Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7]([CH2:10][OH:11])[N:8]=[CH:9][N:4]2[CH:3]=1.C[N+]1([O-])CCOCC1>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1][C:2]1[S:6][C:5]2=[C:7]([CH:10]=[O:11])[N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: OCc1ncn2cc(Br)sc12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=Cc1ncn2cc(Br)sc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 20.7 %

Procedure:
Dried 4A molecular sieves (40 mg) and tetra-n-propylammonium perruthenate (16 mg, 0.05 mmol) were added to a solution of 2-bromo-7-hydroxymethylimidazo[5,1-b]thiazole (53 mg, 0.23 mmol) and N-methylmorpholine-N-oxide (92 mg, 0.79 mmol) in dichloromethane (2 ml), and the mixture was stirred at room temperature for 3 days. The reaction solution was purified by column chromatography on silica gel (ethyl acetate:methanol=60:1) to give 2-bromoimidazo[5,1-b]thiazole-7-carbaldehyde (11 mg, 21%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][O:15][C:14]3[N:18]=[CH:19][C:20]([C:22]#[N:23])=[CH:21][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:26][CH2:27][C:28](N)([CH3:30])[CH3:29].[S]>C1(C)C=CC=CC=1>[CH3:29][C:28]1([CH3:30])[CH2:27][NH:26][C:22]([C:20]2[CH:19]=[N:18][C:14]3[O:15][CH2:16][CH2:17][N:12]([S:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:24])([F:1])[F:25])=[CH:4][CH:5]=4)(=[O:10])=[O:11])[C:13]=3[CH:21]=2)=[N:23]1
Reactant: CC(C)(N)CN
Reactant: N#Cc1cnc2c(c1)N(S(=O)(=O)c1ccc(C(F)(F)F)cc1)CCO2
Agent: [S]
Solvent: Cc1ccccc1
Product: CC1(C)CNC(c2cnc3c(c2)N(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCO3)=N1
Temperature: 95 °C
Reaction time: 2 h
Yield: 32.1 %

Procedure:
To a suspension of 1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbonitrile (30 mg, 0.081 mmol) in toluene (2 mL) was added 1,2-diamino-2-methylpropane (200 μL, 1.908 mmol) and sulfur (20.84 mg, 0.081 mmol). The reaction was heated to 95° C. and stirred at that temperature for 2 h. The reaction mixture was load directly onto a silica gel column and was purified by flash column chromatography using a gradient elution of hexanes with 20-100% EtOAc to provide 7-(4,4-dimethyl-4,5-dihydro-1H-imidazol-2-yl)-1-(4-(trifluoromethyl)phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (12 mg, 0.026 mmol, 31.9% yield) as an off white solid. LCMS (+ESI) m/z=441.1 [M+H]+; 1H-NMR (CDCl3) δ 8.54 (d, 1H), 8.50 (d, 1H), 7.81 (d, 2H), 7.76 (d, 2H), 3.94 (dd, 2H), 3.87 (dd, 2H), 3.57 (br s, 2H), 1.37 (s, 6H).
Reaction SMILES: C12(COC3C(C4CC4)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[CH:26]1([C:29]2[C:30]([O:39][CH2:40][C:41]34[CH2:50][CH:45]5[CH2:46][CH:47]([CH2:49][C:43]([OH:51])([CH2:44]5)[CH2:42]3)[CH2:48]4)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34](O)=[O:35])[CH2:28][CH2:27]1.C([CH:54]1[CH2:57][N:56]([S:58]([NH2:61])(=[O:60])=[O:59])[CH2:55]1)#N.N1(S(N)(=O)=O)CCC1>>[N:56]1([S:58]([NH:61][C:34](=[O:35])[C:33]2[CH:37]=[C:29]([CH:26]3[CH2:28][CH2:27]3)[C:30]([O:39][CH2:40][C:41]34[CH2:50][CH:45]5[CH2:46][CH:47]([CH2:49][C:43]([OH:51])([CH2:44]5)[CH2:42]3)[CH2:48]4)=[CH:31][C:32]=2[F:38])(=[O:59])=[O:60])[CH2:55][CH2:54][CH2:57]1
Reactant: N#CC1CN(S(N)(=O)=O)C1
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(O)(C4)C2)C3)cc1F
Agent: NS(=O)(=O)N1CCC1
Agent: O=C(O)c1cc(C2CC2)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Product: O=C(NS(=O)(=O)N1CCC1)c1cc(C2CC2)c(OCC23CC4CC(CC(O)(C4)C2)C3)cc1F

