Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[N:9]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:8]=1[CH2:26]Br)=[O:6].[C:28]([CH2:30][NH:31][S:32]([C:35]1[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=1)(=[O:34])=[O:33])#[N:29].Cl>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([Cl:16])[CH:14]=2)[N:9]([S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])[C:8]=1[CH2:26][N:31]([CH2:30][C:28]#[N:29])[S:32]([C:35]1[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=1)(=[O:34])=[O:33])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)NCC#N)cc1
Reactant: COC(=O)c1c(CBr)n(S(=O)(=O)c2ccccc2)c2ncc(Cl)cc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(CN(CC#N)S(=O)(=O)c2ccc(C)cc2)n(S(=O)(=O)c2ccccc2)c2ncc(Cl)cc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75.2 %

Procedure:
Sodium hydride (4.1 g, 60% dispersion in mineral oil, 101 mmol) was added portionwise to a cooled (0° C.) solution of 1-benzenesulfonyl-5-chloro-2-bromomethyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid methyl ester (40.8 g, 91.9 mmol) and N-cyanomethyl-4-methyl-benzenesulfonamide (21.3 g, 101 mmol) in DMF (400 mL). The reaction mixture was stirred at 0° C. for 15 minutes, then allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was poured into a cooled, stirred solution of 2M hydrochloric acid (400 mL). The resultant precipitate was collected by filtration (slow) and the cake washed with water, followed by methanol and then diethyl ether. The resulting cake was dried to afford the title compound as a tan solid (39.6 g, 75%). LCMS (Method B: RT=4.58 min, M+H+=573/575. 1H NMR (400 MHz, CDCl3): 8.40 (d, J=2.4 Hz, 1H), 8.33-8.33 (m, 2H), 8.27 (d, J=2.4 Hz, 1H), 7.78 (d, J=8.2 Hz, 2H), 7.64-7.64 (m, 1H), 7.55-7.54 (m, 2H), 7.34 (d, J=8.1 Hz, 2H), 5.43 (s, 2H), 4.28 (s, 2H), 3.96 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:21][CH3:22])[CH:15]=3)[O:11][N:10]=2)[CH:6]=[C:5]([CH3:23])[C:4]=1[OH:24])[CH3:2].[CH2:25]([C@@H:27]1[O:29][CH2:28]1)Cl>[OH-].[Na+].C(O)(C)C.CC(=O)OCC>[CH2:21]([C:16]1[CH:15]=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:7]3[CH:6]=[C:5]([CH3:23])[C:4]([O:24][CH2:25][C@@H:27]4[CH2:28][O:29]4)=[C:3]([CH2:1][CH3:2])[CH:8]=3)[N:13]=2)[CH:19]=[C:18]([CH3:20])[N:17]=1)[CH3:22]
Reactant: ClC[C@H]1CO1
Reactant: CCc1cc(-c2nc(-c3cc(C)c(O)c(CC)c3)no2)cc(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CCc1cc(-c2nc(-c3cc(C)c(OC[C@@H]4CO4)c(CC)c3)no2)cc(C)n1
Reaction time: 24 h

Procedure:
To a solution of 2-ethyl-4-[5-(2-ethyl-6-methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenol (89 mg, 0.276 mmol) in 3 N aq. NaOH (1 mL) and isopropanol (4 mL), (R)-epichlorohydrine (142 mg, 1.53 mmol) is added. The mixture is stirred at rt for 24 h before another portion of (R)-epichlorohydrine (142 mg; 1.53 mmol) is added. Stirring is continued for another 24 h at rt. The mixture is diluted with EA (50 mL) and washed with 1M aq. NaOH (10 mL) and brine (10 mL). The org. phase is dried over MgSO4, filtered and evaporated to give crude (S)-2-ethyl-4-[3-(3-ethyl-5-methyl-4-oxiranylmethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-6-methyl-pyridine; LC-MS*: tR=1.11* min; [M+1]+=380.24.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][C:23]([N:26]6[CH2:30][CH2:29][CH2:28][CH2:27]6)=[N:24][CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:31])[C:8]2=[O:32])=[CH:5][N:4]([CH2:33][C:34](O)=[O:35])[N:3]=1.CN(C=O)C.[Cl-].[CH2:43]([NH:45][CH2:46][CH3:47])[CH3:44]>ClCCl.C([O-])(O)=O.[Na+]>[CH2:43]([N:45]([CH2:46][CH3:47])[C:34](=[O:35])[CH2:33][N:4]1[CH:5]=[C:6]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][C:23]([N:26]6[CH2:30][CH2:29][CH2:28][CH2:27]6)=[N:24][CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:31])[C:8]2=[O:32])[C:2]([CH3:1])=[N:3]1)[CH3:44]
