Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH2:34](I)[CH:35]=[CH2:36].[Cl-].[NH4+]>C(OCC)(=O)C.CCCCCC.O1CCCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:23])[CH:15]([C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH2:36][CH:35]=[CH2:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cc1ccc(F)cc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: C=CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCC(C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)c1ccc(F)cc1
Reaction time: 0.42 h

Procedure:
Combine (S)-4-benzyl-3-(4-fluorophenyl)acetyl-2-oxazolidinone (14.28 g, 45.6 mmol) and tetrahydrofuran (150 mL). Cool in a dry-ice/acetone bath. Add dropwise a solution of sodium hexamethyldisilazide (50 mL, 1.0 M in tetrahydrofuran, 50 mmol). After 25 minutes, add allyl iodide (13 mL, 142.2 mmol) and then replace the bath with a dry-ice/carbon tetrachloride bath. After 1 hour, quench the reaction by the addition of a saturated aqueous ammonium chloride solution, extract with diethyl ether, and separate the layers. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/6 ethyl acetate/hexane. Combine the product containing fractions, evaporate, and recrytallize from chloroform/hexane to give (S)-4-benzyl-3-(2-(4-fluorophenyl)pent-4-enoyl)-2-oxazolidinone: mp; 103-104° C. Rf =0.57 (silica gel, 20% ethyl acetate/hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10]Cl)=[O:8])=[CH:5][C:4]=1[CH3:14].[C:15]([NH:18][C:19]1[C:20]([I:35])=[C:21]([N:30]([C:32](=[O:34])[CH3:33])[CH3:31])[C:22]([I:29])=[C:23]([C:26]([O-:28])=[O:27])[C:24]=1[I:25])(=[O:17])[CH3:16].[K+].[I-].[Na+]>CN(C=O)C>[C:15]([NH:18][C:19]1[C:20]([I:35])=[C:21]([N:30]([C:32](=[O:34])[CH3:33])[CH3:31])[C:22]([I:29])=[C:23]([C:26]([O:28][CH2:10][O:9][C:7](=[O:8])[C:6]2[CH:12]=[CH:13][C:3]([O:2][CH3:1])=[C:4]([CH3:14])[CH:5]=2)=[O:27])[C:24]=1[I:25])(=[O:17])[CH3:16]
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Reactant: COc1ccc(C(=O)OCCl)cc1C
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)OCOC(=O)c2c(I)c(NC(C)=O)c(I)c(N(C)C(C)=O)c2I)cc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Chloromethyl 4-methoxy-3-methylbenzoate (Intermediate 8) (2.38 g, 11.0 mmol) in dry DMF (100 ml) is added dropwise at 50° C. to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (6.7 0 g, 10.0 mmol) and sodium iodide (75 mg, 0.50 mmol) in dry DMF (140 ml). The precipitate is removed by filtration after stirring for 4.5 hours and 16 hours at room temperature, and the solvent is removed at reduced pressure. The residue is dissolved in chloroform (100 ml) and washed four times with a saturated sodium hydrogen carbonate solution. After drying with magnesium sulfate the solvent is removed at reduced pressure to give the title compound:
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])[CH2:2][CH2:3][CH3:4].[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([NH2:29])=[CH:28][C:23]=2[CH:22]=[CH:21]1>CC#N>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([NH:29][C:8]3[C:9](=[O:10])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[S:6](=[O:19])(=[O:18])[C:7]=3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:28][C:23]=2[CH:22]=[CH:21]1
Reactant: CCCCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: Nc1ccc2occc2c1
Solvent: CC#N
Product: CCCCN1C(=O)C(Nc2ccc3occc3c2)=C(c2ccccc2)S1(=O)=O
Yield: 26.8 %

Procedure:
A solution of 2-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.047 g, 0.141 mmol) and 1-benzofuran-5-amine (0.046 g, 0.345 mmol) in MeCN (1.5 ml) was heated in a microwave reactor at 130° C. for 60 mins and at 140° C. for 45 mins. The reaction mixture was evaporated and the residue was purified by column chromatography using EtOAc:heptane (1:3) as eluant. Crystallisation from hexane and EtOH gave the title compound (0.015 g, 27%). 1H NMR (400 MHz, CD3CN): 7.80 (bs, 1H), 7.65 (d, 1H), 7.17-7.09 (m, 4H), 7.07-7.02 (m, 3H), 6.85 (dd, 1H), 6.60-6.58 (m, 1H), 3.76 (t, 2H), 1.87-1.78 (m, 2H), 1.54-1.43 (m, 2H), 1.01 (t, 3H); Mass Spectrum: M+H+ 397.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][N:5]([S:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[S:12][C:11]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])(=[O:9])=[O:8])[CH2:4]1.C(N(CC)C(C)C)(C)C.[C:37]([O:41][CH2:42][CH3:43])(=[O:40])[CH:38]=[CH2:39].CCOC(C)=O>CN(C=O)C>[F:27][C:21]1[CH:22]=[C:23]([I:26])[CH:24]=[CH:25][C:20]=1[NH:19][C:11]1[S:12][C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:18]2[C:10]=1[S:7]([N:5]1[CH2:6][CH:3]([CH2:2][NH:1][CH2:39][CH2:38][C:37]([O:41][CH2:42][CH3:43])=[O:40])[CH2:4]1)(=[O:8])=[O:9]
Reactant: C=CC(=O)OCC
Reactant: NCC1CN(S(=O)(=O)c2c(Nc3ccc(I)cc3F)sc3ncccc23)C1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCNCC1CN(S(=O)(=O)c2c(Nc3ccc(I)cc3F)sc3ncccc23)C1
Reaction time: 18 h
Yield: 37 %

Procedure:
To a stirring mixture of Example 2 (160 mg, 0.31 mmol) and N,N-diisopropyl-ethylamine (57 μL, 31 mmol) in DMF (5 mL) was added ethyl acrylate (51 μL, 0.31 mmol) and the mixture allowed to stir for 18 hours. After this time EtOAc (25 mL) was added to the reaction mixture which was then washed with brine (3×25 mL), dried (sodium sulfate) and then reduced in vacuo. The resulting oil was purified by column chromatography (SiO2, 50% DCM in EtOAc) to afford the title compound as a colourless oil (71 mg, 38%). δH (CDCl3) 8.97 (1H, s), 8.30 (1H, dd, J 1.6, 4.7 Hz), 8.12 (1H, dd, J 1.6, 8.2 Hz), 7.51 (2H, m), 7.33 (1H, dd, J 8.7, 8.7 Hz), 7.23 (1H, dd, J 4.7, 8.2 Hz), 4.04 (2H, q, J 7.2 Hz), 3.88 (2H, dd, J 8.0, 8.0 Hz), 3.55 (2H, dd, J 5.6, 8.0 Hz), 2.71 (2H, t, J 6.3 Hz), 2.64 (2H, d, J 7.3 Hz), 2.53 (1H, m), 2.33 (2H, t, J 6.3 Hz), 1.17 (3H, t, J 7.2 Hz). Exchangeable protons were not observed. LCMS (pH 10) RT 3.19 minutes, (ES+) 619 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)[C:5]([Cl:26])=[CH:4][N:3]=1.[NH2:27][C:28]1[CH:41]=[CH:40][C:31]2[NH:32][C:33](=[O:39])[CH2:34][CH2:35][C:36]([CH3:38])([CH3:37])[C:30]=2[CH:29]=1>>[Cl:26][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[N:21]2[CH:25]=[CH:24][CH:23]=[N:22]2)=[N:7][C:2]([NH:27][C:28]2[CH:41]=[CH:40][C:31]3[NH:32][C:33](=[O:39])[CH2:34][CH2:35][C:36]([CH3:38])([CH3:37])[C:30]=3[CH:29]=2)=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(Nc2ccc(N3CCOCC3)cc2-n2cccn2)n1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Product: CC1(C)CCC(=O)Nc2ccc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4-n4cccn4)n3)cc21

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-(4-morpholin-4-yl-2-pyrazol-1-yl-phenyl)-amine was reacted with 7-amino-5,5-dimethyl-1,3,4,5-tetrahydro-bezo[b]azepin-2-one, in a similar manner as Example 601b, to yield desired product 7-[5-Chloro-4-(4-morpholin-4-yl-2-pyrazol-1-yl-phenylamino)-pyrimidin-2-ylamino]-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as a lyophylate (7%); 1H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 9.39 (s, 1H), 9.31 (s, 1H), 8.25 (s, 1H), 8.09 (s, 1H), 7.98 (bd, 1H), 7.82 (s, 1H), 7.59 (d, J=8.08 Hz, 1H), 7.41 (s, 1H), 7.12 (s, 1H), 6.98 (d, J=11.11 Hz, 1H), 6.79 (d, J=8.59 Hz, 1H), 6.54 (s, 1H), 3.78 (m, 4H), 3.21 (m, 4H), 2.15 (m, 2H), 1.95 (m, 2H), 1.27 (s, 6H); MS (m/e) 559.54 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[Cl:10][C:11]1[CH:12]=[N:13][C:14]2[N:15]([N:17]=[C:18]([S:20](Cl)(=[O:22])=[O:21])[N:19]=2)[CH:16]=1>N1C=CC=CC=1>[Cl:10][C:11]1[CH:12]=[N:13][C:14]2[N:15]([N:17]=[C:18]([S:20]([NH:4][C:3]3[C:2]([F:1])=[CH:8][CH:7]=[CH:6][C:5]=3[F:9])(=[O:22])=[O:21])[N:19]=2)[CH:16]=1
