Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:21])([CH2:8][C:9]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])([CH3:11])[CH3:10])[C:4]([F:7])([F:6])[F:5].[CH2:22]([O:29][C:30](ON1C(=O)CCC1=O)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>ClCCl>[C:23]1([CH2:22][O:29][C:30](=[O:31])[NH:1][CH2:2][C:3]([OH:21])([C:4]([F:7])([F:6])[F:5])[CH2:8][C:9]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])([CH3:11])[CH3:10])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CN)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNC(=O)OCc1ccccc1)C(F)(F)F
Reaction time: 0.08 h
Yield: 87.4 %

Procedure:
Racemic 2-(aminomethyl)-1,1,1-trifluoro-4-[5-fluoro-2-(methyloxy)phenyl]-4-methyl-2-pentanol (which may be prepared according to WO03/082827, 894 mg, 2.89 mmol) was dissolved in dichloromethane (15 mL). N-(benzyloxycarbonyloxy)succinimide (1.08 g, 4.34 mmol) was added and the mixture was stirred for 5 min. Triethylamine (804 μL, 5.78 mmol) was added and stirring was continued for 3.5 hours after which time the reaction mixture was washed with saturated sodium bicarbonate solution and evaporated in vacuo. Purification of the residue by Flashmaster II using a 100 g silica cartridge and a solvent gradient of cyclohexane:EtOAc 100:0 to 0:100 over a period of 1 hour gave the racemic product as an oil (1.12 g). This oil was applied to a 2 inch×20 cm Chiralpak AD column eluted with heptane:IPA 97.5:2.5 with a flow rate of 75 mL/min to give Intermediate 7 (2R isomer, 443 mg) after ca. 42 min and Intermediate 8 (2S isomer, 441 mg) after ca. 60 min.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[P:5]([O-:9])([O-:8])([O-:7])=[O:6]>O>[P:5]([OH:9])([OH:8])([OH:7])=[O:6].[NH2:1][C:2]([NH2:4])=[O:3]
Reactant: O=P([O-])([O-])[O-]
Agent: NC(N)=O
Solvent: O
Product: O=P(O)(O)O

Procedure:
To a 50 mL beaker was added 16 g of urea-phosphate produce as above and 22 g Milli-Q™ water. The solids were stirred with a magnetic stirrer until dissolved. This solution was subsequently added dropwise to the Colloid BP slurry at a mixing speed of 800 rpm. The dispersion quickly increased in viscosity following the addition of the urea-phosphate solution. After 10 minutes of mixing the shear thinning product was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[CH2:4][NH:5][CH3:6].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)=[O:15]>>[Br:22][C:19]1[CH:20]=[CH:21][C:16]([C:14](=[O:15])[CH2:13][N:5]([CH2:4][C:3]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=2[Cl:1])[CH3:6])=[CH:17][CH:18]=1
Reactant: CNCc1ccc(Cl)cc1Cl
Reactant: O=C(CBr)c1ccc(Br)cc1
Product: CN(CC(=O)c1ccc(Br)cc1)Cc1ccc(Cl)cc1Cl
Yield: 69 %

