Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H: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.[CH3:14][C:15]([CH3:17])=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[C:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][CH:2]([NH:1][CH:15]([CH3:17])[CH3:14])[CH2:3]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)=O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)NC1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-3-amino-1-N-Boc pyrrolidine (1.0 eq, 2.68 mmol) in methanol (15 mL) was added acetone (1.07 eq), sodium cyano borohydride (2.0 eq) and few drops of acetic acid and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using gradient elution from hexane/ethyl acetate (5%) to hexane/ethyl acetate (30%). 1H-NMR (CDCl3) δ: 1.05 (6H, d), 1.45 (9H, s), 1.60 (1H, m), 2.80-3.00 (2H, m), 3.20-3.70 (4H, m). ESI-MS m/z: 229 (M+1), UV retention time: 0.77 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][C:14](=O)[CH2:13][CH2:12]1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C@H:14]1[CH2:15][CH2:16][C@@H:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][CH:6]=2)[CH2:12][CH2:13]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCC(c2c[nH]c3ccc(F)cc23)CC1
Product: Fc1ccc2[nH]cc([C@H]3CC[C@@H](NCc4ccccc4)CC3)c2c1

Procedure:
This compound was prepared in similar manner as for Intermediate 17, using 4-(5-Fluoro-1-H-indol-3-yl)-cyclohexanone (0.6 g, 2.6 mmol) and benzylamine (0.3 g, 2.8 mmol) to afford 1.0 of the desired product as a mixture of cis and trans isomers. Flash chromatography on silica gel (3% 2M NH3 in methanol/ethyl acetate) afforded 0.41 g (65%) of cis isomer and 0.22 g (33%) of the trans isomer.
Reaction SMILES: Br[C:2]1[S:6][C:5]([S:7]([NH:10][C:11]2[CH:16]=[C:15]([N:17]3[CH2:22][C@H:21]([CH3:23])[NH:20][C@H:19]([CH3:24])[CH2:18]3)[CH:14]=[CH:13][C:12]=2[O:25][CH3:26])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[CH3:27][O:28][CH2:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.CC(C)([O-])C.[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][C@H:19]1[NH:20][C@@H:21]([CH3:23])[CH2:22][N:17]([C:15]2[CH:14]=[CH:13][C:12]([O:25][CH3:26])=[C:11]([NH:10][S:7]([C:5]3[S:6][C:2]([C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([CH2:29][O:28][CH3:27])[CH:35]=4)=[CH:3][CH:4]=3)(=[O:9])=[O:8])[CH:16]=2)[CH2:18]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)s1
Reactant: COCc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COCc1cccc(-c2ccc(S(=O)(=O)Nc3cc(N4C[C@@H](C)N[C@@H](C)C4)ccc3OC)s2)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 5-bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]-2-thiophenesulfonamide (E122) (100 mg, 0.22 mmol) and {3-[(methyloxy)methyl]phenyl}boronic acid (83 mg, 0.5 mmol) in DME (3 ml) was added potassium tert-butoxide (210 mg, 1.9 mmol) and tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. The resulting mixture was then concentrated in Genevac and residues passed over SCX. Basic fractions were re-concentrated in Genevac and the residue purified using mass directed autoprep HPLC to afford the title compound (E123). MS (ES+) m/e 502 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([N:23]3[CH2:27][CH2:26][CH2:25][CH:24]3[CH2:28][OH:29])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:9]=1)(C)(C)C.[ClH:31].CO>>[ClH:31].[NH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:15]=[CH:16][C:17]([S:20]([N:23]3[CH2:27][CH2:26][CH2:25][C@@H:24]3[CH2:28][OH:29])(=[O:22])=[O:21])=[CH:18][CH:19]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(S(=O)(=O)N3CCCC3CO)cc2)n1
Agent: Cl
Solvent: CO
Product: Nc1cccc(-c2ccc(S(=O)(=O)N3CCC[C@@H]3CO)cc2)n1
Temperature: 25 °C
Yield: 86 %

