Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([C:10]3[N:14]([CH3:15])[CH:13]=[N:12][C:11]=3[C:16]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][N:17]=3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[CH3:25]O>S(=O)(=O)(O)O>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:10]3[N:14]([CH3:15])[CH:13]=[N:12][C:11]=3[C:16]3[CH:21]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[CH:19]=[CH:18][N:17]=3)=[CH:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cn1cnc(-c2cc(C(=O)O)ccn2)c1-c1ccc(C2CC2)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccnc(-c2ncn(C)c2-c2ccc(C3CC3)cc2)c1
Yield: 94 %

Procedure:
To a mixture of 2-[5-(4-cyclopropylphenyl)-1-methyl-1H-imidazol-4-yl]pyridine-4-carboxylic acid (26 mg, 0.08 mmol, Example 7) in MeOH (5 mL) was added 3 drops of concentrated sulfuric acid. The reaction mixture was heated to reflux for 1 hr. It was then concentrated, separated between water and ethyl acetate. Organic layer dried and concentrated to give the title compound as light pink solid (25 mg, 94%). 1H NMR (400 MHz, DMSO-d6): δ 0.77 (2H, m), 1.02 (2H, m), 2.02 (1H, m), 3.54 (3H, s), 3.85 (3H, s), 7.22 (2H, d&s, J=7.8 Hz), 7.36 (2H, d&s, J=8.1 Hz), 7.64 (1H, d, J=4.4 Hz), 7.98 (1H, s), 8.51 (1H, s), 8.63 (1H, s). [M+H] Calc'd for C20H19N3O2, 334. Found, 334.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][CH2:16][O:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][O:23]/[N:24]=[C:25](/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)\[CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[CH:20][CH:19]=1.CO.Cl>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:6][C:5]=1[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:22][O:23]/[N:24]=[C:25](/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)\[CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:38][CH:39]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CO/N=C(\CCC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of methyl E-4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyloxyimino]-4-phenylbutyrate (460 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain E-4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyloxyimino]-4-phenylbutyric acid (443 mg, yield 99%) as colorless crystals. m.p. 106-107° C.
Reaction SMILES: C([CH:3]([C:9]1[CH:14]=[C:13]([C:15]2[CH:16]=[C:17]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[O:30][CH3:31])=[CH:22][N:21]([S:32]([C:35]4[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=4)(=[O:34])=[O:33])[C:18]3=[N:19][CH:20]=2)[N:12]=[CH:11][N:10]=1)[C:4]([N:6]([CH3:8])[CH3:7])=[O:5])#N.C(OO)(=[O:44])C.S(=O)(O)[O-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:23]1[C:17]2[C:18](=[N:19][CH:20]=[C:15]([C:13]3[N:12]=[CH:11][N:10]=[C:9]([C:3](=[O:44])[C:4]([N:6]([CH3:8])[CH3:7])=[O:5])[CH:14]=3)[CH:16]=2)[N:21]([S:32]([C:35]2[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH:22]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(C(C#N)C(=O)N(C)C)ncn3)cc12
Reactant: CC(=O)OO
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3cc(C(=O)C(=O)N(C)C)ncn3)cc12
Temperature: 0 °C
Yield: 64.4 %

Procedure:
2-Cyano-2-{6-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrimidin-4-yl}-N,N-dimethyl-acetamide (500 mg, 0.88 mmole) was suspended in tetrahydrofuran (11 mL) and cooled to 0° C. in an ice bath. Peroxy acetic acid (32% in acetic acid, 174 mg, 2.29 mmole) was added and after 10 min, the heterogeneous solution was removed from the ice bath and maintained at ambient temperature for 6 h. Sodium bisulfite (918 mg, 8.83 mmole) in water (10 mL) was added, followed by saturated aqueous sodium bicarbonate (20 mL) and the mixture extracted with ethyl acetate (3×30 mL). The combined organic portions were dried over magnesium sulfate, filtered, and concentrated to dryness. Silica gel chromatography of the crude residue afforded 2-{6-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyrimidin-4-yl}-N,N-dimethyl-2-oxo-acetamide (315 mg, 89% yield) as a clear residue. MS: m/z 402.2 (M+H+).
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]1[CH2:47][CH2:46][CH2:45][CH2:44]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]2[CH2:47][CH2:46][CH2:45][CH2:44]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCC1
Product: CCN(Cc1ccc(OCCN2CCCC2)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 13.5 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.7 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CCCCC.[CH2:28]([N:35]1[CH2:40][CH2:39][C:38](=[O:41])[CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:17])[CH2:16][C:38]2([OH:41])[CH2:39][CH2:40][N:35]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:36][CH2:37]2)=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)CC2(O)CCN(Cc3ccccc3)CC2)cc1
Reaction time: 2 h
Yield: 65.4 %

