Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C(=O)(O)[O-].[Na+].O.Br[CH2:12][C:13]([CH2:15][C:16]([NH:18][CH:19]1[C:39](=[O:40])[N:21]2[C:22]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[CH:23][CH2:24][S:25][C@H:20]12)=[O:17])=O>O1CCCC1>[NH2:1][C:2]1[S:3][CH:12]=[C:13]([CH2:15][C:16]([NH:18][CH:19]2[C:39](=[O:40])[N:21]3[C:22]([C:26]([O:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=4)=[O:27])=[CH:23][CH2:24][S:25][C@H:20]23)=[O:17])[N:4]=1
Reactant: O=C(CBr)CC(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(CC(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=CCS[C@H]23)cs1
Temperature: 25 °C
Yield: 25.6 %

Procedure:
Thiourea (1.13 g), sodium bicarbonate (1.24 g) and water (20 ml) were added to a solution of 4-nitrobenzyl 7-[2-(2-bromoacetyl)acetamido]-3-cephem-4-carboxylate (6.15 g) in tetrahydrofuran (60 ml), and stirred at room temperature for an hour. After concentrating the resultant solution under reduced pressure, the residue was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The oily residue was subjected to column chromatography on silica gel, and eluted with benzene, a mixture of benzene (1 part) and ethyl acetate (1 part) and then ethyl acetate in turn. The ethyl acetate fractions were collected and concentrated under reduced pressure to give 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)acetamido]-3-cephem-4-carboxylate (1.5 g).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]([NH:13][NH2:14])=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:15]1([C:18](O)=O)[CH2:17][CH2:16]1>P(Cl)(Cl)(Cl)=O>[C:1]1([S:7]([CH2:10][C:11]2[O:12][C:18]([CH:15]3[CH2:17][CH2:16]3)=[N:14][N:13]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNC(=O)CS(=O)(=O)c1ccccc1
Reactant: O=C(O)C1CC1
Solvent: O=P(Cl)(Cl)Cl
Product: O=S(=O)(Cc1nnc(C2CC2)o1)c1ccccc1
Yield: 40.3 %

