Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:34]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=O)[CH:12]=[C:13]([C:15]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:16]=3[CH:17]=[CH:18][N:19]4[Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])[CH:14]=2)=[CH:5][CH:4]=1.Cl.[OH:45][NH2:46]>C(O)C>[CH3:1][O:2][C:3]1[CH:43]=[CH:42][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([C:34]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[N:46][OH:45])[CH:12]=[C:13]([C:15]3[CH:23]=[CH:22][CH:21]=[C:20]4[C:16]=3[CH:17]=[CH:18][N:19]4[Si:24]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:31]([CH3:33])[CH3:32])[CH:14]=2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(COc2cc(C(=O)c3cccnc3)cc(-c3cccc4c3ccn4[Si](C(C)C)(C(C)C)C(C)C)c2)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccc(COc2cc(C(=NO)c3cccnc3)cc(-c3cccc4c3ccn4[Si](C(C)C)(C(C)C)C(C)C)c2)cc1
Reaction time: 2 h

Procedure:
[3-(4-methoxy-benzyloxy)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenyl]-pyridin-3-yl-methanone (50 mg, 0.085 mmol) and hydroxyamine hydrochloride (29 mg, 0.42 mmol) in 2 mL of ethanol was heated to reflux. After 2 hrs, the reaction was completed. The solvent was removed under reduced pressure. The crude product was redissolved in EtOAc and washed with 5% NaHCO3 (aq) and brine. The organic phase was dried and concentrated to provide [3-(4-Methoxy-benzyloxy)-5-(1-triisopropylsilanyl-1H-indol-4-yl)phenyl]-pyridin-3-yl-methanone oxime which was further purified by prep TLC (10:1 EtOAc/MeOH). [3-(4-Methoxy-benzyloxy)-5-(1-triisopropylsilanyl-1H-indol-4-yl)-phenyl]pyridin-3-yl-methanone oxime was hydrolyzed as described above to give [3-hydroxy-5-(1H-indol-4-yl)-phenyl]-pyridin-3-yl-methanone oxime. NMR for the mixture of isomers: 1H NMR (400 MHz, CD3OD): δ 8.69 (d, J=1.8 Hz, 0.3H), 8.59 (d, J=1.4 Hz, 0.7H), 8.55 (dd, J=5.1, 1.6 Hz, 0.7H), 8.50 (dd, J=4.9, 1.4 Hz, 0.3H), 7.95 (dt, J=5.0, 2.6 Hz, 0.3H), 7.89 (dt, J=4.9, 2.5 Hz, 0.7H), 7.53 (dd, J=7.8, 4.9 Hz, 0.7H), 7.42 (dd, J=8.1, 4.8 Hz, 0.3H), 7.37-7.32 (m, 1H), 7.23 (d, J=3.2 Hz, 0.3H), 7.22 (d, J=3.2 Hz, 0.7H), 7.20-7.00 (m, 5H), 6.91 (dd, J=2.3, 1.6 Hz, 0.7H), 6.79 (dd, J=2.4, 1.4 Hz, 0.3H), 6.59 (d, J=3.1 Hz, 0.3H), 6.49 (d, J=3.2 Hz, 0.7H).
Reaction SMILES: C(O)C.[O:4]=[C:5]1[O:10][CH2:9][C@H:8]2[C@:6]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7]2.[BH4-].[Na+].Cl>C(OCC)(=O)C>[OH:4][CH2:5][C@@:6]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:7][C@H:8]1[CH2:9][OH:10]
Reactant: CCOC(=O)[C@]12C[C@H]1COC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)[C@]1(CO)C[C@H]1CO
Temperature: 10 °C
Yield: 44.4 %

