Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][N:26]1[C:30]2[CH:31]=[C:32]([C:35]([OH:37])=O)[CH:33]=[CH:34][C:29]=2[N:28]=[N:27]1.CN(C=O)C.CCN(C(C)C)C(C)C.[CH2:52]([O:54][C:55](=[O:75])[C@H:56]([OH:74])[CH2:57][C@H:58]([NH2:73])[CH2:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([Cl:72])[CH:67]=2)=[CH:62][CH:61]=1)[CH3:53]>>[CH2:52]([O:54][C:55](=[O:75])[C@H:56]([OH:74])[CH2:57][C@H:58]([NH:73][C:35]([C:32]1[CH:33]=[CH:34][C:29]2[N:28]=[N:27][N:26]([OH:25])[C:30]=2[CH:31]=1)=[O:37])[CH2:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([Cl:72])[CH:67]=2)=[CH:62][CH:61]=1)[CH3:53]
Reactant: O=C(O)c1ccc2nnn(O)c2c1
Reactant: CCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1ccc2nnn(O)c2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.3 %

Procedure:
HATU (328 mg, 862 μmol) was added to a solution of 1-hydroxy-1H-1,2,3-benzotriazole-6-carboxylic acid (154 mg, 862 μmol) in DMF (1.5 mL, 19.5 mmol) and the resulting mixture was stirred at room temperature for 10 minutes. DIPEA (0.3 mL, 1.7 mmol) was added to the mixture, followed by (2R,4R)-4-amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester (200 mg, 575 μmol) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and the resulting residue was purified by reverse phase chromatography (35-80% MeCN in water with 0.05% TFA) to yield the title compound (197 mg) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:6]([CH:7]([CH3:9])[CH3:8])[NH:5][C:4](=[O:10])[CH:3]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[CH3:29]>>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3]1[C:4](=[O:10])[NH:5][CH:6]([CH:7]([CH3:9])[CH3:8])[C:2]=1[OH:1])=[C:23]2[CH3:29]
Reactant: O=Cc1ccccc1
Reactant: CC(C)C1NC(=O)C=C1O
Reactant: Cc1c[nH]c2ccc(F)cc12
Product: Cc1c(C(C2=C(O)C(C(C)C)NC2=O)c2ccccc2)[nH]c2ccc(F)cc12

Procedure:
Using general procedure C, 4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one (Lit. 11) was reacted with benzaldehyde and 5-fluoro-3-methyl-1H-indole to give the title compound as a yellow solid. MS: 377.1 ([M−H]−).
Reaction SMILES: [CH3:1][NH:2][CH:3]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[CH3:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:17](NC(C1SC=CC=1)CC1C=CC=CC=1)C>>[CH2:1]([NH:2][CH:3]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[CH3:16])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:17].[CH3:16][C:15]1[CH:14]=[CH:13][S:12][C:11]=1[CH:3]([NH2:2])[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CNC(Cc1ccccc1)c1sccc1C
Reactant: CCNC(Cc1ccccc1)c1cccs1
Product: CCNC(Cc1ccccc1)c1sccc1C
Product: Cc1ccsc1C(N)Cc1ccccc1

Procedure:
By following essentially the same procedure as described for Example 2 but substituting; N-methyl-α-(3-methyl-2-thienyl)benzeneethanamine; N-ethyl-α-(2-thienyl)benzeneethanamine; or N-ethyl-α-(3-methyl-2-thienyl)benzeneethanamine for the α-(3-methyl-2-thienyl)benzeneethanamine results in the preparation of; N-methyl-N-[l-(3-methyl-2-thienyl)-2-phenylethyl]-2-aminoacetamide (Z)-2-butenedioate (1:2) salt (mp 128°-130° C.); N-ethyl-N-[l-(2-thienyl)-2-phenylethyl]-2-aminoacetamide (Z)-2-butenedioate (1:1) salt (mp 134°-138° C.); or N-ethyl-N-[1-(3-methyl-2-thienyl)-2-phenylethyl]-2-aminoacetamide (Z)-2-butenedioate (1:1.5) salt (mp 110°-112° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)=[N:10][C:9]=2[C:23]([NH:25][C:26]2[S:27][CH:28]=[CH:29][N:30]=2)=[O:24])=[CH:4][CH:3]=1.CO.[CH:33](=O)[CH2:34][CH2:35][CH2:36][CH:37]=O.C([BH3-])#N.[Na+]>O1CCCC1.O>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11]2[NH:12][C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:1]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:7][CH:6]=3)=[C:9]([C:23]([NH:25][C:26]3[S:27][CH:28]=[CH:29][N:30]=3)=[O:24])[N:10]=2)=[CH:18][CH:17]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)c1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(N)cc3)[nH]2)cc1
Reactant: O=CCCCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2nc(C(=O)Nc3nccs3)c(-c3ccc(N4CCCCC4)cc3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 408 h
Yield: 10.3 %