Procedure:
(2,4-Dichloro-benzyl)-methyl-amine (see example 1, intermediate 1) and 2-bromo-1-(4-bromo-phenyl)-ethanone was reacted in analogy to the method described in example 1, intermediate 3. After analogous workup and chromatography on silica gel, the alkylation product was isolated in a yield of 69%.
Reaction SMILES: [O:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.[CH3:13]CN=C=NCCCN(C)C.Cl.CO>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:13][O:11][C:10]([C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:1][CH:2]=1)=[O:12]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1coc2ncccc12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1coc2ncccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of furo[2,3-b]pyridine-3-carboxylic acid (53 mmol) in 85 mL DCM were added EDC.HCl (58 mmol), DMAP (16 mmol) and 4.3 mL MeOH. The beige suspension was stirred at RT for 2 h. The reaction mixture was diluted with 50 mL DCM and quenched with sat. aq. NaHCO3 solution. The organic phase was washed 3 times with sat. aq. NH4Cl solution and once with brine. The organic layer was dried over MgSO4 and concentrated in vacuo to obtain the desired compound as grey solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[N:4][C:3]=1[N:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[C@@H:17]([CH3:28])[CH2:16]1.Cl.O1CCOCC1>CO>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]=[N:4][C:3]=1[N:15]1[CH2:20][CH2:19][NH:18][C@@H:17]([CH3:28])[CH2:16]1
Reactant: Cc1c(-c2ccccc2)nnc(N2CCN(C(=O)OC(C)(C)C)[C@@H](C)C2)c1C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2)nnc(N2CCN[C@@H](C)C2)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
Treat a solution of (S)-tert-butyl 4-(4,5-dimethyl-6-phenylpyridazin-3-yl)-2-methylpiperazine-1-carboxylate (2.93 g, 7.66 mmol) in MeOH (20 mL) with 4 M HCl in 1,4-dioxane (10 mL, 40.0 mmol). Stir the reaction mixture at ambient temperature overnight. Concentrate the reaction mixture under reduced pressure. Dissolve the residue in MeOH, and pour onto an SCX column (Varian, 10 g). Rinse the column with MeOH. Elute the desired product with 2M NH3/MeOH. Concentrate under reduced pressure to afford the title compound (2.07 g, 95%). ES/MS m/z 283.0 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[Cl-].[Li+].C(=O)([O-])[O-].[K+].[K+].[CH3:23][O:24][C:25](=[O:29])[C:26]#[C:27][CH3:28]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:23][O:24][C:25]([C:26]1[N:9]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:3]2[N:4]=[C:5]([Cl:8])[N:6]=[CH:7][C:2]=2[C:27]=1[CH3:28])=[O:29]
Reactant: Clc1ncc(Br)c(NC2CCCC2)n1
Reactant: CC#CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)c2cnc(Cl)nc2n1C1CCCC1
Temperature: 120 °C
Yield: 24.8 %

Procedure:
A solution of (5-Bromo-2-chloro-pyrimidin-4-yl)cyclopentylamine (8 g, 28.93 mmol), lithium chloride (1.23 g, 28.9 mmol), potassium carbonate (10 g, 72 mmol) and palladium acetate (324.68 mg, 1.45 mmol) in DMF (300 mL) is degassed and back-filled filled with nitrogen three times. Methyl-2-butynoate (8.5 mL, 87 mmol) is added and the reaction solution is heated at 120° C. for 5 h. LC-MS indicated the formation of two regioisomers and no starting material remaining. After cooling to room temperature the solution is filtered through Celite, diluted with water and extracted with ethyl acetate three times. The organic layers are combined, washed with brine and dried over anhydrous sodium sulfate. The solvent is evaporated and the crude product is purified using silica gel chromatography (˜20% ethyl acetate/80% hexane) to give 2-chloro-7-cyclopentyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methyl ester as a yellow solid (2.11 g, 25%). [M+H]+=294.04.
Reaction SMILES: [C:1]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH2:16][CH2:17][NH2:18])([O:3][CH2:4][CH3:5])=[O:2].[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[BH4-].[Na+]>CCO>[CH2:19]([NH:18][CH2:17][CH2:16][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])[CH:8]=2)[NH:12][CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)Cc1ccc2[nH]cc(CCN)c2c1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)Cc1ccc2[nH]cc(CCNCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 72.7 %