Reactant: CCNCC
Reactant: Cc1nn(CC(=O)O)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc(N5CCCC5)nc4)cc3c21
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCN(CC)C(=O)Cn1cc(-n2c(=O)n(C)c3cnc4ccc(-c5cnc(N6CCCC6)nc5)cc4c32)c(C)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of {3-methyl-4-[3-methyl-2-oxo-8-(2-pyrrolidin-1-yl-pyrimidin-5-yl)-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl]-pyrazol-1-yl}-acetic acid (Stage 247.1.1, 0.12 mmol) and DMF (0.007 ml) in dichloromethane (2 ml) was added oxallyl chloride (0.36 mmol) and the RM was stirred for 45 min at rt. The RM was quenched with diethylamine (Riedel-deHaën, Buchs, Switzerland, 2.4 mmol) and stirred for 5 min at it then diluted with saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organic layers were washed with brine (2×), dried over Na2SO4, filtered and evaporated. The residue was taken in MeOH/DMF and purified by preparative HPLC. The fractions containing pure product were basified with NaHCO3, concentrated, cooled at 4° C. and the precipitate was filtered, washed with water and dried under vacuum to give the title compound as white solid. (HPLC: tR 2.63 min (Method A); M+H=540 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.92 (s, 1H), 8.57 (s, 2H), 8.07-8.04 (m, 2H), 7.87-7.84 (m, 1H), 7.67-7.65 (m, 1H), 5.21-5.04 (m, 2H), 3.57 (s, 3H), 3.52-3.46 (m, 4H), 3.42-3.34 (m, 2H), 3.32-3.34 (m, 2H), 1.96-1.90 (m, 4H), 1.94 (s, 3H), 1.18 (t, 3H), 0.99 (t, 3H))
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].[N:19]([O-:21])=[O:20].[Na+]>C(O)(C(F)(F)F)=O>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:4])=[O:5]
Reactant: O=N[O-]
Reactant: CNS(=O)(=O)c1cccc(Oc2ccccc2)c1
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CNS(=O)(=O)c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
To a solution of 4-(3-(N-methylsulfamoyl)phenyloxy)benzene (0.30 g, 1.14 mmol) in TFA (6 mL) at −10° C. was added NaNO2 (0.097 g, 1.14 mmol) in portions over 5 min. The resulting solution was stirred at −10° C. for 1 h, then was allowed to warm to room 5 temp., and was concentrated under reduced pressure. The residue was separated between EtOAc (10 mL) and water (10 mL). The organic phase was sequentially washed with water (10 mL) and a saturated NaCl solution (10 mL), dried (MgSO4) and concentrated under reduced pressure to give 4-(3-(N-methylsulfamoyl)phenyloxy)-1-nitrobenzene (0.20 g). This material carried on to the next step without further purification. Step 4. Synthesis of 4-(3-(N-methylsulfamoyl)phenyloxy)aniline
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:32])[CH2:9]2)=[C:4]([C:33]([F:36])([F:35])[F:34])[CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:63]([C:65]([F:68])([F:67])[F:66])=[CH2:64]>C1COCC1.CCOCC.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:63]([C:65]([F:68])([F:67])[F:66])=[CH2:64])[CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:32])[CH2:9]2)=[C:4]([C:33]([F:34])([F:36])[F:35])[CH:3]=1
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: C=C(Br)C(F)(F)F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C(c1cccc(S(=O)(=O)N2CCN(c3ccc(F)cc3C(F)(F)F)C[C@H]2C)c1)C(F)(F)F
Yield: 83.6 %

Procedure:
A solution of (R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methyl-1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylsulfonyl)piperazine (106 mg, 0.2 mmol) and Pd(PPh3 (12 mg, 0.01 mmol) in THF (2 mL) was degassed and then added Na2CO3 (0.6 mL, 1.0 M in water, 0.6 mmol) and 2-bromo-3,3,3-trifluoroprop-1-ene (105 mg, 0.6 mmol) under N2. The resultant mixture was heated in a sealed tube in an oil bath at 60° C. overnight. After cooling, diluted with Et2O (10 mL), washed with brine and extracted with Et2O. The combined organic layer was dried over Na2SO4. The crude product was purified on SiO2 gel column eluted with hexanes/EtOAc to give (R)-4-(4-fluoro-2-(trifluoromethyl)phenyl)-2-methyl-1-(3-(3,3,3-trifluoroprop-1-en-2-yl)phenylsulfonyl)piperazine as a colorless oil (83 mg, 85%).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:6][C:5](=O)O[C:3]1=[O:8].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:40][C:41]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:42]=1[C:48]1[N:49]=[C:50]2[N:54]([C:55]=1[C:56]1[CH:57]=[CH:58][C:59]([NH:62][NH2:63])=[N:60][CH:61]=1)[CH:53]=[CH:52][O:51]2.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C1COCC1.C(Cl)Cl.CO.CCOC(C)=O>[F:40][C:41]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:42]=1[C:48]1[N:49]=[C:50]2[N:54]([C:55]=1[C:56]1[CH:57]=[CH:58][C:59]3[N:60]([C:5]([CH2:6][C:2]([CH3:1])([CH3:9])[CH2:3][OH:8])=[N:63][N:62]=3)[CH:61]=1)[CH:53]=[CH:52][O:51]2
Reactant: CC1(C)CC(=O)OC1=O
Reactant: NNc1ccc(-c2c(-c3ccc(F)cc3F)nc3occn23)cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: Ic1ccccc1
Product: CC(C)(CO)Cc1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)cn12
Temperature: -78 °C
Reaction time: 2 h
Yield: 3.1 %

Procedure:
To a 50 mL round-bottom flask was added 3,3-dimethyldihydrofuran-2,5-dione (1.0 g, 7.80 mmol) in THF (25 mL) to give a colorless solution. This solution was cooled to about −78° C. followed by the addition of LAH (1.48 g, 39.0 mmol) in 3 batches. The reaction was warmed to ambient temperature and allowed to stir for about 2 h. 1N NaOH (about 10 mL) and EtOAc (about 10 mL) were added and the reaction was allowed to stir for about 1 h. The reaction was filtered though Celite® and the organic layer was separated, dried over MgSO4 and concentrated under reduced pressure to give a clear colorless oil. To this oil a solution of Dess-Martin periodinane (3.1 g, 7.3 mmol) in DCM (5 mL) was added dropwise and the reaction was allowed to stir for about 1 h. The reaction was then concentrated under reduced pressure, suspended in Et2O, filtered through a short plug of silica gel and subsequently concentrated under reduced pressure. To the resulting oil was added 5-[6-(2,4-difluorophenyl)-imidazo[2,1-b]oxazol-5-yl]-pyridin-2-yl-hydrazine (0.25 g, 0.76 mmol; prepared using C from Example #2, step A with 2-fluoropyridine-5-boronic acid [Asymchem], D with hydrazine) and MeOH (5 mL) followed by heating to about 60° C. for about 1 h. Then the reaction was cooled to ambient temperature and iodobenzene diacetate (0.246 g, 0.764 mmol) was added and the reaction was allowed to stir for about 1 h. The reaction was then concentrated under reduced pressure and purified by silica gel chromatography (40 g of SiO2, gradient from 0% to 10% MeOH in EtOAc) to provide the title compound as a white solid (0.01 g, 3%): LC/MS (Table 1, Method a) R=1.93 min; MS m/z: 424.2 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:29])[CH:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.O>C(OCC)C.[Cl-].[Zn+2].[Cl-]>[C:25]([O:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[CH2:17][CH:11]([CH:10]([C:7]1[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=1)[OH:29])[C:12]([O:14][CH2:15][CH3:16])=[O:13])([CH3:26])([CH3:27])[CH3:28]