Procedure:
Following the procedure as described in Example 230 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-2-fluoro-4-((3-hydroxyadamantan-1-yl)methoxy)benzoic acid and to replace 3-cyanoazetidine-1-sulfonamide with azetidine-1-sulfonamide, the title compound was obtained as colorless solid (0.08 g, 65%): 1H NMR (300 MHz, DMSO-d6) δ 11.60 (s, 1H), 7.15 (d, J=8.3 Hz, 1H), 6.94 (d, J=12.9 Hz, 1H), 4.47 (s, 1H), 4.04 (t, J=7.7 Hz, 4H), 3.70 (s, 2H), 2.21-2.11 (m, 4H), 2.07-1.98 (m, 1H), 1.58-1.53 (m, 12H), 0.95-0.88 (m, 2H), 0.71-0.66 (m, 2H); MS (ES+) m/z 479.1 (M+1); MS (ES−) m/z 477.2 (M−1).
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]#[N:10])=[C:4]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:3]=1.[BH4-].[Na+].II.Cl>C1COCC1>[NH2:10][CH2:9][C:5]1[C:6](=[O:8])[NH:7][C:2]([CH3:1])=[CH:3][C:4]=1[C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1
Reactant: Cc1cc(-c2ccncc2)c(C#N)c(=O)[nH]1
Agent: Cl
Agent: II
Agent: [BH4-]
Solvent: C1CCOC1
Product: Cc1cc(-c2ccncc2)c(CN)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.7 %

Procedure:
To an ice bath cooled THF (100 mL) solution of 6-methyl-2-oxo-1,2-dihydro-4,4′-bipyridine-3-carbonitrile (4 g, 18.9 mmol) was added NaBH4 (1.43 g, 37.9 mmol), and I2 (4.81 g, 18.9 mmol), and the mixture was stirred for 0.5 h. The reaction mixture was then heated at reflux for 4 h. After cooling to 0° C., the reaction mixture was adjusted to pH 5 with 4N HCl. The mixture was concentrated in vacuo to give the crude compound, which was purified by HPLC to give 3-(aminomethyl)-6-methyl-4,4′-bipyridin-2(1H)-one (1.9 g, 31%) as a TFA salt. LCMS MH+=216.0 1H NMR (400 MHz, DMSO-d6 in D2O) δ 8.87 (d, 2H), 7.87 (d, 2H), 6.13 (s, 1H), 3.65 (br s, 2H), 2.17 (s, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1)[C:16](=[O:39])[N:17]1[CH2:22][CH2:21][N:20]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:31]=3)[N:26]=[CH:25][N:24]=2)[CH2:19][CH2:18]1)(C)(C)C>C(Cl)Cl>[NH2:14][CH:15]([CH2:40][C:41]1[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=1)[C:16]([N:17]1[CH2:22][CH2:21][N:20]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH:31]=3)[N:26]=[CH:25][N:24]=2)[CH2:19][CH2:18]1)=[O:39]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3ccc(-c4ccccc4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3ccc(-c4ccccc4)cc23)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (4 mL) was added to a stirred solution of {1-(4-chlorobenzyl)-2-oxo-2-[4-(6-phenyl-quinazolin-4-yl)-piperazin-1-yl]-ethyl}-carbamic acid tert-butyl ester (30 mg) in DCM (10 mL) at room temperature. The solution was stirred at room temperature for 4 hours, quenched with aqueous NaOH (1N, 10 mL), diluted with EtOAc (100 mL) and washed with aqueous NaOH (2×50 mL.) The organic phase was dried over Na2SO4 and concentrated in vacuo to give 2-amino-3-(4-chlorophenyl)-1-[4-(6-phenyl-quinazolin-4-yl)-piperazin-1-yl]-propan-1-one as a colorless oil (23 mg.) 1H NMR (CDCl3, 400 MHz) δ 8.77 (1H, s), 8.02-8.00 (2H, m), 7.98 (1H, s), 7.64 (2H, d, J7.4 Hz), 7.53 (2H, t, J7.7 Hz), 7.44 (1H, t, J7.3 Hz), 7.30 (2H, d, J8.6 Hz), 7.17 (2H, d, J8.6 Hz), 3.98 (1H, t, J7.3 Hz), 3.87-3.60 (6H, m), 3.42-3.34 (2H, m), 2.97 (1H, dd, J7.4 and 13.3 Hz), 2.84 (1H, dd, J7.0 and 13.7 Hz.) The oil was taken up into THF (10 mL) and treated with HCl (1.0M in Et2O, 10 mL) and concentrated in vacuo to give the bis hydrochloride salt of 2-amino-3-(4-chlorophenyl)-1-[4-(6-phenyl-quinazolin-4-yl)-piperazin-1-yl]-propan-1-one as a solid (21 mg).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:39]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[OH:51])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:3]=1[C:14]([N:42]1[CH2:41][CH2:40][N:39]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[OH:51])[CH2:44][CH2:43]1)=[O:16]
Reactant: Oc1ccccc1N1CCNCC1
Reactant: Nc1onc(-c2ccccc2F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Nc1onc(-c2ccccc2F)c1C(=O)N1CCN(c2ccccc2O)CC1
Yield: 62.5 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-amino-3-(2-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 2-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (439 mg, 1.15 mmol, 62%) was obtained.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH2:41][CH3:42])[CH:35]=O)[CH3:30]>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[CH:38][C:39]([O:40][CH2:41][CH3:42])=[C:32]([O:31][CH2:29][CH3:30])[CH:33]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CCOc1ccc(C=O)cc1OCC
Product: CCOc1ccc(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1OCC

