Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[NH2:13].[O:15](C(OC(C)(C)C)=O)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=O>C1COCC1>[CH3:1][O:2][C:3](=[O:14])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[NH:13][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1N
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(Cl)cc1NC(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
(E)-3-(2-Amino-4-chlorophenyl)-acrylic acid methyl ester (Carling, Robert W.; et al. J. Med. Chem. (1993), 36(22), 3397-408) (3.3 g, 15.6 mmol) in THF (63 ml) was combined with (BOC)2O (6.8 g, 31.2 mmol) and refluxed for 4 hours. THF was evaporated and a second portion of (BOC)2O added (6.8 g, 31.2 mmol). The mixture was heated to 100° C. for 18 hours. Recrystallisation from TBME/hexanes rendered the title compound as colorless crystals (4.6 g; 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>O>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:12][N:14]=[C:4]2[OH:5]
Reactant: NC=O
Reactant: Nc1ccc(I)cc1C(=O)O
Solvent: O
Product: Oc1ncnc2ccc(I)cc12
Temperature: 190 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
A mixture of 2-amino-5-iodobenzoic acid (125 g, 475 mmol) and formamide (200 mL) was heated to 190° C. for 2 hours. After cooling to room temperature, the reaction mixture was poured into water (500 mL) and stirred for 2 hours. The solids were filtered and dried under high vacuum to provide the product (108 g, 83%).
Reaction SMILES: [CH3:1][C:2]1[C:12](=[O:13])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:4](=[O:5])[CH:3]=1.[OH-:14].[Na+].OO>CO.O>[CH3:1][C:2]12[C:12](=[O:13])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4](=[O:5])[CH:3]1[O:14]2
Reactant: CC1=CC(=O)c2ccccc2C1=O
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC12OC1C(=O)c1ccccc1C2=O
Reaction time: 0.17 h
Yield: 91.5 %

Procedure:
Menadione crystalline (1) (5 g, 29.04 mmol, 1 equivalent) and 2 M NaOH (7.26 mL, 14.52 mmol, 0.5 equivalents) are dissolved in a mixture of methanol/water 4:1 (50 mL) at 0-2° C. After stirring at this temperature for 10 minutes, 35% hydrogen peroxide is added (4.2 mL, 43.56 mmol, 1.5 equivalents). Work-up: after 30 minutes at 0° C. the product is extracted with ethyl ether. The organic phase is dried over Na2SO4 and evaporated under reduced pressure. A whitish powder is obtained (5 g, 26.57 mmol). Yield: 91.5%.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1O.[Cl:11][CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=1)=[O:14]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[N:15]([C:13](=[O:14])[CH2:12][Cl:11])[C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH3:23])=[CH:20][CH:21]=1
Reactant: Oc1c(F)ccc(F)c1F
Reactant: CCc1ccc(NC(=O)CCl)cc1
Product: CCc1ccc(N(C(=O)CCl)c2c(F)ccc(F)c2F)cc1

Procedure:
Same procedure as example 6a, starting from 2,3,6-trifluorophenol and 2-chloro-N-(4-ethylphenyl)acetamide. The crude intermediate N-(2′,3′,6′-trifluorophenyl)-4-ethylaniline was roughly purified by filtration on silica using toluene as eluent.
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH2:24]([O:26][C:27]([CH2:29][NH:30][CH2:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35])=[O:28])[CH3:25]>CN(C=O)C>[CH2:24]([O:26][C:27]([CH2:29][NH:30][CH2:31][C:32]1[CH:33]=[C:34]([NH:35]/[C:4](=[C:11]2\[C:12](=[O:23])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)/[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:36]=[CH:37][CH:38]=1)=[O:28])[CH3:25]
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CCOC(=O)CNCc1cccc(N)c1
Solvent: CN(C)C=O
Product: CCOC(=O)CNCc1cccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 3-ethoxycarbonylmethylaminomethyl-aniline in DMF.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([Cl:11])(=O)C.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=2)=O)=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[C:20](\[Cl:11])/[C:22]2[CH:27]=[CH:26][C:25]([CH2:28][CH3:29])=[CH:24][CH:23]=2)=[CH:15][CH:14]=1
Reactant: CCc1ccc(C(=O)Cc2ccc(Br)cc2)cc1
Reactant: CC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(/C(Cl)=C/c2ccc(Br)cc2)cc1
Yield: 92 %