Procedure:
A solution of {6-[4-(2-hydroxymethyl-pyrrolidine-1-sulfonyl)-phenyl]pyridin-2-yl}carbamic acid tert-butyl ester (15.0 g, 34.6 mmol) in HCl/MeOH (50 mL, 2M) was heated at reflux for 2 h. After cooling to room temperature, the reaction mixture was evaporated under vacuum and washed with EtOAc to give (R)-(1-(4-(6-aminopyridin-2-yl)phenylsulfonyl)pyrrolidin-2-yl)methanol hydrochloride (C-2; 11.0 g, 86%). 1H NMR (300 MHz, DMSO-d6) δ 8.18 (d, J=8.7 Hz, 2H), 7.93-7.99 (m, 3H), 7.31 (d, J=7.2 Hz, 1H), 7.03 (d, J=8.7 Hz, 1H), 3.53-3.57 (m, 2H), 3.29-35 (m, 2H), 3.05-3.13 (m, 1H), 1.77-1.78 (m, 2H), 1.40-1.45 (m, 2H). MS (ESI) m/z (M+H)+ 334.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[C:18]([C:20]([NH:22][C:23]2[CH:27]=[CH:26][N:25]([CH3:28])[N:24]=2)=[O:21])[CH:17]=[C:16]([O:29][C@@H:30]([CH3:33])[CH2:31][OH:32])[CH:15]=1)[C:5]([O:7]CC)=[O:6].O.[OH-].[Li+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][C:14]1[CH:19]=[C:18]([C:20]([NH:22][C:23]2[CH:27]=[CH:26][N:25]([CH3:28])[N:24]=2)=[O:21])[CH:17]=[C:16]([O:29][C@@H:30]([CH3:33])[CH2:31][OH:32])[CH:15]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)c1ccc(Oc2cc(O[C@@H](C)CO)cc(C(=O)Nc3ccn(C)n3)c2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](CO)Oc1cc(Oc2ccc(C(=O)O)cc2F)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.8 %

Procedure:
A solution of ethyl 3-fluoro-4-(3-[(1S)-2-hydroxy-1-methylethoxy]-5-{[(1-methyl-1H-pyrazol-3-yl)amino]carbonyl}phenoxy)benzoate (1.8 g, 3.94 mmol) in THF (60 mL) was added to a solution of lithium hydroxide monohydrate (0.83 g, 19.7 mmol) in water (30 mL). The mixture was stirred at RT for 72 hours and the THF removed in vacuo. The aqueous layer was extracted into ethyl acetate (100 mL) to remove any impurities, then acidified with 1M hydrochloric acid and extracted into ethyl acetate (2×100 mL). The combined extracts were dried (MgSO4) and the solvent removed in vacuo to give the desired compound (1.62 g).
Reaction SMILES: C1CCC=CC=1.O.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][N:23]2C(OCC2C=CC=CC=2)=O)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>CCO.[Pd]>[C:8]([O:12][C:13]([N:15]1[CH2:16][CH2:17][N:18]([CH2:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][NH:23]2)[CH2:19][CH2:20]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCN(CC2CCCCN2C(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: O
Solvent: C1=CCCC=C1
Product: CC(C)(C)OC(=O)N1CCN(CC2CCCCN2)CC1
Reaction time: 48 h
Yield: 83.2 %

Procedure:
14.5 ml of cyclohexadiene followed by 3.3 g of 10% Pd/C having a 50% water content are added, under an inert atmosphere, to a solution of 6.43 g of the compound obtained in step 6.1, in 50 ml of EtOH. The medium is stirred at AT for 48 hours and then filtered. The filtrate is evaporated, to give 3.63 g of the desired compound.
Reaction SMILES: [OH:1][CH:2]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12].C1(C)C=CC=CC=1.O.[H][H]>[Rh].CO>[OH:1][CH:2]([CH:13]1[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]1)[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][CH3:12]
Reactant: COc1cccc(C(O)c2ccncc2)c1OC
Reactant: [H][H]
Agent: [Rh]
Solvent: O
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cccc(C(O)C2CCNCC2)c1OC

