Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([OH:5])=[O:4].[Cl:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Cl:28])[C:12]=1[NH:13][C:14]1[C:23]2[C:18](=[C:19]([OH:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[O:17][C:16](=[O:27])[CH:15]=1>>[Cl:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Cl:28])[C:12]=1[NH:13][C:14]1[C:23]2[C:18](=[C:19]([O:26][CH2:2][C:3]([OH:5])=[O:4])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[O:17][C:16](=[O:27])[CH:15]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Reactant: O=C(O)CBr
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCC(=O)O

Procedure:
The title compound was prepared from 2-bromoacetic acid and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 12.90 (br, 1H), 9.56 (br s, 1H), 8.83 (s, 2H), 7.97 (d, 1H), 7.23 (d, 1H), 4.66 (s, 1H), 4.65 (s, 2H), 3.94 (s, 3H); MS (ESI): 410.8.
Reaction SMILES: [CH:1]1([C:4](=O)[CH3:5])[CH2:3][CH2:2]1.[CH3:7][C:8]1([CH3:16])[O:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[O:9]1>>[CH:1]1([C:4](=[C:11]2[C:12](=[O:14])[O:13][C:8]([CH3:16])([CH3:7])[O:9][C:10]2=[O:15])[CH3:5])[CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(=O)C1CC1
Product: CC(=C1C(=O)OC(C)(C)OC1=O)C1CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 120, Step 1 starting from 1-cyclopropylethanone (Alfa Aesar, Cat. #A13540) and 2,2-dimethyl-1,3-dioxane-4,6-dione.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8](=[O:13])(=[O:12])[N:9]([CH3:11])[CH3:10])[N:3]=1.O.[NH2:15][NH2:16]>C(O)CCC>[CH3:10][N:9]([CH3:11])[S:8]([C:4]1[N:3]=[C:2]([NH:15][NH2:16])[CH:7]=[CH:6][CH:5]=1)(=[O:13])=[O:12]
Reactant: NN
Reactant: CN(C)S(=O)(=O)c1cccc(Cl)n1
Solvent: O
Solvent: CCCCO
Product: CN(C)S(=O)(=O)c1cccc(NN)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
To 12 g of 2-chloro-6-dimethylsulfamoylpyridine were added 30 ml of n-butanol and 4 g of hydrazine hydrate. The mixture was stirred at room temperature for 30 minutes, followed by heating under reflux for 18 hours. After cooling, crystals obtained were filtered and washed with water to obtain 6.1 g of 6-dimethylsulfamoyl-2-hydrazinopyridine. m.p.: 117° to 120° C.
Reaction SMILES: Cl.[C:2]1(=[O:13])[C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][NH:3]1.C([O-])([O-])=O.[K+].[K+].Cl[C:21]1[O:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1>CN(C=O)C>[O:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[N:10]1[CH2:11][CH2:12][C:7]2([C:2](=[O:13])[NH:3][CH2:4][CH2:5][CH2:6]2)[CH2:8][CH2:9]1
Reactant: Clc1nc2ccccc2o1
Reactant: O=C1NCCCC12CCNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NCCCC12CCN(c1nc3ccccc3o1)CC2
Temperature: 60 °C
Yield: 71.5 %

Procedure:
To the stirred solution of 2,9-diazaspiro[5.5]undecan-1-one hydrochloride [1187173-73-4] (100 mg, 0.49 mmol) in DMF (3 mL) was added K2CO3 (203 mg, 1.47 mmol) and 2-chloro benzoxazole [615-18-9] (82.8 mg, 0.54 mmol). The mixture was heated at 60° C. for 18 h. The reaction mixture was cooled to rt and concentrated under reduced pressure. To the crude mixture water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow solid which was washed with diethyl ether and n-pentane to yield the title compound as solid (100 mg, 72%). [LCMS RtF=0.36 min, [M+H]+=286.1]
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[C:8]([CH3:13])[CH:9]=[CH:10][CH:11]=2)[C:6]([C:14]([OH:16])=O)=[CH:5][CH:4]=1.[CH:17]12[CH2:23][CH:21]([O:22]1)[CH2:20][NH:19][CH2:18]2>>[CH:21]12[CH2:23][CH:17]([O:22]1)[CH2:18][N:19]([C:14]([C:6]1[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:13])[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:16])[CH2:20]2
Reactant: COc1ccc(C(=O)O)c2c(C)cccc12
Reactant: C1NCC2CC1O2
Product: COc1ccc(C(=O)N2CC3CC(C2)O3)c2c(C)cccc12

