Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[S:13][CH:14]=2)=[CH:6][CH:5]=1>CO>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[S:13][CH:14]=2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCc1nc(-c2ccc(F)cc2)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1nc(-c2ccc(F)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
1N NaOH (5 mL) was added to an ice-cooled solution of crude ethyl 3-(4-(4-fluorophenyl)thiazol-2-yl)propanoate (450 mg, 1.61 mmol) in MeOH (5 mL) and the solution was allowed to stir at room temperature for 1 h. Solvent was evaporated and the reaction mixture was diluted with water. The aqueous layer was washed with EtOAc and the pH of the aqueous solution was adjusted to ˜2 using 1N HCl. The organic product was extracted with EtOAc and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 3-(4-(4-fluorophenyl)thiazol-2-yl)propanoic acid (320 mg, yield 79%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 12.29 (br s, 1H), 7.99-7.96 (m, 2H), 7.93 (s, 1H), 7.28-7.22 (t, J=9.0 Hz, 2H), 3.25-3.20 (t, J=7.1 Hz, 2H), 2.78-2.74 (t, J=7.1 Hz, 2H). MS (ESI) m/z: Calculated for C12H10FNO2S: 251.04. found: 252.2 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].C(O[C:16](=O)[CH2:17][C:18](=[O:24])[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)C>C1(C)C=CC=CC=1>[N:1]1[CH:5]=[CH:4][N:3]2[C:2]=1[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[N:8]=[C:16]2/[CH:17]=[C:18](/[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)\[OH:24]
Reactant: Nc1ccccc1-c1ncc[nH]1
Reactant: CCOC(=O)CC(=O)c1cccs1
Solvent: Cc1ccccc1
Product: O/C(=C\c1nc2ccccc2c2nccn12)c1cccs1
Temperature: 25 °C
Yield: 33.2 %

Procedure:
A mixture of 2-(1H-imidazol-2-yl)aniline (60.0 mg, 0.38 mmol), ethyl3-oxo-3-(2-thienyl)propanoate (74.7 mg, 0.38 mmol) and p-tolenesulfonicacid monohydrate (36.1 mg, 0.19 mmol) in toluene (30 ml) was heated at reflux for 2 hours. After cooling to room temperature, the reaction mixture was poured into aqueous saturate NaHCO3 solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica-gel (ethyl acetate/ hexane, 2/3-1/1) to give (Z)-2-imidazo[1,2-c]quinazolin-5-yl-1-(2-thienyl)ethenol (37.0 mg, 33% yield) as a yellow powder.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[N:22][OH:23])=[CH:17][C:16]=2[F:24])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[F:24][C:16]1[CH:17]=[C:18]([CH:21]=[N:22][OH:23])[CH:19]=[CH:20][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(C=NO)cc2F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: ON=Cc1ccc(-c2ccc(O)cc2)c(F)c1

Procedure:
The title compound was prepared by reacting 4′-{[tert-butyl(dimethyl)silyl]oxy}-2-fluoro-[1,1′-biphenyl]-4-carbaldehyde oxime (1.02 mmol) with tetrabutylammonium fluoride (1.12 mL of 1.0 M solution in tetrahydrofuran, 1.12 mmol) according to Method E to yield 198 mg (84%) of a white solid: mp 178-180° C.; 1H NMR (DMSO-d6): δ 6.84-6.89 (2H, m), 7.39-5.54 (5H, m), 8.17 (1H, s), 9.71 (1H, s), 11.43 (1H, s); MS (ESI) m/z 230 (M−H)−, 232 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][N:16]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:11]1.C(N(CC)CC)C.[CH:41]1([S:44](Cl)(=[O:46])=[O:45])[CH2:43][CH2:42]1>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][N:24]([S:44]([CH:41]4[CH2:43][CH2:42]4)(=[O:46])=[O:45])[CH2:23][CH2:22]3)[CH:18]=[CH:17][N:16]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:29])([F:30])[F:31])=[N:11]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cc(N3CCNCC3)ccn2)c(F)c1
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(C1CC1)N1CCN(c2ccnc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.2 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[4-(piperazin-1-yl)-pyridin-2-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 182, triethylamine (42.0 uL, 0.30 mmol) and cyclopropanesulfonyl chloride (9.0 uL, 0.09 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 1 hour, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:15]=O)[N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=1.CC1C=CC(S([CH2:27][N+:28]#[C-])(=O)=O)=CC=1.CC([O-])(C)C.[K+]>COCCOC>[CH3:1][C:2]1[N:3]=[C:4]([CH2:15][C:27]#[N:28])[N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=1
Reactant: Cc1cn(COCC[Si](C)(C)C)c(C=O)n1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cc1cn(COCC[Si](C)(C)C)c(CC#N)n1
Yield: 80.3 %