Procedure:
In a 100 mL flask, TFA (24.7 mL; 322.8 mmol) and acetyl chloride (18.34 mL; 258.23 rnmol) were added in one portion into 2-(4-bromophenyl)-1-(4-ethylphenyl) ethanone (Vc) (9.787 g; 32.28 mmol) at RT. Protocol and work-up was then similar with -those-described above. The title compoumd (m=9.60 g) was obtained in a 92% yield. Melting point: 75° C.
Reaction SMILES: BrBr.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:34]=[CH:33][N:32]([NH:35][C:36](=O)[CH2:37][N:38]2[CH:46]=[N:45][C:44]3[C:39]2=[N:40][CH:41]=[N:42][C:43]=3[NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[C:31]=1[C:56]([NH:58][C@@H:59]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH3:60])=[O:57].N>ClCCl>[Cl:29][C:30]1[CH:34]=[CH:33][N:32]2[C:31]=1[C:56](=[O:57])[N:58]([C@@H:59]([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH3:60])[C:36]([CH2:37][N:38]1[CH:46]=[N:45][C:44]3[C:39]1=[N:40][CH:41]=[N:42][C:43]=3[NH:47][C:48](=[O:54])[O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[N:35]2
Reactant: C[C@@H](NC(=O)c1c(Cl)ccn1NC(=O)Cn1cnc2c(NC(=O)OC(C)(C)C)ncnc21)c1ccccc1
Agent: BrBr
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](c1ccccc1)n1c(Cn2cnc3c(NC(=O)OC(C)(C)C)ncnc32)nn2ccc(Cl)c2c1=O
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
A solution of bromine (37 mg, 0.24 mmol) in dichloromethane (100 μL) was added dropwise to a solution of triphenylphosphine (63 mg, 0.24 mmol) in dichloromethane (1 ml) under nitrogen. The solution was stirred for 30 min, and triethylamine (78 μL, 0.56 mmol) and tert-butyl [9-(2-{[3-chloro-2-({[(1R)-1-phenylethyl]amino}carbonyl)-1H-pyrrol-1-yl]amino}-2-oxoethyl)-9H-purin-6-yl]carbamate (100 mg, 0.19 mmol) were added. The reaction mixture was refluxed for 1.5 h, and quenched with 10% aqueous sodium bicarbonate solution. The organic phase was separated, dried (sodium sulphate) and concentrated to obtain an oil that was treated with 6 ml of a 7M methanolic solution of ammonia at 60° C. in a sealed vessel. The solvent was then evaporated to obtain 66 mg (34% yield, 48% purity) of tert-butyl [9-({5-chloro-4-oxo-3-[(1R)-1-phenylethyl]-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl}methyl)-9H-purin-6-yl]carbamate.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]([O:10][CH3:11])=[O:9].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[H-].[Na+]>CN(C=O)C>[CH3:11][O:10][C:8](=[O:9])[CH:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COC(=O)Cc1cccn1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1ccc([N+](=O)[O-])cc1)c1cccn1C
Temperature: 0 °C
Yield: 96.6 %

Procedure:
Methyl 1-methylpyrrole-2-acetate (5.32 g, 34.73 mmol) and 4-fluoro-nitrobenzene (4.9 g, 34.73 mmol) were dissolved in dry DMF (100 ml), and the solution was cooled to 0° C. under nitrogen. Sodium hydride powder (1.75 g, 72.93 mmol) was added in portions. After 30 min the reaction mixture was quenched with 1 M HCl and the product was extracted into ether. The organic extracts were washed with water and brine, and dried over magnesium sulfate. The solvent was removed in vacuo to give methyl-2-(1-methylpyrrol-2-yl)-2-(4-nitrophenyl)acetate (9.20 g, 97%) as a red oil. ##STR61##
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[N:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7](=[O:9])[CH:8]=1.CCN(CC)CC.CS(Cl)(=O)=O.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([SH:36])=[CH:32][CH:31]=1>C(Cl)Cl>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([S:36][CH2:2][C:3]2[CH:4]=[N:5][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7](=[O:9])[CH:8]=2)=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)n1ncc(CO)cc1=O
Reactant: Sc1ccc(Cl)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1ncc(CSc2ccc(Cl)cc2)cc1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47 %