Reactant: Nc1c(F)cccc1F
Reactant: O=S(=O)(Cl)c1nc2ncc(Cl)cn2n1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1c(F)cccc1F)c1nc2ncc(Cl)cn2n1
Yield: 55.6 %

Procedure:
The starting 2,6-difluoroaniline (1.7 g, 13 mmol) was dissolved in 3.5 ml of pyridine and 3.5 g (14 mmol) of 6-chloro-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonyl chloride was added. After an exothermic reaction subsided the reaction mixture was heated at 60°-70° C. overnight. The solvent was removed by evaporation at reduced pressure and the residue was taken up in aqueous sodium bicarbonate. The aqueous solution was washed with ether, and acidified with acqueous HCl. The solid which separated upon acidification was collected by filtration, dried and recrystallized from methanol to afford 2.5 g (55%) of the desired product as a crystalline solid, mp 224°-226° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: Cl.[CH2:2]([C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([CH2:17][NH:18][C:19]([CH:21]2[CH:26]3[CH:22]2[CH2:23][NH:24][CH2:25]3)=[O:20])[CH:7]=1)[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.[C:34]1([S:40](Cl)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CCCCCC>C(Cl)Cl.C(OCC)(=O)C>[CH2:2]([C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([CH2:17][NH:18][C:19]([CH:21]2[CH:26]3[CH:22]2[CH2:23][N:24]([S:40]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:42])=[O:41])[CH2:25]3)=[O:20])[CH:7]=1)[CH:3]([CH3:5])[CH3:4]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)Cc1cc(CNC(=O)C2C3CNCC32)nn1-c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)Cc1cc(CNC(=O)C2C3CN(S(=O)(=O)c4ccccc4)CC32)nn1-c1ccccc1
Reaction time: 0.08 h
Yield: 79.5 %

Procedure:
The 6-((5-isobutyl-1-phenyl-1H-pyrazole-3-yl)methylcarbamoyl)-3-azabicyclo[3.1.0]hexane hydrochloride (69.5 mg, 0.185 mmol) prepared in Example 11 was dissolved in 2.0 mL of methylene chloride and triethylamine (54.3 μL, 0.389 mmol) was added dropwise at 0° C. After stirring for 5 minutes, benzenesulfonyl chloride (24.9 μL, 0.195 mmol) was added dropwise. 10 minutes later, after stirring at room temperature for 1 hour, the completion of the reaction was confirmed by TLC (hexane:ethyl acetate=1:2). After the reaction was completed, the reaction mixture was extracted with methylene chloride after adding water and saturated sodium bicarbonate. The organic layer was dried with anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and separated by column chromatography (hexane:ethyl acetate=1:1→1:2) to obtain 70.4 mg (79.4%) of the target compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:41])[C@@H:15]([NH2:40])[CH2:16][CH2:17][CH2:18][NH:19]/[C:20](/[NH2:39])=[N:21]/[S:22]([C:25]2[C:26]([CH3:38])=[C:27]([CH3:37])[C:28]3[O:32][C:31]([CH3:34])([CH3:33])[CH2:30][C:29]=3[C:35]=2[CH3:36])(=[O:24])=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH:44]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46][C:45]=1[S:54](Cl)(=[O:56])=[O:55]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:41])[C@@H:15]([NH:40][S:54]([C:45]2[CH:46]=[CH:47][C:48]3[C:53](=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH:44]=2)(=[O:56])=[O:55])[CH2:16][CH2:17][CH2:18][NH:19]/[C:20](/[NH2:39])=[N:21]/[S:22]([C:25]2[C:26]([CH3:38])=[C:27]([CH3:37])[C:28]3[O:32][C:31]([CH3:33])([CH3:34])[CH2:30][C:29]=3[C:35]=2[CH3:36])(=[O:23])=[O:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](N)C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](NS(=O)(=O)c2ccc3ccccc3c2)C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(C)c2c1OC(C)(C)C2
