Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([C:6](O)=[O:7])=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]1=2.C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[S:1]1[C:5]([C:6]([Cl:16])=[O:7])=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]1=2
Reactant: O=C(O)c1cc2c(s1)CCCC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cc2c(s1)CCCC2
Temperature: 0 °C

Procedure:
4,5,6,7-Tetrahydro-benzo[b]thiophene-2-carboxylic acid (1.0 g, 5.50 mmol) is dissolved in dichloromethane [DCM] (25 mL) that contains 5 drops of N,N-dimethylformamide [DMF] under nitrogen and cooled to 0° C. Oxalyl chloride (13.7 mL of a 2.0M solution in DCM) is added via syringe and allowed to warm to RT over 1 hour. All solvent is then removed under reduced pressure, and the resultant oil is reduced from toluene (3×20 mL) to remove residual oxalyl chloride. The residue is then dissolved in ethyl acetate and washed with saturated sodium bicarbonate (1×100 mL), then washed with saturated sodium chloride (1×100 mL) and dried over sodium sulfate. The solution is then filtered and concentrated under reduced pressure to give 4,5,6,7-tetrahydro-benzo[b]thiophene-2-carbonyl chloride (8) as an off-white solid (1.03 g).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[CH:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:32]O.Cl>CO.O.C(OCC)(=O)C>[CH3:28][S:25]([C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH:10]2[CH2:9][CH:8]([C:6]3[O:7][NH:32][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])=[CH:20][CH:21]=1)(=[O:27])=[O:26]
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC)C(Cc2ccc(S(C)(=O)=O)cc2)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)N1CCC(c2cc(=O)[nH]o2)CC1Cc1ccc(S(C)(=O)=O)cc1
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 28.4 %

Procedure:
Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(methylsulfonyl)benzyl)piperidine-1-carboxylate (3.99 g, 9.38 mmol) was dissolved in MeOH (70 mL) and cooled to −30° C. NaOH (0.375 g, 9.38 mmol) dissolved in water (7 mL) was added during 10 min and the resulting colourless solution continued to stir at −30° C. for 20 min. Hydroxylamine (50% by weight in water, 0.575 mL, 9.38 mmol) was added dropwise. The resulting solution was stirred at −30° C. for 30 min. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M HCl (30 mL, 180 mmol) and the mixture continued to stir at 80° C. for 20 min. The mixture was dissolved between ethyl acetate and water. The aqueous layer was extracted three more times with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered through celite and the solvent was evaporated. The residue was purified using reversed phase chromatography, gradient acid buffer and acetonitril, started 35% and ended 40%. Methyl 2-(4-(methylsulfonyl)benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.05 g, 28.4%) was isolated.
Reaction SMILES: [OH:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([I:13])=[CH:8][CH:9]=2)[O:4][C:3]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([O:30][CH3:31])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[CH2:40](Cl)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CC(C)=O>[CH2:40]([O:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([I:13])=[CH:8][CH:9]=2)[O:4][C:3]=1[C:14]1[CH:15]=[C:16]([O:30][CH3:31])[C:17]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:18]([O:20][CH3:21])[CH:19]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: COc1cc(-c2oc3cc(I)ccc3c(=O)c2O)cc(OC)c1OCc1ccccc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(-c2oc3cc(I)ccc3c(=O)c2OCc2ccccc2)cc(OC)c1OCc1ccccc1
Yield: 103.3 %

