Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3](=[O:17])[N:4]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:18][N:19]1[C:23]([CH3:24])=[CH:22][C:21]([NH2:25])=[N:20]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:8][C:6]1[CH:7]=[C:2]([NH:25][C:21]2[CH:22]=[C:23]([CH3:24])[N:19]([CH3:18])[N:20]=2)[C:3](=[O:17])[N:4]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[N:5]=1
Reactant: Cc1cc(N)nn1C
Reactant: C[Si](C)(C)CCOCn1nc(Cl)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(Cl)nn(COCC[Si](C)(C)C)c2=O)nn1C
Temperature: 25 °C
Yield: 71.7 %

Procedure:
To a mixture of 4-bromo-6-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one 110a (1.19 g, 3.50 mmol), 1,5-dimethyl-1H-pyrazol-3-amine (409 mg, 3.68 mmol), in 1,4-dioxane (20 mL) in a 100 mL single-neck round-bottomed flask was added desium darbonate (3.42 g, 10.5 mmol). The mixture was purged with ditrogen for 30 min. Tris(dibenzylideneacetone)dipalladium(0) (321 mg, 0.350 mmol) and 4,5-bis(diphenyl-phosphino)-9,9-dimethylxanthene (344 mg, 0.596 mmol) were then added. The flask was connected to a nitrogen-purged condenser and the mixture was refluxed under nitrogen for 18 h. The mixture was cooled to room temperature, and filtered. The filter cake was suspended in ethyl acetate (30 mL) and water (10 mL) and filtered through Celite®. The layers were separated. The combined organic layers were dried with anhydrous magnesium sulfate. The drying agent was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified on silica eluted with a gradient 0 to 50% ethyl acetate in eeptane to afford 6-chloro-4-(1,5-dimethyl-1H-pyrazol-3-ylamino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one 110b as a yellow solid (928 mg, 72%).
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:15])[CH:14]=[C:10]2[N:9]=[C:8]([CH3:16])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[I:17]N1C(=O)CCC1=O>C(#N)C.ClCCl>[CH2:1]([CH:3]([C:6]1[N:11]2[N:12]=[C:13]([CH3:15])[C:14]([I:17])=[C:10]2[N:9]=[C:8]([CH3:16])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCC(CC)c1cc(C)nc2cc(C)nn12
Solvent: CC#N
Solvent: ClCCl
Product: CCC(CC)c1cc(C)nc2c(I)c(C)nn12
Yield: 97.1 %

Procedure:
Dissolve 7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (2.14 g, 9.84 mmol) in anhydrous acetonitrile (25 mL) and add 6 portions (0.5 g each) of N-iodosuccinimide (3.0 g, 13.3 mmol) at 10 min intervals. Stir the reaction for 4 h. Strip off the acetonitrile and dilute the resulting oil with dichloromethane (100 mL). Wash the orange solution with saturated ammonium chloride solution (2×50 mL). Collect the organic phase, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to yield a dark red oil. Purify using flash chromatography, eluting with 100% pentane/0% (20% ethyl acetate/pentane) to 0% pentane/100% (20% ethyl acetate/pentane) in a step gradient of 50% increments to give an orange oil (3.28 g, 97%). 1H NMR (400 MHz, CDCl3): 6.44 (s, 1H), 3.59 (m, 1H), 2.61 (s, 3H), 2.49 (s, 3H), 1.86-1.76 (m, 4H), 0.85 (t, J=7.5 Hz, 6H).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][C:3]1[C:4]2[C:5]([C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=[CH:8][C:9]=2[NH:1][CH:2]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc2[nH]cc(Cc3cccc(Cl)c3)c12
Temperature: 25 °C
Yield: 70.2 %