Procedure:
To a solution of 2-[5-carboethoxymethyl-1H-indol-3-yl]ethylamine (2.8 g, 11.37 mmol) in EtOH (45 ml) was added freshly distilled benzaldehyde (1.21 g, 11.37 mmol) and the resulting solution was stirred at room temperature for 22 h. NaBH4 (0.434 g, 11.48 mmol) was added portionwise over 10 min at room temperature and the resulting mixture was stirred for a further 0.5 h before the solvent was removed under vacuum. The resulting residue was taken up into water (20 ml) and acidified with 1N HCl (30 ml). The mixture was then basified with 2N NaOH and extracted with EtOAc (4×70 ml). The combined organic phases were washed with brine (50 ml), dried and concentrated. Chromatography of the residue on silica-gel eluting with CH2Cl2 /EtOH (90:10) gave the title-product (2.78 g, 73%); δ(360 MHz, CDCl3) 1.25 (3H, t, J=7.1 Hz, CH3); 2.98 (4H, s, 2 of CH2); 3.68 (2H, s, CH2); 3.81 (2H, s, CH2); 4.14 (2H, q, J=7.1 Hz, CH2); 6.98 (1H, d, J=2.2 Hz, Ar-H); 7.11 (1H, dd, J=1.6 and 8.3 Hz, Ar-H); 7.20-7.32 (6H, m, Ar-H); 7.49 (1H, d, J=0.7 Hz, Ar-H); 7.99 (1H, br s, indole N-H).
Reaction SMILES: B(Br)(Br)Br.[CH:5]1([C:11]2[N:15]=[C:14]([CH:16]=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24]C)=[C:20]([O:26]C)[CH:19]=3)[O:13][N:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>ClCCl>[CH:5]1([C:11]2[N:15]=[C:14]([CH:16]=[CH:17][C:18]3[CH:19]=[C:20]([OH:26])[C:21]([OH:24])=[CH:22][CH:23]=3)[O:13][N:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COc1ccc(C=Cc2nc(C3CCCCC3)no2)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(C=Cc2nc(C3CCCCC3)no2)cc1O
Reaction time: 0.62 h

Procedure:
To a cooled solution of 0.55 mL of 1M boron tribromide (5.8 mmol) in 2 mL dichloromethane, 0.8 g (2.5 mmol) of 3-cyclohexyl-5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1,2,4]oxadiazole (compound of Example 60) dissolved in 8 mL of dichloromethane was added over a period of 15-20 min at −45° C. to −40° C. The reaction mixture was stirred at −45° C. to −40° C. for 30-45 min and allowed to attain a temperature of 25° C. to 30° C. slowly, over a period of 1 h. The reaction mixture was further stirred at 25° C. to 30° C. for 4-5 h. After completion of the reaction, the reaction mixture was quenched with 10 mL of chilled 5% sodium bicarbonate solution, below 20° C. (pH: 8-9). 10 mL of ethyl acetate was added to the reaction mixture to dissolve the solid and stirred for 10-15 min. The organic layer was separated and washed with 10 mL of 10% sodium chloride solution. The organic layer was distilled to obtain a crude residue, which was purified by column chromatography (silica gel, chloroform-methanol) to yield the title compound.
Reaction SMILES: [F:1][CH:2]([F:33])[N:3]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([O:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:14])=[CH:9][CH:10]=2)[C:5]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=2[O:31][CH3:32])=[CH:4]1.Cl.C(N=C=N)C.[C:40]1([CH3:50])[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[S:46]([NH2:49])(=[O:48])=[O:47].CO.C(Cl)Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:33][CH:2]([F:1])[N:3]1[C:11]2[C:6](=[CH:7][C:8]([NH:12][C:13]([O:15][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[O:14])=[CH:9][CH:10]=2)[C:5]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([NH:49][S:46]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[CH3:50])(=[O:47])=[O:48])=[O:28])=[CH:24][C:23]=2[O:31][CH3:32])=[CH:4]1
Reactant: Cc1ccccc1S(N)(=O)=O
Reactant: COc1cc(C(=O)O)ccc1Cc1cn(C(F)F)c2ccc(NC(=O)OC3CCCC3)cc12
Agent: CCN=C=N
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C(=O)NS(=O)(=O)c2ccccc2C)ccc1Cc1cn(C(F)F)c2ccc(NC(=O)OC3CCCC3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.9 %

