Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:15]([NH:17][CH2:18][CH3:19])=[O:16])[CH2:10][CH2:9]2)=[C:4]([F:26])[CH:3]=1.Cl.[CH2:28]([N:30]([CH2:36][CH3:37])[CH2:31][CH2:32][C:33](O)=[O:34])[CH3:29].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:28]([N:30]([CH2:36][CH3:37])[CH2:31][CH2:32][C:33]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]([C:15](=[O:16])[NH:17][CH2:18][CH3:19])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:10][CH2:9]2)=[C:4]([F:26])[CH:3]=1)=[O:34])[CH3:29]
Reactant: CCN(CC)CCC(=O)O
Reactant: CCNC(=O)C(c1ccccc1)N1CCN(c2ccc(N)cc2F)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=O)C(c1ccccc1)N1CCN(c2ccc(NC(=O)CCN(CC)CC)cc2F)CC1
Reaction time: 18 h
Yield: 58.6 %

Procedure:
A mixture of 2-[4-(4-amino-2-fluoro-phenyl)-piperazin-1-yl]-N-ethyl-2-phenyl-acetamide (22 mg, 0.06 mmol), 3-diethylaminopropionic acid hydrochloride (13 mg, 0.07 mmol) and PyBroP (34 mg, 0.07 mmol) in DCM (2 mL) was treated with iPr2NEt (0.032 mL, 0.19 mmol). After 18 h, the mixture was washed with satd. aq. NaHCO3 and brine, dried (MgSO4), and concentrated to give an oil, which was purified by PTLC to give a beige solid (17 mg, 56%). MS (ESI): mass calcd. for C27H38FN5O2, 483.62. m/z found, 484.4 [M+H]+. 1H NMR (CDCl3): 11.15 (s, 1H), 7.38-7.37 (m, 1H), 7.36-7.35 (m, 1H), 7.33-7.32 (m, 3H), 7.31-7.28 (m, 1H), 7.13-7.09 (m, 2H), 6.85 (t, J=9.0, 1H), 3.88 (s, 1H), 3.38-3.33 (m, 2H), 3.06-3.04 (m, 4H), 2.79-2.76 (m, 1H), 2.69-2.65 (m, 4H), 2.59-2.58 (m, 4H), 2.50-2.47 (m, 1H), 1.40-1.38 (m, 1H), 1.35-1.32 (t, J=7.3, 1H), 1.77-1.22 (m, 9H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[N:33]=[C:34]=[O:35])([CH3:23])[CH3:22]>>[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:31])[CH3:32])[C:25]=1[NH:33][C:34](=[O:35])[N:10]([C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=1)([CH3:22])[CH3:23]
Reactant: CC(C)c1ccc(CNc2ccc(C(C)C)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CC(C)c1ccc(CN(C(=O)Nc2c(C(C)C)cccc2C(C)C)c2ccc(C(C)C)cc2)cc1
Yield: 21 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (4-isopropylphenyl)[(4-isopropylphenyl)methyl]amine (1.0 g) and 2,6-diisopropylphenyl isocyanate (0.99 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)-N-[(4-isopropylphenyl)methyl]urea (0.37 g) was obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([OH:13])[CH:8]=[CH:9][C:10]=2[Cl:12])[N:5]=[CH:4][N:3]=1.O.C([O-])(O)=O.[Na+].[CH:20]([OH:23])([CH3:22])[CH3:21]>>[Cl:12][C:10]1[CH:9]=[CH:8][C:7]([OH:13])=[C:6]2[C:11]=1[C:2]([O:23][CH:20]([CH3:22])[CH3:21])=[N:3][CH:4]=[N:5]2
Reactant: CC(C)O
Reactant: Oc1ccc(Cl)c2c(Cl)ncnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)Oc1ncnc2c(O)ccc(Cl)c12
Temperature: 25 °C

Procedure:
A mixture of 4,5-dichloro-8-quinazolinol (3.0 g, 13.95 mmol) in isopropanol is heated at reflux for 30 minutes, cooled to room temperature and filtered to obtain a solid. The solid is mixed with water and saturated NaHCO3 solution. The resultant mixture is filtered and the filter cake is washed with water and dried to give the title product as an off-white solid, 1.71 g, mp 126°-126.5° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH2:2][CH2:3][CH2:4][C:5]#[N:6])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1
Reactant: N#CCCCBr
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCCN1CCN(c2ccc(Cl)cc2)CC1
Reaction time: 3 h
Yield: 86.5 %