Procedure:
To a solution of commercially available methyl 1H-indole-4-carboxylate (5 g, 28.5 mmol) in 100 mL dichloromethane, at 0° C., was added 3-chlorobenzaldehyde (5 mL, 43.8 mmol), triethylsilane (15 mL, 93.9 mmol) and trifluoroacetic acid (5 mL, 64.9 mmol), and the resulting solution was stirred for ON as it warmed to rt. The reaction was then quenched with saturated aqueous sodium bicarbonate and the solution was extracted with dichloromethane. The organic phases were then combined, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The resultant solid was washed with cold 10:1 hexanes:dichloromethane to yield 6 g of the title compound as a white solid. 1H NMR (500 MHz, d6-acetone): δ 8.5 (s, 1H), 8.0 (m, 2H), 7.4-7.1 (m, 5H), 5.7 (s, 2H), 4.0 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1)C.Cl[CH2:14][C:15]([N:17]=[C:18]=[O:19])=[O:16].C1CCN2C(=NCCC2)CC1>O1CCOCC1>[O:19]=[C:18]1[NH:17][C:15](=[O:16])[CH2:14][N:11]1[C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:12]
Reactant: O=C=NC(=O)CCl
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: O=C1CN(c2cccc(C(=O)O)c2)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12 mmol of ethyl-3-aminobenzoate were dissolved in 120 ml Dioxan. 1 eq of chloroacetyl isocyanate were added. The reaction mixture was stirred at rt for 1 h and then heated to 120° C. for an additional 2 h. The reaction was cooled to rt, 2 eq of DBU added and again stirred at rt overnight. The solvent was evaporated and the crude extracted from DCM. The crude material was dissolved in 20 ml MeOH and 4 ml of 4N NaOH were added. The reaction mixture was stirred at rt for 20 h. After evaporation of the organic layer the aqueous phase was acidified to pH=1 and the resulting white solid was filtered off and dried under vacuum. MS(ISO): 219.2 (M−H+)
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.[C:16]([NH:19][C:20]1[S:21][CH:22]=[C:23]([CH:25]=O)[N:24]=1)(=[O:18])[CH3:17].C(N(CC)CC)C.[BH4-].[Na+]>CO>[C:16]([NH:19][C:20]1[S:21][CH:22]=[C:23]([CH2:25][NH:2][CH2:3][CH:4]([OH:15])[C:5]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=2)[N:24]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1nc(C=O)cs1
Reactant: COc1ccc(C(O)CN)cc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(C(O)CNCc2csc(NC(C)=O)n2)cc1OC
Yield: 82 %

Procedure:
α-(Aminomethyl)-3,4-dimethoxybenzyl alcohol hydrochloride (2.88 g) and 2-acetamido-4-formyl-thiazole (2.1 g) were suspended in 14 ml methanol, and 1.8 ml triethylamine was added dropwise to this suspension with stirring. The resulting solution was heated under reflux for 30 minutes, and 0.70 g sodium borohydride was added in small portions with stirring under ice cooling. The crystals which separated out were collected by filtration, washed with water and methanol in that order and vacuum-dried, giving 3.55 g of α-[[[(2-acetamido-4-thiazolyl)methyl]amino]methyl]-3,4-dimethoxybenzyl alcohol, m.p. 204°-206° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([S:9][C:10]2[NH:14][CH:13]=[C:12]([C:15]([O:17]C)=[O:16])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>CO>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[C:5]([S:9][C:10]2[NH:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1c[nH]c(Sc2cccc(C(F)(F)F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(Sc2cccc(C(F)(F)F)c2)c1