Procedure:
To a solution of 4-[1-difluoromethyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid (1.10 grams, 2.37 mmol), 4-dimethylaminopyridine (0.44 grams, 3.63 mmol) and 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1,2-dichloroethane) (0.70 grams, 3.64 mmol) in methylene chloride (100 mL) was added o-tolylsulfonamide (0.41 grams, 2.42 mmol). The resulting solution was stirred for 16 hours at room temperature. The solution was diluted with methylene chloride and washed with 1 M hydrochloric acid (ag) and brine. The organics were dried over sodium sulfate and concentrated. Chromatography on silica gel (5% methanol/methylene chloride gave 4-[1-difluoromethyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide (1.10 grams, 76% yield). HRMS calcd. for C31H31N3O6F2S: 611.1902. Found: 611.1924.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C.CC(=O)OCC>[CH2:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH2:11][C:5]1[CH:6]=[CH:10][CH:2]=[CH:3][CH:4]=1)=[O:8])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccc(O)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(OCc2ccccc2)cc1C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 2.6 g of 5-hydroxy-2-methylbenzoic acid (see below), 7.0 g potassium carbonate and 3.8 ml benzyl chloride in 50 ml DMF are stirred at 50° C. for two hours, until the reaction is completed according to TLC analysis. The reaction mixture is portioned between water and EA, and the phases are separated. The organic phase is washed three times with 1 M sodium carbonate solution and once with brine, dried over MgSO4, and the solvent is removed under reduced pressure yielding benzyl 5-(benzyloxy)-2-methylbenzoate, which is used for the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][CH:12]2[C:25](C(=O)C)([OH:26])[C:24]3[O:30][C@@H:21]4[C@@:22]56[CH2:31][CH2:32][N:33]([CH3:34])[C@@H:16]([C@@H:17]5[CH:18]=[CH:19][C@:20]4([C:36](=[O:38])[CH3:37])[OH:35])[CH2:15][C:14]([C:23]6=3)=[CH:13]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].C(Cl)Cl.CO.O.C(O)(=O)C>[OH-].[Na+]>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[C:25]([OH:26])=[C:24]3[O:30][C@@H:21]4[C@@:22]56[CH2:31][CH2:32][N:33]([CH3:34])[C@@H:16]([C@@H:17]5[CH:18]=[CH:19][C@:20]4([C:36](=[O:38])[CH3:37])[OH:35])[CH2:15][C:14](=[C:23]63)[CH:13]=2)=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: CC(=O)C1(O)C2=C3C(=CC1N=Nc1ccc(C(=O)O)cc1)C[C@@H]1[C@@H]4C=C[C@@](O)(C(C)=O)[C@H](O2)[C@]34CCN1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)[C@]1(O)C=C[C@H]2[C@H]3Cc4cc(N=Nc5ccc(C(=O)O)cc5)c(O)c5c4[C@@]2(CCN3C)[C@H]1O5