Procedure:
4-Methoxy-8-methyl-1-naphthoic acid (Step-5 of Intermediate-22) was reacted with 6-oxa-3-azabicyclo[3.1.1]heptane by following the similar procedure as described in Step-6 of Intermediate-22.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12]C)=[CH:7][CH:6]=2.B(Br)(Br)Br.O>C(Cl)Cl>[OH:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([O:14][C:15]1[CH:16]=[CH:17][C:18](/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])=[CH:19][CH:20]=1)=[C:3]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:2]([CH3:1])=[CH:11]2
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccccc3)c(C)cc2c1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1cc2cc(O)ccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Reaction time: 1 h
Yield: 82.8 %

Procedure:
To a cold (5° C.) solution of (2E)-3-(4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}phenyl)-2-propenoic acid (10) (1.10 g, 2.68 mmol) in CH2Cl2 (60 mL) was added BBr3 (0.8 mL, 8 mmol) slowly. The reaction mixture was stirred between 5° C. and 20° C. for 1 h and poured into water (150 mL) slowly. The layers were separated and the aqueous layer was further extracted with EtOAc (3×150 mL). The combined organic layer was washed with brine (1×100 mL) dried (Na2SO4) and concentrated to afford the crude product. Purification by flash column chromatography on silica gel using CHCl3:MeOH as an eluent, gave 0.88 g (83%) of the title compound as an off-white solid. IR (film): 30.58, 1682, 1632, 1599, 1504, 1227, 1165 cm−1. 1H NMR (400 MHz, MeOH-d4): δ 7.60 (d, J=8.8 Hz, 1H), 7.51 (s, 1H), 7.52 (d, J=16.0 Hz, 1H), 7.33 (d, J=8.8 Hz, 2H), 7.27-7.20 (m, 3H), 7.14-11 (m, 3H), 6.96 and 6.94 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 6.57 (d, J=8.4 Hz, 2H), 6.75 (d, J=16.0 Hz, 1H), 2.19 (s, 3H). 13C NMR (100 MHz, MeOH-d4): δ 169.5, 161.3, 156.1, 147.1, 144.78, 136.82, 136.3, 135.9, 130.3, 129.8, 129.5, 127.8, 126.83, 124.0, 123.9, 120.9, 118.1, 115.8, 115.7, 108.6, 20.32. HRMS Calcd for C26H20O4: 397.1440. Found: 397.1439.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]2[S:20][C:19]3[S:21][C:22]([CH:24]=[O:25])=[CH:23][C:18]=3[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-:26]Cl=O.[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][C:16]2[S:20][C:19]3[S:21][C:22]([C:24]([OH:26])=[O:25])=[CH:23][C:18]=3[CH:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [O-][Cl+][O-]
Reactant: CC(C)(C)OC(=O)N1CCC(CCc2cc3cc(C=O)sc3s2)CC1
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(CCc2cc3cc(C(=O)O)sc3s2)CC1