Procedure:
To a solution of 4-bromobutanenitrile (1.50 g, 10.17 mmol) in dimethyl formamide (20 ml) were added 1-(4-chlorophenyl)piperazine (2.0 g, 10.17 mmol) and potassium carbonate (2.81 g, 20.34 mmol) at room temperature and the reaction mixture was stirred for 3 h at same temperature. The progress of the reaction was monitored by TLC. The reaction mixture was diluted with water (50 ml) and the aqueous layer was extracted with ethyl acetate (3×50 ml). The combined organic layer was dried over anhydrous sodium sulphate. The solvent in the organic layer was removed under reduced pressure to obtain a crude product, which was purified by column chromatography over silica gel (100-200 mesh) using 10% ethyl acetate in hexane to yield the title compound (2.32 g, 86% yield).
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1.[CH3:23][C:24]1[S:25][C:26]([C:32]2[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=2)=[C:27]([C:29](O)=[O:30])[N:28]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:29]([C:27]3[N:28]=[C:24]([CH3:23])[S:25][C:26]=3[C:32]3[CH:33]=[C:34]([CH3:38])[CH:35]=[CH:36][CH:37]=3)=[O:30])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:21]3[C:17]([S:18][CH:19]=[CH:20]3)=[N:16][C:15]=2[CH3:22])=[O:13])[CH2:3]1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CC(C)C[C@@H]21
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)[CH3:2].ClN1C(=[O:25])CCC1=O.P(=O)(O)(O)O>C(Cl)Cl.O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11](=[O:25])[CH2:10][C:7]2=[N:8][CH:9]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOc1cnc2ccn(-c3ccccc3)c2c1
Agent: O=P(O)(O)O
Solvent: O
Solvent: ClCCl
Product: CCOc1cnc2c(c1)N(c1ccccc1)C(=O)C2
Temperature: 25 °C
Reaction time: 72 h
Yield: 29.7 %

Procedure:
The compound of step 3 (2.05 g, 8.60 mmol) was dissolved in DCM (30 ml) and N-chlorosuccinimide (1.26 g, 9.46 mmol) was added. The reaction mixture was stirred at room temperature for 3 days. The solvent was removed, and the obtained solid was dissolved in acetic acid (10 ml) and heated to 70° C. After addition of phosphoric acid (7.31 ml, 107 mmol, 85%), the reaction mixture was heated to 120° C. for 3 days. After cooling, the mixture was diluted with water and extracted with EA. The extracts were dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (EA/HEP 1:6). 650 mg of the title compound were obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[C:28]([C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][N:31]=1)#[N:29]>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:33]3[CH:34]=[CH:35][C:30]([C:28]#[N:29])=[N:31][CH:32]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4ccc(C#N)nc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 2-cyanopyridine-5-boronic acid pinacol ester in General Procedure A. Purification on silica gave 280. NMR (CDCL3): 2.68-2.72 (4H, m), 2.82 (3H, s), 3.29-3.33 (4H, m), 3.90 (2H, s), 3.90-3.94 (4H, m), 4.05-4.10 (4H, m), 7.38 (1H, s), 7.80 (1H, d, J=8.1), 8.84 (1H, d, J=8.2), 9.75 (1H, s). MS (ESI+): MH+541.30 (50%)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH2:12][CH3:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:14][O:15][CH2:16][C:17](Cl)=[O:18]>N1C=CC=CC=1>[CH2:12]([O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:1][C:17](=[O:18])[CH2:16][O:15][CH3:14])[S:3][C:4]=2[CH:10]=1)[CH3:13]
Reactant: CCOc1ccc2nc(N)sc2c1
Reactant: COCC(=O)Cl
Solvent: c1ccncc1
Product: CCOc1ccc2nc(NC(=O)COC)sc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Amino-6-ethoxybenzothiazole (5.8 g) is dissolved in pyridine (100 ml) and thereto is added dropwise methoxyacetyl chloride (3.0 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting solids are washed with water, then with diethyl ether, dried and recrystallized from ethanol to give the title compound (5.1 g) having the following physical properties.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.C([O:10][CH:11]=[C:12]([C:18](OCC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])C>CN(C)C=O>[CH2:16]([O:15][C:13]([C:12]1[C:11](=[O:10])[N:6]2[N:5]=[C:4]([SH:7])[S:3][C:2]2=[N:1][CH:18]=1)=[O:14])[CH3:17]
Reactant: Nc1nnc(S)s1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2sc(S)nn2c1=O
Yield: 79.6 %