Procedure:
A stirring suspension of 3-hydroxy-7-iodo-(4-benzyloxy-3,5-dimethoxyphenyl)-chromen-4-one (5 g, 9 mmol), potassium carbonate (6.2 g, 45 mmol, 4.8 equ), potassium iodide (0.64 A, 4 mmol, 0.4 equ) and benzyl chloride (1.7 ml, 15 mmol, 1.6 equ) in acetone (150 ml) under nitrogen was heated to reflux for 19 hours. The reaction was filtered and the filtrate concentrated in vacuo to give an cream solid. This solid was recrystallised from isopropanol to give 35 (5.77 g, 99%) as a white solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:20]#[CH:21])[CH2:18][C:17](=[O:19])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[BH4-].[Li+].[Cl-].[NH4+].Cl>O1CCCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:20]#[CH:21])[CH2:18][CH:17]([OH:19])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CC(=O)C1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CC(O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-ethynylcyclobutan-1-one (0.50 g, 1.76 mmol) (prepared in example 2b) in tetrahydrofuran (10 mL) at −30-40° C. under an argon atmosphere was added over 15 min a slurry of lithium borohydride (0.12 g, 5.28 mmol) in tetrahydrofuran (16 mL). The reaction was stirred 0.5 h and was poured into 0° C. ammonium chloride. 10% Hydrochloric acid was used to adjust to pH 3-4, the mixture was warmed to room temperature and was extracted with three portions of diethyl ether. The organic extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 2:8 ethyl acetate : hexanes provided product as a colorless oil (0.54 g, 100%). 1H-NMR indicated the cis: trans isomer ratio to be ˜85:15.
Reaction SMILES: [N:1]([CH:4]1[CH2:22][CH2:21][N:7]2[C:8]3[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=3[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH:6]2[CH2:5]1)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>CCOCC.CO.CC(C)=O>[NH2:1][CH:4]1[CH2:22][CH2:21][N:7]2[C:8]3[CH:20]=[CH:19][CH:18]=[CH:17][C:9]=3[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH:6]2[CH2:5]1
Reactant: [N-]=[N+]=NC1CCN2c3ccccc3Cc3ccccc3C2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(C)=O
Solvent: CO
Solvent: O
Product: NC1CCN2c3ccccc3Cc3ccccc3C2C1

Procedure:
4 g of 2-azido-1,2,3,4,10,14b-hexahydro-pyridino[1,2-a]-dibenzo[c,f]-azepine (axial) is added to a suspension of 3 g of LiAlH4 in dry ether. The mixture obtained is heated for 1 hour, and after that cooled down. Then 12 ml of water are added to the mixture dropwise, whereby an inorganic precipitate is formed. The inorganic residue is removed by filtration after which the filtrate is evaporated to dryness. Obtained in this manner: 3.5 g (oil). Rf in methanol:acetone (9:1) = 0.28 (axial position).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:11]=1.[NH2:32][CH2:33][C@H:34]([OH:37])[CH2:35][CH3:36].CCN=C=NCCCN(C)C.Cl.[Cl-].[NH4+]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[OH:37][C@H:34]([CH2:35][CH3:36])[CH2:33][NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][Si:13]([CH:14]([CH3:15])[CH3:16])([CH:17]([CH3:19])[CH3:18])[CH:20]([CH3:21])[CH3:22])[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:30]
Reactant: CC[C@@H](O)CN
Reactant: COC[C@H](C)Oc1cc(O[Si](C(C)C)(C(C)C)C(C)C)cc(-c2ccc(C(=O)O)[nH]2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC[C@@H](O)CNC(=O)c1ccc(-c2cc(O[C@@H](C)COC)cc(O[Si](C(C)C)(C(C)C)C(C)C)c2)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[(triisopropylsilyl)oxy]phenyl}-1H-pyrrole-2-carboxylic acid (1.03 g, 2.30 mmol) synthesized in Example (106c) was dissolved in methylene chloride (20 mL), and (2R)-1-aminobutan-2-ol (0.40 g, 4.49 mmol) synthesized according to a method known to the public (Angew. Chem. Int. Ed. 2007, 46, 2245.), WSC•HCl (1.15 g, 6.00 mmol) and 4-dimethylaminopyridine (280 mg, 2.29 mmol) were added, followed by stirring at room temperature overnight under nitrogen atmosphere. To the reaction solution, a saturated aqueous ammonium chloride solution (30 mL) was added, and extraction was carried out with methylene chloride (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-80%) to afford the desired compound (1.01 g, yield 85%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([F:16])[CH:9]=2)=[CH:6][CH:7]=1.B1([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)C2CCCC1CCC2.C([O-])([O-])=O.[K+].[K+].N#N>CN(C=O)C.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[CH2:26]([C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([F:16])[CH:9]=2)=[CH:6][CH:7]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(-c2ccc(Cl)nn2)cc1F
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: N#N
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(Cc3ccccc3)nn2)cc1F
Temperature: 65 °C

