Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[CH2:3]([S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([C:21]2[O:25][C:24]([C:26]([O:28]C)=[O:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:14]=[C:13]([NH:30][C@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C1COCC1.O>[CH2:3]([S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([C:21]2[O:25][C:24]([C:26]([OH:28])=[O:27])=[CH:23][CH:22]=2)(=[O:19])=[O:20])[CH:14]=[C:13]([NH:30][C@H:31]([CH3:41])[CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])[N:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Nc2cc(N[C@H](C)CO[Si](C)(C)C(C)(C)C)nc(SCc3ccccc3)n2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)Nc1cc(NS(=O)(=O)c2ccc(C(=O)O)o2)nc(SCc2ccccc2)n1

Procedure:
Lithium hydroxide (33 mg) was added to a solution of the subtitle product of step i) (0.23 g) in THF/H2O (1 ml/1 ml) and stirring maintained for 1 h. The THF was removed in vacuo and the residue neutralised with AcOH before extracting with EtOAc. The organics were then washed with H2O, dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase HPLC (gradient 95% to 20% 0.02M ammonium hydroxide/acetonitrile) to yield the title compound as an off-white solid. Yield: 0.14 g.
Reaction SMILES: FC(F)(F)C1C=C(C(C)(C)C(N(C2C=NC([I:31])=CC=2C2C=CC=CC=2Cl)C)=O)C=C(C(F)(F)F)C=1.[F:36][C:37]([F:71])([F:70])[C:38]1[CH:39]=[C:40]([C:48]([CH3:69])([CH3:68])[C:49]([N:51]([C:53]2[CH:54]=[N:55][C:56](Cl)=[CH:57][C:58]=2[C:59]2[CH:64]=[CH:63][C:62]([F:65])=[CH:61][C:60]=2[CH3:66])[CH3:52])=[O:50])[CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1>>[F:36][C:37]([F:71])([F:70])[C:38]1[CH:39]=[C:40]([C:48]([CH3:69])([CH3:68])[C:49]([N:51]([C:53]2[CH:54]=[N:55][C:56]([I:31])=[CH:57][C:58]=2[C:59]2[CH:64]=[CH:63][C:62]([F:65])=[CH:61][C:60]=2[CH3:66])[CH3:52])=[O:50])[CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(I)cc1-c1ccccc1Cl
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: Cc1cc(F)ccc1-c1cc(I)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound is prepared according to the procedure described above for the preparation of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-iodo-pyridin-3-yl]-N-methyl-isobutyramide (Example 25) using 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide instead of 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[CH3:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH:23][C:22]1[CH:24]=[CH:25][C:19]([CH3:18])=[CH:20][CH:21]=1)=[O:9]
Reactant: O=C(Cl)c1cccnc1Oc1cccc(Cl)c1
Reactant: Cc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccc(NC(=O)c2cccnc2Oc2cccc(Cl)c2)cc1

Procedure:
In the same manner as in Example 1(b), 1.1 grams (0.01 mole) 2(3-chlorophenoxy)nicotinoyl chloride, 1.0 grams (0.01 mole) 4-methylaniline, 1.0 grams (0.01 mole) triethylamine and 125 milliliters toluene were combined to yield 2.4 grams (70.9% of theoretical yield) of the desired product, m.p. 140°-143° C. The structure was confirmed by mass spectrometry.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][CH3:15])[C:7]([OH:9])=[O:8])#[C:2][CH3:3]>CCO.[Pd]>[CH2:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][CH3:15])[C:7]([OH:9])=[O:8])[CH2:2][CH3:3]
Reactant: CC#Cc1cc(C(=O)O)ccc1CCC
Agent: [Pd]
Solvent: CCO
Product: CCCc1ccc(C(=O)O)cc1CCC
Yield: 87.7 %

