Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])[N:3]=1.[CH2:15]([Mg]Cl)[CH:16]([CH3:18])[CH3:17]>C1COCC1.CN1C(=O)CCC1>[CH3:14][C:9]1[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:3]=2)[C:12]([CH3:13])=[CH:11][CH:10]=1
Reactant: Cc1ccc(C)n1-c1cccc(Cl)n1
Reactant: CC(C)C[Mg]Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cccc(CC(C)C)n1

Procedure:
The product from Example 12b (1.0 g, 4.84 mmol) was treated with 2.0 M isobutylmagnesium chloride (2.90 mL, 5.81 mmol) in 30 mL THF and 3 mL NMP at room temperature under a N2 atmosphere. Added Fe(acac)3 (85 mg, 0.242 mmol) and stirred at room temperature for 18 h. During the course of the reaction two additional charges of Grignard reagent and catalyst were added. The reaction was quenched by pouring into 5% acetic acid and extracting with ether. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound that was purified by silica gel column chromatography eluting with 10% EtOAc/hexane to give (620 mg, 56%).
Reaction SMILES: COC1C=CC(CS[C@@H:9]2[CH2:13][N:12](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[C@H:11]([C:27](O)=O)[CH2:10]2)=CC=1.O1[CH2:36][CH2:35][CH2:34]C1>C(#N)C>[CH:35]([N:12]([CH2:13][CH3:9])[CH:11]([CH3:27])[CH3:10])([CH3:36])[CH3:34]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: C1CCOC1
Solvent: CC#N
Product: CCN(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (1.28 g) in anhydrous acetonitrile (19 ml), N,N'-carbonyldiimidazole (489 mg) was added, followed by stirring at room temperature for one hour. To the reaction mixture, N,N-diisopropylethylamine (478 μl) and a solution of the compound (2.60 g), which had been obtained in (1), in anhydrous tetrahydrofuran (15 ml ) were added. The resulting mixture was treated in a similar manner to that described in Referential Example 16-(3), whereby the title compound (2.09 g) was obtained as an amorphous substance.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:4]1.[C:19]1([C:25]2[O:29][N:28]=[C:27]([C:30](O)=[O:31])[CH:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][N:2]([CH3:18])[CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([NH:17][C:30]([C:27]4[CH:26]=[C:25]([C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)[O:29][N:28]=4)=[O:31])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:4]1
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Reactant: O=C(O)c1cc(-c2ccccc2)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(c2nc3ccc(NC(=O)c4cc(-c5ccccc5)on4)cc3s2)C1
Reaction time: 3 h

Procedure:
Combine 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (0.100 g, 0.381 mmol) (Example 1, step 3), dissolved in CH2Cl2 (5.0 mL), with 5-phenyl-isoxazole-3-carboxylic acid (0.079 g, 0.419 mmol), HATU (0.145 g, 0.381 mmol), and DIEA (0.20 mL, 1.14 mmol) in a 40 mL reaction vial and shake the mixture overnight at 40° C. Dilute the mixture with CH2Cl2 (25 mL) and wash with 1.0 M NaOH (25 mL) which results in emulsions forming. Wait 3 h for the emulsions to disappear, separate the layers and dry the organic portion over sodium sulfate. Filter and concentrate in vacuo to yield the compound as a yellow solid. Purify using silica gel chromatography (5% MeOH/CH2Cl2) to afford the title compound as a yellowish-white solid (117 mg, 71%). mass spectrum (m/e): 434.2 [M+1], 432.2 [M−1]. 1H NMR (400 MHz, DMSO-d6): δ10.76 (s, 1H), 8.27 (d, 1H, J=2 Hz), 7.98 (m, 2H), 7.56-7.63 (m, 4H), 7.49 (s, 1H), 7.45 (d, 1H, J=8.8 Hz), 3.73 (t, 1H, J=9.2 Hz), 3.64 (t, 1H, J=9.2 Hz), 3.49 (m, 1H), 3.29 (m, 1H), 2.90 (m, 1H), 2.21 (s, 6H), 2.19 (m, 1H), 1.91 (m, 1H).
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][OH:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:13]([O-])([O-:15])=[O:14].[K+].C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O>[N+:13]([C:5]1[CH:6]=[C:1]([S:7]([CH2:10][CH2:11][OH:12])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])[O-]
Reactant: O=S(=O)(CCO)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1cccc(S(=O)(=O)CCO)c1
Temperature: 90 °C
Yield: 30 %