Temperature: 5 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of compound U (28.0 g, 46.2 mmol) in THF (250 mL) was added aqueous 1N NaOH (171 mL). The reaction mixture was cooled to ˜5° C., a solution of 2-naphthalene sulfonylchloride (26.19 g, 115.6 mmol) in THF (125 mL) was added dropwise. The reaction mixture was stirred at ˜5° C. for 10 min, with stirring continued at room temperature for 2 h. The reaction mixture was diluted with EtOAc (1 L), washed with aqueous 1N NaOH (1 L), water (1 L) and brine (1 L). The organic layer was separated, dried over Na2SO4 and removal of the solvent in vacuo to afford compound V (36.6 g, 46.2 mmol). LC-MS [M+H] 785.5 (C38H52N6O8S2+H, calc: 785.9).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:15][O:16][C:17]1[CH:23]=[C:22]([S:24]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:21]=[CH:20][C:18]=1[NH2:19]>CN(C)C(=O)C>[F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4]([NH:19][C:18]1[CH:20]=[CH:21][C:22]([S:24]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)(=[O:25])=[O:26])=[CH:23][C:17]=1[O:16][CH3:15])=[O:5]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: COc1cc(S(=O)(=O)c2ccncc2)ccc1N
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: COc1cc(S(=O)(=O)c2ccncc2)ccc1NC(=O)C(C)(O)C(F)(F)F
Temperature: -10 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.35 g) in N,N-dimethylacetamide (20 mL) was rapidly added thionyl chloride (1.01 g) and the mixture (a precipitate formed after a few minutes) was stirred at -15 to -5° C. for 1 hour. 2-Methoxy-4-(4-pyridylsulfonyl)aniline (1.50 g) was then added in one portion and the mixture allowed to stir at room tmmperature overnight. The solution was poured into ice water (200 mL) and the resulting tan solid was collected and recrystallized from absolute ethanol to yield the title compound as a white solid (1.58 g); mp 220-222° C.; MS: 405(M+1); NMR (250 MHz): 1.53 (s,3,), 4.02 (s,3), 7.62 (d,1, J=1.9), 7.68 (dd,1, J=1.9, J=8.5), 7.92-7.95 (m,2,), 8.02 (s,1,), 8.46 (d,1, J=10) 8.80-8.89 (m,2,), 9.90 (s,1). Analysis for C16H15F3N2O5S: Calculated: C, 47.53; H, 3.74; N, 6.93; Found: C, 47.56; H, 3.77; N, 6.76.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:38][CH2:39][CH2:40][CH3:41])=[C:19]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:27][CH:26]=3)[C:20]=2[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:42]>C(Cl)Cl.O1CCOCC1>[ClH:42].[ClH:42].[CH2:38]([C:18]1[N:17]=[N:16][C:15]([O:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[C:20]([C:21]([F:22])([F:24])[F:23])[C:19]=1[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH:32]2[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]2)=[CH:29][CH:30]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(C(F)(F)F)c1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCNCC2)c(C(F)(F)F)c1-c1ccc(OC2CCCCC2)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-[6-butyl-5-(4-cyclohexyloxy-phenyl)-4-trifluoromethyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (0.294 mmol, 0.17 g) in DCM (1 mL) was added 4 N HCl in dioxane (0.5 mL) and the reaction was stirred for 1 hour. The solvents were removed with reduced pressure and the salt was triturated with diethyl ether and filtered to give 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-5-trifluoromethyl-pyridazine dihydrochloride (0.12 g).