Procedure:
Same procedure as that described in example 1, stage 1.4, starting from 8.7 g (32.7 mmol) of 4-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbaldehyde, 6.7 g (34.3 mmol) of TOSMIC and 7.3 g (65 mmol) of potassium tert-butylate in solution in anhydrous DME (54 ml). 6.6 g of compound is obtained in the form of a yellow oil as 70/30 mixture of regioisomers tau and Pi.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[Br:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([NH:33][OH:34])=N)=[CH:29][CH:28]=1>>[Br:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]2[N:2]=[C:1]([N:3]3[CH2:4][CH2:5][CH:6]([N:9]([CH:23]4[CH2:25][CH2:24]4)[C:10](=[O:22])[C:11]4[CH:12]=[CH:13][C:14]([C:17]5[O:21][CH:20]=[N:19][CH:18]=5)=[CH:15][CH:16]=4)[CH2:7][CH2:8]3)[O:34][N:33]=2)=[CH:29][CH:28]=1
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Reactant: N=C(NO)c1ccc(Br)cc1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(-c3ccc(Br)cc3)no2)CC1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and 4-bromo-N-hydroxy-benzamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=2.08 min; Mass spectrum (ESI+): m/z=534/536 (Br) [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:28]C2CC2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:6]=2[N:7]=1.[NH2:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[N:39]([CH3:43])[C:38](=[O:44])[CH2:37][CH2:36]2.C[Si](Cl)(C)C>C(O)CCC>[NH2:28][C:4]1[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][NH:8][C:6]=2[N:7]=[C:2]([NH:32][C:33]2[CH:34]=[C:35]3[C:40](=[CH:41][CH:42]=2)[N:39]([CH3:43])[C:38](=[O:44])[CH2:37][CH2:36]3)[N:3]=1
Reactant: CN1C(=O)CCc2cc(N)ccc21
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc(F)cc3)c3c(NC4CC4)nc(Cl)nc32)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CN1C(=O)CCc2cc(Nc3nc(N)c4c(-c5ccc(F)cc5)c[nH]c4n3)ccc21

Procedure:
A solution of 2-chloro-N-cyclopropyl-5-(4-fluorophenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (76 mg, 0.17 mmol), 6-amino-1-methyl-3,4-dihydroquinolin-2(1H)-one (60 mg, 0.34 mmol) and trimethylsilyl chloride (0.200 mL, 1.58 mmol) in nBuOH (2 mL) was stirred at 135° C. for 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound. MS 403.4 (M+H); UV 205.3, 293.4 nm.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.N[C:37]1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.CC1C=CC=CC=1N=C=S>>[CH3:33][CH:32]([CH3:34])[C@H:27]([N:22]1[CH2:21][C:20]2[C:24](=[CH:25][C:17]([C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:37])=[S:35])=[CH:12][CH:13]=3)=[CH:18][CH:19]=2)[C:23]1=[O:26])[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: Cc1ccccc1N=C=S
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4C)cc3)cc2C1=O

Procedure:
The compound of example 71 was prepared analogous to compound of example 51 by reaction of compound of example 6 with 2-methyl phenyl isothiocyanate. The compound of example 71 was used directly without isolation for the preparation of compound of example 72.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH:11]1([CH:17]=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[CH:11]1([CH2:17][NH:5][CH2:4][C:3]2[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=2[F:1])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=CC1CCCCC1
Reactant: NCc1ccc(F)cc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: Fc1ccc(CNCC2CCCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50.1 %

