Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1([C:9](=[O:11])[CH3:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CO[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.Cl>C1COCC1>[CH:3]1([C:9](=[O:11])[CH2:10][C:14]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)=[O:22])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: COC(=O)c1ccc(F)cc1
Reactant: CC(=O)C1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C1CCCCC1)c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
0.88 g 60% sodiumhydrid was added 1-cyclohexyl-ethanone in 60 mL THF and stirred for 30 min. Then, 3.25 g 4-fluoro-benzoic acid methyl ester and 200 mg 18-Krone-6 was added to the reaction. The reaction was refluxed 2 h and stirred over night at RT. The reaction was added to 100 mL 1N HCl and extracted with diethylether. The organic layer was concentrated and the residue was purified by chromatography on silica gel and 3 g of the desired compound was obtained.
Reaction SMILES: [C:1]([N:4]([CH3:25])[NH:5][C:6]([C@H:8]1[CH2:14][CH2:13][C@H:12]2[CH2:15][N:9]1[C:10](=[O:24])[N:11]2[O:16]CC1C=CC=CC=1)=[O:7])(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([N:4]([CH3:25])[NH:5][C:6]([C@H:8]1[CH2:14][CH2:13][C@H:12]2[CH2:15][N:9]1[C:10](=[O:24])[N:11]2[OH:16])=[O:7])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)N(C)NC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)N(C)NC(=O)[C@H]1CC[C@H]2CN1C(=O)N2O
Yield: 101.4 %

Procedure:
To a solution of (2R,5S)-N′-acetyl-6-(benzyloxy)-N′-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 213 (0.20 g, 0.57 mml) in methanol (20 mL) was added 5% Pd/C (0.30 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2R,5S)-N′-acetyl-6-hydroxy-N′-methyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 214 (0.15 g, 99%) as a colorless foam.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH:8]([C:14]([CH3:16])=O)[C:9](OCC)=[O:10])[CH:2]=1.[NH2:17][C:18]([NH2:20])=[S:19].[O-]CC.[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[C:9](=[O:10])[NH:17][C:18](=[S:19])[NH:20][C:14]=2[CH3:16])[CH:2]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Cc1cccnc1)C(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1[nH]c(=S)[nH]c(=O)c1Cc1cccnc1

Procedure:
A mixture of pyridine-3-carboxaldehyde (48 g), ethyl acetoacetate (52 g) aqueous piperidine acetate (40% 4.8 g) and 5% palladium on charcoal catalyst (50% wet, 2.48 g) was hydrogenated at 100 p.s.i. at 30° for 22 hours. The mixture was diluted with ether, filtered and the filtrate was evaporated and distilled under reduced pressure to give ethyl α-(3-pyridylmethyl)acetoacetate (b.p. 146°/1 mmHg). This ester was refluxed with thiourea and sodium ethoxide in ethanol, and the mixture was subsequently acidified to give 5-(3-pyridylmethyl)-6-methyl-2-thiouracil m.p. 328°-331°.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:10]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:19](=[O:28])[CH:20](Br)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:16]=[CH:17][CH:18]=1>C(Cl)(Cl)(Cl)Cl>[CH3:33][C:29]1[CH:30]=[CH:31][CH:32]=[C:9]([CH3:8])[C:10]=1[CH2:11][O:12][C:13]1[CH:14]=[C:15]([C:19](=[O:28])[CH:20]=[CH:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)CC(Br)C(=O)c1cccc(OCc2c(C)cccc2C)c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C=CC(=O)c1cccc(OCc2c(C)cccc2C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Triethylamine (5.95 g, 58.9 mmol) was added to a solution of Ethyl 4-(3-(2,6-dimethylbenzyloxy)phenyl)-4-oxo-3-bromo-butyrate (Step D, 2.47 g, 5.8 mmol) in carbon tetrachloride (50 ml). After stirring for 4 hours at room temperature, the reaction mixture was filtered through a pad of silica gel few times, and concentrated to give the title compound.
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:9]3[C:11]([OH:16])=[CH:12][C:13]([OH:15])=[CH:14][C:8]=3[O:7][C:6]=2[CH:5]=[C:4]([OH:17])[CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].C(Cl)(Cl)Cl.[C:26](Cl)(=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29]>C(=S)=S>[OH:1][C:2]1[C:10]2[C:9]3[C:11]([OH:16])=[CH:12][C:13]([OH:15])=[C:14]([C:26](=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29])[C:8]=3[O:7][C:6]=2[CH:5]=[C:4]([OH:17])[C:3]=1[C:2](=[O:1])[CH2:10][CH:9]([CH3:11])[CH3:8]
Reactant: Oc1cc(O)c2c(c1)oc1cc(O)cc(O)c12
Reactant: CC(C)CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: ClC(Cl)Cl
Product: CC(C)CC(=O)c1c(O)cc2oc3c(C(=O)CC(C)C)c(O)cc(O)c3c2c1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
Compound 8 (100 mg, 0.431 mmol) and aluminum trichloride (287 mg, 2.15 mmol) were suspended in 5 mL of carbon disulfide at rt. Chloroform (6 mL) was added to the suspension and the reaction mixture was warmed to 50° C. in a water-bath. Isovaleryl chloride (259 mg, 2.15 mmol) was added dropwise and the reaction was stirred for 2 h at 50° C. After removing solvent in vacuo, and the crude reaction mixture was purified by column chromatography (1-5% ethyl acetate/hexane) to yield 3 (30 mg, 17%) as a white solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[F:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[C:10]([O:18][CH3:19])[CH:9]=1.O>C1COCC1>[F:7][C:8]1[CH:17]=[CH:16][C:11]([CH2:12][OH:13])=[C:10]([O:18][CH3:19])[CH:9]=1
Reactant: COC(=O)c1ccc(F)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(F)ccc1CO
Reaction time: 1 h
Yield: 83 %