Procedure:
A mixture of 2-amino-5-mercapto-1,3,4-thiadiazole (6.7 g), diethyl ethoxymethylenemalonate (16.2 g) and dimethylformamide (80 ml) was refluxed for 16 hours. After removing the solvent by distillation under reduced pressure, the residue was recrystallized from methanol, giving 10.3 g of the objective compound as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[NH:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([F:21])[CH:11]=1.[CH2:22](OC(OCC)OCC)C>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[CH:22][N:9]([C:10]3[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([F:21])[CH:11]=3)[C:3]=2[CH:4]=1
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)c1ccc(Nc2cc(Br)ccc2N)cc1F
Product: CCOC(=O)c1ccc(-n2cnc3ccc(Br)cc32)cc1F

Procedure:
917 mg ethyl 4-(2-amino-5-bromo-phenylamino)-2-fluoro-benzoate (compound in Production Example 333) and 7 mL triethoxymethane were stirred at 140° C. for 3 hours. The solvent was evaporated, and the residue was purified by NH silica gel chromatography (ethyl acetate/hexane). By recrystallization from ethyl acetate/hexane, 734 mg of the title compound was obtained as pale pink crystals.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]([O:12][CH2:13][CH3:14])=[O:11].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:25](Br)[CH:26]=[CH2:27]>C1COCC1>[CH2:27]([C:2]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:1][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1)[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: CCOC(=O)C1Cc2ccccc2C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC1(C(=O)OCC)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl indane-2-carboxylate [Schaaf et al., J. Med. Chem. 1983, 26, 328-334] (6.87 g, 36.1 mmol) in THF (100 mL) at −78° C. was added sodium bis(trimethylsilyl)amide (1.0 M in THF, 39.7 mL, 39.7 mmol) dropwise over 20 min. The resulting yellow solution was stirred for 1 h, and then allyl bromide (3.75 mL, 43.3 mmol) was added over 5 min. Stirring was continued for 1.5 h at −78° C., and then the reaction was quenched by the addition of saturated NH4Cl and warmed to ambient temperature. The reaction mixture was partitioned between saturated NH4Cl (100 mL) and EtOAc (100 mL). The aqueous phase was further extracted with EtOAc (2×50 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 75:25, to give the title compound. MS: m/z=231 (M+1).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:25]([OH:27])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC[N:30](C(C)C)C(C)C.C(OC(Cl)=O)C(C)C.N.C(O)(C)C>C1COCC1>[C:21]([O:20][C:18](=[O:19])[O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C@H:9]([NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[C:25](=[O:27])[NH2:30])=[CH:12][CH:13]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(=O)OC(C)(C)C)cc1)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(=O)OC(C)(C)C)cc1)C(N)=O
Yield: 62.2 %

Procedure:
N,O-Bis-Boc-(S)-tyrosine from example 64 (5.00 g, 13.11 mmol) was dissolved in THF (20 mL), the solution stirred under an argon atmosphere and cooled in an ice bath. DIEA (5.70 mL, 32.7 mmol) was added followed by isobutylchloroformate (2.55 mL, 19.6 mmol). After 45 min a solution of 2M ammonia in isopropanol (39.3 mL, 78.6 mmol) was added and the mixture stirred at room temperature for 18 h. The solvent was evaporated, the residue taken in EtOAC (100 mL), washed with 5% aqueous citric acid (2×50 mL), 5% aqueous sodium bicarbonate (2×50 mL) and brine. After drying (MgSO4) and evaporation of the solvent, the residue was dissolved in chloroform (15 mL), stirred vigorously and Et2O (150 mL) was added. The suspension was stirred for 20 min. then the solid filtered and air dried to yield 3.10 g (62%) of the title compound.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:8]([O:10][C:11](=[O:16])[CH2:12][N+:13]([O-])=[O:14])[CH3:9].C1N2CCN(CC2)C1>CCO>[O:14]1[C:2]2([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:1][C:12]([C:11]([O:10][CH2:8][CH3:9])=[O:16])=[N:13]1
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: C=C1CCCCC1
Agent: C1CN2CCN1CC2
Solvent: CCO
Product: CCOC(=O)C1=NOC2(CCCCC2)C1
Temperature: 80 °C
Yield: 63.4 %