Procedure:
To 3.0 g (14.0 mmol) of benzenesulfonyl-acetic acid hydrazide in 30 mL of phosphorus oxychloride, 1.47 g (17.0 mmol, 1.2 eq) of cyclopropanecarboxylic acid were added, and heated at reflux for 2 hours. The reaction mixture was very carefully poured onto ice, extracted with EtOAc, filtered and evaporated. Column chromatography on silica gel with EtOAc/heptane 2:1 yielded 1.49g (41%) of 2-benzenesulfonylmethyl-5-cyclopropyl-[1,3,4]oxadiazole as a white solid, MS: 265 (MH+).
Reaction SMILES: C([O:3][C:4](=[O:39])[CH:5]=[C:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:38])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C@@H:19]([N:27]3[CH2:32][C@@H:31]([CH3:33])[N:30]([CH2:34][CH:35]=[CH2:36])[CH2:29][C@@H:28]3[CH3:37])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[CH:14]=2)[CH2:8][CH2:7]1)C.C(O)C.[OH-].[Na+].S(=O)(=O)(O)O>O>[CH2:34]([N:30]1[C@H:31]([CH3:33])[CH2:32][N:27]([C@@H:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[C:12]([N:9]2[CH2:8][CH2:7][C:6](=[CH:5][C:4]([OH:39])=[O:3])[CH2:11][CH2:10]2)=[O:38])[C@@H:28]([CH3:37])[CH2:29]1)[CH:35]=[CH2:36]
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N3CCC(=CC(=O)OCC)CC3)c2)C[C@H]1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N3CCC(=CC(=O)O)CC3)c2)C[C@H]1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The preceding ester, Example 137, was hydrolyzed as follows. A 50 mL round bottom flask equipped with a magnetic stir bar was charged with 0.64 g (1.2 mmol, 1 eq) of (1-{3-[(R)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)(3-hydroxyphenyl)methyl]-benzoyl}-4-piperidinylidene)acetic acid ethyl ester, 5.0 mL ethanol, and 3.0 mL (6 mmol, 5 eq) of 2 N aqueous NaOH solution. The reaction was stirred at room temperature for 3 days and neutralized with 3.0 mL (6 mmol, 5 eq) of 2 N aqueous sulfuric acid. After stirring for 30 minutes, the reaction was filtered to remove the sodium sulfate and the solvent was removed in vacuo. The residue was dissolved in 5 mL of ethanol and filtered through a 0.2 □m polypropylene membrane. The filtrate was concentrated in vacuo, leaving an off-white solid. This material was dissolved in 8 mL of water, filtered through a 0.2 □m polypropylene membrane, and lyophilized to give (1-{3-[(R)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)(3-hydroxyphenyl)methyl]-benzoyl}-4-piperidinylidene)acetic acid as a fluffy, white solid, 0.598 g. Calculated for C30H37N3O4 0.25 H2SO4 2.0 H2O: %C, 63.87; H, 7.41; N, 7.45. Found: %C, 64.03; H, 7.31; N, 7.42. 1H NMR (300 MHz, D2O with ˜0.1 N NaOD): {tilde over (□)}□brd, J=7.6 Hz, 1H), 7.30-7.25 (m, 2H), 7.14 (d, J=7.2 Hz, 1H), 6.93 (t, J=7.7 Hz, 1H), 6.46-6.37 (m, 2H), 6.29 (d, J=7.3 Hz, 1H), 5.77-5.66 (m, 1H), 5.61 (d, J=13.3 Hz, 1H), 5.10 (d, J=8.3 Hz, 1H), 5.07 (s, 2H), 3.72-3.51 (m, 2H), 3.26-3.22 (m, 3H), 2.76-2.21 (series of m, 8H), 2.02 (brt, 2H), 1.91 (brt, 1H, 0.96 (d, J=6.1 Hz, 3H), 0.82 (d, J=6.1 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:13]=[CH:12][S:11][CH:10]=2)=O)=[CH:5][N:4]=[CH:3]1.Cl.[NH2:15][OH:16]>N1C=CC=CC=1>[OH:16][N:15]=[C:7]([C:6]1[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=1)[C:9]1[CH:13]=[CH:12][S:11][CH:10]=1
Reactant: Cn1cncc1C(=O)c1ccsc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cn1cncc1C(=NO)c1ccsc1
Reaction time: 72 h

Procedure:
A solution of (1-methyl-1H-imidazol-5-yl)(3-thienyl)methanone (11.6 g, 60.0 mmol) and hydroxylamine hydrochloride (14.6 g, 210 mmol) in pyridine (60 mL) was stirred 9 h at 60° C. then left to stand for 72 h at room temperature. After removal of the solvent in vacuo, addition of water (200 mL), pH adjustment to approx 7 with aq. NaOH (1 M) induced precipitation of a solid. Filtration, sequential washings of the precipitate with water and heptane, and drying of the solid afforded a first crop of N-hydroxy-1-(1-methyl-1H-imidazol-5-yl)-1-(3-thienyl)methanimine. The combined aqueous phases were extracted with dichloromethane, the combined organic layers were dried over MgSO4 and concentrated in vacuo. The residue was purified recrystallized from heptane to afford a second crop of N-hydroxy-1-(1-methyl-1H-imidazol-5-yl)-1-(3-thienyl)methanimine. The crops were combined and recrystallized from diisopropylether to afford final N-hydroxy-1-(1-methyl-1H-imidazol-5-yl)-1-(3-thienyl)methanimine [9.95 g, yield 76%; HPLC/MS m/z=208 (M+H); log P(HCOOH)=0.21].
Reaction SMILES: [OH:1][CH:2]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[C:14](=[O:32])[NH:15][C:16](=[O:31])[C:17]=2[C:18]2[C:26]3[C:21](=[CH:22][C:23]([N+:27]([O-:29])=[O:28])=[CH:24][CH:25]=3)[N:20]([CH3:30])[CH:19]=2)=[CH:5]1)[CH3:3].C(Cl)CCl.CN(C1C=CC=CN=1)C.[CH3:46][O:47][C:48]1[C:56]([O:57][CH3:58])=[CH:55][CH:54]=[CH:53][C:49]=1[C:50](O)=[O:51]>C(Cl)Cl>[CH3:30][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:18]([C:17]2[C:16](=[O:31])[NH:15][C:14](=[O:32])[C:13]=2[C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([CH:2]([O:1][C:50](=[O:51])[C:49]3[CH:53]=[CH:54][CH:55]=[C:56]([O:57][CH3:58])[C:48]=3[O:47][CH3:46])[CH3:3])[CH:5]=2)=[CH:19]1
Reactant: COc1cccc(C(=O)O)c1OC
Reactant: CC(O)n1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccccc21
Agent: CN(C)c1ccccn1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1cccc(C(=O)OC(C)n2cc(C3=C(c4cn(C)c5cc([N+](=O)[O-])ccc45)C(=O)NC3=O)c3ccccc32)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.1 %