Procedure:
3-3 (2.0 g, 5.27 mmol) was treated with NaClO2 (5.27 g, 58.3 mmol) as described for 1-7 to provide 3-4 as a white solid.
Reaction SMILES: [C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([S:20](Cl)(=[O:22])=[O:21])[N:19]=[C:6]2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:4]=1[CH3:34])#[N:2].CN.[CH2:37]([N:39](CC)CC)C>C1COCC1>[C:1]([C:3]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]2[N:17]=[C:18]([S:20]([NH:39][CH3:37])(=[O:22])=[O:21])[N:19]=[C:6]2[N:5]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[C:4]=1[CH3:34])#[N:2]
Reactant: CCN(CC)CC
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(S(=O)(=O)Cl)nc2N1c1cccc(C(F)(F)F)c1
Agent: CN
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1nc2n(n1)[C@H](c1ccc(C#N)cc1)C(C#N)=C(C)N2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon, abs. THF (3 ml) was stirred with molecular sieve (4 Å, 30 mg) for 30 min. (7R)-6-Cyano-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonyl chloride (63%, 50 mg, 62 μmol), methylamine (2 M solution in THF; 94 μl, 0.19 mmol, 3 eq.) and triethylamine (9 μl, 62 μmol, 1 eq.) were added and the mixture was stirred at RT for 12 h. The reaction solution was then concentrated under reduced pressure and the residue was purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (23 mg, 73% of theory).
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=1)[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[N:20]=[C:14]2[CH2:13]1)=[O:11])=O)C.[ClH:35]>CO>[ClH:35].[ClH:35].[NH2:7][C@H:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([F:33])[CH:27]=1)[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[CH:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[N:20]=[C:14]2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2cc(C(F)(F)F)nc2C1)Cc1ccc(F)c(F)c1
Agent: Cl
Solvent: CO
Product: N[C@@H](CC(=O)N1CCn2cc(C(F)(F)F)nc2C1)Cc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 7-[(3R)-3-[(1,1-dimethylethoxycarbonyl)amino]-4-(3,4-difluorophenyl)butanoyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-α]pyrazine (110.8 mg, 0.226 mmol, from Step C) was added 2 mL of methanol saturated with hydrogen chloride. The reaction was stirred at ambient temperature for 1 h. Concentration gave 89.5 mg of the title compound as a foamy solid. 1H NMR (500 MHz, CD3OD) δ 2.97-3.10 (m, 4H), 3.91-4.34 (m, 5H), 4.90-5.04 (m, 2H), 7.16-7.33 (m, 2H), 8.01-8.08 (m, 1H). ESI-MS 389 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:15][N:14]([C:16]3[S:17][C:18]([C:23]([O:25]C)=[O:24])=[C:19]([CH2:21][CH3:22])[N:20]=3)[CH2:13]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].O>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][CH:12]2[CH2:13][N:14]([C:16]3[S:17][C:18]([C:23]([OH:25])=[O:24])=[C:19]([CH2:21][CH3:22])[N:20]=3)[CH2:15]2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1nc(N2CC(NC(=O)c3nc(Cl)c(CC)[nH]3)C2)sc1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1nc(N2CC(NC(=O)c3nc(Cl)c(CC)[nH]3)C2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 33.3 %