Procedure:
Methyl 5-(3-trifluoromethylphenylthio)pyrrole-3-carboxylate (2.9 g.) was combined with 30 ml. of methanol and 30 ml. of 1N sodium hydroxide and refluxed for 2.5 hours. The methanol was allowed to evaporate and the aqueous residue washed twice with ether. The aqueous phase was acidified with conc. hydrochloric acid and the crude product (2.3 g) which precipitated, was recovered by filtration. Recrystallization of the crude from methanol/water gave purified 5-(3-trifluoromethylphenylthio)pyrrole-3-carboxylic acid (1.47 g., m.p. 138°-140° C.).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[C:4]([C:9]2[CH2:13][CH2:12][O:11][N:10]=2)[C:5](Br)=[CH:6][CH:7]=1.CN1C(=O)CCC1.[CH3:22][S-:23].[Na+]>O>[Br:1][C:2]1[C:3]([CH3:14])=[C:4]([C:9]2[CH2:13][CH2:12][O:11][N:10]=2)[C:5]([S:23][CH3:22])=[CH:6][CH:7]=1
Reactant: Cc1c(Br)ccc(Br)c1C1=NOCC1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CSc1ccc(Br)c(C)c1C1=NOCC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
25 g (0.075 mol) of 3-(3,6-dibromo-2-methylphenyl)-4,5-dihydroisoxazole are initially charged in 12 mol of NMP. At a temperature of 100° C. and at a reduced pressure of 100 mbar, 29.3 g (0.09 mol) of a 21.5% strength methanolic solution of sodium thiomethoxide are added dropwise over a period of 40 min. The reaction mixture is stirred at 100° C. for 3 h and then stirred into 250 ml of water and extracted three times with 100 ml of toluene. The combined organic phases are washed once with 100 ml of water and then concentrated under reduced pressure. This gives 17.5 g of a dark oil. GC/MS shows, in addition to other isomers, 52.3% of the desired product. MSm/z: 287.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])(=[O:3])[CH3:2].CN(C1C=CC=CN=1)C.[C:35](=O)([O:41]C(C)(C)C)[O:36][C:37]([CH3:40])([CH3:39])[CH3:38].O>CN(C)C=O>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])[C:35]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:41])(=[O:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: CN(C)c1ccccn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(C(=O)OC(C)(C)C)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
3.03 g (8.70 mmol) of Compound 27 obtained in Example 27 was dissolved in 200 ml of dimethylformamide, 109 mg of dimethylaminopyridine and 3.0 ml of di-tert-butyl carbonate were added and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution and the precipitated crystals were collected by filtration to give 3.44 g (88%) of 2-[4-[N-acetyl-N-(tert-butoxycarbonyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([NH2:12])[CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C.[C:22]([O:26][C:27]([N:29]([CH3:59])[C:30]([C:32]1[C:33]([C:52]2[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=2)=[N:34][N:35]2[C:40]([F:41])=[CH:39][C:38]([C:42]3[CH:43]=[C:44]([CH:48]=[CH:49][C:50]=3[CH3:51])[C:45](O)=[O:46])=[CH:37][C:36]=12)=[O:31])=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:41][C:40]1[N:35]2[N:34]=[C:33]([C:52]3[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=3)[C:32]([C:30]([N:29]([CH3:59])[C:27](=[O:28])[O:26][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:31])=[C:36]2[CH:37]=[C:38]([C:42]2[CH:43]=[C:44]([C:45](=[O:46])[NH:12][C:9]3([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=4)[CH2:11][CH2:10]3)[CH:48]=[CH:49][C:50]=2[CH3:51])[CH:39]=1
Reactant: NC1(c2ccccn2)CC1
Reactant: Cc1ccc(C(=O)O)cc1-c1cc(F)n2nc(-c3ccc(F)cc3)c(C(=O)N(C)C(=O)OC(C)(C)C)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2(c3ccccn3)CC2)cc1-c1cc(F)n2nc(-c3ccc(F)cc3)c(C(=O)N(C)C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C