Procedure:
A suitable inert reactor is charged with 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]pyridine (10) (13.6 kg, 55.5 mol) as a toluene wet cake and 5% rhodium on carbon catalyst (2.7 kg, 50% wet with water) as a water wet cake at about 25° C. About 190 kg of methanol is added and the reactor is pressured to about 100 psig with hydrogen for about 4-12 hours at about 50° C. The catalyst is removed by filtration and the reactor and catalyst are rinsed with about 7 kg of methanol. Deionized water is used as a final wash of the catalyst wet cake. The reactor rinse filtrate and the reaction mixture filtrate are combined. The concentration of 4-[1-hydroxy-1-(2,3-dimethoxyphenyl)methyl]piperidine (11) is about 7 wt %, affording about 13 kg (90% average yield) of the title compound (11).
Reaction SMILES: C([O:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH:12]([NH:34][S:35]([C:38]2[C:39]3[CH:40]=[CH:41][N:42]=[CH:43][C:44]=3[CH:45]=[CH:46][CH:47]=2)(=[O:37])=[O:36])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][S:21]([C:24]3[C:25]4[CH:26]=[CH:27][N:28]=[CH:29][C:30]=4[CH:31]=[CH:32][CH:33]=3)(=[O:23])=[O:22])=[CH:16][CH:15]=2)[CH2:7][CH2:6]1)(=O)C.[CH3:48]I>>[OH:4][CH:5]1[CH2:6][CH2:7][N:8]([CH2:11][CH:12]([N:34]([CH3:48])[S:35]([C:38]2[C:39]3[CH:40]=[CH:41][N:42]=[CH:43][C:44]=3[CH:45]=[CH:46][CH:47]=2)(=[O:37])=[O:36])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][S:21]([C:24]3[C:25]4[CH:26]=[CH:27][N:28]=[CH:29][C:30]=4[CH:31]=[CH:32][CH:33]=3)(=[O:22])=[O:23])=[CH:16][CH:15]=2)[CH2:9][CH2:10]1
Reactant: CI
Reactant: CC(=O)OC1CCN(CC(Cc2ccc(OS(=O)(=O)c3cccc4cnccc34)cc2)NS(=O)(=O)c2cccc3cnccc23)CC1
Product: CN(C(Cc1ccc(OS(=O)(=O)c2cccc3cnccc23)cc1)CN1CCC(O)CC1)S(=O)(=O)c1cccc2cnccc12

Procedure:
The amorphous compound obtained in Example 103 was treated with methyl iodide according to the procedure in Example 89 and the intermediate product was subjected to alkaline hydrolysis according to the procedure in Example 104, to obtain the same product as in Example 99.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][C:11](=[O:13])[CH:10](C(OC)=O)[C:9](=[O:18])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(#N)C>[OH:18][C:9]1[CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:12][C:11](=[O:13])[CH:10]=1
Reactant: COC(=O)C1C(=O)CC(c2ccccc2)NC1=O
Solvent: CC#N
Product: O=C1C=C(O)CC(c2ccccc2)N1

Procedure:
The title compound was prepared by decarboxylation of methyl 6-phenyl-2-,4-dioxopiperidine-3-carboxylate (prepared as per Ashton et al., Heterocycles 28: (2) 1015 (1989)) by refluxing in acetonitrile (as per Toda et al., J. Antibiotics 23: (2) 173 (1980)). Removal of the solvent gave a solid (m.p. 166-169° C.). 1H NMR (CDCl3) δ 2.77 (dd, 1 H), 2.90 (dd, 1 H), 3.38 (s, 2 H), 4.80 (dd, 1 H), 6.40 (s, 1 H), 7.32-7.46 (m, 5 H).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=[O:4].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][C:23](O)([OH:25])[CH3:24].CC1C=CC(S(O)(=O)=O)=CC=1.C(O)CCC>C1C=CC=CC=1>[Br:1][CH2:2][C:3]1([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=2[Cl:12])[O:25][CH:23]([CH2:22][CH2:21][C:15]2[CH:16]=[CH:17][C:18]([Cl:20])=[CH:19][C:14]=2[Cl:13])[CH2:24][O:4]1
Reactant: O=C(CBr)c1ccc(Cl)cc1Cl
Reactant: CC(O)(O)CCc1ccc(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Solvent: c1ccccc1
Product: Clc1ccc(CCC2COC(CBr)(c3ccc(Cl)cc3Cl)O2)c(Cl)c1