Procedure:
2-(Phenylsulfonyl)-ethanol (2.5 g; 13 mmol) was dissolved in 5.5 ml of conc. sulphuric acid and treated in portions with potassium nitrate (2 g; 20 mmol). The reaction mixture was heated for 2 hours at 90° C., then poured onto ice and potassium carbonate was added. The mixture was extracted several times with ethyl acetate and the combined organic layers were concentrated to obtain 0.9 g (3.9 mmol, 30% yield) of 2-(3-nitro-phenylsulfonyl)-ethanol as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:16]3[CH:17]=[C:18]([C:21](O)=[O:22])[S:19][CH:20]=3)=[CH:9][N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:6]=2[CH:5]=[CH:4][NH:3]1.CC[N:26]=C=NCCCN(C)C.Cl>CC(N(C)C)=O.O>[O:1]=[C:2]1[C:7]2[C:8]([C:16]3[CH:17]=[C:18]([C:21]([NH2:26])=[O:22])[S:19][CH:20]=3)=[CH:9][N:10]([CH:11]([CH2:12][CH3:13])[CH2:14][CH3:15])[C:6]=2[CH:5]=[CH:4][NH:3]1
Reactant: CCN=C=NCCCN(C)C
Reactant: CCC(CC)n1cc(-c2csc(C(=O)O)c2)c2c(=O)[nH]ccc21
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCC(CC)n1cc(-c2csc(C(N)=O)c2)c2c(=O)[nH]ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a solution of 4-(4-oxo-1-(pentan-3-yl)-4,5-dihydro-1H-pyrrolo[3,2-c]pyridin-3-yl)thiophene-2-carboxylic acid (23.0 mg) in DMA (2 mL) were added EDCI hydrochloride (16.0 mg) and HOBt ammonium salt (13.1 mg) at room temperature, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate to ethyl acetate/methanol) to give the title compound (20.6 mg).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:13](=[O:27])[CH2:14][N:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:17][CH2:16]1.[BH4-].[Na+].C(O)(=O)C>CO>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH:13]([OH:27])[CH2:14][N:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:20]1
Reactant: Cc1[nH]c(-c2cccnc2)nc1C(=O)CN1CCN(c2ccccc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1[nH]c(-c2cccnc2)nc1C(O)CN1CCN(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
To a suspension of 1 g of 1-[5-methyl-2-(3-pyridinyl)-1H-imidazol-4-yl]-2-(4-phenyl-1-piperazinyl)ethanone in 5 ml of methanol, cooled in an ice-water bath, was added 0.2 g of sodium borohydride. After gas evolution ceased, this mixture was stirred in the bath for 45 minutes, with the addition of 2 ml of methanol after 5 minutes, and then at room temperature for one hour. A 0.1 g portion of sodium borohydride was added, the mixture was stirred in the ice-water bath for 30 minutes, then at room temperature for one hour. The addition of 0.1 g of sodium borohydride and the reaction conditions were repeated twice more, then the mixture was poured into ice-water. The mixture was adjusted to pH 7-8 with glacial acetic acid. The gummy solid was collected, washed with water and then triturated with 30 ml of ether for 15 minutes. The ether was decanted and the solid triturated with 10 ml of fresh ether. The solid was collected, washed with ether and dried in vacuo, giving 0.6 g of the desired product as a pale yellow solid, mp 180°-184° C. (dec.).
Reaction SMILES: [C:1]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][CH:8]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C1COCC1.[OH-].[Na+]>CO>[C:1]([C:7]1[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:16][CH:17]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1ccc(C(=O)C(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1ccc(C(=O)O)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 137.2 %

