Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.[CH2:8]([Li])[CH2:9][CH2:10][CH3:11].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:23]2[CH2:27][CH:26]([CH3:28])[C:25]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)=[N:24]2)=[O:22])=[CH:16][CH:15]=1.CCC(C1C=CC(F)=CC=1)=O.BrC1C=CC(N=C=O)=CC=1.ICCCC>O1CCCC1.CCCCCC.C(O)(=O)C>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([N:23]2[CH2:27][C:26]([CH2:8][CH2:9][CH2:10][CH3:11])([CH3:28])[C:25]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)=[N:24]2)=[O:22])=[CH:18][CH:19]=1
Reactant: CC1CN(C(=O)Nc2ccc(Br)cc2)N=C1c1ccc(F)cc1
Reactant: [Li]CCCC
Agent: CCC(=O)c1ccc(F)cc1
Agent: O=C=Nc1ccc(Br)cc1
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CCCCI
Product: CCCCC1(C)CN(C(=O)Nc2ccc(Br)cc2)N=C1c1ccc(F)cc1
Reaction time: 0.25 h

Procedure:
To 2.1 g of diisopropylamine dissolved in 15 ml of tetrahydrofuran and cooled in an ice salt bath was added 8.0 ml of a 2.7 molar solution of n-butyllithium in hexane. After stirring for 5 minutes a solution of 3.7 g of N-(4-bromophenyl)-3-(4-fluorophenyl)-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide (prepared from 4-fluoropropiophenone and 4-bromophenyl isocyanate by a method analogous to that described above in Examples E, F, and G) in 15 ml of tetrahydrofuran was added and the resulting solution stirred for 15 minutes. To this solution was added 1.5 ml of 1-iodobutane and, after 15 minutes 1.5 ml of acetic acid was added. The reaction mixture was partitioned between diethyl ether and water and the organic layer was dried over anhydrous magnesium sulfate. The resulting solution was filtered evaporated in vacuo and chromatographed to give 2.9 g of N-(4-bromophenyl)-3-(4-fluorophenyl)-4-butyl-4-methyl-4,5-dihydro-1H-pyrazole-1-carboxamide an oil that solidifed on long standing. NMR and IR data were consistent with the structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH:19]2[CH2:21][CH2:20]2)=[C:6]([C:8]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][NH:10][N:9]=2)[CH:7]=1.[H-].[Na+].[CH3:24][Si:25]([CH2:28][CH2:29][O:30][CH2:31]Cl)([CH3:27])[CH3:26]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH:19]2[CH2:21][CH2:20]2)=[C:6]([C:8]2[N:9]([CH2:31][O:30][CH2:29][CH2:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[N:10]=[CH:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1c[nH]nc1-c1cc(Cl)ccc1OC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(COCC[Si](C)(C)C)c1-c1cc(Cl)ccc1OC1CC1
Reaction time: 0.17 h
Yield: 93.9 %

Procedure:
To a solution of ethyl 3-(5-chloro-2-cyclopropoxyphenyl)-1H-pyrazole-4-carboxylate (12 g, 39 mmol) in THF (200 mL) was added 60% sodium hydride in mineral oil (1.72 g, 43 mmol) and the reaction mixture was stirred for 10 min. SEMCl (7.2 g, 43 mmol) was added and the reaction mixture was stirred at room temperature overnight. The mixture was quenched with ice-water and extracted with EtOAc (300 mL×2). The combined organics were dried over sodium sulfate and concentrated in vacuo afford 16 g of the title compounds.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[H-].[Na+].[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br)=[O:20])([CH3:17])([CH3:16])[CH3:15].O>CN(C)C=O>[C:14]([O:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]1=[O:1])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NCCCCCCBr
Reactant: Oc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCCCn1c(=O)ccc2ccccc21
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
2-Hydroxyquinoline (640 mg) was added to a suspension of 600% sodium hydride (205 mg) in N,N-dimethylformamide (15 ml) and the mixture was stirred at 60° C. for 30 minutes. After cooling in ice a solution of N-(tert-butoxycarbonyl)-6-bromo-hexylamine (1.25 g) (Helv. Chim. Acta 76 891 (1993)) in N,N-dimethylformamide (10 ml) was added dropwise and stirring was continued overnight at room temperature. Ice and water were added and the mixture was extracted three times with ethyl acetate. The organic phases were washed with saturated sodium chloride, dried and evaporated to leave a yellow oil which after purification by chromatography on silica gel with ethyl acetate as eluent gave the desired compound as a colourless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:28][O:29][NH:30][CH3:31].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC#N>[CH3:28][O:29][N:30]([CH3:31])[C:16](=[O:18])[C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.9 %

