Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[N:20]=[N:19][C:18]([CH2:21][CH3:22])=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.FC(F)(F)C(O)=O.C1(C(C2C=CC=CC=2)CNC2N=C(NCCN3CCCCC3)N=[C:61]3C=2N=[CH:59][N:60]3[C@@H:74]2[CH2:78][C@H:77]([N:79]3[CH:83]=C(CO)C=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.CN(C)[C@@H]1CCNC1>>[CH3:61][N:60]([CH3:59])[C@@H:74]1[CH2:78][CH2:77][N:79]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@@H:11]3[CH2:15][C@H:14]([N:16]4[N:20]=[N:19][C:18]([CH2:21][CH3:22])=[N:17]4)[C@@H:13]([OH:23])[C@H:12]3[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:3]=2)[CH2:83]1
Reactant: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1
Agent: CN(C)[C@@H]1CCNC1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N(C)C)C5)nc43)[C@H](O)[C@@H]2O)n1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(5-ethyl-tetrazol-2-yl)-cyclopentane-1,2-diol (BA6) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 46) replacing 1-(2-amino-ethyl)piperidine with (3R)-(+)-3-(dimethylamino)pyrrolidine. After purification, the compound is partitioned between DCM and saturated NaHCO3(aq). The organics are dried (MgSO4), filtered and reduced in vacuo to yield the title compound. MS (ES+) m/e 624 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14](O)=[O:15])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[C:21]=2[C:22]([F:25])([F:24])[F:23])[O:11][N:10]=1.[Cl-].[NH4+].CC([N:38](C)C)=O.CCN(C(C)C)C(C)C>C(OC(=O)C)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([NH2:38])=[O:15])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[C:21]=2[C:22]([F:23])([F:25])[F:24])[O:11][N:10]=1
Reactant: CC(=O)N(C)C
Reactant: O=C(O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: NC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
Saponification of the ester of example 11 was achieved following the description for example 19, first step, to give 3-(2-chloro-6-fluorophenyl)-5-(1-(3-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylic acid in 89% yield. To a solution of 6.0 g (12.34 mmol) 3-(2-chloro-6-fluorophenyl)-5-(1-(3-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylic acid and 1.98 g (37.021 mmol) ammoniumchlorid in 20 mL dry DMA 9.36 g (24.681 mmol) HBTU and 6.45 mL (37.021 mmol) DIPEA were added. The mixture was stirred 3 hours at r.t. Ethylacetate was added to the reaction mixture and it was washed twice with sodium hydrogen carbonate (5%, aq) and citric acid (5%, aq). The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed in the vacuum. The oily residue became solid by drying in the vacuum. The solid was washed with petroleum ether, filtrated and dried in the vacuum to yield 5.37 g (90%) of example 121. Result of LC/MS MH+: 484.83; 1H NMR (DMSO-d6; CCl4): 7.39-7.78 (7H, m, CH-arom./2H NH2), 8.43 (1H, s, CH-pyraz.)
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=O)[N:6]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[N:33]1([C:39]2[CH:40]=[C:41]3[C:46](=[CH:47][CH:48]=2)[NH:45][C:44](=[O:49])[CH:43]=[CH:42]3)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>C(N(CC)CC)C.CN(C)C=O>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([N:36]2[CH2:37][CH2:38][N:33]([C:39]3[CH:40]=[C:41]4[C:46](=[CH:47][CH:48]=3)[NH:45][C:44](=[O:49])[CH:43]=[CH:42]4)[CH2:34][CH2:35]2)=[O:10])[N:6]=1
Reactant: Cc1nc(CC(=O)O)cs1
Reactant: O=c1ccc2cc(N3CCNCC3)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(CC(=O)N2CCN(c3ccc4[nH]c(=O)ccc4c3)CC2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A mixture of 2-(2-methyl-4-thiazolyl)acetic acid (628 mg), 1-hydroxybenzotriazole (648 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (917 mg) and N,N-dimethylformamide (25 ml) was stirred for 1 hour at ambient temperature. 6-(1-Piperazinyl)-2(1H)-quinolinone (687 mg) and triethylamine (1 ml) were added thereto, and the mixture was stirred for 3 hours at the same temperature. After the reaction mixture was concentrated in vacuo, to the residue were added ethyl acetate (10 ml) and water (10 ml) and the mixture was stirred. The resulting oil was separated by decantation and dissolved in tetrahydrofuran. The solution was washed with brine, dried over magnesium sulfate and concentrated. The residue was subjected to a column chromatography on silica gel (80 g) and eluted with 3% solution of methanol in chloroform. The fractions containing the desired compound were collected and concentrated to give a residue, which was crystallized from ethyl acetate-diethyl ether to give 6-[4-{2-(2-methyl- 4-thiazolyl)acetyl}-1-piperazinyl]-2(1H)-quinolinone (0.74 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C.O>O1CCCC1>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([O:1][CH2:2][CH2:3][C:4]2[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc(CCO)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(C#N)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.8 %

