Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[F:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][NH:20][C:21]([C:23]2[S:27][C:26]([N:28]3[CH2:32][CH2:31][CH2:30][C:29]3=[O:33])=[N:25][C:24]=2[CH3:34])=[O:22])=[CH:17][CH:16]=1>>[F:14][C:15]1[CH:36]=[CH:35][C:18]([CH2:19][NH:20][C:21]([C:23]2[S:27][C:26]([N:28]3[CH2:32][CH2:31][CH:30]([CH2:2][C:3]4[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=4)[C:29]3=[O:33])=[N:25][C:24]=2[CH3:34])=[O:22])=[CH:17][CH:16]=1
Reactant: Cc1nc(N2CCCC2=O)sc1C(=O)NCc1ccc(F)cc1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Product: Cc1nc(N2CCC(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)NCc1ccc(F)cc1
Yield: 26 %

Procedure:
Following the procedure as described in Example 2, making variation as required to use 1-(bromomethyl)-4-(trifluoromethoxy)benzene in place of 1-(bromomethyl)-4-(trifluoromethyl)benzene to react with N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide, the title compound was obtained as a white solid in 26% yield: mp 165-166° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.34-7.16 (m, 4H), 7.12 (d, J=8.6 Hz, 2H), 7.01 (t, J=8.6 Hz, 2H), 6.02 (t, J=5.6 Hz, 1H), 4.52 (d, J=5.6 Hz, 2H), 4.09-4.02 (m, 1H), 3.93-3.79 (m, 1H), 3.29-3.20 (m, 1H), 3.05-2.95 (m, 1H), 2.85-2.75 (m, 1H), 2.60 (s, 3H), 2.35-2.19 (m, 1H), 1.99-1.81 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 174.6, 162.3, 155.4, 152.8, 148.1, 136.9, 133.7, 131.6, 130.3, 129.6, 121.2, 118.6, 115.7, 45.9, 44.3, 43.4, 35.7, 24.3, 17.2; MS (ES+) m/z 508.3 (M+1).
Reaction SMILES: [CH:1]1([S:4][C:5]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:6]=2/[CH:7]=[N:8]/[S@:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])[CH2:3][CH2:2]1.[CH:22]([Mg]Br)=[CH2:23]>C1COCC1.COC(C)(C)C>[CH:1]1([S:4][C:5]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:6]=2[CH:7]([NH:8][S@:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])[CH:22]=[CH2:23])[CH2:2][CH2:3]1
Reactant: CC(C)(C)[S@](=O)/N=C/c1cc([N+](=O)[O-])ccc1SC1CC1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: C=CC(N[S@@](=O)C(C)(C)C)c1cc([N+](=O)[O-])ccc1SC1CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 75.1 %

Procedure:
To 85A (3.0 g, 9.2 mmol) in THF (30 mL) and methyl tert-butylether (50 mL) at −78° C. was added vinylmagnesium bromide (1.0 M in THF, 20 mL, 20 mmol) dropwise. The mixture was stirred at −78° C. for 1.0 h before it was quenched with sat. NH4Cl (50 mL) at −78° C. The mixture was extracted with EtOAc (3×50 mL), the organic layer was washed with brine and dried over Na2SO4. After removal of solvent, the crude was purified by silica gel column chromatography using gradient EtOAc in hexanes to give 85B (2.45 g, 78% yield). HPLC and 1H NMR indicated 85B is a mixture of two diastereoisomers in a ratio of 5:1. Major isomer: 1H NMR (400 MHz, CDCl3) δ ppm 0.70-0.81 (m, 2H) 1.17-1.24 (m, 2H) 1.26 (s, 9H) 2.17 (m, 1H) 3.53 (d, J=2.64 Hz, 1H) 5.21-5.32 (m, 3H) 5.91 (m, 1H) 7.72 (d, J=8.79 Hz, 1H) 8.09 (dd, J=8.79, 2.64 Hz, 1H) 8.26 (d, J=2.64 Hz, 1H), LC-MS 355 (M+H).
Reaction SMILES: Cl[C:2]1[C:3]([CH2:22][O:23]C2CCCCO2)=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([S:12]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[CH:30]1([B-](F)(F)F)[CH2:32][CH2:31]1.[K+]>>[CH:30]1([C:2]2[CH:10]=[C:9]([CH3:11])[C:8]3[N:7]([S:12]([C:15]4[CH:16]=[CH:17][C:18]([CH3:19])=[CH:20][CH:21]=4)(=[O:13])=[O:14])[CH:6]=[CH:5][C:4]=3[C:3]=2[CH:22]=[O:23])[CH2:32][CH2:31]1
Reactant: F[B-](F)(F)C1CC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(COC4CCCCO4)c(Cl)cc(C)c32)cc1
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)c(C4CC4)cc(C)c32)cc1