Procedure:
To a suspension of LiAlH4 (94.6 mg, 2.49 mmol) in THF (3 ml) was added dropwise a solution of methyl 4-fluoro-2-methoxybenzoate obtained in Example 23-2) (273.3 mg, 1.48 mmol) in THF (3 ml). The mixture was stirred for 1 hour. To the mixture was added dropwise aqueous THF followed by water. The mixture was extracted three times with ethyl acetate and dried over MgSO4. The solvent was evaporated to give the crude title compound (310.8 mg; 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:14][CH2:15][C:16]#[CH:17])[C:9]=1[O:10][CH2:11][C:12]#[CH:13])[CH:5]=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:14][CH2:15][C:16]#[CH:17])[C:9]=1[O:10][CH2:11][C:12]#[CH:13])[CH:5]=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccccc1
Reactant: C#CCOc1cc(C=O)cc(Cl)c1OCC#C
Solvent: c1ccccc1
Product: C#CCOc1cc(C=Nc2ccccc2)cc(Cl)c1OCC#C
Yield: 101.1 %

Procedure:
A mixture of 3-chloro-4,5-dipropargyloxybenzaldehyde (1.00 g) and aniline (0.37 g) in benzene (30 ml) was stirred under reflux for 3 hours, followed by concentration under reduced pressure to give N-(3-chloro-4,5-dipropargyloxybenzyliden)aniline (1.30 g). nD23.0 1.5890.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:11][O:12][C:13]1[CH:18]=[C:17]([N:4]2[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:2]([CH3:1])=[N:3]2)[CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COC(=O)c1c[nH]nc1C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cn(-c2cccc(OC)c2)nc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
Methyl 3-methyl-1H-pyrazole-4-carboxylate (4.6 g) synthesized in Example 1(3) was dissolved in N,N-dimethylacetamide (50 mL), 3-methoxyphenylboronic acid (10.0 g), copper acetate (12.0 g) and pyridine (10.6 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (100 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title object compound (3.9 g, 48%) as a pale-yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]([OH:72])[CH2:10][NH:11][C:12](=[O:71])[C@@H:13]([NH:24][C:25]([C@H:27]1[NH:45][C:44](=[O:46])[C@H:43]([CH2:47][CH2:48][CH2:49][NH:50]C(OC(C)(C)C)=O)[NH:42][C:41](=[O:58])[C@@H:40]([NH:59]C(OC(C)(C)C)=O)[CH2:39][C:38]2[CH:67]=[C:34]([CH:35]=[CH:36][C:37]=2[OH:68])[C:33]2=[CH:69][C:29](=[C:30]([OH:70])[CH:31]=[CH:32]2)[CH2:28]1)=[O:26])[CH2:14][CH2:15][NH:16]C(OC(C)(C)C)=O)(C)(C)C.[ClH:74]>O1CCOCC1>[ClH:74].[ClH:74].[ClH:74].[ClH:74].[NH2:59][C@H:40]1[CH2:39][C:38]2[CH:67]=[C:34]([CH:35]=[CH:36][C:37]=2[OH:68])[C:33]2=[CH:69][C:29](=[C:30]([OH:70])[CH:31]=[CH:32]2)[CH2:28][C@@H:27]([C:25]([NH:24][C@H:13]([C:12]([NH:11][CH2:10][CH:9]([OH:72])[CH2:8][NH2:7])=[O:71])[CH2:14][CH2:15][NH2:16])=[O:26])[NH:45][C:44](=[O:46])[C@H:43]([CH2:47][CH2:48][CH2:49][NH2:50])[NH:42][C:41]1=[O:58]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H]1NC(=O)[C@@H](NC(=O)OC(C)(C)C)Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@@H](C(=O)N[C@@H](CCNC(=O)OC(C)(C)C)C(=O)NCC(O)CNC(=O)OC(C)(C)C)NC1=O
Agent: Cl
Solvent: C1COCCO1
Product: NCCC[C@@H]1NC(=O)[C@@H](N)Cc2cc(ccc2O)-c2ccc(O)c(c2)C[C@@H](C(=O)N[C@@H](CCN)C(=O)NCC(O)CN)NC1=O
Reaction time: 1 h