Procedure:
In a reactor, ethanol (82.4 L) followed by ethyl (1S,5R)-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate (10.3 kg, 64.6 mol) were added and cooled to 10° C. Sodium borohydride (1.85 kg, 51.7 mol) was added in lots over a period of 1 hour by maintaining the reaction temperature between 10-15° C. The reaction temperature was raised to 20-25° C. and maintained for 1 hour. The progress of the reaction was monitored by HPLC. After completion of the reaction, the reaction mass was cooled to 0-5° C. The pH of the reaction mass was adjusted to 7.0 using 1.5 N aqueous HCl at 0-5° C. during 1 hour. Ethyl acetate (34.0 L) was added to the reaction mass and the solid was filtered. The clear filtrate was distilled under reduced pressure at 40-45° C. to remove most of the solvent and the concentrate was dissolved in dichloromethane (103.0 L). The dichloromethane layer was washed with water (2×10.5 L). The aqueous layer was re-extracted with dichloromethane (3×10.5 L). The dichloromethane layers were combined and washed with brine (1×15.0 L). The organic layer was collected and distilled to remove most of the solvent at 40-45° C. under reduced pressure. The concentrate was passed over silica gel 60-120 mesh plug column using petroleum ether followed by 100% ethyl acetate as eluent to afford 5.0 kg (47.4%) of the title compound (2c).
Reaction SMILES: [C:1]([S:5]([NH:7][C@H:8]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])=[CH:22][N:21]=1)[C:9]1[N:10]=[N:11][N:12]([C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=[O:16])[CH:13]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:33]>C1(C)C=CC=CC=1.CO>[C:1]([S:5]([NH:7][C@H:8]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]([F:30])([F:29])[F:31])=[CH:22][N:21]=1)[C:9]1[N:10]=[N:11][N:12]([C:14]([CH3:19])([CH3:18])[C:15]([O:17][CH3:33])=[O:16])[CH:13]=1)=[O:6])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C(=O)O)n1cc([C@H](NS(=O)C(C)(C)C)c2ccc(OCC(F)(F)F)cn2)nn1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C(C)(C)n1cc([C@H](NS(=O)C(C)(C)C)c2ccc(OCC(F)(F)F)cn2)nn1
Reaction time: 4 h
Yield: 38.7 %

Procedure:
To a solution of 0.30 g (0.65 mmol) 2-(4-{(S)-[(tert-butylsulfinyl)amino][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}-1H-1,2,3-triazol-1-yl)-2-methylpropanoic acid in 2.5 ml toluene and 0.81 ml MeOH at rt was added 1.3 ml (2.6 mmol) 2.0 M TMS-diazomethane in hexanes. After 4 h at room temperature, the reaction mixture was concentrated in vacuo. Purification by flash chromatography (silica gel, linear gradient 0-15% MeOH in CH2Cl2) afforded 0.12 g (38%) methyl 2-(4-{(S)-[(tert-butylsulfinyl)amino][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}-1H-1,2,3-triazol-1-yl)-2-methylpropanoate. ES-MS [M+1]+=478.2. 1H NMR (CDCl3, 400 MHz) δ 8.29 (d, J=2.75 Hz, 1H), 7.59 (s, 1H), 7.48 (d, J=8.70 Hz, 1H), 7.24 (m, 1H); 5.87 (d, J=5.31 Hz, 1H,), 5.33 (d, J=5.31 Hz, 1H), 4.38 (q, J=7.70, 2H), 3.71 (d, J=0.82 Hz, 1H); 1.92 (d, J=1.65 Hz, 6H); 1.27 (s, 9H).
Reaction SMILES: CO[C:3]([CH:5]1[CH2:11][CH2:10][O:9][C:8]2[CH:12]=[C:13]([CH2:16][CH3:17])[CH:14]=[CH:15][C:7]=2[C:6]1=[O:18])=[O:4].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>C1(C)C(C)=CC=CC=1>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[NH:19][C:3]([CH:5]1[CH2:11][CH2:10][O:9][C:8]2[CH:12]=[C:13]([CH2:16][CH3:17])[CH:14]=[CH:15][C:7]=2[C:6]1=[O:18])=[O:4]
Reactant: CCc1ccc2c(c1)OCCC(C(=O)OC)C2=O
Reactant: Nc1ccccn1
Solvent: Cc1ccccc1C
Product: CCc1ccc2c(c1)OCCC(C(=O)Nc1ccccn1)C2=O
Temperature: 25 °C
Yield: 5 %

