Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].[Br:5][C:6]1[C:11](N)=[CH:10][C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:8][N:7]=1.[F:20][P-](F)(F)(F)(F)F.[H+]>O.Cl>[Br:5][C:6]1[C:11]([F:20])=[CH:10][C:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:8][N:7]=1
Reactant: Nc1cc(-c2ccc(Cl)cc2)cnc1Br
Reactant: F[P-](F)(F)(F)(F)F
Agent: Cl
Agent: O=N[O-]
Agent: [H+]
Solvent: O
Product: Fc1cc(-c2ccc(Cl)cc2)cnc1Br
Temperature: 0 °C

Procedure:
243 mg (3.53 mmol) sodium nitrite in 0.5 mL water are added dropwise at −5° C. to a solution of 1.00 g (3.53 mmol) 2-bromo-5-(4-chloro-phenyl)-pyridin-3-ylamine in 2 mL water and 2.04 mL concentrated HCl. Then at 0° C. 1.56 mL (10.6 mmol) 60% hexafluorophosphoric acid in water are added and the reaction is stirred for a further hour at 0° C. The diazonium salt is suction filtered, washed with cold water, isopropanol and ether and dried overnight in the desiccator at RT and 7 mbar. This is then added batchwise at 90° C. to 50 mL PE (boiling point 100-140° C.). After the reaction solution has cooled the mixture is made alkaline with saturated Na2CO3 solution. The aqueous phase is extracted with EtOAc and the organic phase is washed successively with saturated Na2CO3 solution and water. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:22](F)=[CH:21][CH:20]=[CH:19][N:18]=2)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:25][NH2:26]>CCO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:22]3[NH:26][N:25]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1ncccc1F
Solvent: O
Solvent: CCO
Product: c1ccc(COc2ccc(-c3n[nH]c4cccnc34)cc2)cc1

Procedure:
A mixture of [4-(benzyloxy)phenyl](3-fluoropyridin-2-yl)methanone (3.0 g) and hydrazine hydrate (5.0 mL) in EtOH (90 mL) was refluxed for 4 days. The mixture was concentrated under reduced pressure. The residue was partitioned between water and AcOEt. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (0.83 g).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][N:19]([S:25]([NH:28][C:29]1[S:33][N:32]=[CH:31][N:30]=1)(=[O:27])=[O:26])[CH2:20]2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>O>[S:33]1[C:29]([NH:28][S:25]([N:19]2[CH2:18][CH2:17][C:16]3[C:21](=[CH:22][CH:23]=[CH:24][C:15]=3[C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=3)[CH2:20]2)(=[O:26])=[O:27])=[N:30][CH:31]=[N:32]1
Reactant: O=S(=O)(Nc1ncns1)N1CCc2c(Br)cccc2C1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(Nc1ncns1)N1CCc2c(cccc2-c2ccc(C(F)(F)F)cc2)C1
Temperature: 120 °C

Procedure:
A vial charged with Cl2Pd(AmPhos) (Sigma-Aldrich, St. Louis, Mo., 9.43 μg, 0.013 μmol), (4-(trifluoromethyl)phenyl)boronic acid (0.200 μmol), 5-bromo-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (0.050 mg, 0.133 μmol), and potassium phosphate (0.085 mg, 0.400 μmol) was treated with 2 mL dioxane and 1 mL water. The reaction mixture was heated to 120° C. for 2 hours at which time the mixture was cooled to room temperature then concentrated and purified by reverse phase column chromatography [RediSep Gold C-18 50 g, 5 to 75% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] to provide N-(1,2,4-thiadiazol-5-yl)-5-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide. [M+H]+=441.0. 1H NMR (400 MHz, MeOH-d4) δ ppm: 8.03 (s, 1H), 7.72 (d, J=8.1 Hz, 2H), 7.49 (d, J=7.9 Hz, 2H), 7.22-7.28 (m, 1H), 7.12 (dd, J=15.5, 7.1 Hz, 2H), 4.40 (s, 2H), 3.33-3.38 (m, 2H), 2.77 (m, 2H)
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:16]([OH:18])=O)[CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=C2[N:25]=NN(O)C2=CC=1.O.C(Cl)CCl.[NH4+].[OH-]>CN(C=O)C.CCOC(C)=O.O>[NH2:25][C:16](=[O:18])[C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1cccs1)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](Cc1cccs1)C(N)=O
Reaction time: 18 h
Yield: 90.3 %