Procedure:
The title compound was synthesized starting from 5-chloro-7-methyl-4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-1-tosyl-1H-indole as described in Example 48-A to 48-C using potassium cyclopropyltrifluoroborate in place of potassium ethylrifluoroborate in Example 48-A. MS (ESI+) m/z 354.2 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N+:7]([O-])=[C:6]([CH3:11])[C:5]=1[CH3:12])[CH3:2].[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>>[C:13]([O:16][CH2:11][C:6]1[C:5]([CH3:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[CH:8][N:7]=1)(=[O:15])[CH3:14]
Reactant: CCOc1cc[n+]([O-])c(C)c1C
Reactant: CC(=O)OC(C)=O
Product: CCOc1ccnc(COC(C)=O)c1C
Yield: 98.4 %

Procedure:
To 22.9 g of 4-ethoxy-2,3-dimethylpyridine-1-oxide, 55.0 g (5.0 eq.) of acetic anhydride was added, and the mixture was allowed to react for 6 hours at 90 to 100° C. The acetic anhydride was distilled off, and the resulting concentrated residue was purified on a silica gel column, to obtain 28.2 g of 2-acetoxymethyl-3-methyl-4-ethoxy-pyridine as an oily matter.
Reaction SMILES: [O:1]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:16][C:17]([CH3:23])([CH2:21][CH3:22])[C:18](Cl)=[O:19]>>[CH3:16][C:17]([CH3:23])([CH2:21][CH3:22])[C:18]([N:13]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8][N:7]([C:18](=[O:19])[C:17]([CH3:23])([CH3:16])[CH2:21][CH3:22])[CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:1][CH2:15][CH2:14]1)=[O:19]
Reactant: CCC(C)(C)C(=O)Cl
Reactant: C1COCCNCCOCCOCCN1
Product: CCC(C)(C)C(=O)N1CCOCCOCCN(C(=O)C(C)(C)CC)CCOCC1

Procedure:
Analogously to Example 2 from 1,4,10-trioxa-7,13-diazacyclopentadecane and 2,2-dimethylbutyryl chloride.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:6]([CH3:11])=[C:5]2[O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1
Reactant: CSc1ccc(Oc2c(C)[nH]c3ccc(F)cc23)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C)c(Oc2ccc(SC)cc2)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of the product from step (ii) (335 mg), potassium carbonate (0.3 g) and ethyl bromoacetate (0.16 ml) in DMF (5 ml) was stirred at RT. After 16 h, ethyl bromoacetate (0.1 ml) and potassium carbonate (0.15 g) were added and the mixture heated at 50° C. for 4 h then partitioned between diethylether/water. The organics were washed with water, dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 10% ethylacetate/iso-hexane. Yield 0.41 g
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].Cl[CH2:11][O:12][CH3:13]>C(#N)C>[CH3:11][O:12][CH2:13][N:5]1[C:4]([CH3:3])=[C:8]([CH3:9])[N:7]=[CH:6]1
Reactant: COCCl
Reactant: Cc1nc[nH]c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: COCn1cnc(C)c1C