Procedure:
To a solution of 3-[1-(1-hydroxy-ethyl)-1H-indol-3-yl]-4-(1-methyl-6-nitro-1H-indol-3-yl)-pyrrole-2,5-dione (165.3 mg, 0.678 mmol) (from step d) above), EDC.HCL (284.5 mg, 1.484 mmol), and dimethylaminopyridine (185.5 mg, 1.58 mmol) in 20 mL of CH2Cl2 was added 2,3-dimethoxybenzoic acid (287.4 mg, 0.668 mmol). The solution was stirred at room temperature for 0.5 hour, washed with saturated NaHCO3, brine, dried over magnesium sulfate, and evaporated. The residue was purified by flash chromatography using EtOAc/hexanes to give 203 mg of 2,3-dimethoxy-benzoic acid 1-{3-[4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-indol-1-yl}-ethyl ester. (Yield 50%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[CH2:14])[C@H:9]1[CH2:15][O:16][Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[CH2:14])[C@H:9]1[CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C=C[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1CO
Temperature: 0 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
2.67 g of 163 (5.73 mmol) was dissolved in 35 ml of anhydrous THF, cooled to 0° C. and added with 8.60 ml of TBAF solution (8.60 mmol, 1.5 eq., 1 M/THF). After reacting at RT overnight, 0.5 ml of water was added, followed by stirring for 30 min. Thereafter, the batch was filtered together with a small amount of MTBE over a small amount of silica gel and concentrated. Column chromatography over silica gel (EE/CH 1:3) afforded 1.28 g of alcohol 165 (5.63 mmol, 98%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[C:14]([F:18])=[CH:13][C:3]=1[C:4](C1C=CC(F)=CC=1)=[O:5].[OH:19]O>OS(O)(=O)=O.O=S(=O)=O>[Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[C:14]([F:18])=[CH:13][C:3]=1[C:4]([OH:5])=[O:19]
Reactant: O=C(c1ccc(F)cc1)c1cc(F)c(Cl)cc1Cl
Reactant: OO
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=C(O)c1cc(F)c(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 8 h