Procedure:
A solution of 3-chloro-6-(3-fluoro-4-methoxy-phenyl)-pyridazine (Step 1, 2.0 g, 8.38 mmol), B-benzyl-9-BBN (0.5 mL in THF, 20 mL) and K2CO3 (3.5 g, 25.1 mmol) in 30 mL of DMF was degassed with N2 for 5 min. Cat. Pd(DPPF)Cl2 (731 mg, 1 mmol) was then added and the reaction was heated at 65° C. for 3 h (preheated oil bath). The mixture was poured into ice water and extracted with 50 mL 2×EtOAc. The combined organic phases were washed with 50 mL of brine and dried over Na2SO4. The solution was concentrated in vacuo and the crude was purified by silica gel column chromatograph (50% EtOAc/Hexane to EtOAc) to give light yellow solid. MS (ESI pos. ion) m/z: 295.3 (M+H). Calc'd Exact Mass for C18H15FN2O: 294.32.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16]C)=[CH:9][CH:10]=3)[C@@:5]3([N:22]=[C:21]([NH2:23])[CH2:20][O:19][CH2:18]3)[C:4]=2[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[NH2:23][C:21]1[CH2:20][O:19][CH2:18][C@@:5]2([C:4]3[CH:3]=[C:2]([Br:1])[CH:15]=[CH:14][C:13]=3[O:12][C:11]3[C:6]2=[CH:7][C:8]([OH:16])=[CH:9][CH:10]=3)[N:22]=1
Reactant: COc1ccc2c(c1)[C@]1(COCC(N)=N1)c1cc(Br)ccc1O2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: NC1=N[C@]2(COC1)c1cc(O)ccc1Oc1ccc(Br)cc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92.3 %

Procedure:
In a 250-mL flask, the (R)-2′-bromo-7′-methoxy-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-5-amine (0.393 g, 1.047 mmol) was dissolved in dcm (10 mL). The solution was cooled to 0° C. A DCM solution of boron tribromide (1.0 M, 3.14 mL, 3.14 mmol) was added. After 1.5 h, the mixture was quenched with 9:1 saturated aqueous NH4Cl/NH4OH (10 mL). The mixture was diluted further with water (10 mL) and the aqueous phase was extracted with 5% MeO/DCM (3×50 mL). The organics were combined, washed with dilute brine (10 mL), dried over sodium sulfate and concentrated to afford crude (R)-5-amino-2′-bromo-2,6-dihydrospiro[[1,4]oxazine-3,9′-xanthen]-7′-ol (349 mg, 0.966 mmol), which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[CH2:15]([O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22](O)=[N:21][C:20]=1[CH3:26])[CH3:16]>>[CH2:15]([O:17][C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:21][C:20]=1[CH3:26])[CH3:16]
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: CCOC(=O)c1ccc(O)nc1C
Product: CCOC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1C
Yield: 55 %

Procedure:
As described for example 4, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (313 mg, 1.66 mmol) was converted using 6-hydroxy-2-methyl-nicotinic acid ethyl ester instead of 2-hydroxy-5-trifluoromethylpyridine to the title compound (SiO2, heptane:ethyl acetate=60:40 to 10:90, 322 mg, 55%) which was obtained as a colourless oil. MS: m/e=353.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([CH:11]=[O:12])=[CH:7][C:6]=2[C:5]([C:13]2[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)=[C:4]([F:25])[CH:3]=1.CC(C)=[O:28].OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[C:11]([C:8]1[O:9][C:10]2[C:2]([Cl:1])=[CH:3][C:4]([F:25])=[C:5]([C:13]3[C:14](=[O:24])[N:15]([CH3:23])[C:16]([C:19]([F:20])([F:22])[F:21])=[CH:17][CH:18]=3)[C:6]=2[CH:7]=1)([OH:28])=[O:12]
Reactant: Cn1c(C(F)(F)F)ccc(-c2c(F)cc(Cl)c3oc(C=O)cc23)c1=O
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cn1c(C(F)(F)F)ccc(-c2c(F)cc(Cl)c3oc(C(=O)O)cc23)c1=O
Temperature: -20 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
0.37 g (0.99 mmol) of 3-(7-chloro-5-fluoro-2-formylbenzofuran-4-yl)-1-methyl-6-trifluoromethyl-2-(1H)-pyridone was dissolved in 20 ml of acetone, and a Jones reagent (CrO3—H2SO4) was added thereto at −20° C. After stirring at −20° C. for 2 hours, the mixture was poured into water and extracted with ethyl acetate. An aqueous sodium hydroxide solution was added to make the extract alkaline, and the aqueous layer was washed with ethyl acetate and acidified by an addition of hydrochloric acid and then extracted with ethyl acetate. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure. Then, the obtained crude crystals were washed with diisopropyl ether to obtain 0.29 g (yield: 75%) of the desired products Melting point: 233-235° C. 1H-NMR (300 MHz, CDCl3) δ value: 3.79(3H,s), 6.87(1H,d), 7.38(1H,d), 7.47(1H,s), 7.61(1H,d)ppm.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([OH:8])=O.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([CH2:27][C@@H:28]2[CH2:33][NH:32][C:31](=[O:34])[CH2:30][NH:29]2)=[CH:19]1.C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl.O>[F:16][C:2]([F:1])([F:17])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:29]1[C@H:28]([CH2:27][C:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:18][CH:19]=2)[CH2:33][NH:32][C:31](=[O:34])[CH2:30]1)=[O:8]
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CN[C@H](Cc2c[nH]c3ccccc23)CN1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1CN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)CN1
Reaction time: 1.5 h
Yield: 26.1 %