Procedure:
At a temperature of 60° C., 500 mg. of picrinic acid and 15.6 g. (0.39 mol) of sodium hydroxide were added to a solution of 31 g. (0.32 mol) of 4,5-dimethylimidazole (H, Bredereck and G. Theilig, Chem. Ber. 86, 88 (1953)) in 150 ml. of acetonitrile. Then 29 g. (0.36 mol) of chloromethoxymethane were added drop-wise, which made the temperature rise to 80° C. The reaction mixture was refluxed for 6 hours and filtered. The filtrate was concentrated by distilling off the solvent and the residue was distilled. 1-(Methoxymethyl)-4,5-dimethylimidazole was obtained. Boiling point 80°-100° C./1.0 mm. Hg. Melting point of the hydrogen oxalate 102°-103° C.
Reaction SMILES: Cl.[C:2](Cl)(=O)[CH3:3].[NH2:6][C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[F:20])[N:10]=[C:9]([C:21]([OH:23])=[O:22])[C:8]=1[Cl:24].C(OCC)(=O)C.CCCCCC>C(O)C>[CH2:2]([O:22][C:21]([C:9]1[C:8]([Cl:24])=[C:7]([NH2:6])[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[F:20])[N:10]=1)=[O:23])[CH3:3]
Reactant: CC(=O)Cl
Reactant: Nc1nc(-c2ccc(Cl)cc2F)nc(C(=O)O)c1Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2F)nc(N)c1Cl
Temperature: 62 °C
Yield: 63.5 %

Procedure:
A 1N solution of HCl in ethanol was generated by adding 0.565 mL of acetyl chloride dropwise to 12 mL of ethanol cooled in an ice bath. This solution was added to 200 mg of 6-amino-5-chloro-2-(4-chloro-2-fluorophenyl)-pyrimidine-4-carboxylic acid and the resulting solution was heated at 62° C. overnight. The reaction mixture was concentrated and the residue partitioned between ethyl acetate and water. The organic phase was dried and concentrated, and the product was purified by column chromatography (dichloromethane/ethyl acetate gradient). A second chromatography utilizing an amine-functionalized silica gel column (Biotage KP-NH) and an ethyl acetate/hexane gradient solvent system yielded the title compound (139 mg, 63.5% yield): mp 131-132° C.: 1H NMR (CDCl3): δ 7.97 (m, 1H), 7.2 (m, 2H), 5.63 (br s, 2H), 4.48 (q, 2H), 1.44 (t, 3H).
Reaction SMILES: CC(C)(NC[CH2:9][CH2:10][NH:11][C:12]([CH3:18])([CH3:17])[C:13](=[N:15][OH:16])[CH3:14])C(=NN)C.[NH2:20]CCN>CO.O>[NH2:20][CH2:9][CH2:10][NH:11][C:12]([CH3:17])([CH3:18])[C:13](=[N:15][OH:16])[CH3:14]
Reactant: CC(=NN)C(C)(C)NCCCNC(C)(C)C(C)=NO
Reactant: NCCN
Solvent: CO
Solvent: O
Product: CC(=NO)C(C)(C)NCCN
Reaction time: 8 h

Procedure:
A solution of Compound A from Example 1 (10 g, 73.8 mmol) was added dropwise to a stirred solution of 1,2-diaminoethane (25 g, 416.7 mmol) in methanol (10 mL) at 0° C. After the addition was complete, the mixture was left overnight at room temperature with stirring. Removal of the methanol in vacuo gave a light yellow oil which was dissolved in water. The pH of the solution was adjusted to about 11. The solvent was removed under vacuum, and the residue was extracted with ethyl acetate. Evaporation of the organic phase gave a light yellow semi-solid which on crystallization with ether gave the product as a crystalline solid. Yield: 5.89 g (50%); mp. 65°-67° C. 1H NMR (CDCl3) δ1.22[s, 6H, C(CH3)2 ], 1.87[s, 3H, C(=N)CH3 ], 2.49(t, 2H, CH2NH2) and 2.88(m, 2H, NHCH2). MS: (M+H)+ =160.
Reaction SMILES: C(O[C:4](=[O:19])[C:5]1[C:10]([Br:11])=[CH:9][N:8]=[C:7]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:6]=1)C.[CH3:20][NH2:21]>>[Br:11][C:10]1[C:5]([C:4]([NH:21][CH3:20])=[O:19])=[CH:6][C:7]([N:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)=[N:8][CH:9]=1
Reactant: CCOC(=O)c1cc(N2CCN(C)CC2)ncc1Br
Reactant: CN
Product: CNC(=O)c1cc(N2CCN(C)CC2)ncc1Br
Yield: 100 %