Procedure:
To a 1-liter round bottom flask were added (R)-5-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)pentanoic acid (10 g, 27 mmol), N-methoxy-N-methylamine-HCl (5.3 g, 55 mmol), PyBOP (21 g, 41 mmol), and MeCN (400 mL). DIEA (19 mL, 110 mmol) was added and the reaction was allowed to stir at room temperature for 12 hours. The solvent was removed under reduced pressure and the residue was suspended in EtOAc and washed with 1N NaOH (aq) (×3) then 2N HCl (aq) (×2), then saturated NaHCO3 (aq) (×1), then brine (×1). The product was then purified by column chromatography (EtOAc/hexanes) to give N-methoxy-N-methyl-(R)-5-(benzyloxycarbonylamino)-2-(tert-butoxycarbonylamino)pentanamide (305) (10.9 g, 26.7 mmol, 99% yield) as a clear oil.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.C1C=NC2N(O)N=NC=2C=1.[CH2:16]([CH:18]([N:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30]([NH:32][C@@H:33]([CH2:37][CH:38]([CH3:40])[CH3:39])[C:34](O)=[O:35])=[O:31])=[CH:29][C:24]=2[N:23]=[C:22]1[CH2:41][C:42]1[S:43][CH:44]=[CH:45][CH:46]=1)[CH2:19][CH3:20])[CH3:17].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:1]1([NH:5][C:34]([C@@H:33]([NH:32][C:30]([C:28]2[CH:27]=[CH:26][C:25]3[N:21]([CH:18]([CH2:19][CH3:20])[CH2:16][CH3:17])[C:22]([CH2:41][C:42]4[S:43][CH:44]=[CH:45][CH:46]=4)=[N:23][C:24]=3[CH:29]=2)=[O:31])[CH2:37][CH:38]([CH3:39])[CH3:40])=[O:35])[CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCC1
Reactant: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)N[C@@H](CC(C)C)C(=O)O)ccc21
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)n1c(Cc2cccs2)nc2cc(C(=O)N[C@@H](CC(C)C)C(=O)NC3CCC3)ccc21
Temperature: 25 °C
Yield: 65.7 %