Reaction SMILES: [N+]([O-])(O)=O.Cl[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH3:12])[CH:7]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)(O)[O-].[Na+].C(O)CCCC>O>[CH3:12][C:8]1[CH:7]=[C:6]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:11]=[CH:10][N:9]=1
Reactant: C1CNCCN1
Reactant: Cc1cc(Cl)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCO
Solvent: O=[N+]([O-])O
Solvent: O
Product: Cc1cc(N2CCNCC2)ccn1
Yield: 60.2 %

Procedure:
A mixture of 4-chloro-2-methylpyridine nitrate (5.00 g), piperazine (9.00 g), anhydrous sodium bicarbonate (6.60 g) and amyl alcohol (60 ml) was heated under reflux for 18 hours. The mixture was cooled and water was added to dissolve inorganic material. The organic layer was washed four times with brine and all the aqueous extracts were combined and extracted with ethyl acetate. The organic layers were combined, dried over sodium sulphate and evaporated. The residue was crystallised from ethyl acetate/hexane to give 1-(2-methylpyrid-4-yl)piperazine (2.80 g), m.p. 93°-94° C.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([N:13]1[C:18](=[O:19])[CH:17]([CH:20]([CH3:22])[CH3:21])[C:16](=O)[NH:15][C:14]1=[O:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)C>[CH2:6]([N:13]1[C:18](=[O:19])[C:17]([CH:20]([CH3:22])[CH3:21])=[C:16]([Cl:3])[NH:15][C:14]1=[O:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)C1C(=O)NC(=O)N(Cc2ccccc2)C1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: CC(C)c1c(Cl)[nH]c(=O)n(Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To 16.8 ml of 50% ethanol, 78.7 ml (844 mmol) of phosphorus oxychloride was added drop by drop, with stirring under ice cooling conditions. To this solution, 26.03 g (100 mmol) of 3-benzyl-5-isopropylpyrimidine-2,4,6(1H,3H)-trione was added little by little. This mixture was stirred at 50° C. for 30 minutes and then at 100° C. for 90 minutes. After cooling, the reaction mixture was poured into ice water and stirred for 1 hour. The resulting precipitate was collected by filtration, washed with water and n-hexane and dried to yield 27.05 g (97.0%, white crystal) of the desired product.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:35]1[N:39]=[CH:38][S:37][N:36]=1)[C:19]([NH:21][CH:22]1[C:33](=[O:34])[N:24]2[C:25]([C:30]([OH:32])=[O:31])=[C:26]([Cl:29])[CH2:27][S:28][C@H:23]12)=[O:20])=[O:14])(C)(C)C.C(OC(C)C)(C)C.CCCCCC>C(Cl)Cl.C1(OC)C=CC=CC=1>[C:13]([CH2:15][O:16][N:17]=[C:18]([C:35]1[N:39]=[CH:38][S:37][N:36]=1)[C:19]([NH:21][CH:22]1[C:33](=[O:34])[N:24]2[C:25]([C:30]([OH:32])=[O:31])=[C:26]([Cl:29])[CH2:27][S:28][C@H:23]12)=[O:20])([OH:14])=[O:12]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1ncsn1
Solvent: CCCCCC
Solvent: COc1ccccc1
Solvent: ClCCl
Product: O=C(O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1ncsn1
Reaction time: 1.5 h
Yield: 69.2 %

Procedure:
Trifluoroacetic acid (5.2 ml) was added to a suspension of 7-[2-tert-butoxycarbonylmethoxyimino-2-(1,2,4-thiadiazol-3-yl)acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer) (1.3 g) in methylene chloride (2.5 ml) and anisole (1.3 ml) at ambient temperature, and the mixture was stirred for 1.5 hours at the same temperature. To the resultant solution was added a mixture of diisopropyl ether (30 ml) and n-hexane (15 ml), followed by stirring. The precipitates were collected by filtration and added to a mixture of ethyl acetate and water, followed by adjusting to pH 7.5 with 20% aqueous sodium carbonate. The separated aqueous layer was adjusted to pH 1.8 with 10% hydrochloric acid and saturated with sodium chloride. The resultant aqueous soluiton was extracted with a mixed solvent of ethyl acetate and tetrahydrofuran (2:1 by volume). The extract was washed with a saturated aqueous sodium chloride, dried over magnesium sulfate and then evaporated to give 7-[2-carboxymethoxyimino-2-(1,2,4-thiadiazol-3-yl)acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer) (0.8 g).