Procedure:
To a 300 mL pressure vessel equipped with a magnetic stir bar was added methylenecyclohexane (5.83 g, 60.6 mmol) and EtOH (150 mL). Nitro-acetic acid ethyl ester (16.8 mL, 152 mmol) and DABCO (680 mg, 6.06 mmol) were then added. Additional EtOH (30 mL) was added to rinse the sides of the vessel, which was tightly capped. The mixture was heated to 80° C. for 42 h and then cooled to RT. The solvent was removed under reduced pressure, and the residue was divided into three equal portions. Each portion was purified by column chromatography using an 80-g SiO2 pre-packed column eluting with EtOAc/hexanes, 0:1 to 1:4, v/v over 30 min, yielding 8.12 g (64%) of the desired ester. 1H-NMR (400 MHz, CDCl3) δ: 4.34 (q, J=7.2 Hz, 2H), 2.91 (s, 2H), 1.71-1.88 (m, 4H), 1.60-1.71 (m, 2H), 1.39-1.53 (m, 4H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Li]CCCC.[C:12](=[O:14])=[O:13].CC(C)=O>C1COCC1>[C:12]([OH:14])(=[O:13])[C:3]1[CH:2]=[CH:1][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCC
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=C(O)c1ccccc1
Reaction time: 0.5 h

Procedure:
After the inside of a 2-liter four-necked flask equipped with a magnetic stirrer, dropping funnel, 3-way cock and thermometer was replaced with nitrogen gas, the flask was charged with 117 ml (0.55 mol) of HN(Si(CH3)3)2 and 200 ml of TFE. After cooling in dry ice/acetone bath, 328 ml (0.525 mol) of 1.6 N hexane solution of n-BuLi was added dropwise over 45 minutes so that the solution temperature did not exceed −50° C. Further after stirring for 30 minutes, thereto was added dropwise over 45 minutes a solution prepared by dissolving, in 200 ml of THF, 136 g (0.5 mol) of benzoic acid (1,1,1,3,3,3-hexafluoro-2-propyl) obtained by usual preparation process so that the solution temperature did not exceed 50° C., followed by 30-minute stirring. 300 Gram of ice and 150 ml of concentrated hydrochloric acid were put in a 3-liter beaker, followed by stirring, and to the obtained slurry was added the reaction solution gradually. Then an organic layer was separated in the dropping funnel and water layer was extracted two times with 300 ml of n-hexane. The organic layer obtained by two extractions was washed with saturated brine, followed by drying with MgSO4, concentrating with an evaporator and refining by distillation under reduced pressure. Thereby 107.3 g of benzoic acid (1,1,1,3,3-pentafluoro-2-propenyl) was synthesized (boiling point: 71° to 73° C./24 mmHg).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC([N:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([C:29]([OH:31])=[O:30])=[CH:21]2)[CH2:17][CH2:16]1)=O)(C)(C)C>ClCCl>[NH:15]1[CH2:20][CH2:19][C:18]2([C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([C:29]([O-:31])=[O:30])=[CH:21]2)[CH2:17][CH2:16]1.[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC2(C=C(C(=O)O)c3ccccc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C([O-])C1=CC2(CCNCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2 mL) was added to a stirred solution of 1′-(tert-butyoxycarbonyl)spiro[indene-1,4′-piperidine]-3-carboxylic acid (C4) (0.25 g, 0.76 mmol) in dichloromethane (5 mL) and the solution was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and dried under high vacuum for 18 h to provide spiro[indene-1,4′piperidine]-3-carboxylate (D1) as an oil (0.26 g, quantitative, TFA salt). LC/MS (10-90% over 3 min with 0.9% FA) m/z 230.3 (M+1), Rt 1.3 minutes. 1HNMR (500 MHz, DMSO-d6): 12.91 (brs, 1H), 7.95 (s, 1H), 7.88 (d, 1H), 7.35 (m, 3H), 3.31-3.43 (m, 4H), 2.27 (m, 2H), 1.42 (m,2H).
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[F:15][C:16]([F:27])([F:26])[C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.N1C=CC=CC=1>C(#N)C>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:14][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:17]([C:16]([F:15])([F:26])[F:27])=[CH:18][CH:19]=1
Reactant: NC1CCc2oc3ccccc3c2C1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(Nc1ccc2oc3c(c2c1)CCCC3)c1ccc(C(F)(F)F)cc1
Yield: 57.8 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (1.0 g, 5.3 mmol), 4-(trifluoromethyl)benzoyl chloride (0.79 mL, 5.3 mmol), and pyridine (1.1 mL, 13 mmol) in acetonitrile (50 mL) provided N-(6,7,8,9-tetrahydrodibenzo[b,d]furan-2-yl)-4-(trifluoromethyl)benzamide (1.1 g). MS (ESI) m/z 358 ([M−H]); m/z 360 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22](O)=[O:23])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[NH:49]1[CH2:54][CH2:53][CH2:52][C@H:51]([NH:55][C:56](=[O:65])[O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH2:50]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([NH:15][C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([N:49]3[CH2:54][CH2:53][CH2:52][C@H:51]([NH:55][C:56](=[O:65])[O:57][CH2:58][C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)[CH2:50]3)=[O:23])[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: O=C(N[C@H]1CCCNC1)OCc1ccccc1
Reactant: C[C@@H](C(=O)O)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](C(=O)N1CCC[C@H](NC(=O)OCc2ccccc2)C1)N1CC[C@H](NS(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (2S)-2-((3S)-3-{[(6-chloro-2-naphthyl)sulfonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid (0.408 g) in DCM (21 ml) was treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.394 g), HOBT (0.278 g) and triethylamine (0.286 ml) and stirred at room temperature for 1 h. A solution of benzyl (3S)-piperidin-3-ylcarbamate (0.3619) in DCM (1 ml) was then added and stirring continued for 72 h. The mixture was partitioned between DCM and water. The separated organic extracts were washed with water and brine, dried (over magnesium sulphate), and concentrated under reduced pressure. The residue was purified using Biotage™ chromatography (eluting with hexane:ethyl acetate 1:7→1:10) to give the title compound (0.268 g) as an oil.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][N:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](OCC)=[O:19].Cl>C(O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][N:11]=1)[NH:8][C:7](=[O:12])[CH:6]2[C:18](=[O:19])[C:14]1[S:13][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1cccs1
Reactant: O=C1Cc2cc(Cl)ncc2N1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=C1Nc2cnc(Cl)cc2C1C(=O)c1cccs1
Temperature: 0 °C
Yield: 34.1 %