Procedure:
9 mg (0.01 mmol) of the compound from Example 173A are cooled to 0° C. and 1 ml of 4N hydrogen chloride in dioxane is added. After 1 h, the mixture is concentrated in vacuo. The residue is taken up in acetonitrile and again concentrated.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:14](O)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=O)(C)(C)C.[F:17][C:18]([F:31])([F:30])[C:19]1[CH:20]=[C:21]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[NH2:22]>>[NH2:8][C@@H:9]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:14]([NH:22][C:21]1[CH:20]=[C:19]([C:18]([F:30])([F:31])[F:17])[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=1)=[O:15]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CC(C)C[C@H](N)C(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 25.2 %

Procedure:
Using N-(tert-butoxycarbonyl)-L-leucine and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 302(1) gave the title compound.
Reaction SMILES: C([NH:8][C:9]([C:28]1([C:31]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[O:32])[CH2:30][CH2:29]1)([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:16][CH:15]=1)[C:10]([F:13])([F:12])[F:11])C1C=CC=CC=1.C(O)=O>CO.[Pd]>[NH2:8][C:9]([C:28]1([C:31]([C:33]2[CH:34]=[CH:35][C:36]([O:39][CH3:40])=[CH:37][CH:38]=2)=[O:32])[CH2:30][CH2:29]1)([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH2:23][C:24]([F:27])([F:25])[F:26])=[CH:18][CH:19]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: COc1ccc(C(=O)C2(C(NCc3ccccc3)(c3ccc(OCCCC(F)(F)F)cc3)C(F)(F)F)CC2)cc1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: COc1ccc(C(=O)C2(C(N)(c3ccc(OCCCC(F)(F)F)cc3)C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a solution of Intermediate 14G (6 mg, 10.6 μmol) in MeOH (1 mL) containing 4.4% formic acid was added 10% palladium on carbon (2 mg, 2 μmol). The reaction was stirred at rt overnight. The reaction was filtered through Celite®. The filtrate was made basic with sat'd aq NaHCO3, and then evaporated to remove MeOH. The aqueous residue was diluted with sat'd aq NaCl and extracted with EtOAc. The combined organic extracts were washed with sat'd aq NaCl, dried over Na2SO4, filtered and concentrated to provide Intermediate 14H (4 mg, 71%) as a tan glass. LCMS Anal. Calc'd for C23H23F6NO3 475.42, found [M+H] 476.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:27][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1ccccc1

Procedure:
The compound prepared in Example 3 was reacted with benzylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][C:3]=1[Cl:10].[CH3:11][CH:12]1[CH2:17][NH:16][CH:15]([CH3:18])[CH2:14][NH:13]1.CCOC(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[Cl:10][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:2]=1[Cl:1])[CH2:8][N:13]1[CH2:14][CH:15]([CH3:18])[NH:16][CH2:17][CH:12]1[CH3:11]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: CC1CNC(C)CN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1CN(Cc2ccc(Cl)c(Cl)c2)C(C)CN1