Procedure:
A solution of N-Boc-β-(2-thienyl)-D-alanine (504 mg, 1.86 mmol), HOBt monohydrate (340 mg, 2.22 mmol) and EDC (460 mg, 2.39 mmol) in DMF (6 mL) was stirred at room temperature for 1 h, conc. NH4OH (0.600 mL, ca. 8.40 mmol) was added. The mixture was stirred for 18 h. Water and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give (R)-tert-butyl 1-amino-1-oxo-3-(thiophen-2-yl)propan-2-ylcarbamate (454 mg)
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]4[N:31]([CH3:41])[C:32]5[C:37]([CH:38]=4)=[C:36]([O:39][CH3:40])[CH:35]=[CH:34][CH:33]=5)=[O:29])=[C:23]([O:42][CH3:43])[CH:22]=3)[N:12]=2)[CH2:7][CH2:6]1)(=O)C.[OH-].[K+].Cl>C(#N)C.O>[OH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]4[N:31]([CH3:41])[C:32]5[C:37]([CH:38]=4)=[C:36]([O:39][CH3:40])[CH:35]=[CH:34][CH:33]=5)=[O:29])=[C:23]([O:42][CH3:43])[CH:22]=3)[N:12]=2)[CH2:7][CH2:6]1
Reactant: COc1cc(-c2nc([C@H]3CC[C@H](OC(C)=O)CC3)n3ccnc(C)c23)ccc1NC(=O)c1cc2c(OC)cccc2n1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COc1cc(-c2nc([C@H]3CC[C@H](O)CC3)n3ccnc(C)c23)ccc1NC(=O)c1cc2c(OC)cccc2n1C
Temperature: 110 °C

Procedure:
To (trans)-4-(1-(3-methoxy-4-(4-methoxy-1-methyl-1H-indole-2-carboxamido)phenyl)-8-methylimidazo[1,5-a]pyrazin-3-yl)cyclohexyl acetate (0.034 mmol, 20 mg) in acetonitrile (0.5 ml) and water (0.5 ml) was added potassium hydroxide (0.172 mmol, 9.65 mg) and the mixture was stirred at 110° C. After one hour the reaction mixture was neutralized with 2N hydrochloric acid, extracted with dichloromethane three times, the combined organic layers were dried (sodium sulfate) and concentrated in vacuo. The crude product was purified using column chromatography (silica gel; gradient dichloromethane to dichloromethane/methanol 25/1) to yield the title compound (7 mg).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][C@@H:12]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)[CH2:13]1.C(N(CC)CC)C>C(Cl)Cl>[O:11]=[C:12]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]#[N:34])=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)[CH2:13]1
Reactant: N#Cc1ccc(-c2ccc(OCCCN3CC[C@@H](O)C3)cc2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(-c2ccc(OCCCN3CCC(=O)C3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
Oxalyl chloride (0.195 mmol) in dry CH2Cl2 (5 mL) under an atmosphere of nitrogen at −78° C. was treated with DMSO (0.39 mmol). After 15 minutes of stirring, the product from Example 153 was added and the mixture was stirred for another 15 minutes. Triethylamine (0.45 mmol) was added and the mixture was gradually allowed to warm to 0° C. The solution was partitioned between water (50 mL) and dichloromethane (50 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate and filtered. The filtrate was evaporated under reduced pressure and the residue purified by chromatography (CHCl3:MeOH:NH4OH, 9:1:0.1) to provide the title compound (60% yield).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1>[Cu]Cl.ClCCCl>[O:1]([N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: Cl[Cu]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1Oc1ccccc1
Temperature: 25 °C
Yield: 90.3 %