Reaction SMILES: C([C@@]12[C@@H]3[C@H]([C@H]4[C@@](CC3)(C)C(=O)CC4)CCC1=CC(=O)CC2)C#C.[CH2:24]=[C:25]1[CH2:42][CH2:41][C@@:40]2([CH2:43][C:44]#[CH:45])[C:27]([CH2:28][CH2:29][C@@H:30]3[C@@H:39]2[CH2:38][CH2:37][C@@:35]2([CH3:36])[C@H:31]3[CH2:32][CH2:33][C:34]2=[O:46])=[CH:26]1>>[CH2:24]=[C:25]1[CH2:42][CH2:41][C@@:40]2([CH2:43][C:44]#[CH:45])[C:27]([CH2:28][CH2:29][C@@H:30]3[C@@H:39]2[CH2:38][CH2:37][C@@:35]2([CH3:36])[C@H:31]3[CH2:32][CH2:33][C@@H:34]2[OH:46])=[CH:26]1
Reactant: C#CC[C@]12CCC(=C)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: C#CC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C#CC[C@]12CCC(=C)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12

Procedure:
The compound 10β-propargyl-estra-4-ene-3,17-dione which is described by Convey et al in J. Biol. Chem., 256, 1076 (1981) is converted to compound 12, which is 3-methylene-10β-propargyl-estra-4-ene-17-one. This latter compound is reduced to form 3-methylene-10β-propargyl-estra-4-ene-17β-ol, compound 8.
Reaction SMILES: C(C1C=CC=CC=1C1C=CC(C[N:14]2[C:18]([C:19]([NH2:21])=[O:20])=[C:17]([NH:22][C:23](=O)CC)[N:16]=[CH:15]2)=CC=1)#N.C[Sn](N=[N+]=[N-])(C)C>C1(C)C=CC=CC=1>[NH:21]1[C:19](=[O:20])[C:18]2[NH:14][CH:15]=[N:16][C:17]=2[N:22]=[CH:23]1
Reactant: CCC(=O)Nc1ncn(Cc2ccc(-c3ccccc3C#N)cc2)c1C(N)=O
Agent: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: O=c1[nH]cnc2nc[nH]c12
Yield: 83 %

Procedure:
2.17 g (5.81 mmol) of the amide thus prepared was suspended in 30 ml of toluene and 5.00 g (24.3 mmol) of trimethyl tin azide was added to the suspension, followed by heating for 23 hours while refluxing. Crystals produced was separated by filtration and dissolved in methanol containing 1N hydrochloric acid. The solution was neutralized with 4 N sodium hydroxide aqueous solution. After evaporating methanol, crystals collected by filtration was purified by suspending them in hot methanol, thereby obtaining 1.93 g of 2-ethyl-7-(4-2-tetrazolylphenyl)benzyl)hypoxanthine (yield 83%).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@@H:16]1[CH2:20][C:19](=C)[CH2:18][C@H:17]1[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CC[O:33]CC1.I([O-])(=O)(=O)=O.[Na+].O1CCCC1>CC(C)=O.O.[Os](=O)(=O)(=O)=O.C(OCC)(=O)C>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@@H:16]1[CH2:20][C:19](=[O:33])[CH2:18][C@H:17]1[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=C1C[C@@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)[C@H](c2ccc(Cl)cc2)C1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C1C[C@@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)[C@H](c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 25 mL round bottom flask equipped with a magnetic stir bar was charged with 1.980 g (5.00 mmol) of the product of Step B dissolved in 9.0 mL acetone. To the reaction mixture was added 0.702 g (5.99 mmol) of 4-methylmorpholine N-oxide dissolved in 2 mL water followed by 1.6 mL (0.26 mmol) of an osmium tetroxide solution (4 wt % in water). The reaction mixture was stirred 1.5 h at room temperature at which point TLC analysis (25% ethyl acetate-hexanes) indicated complete consumption of the starting material. The reaction mixture was quenched with excess 10% aqueous sodium bisulfite, then partitioned between water and ethyl acetate in a separatory funnel. The organic layer was washed with water, separated, then dried (MgSO4), filtered and evaporated in vacuo. The residual oil was redissolved in 12 mL of 1:1 tetrahydrofuran-water in a 25 mL round bottom flask. To this solution was added 1.282 g (5.99 mmol) of sodium periodate and an aditional 3 mL of tetrahydrofuran. After stirring for approximately 30 min at room temperature, a precipitate formed. Stirring was continued for 1.5 h, at which point TLC analysis (50% ethyl acetate-hexanes) revealed a new less polar product spot. The mixture was suspended between ethyl acetate and water and extracted. The organic layer was separated, dried (MgSO4), filtered and evaporated in vacuo. The residual clear oil was used in the next step without further purification.