Procedure:
To a solution of tert-butyl 4-(hydroxymethyl)-6-oxopyridazine-1(6H)-carboxylate Part B (185 mg, 0.82 mmol) and Et3N (0.34 mL, 2.45 mmol) in CH2Cl2 (5 mL) under nitrogen at −10° C. was added a solution of methanesulfonyl chloride (0.076 mL, 0.98 mmol) in CH2Cl2 (2 mL). After stirring at RT for 15 min, 4-chlorobenzenethiol (355 mg, 2.45 mmol) was added to the reaction and the stirring at RT continued for 3 days. Following removal of the volatiles under vacuum, the crude product was purified by flash chromatography (silica gel/hexane-EtOAc 100:0 to 50:50 gradient, using LC-MS to identify fractions containing the desired product) to afford tert-butyl 4-((4-chlorophenylthio)methyl)-6-oxopyridazine-1(6H)-carboxylate 7C (137 mg, 47% yield).
Reaction SMILES: [I:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[Br:13][CH2:12][C:3]1[C:2]([I:1])=[CH:7][N:6]=[C:5]([C:8]([F:11])([F:9])[F:10])[CH:4]=1
Reactant: Cc1cc(C(F)(F)F)ncc1I
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: FC(F)(F)c1cc(CBr)c(I)cn1

Procedure:
A mixture of 5-iodo-4-methyl-2-(trifluoromethyl)pyridine (39.1 mg, 0.136 mmol), N-bromosuccinimide (29.1 mg, 0.163 mmol), and benzoyl peroxide (3.3 mg, 0.0136 mmol) in CCl4 (1 mL) was heated at reflux under N2 overnight. Water was added and the mixture was extracted with CH2Cl2 (3×20 mL). The combined extracts were dried (MgSO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 1-5% EtOAc in hexanes gradient) to afford 4-(bromomethyl)-5-iodo-2-(trifluoromethyl)pyridine. Rf=0.41 (10% EtOAc/hexanes). 1H NMR (600 MHz, CDCl3): δ 9.03 (s, 1H); 7.76 (s, 1H); 4.51 (s, 3H).
Reaction SMILES: [Si]([O:8][C@@H:9]1[CH2:13][N:12](C(OC(C)(C)C)=O)[C@H:11]([CH2:21][O:22][C:23]2[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]3[C:24]=2[C:25]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([Cl:43])[CH:37]=2)=[N:26][CH:27]=[N:28]3)[CH2:10]1)(C(C)(C)C)(C)C.C(#N)C>FC(F)(F)C(O)=O>[Cl:43][C:38]1[CH:37]=[C:36]([CH:41]=[CH:40][C:39]=1[F:42])[NH:35][C:25]1[C:24]2[C:29](=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:23]=2[O:22][CH2:21][C@H:11]2[NH:12][CH2:13][C@@H:9]([OH:8])[CH2:10]2)[N:28]=[CH:27][N:26]=1
Reactant: COc1cc(OC[C@@H]2C[C@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)OC(C)(C)C)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC[C@@H]2C[C@H](O)CN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.8 %

Procedure:
tert-Butyl (2S,4S)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[({4-[3-chloro-4-fluoro-anilino]-7-methoxyquinazolin-5-yl}oxy)methyl]pyrrolidine-1-carboxylate (1.13 g) was dissolved in trifluoroacetic acid (50 ml) and stirred at room temperature for 72 hours. The reaction mixture was then concentrated in vacuo, and excess water was added, followed by the careful addition of saturated aqueous sodium hydrogen carbonate. The mixture was extracted with 3% methanol in DCM and the organic layer was separated, dried (Na2SO4) and concentrated in vacuo to leave a pink solid. Trituration with cold acetonitrile gave (3S,5S)-5[({4-[3-chloro-4-fluoroanilino]-7-methoxy-quinazolin-5-yl}oxy)methyl]pyrrolidin-3-ol as a brown solid (380 mg, 51%); NMR spectrum (DMSO-d6) 10.38-10.54 (br s, 1H), 8.52 (s, 1H), 8.36 (dd, 1H), 7.94-7.99 (m, 1H), 7.43 (t, 1H), 6.84 (d, 1H), 6.79 (d, 1H), 4.75 (d, 1H), 4.41 (dd, 1H), 4.26-4.34 (m, 1H), 4.17 (t, 1H), 3.94 (s, 3H), 3.54-3.73 (m, 1H), 2.96 (dd, 1H), 2.79 (dd, 1H), 2.11-2.20 (m, 1H), 1.41-1.49 (m, 1H); Mass spectrum MH+ 419.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][P:6]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])[OH:7]>CO>[NH2:2][CH2:3][CH2:4][CH2:5][P:6]([CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)(=[O:7])[OH:8]
Reactant: NCCCP(=O)(O)Cc1ccccc1
Agent: Cl
Solvent: CO
Product: NCCCP(=O)(O)CC1CCCCC1
Reaction time: 4 h