Procedure:
A round bottom flask was charged with ethyl 4-pivaloylbenzoate (7.67 g, 32.7 mmol), THF (100 mL) and MeOH (100 mL). Sodium hydroxide 1N, aq. (65.5 mL, 65.5 mmol) was then added in one portion. Reaction stirred at 40° C. for 1 hour. Organic solvent removed under reduced pressure and water (150 mL) added to the flask. Acidification with HCl 1N aq. to ca. pH 1 followed by filtration of the solid formed over a büchner funnel provide 4-pivaloylbenzoic acid as a light yellow solid (9.25 g). 1H NMR (400 MHz, DMSO-d6) δ 1.25-1.27 (m, 9H) 7.70-7.74 (m, 2H) 7.97-8.01 (m, 2H) 13.00 (br. s., 1H); MS (M−1): 205.3.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[BrH:11].[CH2:12]([N:15]([CH2:28][CH2:29][CH3:30])[CH:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([OH:27])[C:22]=2[NH2:26])[CH2:17]1)[CH2:13][CH3:14]>C(OCC)C>[BrH:11].[CH2:28]([N:15]([CH2:12][CH2:13][CH3:14])[CH:16]1[CH2:25][CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([OH:27])[C:22]=2[NH:26][CH:1]=[O:3])[CH2:17]1)[CH2:29][CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: CCCN(CCC)C1CCc2c(ccc(O)c2N)C1
Agent: Br
Solvent: O=CO
Solvent: CCOCC
Product: CCCN(CCC)C1CCc2c(ccc(O)c2NC=O)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
0.42 ml of acetic anhydride is added all at once to 2 ml of 98% formic acid, kept at 0° C., and the mixture is left at 0° C. for 15 minutes. Then, still using an ice-bath, 1.34 g of 2-dipropylamino-5-amino-6-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide are introduced therein with a spatula and the whole is stirred for one hour at 0° C. After 50 ml of diethyl ether have been added and the solid has been filtered off, the latter is recrystallised from a 50/50 methanol/ethyl acetate mixture. This gives 1 g of the final product melting at 213° C. (with decomposition).
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH2:9]([C:11]1([O:15][CH2:14]1)[CH2:12]Cl)[CH3:10].[OH-].[Na+]>O>[OH:15][CH2:14][C:11]1([CH2:9][CH3:10])[O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2][CH2:12]1
Reactant: CCC1(CCl)CO1
Reactant: Oc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC1(CO)COc2ccccc2O1
Yield: 43.8 %

Procedure:
A stirred mixture of catechol (14.0 g), 2-ethyl-epichlorohydrin (15.3 g), sodium hydroxide (5.1 g) and water (50 ml) was heated at 90° under an atmosphere of nitrogen for 4 hours. On cooling water was added and the product was extracted with methylene chloride. The combined extracts were washed with 2 N aqueous sodium hydroxide solution, water and brine, dried and evaporated to leave an oil (10.8 g); IR νmax 3650-3200, 3000-2850 cm-1.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1CC#N.Cl.[C:18]([OH:21])(=[O:20])[CH3:19]>>[F:16][C:2]([F:1])([F:15])[CH2:3][O:4][C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:19][C:18]([OH:21])=[O:20]
Reactant: N#CCc1cccc(Cl)c1OCC(F)(F)F
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)Cc1cccc(Cl)c1OCC(F)(F)F