Procedure:
To a solution of 3,5-bis(trifluoromethyl)benzoic acid (2.63 g) and (5R)-5-(1H-indol-3-ylmethyl)piperazin-2-one (2.34 g) in dichloromethane (50 ml) were added successively triethylamine (3.56 ml) and 2-chloro-1-methylpyridinium iodide (3.13 g) at room temperature. The resulting mixture was stirred for 1.5 hours at the same temperature. Dichloromethane and water were added into the mixture and the organic layer was separated. The organic layer was washed successively with 0.5N hydrochloric acid, water, aqueous sodium bicarbonate solution and brine, and dried over magnesium sulfate. After evaporation in vacuo, the residue was purified by column chromatography on silica gel (75 g) eluting with a mixture of dichloromethane-methanol (from 0% to 5% gradient elution) to give (5R)-4-[3,5-bis(trifluoromethyl)benzoyl]-5-(1H-indol-3-ylmethyl)piperazin-2-one (1.25 g) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:23]([C@H:30]1[CH2:34][O:33][C:32](=[O:35])[NH:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH2:23]([C@H:30]1[CH2:34][O:33][C:32](=[O:35])[N:31]1[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(Br)c1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(N2C(=O)OC[C@@H]2Cc2ccccc2)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 78.5 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (600 mg, 1.7 mmol), (S)-4-benzyl-oxazolidin-2-one (592 mg, 3.34 mmol), copper(I) iodide (96 mg, 0.5 mmol), N,N-dimethylglycine hydrochloride (140 mg, 1.0 mmol) and potassium carbonate (923 mg, 6.7 mmol) in dimethyl sulfoxide (5 mL) was stirred at 120° C. for 16 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-[3-((S)-4-benzyl-2-oxo-oxazolidin-3-yl)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (609 mg, 80%) as a white solid: LC/MS m/e calcd for C28H28N2O4 (M+H)+: 457.55, observed: 457.1.
Reaction SMILES: C(=[O:8])C1C=CC=CC=1.[C:9]([C:11]1[CH:12]=[C:13]([CH:35]=[CH:36][CH:37]=1)[CH2:14][NH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]([N:26]1[CH:30]=[C:29]([C:31]([OH:33])=[O:32])[CH:28]=[N:27]1)[NH:20][C:19]2=[O:34])#[N:10]>>[C:9]([C:11]1[CH:12]=[C:13]([CH:35]=[CH:36][CH:37]=1)[CH2:14][NH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]([N:26]1[CH:30]=[C:29]([C:31]([OH:33])=[O:32])[CH:28]=[N:27]1)[NH:20][C:19]2=[O:34])(=[O:8])[NH2:10]
Reactant: N#Cc1cccc(CNc2ccc3nc(-n4cc(C(=O)O)cn4)[nH]c(=O)c3c2)c1
Reactant: O=Cc1ccccc1
Product: NC(=O)c1cccc(CNc2ccc3nc(-n4cc(C(=O)O)cn4)[nH]c(=O)c3c2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 171, substituting 3-cyanobenzaldehyde for benzaldehyde in step A. Step C yielded a mixture of 1-[6-(3-cyano-benzylamino)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid, the titled compound, and 1-[6-amino-4-oxo-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid, which was separated by reverse-phase HPLC.
Reaction SMILES: Cl.C(OCC)(=O)C.CO.C(OC([NH:17][CH:18]1[CH2:21][N:20]([C:22]2[S:23][C:24]3[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)[CH2:19]1)=O)(C)(C)C.C1COCC1>O1CCOCC1>[NH2:17][CH:18]1[CH2:21][N:20]([C:22]2[S:23][C:24]3[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)[CH2:19]1
Reactant: CCOC(=O)c1cccc2nc(N3CC(NC(=O)OC(C)(C)C)C3)sc12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)c1cccc2nc(N3CC(N)C3)sc12
Reaction time: 17 h
Yield: 94.7 %

