Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[Cl:25][CH2:26][CH2:27][CH2:28][CH2:29]I.[Cl-].[NH4+]>C(COC)OC.CCCCCC>[Cl:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:16]([C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[F:24])[S:13]([C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: ClCCCCI
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: COCCOC
Solvent: CCCCCC
Product: O=S(=O)(c1ccc(Cl)cc1)C(CCCCCl)c1cc(F)ccc1F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Under an argon atmosphere and at −78° C., n-butyl lithium (a 1.57M hexane solution, 3.52 ml) was added to a dimethoxyethane solution (30 ml) of the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (1.52 g, 5.02 mmol) obtained in Example 5. The temperature of the reaction mixture was elevated to room temperature, at which stirring was conducted for 15 minutes. After cooling the reaction mixture to −78° C., 4-chloro-1-iodobutane (672 μl, 5.52 mmol) was added thereto and the mixture was stirred at room temperature for 24 hours. A saturated ammonium chloride solution was added to the reaction mixture, followed by extraction with diethyl ether. The extracts were combined, washed successively with water, a saturated aqueous solution of sodium thiosulfate and brine, dried over MgSO4, and then distilled under reduced pressure to remove the solvent. The residue thus obtained was recrystallized from hexane, whereby the title compound (1.64 g, 83%) was obtained as colorless needle crystals.
Reaction SMILES: C([Li])CCC.[CH:6]1([O:11][C:12]2[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[CH2:29][CH:30]=[O:31].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH:6]1([O:11][C:12]2[CH:13]=[C:14]([CH:30]([OH:31])[CH2:29][C:23]3[C:22]([Cl:21])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:28])[CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=CCc1c(Cl)cccc1Cl
Reactant: COc1ccc(Br)cc1OC1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(O)Cc2c(Cl)cccc2Cl)cc1OC1CCCC1
Temperature: -70 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
A solution of butyl lithium in hexane (5.1 mL; 2.5 M) is treated with a solution of 3-cyclopentyloxy-4-methoxyphenyl bromide (3.45 g) in dry tetrahydrofuran (30 mL) at −70° C. and the solution is then stirred at −70° C. for 1 hour. It is then treated dropwise with 2,6-dichlorophenylacetaldehyde (2.4 g), while keeping the temperature below −60° C. When the addition is complete the temperature is allowed to rise to room temperature and the solution is stirred for a further 2 hours. The reaction mixture is treated with aqueous ammonium chloride solution (50 mL) and the solution is extracted with diethyl ether (2×200 mL). The combined extracts are dried and concentrated, to give a yellow oil, which is subjected to flash chromatography, eluting with a mixture of diethyl ether and pentane (1:8 v/v), to give 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2,6-dichlorophenyl)ethanol (1.6 g), in the form of a white solid, m.p. 87-89° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1>>[CH3:1][O:2][C:3](=[O:27])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([C:23]([F:26])([F:24])[F:25])[CH:17]=2)[CH:12]=[C:13]([O:15][C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([C:29]([F:40])([F:39])[F:28])[CH:35]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: COC(=O)C(CC(C)C)c1cc(Oc2cccc(C(F)(F)F)c2)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Yield: 71 %