Procedure:
4-(2-Hydroxyethyl)benzonitrile (200 mg, 1.35 mmol) in tetrahydrofuran (4 mL) was mixed with 4-methylbenzene-1-sulfonyl chloride (389 mg, 2.04 mmol) and triethylamine (569 μL, 4.08 mmol) and stirred at room temperature for 1 day. After addition of water, the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1→3/1→1/1 (v/v)) to give the title compound as a colorless solid (174 mg, yield 43%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([CH:9]([C:17]([O-:19])=[O:18])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:8].[C:20]([C:22]1[C:23]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-:40])=[O:39])[CH:33]=2)=[N:24][C:25]([S:30][CH3:31])=[N:26][C:27]=1C=C)#[N:21].[CH3:41][CH2:42]O>C1(C)C=CC=CC=1.C(Cl)Cl.CCOC(C)=O>[C:20]([C:22]1[C:23]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([N+:38]([O-:40])=[O:39])[CH:33]=2)=[N:24][C:25]([S:30][CH3:31])=[N:26][C:27]=1[CH2:8][CH2:7][CH:9]([C:17]([O:19][CH2:41][CH3:42])=[O:18])[C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])#[N:21]
Reactant: C=Cc1nc(SC)nc(-c2cccc([N+](=O)[O-])c2)c1C#N
Reactant: CCO
Reactant: CCC(C(=O)[O-])C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CCc1nc(SC)nc(-c2cccc([N+](=O)[O-])c2)c1C#N)C(=O)OC(C)(C)C
Reaction time: 0.67 h

Procedure:
Potassium carbonate (1.88 g) and tert-butyl ethylmalonate were suspended in EtOH (82 ml) and a solution of 5-cyano-2-methylthio-4-(3-nitro-phenyl)-6-vinylpyrimidine (example 27b, 2.71 g) in toluene/CH2Cl2 (33 ml) was slowly added (ca 1.5 h). After the addition was complete, the mixture was stirred for an additional 40 min. The mixture was diluted with EtOAc and washed with water (2×) and brine. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The title compound was purified by chromatography on silica gel with hept/CH2Cl2=1/1 (v/v) as eluent.
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[CH2:16][O:17]C(=O)C(C)C)[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2].[OH-].[K+]>O1CCCC1.O>[CH:1]([C:4]1[N:8]2[CH:9]=[C:10]([O:13][C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[CH2:16][OH:17])[CH:11]=[CH:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)C(=O)OCc1ccccc1Oc1ccc2nnc(C(C)C)n2c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nnc2ccc(Oc3ccccc3CO)cn12
Temperature: 60 °C

Procedure:
A mixture of isobutyric acid 2-(3-isopropyl-[1,2,4]triazolo[4,3-a]pyridin-6-yloxy)-benzyl ester (130 mg, 0.37 mmol) and potassium hydroxide (103 mg, 1.84 mmol) in tetrahydrofuran (6 mL) and water (1 mL) was heated at 60° C. for 7 hours. The reaction was concentrated in vacuo to a solid. The residue was suspended in water, the solid filtered, then the material suspended in methylene chloride and filtered to give the above named compound as a tan solid (84 mg, 80%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[N:3]1.Cl[S:17]([OH:20])(=O)=[O:18].[CH3:21][NH2:22]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[N:3]=2)=[CH:10][C:11]=1[S:17]([NH:22][CH3:21])(=[O:20])=[O:18]
Reactant: O=S(=O)(O)Cl
Reactant: Cn1nc(-c2ccc(Cl)cc2)ccc1=O
Reactant: CN
Product: CNS(=O)(=O)c1cc(-c2ccc(=O)n(C)n2)ccc1Cl