Procedure:
A 4 N hydrochloric acid/ethyl acetate solution (2.66 mL, 10.7 mmol) and methanol (5 mL) were added to a solution of ethyl 2-{3-[(tert-butoxycarbonyl)amino]azetidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained in Example (224a) (402 mg, 1.07 mmol) in 1,4-dioxane (11 mL) at room temperature, followed by stirring for 17 hours. Then, THF (5 mL) was added, and the mixture was further stirred for 31 hours. The reaction solution was concentrated, and saturated aqueous sodium bicarbonate solution was added to the resulting residue. Thereafter, the mixture was extracted with ethyl acetate, and the combined organic layers were dried over anhydrous magnesium sulfate. Following filtration, the solvent was evaporated under reduced pressure to obtain 281 mg of the title compound as a pale yellow solid (95%).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[CH2:21]([NH2:23])[CH3:22].C(OCC)(=O)C.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:19][C:17]1[CH:16]=[C:13]([CH:12]=[C:11]([O:10][C:5]2[C:6]([Cl:9])=[CH:7][CH:8]=[C:3]([CH2:2][NH:23][CH2:21][CH3:22])[C:4]=2[F:20])[CH:18]=1)[C:14]#[N:15]
Reactant: CCN
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CBr)c2F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNCc1ccc(Cl)c(Oc2cc(Cl)cc(C#N)c2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.4 %

Procedure:
A solution of 3-{[3-(bromomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.50 g, 1.33 mmol) in THF (10 mL) was added dropwise to a 2M solution of EtNH2 (6.67 mL, 13.33 mmol) in THF. The flask was sealed and stirred at RT overnight. Ethyl acetate (100 ml) and saturated NaHCO3 solution (100 ml) were added. The organic layer was washed with brine (150 mL), dried over MgSO4, filtered and concentrated to give the title compound (0.48 g, quant.) as a tan solid. 1H NMR shows title compound plus a little residual EtNH2. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.04 (br. s., 1H), 7.83 (s, 1H), 7.62 (s, 2H), 7.45-7.55 (m, 2H), 4.14 (s, 2H), 2.95 (q, 2H), 1.18 (t, 3H). LCMS m/z 340.0 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([O:4][C:5]([NH:7][C@@H:8]([C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][C:14]([OH:22])([CH2:15]3)[CH2:13]1)[CH2:19]2)[C:9](O)=[O:10])=[O:6])[CH3:3].CS(Cl)(=O)=O.C(N(C(C)C)CC)(C)C.Cl.[C@H:39]12[CH2:44][C@H:43]1[CH2:42][C@@H:41]([C:45]([NH2:47])=O)[NH:40]2.OC1C2N=NNC=2C=CC=1>C1COCC1>[C:45]([C@@H:41]1[CH2:42][C@H:43]2[C@H:39]([CH2:44]2)[N:40]1[C:9](=[O:10])[C@H:8]([C:12]12[CH2:19][CH:18]3[CH2:17][CH:16]([CH2:15][C:14]([OH:22])([CH2:20]3)[CH2:13]1)[CH2:21]2)[NH:7][C:5]([O:4][C:2]([CH3:23])([CH3:1])[CH3:3])=[O:6])#[N:47]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C12CC3CC(CC(O)(C3)C1)C2
Reactant: NC(=O)[C@@H]1C[C@@H]2C[C@@H]2N1
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21)C12CC3CC(CC(O)(C3)C1)C2
Temperature: -6 °C
Reaction time: 8 h

Procedure:
A 2 L three-necked flask equipped with a thermometer, a mechanical stirrer and a gas inlet was charged with (αS)-α[[(1,1-dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula 3) (50 grams, 153.8 mmol). THF (200 ml) was added and stirred to produce a clear solution. The solution was cooled to −6° C. in an acetone-dry ice-water bath. Methanesulfonyl chloride (Mes-C1) (13.1 ml, 169 mmol, 1.1 equivalents) was then added as a single portion followed by diisopropylethylamine (94 ml, 539 mmol, 1.1 equivalents). The diisopropylethylamine was added slowly over a period of about 4 minutes to keep the internal temperature below 8° C. The reaction mixture was stirred at 0° C. until all acid was converted to mixed anhydride. (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride salt (32.5 grams, 200 mmol, 1.1 equivalents) and hydroxybenzotriazole (HOBT) (1.04 grams, 7.6 mmol, 0.05 equivalents) were then added in a single portion and the flask was removed from the cooling bath. The reaction mixture was stirred at room temperature for 2 hours and then left overnight at room temperature.