Procedure:
A 20 mL scintillation vial was charged with N-hydroxyphthalimide (163 mg, 1.0 mmol), copper (I) chloride (99 mg, 1.0 mmol), freshly activated 4 Å molecular sieves (˜250 mg), and phenylboronic acid (244 mg, 2.0 mmol). 1,2-Dichloroethane (5 mL) was added followed by pyridine (90 μL, 1.1 mmol), resulting in a light brown suspension. The cap was loosely applied such that the reaction suspension was open to air and stirred at room temperature until completion as detected by analytical RP-HPLC (mixture color turned from brown to emerald green as the reaction proceeded). Upon completion (˜48 h), the mixture was adsorbed onto silica gel and concentrated to a powder. Flash chromatographic purification over silica (25% EtOAc in hexanes) afforded N-phenoxyphthalimide 9 as a white solid (216 mg, 90%); see below for characterization data.
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:35])[NH:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:25])=[O:24])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[Li+].[OH-].O>CO.O1CCCC1>[Cl:32][C:30]1[CH:29]=[CH:28][C:27]([O:33][CH3:34])=[C:26]([S:23]([N:20]2[C:21]3[C:16](=[CH:15][CH:14]=[C:13]([NH:12][C:11]([C:8]4[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:36])=[O:2])=[CH:6][CH:7]=4)=[O:35])[CH:22]=3)[CH2:17][CH2:18][CH2:19]2)(=[O:25])=[O:24])[CH:31]=1
Reactant: COC(=O)Cc1ccc(C(=O)Nc2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCC3)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCCc2ccc(NC(=O)c3ccc(CC(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
{4-[1-(5-Chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-7-ylcarbamoyl]-phenyl}-acetic acid methyl ester (121.00 mg, 0.23 mmol) was dissolved in methanol/tetrahydrofuran 1:1 (1.40 mL) and treated at room temperature with a 1N solution of LiOH in water (0.70 mL, 0.70 mmol). The mixture was stirred at room temperature for 4 hours, then the organic solvents were evaporated and the residual aqueous phase acidified with HCl 1N (0.70 mL). The precipitated solid was filtered washing with ether, then purified by flash chromatography (dichloromethane/methanol gradient) to yield {4-[1-(5-chloro-2-methoxy-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-7-ylcarbamoyl]-phenyl}-acetic acid as an off-white solid, 69.00 mg (59%), MS (ISP): m/e=513.5 (M−H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:42]=[CH:41][C:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:39][CH:38]=2)=[CH:33][C:32]=1[C:48]1[CH:57]=[CH:56][C:55]2[C:54]([CH3:59])([CH3:58])[CH2:53][CH2:52][C:51]([CH3:61])([CH3:60])[C:50]=2[CH:49]=1)(C(C)(C)C)(C)C.O>O1CCCC1>[OH:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:38]=[CH:39][C:40]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:41][CH:42]=2)=[CH:33][C:32]=1[C:48]1[CH:57]=[CH:56][C:55]2[C:54]([CH3:59])([CH3:58])[CH2:53][CH2:52][C:51]([CH3:60])([CH3:61])[C:50]=2[CH:49]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCO[Si](C)(C)C(C)(C)C)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc(-c2ccc(OCCCO)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
6.9 ml (6.9 mmol) of a solution of tetrabutylammonium fluoride (1 M) are added to a solution of 2.75 g (4.6 mmol) of ethyl 4′-[3-(tert-butyldimethylsilanyloxy)propoxy]-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate in 20 ml of tetrahydrofuran, in a three-necked flask. The reaction mixture is stirred for 4 h at ambient temperature. The reaction is stopped by adding 20 ml of water and the mixture is then extracted with ethyl acetate. The organic phases are combined, washed with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. The solvents are evaporated off. The crude obtained in the form of an oil is chromatographed on silica gel (heptane/ethyl acetate: 70/30) to give 2 g of ethyl 4′-(3-hydroxypropoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)biphenyl-4-carboxylate in the form of a colorless oil (yield=89%).
Reaction SMILES: [C:1]1([C:7]([OH:9])=O)([C:4]([OH:6])=[O:5])[CH2:3][CH2:2]1.C(N(CC)CC)C.S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:37]=[CH:36][C:25]([O:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([C:33]([NH2:35])=[O:34])[CH:28]=2)=[CH:24][C:23]=1[F:38]>O1CCCC1>[C:33]([C:29]1[CH:28]=[C:27]([O:26][C:25]2[CH:36]=[CH:37][C:22]([NH:21][C:7]([C:1]3([C:4]([OH:6])=[O:5])[CH2:2][CH2:3]3)=[O:9])=[C:23]([F:38])[CH:24]=2)[CH:32]=[CH:31][N:30]=1)(=[O:34])[NH2:35]
Reactant: O=C(O)C1(C(=O)O)CC1
Reactant: NC(=O)c1cc(Oc2ccc(N)c(F)c2)ccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cc(Oc2ccc(NC(=O)C3(C(=O)O)CC3)c(F)c2)ccn1
Reaction time: 1.5 h
Yield: 44 %