Procedure:
A solution of 0.5g of 2-(4'carboxyphenylazo)-3,6-diacetylmorphine in 10 ml 0.1 N NaOH was stirred at room temperature and examined hourly by silica gel TLC for the presence of the monoacetyl derivative, the solvent system being methylene chloride: methanol: water: acetic acid (80:20:1:1) and the rf value for azomonoacetyl morphine 0.39. When TLC showed most of the starting material to have hydrolyzed the reaction mixture was concentrated and passed down a silica gel column. The fraction containing the desired product was evaporated to dryness to give 2-(4'carboxyphenylazo) -6 acetyl morphine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][C@@H:17]2[CH2:21][CH2:20][C:19]([F:23])([F:22])[CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:30][C:31]1[CH:35]=[CH:34][N:33]([CH2:36][C:37]([CH3:40])([OH:39])[CH3:38])[N:32]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][C@@H:17]2[CH2:21][CH2:20][C:19]([F:22])([F:23])[CH2:18]2)[C:13]([NH:30][C:31]2[CH:35]=[CH:34][N:33]([CH2:36][C:37]([OH:39])([CH3:38])[CH3:40])[N:32]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(C[C@@H]2CCC(F)(F)C2)C(=O)O)cc1Cl
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1ccc(NC(=O)C(C[C@@H]2CCC(F)(F)C2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((S)-3,3-difluoro-cyclopentyl)-propionic acid (210 mg, 0.57 mmol) was dissolved in methylene chloride (10 mL) and N,N-dimethylformamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 329 μL, 0.66 mmol) which produced gas evolution and was stirred at 0° C. for 15 min and then warmed to 25° C. and stirred for 1 h. After this time, the reaction was concentrated in vacuo to about 2 mL. In another round bottom flask was placed 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 97 mg, 0.63 mmol), 2,6-lutidine (95 μL, 0.86 mmol) and methylene chloride (10 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added the solution of the prepared acid chloride diluted with another portion of methylene chloride (2 mL) dropwise. The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture diluted with methylene chloride (10 mL). The organic layers were then washed with a saturated aqueous sodium bicarbonate solution (10 mL). The aqueous layer was then extracted with methylene chloride (2×10 mL). The organics were combined and then washed with a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an Isco flash system (12 g column, 40% ethyl acetate/hexanes to 65% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((S)-3,3-difluoro-cyclopentyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (as a mixture of two diastereomers, 207 mg, 72%) as a light yellow foam: ES-HRMS m/e calcd for C22H28N3O4SClF2 (M+H)+ 504.1530, observed 504.1526; 1H NMR (300 MHz, DMSO-d6) δ 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.42 (m, 1H, CH), 1.65-2.29 (m, 8H, 4×CH2), 3.34 (s, 3H, SO2CH3), 3.87 (s, 2H, NCH2), 3.90 (m, 1H, ArCHCO), 4.65 (s, 1H, OH), 6.45 (d, J=2.0 Hz, 1H, Ar), 7.52 (d, J=2.0 Hz, 1H, Ar), 7.60 (d, Jo=8.3 Hz, 1H, Ar), 7.71 (s, 1H, Ar), 8.01 (d, Jo=8.3 Hz, 1H, Ar), 10.85 (s, 1H, NH).
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[CH:20][C:19](F)=[C:18]([F:23])[CH:17]=1)(=[O:15])=[O:14])[C:8]1[S:9][CH:10]=[CH:11][N:12]=1)(C)(C)C.C([Li])CCC.[C:30]1([C:36]2[N:43]=[CH:42][CH:41]=[CH:40][C:37]=2[CH:38]=[O:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl>O1CCCC1.O.C(OCC)(=O)C>[F:23][C:18]1[CH:17]=[C:16]([S:13]([NH:7][C:8]2[S:9][CH:10]=[CH:11][N:12]=2)(=[O:14])=[O:15])[CH:21]=[CH:20][C:19]=1[CH:38]([OH:39])[C:37]1[C:36]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[N:43][CH:42]=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)N(c1nccs1)S(=O)(=O)c1ccc(F)c(F)c1
Reactant: O=Cc1cccnc1-c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(Nc1nccs1)c1ccc(C(O)c2cccnc2-c2ccccc2)c(F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 15.7 %