Procedure:
A mixture of 3.0 g of 3-aminopropyl(benzyl)phosphinic acid hydrochloride and 0.6 g of Nishimura catalyst in 30 ml of methanol is hydrogenated during 4 hours. The catalyst is filtered off and the solvent removed by evaporation. The residue is dissolved in 20 ml of methanol and 10 ml of propyleneoxide are added to the solution. Stirring for 3 hours affords a white solid which is filtered off and dried over phosphorous pentoxide to yield 3-aminopropyl(cyclohexylmethyl)phosphinic acid, m.p. 230° (dec.).
Reaction SMILES: [CH2:1]([C:4]1[C:14]([OH:15])=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:2]=[CH2:3].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:1]([C:4]1[C:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=[CH:11][C:5]=1[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)cccc1C(=O)OCC
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCc1c(OCc2ccccc2)cccc1C(=O)OCC

Procedure:
A mixture of ethyl 2-allyl-3-hydroxybenzoate (20.6 g, 100 mmol), benzyl bromide (18 g, 105 mmol), and potassium carbonate (17 g, 123 mmol), was heated in DMF to 100° C. for 18 hr. The mixture was cooled and diluted with water (500 ml), and extracted with ethyl acetate three times. The ethyl acetate extracts were dried over brine and concentrated in vacuo to a tan oil (29.6 g, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)=[CH:4][CH:3]=1.[CH3:36][C@@H:37]1[O:39][C@H:38]1[CH3:40].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O>[OH:39][C@@H:38]([CH3:40])[C@H:37]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][CH:35]=[C:9]23)=[CH:6][CH:7]=1)[CH3:36]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(O)cc2)c2ccnn12
Reactant: C[C@@H]1O[C@H]1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(-c2ccc(O[C@H](C)[C@H](C)O)cc2)c2ccnn12
Yield: 54 %

Procedure:
To a solution of 4′-{[4-(4-hydroxyphenyl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.92 g) in N,N-dimethylformamide (10 mL) were added trans-2,3-epoxybutane (1.8 mL) and then cesium carbonate (2.0 g), and the mixture was stirred at 100° C. for 15 hr. The mixture was allowed to cool, to the reaction mixture were added ethyl acetate and then saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.57 g, 54%).
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:32])/[CH:15]=[CH:16]/[C:17]3[CH:18]=[C:19]4[C:24](=[N:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH:21]([C:28](OC)=[O:29])[CH2:20]4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[NH4+:36]>N>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:32])/[CH:15]=[CH:16]/[C:17]3[CH:18]=[C:19]4[C:24](=[N:25][CH:26]=3)[NH:23][C:22](=[O:27])[CH:21]([C:28]([NH2:36])=[O:29])[CH2:20]4)[CH2:10][CH2:9]2)=[CH:33][CH:34]=1
Reactant: [NH4+]
Reactant: COC(=O)C1Cc2cc(/C=C/C(=O)N3CCC(COc4ccc(F)cc4)CC3)cnc2NC1=O
Agent: N
Agent: [OH-]
Product: NC(=O)C1Cc2cc(/C=C/C(=O)N3CCC(COc4ccc(F)cc4)CC3)cnc2NC1=O
Yield: 12 %