Procedure:
Similarly reaction of 2-methyl-6-(4-chlorophenyl)-3(2H)-pyridazinone with chlorosulfonic acid followed by methylamine according to the procedure of this Example gives 2-chloro-5-(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)-N-methylbenzenesulfonamide.
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH:5]=[C:6]([CH3:8])[CH3:7])[C:2]1([CH:10]1[CH:15]([O:16][CH3:17])[CH:14]([OH:18])[CH2:13][CH2:12][C:11]1([CH2:20][S:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][OH:30])[OH:19])[CH3:9].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40].O>ClCCl>[O:1]1[CH:3]([CH2:4][CH:5]=[C:6]([CH3:7])[CH3:8])[C:2]1([CH:10]1[CH:15]([O:16][CH3:17])[CH:14]([OH:18])[CH2:13][CH2:12][C:11]1([CH2:20][S:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][O:30][S:39]([CH3:38])(=[O:41])=[O:40])[OH:19])[CH3:9]
Reactant: CS(=O)(=O)Cl
Reactant: COC1C(O)CCC(O)(CSCc2ccccc2CO)C1C1(C)OC1CC=C(C)C
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC1C(O)CCC(O)(CSCc2ccccc2COS(C)(=O)=O)C1C1(C)OC1CC=C(C)C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
In dichloromethane (0.5 ml) were dissolved 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-hydroxymethylbenzyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (100 mg) and triethylamine (64 μl). To the solution was added dropwise, under ice-cooling, methanesulfonylchloride (20 μl ). The mixture was stirred for 15 minutes, to which was added water to suspend the reaction. The product was extracted with ethyl acetate. The extract solution was washed with a saturated aqueous solution of sodium chloride, which was then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a silica gel column chromatography (carrier 10 g, developing solvent: ethyl acetate - hexane=2:1) to give 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-1-(2-methanesulfonyloxymethylbenzyl)thiomethyl-3-methoxy-1,4-cyclohexanediol (98 mg: yield 83%) as a colorless oily product.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)=[C:9]([NH2:22])[N:8]=2)[CH2:3][CH2:2]1.[Br:23]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl>[Br:23][C:12]1[N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:14]2[C:10]([N:11]=1)=[C:9]([NH2:22])[N:8]=[C:7]([O:6][CH2:5][CH2:4][CH:1]1[CH2:2][CH2:3]1)[N:15]=2
Reactant: Nc1nc(OCCC2CC2)nc2c1ncn2C1CCCCO1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: Nc1nc(OCCC2CC2)nc2c1nc(Br)n2C1CCCCO1
Temperature: 25 °C

Procedure:
To an ice cooled stirring solution of 2-[(2-cyclopropylethyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (6.53 g) in chloroform (75 ml), was added N-bromosuccinimide (4.02 g). The reaction mixture was allowed to warm to room temperature and after 16 h treated with water and extracted twice with DCM. The combined extracts were washed with dilute sodium metabisulphite then dilute brine, dried by passing through a hydrophobic frit and evaporated to give the title compound as an orange foam, yield 7.96 gm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:14][NH:15][CH3:16]>>[CH3:14][N:15]([CH3:16])[C:11]([C:8]1([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[CH2:10][CH2:9]1)=[O:13]
Reactant: CNC
Reactant: O=C(O)C1(c2ccc(Br)cn2)CC1
Product: CN(C)C(=O)C1(c2ccc(Br)cn2)CC1

Procedure:
The title compound was prepared from 1-(5-bromo-pyridin-2-yl)-cyclopropanecarboxylic acid and dimethylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Step 2 for Intermediate 5. Yield: quantitative; LC (method 1): tR=1.65 min; Mass spectrum (ESI+): m/z=269/271 (Br) [M+H]+.
Reaction SMILES: Cl.N[C:3]1[O:7][N:6]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:4]=1.C([OH:15])CC>>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:4]=[C:3]([OH:15])[O:7][N:6]=1
Reactant: CCCO
Reactant: Nc1cc(C(F)(F)F)no1
Agent: Cl
Product: Oc1cc(C(F)(F)F)no1
Yield: 0.7 %

Procedure:
A solution of 36% HCl (9.12 g, 15 eq.) and n-propanol (9.0 ml) was added to 5-amino-3-trifluoromethylisoxazole (0.91 g, 6.0 mmole) from Preparation 1 and heated at reflux for 23 hours. The reaction mixture was cooled, extracted with methylene chloride and distilled under reduced pressure to give 0.006 g (0.7%) of the titled compound as a colorless liquid, b.p. 35°-37° C./1.4 mmHg. This product was thought to be the keto form or a mixture of the keto and enol form by NMR and IR.
Reaction SMILES: [CH3:1][C@H:2]([CH2:8][CH2:9][OH:10])[CH2:3][C:4]([O:6][CH3:7])=[O:5].N1C=CN=C1.CN(C)C=O.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>O>[CH3:1][C@H:2]([CH2:8][CH2:9][O:10][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C[C@H](C)CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C[C@H](C)CCO[Si](C)(C)C(C)(C)C