Procedure:
A mixture of the product of Step B (0.19 g; 0.94 mmol) and 10% Pd/C (0.1 g) in EtOH (15 ml) was stirred over the weekend under H2 (10 psi; Parr apparatus). The catalyst was removed by filtration through Celite pad, washed with CH2Cl2 (2×20 ml) and combined filtrates were evaporated to dryness to give the title compound (0.17 g; 88%) as creamy solid. 1H-NMR (CDCl3) 0.93-1.0 (m, 6H); 1.55-1.69 (m, 4H); 2.6-2.66 (m, 4H); 6.6 (broad s, 1H); 7.2-7.27 (m, 1H+CDCl3); 7.83-7.88 (m, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:16]([F:19])([F:18])[F:17])=[N:8][C:9]([C:12]([F:15])([F:14])[F:13])=[N:10][CH:11]=1)=[O:5])C.[OH-].[Na+].Cl>CCO.O>[F:15][C:12]([F:13])([F:14])[C:9]1[N:8]=[C:7]([C:16]([F:19])([F:18])[F:17])[C:6]([C:4]([OH:5])=[O:3])=[CH:11][N:10]=1
Reactant: CCOC(=O)c1cnc(C(F)(F)F)nc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnc(C(F)(F)F)nc1C(F)(F)F
Yield: 33.9 %

Procedure:
A solution of ethyl-2,4-bis(trifluoromethyl)pyrimidine-5-carboxylate (5.0 g, 17 mmol) and NaOH (0.72 g, 18 mmol) in EtOH (20 mL) and H2O (50 mL) was stirred at room temperature for 1 h. The solution was acidified (HCl) and the resulting solid was filtered and dried to give 2,4-bis (trifluoromethyl)-pyrimidine-5-carboxylic acid (1.5 g, 25%), m.p. 59° C., 1HNMR (DMSO-d6) δ 9.62 (s, 1H).
Reaction SMILES: [N:1]1([CH2:10][CH2:11][OH:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:12][CH2:11][CH2:10][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1)(=[O:15])[CH3:14]
Reactant: OCCn1cnc2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCn1cnc2ccccc21
Temperature: 20 °C
Reaction time: 10 h
Yield: 87 %

Procedure:
To a mixture of the crude 2-(1H-benzimidazol-1-yl)-ethanol and 500 g of pyridine, 122 g of acetic anhydride was added dropwise. In a nitrogen atmosphere, the reaction mixture was stirred at 20° C. for 10 hours. The reaction mixture was subjected to conventional aqueous work-up and then purified by vacuum distillation, obtaining 165 g of 2-(1H-benzimidazol-1-yl)ethyl acetate (boiling point 145° C./27 Pa, yield 87%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:12][CH:11]=2)[C:5]([C:21]#[N:22])=[C:4]([SH:23])[N:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:34][CH:35]=1.O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:5]([C:21]#[N:22])=[C:4]([S:23][CH2:30][C:31]2[N:32]=[C:33]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[S:34][CH:35]=2)[N:3]=1
Reactant: COCCOc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOc1ccc(-c2c(C#N)c(N)nc(SCc3csc(-c4ccccc4)n3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.31 mmol) of 2-amino-4-[4-(2-methoxyethoxy)phenyl]-6-sulphanyl-pyridine-3,5-dicarbonitrile are dissolved in 1 ml of DMF. 103 mg (1.23 mmol) of sodium bicarbonate and 96.4 mg (0.46 mmol) of 4-chloromethyl-2-phenyl-1,3-thiazole are then added. The suspension is shaken at RT overnight, and water is added. The precipitate is filtered off with suction, washed with ethanol and diethyl ether and dried at 40° C. under reduced pressure. This gives 149 mg (97% theory) of product.
Reaction SMILES: C([N:8]([CH:27]1[CH2:31][CH2:30][N:29]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH2:44][CH3:45])=[CH:37][CH:36]=2)(=[O:34])=[O:33])[CH2:28]1)[CH2:9][CH:10]([OH:26])[CH2:11][O:12][C:13]1[C:25]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]=2[CH:16]=[CH:15][CH:14]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[CH2:42]([O:41][C:38]1[CH:39]=[CH:40][C:35]([S:32]([N:29]2[CH2:30][CH2:31][CH:27]([NH:8][CH2:9][C@H:10]([OH:26])[CH2:11][O:12][C:13]3[C:25]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[NH:18][C:17]=4[CH:16]=[CH:15][CH:14]=3)[CH2:28]2)(=[O:34])=[O:33])=[CH:36][CH:37]=1)[CH2:43][CH2:44][CH3:45]
Reactant: CCCCOc1ccc(S(=O)(=O)N2CCC(N(Cc3ccccc3)CC(O)COc3cccc4[nH]c5ccccc5c34)C2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCCCOc1ccc(S(=O)(=O)N2CCC(NC[C@H](O)COc3cccc4[nH]c5ccccc5c34)C2)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
To a solution of 1-{Benzyl-[1-(4-butoxy-benzenesulfonyl)-pyrrolidin-3-yl]-amino}-3-(9H-carbazol-4-yloxy)-propan-2-ol (0.19 g, 0.3 mmol) in methanol (2 ml) was added ammonium formate (0.29 g, 4.5 mmol), and 45 mg of 10% Pd/C. The mixture was stirred at reflux for 18 h. After cooling to room temperature, it was filtered through Celite. The solvent was evaporated and the residue triturated with ether-hexanes to give 0.15 g of a white solid; m.p. 118-119° C.; MS (ES) m/z 538.1 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([CH2:13][CH3:14])[C:5]=1O)([O-:3])=[O:2].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:5]1[C:6]([CH2:13][CH3:14])=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1O
Product: CCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl

Procedure:
2,4-Dinitro-6-ethylphenol (10 g) was placed in a 250 ml round bottom flask, and phosphorous oxychloride (60 ml, Fisher) was added. N,N-diethylamiline (15 ml, Aldrich) was added portionwise, and the mixture became hot. The flask was placed under a condenser equiped with a drying tube heated on a steam bath for two hours and cooled. The mixture was then carefully poured onto ice, with stirring and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over MgSO4 and evaporated to a dark oil which was columned on silica gel using 10% ethyl acetate petroleum ether. The evaporated filtrates gave a reddish oil, which solidified upon being pumped dry. The solid was recrystallized from ethyl acetate-petroleum ether to give pale yellow needles of 1-chloro-2,4-dinitro-6-ethylbenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[C:7]3[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1.[CH3:19][C:20]1([CH3:37])[O:24][C@@H:23]([CH2:25]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:22][O:21]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6](=[O:16])[C:7]3[CH:14]=[CH:13][C:12]([O:15][CH2:25][C@H:23]4[CH2:22][O:21][C:20]([CH3:37])([CH3:19])[O:24]4)=[CH:11][C:8]=3[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COC(C)(C)O2)cc1
Reactant: O=C1c2ccc(O)cc2CCc2cc(Cl)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](COc2ccc3c(c2)CCc2cc(Cl)ccc2C3=O)O1

Procedure:
For the preparation of the title compound, 0.50 g (1.9 mmol) of 2-chloro-8-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.75 g (2.6 mmol) of (R)-toluene-4-sulfonic acid 2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester and 0.80 g (5.8 mmol) of K2CO3 in 10 ml of dry DMF are reacted by method M. C21H21ClO4 (Mr=372.85)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[O:12])=[CH:6][CH:5]=1.CC(C)([O-])C.[K+].Br[CH2:28][C:29]1[CH:45]=[CH:44][C:32]([O:33][C:34]([F:43])([F:42])[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[CH:31][CH:30]=1>C1COCC1>[C:38]([O:37][C:35](=[O:36])[C:34]([F:43])([F:42])[O:33][C:32]1[CH:31]=[CH:30][C:29]([CH2:28][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:20])=[CH:9][CH:8]=2)[C:11]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[O:12])=[CH:45][CH:44]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: COC(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Reactant: CC(C)(C)OC(=O)C(F)(F)Oc1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(Cc2ccc(OC(F)(F)C(=O)OC(C)(C)C)cc2)C(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 60.4 %