Procedure:
Pellets of sodium metal (232 mg, 10 mmol) were added to dry ethanol (10 mL) in a dry round-bottomed flask. When dissolution of the sodium was complete, solid 5-chloro-6-azaoxindole (340 mg, 2.0 mmol) was added followed by ethyl 2-thiophenecarboxylate (0.54 mL, 4.0 mmol). The mixture was heated under nitrogen at reflux overnight during which a precipitate formed. The mixture was cooled, poured into ice/water and acidified to pH 4 with 6N HCl solution. The solid product (475 mg) was collected by filtration, washed with water, and dried in the air. This material was recrystallized from methanol to afford the title compound (190 mg, 34%). 1H NMR (DMSO-d6): δ10.62 (br s, 1H), 8.79 (d, J=3.2 Hz, 1H), 7.92 (s, 1H), 7.77 (d, J=5 Hz, 1H), 7.65 (s, 1H), 7.17-7.14 (m, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]([O:20]C)=[O:19])[CH:15]=[C:14]([O:22][CH2:23][CH:24]=[CH2:25])[CH:13]=2)[O:9][N:8]=1.[OH-].[Na+]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[C:14]([O:22][CH2:23][CH:24]=[CH2:25])[CH:13]=2)[O:9][N:8]=1
Reactant: C=CCOc1cc(C(=O)OC)cc(-c2nc(-c3ccccn3)no2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCOc1cc(C(=O)O)cc(-c2nc(-c3ccccn3)no2)c1
Reaction time: 16 h
Yield: 68.8 %

Procedure:
A stirred suspension of 3-(2-pyridyl)-5-(3-alloxy-5-(methoxycarbonyl)phenyl)-1,2,4-oxadiazole (160 mg, 0.47 mmol) in methanol (5 mL) at ambient temperature was treated with 1 M sodium hydroxide (0.8 mL, 0.80 mmol). The reaction was stirred 16 hours and solvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified with 1 N hydrogen chloride. Extraction of the aqueous phase with dichloromethane followed by concentration in vacuo afforded 104.5 mg of 3-(2-pyridyl)-5-(3-alloxy-5-(hydroxycarbonyl)phenyl)-1,2,4-oxadiazole.