Procedure:
A solution of 1.45 g (5.8 mmol) 5-bromo-2-(4-methyl-piperazin-1-yl)-isonicotinic acid ethyl ester in 25 ml methylamin (33% in ethanol) was heated in a high pressure vessel at 85° for 12 h. Evaporation of the solvent afforded 1.81 g (100%) of the title compound as yellow crystals. M.p. 122-125° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28]Br)[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:38]([O-:41])(=[S:40])[CH3:39].[K+]>CC(C)=O.CCCCCC>[C:38]([S:40][CH2:28][C:20]1[C@:21]2([CH2:23][CH2:24][C@H:25]3[C:16](=[CH:15][CH:14]=[C:13]4[C@:26]3([CH3:27])[C@@H:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2])[CH2:10][C@H:11]([O:30][Si:31]([C:34]([CH3:36])([CH3:37])[CH3:35])([CH3:33])[CH3:32])[CH2:12]4)[C@@H:17]2[CH2:18][CH:19]=1)[CH3:22])(=[O:41])[CH3:39]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@H](CC[C@]4(C)C(CBr)=CC[C@@H]34)[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CC(=O)SCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
To a solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene (100 mg, 0.183 mmol), triphenylphosphine (96.0 mg, 0.366 mmol) and imidazole (49.8 mg, 0.732 mmol) in dichloromethane (2 ml), was added N-bromosuccinimide (65.1 mg, 0.366 mmol) at 0° C., followed by stirring at room temperature. After 1 hour, hexane was added to the mixture and washed with water and then saturated brine. The organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to remove the solvent, giving a mixture (150 mg) containing 1α,3β-bis(tert-butyldimethylsilyloxy)-17-(bromomethyl)androsta-5,7,16-triene. The mixture was dissolved in acetone (1.5 ml), to which potassium thioacetate (31.4 mg, 0.275 mmol) was added, followed by stirring for 30 min. The reaction mixture was diluted with hexane, filtered and the resulting filtrate was evaporated under reduced pressure to remove the solvent. The residue was purified by preparative thin layer chromatography (2 sheets (each 0.5 mm thickness), hexane:ethyl acetate=20:1, developed once) to give the titled compound (70.2 mg, 64%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:12][CH3:13])[C:10]=1[OH:11])[CH:6]=O.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15][C:16]([CH3:18])=[O:17].N1(CC(O)=O)CCCCC1>C1C=CC=CC=1>[CH2:21]([O:20][C:14](=[O:19])[C:15]([C:16](=[O:17])[CH3:18])=[CH:6][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:10]([OH:11])=[C:9]([O:12][CH3:13])[CH:8]=1)[CH3:22]
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: O=C(O)CN1CCCCC1
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1cc(OC)c(O)c(OC)c1)C(C)=O

Procedure:
Condensation of 3,5-Dimethoxy-4-hydroxy benzaldehyde (syringaldehyde) with ethyl acetoacetate in the presence of piperidine-acetic acid and benzene as the reaction medium at reflux temperature yields the title product. The reaction takes about 3.5 hours for completion.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:11][C:12](=[O:14])[CH3:13])[CH:8]=2)[NH:3]1.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH:24]=O)[CH:22]=2)[CH:17]=[N:16]1.N1CCCCC1>CO>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21](/[CH:24]=[C:10]3/[C:2](=[O:1])[NH:3][C:4]4[C:9]/3=[CH:8][C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:5]=4)[CH:22]=2)[CH:17]=[N:16]1
Reactant: O=Cc1ccc2cn[nH]c2c1
Reactant: CC(=O)Nc1ccc2c(c1)CC(=O)N2
Solvent: C1CCNCC1
Solvent: CO
Product: CC(=O)Nc1ccc2c(c1)/C(=C\c1ccc3cn[nH]c3c1)C(=O)N2
Temperature: 85 °C
Yield: 34.6 %