Procedure:
2-(2,2,2-trifluoroethoxy)-3-chlorophenyl-acetonitrile (1.2 g, 5.1 mmol) from Step 3 above was refluxed in a 2:1 mixture of acetic acid and concentrated aqueous HCl (25 mL) for 12 h. The solvents were removed under reduced pressure and the residue was partitioned between EtOAc and water. The organic phase was washed with water, dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 2-(2,2,2-trifluoroethoxy)-3-chlorophenylacetic acid as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[I:9]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([I:9])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1ccc(Cl)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ncc(Cl)cc1I
Temperature: 55 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
A mixture of 6.43 g of 5-chloropyridin-2-ylamine and 12.38 g of N-iodosuccinimide in 300 ml of glacial acetic acid is heated at around 55° C. for 6 hours. After returning to a temperature of approximately 20° C., the mixture is agitated for approximately 18 hours and then concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 400 ml of water; the pH of the suspension obtained is brought back to approximately 8 by adding a saturated aqueous sodium hydrogen carbonate solution. The precipitate is filter-dried, washed with water, and dried at 40° C. under reduced pressure (13 kPa) for approximately 3 hours. 12.35 g of 5-chloro-3-iodopyridin-2-ylamine are obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: O.[NH2:2]N.C[N:5]([CH:7]=[N:8][C:9]([C:11]1[O:15][N:14]=[C:13]([O:16][CH2:17][CH3:18])[C:12]=1[CH3:19])=O)C>C(O)(=O)C>[CH2:17]([O:16][C:13]1[C:12]([CH3:19])=[C:11]([C:9]2[N:8]=[CH:7][NH:5][N:2]=2)[O:15][N:14]=1)[CH3:18]
Reactant: NN
Reactant: CCOc1noc(C(=O)N=CN(C)C)c1C
Solvent: CC(=O)O
Solvent: O
Product: CCOc1noc(-c2nc[nH]n2)c1C
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 77.2 %

Procedure:
To a solution of hydrazine hydrate (0.6 mL, 12.4 mmol) in acetic acid (15 mL) was added N-(dimethylamino)methylidene 3-ethoxy-4-methylisoxazole-5-carboxamide (1.8 g, 8.0 mmol). The reaction mixture was stirred at 90° C. for 15 min and then left at room temperature to crystallize affording pure title compound (1.2 g, 77%): mp 194-196° C. Water was added (40 mL) and the aqueous phase was extracted with EtOAc (3×30 mL). The organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give crude title compound (0.3 g, 20%). The two crops were combined.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][CH:21]([O:29][Si](C(C)(C)C)(C)C)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:6][CH:5]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][O:2][C:3](=[O:37])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[C:17](=[O:18])[CH2:16][CH2:15][CH:14]2[CH2:19][CH2:20][CH:21]([OH:29])[CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(Cc2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCCN2C(=O)CCC2CCC(O)Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.6 %