Procedure:
Into a reaction vial were placed 10 mg of cyclobutylamine, 20 mg of HOAt, 53 mg of (S)-2-{[1-(1-Ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carbonyl]-amino}-4-methyl-pentanoic acid. Then 0.11 ml DIPEA in 1 ml DMF were added, followed by 67 mg PyBrOP in 0.5 ml DMF. The reaction was shaken at RT over night, then filtered and purified by HPLC to yield 39 mg (74%) of 1-(1-ethyl-propyl)-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid ((S)-1-cyclobutylcarbamoyl-3-methyl-butyl)-amide.
Reaction SMILES: [CH2:1]([C:3]1[C:7](I)=[C:6]([CH3:9])[N:5]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=2)[N:4]=1)[CH3:2].[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:1]([C:3]1[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:6]([CH3:9])[N:5]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(-c2ccc(CCO)cc2)c(C)c1I
Reactant: OB(O)c1ccccc1
Product: CCc1nn(-c2ccc(CCO)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 12 from 2-[4-(3-ethyl-4-iodo-5-methyl-1H-pyrazol-1-yl)phenyl]ethanol (step 2) and benzeneboronic acid: MS (EI) m/z 306 [M]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])(=[O:3])[CH3:2].CO>C(Cl)Cl>[C:10]([O:9][C:7]([C:6]1[CH:5]=[C:4]([C@H:1]([OH:3])[CH3:2])[CH:16]=[CH:15][CH:14]=1)=[O:8])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(=O)c1cccc(C(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: CO
Product: C[C@@H](O)c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
In a dry flask under nitrogen, (S)-oxazaborolidine (4.81 mmol) was dissolved in dry CH2Cl2 (12 mL). This solution was maintained between −20° C. and −25° C. as a solution of tert-butyl (3-acetyl)benzoate (4.20 mmol) in dry CH2Cl2 (12 mL) was added dropwise over 20 minutes. The reaction mixture was then allowed to warm to room temperature for 45 minutes. This mixture was then cooled to −78° C. and methanol (20 mL) added dropwise. The mixture was allowed to warm to room temperature. Solvent was removed under reduced pressure then the residue dissolved in methanol and concentrated under reduced pressure twice more. The dried residue was purified by silica gel chromatography in 10-30% ethyl acetate/hexanes to yield 865 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.00 (m, 1H); 7.92 (m, 1H); 7.58 (d, J=7.5 Hz, 1H); 7.42 (t, J=7.7 Hz, 1H); 4.98 (m, 1H); 1.62 (s, 9H); 1.54 (d, J=6.4 Hz, 3H).
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6](=[O:32])[C@@H:7]([NH:12][C:13]([N:15]1[C:19]2[CH2:20][CH2:21][O:22][CH2:23][C:18]=2[C:17]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=2)=[N:16]1)=[O:14])[C:8]([CH3:11])([CH3:10])[CH3:9])#[N:2].[NH2:33][CH2:34][C:35]1[CH:40]=NC(C)=CN=1>>[F:31][C:26]1[CH:25]=[C:24]([C:17]2[C:18]3[CH2:23][O:22][CH2:21][CH2:20][C:19]=3[N:15]([C:13]([NH:12][C@@H:7]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:6]([NH:5][CH2:4][C:3]3[CH:1]=[N:2][C:35]([CH3:40])=[CH:34][N:33]=3)=[O:32])=[O:14])[N:16]=2)[CH:29]=[CH:28][C:27]=1[F:30]
Reactant: CC(C)(C)[C@H](NC(=O)n1nc(-c2ccc(F)c(F)c2)c2c1CCOC2)C(=O)NCCC#N
Reactant: Cc1cnc(CN)cn1
Product: Cc1cnc(CNC(=O)[C@@H](NC(=O)n2nc(-c3ccc(F)c(F)c3)c3c2CCOC3)C(C)(C)C)cn1

Procedure:
Compound 106 was prepared by the procedure described for the synthesis of compound 104 by replacing 2-cyanoethylamine with 2-aminomethyl-5-methylpyrazine. LCMS (+ESI) m/z=499.3 [M+H]+. 1H NMR (CDCl3) δ 8.48 (s, 1H), 8.35 (s, 1H), 7.92 (d, J=9.4 Hz, 1H), 7.47-7.52 (m, 1H), 7.28-7.32 (m, 1H), 7.19-7.27 (m, 1H), 6.98 (br, 1H), 4.82 (s, 2H), 4.57-4.62 (m, 2H), 4.30 (d, J=10.4 Hz, 1H), 3.93 (t, J=5.4 Hz, 2H), 3.18 (br, 2H), 2.80 (s, 3H), 1.11 (s, 9H).
Reaction SMILES: [CH2:1]([N:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([O:26]CC)=[O:25])[C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.C1C=CC=CC=1>[CH2:1]([N:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([OH:26])=[O:25])[C:9]1[C:14]([Cl:15])=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1ccccc1N(Cc1ccccc1)c1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccccc1
Product: O=C(O)Cc1ccccc1N(Cc1ccccc1)c1c(Cl)cccc1Cl
Temperature: 80 °C
Reaction time: 9 h
Yield: 77.7 %