Procedure:
Methyl 2-(3-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}azetidin-1-yl)-4-ethyl-1,3-thiazole-5-carboxylate obtained in Example (222c) (143 mg, 0.36 mmol) was dissolved in methanol (3.6 mL). A 2 N aqueous lithium hydroxide solution (1.80 mL, 3.59 mmol) was added, and the mixture was stirred at room temperature for 18.5 hours. Water was added to the reaction solution, and then the mixture was washed with ethyl acetate. A 1 N aqueous hydrochloric acid solution (3 mL) was added to the aqueous layer. The precipitated solid was collected by filtration to obtain 46 mg of the title compound as a white solid (33%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:33])[C:5]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1.[O:34]([C:41]([NH:43][OH:44])=O)C1C=CC=CC=1>C1COCC1>[OH:44][NH:43][C:41]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:8][C:5]2[C:4]([CH3:33])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:16][C:17]2[C:22]([C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12]1)=[O:34]
Reactant: O=C(NO)Oc1ccccc1
Reactant: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)(C)c1ccc(F)cc1)C1CCNCC1
Solvent: C1CCOC1
Product: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)(C)c1ccc(F)cc1)C1CCN(C(=O)NO)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
(5-Chloro-3-methyl-pyridin-2-ylmethyl)-{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-piperidin-4-yl-amine (0.160 g, 0.34 mmol) and N-(phenoxycarbonyl)-hydroxylamine (0.068 g, 0.44 mmol) were combined in THF (4 mL) and the mixture was stirred at 70° C. for 2 hours and then 45° C. for 48 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 85:10:5, v/v/v) to give 4-((5-chloro-3-methyl-pyridin-2-ylmethyl)-{3-[1-(4-fluoro-phenyl)-1-methyl-ethyl]-pyridin-2-ylmethyl}-amino)-piperidine-1-carboxylic acid hydroxyamide (0.082 g, 45%) as a white solid. 1H NMR (CDCl3) δ 1.25-1.37 (m, 2H), 1.61 (s+m, 8H), 2.26 (s, 3H), 2.55 (t, 2H. J=12.0 Hz), 2.64 (m, 1H), 3.45 (s, 2H), 3.73 (s, 2H), 3.92 (d, 2H, J=12.0 Hz), 6.89-6.95 (m, 4H), 7.21 (m, 1H), 7.39 (s, 1H), 7.87 (d, 1H, J=9.0 Hz), 8.21 (d, 1H, J=3.0 Hz), 8.50 (d, 1H, J=6.0 Hz). 13C NMR (CDCl3) δ 18.7, 27.9, 31.3, 42.5, 43.7, 54.4, 58.7, 115.5, 115.7, 121.8, 122.3, 127.6, 127.7, 129.7, 130.8, 134.6, 135.0, 138.0, 143.5, 145.0, 146.9, 161.0, 163.0. HPLC: 90%. ES-MS m/z 527 [M+H]+. Anal. Calcd. for C28H33N5O2ClF.0.6H2O.0.1 CH2Cl2: C, 61.89; H, 6.36; N, 12.84; Cl, 7.80. Found: C, 61.83; H, 6.19; N, 12.62; Cl, 8.06.
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.CS(O)(=O)=O.[NH2:14][C:15]1[CH:29]=[CH:28][CH:27]=[CH:26][C:16]=1[C:17]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[C:5]([C:6]#[N:7])=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:16]3[C:15](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:14]=2)[CH2:3][CH2:2]1
Reactant: N#CCC(=O)C1CC1
Reactant: Nc1ccccc1C(=O)c1ccc(F)cc1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: N#Cc1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
Into a glass flask having an internal volume of 50 mL, equipped with a stirring apparatus, a thermometer and a reflux condenser, 0.72 g (6.6 mmol) of 3-cyclopropyl-3-oxopropanenitrile, 1.92 g (6.0 mmol) of 2-amino-4′-fluorobenzophenone methanesulfonate having a purity of 97.3% and 10 mL of toluene were put in an atmosphere of nitrogen, and reaction was carried out at 80° C. for 2 hours. After completion of the reaction, the reaction liquid was cooled to room temperature, 7.0 mL (7.0 mmol) of a 1 mol/L sodium hydroxide aqueous solution was added thereto to make the reaction liquid basic, followed by liquid separation, and the obtained organic layer was analyzed by high performance liquid chromatography (absolute quantitative analysis), whereupon 1.70 g (yield: 98%) of 2-cyclopropyl-4-(4′-fluorophenyl)quinoline-3-carbonitrile was formed.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:20]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=O)=[CH:4][CH:3]=1.[OH-].[K+].C(O)CO.NN>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:20][C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)c1ccc2c(c1)cc(C(=O)c1nccs1)n2Cc1ccc(F)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CS(=O)(=O)c1ccc2c(c1)cc(Cc1nccs1)n2Cc1ccc(F)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 45.9 %

Procedure:
To a mixture of the compound obtained in Example 27 (6) (88 mg), potassium hydroxide (25 mg) and ethylene glycol (2.5 ml), hydrazine (65 mg) was added and the mixture was stirred at 120° C. for 3 hours. The reaction mixture was poured into water, extracted with chloroform, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was separated and purified twice with silica gel preparative thin-layer chromatography (hexane:ethyl acetate=1:1) and (chloroform:methanol=15:1) to obtain 39 mg of the desired product as a yellow oil.
Reaction SMILES: [NH:1]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C@H:2]([C:11]([O:13]C(C)(C)C)=[O:12])[CH2:3][O:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[NH:1]([N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][O:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6]
Reactant: C=CCOC(=O)OC[C@H](NN1CCOCC1)C(=O)OC(C)(C)C
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: C=CCOC(=O)OC[C@H](NN1CCOCC1)C(=O)O