Procedure:
The title compound was prepared in 71% yield from 2-(5-hydroxy-4′-chloro-3′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example A) and 3-trifluoromethylphenylboronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([C:15]([O:17][CH3:18])=[O:16])#[C:10][C:11]([O:13][CH3:14])=[O:12]>CO>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4]/[C:10](=[CH:9]/[C:15]([O:17][CH3:18])=[O:16])/[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1ccccc1F
Solvent: CO
Product: COC(=O)/C=C(/Nc1ccccc1F)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
To a solution 2-fluoroaniline (P1) (1.00 g, 9.00 mmol) in MeOH (11.1 mL) at 0° C. was added dimethyl acetylenedicarboxylate (P2) (DMAD, 1.34 mL, 10.8 mmol). The reaction was stirred at room temperature for 2 h. The mixture was concentrated and the residue was purified by silica gel flash chromatography (gradient 0-25% EtOAc in Hex) to give dimethyl (2E)-2-[(2-fluorophenyl)amino]but-2-enedioate (P3) (1.9 g, 83%). ES-MS [M+1]+=254.4. The above compound (1.90 g, 7.50 mmol) was dissolved in Eaton's reagent (8.00 mL, 50.4 mmol) and heated at 55° C. for 1 h. The LC-MS showed clean conversion. The reaction mixture was cooled to room temperature and slowly poured into a cold saturated solution of NaHCO3. The light-yellow precipitate formed was collected by filtration, washed with H2O and dried in vacuum to provide methyl 8-fluoro-4-hydroxyquinoline-2-carboxylate (P4) that gave a mass ion of 222.4 for M+H+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([CH:22]=O)[C:19]([C:24](OC)=[O:25])=[C:18]([C:28]2[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=2)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][O:35][C:36]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=1[CH2:44][NH2:45].C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+]>C(Cl)Cl.CO>[CH3:34][O:35][C:36]1[CH:41]=[C:40]([O:42][CH3:43])[CH:39]=[CH:38][C:37]=1[CH2:44][N:45]1[C:24](=[O:25])[C:19]2[C:18]([C:28]3[CH:29]=[N:30][N:31]([CH3:33])[CH:32]=3)=[N:17][C:16]([NH:15][C@@H:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]3[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[N:21][C:20]=2[CH2:22]1
Reactant: COC(=O)c1c(C=O)nc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1-c1cnn(C)c1
Reactant: COc1ccc(CN)c(OC)c1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(CN2Cc3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4cnn(C)c4)c3C2=O)c(OC)c1
Reaction time: 1 h
Yield: 3 %

Procedure:
Methyl 2-((1R,2S)-2-(tert-butoxycarbonylamino)cyclohexylamino)-4-formyl-6-(1-methyl-1H-pyrazol-4-yl)pyrimidine-5-carboxylate (0.175 g, 0.382 mmol) was dissolved in DCM (2 mL) and MeOH (1 mL). To this mixture was added (2,4-dimethoxyphenyl)methanamine (0.057 mL, 0.382 mmol) and sodium acetate (0.094 g, 1.145 mmol). The mixture was stirred in a capped 20 mL vial for 1 h, after which sodium cyanoborohydride (0.060 g, 0.954 mmol) was added. The reaction mixture was stirred at RT overnight. After the solvent was removed under reduced pressure, the residue was dissolved in DMSO/MeOH (1/1) solution. An off-white solid precipitate was initially formed, which was isolated by vacuum filtration, rinsed with MeOH, and air dried to give a first batch of the title compound (6.7 mg). The mother liquor was purified via preparative HPLC. The fractions were concentrated under reduced pressure until an off-white solid precipitate was formed, which was collected by vacuum filtration and air dried to give a second batch (46 mg) of the title compound (total 62.5 mg, 28%). [M+H] calc'd for C30H39N7O5, 578. found, 578.
Reaction SMILES: [OH-].[Na+].O.[CH:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH2:13]1>CCCCCC>[OH:11][CH:4]([CH:13]1[CH2:14][CH2:15][CH2:16][C:12]1=[O:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: O=C1CCCC1
Reactant: CCCCCCC=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Product: CCCCCCC(O)C1CCCC1=O
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
Into a 2-litter four-neck flask fitted with a thermometer, a reflux condenser and a stirrer were added sodium hydroxide (3.2 g) and water (300 ml). Then, a mixture of heptanal (114 g) and cyclopentanone (152 g) was added dropwise thereto under stirring at 0-5° C. over a period of 2 hours. After the addition, the reaction mixture was stirred at room temperature for 1 hour to complete the reaction. Hexane (150 ml) was added to the reaction mixture and the layers were separated from each other. The resulting organic layer was washed with an aqueous solution (200 ml) of acetic acid (1 g) and separated. Then, the resulting organic layer was washed with saturated brine and separated. The organic layer was evaporated on a rotary evaporator under reduced pressure to recover hexane and unreacted cyclopentanone, whereby a product (202 g) was obtained. The product was distilled using a Claisen distillation apparatus to obtain 154 g of 2-(1-hydroxyheptyl)cyclopentanone (boiling point: 112-114° C./666 Pa; GC purity: 92%). The remaining 8% was 2-heptylidenecyclopentanone which is a dehydration product.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:22][N:21]=[C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:19]=1)C1C=CC=CC=1>CO.C1COCC1.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:22][N:21]=[C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[N:19]=1
Reactant: CCOC(=O)c1noc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1noc([C@@H]2CC[C@@H]3CN2C(=O)N3O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.7 %