Procedure:
8-Ethyl-5-oxo-2,3,4,5-tetrahydro-benzo[b]oxepine-4-carboxylic acid methyl ester (0.6 mmol) and 2-aminopyridin (0.6 mmol) were dissolved in 2.5 ml xylene. Reaction was performed by microwave irradiation for one hour at 150° C. The solution obtained from this reaction was cooled to room temperature and extracted by 2 mol/l hydrochloric acid and ethyl acetate. The ethyl acetate extract was dried over sodiumsulfate and the solvent removed in vacuo. After evaporation of the solvent in vacuo 8-Ethyl-5-oxo-2,3,4,5-tetrahydro-benzo[b]oxepine-4-carboxylic acid pyridine-2-ylamide was obtained as a white powder in a yield of 5%. LC-MS: 1.8 min, 311.2 (MH+), 1H-NMR: (DMSO-d6, 500 MHz): □ [ppm]: 10.543 (s, 1H), 8.296 (s, 1H), 8.152 (d, 1H, J=8.1 Hz), 7.798 (t, 1H, J=7.2 Hz), 7.605 (m, 1H, J=8.1 Hz), 7.102 (t, 1H, J=6.3 Hz), 7.032 (m, 1H, J=8.1 Hz), 6.983 (s, 1H), 4.594 (m, 1H, J=3.0 Hz), 4.364 (t, 1H, J=4.8 Hz), 3.942 (m, 1H, J=5.2 Hz), 2.640 (q, 2H, J=7.7 Hz), 2.512 (t, 2H, J=1.7 Hz), 1.193 (t, 3H, J=7.5 Hz)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@@H:16]3[O:17]C(C)(C)[O:19][C@@H:15]3[C@@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[O:13]2)=[C:5]([NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:4]=1.C(N(CC)CC)C.[CH3:49][S:50](Cl)(=[O:52])=[O:51]>ClCCl>[C:30]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:28][NH:27][C:5]2[N:4]=[C:3]([CH2:2][NH:1][S:50]([CH3:49])(=[O:52])=[O:51])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@@H:12]2[O:13][C@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[C@@H:15]([OH:19])[C@H:16]2[OH:17])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(C)(=O)=O)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.7 %

Procedure:
A solution of (3aS,4S,6R,6aR)-6-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide (Preparation 10) (140 mg, 0.25 mmol) and triethylamine (0.05 ml, 0.36 mmol) in anhydrous dichloromethane (1 ml) was treated with a solution of methanesulfonyl chloride (32 mg, 0.28 mmol) in anhydrous dichloromethane (1 ml). The mixture was stirred at room temperature for 18 hours during which time the solvent was allowed to evaporate off freely. The residue was dissolved in ethanol (1 ml), treated with hydrochloric acid (1M, 1 ml) and heated at 60° C. for 4 hours. The solvent was removed under reduced pressure and the residue was azeotroped with ethanol (×2). The residue was then purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (95:5 by volume) gradually changing to dichloromethane:methanol (90:10 by volume) to give a solid which was triturated with diethyl ether, washed with pentane and dried to afford the title compound as a solid (80 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[O:10][C@@H:9]([C:14]([OH:16])=O)[CH2:8][CH2:7]2)([O-:3])=[O:2].[NH2:17][CH2:18][C@@H:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[OH:20].C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[OH:20][C@H:19]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:18][NH:17][C:14]([C@H:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[O:10]1)=[O:16]
Reactant: NC[C@H](O)c1cccnc1
Reactant: O=C(O)[C@H]1CCc2cc([N+](=O)[O-])ccc2O1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC[C@H](O)c1cccnc1)[C@H]1CCc2cc([N+](=O)[O-])ccc2O1
Reaction time: 18 h