Procedure:
To a solution of N-(2-oxoindolin-5-yl)acetamide (19 mg, 0.1 mmol) was added 1H-indazole-6-carbaldehyde (16 mg, 0.12 mmol), piperidine (2 uL, 0.011 mmol) and MeOH (2 mL). The reaction was then heated to 85° C. for 30 min. The MeOH was removed in vacuo and the solid triturated with ether to give 11 mg, 34% of the title compound as an orange solid. 1H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 8.06 (s, 1H), 7.92-7.88 (m, 2H), 7.84 (s, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.35 (d, 1H), 6.88 (d, J=8.3 Hz, 1H), 2.04 (s, 3H); MS ESI 319.1 [M+H]+, calcd for [C18H17N5O3S+H]+ 319.11.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:23]([S:26]([OH:29])(=[O:28])=[O:27])([NH2:25])=[NH:24]>CN(C=O)C>[S:26]([OH:29])([OH:28])=[O:27].[NH2:25][C:23](=[NH:24])[N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:3][CH2:2]1.[C:11]([O:10][C:9](=[O:15])[NH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:23](=[NH:24])[NH2:25])[CH2:2][CH2:3]1)([CH3:12])([CH3:14])[CH3:13]
Reactant: N=C(N)S(=O)(=O)O
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC1CCN(C(=N)N)CC1
Product: O=S(O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 130g of 1,1-dimethylethyl (4-piperidinyl-methyl)-carbamate in 1300 ml of DMF is treated with 138 ml of triethylamine and 61.8 g of formamidinesulfonic acid and the mixture is stirred at room temperature overnight. The precipitated material is filtered, suspended in 500 ml of ethanol, again filtered off and dried. There are obtained 65.6 g of tert-butyl 1-(amino-imino-methyl)-piperidin-4-ylmethylcarbamate hemisulfite, MS (ISP): 257.4 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18]C(O)=[C:16]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[O:22])[CH:15]=1.Cl>O1CCCC1.N1C=CC=CC=1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][C:5]2[O:4][C:2](=[O:3])[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=3)[C:21](=[O:22])[C:16]=2[CH:15]=1
Reactant: COc1cccc(NC(=O)c2cc(-c3ccc(F)cc3F)ccc2O)c1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1cccc(-n2c(=O)oc3ccc(-c4ccc(F)cc4F)cc3c2=O)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 12 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 12 (1.42 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0□. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 24.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25](=[O:38])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([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)=[O:10].[F:39][C:40]1[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=1>>[F:39][C:40]1[CH:45]=[CH:44][C:43]([O:1][CH2:2][C:3]2[CH2:4][S:5][C@@H:6]3[CH:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25](=[O:38])[N:7]3[C:8]=2[C:9]([O:11][CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:10])=[CH:42][CH:41]=1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Reactant: Oc1ccc(F)cc1
Product: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COc3ccc(F)cc3)CS[C@H]12

Procedure:
The procedure described in Example 1(a) was repeated, but using 2.00 g of diphenylmethyl 3-hydroxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylate and p-fluorophenol, to afford 400 mg of the title compound as a powder.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([N:5]1[CH:9]=[CH:8][C:7]([C:10]2[CH:17]=[C:16]([F:18])[C:13]([C:14]#[N:15])=[C:12]([F:19])[CH:11]=2)=[N:6]1)[CH3:4].[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]>>[C:20]([C:23]1[CH:27]=[C:26]([C:28]([NH:1][CH2:2][C@@H:3]([N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:17]=[C:16]([F:18])[C:13]([C:14]#[N:15])=[C:12]([F:19])[CH:11]=3)=[N:6]2)[CH3:4])=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21]
Reactant: C[C@@H](CN)n1ccc(-c2cc(F)c(C#N)c(F)c2)n1
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Product: CC(=O)c1cc(C(=O)NC[C@H](C)n2ccc(-c3cc(F)c(C#N)c(F)c3)n2)[nH]n1