Procedure:
To a solution of ethyl 5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazole-3-carboxylate (323 mg, 0.867 mmol) in MeOH (6.0 mL) and THF (3.0 mL) was added 10% Pd/C (18.46 mg, 0.017 mmol). The reaction mixture was stirred under hydrogen balloon at rt for 1 h. The reaction mixture was then filtered and concentrated. The residue was purified by silica gel column chromatography (0 to 5% MeOH/DCM) to afford ethyl 5-((2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazole-3-carboxylate (85 mg, 35%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][CH3:13].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH3:10][O:9][C:6]1[CH:5]=[C:4]([CH2:11][CH2:12][CH3:13])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:21]
Reactant: CCCc1cc(OC)ccc1OC
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCCc1cc(OC)c(C(=O)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 95 %

Procedure:
0.254 gram (1.4 mmole, 1.0 eq.) of product from step D was dissolved in 7 ml of 1,2-dichloroethane, after which 0.20 ml of benzoyl chloride and 0.225 gram aluminum (III) chloride (1.7 mmole, 1.2 eq. each) were added. Stirred at room temperature under nitrogen atmosphere for 75 minutes, then quenched with aqueous potassium carbonate. Diluted further with water and extracted 3× with dichloromethane. The combined organics were dried over sodium sulfate, filtered and evaporated. The resulting crude material was chromatographed to give 0.38 gram (95% yield) of the title compound.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[C:22]1([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[C:35]2[C:26](=[CH:27][C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:25]=[CH:24][CH:23]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:39]2[CH2:38][CH2:37][N:36]([C:22]3[C:35]4[C:26](=[CH:27][C:28]5[C:33]([CH:34]=4)=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:25]=[CH:24][CH:23]=3)[CH2:41][CH2:40]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: c1ccc2cc3c(N4CCNCC4)cccc3cc2c1
Product: CCc1cc(NC(=O)N2CCN(c3cccc4cc5ccccc5cc34)CC2)c(OC)nc1C
Yield: 57 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(1-anthryl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:5]=1[NH:12][C:13]([C:15]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[N:26][C:27]=3[C:18]=2[N:17]([CH3:35])[N:16]=1)=[O:14])[CH3:3].CCN(C(C)C)C(C)C.Cl[CH2:46][CH2:47][S:48](Cl)(=[O:50])=[O:49]>ClCCl>[CH2:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:2][CH3:3])[C:5]=1[NH:12][C:13]([C:15]1[C:19]2[CH2:20][CH2:21][C:22]3[CH:23]=[N:24][C:25]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([S:48]([CH:47]=[CH2:46])(=[O:50])=[O:49])[CH2:33][CH2:34]4)=[N:26][C:27]=3[C:18]=2[N:17]([CH3:35])[N:16]=1)=[O:14])[CH3:11]
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(NC3CCNCC3)nc1-2
Reactant: O=S(=O)(Cl)CCCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CS(=O)(=O)N1CCC(Nc2ncc3c(n2)-c2c(c(C(=O)Nc4c(CC)cccc4CC)nn2C)CC3)CC1
Temperature: -78 °C
Yield: 55.5 %

Procedure:
To a solution of N-(2,6-diethylphenyl)-1-methyl-8-(piperidin-4-ylamino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide hydrochloride (300 mg, 0.606 mmol) under nitrogen, in dry dichloromethane (15 mL), DIPEA (0.527 mL, 3.03 mmol) and 300 mg of molecular sieves were added, and the mixture was cooled at −78° C. 2-chloroethanesulfonyl chloride (0.063 mL, 0.606 mmol) was added. Temperature was allow to rise to room temperature then the solvent was evaporated to dryness and the crude was purified by flash chromatography on silica gel (eluant: ethyl acetate/dichloromethane: 2/8) to give 185 mg of the title compound (56% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[CH2:23](I)[CH3:24]>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:23][CH3:24])[CH2:10][C@@H:9]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCN1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Reaction time: 1 h