Procedure:
30 ml of tetrahydrofuran was added to 2.00 g of N-t-butoxycarbonyl-4-acetylaniline, and 8.8 ml of a 1.7M t-butyl lithium·pentane solution was added thereto under an argon stream at -78° C. Then, 1.41 g of 1-benzyl-4-piperidone was dissolved in 20 ml of tetrahydrofuran, and the solution was added dropwise. After stirring for 2 hours, a saturated ammonium chloride aqueous solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the obtained residue was applied to silica gel column chromatography to obtain 2.07 g of the title compound as white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][C:43]([C:44](O)=[O:45])=[CH:42][CH:41]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:44](=[O:45])[C:43]1[CH:47]=[CH:48][C:40]([CH2:39][N:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]3([CH2:31][O:30][C:29]4[CH:32]=[C:33]5[C:37](=[CH:38][C:28]3=4)[CH2:36][CH2:35][O:34]5)[C:19]2=[O:18])=[CH:41][CH:42]=1
Reactant: Cc1cccc(C)c1N
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: Cc1cccc(C)c1NC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 2,6-dimethylaniline to replace cyclohexanemethylamine, and 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(2,6-dimethylphenyl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (28%) as a colorless solid: mp>250° C.; 1H NMR (300 MHz, CDCl3) δ7.95-7.89 (m, 2H), 7.51-7.45 (m, 2H), 7.37 (s, 1H), 7.24-7.02 (m, 6H), 6.82-6.75 (m, 1H), 6.49 (s, 1H), 6.44 (s, 1H), 5.04 (ABq, 2H), 4.86 (ABq, 2H), 4.60-4.50 (m, 2H), 3.12-2.91 (m, 2H), 2.27 (s, 6H); 13C NMR (75 MHz, CDCl3) δ178.0, 165.3, 161.9, 161.4, 141.8, 139.8, 135.5, 134.1, 133.6, 132.7, 128.8, 128.3, 127.9, 127.8, 127.6, 124.0, 123.7, 120.0, 118.8, 109.1, 93.3, 80.7, 72.4, 57.8, 43.8, 29.0, 18.5; MS (ES+) m/z 517.2 (M+1).
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[O-]CC.[Na+].[NH2:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O>C(O)C>[NH2:2][C:1]1[C:3]([C:4]([NH2:6])=[O:5])=[CH:14][C:13]2[C:12](=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]=1
Reactant: N#CCC(N)=O
Reactant: Nc1ccccc1C=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cc2ccccc2nc1N
Temperature: 50 °C
Yield: 80.1 %

Procedure:
Cyanoacetamide (19.4 g., 0.23 mole) is added to a solution of sodium ethoxide (6.65 g., 0.29 mole) in absolute ethanol (460 ml.) maintained at 50° C. The mixture is stirred and o-aminobenzaldehyde (28.0 g., 0.23 mole) in absolute ethanol (100 ml.) added. After fifteen minutes stirring at 50° C., the reaction mixture is cooled in an ice bath, filtered and dried to give 34.5 g (84% yield) of product; m.p. 240°-242° C.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][C:11]2[C:13]([O:20][CH:21]([CH3:23])[CH3:22])=[CH:14][C:15]([C:17](O)=[O:18])=[CH:16][C:10]=2[O:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(O[N:41]1N=N[C:43]2[CH:44]=[CH:45][CH:46]=[N:47][C:42]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C=CC=CC=1N>CN(C=O)C>[N:47]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[NH:41][C:17]([C:15]1[CH:14]=[C:13]([O:20][CH:21]([CH3:22])[CH3:23])[C:11]2[CH2:12][CH:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[O:9][C:10]=2[CH:16]=1)=[O:18]
Reactant: CC(C)Oc1cc(C(=O)O)cc2c1CC(Cc1ccccc1)O2
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1ccccn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(C(=O)Nc2ccccn2)cc2c1CC(Cc1ccccc1)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.9 %