Procedure:
A mixture of 13.6 parts of 2-bromo-1-(2,4-dichlorophenyl)-1-ethanone, 14.1 parts of 1-[2-(2,4-dichlorophenyl)ethyl]ethanediol, 3 parts of 4-methylbenzenesulfonic acid, 80 parts of butanol and 180 parts of benzene is stirred and refluxed for 24 hours. The reaction mixture is evaporated and the residue is stirred for 2 hours with 160 parts of methanol. The precipitated product is filtered off, yielding 2-(bromomethyl)-2-(2,4-dichlorophenyl)-4-[2-(2,4-dichlorophenyl)ethyl]-1,3-dioxolane.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>C(Cl)Cl>[CH2:8]([NH:9][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:22][CH:23]=1)[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: NCCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCCc1ccccc1)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C

Procedure:
To a solution of phenylethylamine (14.0 g, 14.6 mL, 0.11 mol) and DIEA (20.1 mL, 0.11 mol in DCM (500 mL) at 0° C. was added 4-(trifluoromethyl)benzoyl chloride (17.2 mL, 0.11 mol) dropwise. After the addition was completed, the reaction mixture was stirred at 0° C. and warmed up itself to RT for 16 h. An off-white solid precipitated was observed. The off-white solid was collected by filtration. The solid was then washed with DCM (2×50 mL), and dried under vacuum to give the title compound as a white solid. MS (ESI, positive ion) m/z: 294 (M+H).
Reaction SMILES: [P:1]([O-:5])([O-:4])([O-:3])=[O:2].[P:6](=[O:10])([OH:9])([OH:8])[OH:7].[Zr:11]>>[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Zr+4:11].[P:6]([O-:10])([O-:9])([O-:8])=[O:7].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[P:1]([O-:5])([O-:4])([O-:3])=[O:2].[Zr+4:11].[Zr+4:11]
Reactant: [Zr]
Reactant: O=P(O)(O)O
Agent: O=P([O-])([O-])[O-]
Product: [Zr+4]
Temperature: 350 °C