Procedure:
A solution of methyl 6-[(1E)-3-{4-[(4-fluorophenoxy)methyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxylate (13 mg, 0.028 mmol) in ammonium hydroxide (33% in water, 0.5 mL) and in ammonia (2M in ethanol, 0.5 mL) was stirred at 90° C. for 1 h 30. The mixture was concentrated to dryness and the residue was purified on preparative TLC (eluent: dichloromethane/MeOH 90/10) to give 6-[(1E)-3-{4-[(4-fluorophenoxy)methyl]piperidin-1-yl}-3-oxoprop-1-en-1-yl]-2-oxo-1,2,3,4-tetrahydro-1,8-naphthyridine-3-carboxamide (1.6 mg, 12%) as a white solid.
Reaction SMILES: I[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([I:8])[N:3]=1.[CH2:9]([OH:12])[CH:10]=[CH2:11].C=O>ClCCl>[I:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:12][CH2:9][CH:10]=[CH2:11])[N:3]=1
Reactant: Ic1cncc(I)n1
Reactant: C=CCO
Agent: C=O
Solvent: ClCCl
Product: C=CCOc1cncc(I)n1

Procedure:
This was prepared from 2,6-diiodopyrazine (5.5 g, 16.6 mmol) and allyl alcohol by the procedure described for Example 31 part 1. Chromatography through silica gel using dichloromethane as eluant gave the pure product (2 g), δ (250 MHz, CDCl3) 4.83-4.86 (2H, m, CH2O); 5.29-5.35 (1H, m, cis-vinyl-H); 5.39-5.48 (1H, m, trans-vinyl-H); 5.98-6.13 (1H, m, vinyl-H); 8.16 (1H, s, pyrazine-H); 8.40 (1H, s, pyrazine-H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([O:9]C)=O.[NH2:11][CH2:12][CH2:13][OH:14]>C(OCC)(=O)C>[OH:14][CH2:13][CH2:12][NH:11][C:7]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: COC(=O)c1cnccn1
Reactant: NCCO
Solvent: CCOC(C)=O
Product: O=C(NCCO)c1cnccn1
Reaction time: 8 h
Yield: 80 %

Procedure:
A mixture of 55.2 parts of methyl 2-pyrazinecarboxylate, 48.9 parts of 2-aminoethanol and 360 parts of ethyl acetate was allowed to stand overnight at room temperature. The precipitated product was filtered off, washed with ethyl acetate and dried, yielding 54.5 parts (80%) of N-(2-hydroxyethyl)-2-pyrazinecarboxamide; mp. 125° C. (intermediate 22).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH3:14][C:15](OC(C)=O)=O>>[CH3:14][C:15]1[NH:13][S:10](=[O:12])(=[O:11])[C:3]2[CH:4]=[C:5]([Br:9])[CH:6]=[C:7]([Br:8])[C:2]=2[N:1]=1
Reactant: Nc1c(Br)cc(Br)cc1S(N)(=O)=O
Reactant: CC(=O)OC(C)=O
Product: CC1=Nc2c(Br)cc(Br)cc2S(=O)(=O)N1

Procedure:
A stirred solution of 2-amino-3,5-dibromobenzenesulfonamide (see compound 125) (660 mg; 2 mmol) was refluxed in Ac2O (25 ml; 265 mmol) over night. The reaction mixture was poured onto ice and filtered. The isolated solid was washed with Et2O. M.p. 287-289° C.
Reaction SMILES: [N:1]1[NH:2][C:3](=[O:10])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH2:11](O)[CH2:12][C:13]#[CH:14]>>[CH2:14]([N:2]1[C:3](=[O:10])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]2=[N:1]1)[CH2:13][C:12]#[CH:11]
Reactant: O=c1[nH]nc2ccccn12
Reactant: C#CCCO
Product: C#CCCn1nc2ccccn2c1=O
Yield: 26.3 %

Procedure:
The title compound was prepared in accordance with the general method of Example 109(D), from [1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (405 mg, 3.00 mmol) and but-3-yn-1-ol (200 mg, 2.85 mmol). The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 140 mg (0.75 mmol, 26%) of 2-(but-3-ynyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1.[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>O1CCCC1>[O:23]=[C:22]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:11][CH2:10]2)[C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[NH:1]1
Reactant: Nc1ccncc1NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2ccncc2n1C1CCN(Cc2ccccc2)CC1
Yield: 91.7 %