Procedure:
A mixture of 2-benzyl-4-isopropoxy-2,3-dihydro-benzofuran-6-carboxylic acid (220j) (0.5 g, 1.9 mmol), DIPEA (0.37 g, 2.85 mmol) and HATU (0.74 g, 1.94 mmol) in DMF (15 mL) was stirred at room temperature for 1 hr, and then pyridin-2-amine (0.18 g, 1.94 mmol) was added in one portion. The mixture was stirred at room temperature overnight. TLC (EtOAc/petroleum ether=1/2) indicated that the reaction was complete. The mixture was concentrated. The residue was purified by prep. HPLC to give the title compound (73 mg, 21% yield, TFA salt) as a white solid. 1H NMR (400 MHz, CDCl3): δ11.71 (br, 1H), 8.76 (d, 1H), 8.27 (d, 1H), 8.14 (t, 1H), 7.17˜7.46 (m, 9H), 4.96 (d, 1H), 4.78 (t, 1H), 2.82 (m, 1H), 2.67 (m, 1H), 2.19 (m, 1H), 1.96 (m, 1H), 1.32 (d, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][S:13](Cl)(=[O:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:31][NH:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1>C(Cl)Cl>[CH2:17]([CH:11]([CH2:12][S:13]([N:32]([CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)[CH3:31])(=[O:15])=[O:14])[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(OCc1ccccc1)C(Cc1ccccc1)CS(=O)(=O)Cl
Reactant: CNCCc1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCc1ccccn1)S(=O)(=O)CC(Cc1ccccc1)C(=O)OCc1ccccc1

Procedure:
To the resultant compound from Example 62 (1 mmol) in methylene chloride (10 mL) at -10° C. was added triethylamine (1.2 mmol) and 2-(2-methylaminoethyl)pyridine (1 mmol). After 30 min the mixture was evaporated, suspended in ethyl acetate, washed with saturated NaHCO3 solution, water, and brine, and then dried over Na2SO4 and evaporated. Chromatography of the residue on silica gel afforded the desired product.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[S:9][CH:10]=[CH:11][C:12]=1[NH:13][C:14](=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:7])(=O)[CH3:2].C(N(C(C)C)CC)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C(#N)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:14]([NH:13][C:12]2[CH:11]=[CH:10][S:9][C:8]=2[C:6]2[O:7][C:1]([CH3:2])=[N:4][N:5]=2)=[O:24])=[CH:17][CH:18]=1
Reactant: COc1ccc(CC(=O)Nc2ccsc2C(=O)NNC(C)=O)cc1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccc(CC(=O)Nc2ccsc2-c2nnc(C)o2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 8.8 %

Procedure:
To a solution of N-(2-(2-acetylhydrazinecarbonyl)thiophen-3-yl)-2-(4-methoxyphenyl)acetamide (300 mg, 0.86 mmol) in anh. acetonitrile (6 mL) was added diisopropylethylamine (0.8 mL, 4.84 mmol) and triphenylphosphine (396 mg, 1.51 mmol). After 5 min, hexachloroethane (292 mg, 1.23 mmol) was added to the reaction mixture and then stirred at room temperature overnight under N2(g) inlet. The reaction mixture was evaporated under reduced pressure, partitioned between ethyl acetate and H2O, dried (sodium sulfate), filtered and concentrated under reduced pressure. Purification by flash column chromatography (silica, 40:60 ethyl acetate/hexane) gave 2-(4-methoxyphenyl)-N-(2-(5-methyl-1,3,4-oxadiazol-2-yl)thiophen-3-yl)acetamide (25 mg, 9%). See James, C. A. et al., Tet. Lett. 47 (2006) 511-514. Method [7] m/z 330.0 (M+H); retention time=4.805. 1H-NMR (CDCl3) δ 10.15 (broad s, 1H), 8.18 (d, J=5.4 Hz, 1H), 7.43 (d, J=5.4 Hz, 1H), 7.31 (d, J=7.6 Hz, 2H), 6.92 (d, J=7.6 Hz, 2H), 3.81 (s, 3H), 3.75 (s, 2H), 2.75 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>CC#N>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(NS(C)(=O)=O)C1
Reaction time: 2.5 h