Procedure:
5-(4-Aminophenyl)-2-(4-tert-butylphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (1.0 g) obtained in Example 77 was dissolved in tetrahydrofuran (55 ml), methanol (55 ml) and KH2PO4-Na2HPO4 buffer (pH 6.5, 70 ml), and 25% glutaraldehyde aqueous solution (1.22 g) and sodium cyanoborohydride (1.32 g) were added under ice-cooling. The mixture was stirred at room temperature for 17 days. Water (100 ml) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was subjected to silica gel column chromatography to give the objective 2-(4-tert-butylphenyl)-5-(4-piperidinophenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide (0.12 g), melting point 250-252° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:33](O)[C:34]([F:37])([F:36])[F:35]>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:17])[C@@H:4]([C:5]#[C:6][C:7](=[O:9])[O:8][CH2:33][C:34]([F:37])([F:36])[F:35])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)O)C1(C)C
Reactant: OCC(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)OCC(F)(F)F)C1(C)C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
4 g of the product of Step A and 3.5 g of dicyclohexylcarbodiimide were added to a solution of 20 ml of methylene chloride and 1 ml of pyridine and the reaction mixture was stirred for 1 hour. 2.15 g of trifluoroethanol and 5 ml of methylene chloride were then added to the mixture which was stirred at 20° C. for 16 hours and was filtered. The filtrate was rinsed with methylene chloride and the filtrate was evaporated to dryness. The residue was taken up in ether and the solution was washed with N hydrochloric acid, then with water and dried and evaporated to dryness. The 5 g of residue was chromatographed over silica gel and was eluted with a 95-5 benzene-ethyl acetate mixture to obtain 3.5 g of 1,1-dimethylethyl(1R,cis)2,2-dimethyl-3-[3-oxo-3-(2,2,2-trifluoroethoxy)-1-propynyl]-cyclopropane-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].[OH-].[K+].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24]>CC(C)=O>[F:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[CH2:16][N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[N:7]1
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Reactant: Fc1ccc(CBr)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc2c1cnn2Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
To a solution of 4-nitro-1H-indazole (0.200 g, 1.226 mmol) in acetone (3 mL) cooled to 0° C., was added KOH (0.103 g, 1.839 mmol). After 15 minutes at 0° C., 1-(bromomethyl)-2,4-difluorobenzene (0.173 mL, 1.349 mmol) was added. The mixture was allowed to stir at ambient temperature overnight, concentrated and the residue purified on silica gel (5-25% EtOAc in hexanes) to provide 1-(2,4-difluorobenzyl)-4-nitro-1H-indazole (0.142 g, 40% yield) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C@@H:5]([CH3:9])[C:6](O)=[O:7].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([NH2:28])=[N:24]1>C1COCC1.C(N(CC)CC)C>[CH3:9][C@@H:5]([C:6]([NH:28][C:25]1[CH:26]=[CH:27][N:23]([CH3:22])[N:24]=1)=[O:7])[CH2:4][C:3]([O:2][CH3:1])=[O:10]
Reactant: Cn1ccc(N)n1
Reactant: COC(=O)C[C@@H](C)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C[C@@H](C)C(=O)Nc1ccn(C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2R)-4-methoxy-2-methyl-4-oxobutanoic acid (0.30 mL) and DMF (20 μL) in THF (5.0 mL) was added oxalyl chloride (0.25 mL). The reaction mixture was stirred at room temperature for 3 hr, and 1-methyl-1H-pyrazol-3-amine (200 mg) and triethylamine (0.62 mL) were added thereto. The reaction mixture was stirred at room temperature for 15 hr, and extracted with ethyl acetate. The extract was washed with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (345 mg).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.S([O-])([O-])(=O)=O.[Mg+2].C(N(CC)CC)C.Cl.[NH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[N:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: O=Cc1ccco1