Procedure:
To a solution of 2,4-difluorobenzylamine (2.84 g, 20.0 mmol) and cyclohexanecarbaldehyde (2.60 mL, 20.0 mmol) in methanol (100 mL) were added acetic acid (4.6 mL, 80 mmol) and sodium cyanoborohydride (1.51 g, 24.0 mmol) and the solution was stirred at room temperature for three days. Water (10 mL) was added and the mixture was concentrated in vacuo. The residue was diluted with aqueous 1 M KOH (125 mL) and ethyl acetate (100 mL) and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×100 mL) and the combined organic phase was dried over Na2SO4 and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 50 g Si/150 mL) with ethyl acetate (33-100% gradient) in heptane as the eluent yielded 2.40 g (50%) of white solids.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][C:8]([CH3:29])([CH3:28])[C:9]#[C:10][C:11]1[CH:12]=[CH:13][C:14]2[N:18]=[C:17]([CH3:19])[N:16]([C:20]3[N:25]=[CH:24][N:23]=[C:22]([NH2:26])[N:21]=3)[C:15]=2[CH:27]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[NH2:26][C:22]1[N:23]=[CH:24][N:25]=[C:20]([N:16]2[C:15]3[CH:27]=[C:11]([C:10]#[C:9][C:8]([CH3:28])([CH3:29])[CH2:7][OH:6])[CH:12]=[CH:13][C:14]=3[N:18]=[C:17]2[CH3:19])[N:21]=1
Reactant: Cc1nc2ccc(C#CC(C)(C)CO[Si](C)(C)C(C)(C)C)cc2n1-c1ncnc(N)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc2ccc(C#CC(C)(C)CO)cc2n1-c1ncnc(N)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.1 %

Procedure:
In a solution of 4-{6-[4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-but-1-ynyl]2-methyl-benzoimidazol-1-yl}-[1,3,5]triazin-2-ylamine (140 mg, 0.32 mmol) in THF (10 ml) was added tetrabutyl-ammonium fluoride (170 mg, 0.64 mmol). Then the solution stirred overnight at room temperature. The reaction mixture was washed with water and purified by column to afford the title compound 4-[3-(4-amino-[1,3,5]triazin-2-yl)-2-methyl-3H-benzoimidazol-5-yl]-2,2-dimethyl-but-3-yn-1-ol (5-e) (30 mg, 29%): 1H NMR (400 MHz, DMSO) delta 1.23 (s, 6H), 2.89 (s, 3H), 3.39 (d, J=6.0 Hz, 2H), 5.00 (t, J=5.6 Hz, 2H), 7.29 (dd, J=1.6, 8.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.99 (s, 1H), 8.02 (s, 1H), 8.33 (t, J=0.4 Hz, 1H), 8.65 (s, 1H). LCMS m/z=+323.1 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[CH:7][C:6]([C:9]([O:11]C)=[O:10])=[N:5]2)[CH2:3][CH2:2]1.O[Li].O>C1COCC1.O>[CH:1]1([N:4]2[CH:8]=[CH:7][C:6]([C:9]([OH:11])=[O:10])=[N:5]2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccn(C2CC2)n1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccn(C2CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 1-cyclopropyl-1H-pyrazole-3-carboxylate (2.5 g, 15 mmol) was dissolved in THF (40 ml) and H2O (10 ml). LiOH.H2O (1.50 g, 22.5 mmol) was added and the mixture was stirred at RT overnight. The reaction mixture was concentrated and acidified to pH 2 using 1 N HCl. The mixture was extracted with EtOAc and the organic layer was concentrated. Yield 1.6 g. 1H-NMR (400 MHz; DMSO-d6): δ 0.96-1.02 (m, 2H), 1.04-1.09 (m, 2H), 3.79-3.84 (m, 1H), 6.66 (d, 1H), 7.88 (d, 1H), 12.6 (bs, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH:8]=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:28][C:29]([Si](C)(C)C)([F:31])[F:30]>O1CCCC1>[F:28][C:29]([F:31])([F:30])[CH:8]([C:2]1([CH3:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)[OH:9]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: CC1(C=O)CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC1(C(O)C(F)(F)F)CCOCC1
Yield: 46.5 %

Procedure:
According to Reference Example 8-12, by use of 4-methyltetrahydro-2H-pyran-4-carbaldehyde (165 mg, 1.29 mmol) dissolved in tetrahydrofuran (5 mL), a 1 mol/L solution of tetrabutylammonium fluoride in tetrahydrofuran (0.258 mL, 0.258 mmol) and (trifluoromethyl)trimethylsilane (0.229 mL, 1.55 mmol), the mixture was stirred and reacted at room temperature for 1.7 hours. Then, purification by extraction gave 2,2,2-trifluoro-1-(4-methyltetrahydro-2H-pyran-4-yl)ethanol (Compound EC) (119 mg, yield: 47%).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:49](=[O:50])[N:13]3[C:14]([C:33]([O:35][CH:36]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])=[C:15]([CH2:19][O:20][C:21](=[O:32])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[CH2:16][S:17](=O)[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)Cl>>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:49](=[O:50])[N:13]3[C:14]([C:33]([O:35][CH:36]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[O:34])=[C:15]([CH2:19][O:20][C:21](=[O:32])[CH2:22][O:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(OCC(=O)OCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4ccccc4)[C@H]3S(=O)C2)cc1
Solvent: ClP(Cl)Cl
Product: COc1ccc(OCC(=O)OCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4ccccc4)[C@H]3SC2)cc1
Yield: 90.5 %

