CH:10]=1.[CH3:18][NH:19][O:20][CH3:21].C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[CH3:21][O:20][N:19]([CH3:18])[C:15]([C:12]1[CH:13]=[CH:14][C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:10][CH:11]=1)=[O:16]
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)c1ccc(-c2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2′,4′-Dichloro-biphenyl-4-carbonyl chloride was dissolved in chloroform (10 mL) and added dropwise to a chilled solution of N,O-dimethyl hydroxylamine (2.5 g) and triethylamine (7 mL) in chloroform (40 mL). Following addition, the mixture was allowed to warm to room temperature and stirred for a further 30 minutes. The mixture was poured into water and the organic phase separated, washed with water, and dried. Evaporation gave an oil, which was purified by column chromatography (petrol/ethyl acetate) to give a pale yellow oil which slowly crystallised upon standing to give the title compound as a white solid. 13C NMR (CDCl3): δ 33.8, 61.2, 127.3, 128.2, 129.1, 129.9, 132.0, 133.2, 133.5, 134.2, 138.3, 140.5 and 169.5. 1H NMR (CDCl3): δ 3.39 (3H, s), 3.58 (3H, s), 7.26 (2H, m), 7.45 (2H, d, J=8.5 Hz), 7.54 (1H, s) and 8.08 (2H, d, J=8.5 Hz).