Procedure:
To a solution of methyl-4-[2-(4-fluorophenyl)-2-oxoethyl]benzoate (0.150 g, 0.551 mmol) (Example 1, Step 2) in degassed THF at −20° C. was added potassium tert-butoxide (0.606 ml), followed by a solution of tert-butyl 2-[4-(bromomethyl)phenoxy]-2,2-difluoroacetate (H. Fretz, Tetrahedron 54, 4849, 1998) (0.203 g, 0.604 mmol) in THF (0.5 ml). The reaction was allowed to warm slowly to room temperature, and was then quenched with saturated ammonium acetate solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography using toluene/ethyl acetate 5% giving 0.176 g of the title compound.
Reaction SMILES: Cl.C([O:4][C:5](=[O:25])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1)C.C(N(C(C)C)C(C)C)C.[CH3:35][O:36][C:37]1[CH:46]=[CH:45][CH:44]=[CH:43][C:38]=1[CH2:39][N:40]=[C:41]=[S:42]>C(Cl)Cl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]([OH:4])=[O:25])=[C:9]([CH:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][N:16]2[C:41](=[S:42])[NH:40][CH2:39][C:38]2[CH:43]=[CH:44][CH:45]=[CH:46][C:37]=2[O:36][CH3:35])[CH:10]=1
Reactant: COc1ccccc1CN=C=S
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1NCCc2ccccc21
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccccc1CNC(=S)N1CCc2ccccc2C1c1cc(Cl)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of (±)-[4-chloro-2-(1,2,3,4-tetrahydro-isoquinolin-1-yl)-phenoxy]-acetic acid ethyl ester hydrochloride (76 mg, 0.20 mmol, 1.0 eq.) and N-ethyldiisopropylamine (42 μL, 0.24 mmol, 1.2 eq) in DCM (2 mL), 2-methoxybenzyl isothiocyanate (36 mg, 0.20 mmol, 1.0 eq.) was added. The resulting mixture was stirred at r.t. for 19 hours. The mixture was diluted with DCM (20 mL), washed with 10% aq. AcOH (2×5 mL) and with sat. aq. NaCl (1×5 mL). The org. layer was concentrated in vacuo. The residue was dissolved in DMF (1 mL). 1M aq. NaOH soln. (0.5 mL) was added. The mixture was stirred at r.t. for 7 hours. The solution was carefully neutralized with formic acid (0.5 mL), filtered, and purified by prep. HPLC (column: Waters X-bridge, 30×75 mm, 10 um, UV/MS, acidic conditions) to give the desired acid as a white solid.
Reaction SMILES: CN1CCN(C2C=CC(NC3C4N(N=CN=4)C(C4C=C(C(N)=O)SC=4)=CN=3)=CC=2)CC1.[C:32]([O:36][C:37](=[O:61])[N:38]([C:51]1[C:52]2[N:53]([N:58]=[CH:59][N:60]=2)[C:54](Br)=[CH:55][N:56]=1)[C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[CH:41][CH:40]=1)([CH3:35])([CH3:34])[CH3:33].[O:62]=[S:63]1(=[O:82])[C:67]2[CH:68]=[C:69](B3OC(C)(C)C(C)(C)O3)[CH:70]=[CH:71][C:66]=2[C:65](=[O:81])[NH:64]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:32]([O:36][C:37](=[O:61])[N:38]([C:39]1[CH:44]=[CH:43][C:42]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)=[CH:41][CH:40]=1)[C:51]1[C:52]2[N:53]([N:58]=[CH:59][N:60]=2)[C:54]([C:69]2[CH:70]=[CH:71][C:66]3[C:65](=[O:81])[NH:64][S:63](=[O:62])(=[O:82])[C:67]=3[CH:68]=2)=[CH:55][N:56]=1)([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)cc1)c1ncc(Br)n2ncnc12
Reactant: CC1(C)OB(c2ccc3c(c2)S(=O)(=O)NC3=O)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1CCN(c2ccc(Nc3ncc(-c4csc(C(N)=O)c4)n4ncnc34)cc2)CC1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)cc1)c1ncc(-c2ccc3c(c2)S(=O)(=O)NC3=O)n2ncnc12
Yield: 43.8 %

Procedure:
This compound may be prepared using methods as described for Compound 6, step 4 using (5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-(4-morpholin-4-yl-phenyl)-carbamic acid tert-butyl ester (170 mg, 0.36 mmol), 1,1-dioxo-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2-dihydro-1λ6-benzo[d]isothiazol-3-one (374 mg, 0.72 mmol) and Pd(PPh3)4 (100 mg, 0.082 mmol) in 1.5M Na2CO3 (2 mL, 3 mmol) and dioxane (6 mL). Purification of the reaction mixture by silica gel column chromatography using 1:1 petroleum ether:ethyl acetate affords a compound still impure. A second silica gel column chromatography eluting with 10:1 DCM:MeOH affords the title compound (91 mg, 44%).
Reaction SMILES: [C:1]1([C:7]2[CH:20]=[CH:19][C:10]3[N:11]=[C:12]([CH2:14][C:15]([NH:17][NH2:18])=[O:16])[S:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21]1([CH3:33])[CH:26]=[CH:25][C:24]([S:27]([N:30]=[C:31]=O)(=[O:29])=[O:28])=[CH:23][CH:22]=1.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O1CCOCC1.CO>[CH3:33][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:31]2[O:16][C:15]([CH2:14][C:12]3[S:13][C:9]4[CH:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:20]=[CH:19][C:10]=4[N:11]=3)=[N:17][N:18]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: NNC(=O)Cc1nc2ccc(-c3ccccc3)cc2s1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)Nc2nnc(Cc3nc4ccc(-c5ccccc5)cc4s3)o2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11.7 %

