Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([Si](C)(C)C)=[N+:2]=[N-:3].[C:8]([C:10]1[CH:11]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]3[O:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[C:21]([C:31]([NH:33][CH3:34])=[O:32])[C:20]=3[CH:35]=2)[CH:13]=[CH:14][CH:15]=1)#[N:9].C([Sn](CCCC)=O)CCC>C1(C)C=CC=CC=1>[NH:1]1[C:8]([C:10]2[CH:11]=[C:12]([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22]([C:24]5[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=5)=[C:21]([C:31]([NH:33][CH3:34])=[O:32])[C:20]=4[CH:35]=3)[CH:13]=[CH:14][CH:15]=2)=[N:9][N:3]=[N:2]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C#N)c3)cc12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(-c4nnn[nH]4)c3)cc12
Temperature: 105 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
Azidotrimethylsilane (161 μL, 1.215 mmol) was added to a stirring solution of 5-(3-cyanophenyl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (225 mg, 0.607 mmol) and dibutylstannanone (30 mg, 0.121 mmol) in toluene (6 mL) at rt. It was heated to 105° C. and allowed to stir overnight. The reaction, which remained a slurry, resulted in ˜70% conversion. Additional equiv of reagents and solvents were added and the mixture was allowed to stir overnight at 105° C. The reaction was allowed to cool and filtered to give the titled compound (205 mg, 82%). LC-MS retention time: 1.03 min; m/z (MH+): 414. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([N:29]1[CH2:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C@@:14]2([CH3:24])[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:32]4[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH:31]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC([C@]2(C)Cc3cc(Cl)ncc3O2)CC1
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Product: CC(C)(C)OC(=O)N1CCC([C@]2(C)Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1

Procedure:
The title compound is prepared from (S)-4-(5-chloro-2-methyl-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine following a procedure analogous to that described for Intermediate 6. Mass spectrum (ESI+): m/z=478 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[O:6][CH:7]=1.[F:16][C:17]1[C:25]([OH:26])=[CH:24][CH:23]=[C:22]([F:27])[C:18]=1[C:19]([NH2:21])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:16][C:17]1[C:25]([O:26][CH2:2][C:3]2[N:4]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=3)[O:6][CH:7]=2)=[CH:24][CH:23]=[C:22]([F:27])[C:18]=1[C:19]([NH2:21])=[O:20]
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: COc1ccc(-c2nc(CCl)co2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc(COc3ccc(F)c(C(N)=O)c3F)co2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.5 %

Procedure:
To a solution of 4-Chloromethyl-2-(4-methoxy-phenyl)-oxazole (0.100 g, 0.4 mmol) in 2 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (0.077 g, 0.40 mmol) and potassium carbonate (0.216 g, 1.50 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.044 g, 27%). 1H NMR (DMSO-d6, 400 MHz): δ 4.01 (s, 3H), 5.12 (s, 2H), 7.10 (m, 3H), 7.40 (m, 1H), 7.85 (br s, 1H), 7.93 (d, J=8.80 Hz, 2H), 8.13 (br s, 1H) and 8.25 (s, 1H). MS ES+(361.16), HPLC (method I) Rt=15.47 min.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[N+:10]([C:13]1[CH:14]=[C:15]2[C:20](=[O:21])OC(=O)[C:16]2=[CH:22][CH:23]=1)([O-:12])=[O:11].[C:24](O)(=O)C>>[N+:10]([C:13]1[CH:23]=[CH:22][CH:16]=[C:15]2[C:14]=1[CH2:24][N:1]([CH:2]([CH2:3][C:4]([OH:6])=[O:5])[C:7]([OH:9])=[O:8])[C:20]2=[O:21])([O-:12])=[O:11]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: CC(=O)O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Product: O=C(O)CC(C(=O)O)N1Cc2c(cccc2[N+](=O)[O-])C1=O

Procedure:
A mixture of aspartic acid (10 mmol) and 4-nitrophthalic anhydride (10 mmol) in 20 mL of acetic acid is heated to reflux. The cooled reaction is then concentrated in vacuo. The residue is slurried in ethyl acetate and the resulting slurry filtered to afford the desired product. As an alternative to slurry filtering, simulated moving bed chromatography can be used to purify the desired product.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:3]1.C(N(CC)CC)C.[CH3:26][C:27]([Si:30](Cl)([CH3:32])[CH3:31])([CH3:29])[CH3:28]>ClCCl.CN(C1C=CN=CC=1)C.O>[Si:30]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:3]1)([C:27]([CH3:29])([CH3:28])[CH3:26])([CH3:32])[CH3:31]
Reactant: CCOC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.6 %