Procedure:
To a solution containing 1-(pyridin-2-yl)cyclopropanamine dihydrochloride (0.011 g, 0.054 mmol), diisopropylethylamine (0.075 mL, 0.43 mmol), 3-(3-(tert-butoxycarbonyl(methyl)carbamoyl)-7-fluoro-2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-yl)-4-methylbenzoic acid (0.028 g, 0.054 mmol) and DMF (0.36 mL) was added HATU (0.041 g, 0.11 mmol) in one portion. The solution was maintained at room temperature for 1 h and concentrated. The resultant residue was purified on silica gel (30-100% ethyl acetate/hexanes, 45 min. gradient) to afford tert-butyl 7-fluoro-2-(4-fluorophenyl)-5-(2-methyl-5-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carbonyl(methyl)carbamate as a residue. LCMS retention time: 2.428 mM. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10 micron, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3OH/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3OH/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 638 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8](O)[C@@H:9]([C:13]2[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1.[Br:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[C:33]([CH3:41])[CH:32]=1>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:36]2[C:35]3[C:40](=[C:31]([Br:30])[CH:32]=[C:33]([CH3:41])[CH:34]=3)[CH:39]=[CH:38][CH:37]=2)[C@@H:9]([C:13]2[CH:28]=[CH:27][C:16]([C:17]([NH:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:18])=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)[C@@H](O)c1ccc(Cl)cc1
Reactant: Cc1cc(Br)c2ccccc2c1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(Cl)cc1)c1cccc2c(Br)cc(C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (50 mL) was added to ethyl N-(4-{(1R)-1-[(R)-(4-chlorophenyl)(hydroxy)methyl]butyl}benzoyl)-β-alaninate (EXAMPLE 1, Step A, 2.00 g, 4.79 mmol) and 1-bromo-3-methylnaphthalene (1.16 g, 5.26 mmol). The solution was stirred overnight at RT, then the solvent was evaporated and the residue was purified by silica gel chromatography eluting with 0-15% EtOAc/hexanes to afford the title compound. LC3 4.49 min. [M+H]+ 622.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]2[CH2:36][CH2:35][N:34]([CH3:37])[C:33]2=[O:38])/[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:39][C@@H:40]1[C:71](=[O:72])[N:42]2[C:43]([C:55]([O:57][CH:58]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[O:56])=[C:44]([CH2:47][S:48][C:49]3[N:53]([CH3:54])[N:52]=[N:51][N:50]=3)[CH2:45][S:46][C@H:41]12.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]2[CH2:36][CH2:35][N:34]([CH3:37])[C:33]2=[O:38])/[C:27]([NH:39][C@@H:40]2[C:71](=[O:72])[N:42]3[C:43]([C:55]([O:57][CH:58]([C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)[C:59]4[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=4)=[O:56])=[C:44]([CH2:47][S:48][C:49]4[N:53]([CH3:54])[N:52]=[N:51][N:50]=4)[CH2:45][S:46][C@H:41]23)=[O:28])[N:25]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cn1nnnc1SCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CN1CCC(O/N=C(\C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CN1CCC(O/N=C(\C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(CSc4nnnn4C)CS[C@H]23)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
1.5 g of (Z)-2-(2-tritylaminothiazol-4-yl)-2-[(1-methyl-2-pyrrolidon-3-yl)oxyimino]acetic acid are dissolved in 50 ml of tetrahydrofuran, and 1.4 g of benzhydryl 7β-amino-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylate, 0.6 g of 1-hydroxybenzotriazole and 0.92 g of dicyclohexylcarbodiimide are added thereto. The mixture is stirred at room temperature for 2 hours. Then, the reaction mixture is treated in the same manner as described in Example 3-(1). 1.58 g of benzhydryl 7β-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-[(1-methyl-2-pyrrolidon-3-yl)oxyimino]acetamido}-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylate are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:12].[F:13][C:14]([F:29])([F:28])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[O:25][C:24]([CH:26]=O)=[CH:23][CH:22]=1>>[C:8]([C:6]1[CH:5]=[CH:4][C:3]([OH:12])=[C:2]([N:1]=[CH:26][C:24]2[O:25][C:21]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]([F:28])([F:13])[F:29])=[CH:22][CH:23]=2)[CH:7]=1)([CH3:9])([CH3:11])[CH3:10]
Reactant: O=Cc1ccc(-c2ccccc2C(F)(F)F)o1
Reactant: CC(C)(C)c1ccc(O)c(N)c1
Product: CC(C)(C)c1ccc(O)c(N=Cc2ccc(-c3ccccc3C(F)(F)F)o2)c1