Procedure:
To a solution of 4-(3-{2-[3-(tert-butyl-dimethyl-silanyloxy)-4-phenyl-butyl]-5-oxo-pyrrolidin-1-yl}-propyl)-benzoic acid methyl ester (3.37 g, 6.43 mmol) in THF (40 mL) at 0° C. was added tetra-butylammonium fluoride (1M in THF, 9.6 mL, 9.6 mmol). The reaction mixture was stirred at room temperature for 18 h and the volatiles were removed in vacuo. EtOAc was added and the organic solution was washed with saturated aqueous NaHCO3 (2×), water (1×), and brine (1×). The organic solution was dried (MgSO4), filtered and concentrated. The residue was purified by medium pressure chromatography eluting with EtOAc to yield 2.28 g of 4-{3-[2-(3-hydroxy-4-phenyl-butyl)-5-oxo-pyrrolidin-1-yl]-propyl}-benzoic acid methyl ester. 1H NMR (CDCl3) (selected peaks) δ7.91 (d, 2H), 7.32–7.15 (m, 7H), 3.86 (s, 3H), 3.75 (m, 1H), 3.63 (m, 1H), 3.54 (m, 1H), 2.94 (m, 1H), 2.78 (m, 1H), 2.61 (m, 3H); MS 410.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:16][C:17]([F:34])([F:33])[C:18]1[CH:23]=[CH:22][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[O:25])=[CH:20][CH:19]=1>>[F:16][C:17]([F:33])([F:34])[C:18]1[CH:19]=[CH:20][C:21]([C:24]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:28][CH:27]=2)=[O:25])=[CH:22][CH:23]=1
Reactant: O=C(c1ccc(O)cc1)c1ccc(C(F)(F)F)cc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccc(C(F)(F)F)cc4)cc3)c2cc1OC
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 59.7 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (81 mg) and 4-hydroxyphenyl 4-trifluoromethylphenyl ketone (288 mg) obtained in Example 23 were mixed and stirred at 180° C. for 20 minutes, and the reaction mixture was then purified by thin layer chromatography on silica gel eluting with hexane/acetone (2/1) to obtain 98 mg of the title compound (yield: 60%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:16][C:17]([C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:20]=1[OH:27])=[O:18]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][N:3]=[C:2]2[O:27][C:20]1[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:19]=1[C:17](=[O:18])[CH3:16]
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: COc1ccc(O)c(C(C)=O)c1
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)c(C(C)=O)c1
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
4-Chloro-6,7-dimethoxyquinazoline (59 mg), 2-hydroxy-5-methoxyacetophenone (213 mg), and 4-dimethylaminopyridine (173 mg) were suspended in o-dichlorobenzene (5 ml), and the suspension was stirred at 160° C. for 10 min. The reaction solution was cooled to room temperature, the solvent was then removed therefrom by distillation under the reduced pressure, and chloroform was added to the residue. The mixture was washed with a 1 N aqueous potassium hydroxide solution and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using chloroform and by thin layer chromatography using acetone-hexane to give the title compound (46.5 mg, yield 50%).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([CH:21]2[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]2)[C:14](=[O:20])[C:15]([CH3:19])([CH3:18])[CH2:16][OH:17])[CH2:9]1)(OC(C)(C)C)=[O:2].[C:29]([N:33]1[CH2:37][C@@H:36]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)[C@H:35](C(O)=O)[CH2:34]1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([N:33]1[CH2:37][C@@H:36]([C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=2)[C@H:35]([C:1]([N:8]2[CH2:12][CH2:11][C@H:10]([N:13]([CH:21]3[CH2:26][CH2:25][C:24]([CH3:27])([CH3:28])[CH2:23][CH2:22]3)[C:14](=[O:20])[C:15]([CH3:18])([CH3:19])[CH2:16][OH:17])[CH2:9]2)=[O:2])[CH2:34]1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)CO)[C@H]2CCN(C(=O)OC(C)(C)C)C2)CC1
Reactant: CC(C)(C)N1C[C@@H](C(=O)O)[C@H](c2ccc(Cl)cc2)C1
Product: CC1(C)CCC(N(C(=O)C(C)(C)CO)[C@H]2CCN(C(=O)[C@@H]3CN(C(C)(C)C)C[C@H]3c3ccc(Cl)cc3)C2)CC1

Procedure:
The title compound was prepared according to the procedure described in Step F-G of Example A1, using N-(4,4-dimethylcyclohexyl)-3-hydroxy-2,2-dimethyl-N-[(3S)-pyrrolidine-3-yl]propaneamide (500 mg, 1.21 mmol) prepared in Step B and (3S,4R)-1-t-butyl-4-(4-chlorophenyl)pyrrolidine-3-carboxylic acid prepared in Preparation Example A9-2 (672 mg, 91.9%).
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:14](#[N:17])[CH:15]=[CH2:16]>CCO>[OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][N:5]([CH2:16][CH2:15][C:14]#[N:17])[CH2:4][CH2:3]1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: C=CC#N
Solvent: CCO
Product: N#CCCN1CCC(O)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 92.1 %