Procedure:
To a solution of 1-tert-butyl 2-ethyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate (100 g, 0.38 mol) in dry dichloromethane (1.51) at 25° C. was added DMAP (47 g, 0.38 mol), followed by triethylamine (39 g, 0.38 mol). To the above reaction mixture was added TBDMSCl (64 g, 0.42 mol) dissolved in dry dichloromethane (200 ml) drop-wise over a period of 45 min. After stirring at RT for 20 h, the reaction mixture was diluted with water and separated the organic layer. The organic layer was washed with 5% aq. citric acid, brine and dried over Na2SO4. The solvent was removed under vacuum to give 1-tert-butyl 2-ethyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidine-1,2-dicarboxylate (140 g) as a colorless liquid. Yield: 97%
Reaction SMILES: [C:1]([C:3](=[C:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)C=O)#[N:2].C1(P(=[CH:40][CH:41]=[O:42])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:43]1C=CC=CC=1>>[C:1]([C:3](=[C:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1)[CH:43]=[CH:40][CH:41]=[O:42])#[N:2]
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#CC(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: c1ccccc1
Product: N#CC(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 100 %

Procedure:
To a dry mixture of 2-cyano-3,3-bis(4-fluorophenyl)-2-propenal (1.29 g, 4.8 mmol) and triphenylphosphoranylidene acetaldehyde (1.54 g, 5.04 mmol) under an inert atmosphere at ambient temperature was added 60 mL of dry benzene. The suspension was warmed to reflux temperature under an inert atmosphere and the reaction was allowed to proceed at reflux temperature for one hour. The crude reaction mixture was poured on a silica gel column saturated with hexanes. The desired product was eluted with 1 liter of hexanes followed by 1 liter of 20% ethyl acetate in hexanes (v/v) to give 1.43 g (100%) of the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[C:7]([C:9](=[O:23])/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20](O)=[O:21])=[CH:14][CH:13]=2)[CH:8]=1.C1C=CC2[N:39]([OH:40])N=NC=2C=1.C(Cl)CCl.NOC1CCCCO1>C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[C:7]([C:9](=[O:23])/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([NH:39][OH:40])=[O:21])=[CH:14][CH:13]=2)[CH:8]=1
Reactant: CN1CCN(c2ccc(Cl)cc2C(=O)/C=C/c2ccc(/C=C/C(=O)O)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: Cl
Agent: NOC1CCCCO1
Solvent: ClCCl
Solvent: ClCCCl
Product: CN1CCN(c2ccc(Cl)cc2C(=O)/C=C/c2ccc(/C=C/C(=O)NO)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.1 %

Procedure:
A mixture of (E)-3-(4-{(E)-3-[5-chloro-2-(4-methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid hydrochloride (250 mg, 0.56 mmol), HOBT (139 mg, 1.03 mmol), EDC (196 mg, 1.03 mmol), TEA (0.568 ml, 4.08 mmol) and NH2OTHP (89 mg, 0.765 mmol) in DCM (5 ml) was stirred overnight at room temperature. The solvent was evaporated and the residue was partitioned between water and AcOEt. The phases were separated and the aqueous layer was brought to basic conditions with NH4OH and extracted with DCM. The collected organic extract were dried over Na2SO4 and evaporated in vacuo. The crude mixture was purified by silica gel chromatography (eluent: DCM/MeOH/NH4OH 97:3:0.1) and the resulting product was dissolved in DCM and treated with HCl/Et2O for 2.5 h. The precipitate was filtered and triturated with isopropanol and di-isopropylether to give 61 mg of (E)-3-(4-{(E)-3-[5-chloro-2-(4-methyl-piperazin-1-yl)-phenyl]-3-oxo-propenyl}-phenyl)-N-hydroxy-acrylamide hydrochloride.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:9]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:40]=[N+:41]=[N-:42].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]4[NH:42][N:41]=[N:40][N:24]=4)=[CH:19][CH:18]=3)=[CH:14][CH:15]=2)[C:10]([CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[C:9]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCOc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(-c2ccccc2)n3Cc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(Cc2c(-c3ccccc3)n(Cc3ccccc3)c3ccc(-c4ccc(OCc5nnn[nH]5)cc4)cc23)cc1