Procedure:
To (2R)-1-(tert-butoxycarbonyl)piperazine-2-carboxylic acid (1.406 g) and Na2CO3 (2.59 g) was added dry EtOH (28 ml) then ethyl iodide (0.54 ml) and the mixture heated at reflux for 18 h under argon. The solvent was then removed under reduced pressure and 5% MeOH/DCM (40 ml) was added and stirred for 1 hour in a sealed flask. The solution was filtered and washed with dichloromethane (2×10 mL). The filtrate was then placed directly onto a 120 g-silica cartridge and was purified using eluent 10-70% MeOH/DCM. After evaporation, the product was isolated as a white foam (1.00 g), which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1.Br[CH2:17][CH3:18]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:17][CH3:18])[N:5]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:3]=1
Reactant: CCBr
Reactant: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Product: CCCc1cc(C)cc(-n2c(C)ccc2C)n1

Procedure:
By analogy to Example 53, Step B, the anion of 4,6-dimethyl-2-(2,5-dimethylpyrrol-1-yl)pyridine was alkylated with bromoethane to give 4-methyl-2-(2,5-dimethylpyrrol-1-yl)-6-propylpyridine.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[CH:4]=O.[NH2:13]OS(O)(=O)=O>O>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[C:4]#[N:13]
Reactant: COc1cc(F)cc(F)c1C=O
Reactant: NOS(=O)(=O)O
Solvent: O
Product: COc1cc(F)cc(F)c1C#N
Temperature: 110 °C
Yield: 95 %

Procedure:
2,4-Difluoro-6-methoxybenzaldehyde (for a preparation see Intermediate 47) (34.5 g, 0.20 mol) and hydroxylamine-o-sulfonic acid (24.95 g, 0.22 mol) were charged to a round-bottom flask. Water (500 mL) was added and the suspension was heated at 110° C. for 3 h. After TLC shows reaction to be complete, it was cooled in ice-water and extracted thrice with ethyl acetate. The organic solutions were dried (MgSO4) and evaporated, and the residue was purified by dry flash chromatography (DCM eluent) to give the title compound (32.05 g, 95%) as a pale pink solid.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:3]=1[C:4]([NH:6][C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][NH:10][C:9]=2[N:8]=1)=[O:5].N1C=CC=CC=1.[F:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl>[F:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:3]=1[C:4]([NH:6][C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][N:10]([S:35]([C:32]3[CH:33]=[CH:34][C:29]([F:28])=[CH:30][CH:31]=3)(=[O:37])=[O:36])[C:9]=2[N:8]=1)=[O:5]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: O=C(Nc1ccc2c(n1)NCCC2)c1c(F)cccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc2c(n1)N(S(=O)(=O)c1ccc(F)cc1)CCC2)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2,6-Difluoro-N-(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)benzamide (30 mg, 0.10 mmol) was dissolved in dichloromethane (0.3 mL) and pyridine (0.025 mL, 0.31 mmol). 4-Fluorobenzenesulfonyl chloride (23 mg, 0.12 mmol) was then added and the reaction mixture was stirred at room temperature for 12 hours. Next, the reaction mixture was washed with 1M HCl(aq), sat'd NaHCO3(aq), and brine. The resulting organic solution was concentrated, dissolved in DMSO, and purified by HPLC to give 2,6-difluoro-N-(8-(4-fluorobenzenesulfonyl)-5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl]benzamide. 1H NMR 250 MHz CDCl3 δ 8.13 (bs, 1H), 8.03 (dd, J=7.9, 4.3 Hz, 2H), 7.83 (d, J=7.9 Hz, 1H), 7.48 (p, J=6.5 Hz, 1H), 7.38 (d, J=7.9 Hz, 1H), 7.15 (t, J=7.9 Hz, 2H), 7.06 (t, J=7.8 Hz, 2H), 4.07 (dd, J=5.8, 4.3 Hz, 2H), 2.76 (t, J=6.5 Hz, 2H), 2.06 (p, J=5.8 Hz, 2H). LCMS (ESI): calc. C21H16F3N3O3S=447; obs. M+H=448.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([C:13]2[O:14][C:15]3[N:16]=[C:17]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[N:18]=[C:19]([O:22][CH2:23][CH2:24][CH3:25])[C:20]=3[N:21]=2)=[CH:8][C:7]=1[CH3:34].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][C:17]2[N:18]=[C:19]([O:22][CH2:23][CH2:24][CH3:25])[C:20]3[N:21]=[C:13]([C:9]4[CH:10]=[C:11]([CH3:12])[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[C:7]([CH3:34])[CH:8]=4)[O:14][C:15]=3[N:16]=2)=[CH:28][CH:29]=1
Reactant: C1COCCN1
Reactant: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCCCBr)c(C)c3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCCCN4CCOCC4)c(C)c3)nc12
Temperature: 60 °C
Yield: 58.9 %