Procedure:
To a solution of (+/−)-3-amino-1N—BOC-pyrrolidine (0.5 g) in MeCN (10 mL) was added triethylamine (0.41 mL) then methanesulfonyl chloride (0.22 mL). The mixture was stirred for 2.5 h. An aqueous work-up followed by purification on silica gave 3-methanesulfonylamino-pyrrolidine-1-carboxylic acid tert-butyl ester (0.49 g).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(OC([NH:23][C@@H:24]([CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][C:38]([F:41])([F:40])[F:39])[C:25](O)=[O:26])=O)(C)(C)C>>[NH2:23][C@@H:24]([CH2:28][O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][C:38]([F:39])([F:40])[F:41])[C:25]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:26]
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1OC(F)(F)F)C(=O)O
Product: N[C@@H](COCc1ccccc1OC(F)(F)F)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 80 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(4-fluorophenoxy)aniline and (S)-2-(tert-butoxycarbonylamino)-3-(2-(trifluoromethoxy)benzyloxy)propanoic acid, gave (S)-2-amino-N-(4-(4-fluorophenoxy)phenyl)-3-(2-(trifluoromethoxy)benzyloxy)propanamide (150 mg, 80%).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[N:4]1)[CH3:2].[NH2:17][CH:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]1>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:21]2[N:20]=[CH:19][C:6]3[CH:5]=[N:4][N:3]([C:1]4[N:17]=[C:18]([NH:17][CH:18]5[CH2:24][CH2:23][CH2:22][CH2:21][NH:20][CH2:19]5)[CH:24]=[CH:23][CH:2]=4)[C:7]=3[CH:22]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)OC(=O)N1CCCCC(N)C1
Product: CCn1cc(-c2cc3c(cn2)cnn3-c2cccc(NC3CCCCNC3)n2)cn1
Yield: 2.8 %

Procedure:
Following the procedures as described in EXAMPLE 8 and starting with 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and tert-butyl 3-aminoazepane-1-carboxylate, 143 was obtained as an off-white solid (3.6 mg, 2.8%) over 2 steps. MS (ESI) m/z: 403.2 [M+H]+
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH:18]=[C:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH2:14][CH2:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].O1CCOC[CH2:23]1.COC(OC)OC.C1(C)C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1>[CH3:23][O:20][C:12]1[CH2:13][CH2:14][C@@:15]2([CH3:16])[C:10](=[CH:9][CH2:8][C@@H:7]3[C:17]2=[CH:18][CH2:19][C@@:2]2([CH3:1])[C@H:6]3[CH2:5][CH2:4][C:3]2=[O:21])[CH:11]=1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: C1COCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: c1ccncc1
Product: COC1=CC2=CC[C@@H]3C(=CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(C)CC1
Reaction time: 48 h

Procedure:
11.5 g of 4,9(11)-androstadiene-3,17-dione [U.S. Pat. No. 3,441,559 (1969)]in 200 ml of dioxane is reacted with 20 ml of orthoformic acid trimethyl ester and 100 mg of p-toluenesulfonic acid. After 48 hours, 5 ml of pyridine is added to the solution, the latter is concentrated under vacuum, the residue taken up in ethyl acetate, washed with water, and dried over sodium sulfate. After chromatography of the crude product with a hexane-ethyl acetate gradient on silica gel containing 2% triethylamine, 9.2 g of 3-methoxy-3,5,9(11)-androstatrien-17-one is isolated; mp 153.4° C.
Reaction SMILES: C[O-].[Na+].[C:4]1([C:10]2[CH:15]=[C:14](Cl)[N:13]=[N:12][C:11]=2[Cl:17])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:18]([O:20]CC)C.CCCCCC>CO>[Cl:17][C:11]1[N:12]=[N:13][C:14]([O:20][CH3:18])=[CH:15][C:10]=1[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOCC
Reactant: Clc1cc(-c2ccccc2)c(Cl)nn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Product: COc1cc(-c2ccccc2)c(Cl)nn1
Temperature: 25 °C