Reactant: CCOC(=O)C(Cc1cccc(OC(C)(C)C)c1)C(=O)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(Cc1cccc(OC(C)(C)C)c1)C(O)c1ccc(F)cc1
Reaction time: 2 h

Procedure:
To a suspension of anhydrous zinc chloride (8.17 g, 60 mmol) in diethyl ether (100 ml) was added sodium borohydride (4.54 g, 120 mmol) by small portions, and the mixture was stirred for 2 hrs. Insoluble material was filtered off and washed with diethyl ether. The filtrate was ice-cooled, and a solution of ethyl 3-(4-fluorophenyl)-2-[3-(tert-butyloxy)benzyl]-3-oxopropanoate (10.8 g, 30 mmol) in diethyl ether (20 ml) was added. The mixture was stirred at room temperature for 1 hr., ice-cooled again and water was added to stop the reaction. The mixture was washed with 5% aqueous potassium hydrogen sulfate solution and water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1) to give the objective substance (8.9 g, 79%) as a colorless oil. IR ν maxNeatcm−1: 1728, 1605, 1510, 1260, 1225, 1179, 1154. 1H-NMR (CDCl3) δ: 0.93(3H, t, J=7.2 Hz), 1.31(9H, s, But), 2.90-3.05(3H, m), 3.87(2H, d, J=7.2 Hz), 4.95-5.10(1H, m), 6.70-6.80(1H, m), 6.80(1H, d, J=7.8 Hz), 7.00-7.20(3H, m), 7.30-7.45(2H, m).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][O:8][NH2:9].[NH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16](=O)[C:17]([OH:19])=[O:18])[N:15]=1>>[NH2:10][C:11]1[S:12][CH:13]=[C:14](/[C:16](=[N:9]/[O:8][CH2:7][C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][N:4]=2)/[C:17]([OH:19])=[O:18])[N:15]=1
Reactant: Nc1nc(C(=O)C(=O)O)cs1
Reactant: Cn1ccnc1CON
Product: Cn1ccnc1CO/N=C(\C(=O)O)c1csc(N)n1

Procedure:
N.m.r. in solvent B: 4.73 (q, 2H), 6.93 (s, 1H). 15. The method of condensation was that described in Footnote 11. 16. N.m.r. in solvent B: 3.5 (d, 1H), 3.75 (d, 1H), 3.95 (d, 1H), 4.5 (d, 1H), 4.75 (d, 1H), 4.95 (d, 1H), 5.3 (d, 1H), 5.9 (d, 1H), 7.2 (s, 1H). 17. The starting material was prepared by reaction of O-(1-methylimidazol-2-yl)methylhydroxylamine with 2-(2-aminothiazol-4-yl)glyoxylic acid to give 2-(2-aminothiazol-4-yl)-2-[(Z)-(1-methylimidazol-2-yl)-methoxy-imino]acetic acid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33][CH2:34][C:35]=1[C:36]1[S:40][C:39]([NH:41][C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[N:38][CH:37]=1)[CH:31]([NH:48][C:49](=[O:88])[C:50](=[N:76][O:77][C:78]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])([CH3:80])[CH3:79])[C:51]1[N:52]=[C:53]([NH:56][C:57]([C:70]3[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=3)([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[S:54][CH:55]=1)[C:30]2=[O:89])=[O:27])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH:12]([O:25][C:26]([C:28]1[N:29]2[CH:32]([S:33](=[O:9])[CH2:34][C:35]=1[C:36]1[S:40][C:39]([NH:41][C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)=[N:38][CH:37]=1)[CH:31]([NH:48][C:49](=[O:88])[C:50](=[N:76][O:77][C:78]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])([CH3:80])[CH3:79])[C:51]1[N:52]=[C:53]([NH:56][C:57]([C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)([C:64]3[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=3)[C:70]3[CH:71]=[CH:72][CH:73]=[CH:74][CH:75]=3)[S:54][CH:55]=1)[C:30]2=[O:89])=[O:27])([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Nc4cccnc4)s3)CSC12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(C)(C)ON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Nc4cccnc4)s3)CS(=O)C12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 5.1 %

Procedure:
A solution of m-chloroperbenzoic acid (2.59 g) in methylene chloride (52 cc) is run, over a period of 30 minutes, into a solution, cooled to 0° C., of the syn isomer of 2-benzhydryloxycarbonyl-7-{2-[(2-t-butoxycarbonylprop-2-yl)-oxyimino]-2-(2-tritylaminothiazol-4-yl)-acetamido}-8-oxo-3-[2-(pyridin-3-yl-amino)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene (13.46 g) in methylene chloride (123 cc). The mixture is stirred for 15 minutes at 0° C. and the reaction solution is then diluted with methylene chloride (200 cc). The mixture is washed successively with a semi-saturated solution of sodium bicarbonate (200 cc) and distilled water (2×200 cc). The organic phase is then dried over anhydrous magnesium sulphate and filtered and the filtrate is then concentrated under reduced pressure (100 mm Hg; 13.3 kPa) at 30° C. The residue is purified by chromatography on a column (height=29 cm, diameter=5.8 cm) containing silica gel (0.04-0.06 mm), elution being carried out under a pressure of 0.4 bar with a mixture of cyclohexane and ethyl acetate (10/90 by volume) (2 liters) and 125 cc fractions being collected. Fractions 11 to 15 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. to give the syr isomer of 2-benzhydryloxycarbonyl-7-{2-[(2-t-butoxycarbonyl-prop-2-yl)-oxyimino]-2-(2-tritylaminothiazol-4-yl)-acetamido}-8-oxo-3-[2-(pyridin-3-yl-amino)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene 5-oxide (0.70 g) in the form of a hard yellow foam.
Reaction SMILES: [C:1]1([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH:19]=[C:20]([C:23]#[N:24])[C:21]#[N:22])[CH2:15][CH2:14]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O.O>O1CCCC1>[C:1]1([C@H:13]2[CH2:14][CH2:15][C@H:16]([CH2:19][CH:20]([C:23]#[N:24])[C:21]#[N:22])[CH2:17][CH2:18]2)[N:2]=[N:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2
Reactant: N#CC(C#N)=C[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Solvent: O
Solvent: C1CCOC1
Product: N#CC(C#N)C[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-{[trans-4-(7H-Pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)cyclohexyl]methylene}malononitrile (25.8 mg, 0.0812 mmol) in tetrahydrofuran (3 mL) was mixed with diethyl 1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate (30.8 mg, 0.122 mmol) and stirred at room temperature for 1 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1→1/2→0/1 (v/v)) to give the title compound as a colorless solid (14.2 mg, yield 55%).
Reaction SMILES: [BH4-].[Na+].[CH:3]([C:5]1[C:6]([O:12][CH3:13])=[N:7][CH:8]=[CH:9][C:10]=1[I:11])=[O:4]>CO>[OH:4][CH2:3][C:5]1[C:6]([O:12][CH3:13])=[N:7][CH:8]=[CH:9][C:10]=1[I:11]
Reactant: COc1nccc(I)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1nccc(I)c1CO

Procedure:
Solid NaBH4 (28 mg, 0.74 mmol) was added in one portion to a solution of 3-formyl-4-iodo-2-methoxypyridine (prepared according to the method of Fang et al., J. Org. Chem., 1994, 59, 6142) (98 mg, 0.37 mmol) in methanol (4 mL) at −5° C. Vigorous bubbling was observed and the yellow reaction solution turned colorless. The reaction was immediately quenched by the addition of water (2 mL) and the methanol was removed under reduced pressure. The resulting residue was diluted with ethyl acetate (20 mL) and water (20 mL). The aqueous layer was separated and extracted with ethyl acetate (3×10 mL). The organic fractions were combined, dried (MgSO4), filtered and concentrated to give 3-(hydroxymethyl)-4-iodo-2-methoxypyridine as a colorless, crystalline solid. This material was used in the next reaction without further purification. R/0.4 (30% ethyl acetate/petrol elution). MS (APCI, m/z 266 (M++1, 100%). 1H NMR (200 MHz, CDCl3): δ3.98 (s, 3H), 4.80 (s, 2H), 7.34 (d, J=4.0 Hz, 1H), 7.70 (d, J=4.0 Hz, 1H).