Reactant: CCOC(=O)CCN
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN=Cc1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
2-Furaldehyde (10 g) was dissolved in 170 mL of methylene chloride, then 10 g of magnesium sulfate, 16 mL of triethylamine and 16 g of ethyl 3-aminopropionate hydrochloride were successively added thereto and the mixture was stirred overnight at room temperature. The reaction solution was poured over 100 mL of water, the mixture was subjected to extraction with methylene chloride and the solvent was evaporated therefrom in vacuo. The residue was dissolved in 100 mL of ethyl acetate, washed with water and a saturated solution of sodium chloride successively and dried over anhydrous magnesium sulfate and the solvent was evaporated therefrom in vacuo to give 19.2 g of the objective compound as yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[C:12]([CH3:13])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[CH3:14].O1CCCC1.[H-].[Na+].[C:22](Cl)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>O>[C:22]([NH:1][C:2]1[C:3]([CH3:14])=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][C:12]=1[CH3:13])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]
Reactant: CCOC(=O)c1cc(C)c(N)c(C)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cc(C)c(NC(=O)OCc2ccccc2)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 4-amino-3,5-dimethylbenzoate (2.0 g) was added to a tetrahydrofuran (THF) suspension of sodium hydride (0.82 g) in a nitrogen atmosphere and the mixture was stirred at room temperature for 30 min. Subsequently, carbobenzoxychloride (4.4 ml) was added to the suspension and the mixture was stirred overnight. A small amount of water was added to the reaction solution and the mixture was poured into ice water, followed by extraction with ethyl acetate. Following washing and drying (with magnesium sulfate), the solvent was distilled off under vacuum. The resulting crystal was recovered by filtration in the presence of ethanol and dried under vacuum to yield the end product (3.2 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([Br:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([OH:15])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:28]([NH2:31])[CH:29]=[CH2:30]>CN(C)C=O>[CH2:28]([NH:31][C:13]([C:3]1[N:4]=[N:5][C:6]2[C:11]([C:2]=1[NH2:1])=[CH:10][CH:9]=[CH:8][C:7]=2[Br:12])=[O:15])[CH:29]=[CH2:30]
Reactant: Nc1c(C(=O)O)nnc2c(Br)cccc12
Reactant: C=CCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: C=CCNC(=O)c1nnc2c(Br)cccc2c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To an ice-cooled suspension of 4-amino-8-bromo-cinnoline-3-carboxylic acid (360 mg, 1.34 mmol) in dimethylformamide (5 mL) was added CDI (370 mg, 2.3 mmol) and the mixture was stirred at room temperature for 1 hour. Additional DMF (14 mL) was added to enable stirring. After an additional 1 hour at room temperature, the mixture was treated with allyl amine (120 uL, 91 mg, 1.60 mmol) in one portion. The reaction was stirred at room temperature for 1 hour and then concentrated. Purification on silica gel using a gradient of 20 to 80% ethyl acetate in hexanes afforded the title compound (300 mg, 73%). 1H NMR (300.132 MHz, CDCl3) δ 8.14 (dd, J=7.4, 1.0 Hz, 1H), 7.83 (dd, J=8.4, 1.0 Hz, 1H), 7.51 (dd, J=8.4, 7.5 Hz, 1H), 6.04-5.91 (m, 1H), 5.33 (dq, J=17.1, 1.6 Hz, 1H), 5.21 (dq, J=10.4, 1.4 Hz, 1H), 4.15 (ddt, J=6.2, 5.8, 1.6 Hz, 2H). MS APCI, m/z=307/309 (M+H). HPLC 1.59 min.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH2:15](O)[CH3:16].C(Cl)(Cl)Cl>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCO
Reactant: O=C(O)CCCCCCCCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)CCCCCCCCCCBr
Temperature: 25 °C
Yield: 72 %