Procedure:
The title compound was synthesized from (S)-4-(1-(1-aminopropan-2-yl)-1H-pyrazol-3-yl)-2,6-difluorobenzonitrile (380 mg, 1.45 mmol) and 3-acetyl-1H-pyrazole-5-carboxylic acid (229 mg, 1.48 mmol) using the method of Example 34(d). Yield 249 mg. 1H NMR (400 MHz; d6-DMSO): δ 1.49 (d, 3H), 2.48 (s, 3H), 3.62 (m, 2H), 4.67 (m, 1H), 6.98 (d, 1H), 7.25 (bs, 1H), 7.76 (m, 2H), 7.89 (d, 1H), 8.52 (bs, 1H), 14.18 (bs, 1H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:16]#[N:17])[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.[F-:18].[K+]>CS(C)=O>[C:16]([C:4]1[C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=[C:2]([F:18])[N:3]=1)#[N:17]
Reactant: CC(C)(C)OC(=O)Nc1ncc(Br)nc1C#N
Reactant: [F-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1ncc(F)nc1C#N
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
In 10.5 mL of dimethyl sulfoxide was dissolved 0.35 g of t-butyl 5-bromo-3-cyano-2-pyrazinylcarbamate. After adding 0.17 g of potassium fluoride, the mixture was stirred first at 70° C. for 30 minutes and then at 90° C. for 30 minutes to form t-butyl 3-cyano-5-fluoro-2-pyrazinylcarbamate in the reaction system. Then, 0.17 g of potassium fluoride was added and stirred at 90° C. for 40 minutes. The reaction mixture was returned to room temperature and added to a mixture of 30 ml of ethyl acetate and 60 mL of water, pH was adjusted to 8 with saturated aqueous solution of sodium hydrogen carbonate, and the organic layer was separated. The organic layer thus obtained was washed with saturated aqueous solution of sodium chloride and dried on anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: n-hexane:ethyl acetate=3:1] to obtain 20 mg of 3-amino-6-fluoro-2-pyrazinecarbonitrile as a yellow-colored solid product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Br[CH2:13][CH2:14][CH2:15][CH2:16][Cl:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][CH2:14][CH2:15][CH2:16][Cl:17])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: ClCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(OCCCCCl)cc1
Yield: 91.3 %

Procedure:
A mixture of 30.4 g (0.2 mole) of methyl-4-hydroxybenzoate, 68.6 g (0.4 mole) of 1-bromo-4-chlorobutane and 82.9 g (0.6 mole) of anhydrous potassium carbonate in 1 liter of acetone was heated at reflux for 17 hr. The mixture was cooled, filtered, and the filtrate concentrated under reduced pressure to give an oil which crystallized. The solid was triturated with cold petroleum ether (30°-60° C.), collected by filtration, and dried to yield 44.3 g (92%) of title compound as a white solid. An analytical sample, mp 28.5°-29° C., was prepared from petroleum ether (30°-60° C.).
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]([C:8]1[C:13]2[C:14]([O:36][CH3:37])=[N:15][N:16]([C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]=2[CH:11]=[C:10]([Cl:38])[N:9]=1)=O)(=O)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:48])=CC=1>O1CCOCC1.C(Cl)Cl.CO>[Cl:38][C:10]1[N:9]=[C:8]([C:6]2[S:48][C:1]([CH3:2])=[N:4][N:5]=2)[C:13]2[C:14]([O:36][CH3:37])=[N:15][N:16]([C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]=2[CH:11]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(C(=O)NNC(C)=O)c12
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)nc(-c3nnc(C)s3)c12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
N′-acetyl-6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridine-4-carbohydrazide (48 mg, 0.091 mmol, see synthesis of intermediate 43B) was taken up in 1,4-dioxane (1.0 ml) and Lawesson's Reagent (27.7 mg, 0.068 mmol) was added. The reaction mixture was stirred at 100° C. for 1 hr. Room temperature was attained. The reaction mixture was diluted with DCM and MeOH and was concentrated in vacuo while loading onto silica gel. The products were purified by MPLC 5-30% EtOAc/hexanes to give 2-(6-chloro-3-methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)-5-methyl-1,3,4-thiadiazole (44B). MS: [M+H]+ m/z 524.