Reaction SMILES: [H-].[Na+].C(=O)=O.CC(C)=O.[C:10]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:11][C:12]([O:14]CC)=O.[N+:21]([C:24]1C=CC=[C:26]([CH:27](Cl)Cl)[C:25]=1O)([O-:23])=[O:22]>C(COC)OC.C(Cl)Cl>[OH:14][C:12]1[C:20]2[C:19](=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=[CH:26][CH:27]=2)[O:18][C:10](=[O:17])[CH:11]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1cccc(C(Cl)Cl)c1O
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC(C)=O
Solvent: ClCCl
Product: O=c1cc(O)c2cccc([N+](=O)[O-])c2o1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of NaH (6.94 g, 0.291 mole) in dimethoxyethane is cooled using dry ice/acetone cooling, treated dropwise with diethyl malonate (46.6 g, 0.29 mole), allowed to warm to 0° C., treated dropwise with a solution of 3-nitrosalicylyl chloride (19.5 g, 0.10 mole) in dimethoxyethane, allowed to warm to room temperature, stirred for 3 hours at room temperature, heated at 60° C. until reaction is complete by HPLC analysis, cooled to room temperature, poured onto a mixture of ice water and methylene chloride and stirred for about 0.5 hour. The phases are separated, the aqueous phase is acidified with 50% HCl to pH 5 and filtered. The filtercake is dispersed in acetic acid, heated and filtered. This filtercake is air-dried and 8.6 g is dispersed in dimethyl sulfoxide, heated at 100° C. for about 2 hours, cooled to room temperature, poured onto ice water and filtered. The solid is taken up in acetonitrile, filtered hot, cooled and filtered to give the title product, mp 242°-245° C., identified by IR, 1HNMR and mass spectral analyses.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:12]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8].Cl.[C:26]1([C:32]2[CH2:33][CH2:34][NH:35][CH2:36][CH:37]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:26]1([C:32]2[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]([C:12]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:13]=3[C:14]([O:16][CH3:17])=[O:15])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:34][CH:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: CCOC(=O)N(CCCCCl)c1cc([N+](=O)[O-])ccc1C(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)N(CCCCN1CC=C(c2ccccc2)CC1)c1cc([N+](=O)[O-])ccc1C(=O)OC
Temperature: 80 °C
Reaction time: 16 h
Yield: 53.5 %

Procedure:
A mixture of methyl 2-[N-(4-chlorobutyl)-N-ethoxycarbonylamino]-4-nitrobenzoate (2.20 g), 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (1.32 g), sodium iodide (921 mg), and potassium carbonate (1.69 g) in dry dimethylformamide (30 ml) was stirred at 80° C. for 16 hours. The reaction mixture was poured into ice-water, extracted with ethyl acetate. Combined organic extract was washed in turn with water and brine, dried over magnesium sulfate, and evaporated. The crude residue was chromatographed on silica gel (40 g), eluting with a mixed solvent of chloroform and methanol (50:1 V/V) to give methyl 2-[N-{4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)butyl}-N-ethoxycarbonylamino]-4-nitrobenzoate (1.58 g).
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:11](Br)[CH:12]=[CH2:13]>CN(C=O)C>[CH2:13]([O:7][CH2:6][CH:1]=[CH2:8])[CH:12]=[CH2:11].[C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCBr
Agent: Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCC=C
Reaction time: 19 h

Procedure:
An o-cresol novolac resin (9.8 g, 0.082 mol) and DMF (70 mL) are added under nitrogen to a 250 ml 3-neck flask. NaH (2.55 g, 0.106 mol) is slowly added to the stirred solution. Allyl bromide (14.9 g, 0.123 mol) is then added drop-wise over 30 minutes. The reaction is continued for 19 hours at room temperature. The solids are filtered off and 70 mL toluene is added. The resulting solution is washed with 70 mL of water. The product allyl ether of the o-cresol novolac resin is isolated by evaporating off toluene, then drying overnight in vacuum oven at 60° C.