Procedure:
Morpholino-Ser(OAloc) was prepared from SER(OtBu)-OtBu. Reaction of Ser(OtBu)-OtBu with 4-morpholineacarbonyl chloride in pyridine yielded morpholino-Ser(OtBu)-OtBu. Morpholino-Ser(OtBu)-OtBu was hydrolyzed with TFA to yield morpholino-Ser. Esterification of morpholino-Ser with isobutylene in the presence of a catalytic amount of H2SO4 afforded morpholino-Ser-OtBu. Reaction of morpholino-Ser-OtBu with allyl 1-benzotriazolyl carbonate yielded morpholino-Ser(OAloc)-OtBu. Morpholino-Ser(OAloc)-OtBu was hydrolyzed with TFA in CHCl3 (1:1) to yield morpholino-Ser(OAloc).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:16])[O:5][C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][CH3:15])=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].[N-:17]=[N+:18]=[N-:19].[NH4+]>CCO>[CH2:13]([C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:16])[C:3]=1[C:1]1[NH:19][N:18]=[N:17][N:2]=1)[CH2:14][CH3:15]
Reactant: CCCc1c(C#N)c(=O)oc2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [NH4+]
Solvent: CCO
Product: CCCc1c(-c2nnn[nH]2)c(=O)oc2ccccc12

Procedure:
The reaction of 3-cyano-4-n-propyl coumarin (41.67 g; 0.196 mole) with ammonium azide as described in Example 1 afforded the title product, m.p. (EtOH) 178°-181° C (Found; C, 61.03; H, 4.95; N, 22.48; C13H12N4O2 requires; C, 60.93; H, 4.72; N, 21.86%).
Reaction SMILES: [C:1]([CH:8]([NH2:16])[CH2:9][NH:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:17]1[C:26]2[N:25]=[C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]3=[CH:22][C:21]=2[CH:20]=[CH:19][C:18]1=[O:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH:17]1[C:26]2[N:25]=[C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]3=[CH:22][C:21]=2[CH:20]=[C:19]([N:10]([CH2:9][CH:8]([NH2:16])[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:11][C:12]([O:14][CH3:15])=[O:13])[C:18]1=[O:31]
Reactant: O=c1ccc2cc3ccccc3nc2[nH]1
Reactant: COC(=O)CNCC(N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COC(=O)CN(CC(N)C(=O)OC(C)(C)C)c1cc2cc3ccccc3nc2[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.1 %

Procedure:
Methyl N-(2-Boc-aminoethyl)glycinate (0.812 g, 3.5 mmol) was dissolved in DMF (10 mL) and benzo[b][1,8]napthyridin-2(1H)-one 3 acetic acid (883 mg, 3.5 mmol) was added. The mixture was cooled in an ice bath and HBTU (1.52 g, 4.0 mmol) was added. After 1 hour the ice bath was removed and the mixture was stirred overnight at room temperature. The mixture was evaporated in vacuo, redissolved in dichloromethane (100 mL) and washed with saturated aqueous NaHCO3 (2×50 mL). The organic phase was dried (MgSO4) and evaporated in vacuo. The crude product was purified on a silica column eluted with dichloromethane/methanol (97:3, v/v). Fractions containing the product were pooled and evaporated in vacuo to give 345 mg (21%) of the title compound as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=[O:5].C(N)(N)=[O:14].OO.FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N+:10]([O-:14])=[C:9]([Cl:11])[CH:8]=[C:7]([CH3:12])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)O
Reactant: NC(N)=O
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Cl)[n+]([O-])c(Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.7 %

Procedure:
2,6-Dichloro-4-methyl-nicotinic acid (0.234 g, 1.14 mmol) and hydrogen peroxide-urea adduct (0.537 g, 5.70 mmol) were suspended in CH2Cl2 to give a white slurry. Trifluoroacetic anhydride (0.65 ml, 4.67 mmol) was added dropwise over 5 minutes and the resulting pale yellow solution was stirred overnight at rt. The reaction mixture was quenched with water (10 ml) and then dry loaded onto silica gel and purified using column chromatography (MeCN/MeOH/NH4OH, 8:1:1, v/v/v) to give 2,6-dichloro-4-methyl-nicotinic acid-N-oxide as a pale yellow crystalline solid (0.103 g, 41%). 1H NMR (CD3OD) δ 2.37 (s, 3H), 7.60 (s, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][N:8]=[C:9]([C:35]2[N:36]=[C:37]([NH:40]C=O)[S:38][CH:39]=2)[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH:28]=[CH2:29])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])=[N:2]1.Cl.CO>O1CCCC1>[O:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][N:8]=[C:9]([C:35]2[N:36]=[C:37]([NH2:40])[S:38][CH:39]=2)[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:30]([OH:32])=[O:31])=[C:17]([CH2:20][S:21][C:22]4[N:26]([CH2:27][CH:28]=[CH2:29])[N:25]=[N:24][N:23]=4)[CH2:18][S:19][C@H:14]23)=[O:11])=[N:2]1
Reactant: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCc3ccon3)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: C=CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCc3ccon3)c3csc(N)n3)[C@H]2SC1
Yield: 45.3 %