Procedure:
1000 g of 90% pure 11-bromoundecanoic acid (equivalent to 3.39 mol), 304.0 g (6.60 mol) of ethanol and 20.0 g of p-toluenesulfonic acid were introduced into 400 ml of chloroform in an experimental apparatus with water trap (for entrainers with higher specific gravity than water). The mixture was heated under reflux until water no longer separated out (about 6 hours). After the solution had cooled to room temperature it was washed successively with 1 l of water, 500 ml of saturated NaHCO3 solution and 1 l of water. The solvent was removed in vacuo. Vacuum distillation (b.p. 131-133° C./1 mbar) resulted in 716.3 g (2.44 mol, 72%) of ethyl 11-bromoundecanoate.
Reaction SMILES: Cl.[O:2]=[C:3]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:4][NH:5][C:6](=[O:20])[C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>C(Cl)Cl>[C:27]1([S:33]([N:24]2[CH2:23][CH2:22][N:21]([C:3](=[O:2])[CH2:4][NH:5][C:6](=[O:20])[C:7]3[CH:8]=[CH:9][C:10]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:11][CH:12]=3)[CH2:26][CH2:25]2)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: O=C(NCC(=O)N1CCN(S(=O)(=O)c2ccccc2)CC1)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 47 %

Procedure:
TEA (0.074 mL, 0.53 mmol) was added dropwise to a chilled (0° C.) mixture of N-(2-Oxo-2-piperazin-1-yl-ethyl)-4-phenoxy-benzamide hydrochloride (100 mg, 0.27 mmol) in DCM (5 mL). After 5 minutes, benzenesulfonyl chloride (0.032 mL, 0.26 mmol) was added and the resulting mixture was stirred at room temperature for 5 hours. DCM was added, followed by the addition of iced water. The product was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (using silica gel of mesh size of 60-120 and 70:30 EtOAc:hexane as eluent) to afford N-[2-(4-benzenesulfonyl-piperazin-1-yl)-2-oxo-ethyl]-4-phenoxy-benzamide in 47% yield. LC-MS purity: 98%, 1H NMR (DMSO-D6): δ 8.5 (t, 1H), 7.9 (d, 2H), 7.8 (m, 3H), 7.6 (m, 2H), 7.4 (t, 2H), 7.2 (t, 1H), 7.1 (d, 2H), 7 (d, 2H), 4.1 (d, 2H), 3.6 (m, 4H), 2.9 (m, 4H).
Reaction SMILES: [C:1]([N:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:7]([C:13]([C:15]2[CH:20]=[CH:19]C(C3OCC(C)(C)N=3)=[CH:17][CH:16]=2)=[CH2:14])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl.ClCCl.[C:34]([O:37]CC)(=[O:36])[CH3:35]>C(O)C>[C:1]([N:5]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:7]([C:13]([C:15]2[CH:16]=[CH:17][C:35]([C:34]([OH:37])=[O:36])=[CH:19][CH:20]=2)=[CH2:14])=[N:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=C(c1ccc(C2=NC(C)(C)CO2)cc1)c1cc(C(C)C)n(C(C)(C)C)n1
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: C=C(c1ccc(C(=O)O)cc1)c1cc(C(C)C)n(C(C)(C)C)n1
Temperature: 100 °C