Procedure:
(2R)-6-Nitro-3,4-dihydro-2H-chromene-2-carboxylic acid (4.1 g, 18 mmol) and (1R)-2-amino-1-(3-pyridinyl)ethanol (5.0 g, 24 mmol) (both described in U.S. Pat. No. 6,051,586) were suspended in CH2Cl2 and stirred vigorously. Triethylamine (9.2 mL, 66 mmol) was added followed by hydroxybenzotriazole (4.9 g, 36 mmol) and EDCI (6.9 g, 36 mmol), and the reaction was stirred overnight. After 18 hours, TLC showed no remaining acid starting material, so the reaction was partitioned between water and CH2Cl2 and the organic layer was washed 3×100 mL of water. The organic layer was washed with 1N HCl, which removed the product into the aqueous layer. This aqueous layer was washed with CH2Cl2 and the organic was discarded. The aqueous solution was then basified and became cloudy with a white precipitate. The basified mixture was extracted with 3×100 mL of CH2Cl2.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][N:14]=1)[C:8]([O:10]C)=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]C(OC)=O)=[CH:18][CH:17]=1>CO>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:8]([C:7]2[CH:12]=[CH:13][N:14]=[C:5]([CH3:4])[CH:6]=2)=[O:10])=[CH:18][CH:17]=1
Reactant: COC(=O)Cc1ccc(F)cc1
Reactant: COC(=O)c1ccnc(C)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C(=O)Cc2ccc(F)cc2)ccn1
Temperature: 95 °C
Reaction time: 17.5 h

Procedure:
To a freshly prepared solution of NaOMe (3.0 M in MeOH) was added a solution of methyl 2-methyl-isonicotinate (6.81 g, 45.1 mmol) in MeOH (10 mL). This was followed by the dropwise addition of a solution of methyl 4-fluorophenylacetate (8.34 g, 49.6 mmol) in MeOH (10 mL). The MeOH was distilled off while heating the reaction mixture at 95° C. After 17.5 h, the solid residue was cooled. Concentrated HCl (15 mL) was added, and the mixture was heated at reflux. After 4 h, the mixture was cooled then diluted with H2O. The aqueous mixture was washed with Et2O, adjusted to pH 5 with 1N NaOH, then adjusted to pH 8 with saturated NaHCO3. The alkaline aqueous was extracted with EtOAc. The EtOAc extracts were washed with saturated NaCl, then dried over Na2SO4. Evaporation of solvent in vacuo afforded a red oil which was purified by column chromatography, eluting with a gradient of 0-3% MeOH/CHCl3. The title compound was isolated as a red oil (1.5 g, 15%).
Reaction SMILES: [CH3:1][O-].[Na+].CO.[OH:6][C:7]1[C:8]([CH3:13])=[N:9][CH:10]=[CH:11][CH:12]=1>CN(C=O)C>[CH3:1][O:6][C:7]1[C:8]([CH3:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: C[O-]
Reactant: Cc1ncccc1O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cccnc1C
Reaction time: 5 h

Procedure:
A mixture of sodium methoxide (prepared from sodium metal) (10.2 g) and methanol (175 ml), 3-hydroxy-2-methylpyridine (43.0 g) phenyltrimethylammonium chloride (81.9 g) and DMF (400 ml) was boiled under reflux with stirring for 5 hours under nitrogen. The mixture was filtered and distilled. The fraction boiling at 167°-195° C. was collected and purified by flash chromatography on silica using dichloromethane and then IMS as the mobile phase to give 3-methoxy-2-methylpyridine which was used without further purification.
Reaction SMILES: [C:1]1([CH:7]([CH3:10])[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11](O)[CH:12]=[CH2:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>C1C=CC=CC=1.O>[CH3:10][C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:13][CH:12]=[CH2:11])[CH:8]=[O:9]
Reactant: CC(C=O)c1ccccc1
Reactant: C=CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: C=CCC(C)(C=O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 2-phenylpropionaldehyde (9.90 mL, 74.5 mmol), allyl alcohol (20.4 mL, 300 mmol) and p-toluene sulfonic acid (0.8560 g, 4.5 mmol) in benzene (37 mL) was heated to reflux for 19 hours and a Dean-Stark trap was used to collect the water formed. The mixture was cooled to room temperature and saturated aqueous NaHCO3 (5 mL) and H2O (5 mL) were added. The phases were separated and the organic layer was washed a second time with saturated aqueous NaHCO3 (5 mL) and H2O (5 mL). The organic layer was dried (MgSO4) and concentrated under reduced pressure. A solution of the resultant yellow residue in p-xylene (150 mL) was heated to reflux for 24 hours. The solution was cooled to room temperature and concentrated under reduced pressure. The resultant aldehyde (13.0 g) was used in the next reaction without further purification.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:22]([NH2:24])=[O:23])[CH:13]=[C:14]([C:17]4[CH:21]=[CH:20][S:19][CH:18]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26].C(N(CC)CC)C>C(Cl)Cl>[CH2:25]([S:27]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:22]([NH2:24])=[O:23])[CH:13]=[C:14]([C:17]4[CH:21]=[CH:20][S:19][CH:18]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1)(=[O:29])=[O:28])[CH3:26]
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCNCC3)n[nH]c12
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccsc4)cc23)CC1