Procedure:
A mixture of 7-[2-(3-isoxazolyl)methoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (1.5 g), conc.hydrochloric acid (0.497 g), methanol (15 ml) and tetrahydrofuran (3 ml) was stirred for 2 hours at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a saturated aqueous solution of sodium bicarbonate. The aqueous solution was washed with ethyl acetate (25 ml) and adjusted to pH 1.5 with 10% hydrochloric acid. Precipitates were collected by filtration, washed with water and dried to give 7-[2-(3-isoxazolyl)methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-allyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer)(0.65 g).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([S:16][CH3:17])[CH:6]=2)[CH2:3][CH2:2]1.[NH:18]1[CH2:24][C:22](=[O:23])[NH:21][C:19]1=[O:20].N1CCCCC1>C(O)C>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:24]4/[C:22](=[O:23])[NH:21][C:19](=[O:20])[NH:18]/4)=[C:9]3[N:8]=[C:7]([S:16][CH3:17])[CH:6]=2)[CH2:3][CH2:2]1
Reactant: CSc1cc(NC2CC2)n2ncc(C=O)c2n1
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CSc1cc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Temperature: 80 °C
Yield: 90 %

Procedure:
The above product 7-(cyclopropylamino)-5-(methylthio)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde was dissolved in 20.0 mL ethanol, added hydantoin (2.82 g, 28.17 mmol) and piperidine (2.70 mL). The reaction was heated to 80° C. for overnight. Cooled the reaction mixture and yellow precipitate was filtered, washed with ethanol, dried to yield (Z)-5-((7-(cyclopropylamino)-5-(methylthio) pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione 4.18 g (90% yield). LCMS (M+1=331)
Reaction SMILES: CN(C=[N:5][S:6]([CH2:9][C:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][OH:12])(=[O:8])=[O:7])C.[H-].[Na+].Cl[C:20]1[C:21]([CH3:29])=[CH:22][C:23]2[N:24]([N:26]=[CH:27][N:28]=2)[N:25]=1.Cl>O1CCCC1>[CH2:15]([C:10]([CH2:13][CH3:14])([CH2:9][S:6](=[O:7])(=[O:8])[NH2:5])[CH2:11][O:12][C:20]1[C:21]([CH3:29])=[CH:22][C:23]2[N:24]([N:26]=[CH:27][N:28]=2)[N:25]=1)[CH3:16]
Reactant: Cc1cc2ncnn2nc1Cl
Reactant: CCC(CC)(CO)CS(=O)(=O)N=CN(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(COc1nn2ncnc2cc1C)CS(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a solution of 1.38 g of 3-(N,N-dimethylamino-methylene)aminosulfonyl-2,2-diethyl-1-propanol in 30 ml of tetrahydrofuran was added 0.23 g of 60% sodium hydride in oil and the mixture was stirred at room temperature for 1 hour. To this reaction mixture was added 0.74 g of 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine and the mixture was refluxed with stirring for 1 hour. After cooling, the reaction mixture was adjusted to pH 6 with 1N-hydrochloric acid and extracted with ethyl acetate-tetrahydrofuran (1:1). The extract was washed with water and dried and the solvent was distilled off. To the residue was added 14 ml of 6N-hydrochloric acid and the mixture was stirred at 110° C. for 30 minutes. After cooling, 100 ml of water was added to the reaction mixture and the resulting crystals were recovered by filtration and recrystallized from methanol to provide 1.16 g of the title compound. m.p. 208°-209° C.