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 3,4-diethoxy-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 557.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:13])([CH3:12])[CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16]>CCN(CC)CC.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:14][Si:15]([CH3:17])([CH3:16])[CH2:18][CH2:19][CH:7]1[C:6]([CH3:13])([CH3:12])[C:5]2[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=2)[C:8]1=[O:11]
Reactant: C#C[Si](C)(C)C
Reactant: CC1(C)CC(=O)c2cc(Br)ccc21
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1(C)c2ccccc2C(=O)C1CC[Si](C)(C)C
Temperature: 70 °C

Procedure:
To a solution of 815.0 mg (3.41 mmol) 6-bromo-2,3-dihydro-3,3-dimethyl-1H-inden-1-one (See Smith et al. Org. Prep. Proced. Int. 1978 123-131) in 100 ml of degassed Et3N (sparged with argon for 20 min) was added 259.6 mg (1.363 mmol) of copper(I) iodide, 956.9 mg (1.363 mmol) of bis(triphenylphosphine)palladium(II)chloride, and 3.14 g (34.08 mmol) of (trimethylsilyl)acetylene. This mixture was heated at 70° C. for 42 hours, cooled to room temperature, and filtered through a pad of silica gel and washed with ether. The filtrate was washed with water, 1M HCl, water, and finally with saturated aqueous NaCl before being dried over MgSO4. Concentration of the solution under reduced pressure, followed by column chromatography (silica gel; 10% Et2O -hexanes) afforded the title compound as a brown oil. 1H NMR (300 MHz, CDCl3): δ 7.79(1H, d, J=1.4 Hz), 7.69 (1H, dd, J=1.6, 8.3 Hz), 7.42 (1H, d, J=8.5 Hz), 2.60 (2H, s), 1.41 (6H, s), 0.26 (9H, s).
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:5]=1[CH2:6][N:7]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:8](=[O:29])[CH2:9][CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21]C)=[O:20])=[CH:13][CH:12]=1>O.C1COCC1>[F:3][C:4]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:5]=1[CH2:6][N:7]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:8](=[O:29])[CH2:9][CH2:10][C:11]1[CH:28]=[CH:27][C:14]([O:15][CH2:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1
Reactant: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCN(Cc1ccc(F)cc1F)C(=O)CCc1ccc(OCc2ccccc2C(=O)O)cc1
Reaction time: 0.12 h
Yield: 83.4 %