Procedure:
Benzhydryl 7-(2-phenylacetamido)-3-[2-(4-methoxyphenoxy)acetoxymethyl]-3-cephem-4-carboxylate-1-oxide (6.9 g.) and phosphorus trichloride (2.7 g.) were reacted according to a similar manner to that of Preparation 30 (3) to give benzhydryl 7-(2-phenylacetamido)-3-[2-(4-methoxyphenoxy)acetoxymethyl]-3-cephem-4-carboxylate (6.1 g.).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[S:9][CH:8]2[CH:10]=[CH:11][S:12][CH:7]2[CH:6]=1)=[O:4].[C:13]([N:20]1[CH2:27][CH2:26][CH2:25][C@H:21]1[C:22]([OH:24])=[O:23])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].CC#N>C(N(CC)CC)C>[S:9]1[C:5]([C:3](=[O:4])[CH2:2][O:24][C:22]([CH:21]2[CH2:25][CH2:26][CH2:27][N:20]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:23])=[CH:6][CH:7]2[S:12][CH:11]=[CH:10][CH:8]12
Reactant: O=C(CBr)C1=CC2SC=CC2S1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)OCC(=O)C1=CC2SC=CC2S1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
Crude 2-Bromo-1-(3a,6a-dihydro-thieno[3,2-b]thiophen-2-yl)-ethanone (2.48 mmol assuming complete conversion from starting material) was treated with Boc-proline and MeCN (25 mL). Triethylamine was added and the solution was stirred at RT for 1 h then concentrated. The crude residue was purified by silica column chromatography (14% to 35% EtOAc/Hex) to afford the title compound (595 mg, 61%).
Reaction SMILES: [NH:1]([C:3]1[N:8]=[N:7][C:6]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:5]=2[CH:4]=1)[NH2:2].[CH3:15][C:16]([CH3:18])=O>>[C:16](=[N:2][NH:1][C:3]1[N:8]=[N:7][C:6]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:5]=2[CH:4]=1)([CH3:18])[CH3:15]
Reactant: NNc1cc2c(nn1)CCCCCC2
Reactant: CC(C)=O
Product: CC(C)=NNc1cc2c(nn1)CCCCCC2

Procedure:
A solution of 0.5 g of 3-hydrazino-5,6,7,8,9,10-hexahydrocycloocta[c]pyridazine in 15 cc of absolute acetone is heated on a water bath for 1 hour. After cooling the title compound crystallizes. M.P. 165°-167° (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:10](/[C:28]([F:31])([F:30])[F:29])=[CH:11]\[C:12]([C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:16]([CH3:27])[CH:15]=2)=O)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[NH2:32][OH:33].[OH-].[Cs+]>C(Cl)(Cl)Cl.O.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:10]2([C:28]([F:31])([F:30])[F:29])[O:33][N:32]=[C:12]([C:14]3[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[C:16]([CH3:27])[CH:15]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8]
Reactant: NO
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)c(F)c(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Agent: [Cs+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C2=NO[C@@](c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
A 1500 mL reaction-vessel was charged at room temperature with 1-Anthracen-9-ylmethyl quininium chloride (2.93 g, 5.32 mmol) and tert-butyl 4-[(E)-3-(3,5-dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoate (12.7 g, 26.6 mmol) and dissolved in chloroform (700 mL). The mixture cooled down to −20° C. Then, a solution hydroxylamine (50 mass % in water, 3.3 mL) in water (16.7 mL) and cesium hydroxide (10.8 g, 71.8 mmol) in water (20 mL) were added simultaneously dropwise to the reaction mixture over 12 min. After the addition the reaction was kept 1.5 h at −20° C. after which time the conversion was complete. The reaction was brought to room temperature diluted with dichloromethane and washed three times with water. The organic phase was dried over MgSO4 and evaporated to yield 24.2 g of the crude title product. The product was purified over a silica gel column (eluent: EtOAc/Heptane) to obtain 12.6 gr of the title product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH2:5][NH2:6].[Br:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19](O)=[O:20])[CH:15]=[CH:16][CH:17]=1>>[Br:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([CH3:10])=[C:2]([CH3:1])[CH:3]=2)=[O:20])[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccc(CN)cc1C
Reactant: O=C(O)Cc1cccc(Br)c1
Product: Cc1ccc(CNC(=O)Cc2cccc(Br)c2)cc1C
Yield: 93 %