Procedure:
In a mixture of 50 ml of ethanol and 30 ml of benzene, 7.0 g (0.017 mole) of ethyl N-benzyl-o-(2,6-dichloroanilino)phenylacetate was dissolved and 31 ml of 2 N-NaOH aq. sol. was added and the mixture was stirred at about 80° C. for 9 hours. The reaction mixture was concentrated under reduced pressure and 70 ml of ether was added to the residue and the reaction product was extracted with 2 N-NaOH aq. sol. The pH of the water phase was adjusted with a dilute hydrochloric acid to 2.0 and the precipitate was extracted with ether and the ether phase was dried over anhydrous sodium sulfate and concentrated under a reduced pressure. The reaction product was recrystallized and 5.1 g of N-benzyl-o-(2,6-dichloroanilino)phenyl acetic acid was obtained as colorless crystals. Yield: 78%
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[O:38]1[CH2:42][CH2:41][CH2:40][CH:39]1[CH2:43][NH2:44]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:44][CH2:43][CH:39]3[CH2:40][CH2:41][CH2:42][O:38]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: NCC1CCCO1
Product: O=C(Nc1ccc(Oc2ccnc(NCC3CCCO3)n2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and C-(tetrahydrofuran-2-yl)-methylamine according to conditions described in general procedure C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.Cl[C:16]1[C:25]2[C:20](=[C:21]([CH3:26])[CH:22]=[CH:23][CH:24]=2)[N:19]=[CH:18][CH:17]=1>>[CH3:26][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[C:20]=1[N:19]=[CH:18][CH:17]=[C:16]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2
Reactant: Cc1cccc2c(Cl)ccnc12
Reactant: O=C(O)c1cccc2cc(O)ccc12
Product: Cc1cccc2c(Oc3ccc4c(C(=O)O)cccc4c3)ccnc12
Yield: 49.9 %

Procedure:
The title compound (1.25 g, 55% yield) was prepared as a brown solid from 6-hydroxy-1-naphthoic acid (1.43 g, 7.6 mmol) and 4-chloro-8-methylquinoline (1.62 g, 9.14 mmol) by an analogous procedure to that described in example 1. LC-MS (m/z) 330 (M+1).
Reaction SMILES: [H-].[Na+].[CH:3]1([NH:6][S:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)(=[O:9])=[O:8])[CH2:5][CH2:4]1.Br[CH2:22][C:23]([NH2:25])=[O:24].O>CN(C)C=O>[CH:3]1([N:6]([CH2:22][C:23]([NH2:25])=[O:24])[S:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)(=[O:9])=[O:8])[CH2:5][CH2:4]1
Reactant: NC(=O)CBr
Reactant: O=S(=O)(Cc1cccc(C(F)(F)F)c1)NC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)CN(C1CC1)S(=O)(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
0.26 Gram of sodium hydride is added portionwise to a solution containing 2.77 g of N-cyclopropyl-3-trifluoromethylbenzylsulfonamide in 50 ml of dimethylformamide over an ice bath. The mixture is stirred 15 minutes at 0° C. and then 0.0105 moles of bromoacetamide is added dropwise with cooling. The mixture is stirred overnight at room temperature. Water is then added. This will result in the formation of a precipitate and oil. Water is continued to be added until no further precipitate or oil is formed. The mixture is cooled over an ice bath and then filtered. The filter cake is dissolved in hot cyclohexane and then recrystallized affording the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=1.[Cl:23][C:24]1[S:28][C:27]([C:29]([C:31]2[N:32]([CH3:36])[CH:33]=[N:34][CH:35]=2)=[O:30])=[CH:26][CH:25]=1>>[Cl:23][C:24]1[S:28][C:27]([C:29]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]3[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH3:22])[CH:15]=2)([C:31]2[N:32]([CH3:36])[CH:33]=[N:34][CH:35]=2)[OH:30])=[CH:26][CH:25]=1
Reactant: CCOc1cccc(-c2cc(OC)nc3ccc(Br)cc23)c1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)s1
Product: CCOc1cccc(-c2cc(OC)nc3ccc(C(O)(c4ccc(Cl)s4)c4cncn4C)cc23)c1
Yield: 71.8 %