Procedure:
Lithium hydroxide (13.3 mg, 0.554 mmol) in water (1 ml) was added into methyl 2-[(4-{3-[(2,4-difluorobenzyl)(heptyl)amino]-3-oxopropyl}phenoxy)methyl]benzoate (149 mg, 0.277 mmol) dissolved in THF (2 ml). The mixture was then placed in microwave oven (Smith Synthesizer) at 150° C. for 7 minutes and then evaporated to remove THF. The residue was acidified with 1% hydrochloric acid, pH˜4, and extracted with ethyl acetate (×2). The organic extracts were combined and washed with brine and dried with magnesium sulphate and then evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 2 g/6 ml) using DCM, then MeOH/DCM (1:99) as eluant gave 121 mg desired product, yield 83%.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]=[C:6]([C:8]1[O:12][C:11]2[C:13]([C:17]3[CH:22]=[C:21]([CH:23]([CH3:25])[CH3:24])[CH:20]=[C:19]([CH:26]([CH3:28])[CH3:27])[C:18]=3[O:29][CH2:30][CH2:31][CH3:32])=[CH:14][CH:15]=[CH:16][C:10]=2[CH:9]=1)[CH3:7])C.C1COCC1.[Li+].[OH-]>CO>[CH2:30]([O:29][C:18]1[C:19]([CH:26]([CH3:28])[CH3:27])=[CH:20][C:21]([CH:23]([CH3:24])[CH3:25])=[CH:22][C:17]=1[C:13]1[C:11]2[O:12][C:8]([C:6]([CH3:7])=[CH:5][C:4]([OH:33])=[O:3])=[CH:9][C:10]=2[CH:16]=[CH:15][CH:14]=1)[CH2:31][CH3:32]
Reactant: CCCOc1c(-c2cccc3cc(C(C)=CC(=O)OCC)oc23)cc(C(C)C)cc1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCOc1c(-c2cccc3cc(C(C)=CC(=O)O)oc23)cc(C(C)C)cc1C(C)C
Temperature: 25 °C

Procedure:
A mixture of 0.450 mmol of 3-[7-(2-propoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-enoic acid ethyl ester, 3 mL of THF, 3 mL of methanol and 1 mL of LiOH (2N aqueous) was refluxed for 2 hours. After cooling at room temperature, the mixture was acidified to pH=2 and extracted with ethyl acetate. The organic layer was dried over MgSO4 and after evaporation of the solvents, the crude acid was recrystallized from acetonitrile. 3-[7-(2-Propoxy-3,5-diisopropylphenyl)-benzo[b]furan-2-yl]-but-2-enoic acid was isolated as a white solid. 1H-NMR (400 MHz, CDCl3) δ 7.55 (m, 2H, Ar—H), 7.54 (s, 1H, Ar—H), 7.28 (t, J=7.6 Hz, 1H, Ar—H), 7.10 (s, 1H, furan-H), 6.94 (s, 1H, Ar—H), 6.62 (s, 1H, C═C—H), 4.06 (q, J=6.9 Hz, 2H, O—CH2—CH3), 2.56 (s, 3H, C═C—CH3), 1.74 (s, 4H, ring-CH2), 1.37 (s, 6H, ring-CH3), 1.33 (s, 6H, ring-CH3), 1.27 (t, J=6.9 Hz, 3H, O—CH2—CH3).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([S:14]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH:24]4[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]4)[C:19](=[O:30])[CH2:18]3)(=[O:16])=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl.Cl[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.C(=O)(O)[O-].[Na+]>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([S:14]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH:24]4[CH2:29][CH2:28][N:27]([C:37]5[CH:36]=[CH:35][N:34]=[CH:33][CH:38]=5)[CH2:26][CH2:25]4)[C:19](=[O:30])[CH2:18]3)(=[O:16])=[O:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=C1CN(S(=O)(=O)c2ccc(-c3ccc(Cl)cc3)s2)CCN1CC1CCNCC1
Reactant: Clc1ccccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C1CN(S(=O)(=O)c2ccc(-c3ccc(Cl)cc3)s2)CCN1CC1CCN(c2ccncc2)CC1
Temperature: 130 °C
Reaction time: 15 h