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 3-(4-piperidinyl)-5-(3-thienyl)-1H-indazole-7-carboxamide hydrochloride (Intermediate 19) (0.117 mmol) was reacted with ethane sulfonyl chloride (0.02 mL, 0.234 mmol) in the presence of triethylamine (0.04 mL, 0.468 mmol) in methylene chloride (10 mL) to give the title compound (9.4 mg, 19% for the last two steps)
Reaction SMILES: [C-:1]#[N:2].[K+].[C:4]([C:8]1[C:13]([OH:14])=[C:12]([CH3:15])[C:11]([CH2:16]Cl)=[C:10]([CH3:18])[CH:9]=1)([CH3:7])([CH3:6])[CH3:5].O>CN(C)C=O>[C:4]([C:8]1[CH:9]=[C:10]([CH3:18])[C:11]([CH2:16][C:1]#[N:2])=[C:12]([CH3:15])[C:13]=1[OH:14])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CCl
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C(C)(C)C)c(O)c(C)c1CC#N
Temperature: 0 °C
Reaction time: 7 h

Procedure:
To 41 grams of potassium cyanide dispersed in 300 ml of N,N-dimethylformamide, was slowly added a solution of 97.2 grams of the compound of Example 1, the reaction temperature rising from 25° to 35° C. The reaction mixture was then heated at 70° to 75° for 71/2 hours. Since a sample analyzed after 7 hours reaction time indicated that some unreacted starting 6-tert.-butyl-3-chloromethyl-2,4-dimethylphenol remained unreacted, an additional 13.7 grams of potassium cyanide was added and the reaction mixture heated for an additional 2 hours at 60° to 65° C. The reaction mixture was poured on crushed ice, and water added to make the total volume 1.8 liters. The mixture was stirred until the ice melted, the aqueous solid dispersion was filtered by suction, and the filtercake washed well with water. The filtercake was taken up in a toluene-benzene mixture, the resulting solution being successively washed with water, 6N aqueous hydrochloric acid and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration and treating the clear filtrate with activated charcoal, the solvent was evaporated at reduced pressures. The resulting residue was allowed to crystallize from toluene yielding white crystals melting at 134° to 139°.
Reaction SMILES: [C:1]([C:6]1[N:10]2[C:11]([CH2:15]Cl)=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1)([O:3]CC)=O.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][NH2:31])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C>C(O)C>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][N:31]2[CH2:15][C:11]3[N:10]4[C:6](=[CH:7][N:8]=[C:9]4[CH:14]=[CH:13][CH:12]=3)[C:1]2=[O:3])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)c1cnc2cccc(CCl)n12
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(CN2Cc3cccc4ncc(n34)C2=O)CC1
Yield: 72.5 %