Procedure:
To a solution of 37 g. (0.253 m) of methyl 3-(R)-methyl-5-hydroxypentanoate and 37 g. (0.543 m) of imidazole in 500 ml. of dimethylformamide was added 37 g. (0.249 m) of t-butyldimethylsilyl chloride and the reaction stirred at room temperature for 2 hours. The reaction mixture was poured into water and extracted (4×100 ml.) with ether. The combined extracts were washed with 10% hydrochloric acid, a saturated sodium bicarbonate solution, water and a brine solution, and dried over magnesium sulfate. Removal of the solvent gave 121.88 g. of crude product which, on distillation, gave 107.12 g. of pure product, b.p. 80°-81° C./0.4 torr.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[CH:23]=[CH2:24]>CN(C=O)C>[CH2:24]([O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)[CH:23]=[CH2:22]
Reactant: Oc1ccc(Oc2ccc(F)cc2)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Oc2ccc(F)cc2)cc1

Procedure:
A solution of 4-(4-fluorophenoxy) phenol (4.75 g, 23.30 mmol), potassium carbonate (4.17 g, 30.30 mmol) and allyl bromide (2.22 mL, 25.60 mmol) in DMF (50 mL) was stirred for 5 h at 60° C. After cooling, the reaction mixture was neutralized with 1 N HCL and extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated to afford an oil which was chromatographed on silica gel (15% ethyl acetate/hexane) to afford the title compound.
Reaction SMILES: Cl[CH2:2][S:3][C:4]1[N:5]=[N:6][N:7]([CH3:9])[N:8]=1.[I-:10].[Na+]>CC(C)=O.O>[I:10][CH2:2][S:3][C:4]1[N:5]=[N:6][N:7]([CH3:9])[N:8]=1
Reactant: Cn1nnc(SCCl)n1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cn1nnc(SCI)n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
To a solution of 5-chloromethylthio-2-methyltetrazole (987 mg: 6.0 mMol.) in acetone (10 ml) is added sodium iodide (1.78 g: 12.00 mMol.), and the mixture is stirred at 50° C. for 3 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, and concentrated to give 5-iodomethylthio-2-methyltetrazole (1.43 g) as yellow oil.
Reaction SMILES: [I:1][Si](C)(C)C.[CH3:6][Si:7]([O:10][C:11]([C:13]1[N:18]2[C:19](=[O:26])[CH:20]([NH:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C@H:17]2[S:16][CH2:15][C:14]=1[CH:27]=[CH:28][CH2:29]OC(=O)C)=[O:12])([CH3:9])[CH3:8]>>[CH3:6][Si:7]([O:10][C:11]([C:13]1[N:18]2[C:19](=[O:26])[CH:20]([NH:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C@H:17]2[S:16][CH2:15][C:14]=1[CH:27]=[CH:28][CH2:29][I:1])=[O:12])([CH3:9])[CH3:8]
Reactant: C[Si](C)(C)I
Reactant: CC(=O)OCC=CC1=C(C(=O)O[Si](C)(C)C)N2C(=O)C(N[Si](C)(C)C)[C@H]2SC1
Product: C[Si](C)(C)NC1C(=O)N2C(C(=O)O[Si](C)(C)C)=C(C=CCI)CS[C@H]12
Reaction time: 15 h

Procedure:
0.71 ml of iodotrimethylsilane are added at 0° to the solution, produced as described under a), of 7-trimethylsilylamino-3-(3-acetoxy-1-propen-1-yl)-3-cephem-4-carboxylic acid trimethylsilyl ester. The solution is stirred for 15 hours at 0°. Due to the extreme hydrolyzability, characterization is again effected by NMR.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]([NH:5][CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:8]=1)=[O:4].B.[OH2:31]>O1CCCC1>[F:1][C:2]([F:29])([F:28])[C:3]([OH:31])=[O:4].[F:29][C:2]([F:1])([F:28])[CH2:3][NH:5][CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:9]([S:18]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)(=[O:20])=[O:19])[CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(CNC(=O)C(F)(F)F)cc2-c2ccccc2)cc1
Reactant: O
Agent: B
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(CNCC(F)(F)F)cc2-c2ccccc2)cc1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 20 %