Procedure:
A solution of 1,2-dichloro-4-chloromethyl-benzene (1.1 ml 7.89 mmol) in DMF (5 ml) was added to 2,5-dimethyl-piperazine (1.0 g, 8.77 mmol) dissolved in DMF (25 ml). The reaction was stirred over night, poured into a mixture of EtOAc and sodium carbonate (5%). The water phase was washed twice with EtOAc and the combined organic phase once with brine, and dried over sodium sulfate. After evaporation the crude was dissolved in methanol. The dibensylated piperazine does not dissolve. The filtrate was filtered through a short silica column, using methanol as eluant and evaporated to give the pure product. Yield 812 mg, 38%
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[NH2:30][CH2:31][CH:32]([CH2:35][OH:36])[CH2:33][OH:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[OH:34][CH2:33][CH:32]([CH2:35][OH:36])[CH2:31][NH:30][C:27]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[NH:10]1)=[O:28]
Reactant: NCC(CO)CO
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCC(CO)CO)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 2-aminomethyl-propane-1,3-diol (31.5 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (3-hydroxy-2-hydroxymethyl-propyl)-amide (31.2 mg, 30.9%) as an off-white powder. HRMS (ES+) m/z Calcd for C26H31Cl2N3O3S+H [(M+H)+]: 504.455. found: 504.1815.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH3:9])=[CH:5][C:4]([NH:10][S:11]([C:14]2([CH2:17][CH:18]=[O:19])[CH2:16][CH2:15]2)(=[O:13])=[O:12])=[C:3]1[N:20]([C:28]1[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=1[F:35])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].[BH4-].[Na+]>CO>[F:35][C:29]1[CH:30]=[C:31]([I:34])[CH:32]=[CH:33][C:28]=1[N:20]([C:3]1[N:2]([CH3:1])[C:7](=[O:8])[C:6]([CH3:9])=[CH:5][C:4]=1[NH:10][S:11]([C:14]1([CH2:17][CH2:18][OH:19])[CH2:16][CH2:15]1)(=[O:13])=[O:12])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1cc(NS(=O)(=O)C2(CC=O)CC2)c(N(C(=O)OC(C)(C)C)c2ccc(I)cc2F)n(C)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(NS(=O)(=O)C2(CCO)CC2)c(N(C(=O)OC(C)(C)C)c2ccc(I)cc2F)n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.2 %

Procedure:
To a solution of tert-butyl [1,5-dimethyl-6-oxo-3-({[1-(2-oxoethyl)cyclopropyl]sulfonyl}amino)-1,6-dihydropyridin-2-yl](2-fluoro-4-iodophenyl)carbamate (304 mg, 0.491 mmol) in MeOH (6 ml) at 0° C. under a nitrogen atmosphere was added NaBH4 (4 eq, 74 mg, 1.963 mmol). The reaction mixture was stirred at this temperature for 1 hour and then allowed to warm up to room temperature. The solvent was removed under reduced pressure, the residue partitioned between ethyl acetate (10 ml), H2O (5 ml) and 1N aq HCl (5 ml). The aqueous phase was separated and extracted twice with ethyl acetate (10 ml). The combined organic layers were washed with brine (20 ml), dried (silicone filter) and concentrated under reduced pressure. The crude material was purified by flash chromatography (Biotage system) to afford the title compound (321 mg, quant.).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.C(N(CC)CC)C.[Cl:18][C:19]([Cl:23])([Cl:22])[S:20]Cl>C1C=CC=CC=1>[Cl:18][C:19]([Cl:23])([Cl:22])[S:20][NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Reactant: ClSC(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: ClC(Cl)(Cl)SNc1nc(C(Cl)(Cl)Cl)ns1
Yield: 23.9 %