Procedure:
A solution prepared by dissolving 5.78 g (24.22 mM) of 3-carbethoxy-5-chloromethylimidazo[1,2-a]pyridine, 7.78 g (36.33 mM) of 1-tert-butoxycarbonyl-4-aminomethylpiperidine, and 6.75 ml (48.44 mM) of triethylamine in 100 ml of ethanol was refluxed under argon gas for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was extracted with 100 ml of chloroform. The organic layer was washed with saturated aqueous NaCl solution and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-methanol=20:1) to provide 6.50 g (yield 72.4%) of the title compound as yellow liquid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)[Br:21].[CH2:25]([O:32][C:33]1[CH:40]=[C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:38]=[CH:37][C:34]=1[CH:35]=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CCCCC>ClCCl>[CH2:25]([O:32][C:33]1[CH:40]=[C:39]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:38]=[CH:37][C:34]=1[CH:35]=[C:20]([Br:24])[Br:21])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCC
Product: BrC(Br)=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
A mixture of triphenylphosphine (15.7 g) and carbon tetrabromide (9.93 g) in dry dichloromethane (100 mL) is cooled to 0° C. and stirred for 30 minutes. A solution of 2,4-dibenzyloxybenzaldehyde (4.76 g) in dichloromethane (30 mL) is added and the solution stirred at 0° C. for 2 hours. The solution is treated with pentane to precipitate triphenylphosphine oxide. The filtrate is evaporated to give 1-(2,4-dibenzyloxyphenyl)-2,2-dibromoethylene as a yellow oil (4.85 g, 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:38])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:33][CH3:34])([CH3:32])[CH3:31])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[O:41]=[S:42]1(=[O:54])[CH2:47][CH2:46][CH:45]([N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH2:44][CH2:43]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:38])[C@:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:21]([N:51]3[CH2:52][CH2:53][N:48]([CH:45]4[CH2:44][CH2:43][S:42](=[O:41])(=[O:54])[CH2:47][CH2:46]4)[CH2:49][CH2:50]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:33][CH3:34])([CH3:31])[CH3:32])=[CH:26][C:25]=3[O:35][CH2:36][CH3:37])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOc1cc(C(C)(C)OC)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=S1(=O)CCC(N2CCNCC2)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)OC)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(C2CCS(=O)(=O)CC2)CC1

Procedure:
In a manner analogous to the method described in example 5, 4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(1-methoxy-1-methyl-ethyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-(1,1-dioxo-tetrahydro-2H-thiopyran-4-yl)-piperazine dihydrochloride (example 22) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C39H49N4O5SCl2 [(M+H)+] 755.2795, observed 755.2792.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[CH:11]=[N:10]1.P(Br)(Br)[Br:20]>C(Cl)Cl.O>[Br:20][CH2:14][C:13]1[N:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[N:10]=[CH:11][C:12]=1[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)c1cnn(-c2c(Cl)cccc2Cl)c1CO
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: O
Product: CC(C)c1cnn(-c2c(Cl)cccc2Cl)c1CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.3 %

Procedure:
To a solution of (1-(2,6-dichlorophenyl)-4-isopropyl-1H-pyrazol-5-yl)methanol (4.0 g, 0.014 mol) in CH2Cl2 (50 ml) is added phosphorus tribromide (5.69 g, 0.021 mol) at 0° C. Stir the mixture for 3 h at room temperature. Dilute with water and extract with ethyl acetate. Concentrate under reduced pressure, to give crude product, which is purified by column chromatography over silica gel eluting with 7:3 hexane/ethyl acetate to give 0.50 g (10%) of the title compound. ES/MS m/e (81Br) 348.93 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[NH:5][C:6](=[O:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9].C(N(CC)CC)C.[C:25](Cl)(Cl)=[O:26]>O1CCCC1>[F:13][C:7]([F:12])([C:8]([F:9])([F:10])[F:11])[C:6]([NH:5][C:4]1[CH:3]=[C:2]([N:1]=[C:25]=[O:26])[CH:17]=[CH:16][CH:15]=1)=[O:14]
Reactant: O=C(Cl)Cl
Reactant: Nc1cccc(NC(=O)C(F)(F)C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C=Nc1cccc(NC(=O)C(F)(F)C(F)(F)F)c1
Temperature: -5 °C

Procedure:
Sixty-three and one half grams of m-amino pentafluoropropionanilide is dissolved in 150 ml of tetrahydrofuran containing 65 g. of triethylamine. This mixture is added dropwise with coolng to 37 g. of phosgene dissolved in 150 ml of tetrahydrofuran cooled to -5° C. When addition is complete the mixture is allowed to warm up to room temperature. The triethylamine hydrochloride is filtered off and the solvent is removed under vacuum. The product, 70 g., was not isolated but diluted to 140 ml with tetrahydrofuran and used in subsequent reactions.