Procedure:
Following the same procedure as that described in example 1E, 6-bromo-4-(3-ethoxy-phenyl)-2-methoxy-quinoline (800 mg, 2.23 mmol) and (5-chloro-thiophen-2-yl)-(3-methyl-3H-imidazol-4-yl)-methanone (610 mg, 2.68 mmol) generated the title compound of 23B (810 mg, 72% yield).
Reaction SMILES: CC1(C)[O:6][C:5](=[O:7])[CH:4]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=O)[O:3]1.[NH:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[O:23][CH:24]=[CH:25][N:26]=1>>[OH:3][C@@H:4]([C@H:8]([C:9]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[O:23][CH:24]=[CH:25][N:26]=1)=[O:11])[CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:6])=[O:7]
Reactant: CCCCC(C(=O)O)C1OC(C)(C)OC1=O
Reactant: c1coc([C@@H]2CCCN2)n1
Product: CCCC[C@@H](C(=O)N1CCC[C@H]1c1ncco1)[C@H](O)C(=O)O

Procedure:
The title compound is prepared from 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid B-5 and 2-(S)-pyrrolidin-2-yl-oxazole A-5 (synthesis is described in Procedure E) according to General Procedure B.
Reaction SMILES: C(O)(=O)C.[NH2:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[CH2:7]1.[Cl:16][C:17]1[C:18]([Cl:30])=[C:19]([Cl:29])[C:20]([Cl:28])=[C:21]2[C:26](=[O:27])[O:25][C:23](=[O:24])[C:22]=12>C(OC(=O)C)(=O)C>[CH3:12][C:10]1([CH3:13])[CH2:11][CH:6]([NH:5][C:26](=[O:27])[C:21]2[C:22](=[C:17]([Cl:16])[C:18]([Cl:30])=[C:19]([Cl:29])[C:20]=2[Cl:28])[C:23]([OH:25])=[O:24])[CH2:7][C:8]([CH3:15])([CH3:14])[NH:9]1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC1(C)CC(NC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)CC(C)(C)N1

Procedure:
The acetic acid salt of N-(2,2,6,6-tetramethyl-4-piperidinyl)tetrachlorophthalamic acid was prepared by refluxing 7.8 grams (0.05 mole) of 4-amino-2,2,6,6-tetramethylpiperidine, 14.3 grams (0.05 mole) of tetrachlorophthalic anhydride in 100 ml of acetic anhydride for 4 hours. The acetic anhydride was stripped off on a rotary evaporator under reduced pressure. The light yellow residue was slurried in 300 ml hexane and filtered. The filter cake was reslurried in fresh hexane and refiltered. The filter cake was air dried for 3 days on a watch glass. The dried product weighed 26.5 grams.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][CH3:8])[N:6]=1.[CH3:9][O:10][C:11]1[CH:24]=[CH:23][C:22]2[O:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]([C:25](Cl)=[O:26])[C:13]=2[CH:12]=1>>[CH2:7]([N:5]1[N:4]=[N:3][C:2]([NH:1][C:25]([CH:14]2[C:13]3[CH:12]=[C:11]([O:10][CH3:9])[CH:24]=[CH:23][C:22]=3[O:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:26])=[N:6]1)[CH3:8]
Reactant: CCn1nnc(N)n1
Reactant: COc1ccc2c(c1)C(C(=O)Cl)c1ccccc1O2
Product: CCn1nnc(NC(=O)C2c3ccccc3Oc3ccc(OC)cc32)n1