Procedure:
To a 3-neck flask equipped with condenser, thermometer, and stirring bar was added 11.7 g (0.05 mole) 5-amino-3trichloromethyl-1,2,4-thiadiazole, 5.1 g (0.05 mole) triethylamine and 150 milliliters of benzene. After 9.3 g (0.05 mole) trichloromethane-sulfenyl chloride was added, the reaction mixture was heated at reflux for 16 hours and filtered hot. The filtrate was evaporatd under vacuum to give an orange paste which was triturated with acetonitrile, filered and washed with petroleum ether to obtain 4.4 g (24% yield) of product; mp=180° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:29][CH3:30])[CH:4]=1.Cl.[CH3:32][C:33]1[S:37][C:36]([N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[N:35][C:34]=1/[CH:44]=[CH:45]/[C:46]1[C:47]([OH:57])=[N:48][N:49]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:50]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:30][O:29][C:5]1[CH:4]=[C:3]([CH2:2][O:57][C:47]2[C:46](/[CH:45]=[CH:44]/[C:34]3[N:35]=[C:36]([N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[S:37][C:33]=3[CH3:32])=[CH:50][N:49]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[N:48]=2)[CH:28]=[CH:27][C:6]=1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14]
Reactant: Cc1sc(N2CCCCC2)nc1/C=C/c1cn(-c2ccccc2)nc1O
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4nc(N5CCCCC5)sc4C)cc3OC)c(C)o2)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A mixture of ethyl (4-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl)acetate (0.66 g), 4-{(E)-2-[5-methyl-2-(piperidin-1-yl)-1,3-thiazol-4-yl]ethenyl}-1-phenyl-1H-pyrazol-3-ol hydrochloride (0.44 g), potassium carbonate (0.30 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give ethyl [4-{4-[(2-methoxy-4-{[(4-{(E)-2-[5-methyl-2-(piperidin-1-yl)-1,3-thiazol-4-yl]ethenyl}-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}phenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}phenyl]acetate (0.59 g, yield 72%) as crystals. Recrystallization from ethyl acetate-hexane gave yellow prism crystals. melting point: 131-132° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[C:5]([N:13]2[CH2:18][C@H:17]([CH3:19])[O:16][C@H:15]([CH3:20])[CH2:14]2)=[C:4]([F:21])[C:3]=1[F:22].CN(C)CCN(C)C.CN(C)[CH:33]=[O:34]>O1CCCC1.C(OC(=O)C)C>[CH3:19][C@@H:17]1[CH2:18][N:13]([C:5]2[C:6]([CH:8]3[O:12][CH2:11][CH2:10][O:9]3)=[CH:7][C:2]([CH:33]=[O:34])=[C:3]([F:22])[C:4]=2[F:21])[CH2:14][C@H:15]([CH3:20])[O:16]1
Reactant: C[C@@H]1CN(c2c(C3OCCO3)cc(Br)c(F)c2F)C[C@H](C)O1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2c(C3OCCO3)cc(C=O)c(F)c2F)C[C@H](C)O1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of (2R,6S)-4-(4-bromo-6-(1,3-dioxolan-2-yl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (previously described in WO2004031195, page 81, 0.500 g, 1.32 mmol) and tetramethylethylene-diamine (0.12 mL, 2.12 mmol) in tetrahydrofuran (12 mL) at −78° C. is added t-buthyllithium (1.94 mL, 3.31 mmol). The reaction is stirred at −78° C. for 1.5 h and dimethylformamide is added. The reaction is stirred at −78° C. for an additional 30 min and warmed to rt. Mixture is diluted with ethylacetate (50 mL) and washed with saturated aqueous NH4Cl. (50 ml) and brine (30 mL). Dried over Na2SO4 and concentrated to give the title compound (433 mg): LCMS (M+H) 327.1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[NH:8][C:9]([CH3:20])=[C:10]([N+:17]([O-:19])=[O:18])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2].C1(P(Cl)([Cl:30])=O)C=CC=CC=1>O>[Cl:30][C:7]1[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([N+:17]([O-:19])=[O:18])=[C:9]([CH3:20])[N:8]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: CCOC(=O)c1c([N+](=O)[O-])c(C)[nH]c(=O)c1C(=O)OCC
Solvent: O
Product: CCOC(=O)c1c(Cl)nc(C)c([N+](=O)[O-])c1C(=O)OCC
Temperature: 170 °C

Procedure:
To 1.0 g of 3,4-diethoxycarbonyl-6-methyl-5-nitro-2-pyridone was added 1.3 ml (3.2 eq.) of phenylphosphonic dichloride. The mixture was heated at 170° C. for 20 mintues. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (eluent:ethyl acetate) to give an oily product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CC(C)=O>[CH2:16]([O:9][C:3]1[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][CH:2]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1cc(F)ccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1cccc(OCc2ccccc2)c1
Temperature: 25 °C

Procedure:
To a solution containing 2-bromo-5-fluorophenol (50 g, 0.26 mol) in 500 mL acetone was added potassium carbonate (54.2 g, 0.39 mmol) and benzyl bromide (34.3 mL, 0.288 mol). The reaction was heated at reflux under an argon atmosphere for 2 h and then allowed to cool to 25° C. The acetone was removed under reduced pressure and the residue was taken up in ether (400 mL). The organic layer was washed with water (5×100 mL) and brine (1×100 mL) and then dried (MgSO4). The solution was then concentrated under reduced pressure and subjected to flash chromatography using hexane as the eluent. In this manner, 2-benzyloxy-4-fluorobenzene was obtained as a white solid. 1H NMR (300 MHz, CDCl3): δ 5.14 (s, 2 H), 6.57-6.63 (m, 1 H), 6.69 (dd, J=2.7, 10.2 Hz, 1 H), 7.32-7.52 (m, 6 H).