Procedure:
The title compound was prepared from 3,4-dimethylbenzylamine and 3-bromophenylacetic acid, using a method similar to that of preparation 27, as a white solid in 93% yield. 1H NMR (400 MHz, CDCl3) δ: 2.20 (6H, s), 3.50 (2H, s), 4.30 (2H, d), 5.80 (1H, brs), 7.60–7.80 (7H, m); LRMS ESI 332 [M]+
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH2:20]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][N:21]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CS(C)=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:26]2[CH2:27][CH2:28][C:23]3([CH2:22][N:21]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[CH2:20]3)[CH2:24][CH2:25]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N1CC2(CCNCC2)C1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC2(CCN(c3ccc([N+](=O)[O-])cc3)CC2)C1
Temperature: 100 °C

Procedure:
To a solution of 1-fluoro-4-nitrobenzene (0.155 ml, 1.458 mmol) in DMSO was added N,N-diisopropylethylamine (0.926 ml, 5.30 mmol) followed by tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (300 mg, 1.326 mmol). The reaction mixture was heated to 100° C. overnight, and cooled to room temperature. The reaction mixture was quenched with 75 mL water, filtered, washed with water and dried over high-vac to provide the title compound. MS (ESI+) m/z 348.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:13][CH2:12]1)=O.[CH3:14][C:15]1[N:16]=[CH:17][NH:18][C:19]=1[CH3:20]>C(OCC)(=O)C>[CH3:14][C:15]1[N:16]=[C:17]2[C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[CH:11][CH2:13][CH2:12][N:18]2[C:19]=1[CH3:20]
Reactant: O=C(c1ccc(Cl)cc1Cl)C1CC1
Reactant: Cc1nc[nH]c1C
Solvent: CCOC(C)=O
Product: Cc1nc2n(c1C)CCC=C2c1ccc(Cl)cc1Cl
Temperature: 205 °C

Procedure:
Cyclopropyl 2,4-dichlorophenyl ketone (1) (54 g, 0.25 mol) and 4,5-dimethylimidazole (2) (90 g, 1 mol) are combined and heated at 200 to 210° C. under nitrogen for 20 hours. The reaction is cooled and diluted with ethyl acetate (700 ml). The ethyl acetate solution is washed with saturated aq potassium carbonate (300 ml) and water (4×200 ml) and dried over sodium sulfate. The drying agent is removed by filtration and the solvent is removed in vacuo to provide 3.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH3:24][C:25]([CH3:29])([CH3:28])[C:26]#[CH:27]>>[CH3:24][C:25]([CH3:29])([CH3:28])[C:26]#[C:27][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([NH2:23])(=[O:22])=[O:21])(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)CCc1ccc(Br)nc1
Reactant: C#CC(C)(C)C
Product: CC(C)(C)C#Cc1ccc(CCS(=O)(=O)Nc2ccccc2S(N)(=O)=O)cn1
Yield: 34 %

Procedure:
The title compound was synthesized as described for Example 179 a) in 34% yield, starting from 2-(2-(6-bromopyridin-3-yl)ethylsulfonamido)benzenesulfonamide and 3,3-dimethyl-1-butyne. Purification by column chromatography, using 10 to 60% ethyl acetate in heptane as the eluent.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@@H:10]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[O:8])=[CH:4][C:3]=1[C:30]1[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=1.O.NN>CO.C1COCC1>[NH2:12][CH2:11][C@@H:10]([NH:9][C:7]([C:5]1[S:6][C:2]([Cl:1])=[C:3]([C:30]2[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=2)[CH:4]=1)=[O:8])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Cn1nccc1-c1cc(C(=O)N[C@@H](Cc2ccccc2)CN2C(=O)c3ccccc3C2=O)sc1Cl
Agent: NN
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(C(=O)N[C@H](CN)Cc2ccccc2)sc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-chloro-N-[(1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-(phenylmethyl)ethyl]-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxamide (200 mg, 0.40 mmol) in MeOH/THF (10 mL, 1:1) at RT was added hydrazine hydrate (0.20 mL, 4.0 mmol). After stirring for 24 h at RT, the reaction solution was concentrated under vacuum and purified via column chromatography (silica, 3% MeOH in DCM (1% NH4OH)) yielding the title compound as a light yellow solid.