Procedure:
To 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-[5-(4-chlorophenyl)-2-thiophenesulfonyl]-2-piperazinone (115 mg) were added 4N hydrochloric acid in ethyl acetate (10 ml) and methanol (4 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated to give crude crystals of 4-[5-(4-chlorophenyl)-2-thiophenesulfonyl]-1-(piperidin-4-ylmethyl)-2-piperazinone hydrochloride. A mixture of the obtained 4-[5-(4-chlorophenyl)-2-thiophenesulfonyl]-1-(piperidin-4-ylmethyl)-2-piperazinone hydrochloride and chloropyridine hydrochloride (85 mg) was added to sodium bicarbonate solution, and the mixture was extracted with dichloromethane (twice), dried and concentrated. To the residue was added isoamylalcohol (10 ml), and the mixture was stirred at 130° C. for 15 hours. The reaction solution was concentrated, and the residue was dissolved in dichloromethane. The solution was washed with 1N sodium hydroxide solution, dried and concentrated, and the residue was purified with silica gel column chromatography (dichloromethane:methanol containing 10% ammonia solution=10:1) to give colorless solid of the title compound (42 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH2:14][N:15]([CH3:24])[C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[S:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[S:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[O:31]=[C:26]1[NH:27][C:28](=[O:30])[C:29](=[CH:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:10]=[C:11]([CH2:14][N:15]([CH3:24])[C:16](=[O:23])[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[S:12][CH:13]=3)=[CH:5][CH:4]=2)[S:25]1
Reactant: CN(Cc1cc(-c2ccc(C=O)cc2)cs1)C(=O)c1ccccc1
Reactant: O=C1CSC(=O)N1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CN(Cc1cc(-c2ccc(C=C3SC(=O)NC3=O)cc2)cs1)C(=O)c1ccccc1
Yield: 76.7 %

Procedure:
A solution of 4 g (9 mmol) of N-[4-(4-formylphenyl)thiophen-2-ylmethyl]-N-methylbenzamide, 1.1 g (9 mmol) of 2,4-thiazolidinedione and 0.3 g (1.8 mmol) of piperidinium acetate in 40 ml of toluene is refluxed for 2 hours in a Dean-Stark system. The reaction medium is cooled and the precipitate is filtered off under vacuum. 3 g (78%) of N-{4-[4-(2,4-dioxothiazolidin-5-ylidenemethyl)phenyl]thiophen-2-ylmethyl}-N-methylbenzamide are obtained.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:22](=[O:23])[O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:19])([F:20])[F:18])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2ccccc2C(F)(F)F)n1
Reactant: O=C(Cl)Oc1ccccc1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2C(F)(F)F)n1
Yield: 70.7 %

Procedure:
The title compound was prepared from 3-tert-butyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (1.45 g, 5.12 mmol) and phenyl chloroformate (1.95 mL, 15.4 mmol) using the procedure in Example 118A to give phenyl 3-tert-butyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrazol-5-ylcarbamate (1.46 g, 3.62 mmol, 71%). 1H NMR (300 MHz, DMSO-d6) δ 10.20 (br s, 1H), 7.92 (d, 1H), 7.85 (t, 1H), 7.74 (t, 1H), 7.54 (d, 1H), 7.38-7.36 (m, 2H), 7.23 (t, 1H), 7.09 (br s, 2H), 6.32 (s, 1H), 1.25 (s, 9H); LC-MS (ESI) m/z 404 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=[O:32]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH:24][C:31]([C:27]2[O:26][CH:30]=[CH:29][CH:28]=2)=[O:32])[CH2:20][CH:21]([CH3:22])[CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)C[C@H](N)CN1CCC[C@H]1C(=O)NCCCCc1ccccc1
Reactant: O=C(Cl)c1ccco1
Product: CC(C)C[C@@H](CN1CCC[C@H]1C(=O)NCCCCc1ccccc1)NC(=O)c1ccco1
Yield: 19 %