Procedure:
A commercial solution of 25 wt % sodium methoxide in methanol (0.49 mL, 2.0 mmol) was added drop wise to an ice-cooled solution of 4-phenyl-3,6-dichloropyridazine (1-1; 448 mg, 2.0 mmol) in dry methanol (10 mL). This solution was gradually warmed to room temperature over three hours. The solvent was evaporated and the residue dissolved in methylene chloride, washed with aq. NaHCO4, the organic layer dried over anhydrous Na2SO4, filtered and evaporated to give a 2:1 mixture of isomeric products. Upon chromatography on silica gel and elution with 15% ethyl acetate/hexane, the desired and major isomer was isolated. Trituration of this material with diethyl ether/hexane afforded 3-chloro-6-methoxy-4-phenylpyridazine as a white solid (2-1). NMR (CDCl3): δ7.49 (5H, br s), 6.96 (1H, s), 4.17 (3H, s).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:37]=[CH:36][C:16]([CH2:17][N:18]2[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:19]2)=[CH:15][CH:14]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:37]=[CH:36][C:16]([CH2:17][N:18]2[CH:22]=[C:21]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])[C:20]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:19]2)=[CH:15][CH:14]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc4ccccc4n3C)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1c(COc2ccc(Cn3cc(CCC(=O)O)c(-c4ccccc4)n3)cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
After a mixture of ethyl 3-[1-[4-(1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionate (520 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (2 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[1-[4-(1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]-3-phenyl-1H-pyrazol-4-yl]propionic acid (420 mg, yield: 86%). This was recrystallized from ethanol-hexane. Melting point: 225–226° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([NH2:30])=O)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[Si]([N:35]=[N+:36]=[N-:37])(C)(C)C>COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]3[NH:30][N:37]=[N:36][N:35]=3)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(N)=O)cc3)c(-c3ccc(F)cc3)sc2c1
Solvent: COCCOC
Product: COc1ccc2c(Oc3ccc(/C=C/c4nnn[nH]4)cc3)c(-c3ccc(F)cc3)sc2c1
Temperature: 180 °C
Yield: 71.4 %

Procedure:
To a microwave vial, (E)-3-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylamide (41 mg, 0.098 mmol) and Bu2SnO (2.433 mg, 9.77 mol) were suspended in DME (3 mL). The vial was charged with TMSN3 (0.013 mL, 0.098 mmol) and the reaction was heated for 60 min at 180° C. under microwave radiation. The reaction mixture was filtered to remove solids and concentrated onto silica gel. The crude material was purified by column chromatography (SiO2, 1-20% DCM/MeOH) to afford (E)-5-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-1H-tetrazole (31 mg, 0.070 mmol, 71.4% yield) as an orange solid. 1H NMR (400 MHz, CD3OD) δ ppm=3.78 (s, 3H) 6.80-6.91 (m, 3H) 6.96-7.07 (m, 3H) 7.19 (d, J=8.59 Hz, 1H) 7.34 (d, J=2.53 Hz, 1H) 7.35-7.52 (m, 3H) 7.58-7.74 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:24]4[C:33]5[C:28](=[CH:29][C:30]([C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[CH:20][CH:21]=3)[CH2:13][CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(N2CCN(Cc3ccc(N)cc3)CC2)c1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Product: COc1cccc(N2CCN(Cc3ccc(Nc4ccnc5cc(C(F)(F)F)ccc45)cc3)CC2)c1

Procedure:
In the manner given in Example 1C, 1-(m-methoxyphenyl)-4-[(4-aminophenyl)methyl]piperazine and 4-chloro-7-(trifluoromethyl)quinoline are reacted together at reflux to give 4-[[4-[[4-(m-methoxyphenyl)-1-piperazinyl]methyl]phenyl]amino]-7-(trifluoromethyl)quinoline.