Procedure:
To a solution of 4-hydroxy-4-phenylpiperidine (3.11 g, 17.5 mmol, 1.00 equiv) in EtOH (30 mL) was added acrylonitrile (2.89 mL, 43.8 mmol, 2.50 equiv) dropwise at 0° C. The mixture was stirred at room temperature for 1.5 hours and then concentrated to afford 3.71 g (92%) of white solid, which was characterized spectroscopically.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:48])([F:47])[C:9]1[CH:10]=[C:11]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:12][N:13]([CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[C:29]1[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[C:31]([C:37]([OH:39])=O)[CH:30]=1)[C:14]([O:16][CH3:17])=[O:15].[C:49](=[N:52]O)([NH2:51])[CH3:50]>CN(C)C=O.C(Cl)Cl>[F:44][C:43]([F:46])([F:45])[C:41]1[CH:40]=[C:11]([CH:10]=[C:9]([C:8]([F:7])([F:48])[F:47])[CH:42]=1)[CH2:12][N:13]([CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[C:29]1[CH:30]=[C:31]([C:37]2[O:39][N:52]=[C:49]([CH3:50])[N:51]=2)[CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[C:14](=[O:15])[O:16][CH3:17]
Reactant: CC(N)=NO
Reactant: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(=O)O)ccc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(-c2nc(C)no2)ccc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (0.14 mL, 0.28 mmol) and a few drops of dimethylformamide were added to a solution of the title compound from Example 145 (86 mg, 0.14 mmol) in methylene chloride. The reaction mixture was stirred at room temperature for 1 h then concentrated in vacuo. The crude product was re-dissolved in anhydrous dichloroethane, and acetamide oxime (16 mg, 0.21 mmol) was added along with a few drops of dimethylformamide to increase solubility. The reaction was heated to and maintained at reflux overnight. Once the reaction cooled to room temperature, the solvent was removed through evaporation. The oil was taken up in methylene chloride, washed with water, then brine, dried over anhydrous sodium sulfate, filtered and concentrated. The title compound was obtained by preparative thin layer chromatography using 50% EtOAc/hexane. 1H NMR (CDCl3, 600 MHz) δ 8.15 (s, 1H), 7.86 (s, 1H), 7.71 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.43-7.56 (m, 3H), 7.35 (d, J=7.8 Hz, 1H), 7.07 (m, 1H), 4.20-4.60 (m, 4H), 3.81 (s, 3H), 3.70 (m, 3H), 2.46 (s, 3H). LC-MS (M+1) 647.9 (4.40 min).
Reaction SMILES: CC[O-].[Na+].[CH3:5][N:6]1[C:10]([C:11]2[O:15][CH:14]=[N:13][C:12]=2[CH3:16])=[N:9][NH:8][C:7]1=[S:17].Br[CH2:19][CH2:20][CH2:21][Cl:22]>CCO>[Cl:22][CH2:21][CH2:20][CH2:19][S:17][C:7]1[N:6]([CH3:5])[C:10]([C:11]2[O:15][CH:14]=[N:13][C:12]=2[CH3:16])=[N:9][N:8]=1
Reactant: Cc1ncoc1-c1n[nH]c(=S)n1C
Reactant: ClCCCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ncoc1-c1nnc(SCCCCl)n1C
Temperature: 25 °C

Procedure:
NaOEt (21% solution in EtOH, 2.08 vol, 1.1 eq) was added to EtOH (20 vol) under nitrogen atmosphere. 4-Methyl-5-(4-methyl-1,3-oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (respectively a tautomeric form thereof; 290 g, 1 wt) was added in one portion and the resulting mixture stirred at 25±2° C. until a clear solution was obtained. Then 1-bromo-3-chloropropane (0.54 vol, 1.1 eq) was added and the solution stirred at 40° C. for 24 h then cooled to 25° C. After filtration water (20 vol) was added and the ethanolic phase was removed by vacuum distillation (internal temperature ˜40° C.). The mixture was extracted with EtOAc (41 vol). The aqueous layer was removed and the organic phase was evaporated to dryness. Dichloromethane (4 vol) was added. The organic solution is purified through a short silica gel column (18 wt of silica), eluting with EtOAc (200 vol) to give the title compound as a solid foam (267.64 g, 66%).