Procedure:
To 5 ml of 130 mg of α-(1-tert-butyl-5-isopropylpyrazol-3-yl)-4-(4,4-dimethyl-1,3-oxazolin-2-yl)styrene in ethanol was added 0.4 ml of a 3N aqueous solution of an acid at room temperature. The resulting mixture was heated under reflux for 30 minutes. To the reaction mixture was added a 5N aqueous solution of sodium hydroxide to adjust its pH to 11, followed by extraction with dichloromethane. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced -pressure. To a solution of the residue in 3 ml of 1,4-dioxane were added 100 mg of lithium hydroxide and the resulting mixture was heated at 100° C. for 2 hours. After the completion of the reaction, a 3N aqueous solution of hydrochloric acid was added to adjust the pH to 5, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue so obtained was subjected to chromatography on a silica gel column (developing solvent: 50% dichloromethane/ethyl acetate), whereby 4 mg of the title compound were obtained as a pale yellow solid.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C@H:14]1[CH2:20][N:19]2[C:21]([C:24]([OH:27])([CH3:26])[CH3:25])=[CH:22][N:23]=[C:18]2[C@H:17]([NH:28]C(=O)OC(C)(C)C)[CH2:16][CH2:15]1.[CH3:36]O>>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[C@H:14]1[CH2:20][N:19]2[C:21]([C:24]([O:27][CH3:36])([CH3:26])[CH3:25])=[CH:22][N:23]=[C:18]2[C@H:17]([NH2:28])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2c(F)cccc2F)Cn2c(C(C)(C)O)cnc21
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(C)(C)c1cnc2n1C[C@H](c1c(F)cccc1F)CC[C@H]2N
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Sulfuric acid (0.15 mL, 2.85 mmol) was added to a solution of tert-butyl [(6S,9R)-6-(2,6-difluorophenyl)-3-(1-hydroxy-1-methylethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]carbamate (120 mg, 0.285 mmol) in methanol (1.5 mL). The reaction mixture was heated to 60° C. After 3 h, the reaction was quenched with saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane (3×), washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 336.2 (M+1).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].F[B-](F)(F)F.[O:29]=[N+:30]=[O:31].C(=O)([O-])O.[Na+]>C(#N)C>[CH2:1]([N:7]1[CH2:8][CH:9]2[CH:11]([C:10]2([C:14]2[CH:19]=[CH:18][C:17]([N+:30]([O-:31])=[O:29])=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:15]=2)[CH3:13])[CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=[N+]=O
Reactant: CCCCCCN1CC2C(C1)C2(C)c1cccc(NC(C)=O)c1
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCCCCN1CC2C(C1)C2(C)c1ccc([N+](=O)[O-])c(NC(C)=O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
To a solution of N-[3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]acetamide (Preparation 45, 1.5 g, 4.78 mmol) in acetonitrile (20 ml) at 0° C. was added nitronium tetrafluoroborate (1.0 g, 7.53 mmol) in several portions over 5 minutes. The mixture was stirred at 0° C. for 30 minutes and then saturated sodium hydrogen carbonate solution (30 ml) was added. The aqueous mixture was extracted with ethyl acetate (3×15 ml) and the combined extracts were dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica column chromatography eluting with ethyl acetate:hexane (50:50) to afford the title compound (534 mg, 32%) as pale yellow platelets.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:21]2[CH:22]=[N:23][C:24]([C:27](=[O:29])[CH3:28])=[N:25][CH:26]=2)=[N:6][CH:7]=1.[CH3:30][Mg]Br>C1COCC1.[NH4+].[Cl-]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:21]2[CH:22]=[N:23][C:24]([C:27]([OH:29])([CH3:30])[CH3:28])=[N:25][CH:26]=2)=[N:6][CH:7]=1
Reactant: C[Mg]Br
Reactant: CC(=O)c1ncc(-c2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(O)c1ncc(-c2nc(-c3ccc(F)cc3)oc2Sc2ccc(Cl)cn2)cn1
Yield: 47.4 %

Procedure:
A solution of 1-(5-{5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}pyrimidin-2-yl)ethanone (Example 73) (12 mg, 0.03 mmol) in THF (5 mL) was treated with methylmagnesium bromide (0.09 mL, 0.3 mmol, 3.0 M in THF) at it. Upon completion of the reaction as judged by TLC analysis, the solution was diluted with saturated aq NH4Cl solution and extracted with EtOAc. The organic layer was removed, dried over MgSO4, filtered and concentrated giving rise to an oil. The oil was purified on silica gel to afford the title compound (6.3 mg). LC/MS: m/e 443.0 (M+H)+. 1H NMR (500 MHz, Acetone-d6): δ 1.54 (s, 6H), 4.56 (s, 1H), 7.39 (m, 2H), 7.47 (d, J=8.5 Hz, 1H), 7.82 (m, 1H), 8.25 (m, 2H), 8.45 (d, J=2.5 Hz, 1H), 9.39 (s, 2H).
Reaction SMILES: [CH3:1]OC1C=CC=CC=1CCN.C(N)CC1C=CC=CC=1.[CH3:21][S:22][C:23]1[NH:28][C:27](=[O:29])[N:26]=[C:25]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[N:24]=1>>[CH3:1][N:28]1[C:23]([S:22][CH3:21])=[N:24][C:25]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[N:26][C:27]1=[O:29]
Reactant: COc1ccccc1CCN
Reactant: CSc1nc(-c2ccncc2)nc(=O)[nH]1
Agent: NCCc1ccccc1
Product: CSc1nc(-c2ccncc2)nc(=O)n1C

Procedure:
By analogy with the method described in example 1 (step 1.2), using 2-(2-Methoxy-phenyl)-ethylamine (commercially available) in place of phenethylamine and 6-Methylsulfanyl-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one (synthesis as described in U.S. Pat. No. 4,406,897) in place of 1-Methyl-6-methylsulfanyl-4-pyridin-4-yl-1H-[1,3,5]triazin-2-one, to afford the product which was transformed into the hyrdochloride salt in the usual manner to give 0.11 g (51%) of a white solid.