Procedure:
To a suspension of 2-(6-phenylbenzo[d]thiazol-2-yl)acetohydrazide (26 mg, 0.092 mmol) (described in WO 2011/074560) in dioxane (0.8 mL) was added p-toluenesulfonyl isocyanate (15 μL, 0.10 mmol), and the reaction mixture stirred for 15 min. 1-Propanephosphonic acid cyclic anhydride (50% in EtOAc) (0.164 mL, 0.275 mmol) was added and the reaction mixture stirred at 105° C. for 18 h. The reaction mixture was allowed to cool to rt, diluted with MeOH then purified by preparative HPLC (RT=8.79 min using Axia Luna 5 u C18 30×100 mm column with flow rate of 40 mL/min over 10 min period. Solvent A=10/90/0.1% ACN/H2O/TFA, Solvent B=90/10/0.1%, 10 to 100% B). The fraction containing product was evaporated to dryness and the residue chromatographed on silica gel eluting with 0 to 10% MeOH/DCM to give Compound 90a (5 mg, 12%) as a white solid. LCMS=1.01 min using analytical method (M), 462.9 (M+H). 1H NMR (400 MHz, CDCl3, 60° C.) δ 8.08-7.99 (m, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.59 (d, J=7.0 Hz, 2H), 7.48-7.39 (m, 2H), 7.36 (t, J=7.0 Hz, 1H), 7.24 (d, J=4.3 Hz, 2H), 4.50-4.44 (m, 2H), 2.37 (s, 3H).
Reaction SMILES: C[Si](C)(C)[N:3]=[S:4]([CH2:12][CH2:13][CH2:14][Cl:15])([O:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[O:5].CO>>[Cl:15][CH2:14][CH2:13][CH2:12][S:4](=[NH:3])([O:6][CH2:7][C:8]([F:11])([F:9])[F:10])=[O:5]
Reactant: C[Si](C)(C)N=S(=O)(CCCCl)OCC(F)(F)F
Solvent: CO
Product: N=S(=O)(CCCCl)OCC(F)(F)F
Reaction time: 5 h
Yield: 99 %

Procedure:
Reactants used in the general procedure were 2,2,2-trifluoroethyl N-trimethylsilyl-3-chloropropanesulfonimidate (0.005 mol, 1.56 g) and methanol (0.03 mol, 1.3 ml). Reaction temperature was 45° C.; reaction time was 5 hours. The temperature at which volatile materials were removed did not exceed 55° C. and product yield was greater than 99%. The 1H NMR spectrum of the product (90 MHz, 30% in C6H6) exhibited maxima at the following shift values: 1.96 (m, SCH2CH2CH2Cl); 2.93 (apparent triplet with indication of multiplicity, SCH2); 3.17 (t, ClCH2, 3JHH =6.3 Hz); 3.48 (s, broad, 1H, NH); 4.03 (apparent quartet, OCH2CF3, 3JFH =8.4 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:41])[C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:40])[NH:26][C:27]2[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=2)[C:30]([OH:32])=O)=[CH:20][CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CO.[NH2:50][CH:51]([CH2:54][OH:55])[CH2:52][OH:53]>ClCCl.O1CCCC1>[C:1]([O:5][C:6](=[O:7])[N:8]([C:9]1[N:17]=[CH:16][N:15]=[C:14]2[C:10]=1[N:11]=[CH:12][N:13]2[C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25]([NH:26][C:27]2[CH:35]=[C:34]([C:36]([F:38])([F:39])[F:37])[CH:33]=[C:29]([C:30](=[O:32])[NH:50][CH:51]([CH2:54][OH:55])[CH2:52][OH:53])[CH:28]=2)=[O:40])=[CH:22][CH:23]=1)[CH3:41])([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2cc(C(=O)O)cc(C(F)(F)F)c2)cc1
Reactant: NC(CO)CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)c1ncnc2c1ncn2-c1ccc(NC(=O)Nc2cc(C(=O)NC(CO)CO)cc(C(F)(F)F)c2)cc1
Yield: 60.3 %