Procedure:
A mixture of 230 mg of 2-[4-(3-bromo-propoxy)-3,5-dimethyl-phenyl]-5-(4-chloro-benzyl)-7-propoxy-oxazolo[5,4-d]pyrimidine, 74 mg of morpholine and 233 mg of potassium carbonate in 5 ml of dimethylformamide was heated to 60° C. for 3 h. After cooling to room temperature, the solids were removed by filtration. The solvent was distilled off in vacuo and the residue was purified by preparative HPLC to yield 137 mg of the title compound in the form of the 5-(4-chloro-benzyl)-2-[3,5-dimethyl-4-(3-morpholin-4-yl-propoxy)-phenyl]-7-propoxy-oxazolo[5,4-d]pyrimidine trifluoroacetic acid salt.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH3:29])=[O:8])[CH2:5][CH2:4]1)#[N:2].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+]>CC(N(C)C)=O.O>[C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:28][CH3:29])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Reactant: C1COCCN1
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(N3CCOCC3)cc2C(F)(F)F)C[C@@H]1C(=O)NC1(C#N)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
A solution of (1R,2R,4R) and (1S,2S,4S)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (50 mg, 0.1009 mmol, example 58), morpholine (22 μl, 0.252 mmol) and 2,6-di-tert-butylpyridine (45.4 μl, 0.202 mmol) in DMA (1 ml) was heated in a sealed tube at 100° C. overnight. Then additional morpholine (8.8 μl, 0.1009 mmol) was added and the solution was stirred another 2 h at 100° C. The mixture was then cooled to room temperature and diluted with water. The pH was adjusted to 10 by addition of saturated Na2CO3 solution and the mixture was extracted 3 times with EtOAc. The combined organic layers were washed two times with Na2CO3 solution (pH 10) and with brine, dried over Na2SO4 and evaporated. The remaining light brown solid was purified by silica gel chromatography (DCM/EtOAc 4:1-1:1) to obtain the title compound (33 mg, 65%) as white foam. MS (EI): 502.2 (M+H)+.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([F:22])[C:20]=1[F:21])[C:15](O)=O.N>>[F:11][C:12]1[CH:13]=[C:14]([C:15]2[O:1][N:2]=[C:3]([C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]=2)[CH:18]=[C:19]([F:22])[C:20]=1[F:21]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: Fc1cc(-c2nc(-c3cccnc3)no2)cc(F)c1F

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3,4,5-trifluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.64 (ddd, J=8.0, 4.9, 1.0 Hz, 1H), 8.01-8.13 (m, 2H), 8.56 (ddd, J=8.1, 1.8, 1.6 Hz, 1H), 8.75 (dd, J=4.8, 1.6 Hz, 1H), 9.29 (dd, J=2.0, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 278 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH3:2].[CH2:24]([N:28]([CH2:32][CH2:33]Cl)[CH2:29][CH2:30]Cl)[CH2:25][CH2:26][CH3:27]>>[CH2:1]([O:3][C:4]([C:5]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:33][CH2:32][N:28]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:29][CH2:30]1)=[O:23])[CH3:2]
Reactant: CCOC(=O)CS(=O)(=O)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CCCCN(CCCl)CCCl
Product: CCCCN1CCC(C(=O)OCC)(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC1

Procedure:
1-Butyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4-carboxyic acid ethyl ester was prepared according to the general method outlined in example 83 starting from [4-(4-chloro-phenoxy)-benzenesulfonyl]-acetic acid ethyl ester (6 g, 18.3 mmol) and butyl-bis-(2-chloro-ethyl)-amine (5.2 g, 22 mmol). Yield 3.3 g (38%); yellow oil; MS: 480 (M+H)+