Procedure:
The title compound, white solid, m.p. 208-210° C. (dec.) and MS: (pos. ions): m/e=352.3 (M++H) was prepared in accordance with the general method of example 1 from 5-amino-2-ethyl-2H-tetrazole and (RS)-2-methoxy-9H-xanthene-9-carbonyl chloride.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]3[C:11]4([CH2:21][O:22][C:8]3=[CH:7][C:5]=2[N:6]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:13][C:12]4=[O:20].CC1C=CC(S(O[CH2:34][C@H:35]2[CH2:39][CH2:38][CH2:37][O:36]2)(=O)=O)=CC=1.BrCC1CCCCO1>>[CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]3[C:11]4([CH2:21][O:22][C:8]3=[CH:7][C:5]=2[N:6]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[N:13]([CH2:34][C@H:35]1[CH2:39][CH2:38][CH2:37][O:36]1)[C:12]4=[O:20]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Reactant: Cc1nc2cc3c(cc2o1)C1(CO3)C(=O)Nc2ccccc21
Agent: BrCC1CCCCO1
Product: Cc1nc2cc3c(cc2o1)C1(CO3)C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-methylspiro[furo[2,3-f][1,3]benzoxazole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 2-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[furo[2,3-f][1,3]benzoxazole-7,3′-indol]-2′(1′H)-one was obtained (52%) as a colorless solid: mp 188-190° C. (ethyl acetate); 1H NMR (300 MHz, CDCl3) δ7.37-7.30 (m, 2H), 7.23-7.05 (m, 2H), 6.98-6.93 (m, 2H), 6.00-5.93 (m, 1H), 5.43-5.38 (m, 1H), 4.42-4.26 (m, 1H), 4.05-3.75 (m, 4H), 2.35-2.33 (m, 3H) 2.09-1.79 (m, 4H); 13C NMR (75 MHz, CDCl3) δ175.6, 175.3, 164.4, 164.3, 151.2, 151.1, 146.2, 146.1, 144.9, 144.6, 138.7, 138.6, 130.5, 130.4, 129.6, 124.6, 124.4, 123.0 (2C), 114.0, 113.9, 111.8, 111.6, 110.6, 110.5, 110.3, 109.8, 88.7, 88.4, 76.1, 76.0, 68.5, 68.3, 44.7, 44.4, 29.8, 28.9, 26.2, 25.7, 14.7, 14.6; MS (ES+) m/z 414.9 (M+39).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]([CH:8]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:9]([NH:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:14][CH:13]=2)=[O:10])[C:4](=[O:29])[CH:3]=1.[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([O:40][C:41]([F:44])([F:43])[F:42])=[C:35](B(O)O)[CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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>[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([O:40][C:41]([F:42])([F:43])[F:44])=[C:35]([C:2]2[CH:7]=[CH:6][N:5]([CH:8]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[C:9]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:23][CH:24]=3)=[O:10])[C:4](=[O:29])[CH:3]=2)[CH:36]=1
Reactant: CC(C)(C)OC(=O)c1ccc(NC(=O)C(CC2CC2)n2ccc(Br)cc2=O)cc1
Reactant: OB(O)c1cc(Cl)ccc1OC(F)(F)F
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: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)C(CC2CC2)n2ccc(-c3cc(Cl)ccc3OC(F)(F)F)cc2=O)cc1

Procedure:
110 mg (purity 80%, 0.19 mmol) of tert-butyl 4-{[2-(4-bromo-2-oxopyridin-1(2H)-yl)-3-cyclopropylpropanoyl]amino}benzoate (racemate), 46 mg (0.19 mmol) of 5-chloro-2-trifluoromethoxyphenylboronic acid and 22 mg (0.02 mmol) of tetrakis(triphenylphosphine)palladium(0) were taken up in 2.5 ml of dioxane and 2.5 ml of saturated aqueous sodium carbonate solution and irradiated in a microwave at 130° C. for 12 min. The crude product was purified by flash chromatography (silica gel 60, cyclohexane/ethyl acetate mixtures). Yield: 77 mg (purity 92%, 64% of theory)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.O1CCCC1.[Br:24]N1C(=O)CCC1=O>O>[Br:24][C:5]1[N:1]=[C:2]([CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[NH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncc[nH]2)CC1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(Br)c[nH]2)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
A 100-mL round-bottom flask was charged with tert-butyl 4-(1H-imidazol-2-yl)piperidine-1-carboxylate (0.300 g, 1.19 mmol) and tetrahydrofuran (10 mL), and the solution was cooled to −78. N-Bromosuccinimide (0.185 g, 1.04 mmol) was added, and the resulting solution stirred at −78° C. for 2 h. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 2:1, ethyl acetate/petroleum ether) to afford tert-butyl 4-(4-bromo-1H-imidazol-2-yl)piperidine-1-carboxylate (0.26 g, 66%) as a white solid. MS (ESI, pos. ion) m/z 330, 332 [M+H]+.