Procedure:
To a solution of 1,1-cyclopropanedicarboxylic acid (3.12 g) in tetrahydrofuran (90 ml) was added dropwise triethylamine (2.43 g) while cooling in an ice water bath under a nitrogen atmosphere, followed by stirring for 1.5 hr. To the reaction mixture, was then added thionyl chloride (1.75 ml), followed by stirring at the same temperature for 30 min. To the reaction mixture were added 4-(4-amino-3-fluorophenoxy)pyridine-2-carboxamide (2.97 g) and triethylamine (2.43 g) in this order while cooling in an ice water bath under a nitrogen atmosphere, followed by stirring for 70 min. The reaction mixture was partitioned after addition of tert-butyl methyl ether (30 ml) and a 1N aqueous solution of sodium hydroxide (90 ml). The aqueous layer was partitioned with tert-butyl methyl ether (30 ml) again, and the separated aqueous layer was treated with 1N hydrochloric acid to precipitate a solid. The solid was collected by suction filtration and washed with water (10 ml, four times). Drying under reduced pressure at 50° C. provided 1-[4-(2-carbamoylpyridin-4-yl)oxy-2-fluorophenylaminocarbonyl]cyclopropanecarboxylic acid as a pale purple solid (1.90 g, 44%). After the filtrate was stood overnight, further precipitated solid was collected by suction filtration and washed with water (10 ml, twice). Drying under reduced pressure provided additional 1-[4-(2-carbamoylpyridin-4-yl)oxy-2-fluorophenylaminocarbonyl]cyclopropanecarboxylic acid as a pale purple solid (758 mg, 18%).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:25]5[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=5)[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([C:37]#[N:38])[CH:3]=1.[CH:39]1(B(O)O)[CH2:41][CH2:40]1.C(=O)([O-])[O-].[K+].[K+].O>C(COC)OC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:37]([C:4]1[CH:3]=[C:2]([CH:39]2[CH2:41][CH2:40]2)[C:10]2[O:9][C:8]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:25]5[N:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[CH:27][N:26]=5)[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=1)#[N:38]
Reactant: N#Cc1cc(Br)c2oc(-c3ccc(C(=O)NCC4CCN(c5nccc(C(F)(F)F)n5)CC4)cc3)nc2c1
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: N#Cc1cc(C2CC2)c2oc(-c3ccc(C(=O)NCC4CCN(c5nccc(C(F)(F)F)n5)CC4)cc3)nc2c1
Reaction time: 96 h

Procedure:
A mixture of 4-(7-bromo-5-cyano-1,3-benzoxazol-2-yl)-N-({1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}methyl)benzamide (EXAMPLE 113, Step A) (59 mg, 0.10 mmol), cyclopropylboronic acid (86 mg, 1.0 mmol), potassium carbonate (138 mg, 1.0 mmol), and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol) in dimethoxyethane (7 ml)/water (0.7 ml) was heated to reflux and stirred at this temperature for 4 d. The mixture was diluted with ethyl acetate, filtered, and concentrated. The residue was purified by flash column chromatography to afford the title compound. Mass spectrum (ESI) 547.2 (M+1). 1H NMR (500 MHz, DMSO-d6) δ: 8.77 (t, J=5.5 Hz, 1H), 8.65 (d, J=4.8 Hz, 1H), 8.31 (d, J=8.2 Hz, 2H), 8.18 (s, 1H), 8.08 (d, J=8.3 Hz, 2H), 7.56 (s, 1H) 6.96 (d, J=4.8 Hz, 1H), 5.74 (s, 1H), 4.65 (br d, J=12.6 Hz, 2H), 3.22 (t, J=6.2 Hz, 2H), 2.95 (t, J=12.4 Hz, 2H), 2.40 (m, 1H), 1.93 (m, 1H), 1.81 (br d, J=11.9 Hz, 2H), 1.15 (m, 5H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=O)=[CH:11][CH:12]=2)[C@H:7]([N:17]([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:26][CH:25]=2)[C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:6][C@@H:5]1[CH3:36])(=[O:3])[CH3:2].[NH3:37]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH2:37])=[O:16])=[CH:11][CH:12]=2)[C@H:7]([N:17]([C:24]2[CH:25]=[CH:26][C:27]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:28][CH:29]=2)[C:18](=[O:23])[C:19]([F:20])([F:22])[F:21])[CH2:6][C@@H:5]1[CH3:36])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](N(C(=O)C(F)(F)F)c2ccc(N3CCOCC3)cc2)C[C@@H]1C
Reactant: N
Product: CC(=O)N1c2ccc(C(N)=O)cc2[C@H](N(C(=O)C(F)(F)F)c2ccc(N3CCOCC3)cc2)C[C@@H]1C
Yield: 100 %