Procedure:
Using the procedure described in Example 7, treatment of 1-[2-(S)-amino-4-methylpentyl]-L-proline 4phenylbutylamide (125 mg) with 2-furoyl chloride (50 uL) provided 27 mg (19%) of the title compound. The 1H NMR and Mass spectrum analysis of this compound was consistent with the structure.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:10]=[CH:9][C:8]([N:11]=C(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:7][N:6]=1)=[O:4].C([O-])(=O)C.[Na+].Cl.NO>CO>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]([NH2:11])=[CH:9][N:10]=1)=[O:4]
Reactant: COC(=O)c1ncc(N=C(c2ccccc2)c2ccccc2)cn1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: COC(=O)c1ncc(N)cn1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
5-(Benzhydrylidene-amino)-pyrimidine-2-carboxylic acid methyl ester (9.83 g, 31.0 mmol) was dissolved in methanol (100 mL) and sodium acetate (12.2 g, 149 mmol) was added followed by hydroxylamine hydrochloride (7.75 g, 112 mmol). This was stirred at room temperature as a pale yellow mixture. At 3 h another 7.75 g of hydroxylamine hydrochloride and 12.2 g of sodium acetate were added. At 4 d, silica gel was added directly to the reaction mixture for dry loading purposes. Purification by silica gel flash chromatography (methanol/ethyl acetate) gave 5-amino-pyrimidine-2-carboxylic acid methyl ester impure with acetic acid (6.074 g, 79%) as a white solid. After placing in a vacuum oven for 6 d, some of the acetic acid was removed. The material was carried on as is. 1H NMR (400 MHz, DMSO-d6, δ): 8.15 (s, 2H) 6.35 (s, 2H) 3.79 (s, 3H); MS (M+1): 154.8.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]3[CH:27]=[CH:26][O:25][C:22]=3[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]5[O:25][CH:26]=[CH:27][C:21]=5[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cc3ccoc3cc21
Product: CC1c2cc3occc3cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-Methyl-5,6,7,8-tetrahydro-furo[3,2-g]isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:11]([CH3:10])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:4]=1)#[N:7]
Reactant: CNc1ccccc1
Reactant: N#Cc1ccc(Cl)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CN(c1ccccc1)c1ccc(C#N)cc1
Yield: 98 %

Procedure:
According to the general procedure B, 4-chlorobenzonitrile (74 mg, 0.50 mmol) reacted with N-methylaniline (64 mg, 0.60 mmol) using 1 mol % of Pd(dba)2, 2 mol % of Ph5FcP(t-Bu)2, and sodium tert-butoxide (58 mg, 0.60 mmol) in toluene at 45° C. to give the title compound (102 mg, 91%): 1H-NMR(400 MHz, CDCl3): δ 7.47-7.39 (m, 4H), 7.28 (t, 1H), 7.21 (d, 2H), 6.74 (d, 2H, J=9.0 Hz), 3.36 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ. GC/MS(EI): m/z 208 (M+), 192.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]=[C:5]([C:7]1[CH:28]=[CH:27][C:10]2[S:11][CH:12]=[C:13]([C:14]3[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:17]=[C:16]([CH:23]([CH3:25])[CH3:24])[C:15]=3[OH:26])[C:9]=2[CH:8]=1)[CH3:6].I[CH3:31].[F-].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:29])[CH:4]=[C:5]([C:7]1[CH:28]=[CH:27][C:10]2[S:11][CH:12]=[C:13]([C:14]3[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:17]=[C:16]([CH:23]([CH3:24])[CH3:25])[C:15]=3[O:26][CH3:31])[C:9]=2[CH:8]=1)[CH3:6]
Reactant: CI
Reactant: COC(=O)C=C(C)c1ccc2scc(-c3cc(C(C)C)cc(C(C)C)c3O)c2c1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C=C(C)c1ccc2scc(-c3cc(C(C)C)cc(C(C)C)c3OC)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
3-[3-(2-Hydroxy-3,5-di-iso-propylphenyl)-benzo[b]thien-5-yl]-but-2-enoic acid methyl ester (100 mg, 0.24 mmol) was dissolved in DMF (5 ml), and iodomethane (0.0183 ml, 0.29 mmol) and cesium fluoride (149 mg, 0.98 mmol) were added to this solution. The reaction was stirred at ambient temperature under nitrogen overnight, then water (2 ml) was added and the mixture extracted with ethyl acetate (2×5 mL). The combined organics were washed with brine, then dried over MgSO4 and concentrated in vacuo to yield 3-[3-(3,5-di-iso-propyl-2-methoxyphenyl)-benzo[b]thien-5-yl]but-2-enoic acid methyl ester as a pale yellow solid (101 mg, 98%). 1H NMR (250 MHz, CDCl3): δ 7.85 (d, 1H, J=6.2), 7.80 (s, 1H), 7.46 (s, 1H), 7.40 (dd, 1H, J=0.6, J=8.8), 7.09 (d, 1H, J=1.2), 7.03 (d, 1H, J=1.2), 6.12 (d, 1H, J=0.6), 3.65 (s, 3H), 3.32 (m, 1H), 3.18 (s, 3H), 2.85 (m, 1H), 2.53 (d, 3H, J=0.6), 1.24 (s, 3H), 1.22 (s, 6H), 1.18 (s, 3H).