Procedure:
A zirconium phosphate film was prepared by adding a stoichometric amount of phosphate in the form of phosphoric acid to a solution of zirconium bound to PEI. The solution was then spin coated onto a glass slide and thermally treated at 1° C. to 120° C. with a dwell time of 30 minutes followed by heating to 350° C. at 1° C./minute with a dwell time of 30 minutes followed by heating to 450° C. at 1° C./minute with a dwell time of 1 hour and then cooling to 25° C.
Reaction SMILES: C(OC(O[CH2:8][CH3:9])CBr)C.Br.C(=O)([O-])O.[Na+].[NH2:16][C:17]1[C:22]([Cl:23])=[N:21][CH:20]=[CH:19][N:18]=1>CC(O)C.C(OCC)C.O>[Cl:23][C:22]1[C:17]2[N:18]([CH:8]=[CH:9][N:16]=2)[CH:19]=[CH:20][N:21]=1
Reactant: Nc1nccnc1Cl
Reactant: CCOC(CBr)OCC
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CC(C)O
Product: Clc1nccn2ccnc12
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
Bromoacetaldehyde diethyl acetal (45 ml, 0.29 mol) was treated with water (33 ml) and 48% hydrobromic acid (33 ml) and this mixture was heated at 95° C. for 90 min. The reaction was cooled, diluted with propan-2-ol (300 ml) and treated with sodium hydrogencarbonate (33 g) added in portions. This mixture was stirred for 30 min then filtered. The filtrate was treated with 2-amino-3-chloropyrazine (25 g, 0.19 mol) and then heated at 90° C. for 16 h. The reaction was cooled to ambient temperature, concentrated to about one-third volume and then treated with 48% hydrobromic acid (25 ml). More propan-2-ol (300 ml) was added and the mixture aged for 1 h. The resulting solid was collected by filtration, washed with propan-2-ol and then dissolved in water (500 ml). This solution was made basic by adding solid sodium hydrogencarbonate and then extracted with chloroform (3×250 ml). The organics were combined, dried over anhydrous magnesium sulphate, filtered and concentrated to give a solid. Trituration with diethyl ether afforded 8-chloroimidazo[1,2-a]pyrazine as an off-white solid (18.6 g, 63%): δH (360 MHz, DMSO) 7.73 (1H, d, J 4.5), 7.87 (1H, d, J 1), 8.28 (1H, d, J 1), 8.67 (1H, d, J 4.5).
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[NH2:11][C@@H:12]([CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:18][CH:17]=1)=[O:14]>>[N:2]1([CH2:7][C:8]([NH:11][C@@H:12]([CH2:30][O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([S:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:20][CH:21]=2)=[O:14])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Sc2ccc(F)cc2)cc1
Reactant: O=C(O)Cn1cncn1
Agent: Cl
Product: O=C(Cn1cncn1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Sc2ccc(F)cc2)cc1
Yield: 18 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenylthio)phenyl)propanamide, gave Compound 178, (S)-2-(2-(1H-1,2,4-triazol-1-yl)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenylthio)phenyl)propanamide (100.1 mg, 18%). 1H-NMR (400 MHz, CDCl3): δ 8.57 (s, 1H), 8.19 (s, 1H), 8.03 (s, 1H), 7.38-7.21 (m, 13H), 7.03-6.96 (m, 2H), 4.92 (s, 2H), 4.73-4.67 (m, 1H), 4.61 (d, 1H), 4.52 (d, 1H), 3.97-3.91 (dd, 1H), 3.57 (t, 1H). MS (EI) for C26H25FN5O3S found 506 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])(=[O:3])[CH3:2].Br[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+]>[I-].[Na+]>[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH:14]([CH2:13][CH3:12])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccccc1O
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(=O)C(CC)Oc1ccccc1C(C)=O
Yield: 100.2 %

Procedure:
2-Acetylphenol (1 g, 7.34 mmol) is treated with 1.79 g (9.18 mmol) of ethyl 4-bromobutyrate, 3.55 g (25.71 mmol) of potassium carbonate and a catalytic amount (11 mg, 0.07 mmol) of sodium iodide as described in Preparation 3 to give 1.84 g of (2-acetylphenoxy)butyric acid, ethyl ester as a light yellow oil which solidified upon standing: m.p. 43°-45° C.; The 1H NMR (300 MHz, CDCl3) is consistent with the desired product; IR (neat) 1730, 1660, 1600 cm-1 ; MS (CI) m/e 251 (M+H), 232, 205.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].[N+:12]([CH3:15])([O-:14])=[O:13].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:15][N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: C[N+](=O)[O-]
Reactant: COc1cc(C=O)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C=C[N+](=O)[O-])ccc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 63.7 %