Procedure:
[Step 4] Reactions and treatments were carried out in the same manner as in Example 118, using 83.5 mg of (2S,4R)-1-acetyl-2-methyl-4-[2,2,2-trifluoro-N-(4-morpholin ophenyl)acetamido]-1,2,3,4-tetrahydroquinoline-6-carboxylic acid instead of (2S,4R)-1-acetyl-2-methyl-4-(4-morpholinophenoxy)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid, and using aqueous ammonia instead of monomethylamine. Thus, 86.9 mg (100%) of (2S,4R)-1-acetyl-2-methyl-4-[2,2,2-trifluoro-N-(4-morpholin ophenyl)acetamido]-1,2,3,4-tetrahydroquinoline-6-carboxamide was obtained as a pale yellow amorphous substance.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C@H:14]([NH:32][C:33]([O:35][C@@H:36]2[CH:41]3[CH2:42][CH2:43][N:38]([CH2:39][CH2:40]3)[CH2:37]2)=[O:34])[C:15]2[CH:16]=[C:17]([CH:29]=[CH:30][CH:31]=2)[O:18][CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.OC1C=CC=C[N+]=1[O-].C(Cl)CCl.[CH2:56]([NH:63][CH2:64][CH2:65][CH:66]1[O:70][CH2:69][CH2:68][O:67]1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>CN(C=O)C.C(OCC)(=O)C>[N:38]12[CH2:43][CH2:42][CH:41]([CH2:40][CH2:39]1)[C@@H:36]([O:35][C:33](=[O:34])[NH:32][C@H:14]([C:15]1[CH:31]=[CH:30][CH:29]=[C:17]([O:18][CH2:19][C:20]3[CH:28]=[CH:27][C:23]([C:24](=[O:26])[N:63]([CH2:64][CH2:65][CH:66]4[O:67][CH2:68][CH2:69][O:70]4)[CH2:56][C:57]4[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=4)=[CH:22][CH:21]=3)[CH:16]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:37]2
Reactant: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)O)cc2)c1)O[C@H]1CN2CCC1CC2
Reactant: c1ccc(CNCCC2OCCO2)cc1
Agent: [O-][n+]1ccccc1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(N[C@@H](c1ccccc1)c1cccc(OCc2ccc(C(=O)N(CCC3OCCO3)Cc3ccccc3)cc2)c1)O[C@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 87.1 %

Procedure:
Triethylamine (0.278 mL, 2.00 mmol) was added to a solution of 4-((3-((S)-phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoic acid (0.418 g, 0.80 mmol) in DMF (2 mL). This mixture was stirred at room temperature for 5 minutes and then 2-hydroxypyridine-N-oxide (0.107 g, 0.96 mmol) and EDC (0.184 g, 0.96 mmol) and the mixture stirred for a further 10 minutes. A solution of N-benzyl-2-(1,3-dioxolan-2-yl)ethanamine (0.331 g, 1.6 mmol) in DMF (2 mL) was added. The reaction mixture was heated at 40° C. for 4 hours followed by stirring at room temperature for 48 hours. The reaction mixture was diluted with ethyl acetate and washed with 10% aqueous potassium carbonate and twice with brine. The organic phase was dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure. The residue was purified by flash column chromatography eluting with 100% ethyl acetate to 8% methanolic ammonia/ethyl acetate to afford the title compound (0.471 g, 87%). The material was used in the next step with no further characterisation.
Reaction SMILES: [C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N-]C(C)C)(C)C.[Li+].[C:25]([CH2:27][C@@H:28]([OH:35])[CH2:29][C:30](OCC)=[O:31])#[N:26].Cl>O1CCCC1.O1CCCC1.CCCCCCC>[C:25]([CH2:27][C@@H:28]([OH:35])[CH2:29][C:30](=[O:31])[CH2:9][C:8]([N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:10])#[N:26]
Reactant: CCOC(=O)C[C@H](O)CC#N
Reactant: CC(=O)N(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: N#CC[C@@H](O)CC(=O)CC(=O)N(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a stirred -10° C. solution of N,N-diphenylacetamide (211 g, 1.0 mol) in tetrahydrofuran (1.0 L) is slowly added a solution of lithium diisopropylamide in tetrahydrofuran-heptane (0.5 L of 2M) while maintaining the temperature between -10° C. to -5° C. The mixture is stirred at -0° C. to 20° C. for 30 minutes. (R)-4-cyano-3-hydroxybutyric acid, ethyl ester (Brower, supra) (40 g, 0.25 mol) as a solution in 200 mL of tetrahydrofuran is added to the previously prepared anion. The reaction mixture is stirred for 30 minutes at -5° C. to -20° C., and transferred to a 2.2N aqueous hydrochloric acid solution (1 L). The aqueous layer is extracted with 500 mL of ethyl acetate, the aqueous layer is separated and reextracted with 100 mL of ethyl acetate, the extracts are combined and concentrated in vacuo to afford crude (R)-6 -cyano-5-hydroxy-3-oxo-N,N-diphenylhexanamide which is not isolated. A small sample is purified by column chromatography on flash silica gel (60:40 hexane:ethyl acetate) as an oil.