Procedure:
In dichloromethane (3.5 mL), 60 mg (0.105 mmol) of 3-(3-{4-[6-(tert-butoxycarbonyl-methylamino)-purin-9-yl]phenyl}ureido)-5-(trifluoromethyl)benzoic acid was dissolved, and 54.9 μL (0.63 mmol) of oxalyl chloride was slowly added thereto and the mixture solution was stirred under refluxing for 1.5 hours. The solvent was distilled under reduced pressure from the reaction solution and the obtained residue was dissolved in tetrahydrofuran (0.75 mL). The tetrahydrofuran solution thus prepared was added dropwise to a methanol (0.5 mL)/tetrahydrofuran (0.25 mL) solution of 28.7 mg (0.315 mmol) of 2-amino-1,3-propanediol and the resulting solution was stirred at room temperature for 1.5 hours. The solvent was distilled under reduced pressure from the reaction solution and the obtained residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1 to 5:1) to obtain 40.8 mg (60%) of a target product as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3][CH2:2]1.[CH3:14][C@@H:15]1[CH2:17][O:16]1>C(O)C>[OH:16][C@H:15]([CH3:17])[CH2:14][N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8](=[O:13])[C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:3][CH2:2]1
Reactant: CC(C)(C)C(=O)OC1CCNCC1
Reactant: C[C@@H]1CO1
Solvent: CCO
Product: C[C@@H](O)CN1CCC(OC(=O)C(C)(C)C)CC1

Procedure:
A solution of piperidine 52 (2 g, 10.8 mmol) and (R)-2-Methyl-oxirane (3.78 ml, 54 mmol) in 2 ml of ethanol is stirred for 24 hours in a closed flask. The solvent is evaporated and the residue distilled in a Kugelrohr apparatus (0.08 mbar, 75-90 C).
Reaction SMILES: CO[C@H](C1C=CC=CC=1)C([O:6][C@H:7]1[CH2:16][CH2:15][C:14]2[C:9](=[C:10]([NH2:17])[CH:11]=[CH:12][CH:13]=2)[CH2:8]1)=O.[OH-].[Li+].C([O-])(O)=O.[Na+]>O1CCCC1.C(OCC)(=O)C>[NH2:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH2:8][C@@H:7]([OH:6])[CH2:16][CH2:15]2
Reactant: CO[C@@H](C(=O)O[C@H]1CCc2cccc(N)c2C1)c1ccccc1
Agent: O=C([O-])O
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1cccc2c1C[C@@H](O)CC2
Yield: 92.3 %

Procedure:
A mixture of Example 25A (300 mg, 0.963 mmol) in tetrahydrofuran (4 mL) and aqueous lithium hydroxide (1 M aq, 3 mL, 3.00 mmol) was stirred at ambient temperature for 1.5 hour. The reaction was diluted with ethyl acetate and poured into aqueous saturated NaHCO3 solution. The separated organic phase was washed with brine, dried over Na2SO4, and concentrated in vacuo. The result was 145 mg (92% yield) of the title compound as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 6.76 (t, 1H), 6.41 (d, 1H), 6.28 (d, 1H), 4.74, (d, 1H), 4.66 (bs, 2H), 3.90 (m, 1H), 2.52-2.79 (m, 3H), 2.17 (m, 1H), 1.83 (m, 1H), 1.55 (m, 1H). MS (DCI+) m/z 164 (M+H)+, 181 (M+NH4)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:34](=[O:35])[N:12]2[C:13]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:14](O)[CH2:15][S:16][C@H:11]12)=[O:8].CN(C)C=O.P(Cl)(Cl)[Cl:42]>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:34](=[O:35])[N:12]2[C:13]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:14]([Cl:42])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: ClP(Cl)Cl
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(Cl)CS[C@H]12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4.2 g. of diphenylmethyl 7-[2-(2-thienyl)acetamido]-3-hydroxy-3-cephem-4-carboxylate in 44 ml. of dry dimethylformamide was added 865 mg. of phosphorus trichloride. The mixture was stirred for 1.5 hours at room temperature and was poured into an ethyl acetate 5% aqueous hydrochloric acid mixture. The ethyl acetate layer was evaporated, was washed with 5% hydrochloric acid, water and was dried. The dried solution was concentrated in vacuo and the product crystallized. The 3-chloro ester was filtered, washed with cold ethyl acetate and dried to yield 2.2 g.