Procedure:
Using 2-amino-4-tert-butylphenol and 5-(2-(trifluoromethyl)phenyl)furan-2-carbaldehyde, 4.25 g of 4-tert-butyl-2-{[5-(2-(trifluoromethyl)phenyl)furan-2-yl]methyleneamino}phenol were obtained as a yellow powder (yield 91%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[CH:32]=[CH:31][C:29]([OH:30])=[CH:28][C:27]=1[OH:33]>C(OCCO)C>[OH:33][C:27]1[CH:28]=[C:29]([OH:30])[CH:31]=[CH:32][C:26]=1[NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: Nc1ccc(O)cc1O
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3ccc(O)cc3O)c2cc1OC
Yield: 97.9 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 12 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 210.0 mg (1.3 mmol) of 4-aminoresorcinol to give 330.4 mg (98.0%) of the product as a deep purple solid, m.p.>250° C., mass (electrospray, m/e): M+H 337.9.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]([O:16][C:17](=[O:25])[NH:18][C@@H:19]([CH2:23]O)[CH2:20][CH2:21][CH3:22])([CH3:15])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[C:12]([O:16][C:17](=[O:25])[NH:18][C@@H:19]([CH2:23][N:5]1[C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]1=[O:6])[CH2:20][CH2:21][CH3:22])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCC[C@H](CO)NC(=O)OC(C)(C)C
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC[C@H](CN1C(=O)c2ccccc2C1=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of phthalimide (1.43 g, 9.72 mmol), ((R)-1-hydroxymethyl-butyl)-carbamic acid tert-butyl ester (prepared according to the procedure described in Tetrahedron Letters (1987), 28(48), 6069-72) (1.97 g, 9.69 mmol) and triphenylphosphine (2.55 g, 9.72 mmol) in DCM (25 mL) at 0° C. is added DEAD (1.6 mL, 10.2 mmol) dropwise. The reaction mixture is stirred at RT overnight. The reaction mixture is adsorbed onto silica gel and purification by column chromatography (SiO2, EtOAc/iso-hexane, gradient of 0-15% EtOAc) affords the title compound as white solid. [M+H]+ 233.
Reaction SMILES: Cl.[S:2]1([C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:6](=[O:7])[NH:5]1)(=[O:4])=[O:3].[CH2:14]([OH:17])[CH2:15][OH:16]>>[NH2:5][S:2]([C:13]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:6]([O:16][CH2:15][CH2:14][OH:17])=[O:7])(=[O:4])=[O:3]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: OCCO
Agent: Cl
Product: NS(=O)(=O)c1ccccc1C(=O)OCCO
Temperature: 41 °C
Reaction time: 65 h

Procedure:
Hydrogen chloride gas was passed through a mixture of 54.9 g of saccharin and 500 ml of ethylene glycol for 11/2 hours. The mixture, which had warmed to 41° C., was then stirred at ambient temperature for 65 hours. The resulting solution was poured into 2 liters of ice water and the product extracted with ethyl acetate. The extracts were washed with water, dried (MgSO4), and the solvent removed under reduced pressure to give a colorless oil which slowly crystallized. The white solid was triturated with n-butylchloride to give 44.9 g of the title compound, m.p. 84°-86.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][O:18][C:19]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[C:26]([O:27][CH3:28])[C:19]=2[O:18][CH3:17])[N:3]=1
Reactant: COc1cccc(CN)c1OC
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: COc1cccc(CNc2nc(Cl)nc3c2ncn3C2CCCC2)c1OC

Procedure:
2-Chloro-6-[(2,3-dimethoxybenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2,3-dimethoxybenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[N:32]1([C:37]2[CH:38]=[C:39]([CH:42]=[CH:43][N:44]=2)[CH:40]=O)[CH2:36][CH2:35][CH2:34][CH2:33]1.CC(O)=O>ClCCCl>[CH:1]1([N:4]([CH2:18][C:19]2[O:20][CH:21]=[C:22]([C:24]([N:26]3[CH2:31][CH2:30][N:29]([CH2:40][C:39]4[CH:42]=[CH:43][N:44]=[C:37]([N:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)[CH:38]=4)[CH2:28][CH2:27]3)=[O:25])[N:23]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:6])=[O:7])[CH2:2][CH2:3]1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCNCC3)co2)C2CC2)c(C)c1
Reactant: O=Cc1ccnc(N2CCCC2)c1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2nc(C(=O)N3CCN(Cc4ccnc(N5CCCC5)c4)CC3)co2)C2CC2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-cyclopropyl-4-methoxy-2,6-dimethyl-N-{[4-(piperazin-1-ylcarbonyl)-1,3-oxazol-2-yl]methyl}benzenesulfonamide (30 mg, 0.07 mmol) in DCE (2 mL) were added 2-pyrrolidin-1-ylisonicotinaldehyde (14 mg, 0.08 mmol) and AcOH (3 μL, 0.07 mmol) and the reaction mixture was stirred for 1 h at ambient temperature. STAB (20 mg, 0.09 mmol) was added and the reaction was stirred for 16 h. The reaction mixture was quenched with H2O (2 mL) and extracted with DCM (3×2 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep method D to afford the title compound.