Procedure:
A solution of 4-amino-3-[(1-benzylpiperidin-4-yl)amino)pyridine (2.8 g, 9.9 mmol) and carbonyldiimidazole (3.0 g, 18.5 mmol) in tetrahydrofuran (100 mL) was refluxed overnight. The reaction was cooled, concentrated and partitioned between chloroform (500 mL) and saturated sodium carbonate (100 mL). The organic phase was dried over magnesium sulfate and concentrated to give the title compound (2.8 g). MS 209 (M+1).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=3[F:25])[CH2:12][CH2:11]2)[CH2:4][CH2:3]1.[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](O)=[O:32]>>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([O:16][CH:13]2[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][C@H:5]3[CH2:6][CH2:7][C@H:2]([NH:1][C:31]([C:27]4[S:26][CH:30]=[CH:29][CH:28]=4)=[O:32])[CH2:3][CH2:4]3)[CH2:15][CH2:14]2)=[C:18]([F:25])[CH:19]=1)#[N:22]
Reactant: O=C(O)c1cccs1
Reactant: N#Cc1ccc(OC2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)c(F)c1
Product: N#Cc1ccc(OC2CCN(CC[C@H]3CC[C@H](NC(=O)c4cccs4)CC3)CC2)c(F)c1

Procedure:
According to the synthesis of example 1, the title compound was prepared from Trans 4-{1-[2-(4-Amino-cyclohexyl)-ethyl]-piperidin-4-yloxy}-3-fluoro-benzonitrile and Thiophene-2-carboxylic acid. Preparative HPLC on reversed phase eluting with acetonitrile/water yielded the title compound. MS (m/e): 456.3 (M+H+).
Reaction SMILES: C(OC([N:7]1[CH2:12][CH:11]=[C:10]([C:13]2[N:14]=[C:15]([S:18][C:19]3[C@H:25]([CH3:26])[C@H:24]4[N:21]([C:22](=[O:30])[C@@H:23]4[C@H:27]([OH:29])[CH3:28])[C:20]=3[C:31]([O:33]CC=C)=[O:32])[S:16][CH:17]=2)[CH2:9][C@H:8]1[CH2:37][OH:38])=O)C=C.C(O)(=O)C.C([SnH](CCCC)CCCC)CCC.P([O-])([O-])([O-])=O>ClCCl>[OH:29][C@@H:27]([C@H:23]1[C:22](=[O:30])[N:21]2[C@@H:24]1[C@@H:25]([CH3:26])[C:19]([S:18][C:15]1[S:16][CH:17]=[C:13]([C:10]3[CH2:9][C@@H:8]([CH2:37][OH:38])[NH:7][CH2:12][CH:11]=3)[N:14]=1)=[C:20]2[C:31]([OH:33])=[O:32])[CH3:28]
Reactant: C=CCOC(=O)C1=C(Sc2nc(C3=CCN(C(=O)OCC=C)[C@H](CO)C3)cs2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: CCCC[SnH](CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(Sc3nc(C4=CCN[C@H](CO)C4)cs3)[C@H](C)[C@H]12
Temperature: 0 °C
Yield: 17.8 %

Procedure:
To a solution of allyl (4R,5S,6S)-3-({4-[(2S)-1-[(allyloxy)carbonyl]-2-(hydroxymethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-1,3-thiazol-2-yl}sulfanyl)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (28 mg, 0.05 mmol) in dichloromethane (4 ml) were added acetic acid (7.2 μl) and tributyltin hydride (135 ml, 0.50 mmol) and then was added at room temperature bis(triphenylphosphine)palladium chloride(II) (3.5 mg, 0.005 mmol). Ten minutes later the reaction mixture was poured into a mixture of ice (10 g) and phosphate buffer (pH7.0, 10 ml). After separation of the mixture with a separating funnel, the organic layer was extracted twice with water and the aqueous layer was washed twice with dichloromethane (3 ml). The organic solvent in the aqueous layer was evaporated under reduced pressure, and the residue was purified by polymer chromatography (CHP-20P). The fractions eluted with 1–3% aqueous THF solution were combined and lyophilized to give (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-3-({4-[(2S)-2-(hydroxymethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-1,3-thiazol-2-yl}sulfanyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (3.9 mg) as a white amorphous.