Procedure:
100 mg (0.26 mmol) of tert-butyl((3,4-difluorophenyl)sulfonyl)(thiazol-2-yl)carbamate was dissolved in 5 mL of tetrahydrofuran under nitrogen gas, and cooled to −78° C. After adding 0.25 mL (0.39 mmol) of n-butyllithium (1.6 M in tetrahydrofuran) slowly, the mixture was stirred for 30 minutes as maintaining −78° C. 24.3 mg (0.13 mmol) of 2-phenylnicotinaldehyde was dissolved in 0.5 mL of tetrahydrofuran, and added to the above reacting solution. As warming from −78° C. to room temperature, the reacting solution was stirred for 24 hours. Ethyl acetate and water/1 N-hydrochloride were added to the reacting solution, and it was stirred. After separating layers, the organic layer only was collected and concentrated under reduced pressure. The obtained residue was separated by column chromatography (developing solvent, hexane:ethyl acetate=1:1) to obtain 9 mg (7.6% yield) of the title compound.
Reaction SMILES: [C:1]([C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:11][C:10]=1[NH:20]C(=O)C)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[NH4+].[Cl-]>CCO>[NH2:20][C:10]1[S:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:13][C:9]=1[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: CC(=O)Nc1sc(-c2ccccc2)cc1C(=O)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCO
Product: Nc1sc(-c2ccccc2)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 132 %

Procedure:
To a stirred solution of 0.393 g (1.22 mmol) of N-(3-benzoyl-5-phenyl-thiophen-2-yl)-acetamide in 15 ml EtOH was added 2.5 ml of aq. NaOH (4N). The reaction mixture stirred at RT for 1 hour, and then poured onto an aq. solution of NH4Cl sat. and the product was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo to yield 0.45 g (98%) of (2-amino-5-phenyl-thiophen-3-yl)-phenyl-methanone as a light brown solid. ES-MS m/e (%): 280 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][N:19]2[C:24](OCC)=[O:25])=[O:17])=[CH:13][C:5]2[N:6]([CH2:10][CH:11]=[CH2:12])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.C[O-].[Na+]>O>[CH2:10]([N:6]1[C:5]2[CH:13]=[C:14]([N:15]3[C:24](=[O:25])[N:19]4[CH2:20][CH2:21][CH2:22][CH2:23][N:18]4[C:16]3=[O:17])[C:2]([F:1])=[CH:3][C:4]=2[S:8][C:7]1=[O:9])[CH:11]=[CH2:12]
Reactant: C=CCn1c(=O)sc2cc(F)c(NC(=O)N3CCCCN3C(=O)OCC)cc21
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: C=CCn1c(=O)sc2cc(F)c(-n3c(=O)n4n(c3=O)CCCC4)cc21
Yield: 10.9 %

Procedure:
Ethyl 2-[6-fluoro-3-(2-propenyl)-2(3H)-benzothiazolon-5-ylaminocarbonyl]-hexahydropyridazine-1-carboxylate (1.55 g) was added to a methanolic solution (2.05 g) of 10% sodium methoxide, and the resultant mixture was heated under reflux for 1.5 hours and allowed to cool. Water was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried, concentrated and purified by silica gel thin layer chromatography with a mixture of ethyl acetate and hexane (1:1) as an eluent to give 2-[3-(2-propenyl)-6-fluoro-2(3H)-benzothiazolon-5-yl]-hexahydro-1H-[1,2,4]triazolo[1,2-a]pyridazine-1,3-dione (0.15 g). m.p., 199.5° C.
Reaction SMILES: [C:1]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[O:20]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH2:30]Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[C:1]([CH2:9][CH2:10][C:11]([O:13][CH2:30][C:29]1[CH:32]=[CH:33][CH:34]=[C:27]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:28]=1)=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCC(=O)c1ccccc1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCC(=O)c1ccccc1)OCc1cccc(Oc2ccccc2)c1
Reaction time: 4 h

Procedure:
To 12 g of 3-benzoylpropionic acid and 9.3 g of potassium carbonate in 100 ml of dimethylformamide (DMF), under nitrogen, is added m-phenoxybenzyl bromide (17.1 g). The reaction is stirred about 4 hr and then water added followed by extraction with ether. The combined extracts are washed with water, saturated sodium chloride, dried over calcium sulfate and rotoevaporated to give m-phenoxybenzyl 3-benzoylpropionate which can be further purified by prep. TLC eluting with 15% ethyl acetate/hexane.