Procedure:
The desired product was prepared using a procedure similar to step 6 of example 3. Thus, [4-(1,3-dibenzyl-2-phenyl-1H-indol-5-yl)-phenoxy]-acetonitrile (0.481 g, 0.953 mmol) was reacted with NaN3 (0.310 g, 4.766 mmol) and NH4Cl (0.255 g, 4.766 mmol) in DMF (5 ml) to give the product (0.394 g, 0.719 mmol, 75%) as an off-white solid, dec. 191-194° C. 1H NMR (DMSO-d6) δ 4.08 (s, 2H), 5.35 (s, 2H), 5.51 (s, 2H), 6.89 (d, J=7.2 Hz, 2H), 7.10-7.25 (m, 10H), 7.37 (dd, J=1.7 Hz, 8.5 Hz, 1H), 7.40-7.54 (m, 8H), 7.61 (s, 1H), 16.80 (broad s, 1H); IR (solid) 3020, 2920, 1605, 1520, 1470, 1450, 1360, and 1240 cm−1; [ESI(−)], m/z 546 (M−H)−; Anal. Calcd. for C36H29N5O: C, 78.95; H, 5.34; N, 12.79; Found: C, 78.53H, 5.25; N, 12.77.
Reaction SMILES: [C:1]([Si:5]([CH3:28])([CH3:27])[O:6][C:7]1[CH:26]=[CH:25][C:10]2[C:11]3[CH:20]([OH:21])[O:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]=3[CH2:22][CH2:23][O:24][C:9]=2[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].I[C:30]1[CH:44]=[CH:43][C:33]([O:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[CH:32][CH:31]=1>>[C:1]([Si:5]([CH3:27])([CH3:28])[O:6][C:7]1[CH:26]=[CH:25][C:10]2[C:11]([CH:20]([OH:21])[C:30]3[CH:31]=[CH:32][C:33]([O:34][CH2:35][CH2:36][N:37]4[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]4)=[CH:43][CH:44]=3)=[C:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=3[OH:19])[CH2:22][CH2:23][O:24][C:9]=2[CH:8]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Ic1ccc(OCCN2CCCCC2)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OCCC1=C2C(O)Oc2ccccc21
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OCCC(c1ccccc1O)=C2C(O)c1ccc(OCCN2CCCCC2)cc1

Procedure:
Following the procedure described in Examples 76, 2-(tert-Butyl-dimethyl-silyloxy)-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-5-ol, the compound prepared as in Example 105 above, was reacted with 1-[2-(4-Iodo-phenoxy)-ethyl]-piperidine to yield 2-(8-(tert-Butyl-dimethyl-silyloxy)-5-{hydroxy-(4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-2,3-dihydro-benzo[b]oxepin-4-yl)-phenol as a crude oil. The crude 2-(8-(tert-Butyl-dimethyl-silyloxy)-5-{hydroxy-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methyl}-2,3-dihydro-benzo[b]oxepin4-yl)-phenol was then further treated with HCl (12N, 4 eq., 0.67 mL) in toluene (100 mL) to generate yield 1-(2-{4-[2-(tert-Butyl-dimethyl-silyloxy)-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-5-yl]-phenoxy}-ethyl)-piperidine as a crude oil. The crude 1-(2-{4-[2-(tert-Butyl-dimethyl-silyloxy)-11,12-dihydro-5H-6,13-dioxa-benzo[3,4]cyclohepta[1,2-a]naphthalen-5-yl]-phenoxy}-ethyl)-piperidine was then further treated with HF•Pyridine (70% HF, 30% Pyridine, 0.5 mL) in CH3CN (20 mL) at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate:THF (1:1) and then washed with 5% NaHCO3 and brine. The reaction mixture was dried, concentrated and purified by flash chromatograph eluted with 5% MeOH in DCM to yield the title compound as a slightly yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][NH2:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:11]([O:16][CH2:17][CH3:18])(=[O:15])[C:12]([CH3:14])=O.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][N:10]=[C:12]([CH3:14])[C:11]([O:16][CH2:17][CH3:18])=[O:15])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NNc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)C(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)=NNc1cc(Cl)cc(Cl)c1
Reaction time: 3 h