Procedure:
A solution (15 mL) of 2,2,2-trifluoro-N-({1-[(4-methylphenyl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)acetamide (300 mg) in tetrahydrofuran was cooled at 0° C., 1 mol/L tetrahydrofuran solution of borane (2.84 mL) was added, and the mixture was stirred at room temperature for 5 hr and then at 50° C. for 3 hr. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=9:1→2:1), and the obtained oil was purified by preparative HPLC. The purified product was concentrated under reduced pressure, and the crystals precipitated during the process were collected by filtration. The crystals were recrystallized from ethyl acetate to give the title compound as colorless crystals (yield 70 mg, 20%).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][O:16][C:17](=[O:28])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([NH2:27])[CH:21]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:15][O:16][C:17](=[O:28])[CH:18]=[CH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[C:22]([NH:27][C:12]([C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[O:14])[CH:21]=1
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Reactant: COC(=O)C=Cc1ccc(F)c(N)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(F)c(NC(=O)c2ccc(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
5-phenyl-2-furoic acid (36) (18 mg, 0.15 mmol) was coupled to aniline (43) (30 mg, 0.15 mmol) using Method B, except that DIPEA (40 mg, 0.31 mmol) and DMF (2 mL) were used and the reaction was stirred at ambient temperature for 2.5 hours, then at 40° C. for 24 hours. Further TBTU (1 eq) and acid (1 eq) were added and the reaction heated at 60° C. for a further 6 hours to give the crude title compound after work-up. The residue was purified using column chromatography eluting with 20% EtOAc in heptane to give the title compound. Yield: 18 mg, 32%; LC-MS tr 1.55 min; HPLC Purity: 83%; MS (ES+) m/z 366 (M+H)
Reaction SMILES: [F:1][CH:2]([F:41])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([C:20]3[CH:25]=[CH:24][C:23]([N:26](C)[C:27](=O)OC(C)(C)C)=[CH:22][CH:21]=3)[N:9]=2)[C:6]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O.N>C(Cl)Cl>[F:41][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([C:20]3[CH:21]=[CH:22][C:23]([NH:26][CH3:27])=[CH:24][CH:25]=3)[N:9]=2)[C:6]2[CH:35]=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(-c2ccc(N(C)C(=O)OC(C)(C)C)cc2)nc(N2CCOCC2)n1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1ccc(-c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OC)cccc43)n2)cc1
Yield: 86.8 %

Procedure:
Reaction of the above carbamate (235 mg, 0.414 mmol) with an excess of TFA (1.2 mL) in CH2Cl2 (6 mL) at room temperature for 2 hrs, followed by treatment with aq. NH3 gave 4-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-N-methylaniline (168 mg, 87%): 1H NMR (DMSO-d6) δ 8.23 (d, J=8.9 Hz, 2H), 8.06 (d, J=8.0 Hz, 1H), 7.80 (t, JHF=52.9 Hz, 1H), 7.47 (t, J=8.2 Hz, 1H), 6.99 (d, J=7.8 Hz, 1H), 6.67 (d, J=8.9 Hz, 2H), 6.63 (q, J=4.8 Hz, 1H), 4.01 (br s, 2H), 3.99 (s, 3H), 3.88 (br s, 2H), 3.76 (t, J=4.8 Hz, 4H), 2.79 (d, J=4.9 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:29]([F:30])=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[C:4]([F:31])[CH:3]=1.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34].[CH:45]1([NH2:49])[CH2:48][CH2:47][CH2:46]1>ClCCl.O>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:10][CH2:9][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[C:29]([F:30])[C:2]([NH:1][C:33]([NH:49][CH:45]4[CH2:48][CH2:47][CH2:46]4)=[O:34])=[CH:3][C:4]=3[F:31])[CH2:13][CH2:12]2)[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3cc(F)c(N)cc3F)CC2)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NC1CCC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3cc(F)c(NC(=O)NC4CCC4)cc3F)CC2)c1
Reaction time: 0.5 h
Yield: 2.3 %

Procedure:
3-((4-(4-Amino-2,5-difluorobenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (1 g, 0.023 mol) and 4-nitrophenol chloroformate (0.4636 g, 0.0023 mol) were combined and stirred in dichloromethane for 1 hour at room temperature. Cyclobutylamine (0.8969 g, 0.0017 mol, 0.108 mL) was added and the reaction was stirred for 30 minutes. The reaction mixture was diluted with water and flushed through a hydrophobic frit. The organic phase was concentrated under vacuum and purified by acidic reverse phase HPLC to afford the title compound (21 mg).