Procedure:
4-Chloro-3-methoxybenzaldehyde (1 g, 5.88 mmol) in ethanol (10 mL) was reacted with nitro methane (358 mg, 5.88 mmol) and 10N NaOH (0.6 mL, 28.11 mmol). The resulting mixture was stirred at 0° C. for 3 hours to afford 800 mg of the product (66.6% yield).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: FC(F)(F)c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(Cl)nc2s1
Reactant: c1nc[nH]n1
Product: FC(F)(F)c1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-trifluoromethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-trifluoromethyl-4-(3,4-dichlorobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:3]=1[C:20]([CH:22]=[CH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1)=[O:21].[OH-].[Na+].OO.C(OCC)(=[O:40])C>CO.O>[OH:40][C:22]1[C:20](=[O:21])[C:3]2[CH:4]=[C:5]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:7][C:2]=2[O:1][C:23]=1[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([O:32][CH3:33])[CH:25]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(C=CC(=O)c2cc(Oc3ccccc3)c(NS(C)(=O)=O)cc2O)cc1OC
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2oc3cc(NS(C)(=O)=O)c(Oc4ccccc4)cc3c(=O)c2O)cc1OC
Reaction time: 10 h
Yield: 10.7 %

Procedure:
2.0 g of 2-(3,4-dimethoxyphenyl)vinyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone was suspended in 20 ml of methanol. Thereto was added 3.7 ml of a 15% aqueous sodium hydroxide solution to obtain a solution. Thereto was dropwise added 2.5 ml of a 15% aqueous hydrogen peroxide solution in 10 minutes at 0°-5° C. The mixture was stirred for 10 hours at the same temperature. The reaction mixture was introduced into a mixture of 50 ml of ethyl acetate and 50 ml of water. The organic layer was separated, washed with water, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: a 200 : 1 mixture of chloroform and methanol) to obtain 220 mg (yield: 10.7%) of 3-hydroxy-7-methylsulfonylamino-2-(3,4-dimethoxyphenyl)-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: [Br-].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:3]1.C[O:32][C:33](=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH:40]=O.C(=O)([O-])[O-].[K+].[K+].O>CO>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:40]/[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[C:33]([OH:42])=[O:32])=[N:3]1
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1ccccc1C=O
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccccc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.7 %

Procedure:
(1H-Indazol-3-ylmethyl)triphenylphosphonium bromide (2.5 g, 5.30 mmol) was dissolved in methanol (40 mL) and the solution was added with 2-formylbenzoic acid methyl ester (954 mg, 5.80 mmol) and potassium carbonate (2.20 g, 15.8 mmol), followed by stirring at room temperature for 2.5 hours. The reaction mixture was added with water and the precipitated solid was collected by filtration. The solid was added with 2 mol/L aqueous sodium hydroxide solution (75 mL) and heated under reflux in THF (50 mL). The mixture was extracted with ethyl acetate and the aqueous layer was neutralized by 6 mol/L hydrochloric acid. The precipitated solid was collected by filtration and the obtained solid was dried to obtain (E)-2-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg, 36%).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=[C:7]2[C:15]([O:17]CC)=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>C(O)C>[CH:1]1([N:6]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[N:8]=[C:7]2[C:15]([NH:23][CH:20]2[CH2:22][CH2:21]2)=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)c1nc2cccnc2n1C1CCCC1
Reactant: NC1CC1
Solvent: CCO
Product: O=C(NC1CC1)c1nc2cccnc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 3-cyclopentyl-3H-imidazo[4,5-b]pyridine-2-carboxylate (C7) (0.12 g, 0.46 mmol) in ethanol (10 mL) was added cyclopropylamine (0.55 g, 9.6 mmol), and the reaction mixture was stirred at room temperature for 18 hours. After concentration in vacuo, purification was effected via preparative thin layer chromatography on silica gel (Eluent: 5:1 petroleum ether/ethyl acetate) to afford the product as a yellow solid. Yield: 36 mg, 0.13 mmol, 28%. LCMS m/z 270.9 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.47 (dd, J=4.6, 1.5 Hz, 1H), 8.02 (br d, J=8 Hz, 1H), 7.85 (br s, 1H), 7.27 (dd, J=8.2, 4.6 Hz, 1H, assumed; partially obscured by solvent peak), 6.16-6.27 (m, 1H), 2.89-2.97 (m, 1H), 2.51-2.64 (m, 2H), 2.06-2.19 (m, 4H), 1.69-1.81 (m, 2H), 0.87-0.95 (m, 2H), 0.69-0.76 (m, 2H).