Procedure:
Combine 3,5-dichlorophenylhydrazine (300 g) and ethanol (2 L). Add ethyl pyruvate (153.6 mL) and sulfuric acid (25 mL). After 3 hours, evaporate in vacuo to obtain a residue. Cover the residue with ethyl acetate and water. Add solid sodium bicarbonate until the aqueous layer is neutralized. Separate the layers and extract the aqueous layer with ethyl acetate. Combine the organic layers, dry over MgSO4, filter, and evaporate in vacuo to give ethyl pyruvate-3,5-dichlorophenylhydrazone.
Reaction SMILES: [CH:1]([N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH3:9][O:10][CH2:11][Cl:12]>CC(=O)CC>[Cl-:12].[CH3:9][O:10][CH2:11][N+:4]1([CH:1]([CH3:3])[CH3:2])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CC(C)N1CCCC1
Reactant: COCCl
Solvent: CCC(C)=O
Product: COC[N+]1(C(C)C)CCCC1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A 40.00 g quantity of N-isopropylpyrrolidine was dissolved in 361 g of dehydrated 2-butanone (reagent, product of Wako Pure Chemical Ind. Ltd.), followed by replacement with nitrogen. To the solution was added dropwise 28.76 g of chloromethyl methyl ether (reagent, product of Tokyo Kasei Co., Ltd. as purified by distillation) at 5° C. over a period of 0.5 hour. The mixture was thereafter heated to a gradually elevated temperature and stirred at room temperature for 10 hours, whereby the reaction was terminated. The reaction mixture was cooled to 5° C., and the resulting solids were filtered off in nitrogen. The filter cake was washed with 200 ml of 2-butanone and thereafter dried in a vacuum, giving 66.40 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=O)[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].Cl.[CH3:27][O:28][NH2:29]>N1C=CC=CC=1>[CH3:27][O:28][N:29]=[CH:19][C:4]1[C:3]([S:21][C:22]([F:25])([F:24])[F:23])=[C:2]([NH2:1])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:17])[F:16])=[CH:9][C:8]=2[Cl:18])[N:5]=1
Reactant: Nc1c(SC(F)(F)F)c(C=O)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Temperature: 25 °C
Reaction time: 26 h
Yield: 42.5 %

Procedure:
A mixture of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-trifluoromethylthio-1H-pyrazole-3-carboxaldehyde (0.66 g), methoxyamine hydrochloride (0.2 g) and pyridine was stirred at room temperature for 26 hours. Pyridine was evaporated and the residue dissolved in ethyl acetate/acetonitrile, washed with 1% aqueous HCl, dried (MgSO4) and evaporated. The residue was purified by silica gel column chromatography, eluting with hexane/ethyl acetate, to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-trifluoromethylthio-1H-pyrazole-3-carboxaldehyde O-methyloxime (0.3 g) as a white solid m.p. 129-131.50° C. Compound 9.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[N:6]=[CH:7][N:8]=[CH:9][C:10]=2[N:11]=1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1.CN(C)C=O>O>[Si:12]([O:1][CH2:2][C:3]1[NH:4][C:5]2[N:6]=[CH:7][N:8]=[CH:9][C:10]=2[N:11]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: OCc1nc2cncnc2[nH]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1nc2cncnc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
A mixture of 1.81 g of 2-hydroxymethyl-3H-imidazo[5,4-d]pyrimidine (prepared as described in Preparation 48), 2.71 g of t-butyldimethylsilyl chloride, 2.45 g of imidazole and 100 ml of dimethylformamide was stirred at room temperature for 1 hour. At the end of this time, the reaction mixture was freed from dimethylformamide by distillation under reduced pressure. The residue thus obtained was diluted with water, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 1.89 g of the title compound, melting at 104°-107° C.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].[Cl:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=O>CO>[Cl:13][CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH:21]=[C:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:1]1=[O:10]
Reactant: O=Cc1cccc(OCCCCl)c1
Reactant: O=C1CCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1C(=Cc2cccc(OCCCCl)c2)Cc2ccccc21
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
A solution of indan-1-one (0.4 g, 3.03 mmol) and sodium hydroxide (0.6 g, 15 mmol) in methanol (25 ml) was added to the solution of 3-(3-chloropropoxy)benzaldehyde in methanol (10 ml). The resulting solution was shaken for 30 min and allowed to stand at room temperature with intermittent shaking. The completion of reaction was monitored by TLC. After the completion, excess of methanol was removed; crushed ice was added and allowed to stand overnight. The precipitates obtained were filtered, washed thoroughly with distilled water and dried. The crude product was crystallized from a mixture of acetone and petroleum ether to yield white colored crystals of 2-[3-(3-chloropropoxy)benzylidene]-indan-1-one (1) (0.21 g, 33.5%), mp 73-75° C.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)(=[O:4])[CH:2]=[CH2:3].[CH2:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[CH2:13]([N:20]1[CH2:25][CH2:24][N:23]([CH2:3][CH2:2][C:1]([NH:5][C:6]2[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=2)=[O:4])[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: C=CC(=O)Nc1ccc(F)cc1
Solvent: CO
Product: O=C(CCN1CCN(Cc2ccccc2)CC1)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
N-Acryloyl-4-fluoroaniline (12.2 g) and 1-benzyl piperazine (19.7 g) were dissolved in methanol (150 ml), and the mixture was stirred overnight at room temperature. The reaction mixture was evaporated, and the residue was purified by Cromatorex NH silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (25 g, 100%) as a colorless oil.
Reaction SMILES: C(O[C:9]([NH:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=1)[NH2:15])=[O:10])C1C=CC=CC=1.[C:19]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:34]C(=O)[C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[N:30]=2)=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>>[NH2:15][C:14]1[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:32]2[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=2[NH:30][C:29](=[O:34])[C:26]2[CH:25]=[CH:24][C:23]([C:19]([CH3:21])([CH3:20])[CH3:22])=[CH:28][CH:27]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1cccc(NC(=O)OCc2ccccc2)c1
Reactant: CC(C)(C)c1ccc(-c2nc3ccccc3c(=O)o2)cc1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)Nc2cccc(N)c2)cc1
Yield: 6.9 %

Procedure:
By methods substantially equivalent to those described in Example 96, the title compound (40 mg, 9% for two steps) was prepared from m-(benzyloxycarbonylamino)aniline 1.5 mmol) and 2-(4-tert-butylphenyl)-4H-3,1-benzoxazin-4-one (1.5 mmol).
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.C1(C)C=CC=CC=1.[CH3:19][O:20]C1C=CC2N=CC=C([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)C=2C=1.CO>C(Cl)(Cl)(Cl)Cl>[CH3:19][O:20][C:7]([C@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]1[C:10]([OH:9])=[O:11])=[O:8]
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Solvent: Cc1ccccc1
Solvent: CO
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@H]1CCCC[C@H]1C(=O)O
Temperature: -55 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
(1S,2R)-Cyclohexane-1,2-dicarboxylic acid monomethyl ester was prepared as described in J. Org. Chem. 2000, 65, 6984-6991. cis-1,2-Cyclohexanedicarboxylic anhydride (4.48 g, 29.1 mmol) was suspended in a 1:1 mixture of toluene and carbon tetrachloride (582 mL). The mixture was stirred for 20 min. Quinine (10.38 g, 32 mmol) was added and the flask was degassed and backfilled with nitrogen. The solution was cooled to −55° C. While stirring, methanol (3.55 mL, 87.3 mmol) was added dropwise. The mixture was stirred at −55° C. for 20 h. Upon warming to 25° C., the mixture was concentrated in vacuo to dryness. The resulting residue was dissolved in ethyl acetate (400 mL), washed with 3.0 M aqueous hydrochloric acid solution (2×150 mL), saturated aqueous brine solution (100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the desired product, (1S,2R)-cyclohexane-1,2-dicarboxylic acid monomethyl ester (5.41 g, 29.1 mmol, 100%), as a light yellow oil. 1H NMR (400 MHz, CDCl3) δ: 1.37-2.05 (8H, m), 2.84-2.86 (2H, m), 3.68 (3H, s), 11.47 (1H, s).