Procedure:
28.7 g (0.1 mol) of 2,4-dichloro-4',5-difluorobenzophenone are dissolved in 250 g of 10% oleum, and 25 g of 50% hydrogen peroxide solution are added at temperatures up to 30° C. When the metered addition has ended (30 min), the mixture is heated for 8 h at 50° C. and, after cooling, is poured on to 250 g of ice. This mixture is kept for 8 h at 140° C. and 4-fluorophenol is then recovered by steam distillation (7.5 g, 0.0673 mol, 67%, m.p. (DSC) 42.6° C.). 2,4-dichloro-5-fluorobenzoic acid is isolated as described in Example 1 (17.0 g, 0.0813 mol, 81%, m.p. 143°-145° C.). (DSC =differential scanning calorimetry)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[C:8]([CH3:24])[C:6]=2[N:7]=1.[NH2:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1>>[CH3:24][C:8]1[C:6]2[N:7]=[C:2]([C:35]3[CH:34]=[N:33][C:32]([NH2:31])=[N:37][CH:36]=3)[N:3]=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[C:5]=2[S:10][C:9]=1[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH2:14][CH2:13]1
Reactant: Cc1c(CN2CCN(S(=O)(=O)C(C)C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12
Reactant: Nc1ncc(B(O)O)cn1
Product: Cc1c(CN2CCN(S(=O)(=O)C(C)C)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12

Procedure:
2-Chloro-7-methyl-4-morpholin-4-yl-6-[4-(propane-2-sulfonyl)-piperazin-1-ylmethyl]-thieno[3,2-d]pyrimidine (105 mg) was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica and recrystallization from hot DCM/hexane gave 273. NMR (CDCl3): 1.37 (6H, d, J=6.8), 2.44 (3H, s), 2.63-2.66 (4H, m), 3.18-3.25 (1H, m), 3.43-3.46 (4H, m), 3.86 (2H, s), 3.89-3.91 (4H, m), 4.03-4.05 (4H, m), 5.23 (2H, br), 9.35 (2H, s). MS (ESI+): MH+533.31 (40%)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].[C:27]([CH:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([CH:31]1[CH2:32][CH2:33][CH:34]([NH:37][C:18]([C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[CH:22][CH:21]=2)=[O:20])[CH2:35][CH2:36]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)C1CCC(N)CC1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)NC4CCC(C(C)(C)C)CC4)cc3)c(C#N)cc21
Yield: 97 %

Procedure:
Prepared according to Example 110, Step A where the reacting carboxylic acid replacing 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid with 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid and replacing 2-(benzo[d][1,3]dioxol-5-yl)ethanamine with 4-tert-Butylcyclohexylamine to provide the title compound (73 mg, 97% yield) as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[C:15]([N:18]1[CH:23]([CH3:24])[CH2:22][N:21]([C:25]2[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=2)[CH2:20][CH:19]1[CH3:33])(=[O:17])[CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S(=O)(O)[O-].[Na+]>CN(C)C(=O)C>[C:15]([N:18]1[C@@H:23]([CH3:24])[CH2:22][N:21]([C:25]2[CH:26]=[CH:27][C:28]([C:29]3[NH:6][C:4](=[O:5])[C:3]4[C:7]([O:13][CH3:14])=[CH:8][C:9]([O:11][CH3:12])=[N:10][C:2]=4[N:1]=3)=[CH:31][CH:32]=2)[CH2:20][C@H:19]1[CH3:33])(=[O:17])[CH3:16]
Reactant: CC(=O)N1C(C)CN(c2ccc(C=O)cc2)CC1C
Reactant: COc1cc(OC)c(C(N)=O)c(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4C[C@@H](C)N(C(C)=O)[C@@H](C)C4)cc3)nc2n1
Temperature: 135 °C
Reaction time: 16 h

Procedure:
A mixture of 2-amino-4,6-dimethoxy-nicotinamide (0.25 g, 1.26 mmol), 4-(4-acetyl-3,5-dimethyl-piperazin-1-yl)-benzaldehyde (0.43 g, 1.64 mmol), p-toluenesulfonic acid monohydrate (0.53 mg, 2.77 mmol) and sodium bisulfite (0.45 g, 2.52 mmol) in N,N-dimethylacetamide (5.0 mL) was stirred at 135° C. under N2 for 16 hours and then cooled to room temperature. The mixture was concentrated to dryness under reduced pressure. Water (40 mL) was added to the residue and stirred for 0.5 hours. The precipitate was filtered and the solid was rinsed with water and dried over Na2SO4. The crude solid was purified by column chromatography (silica gel 230-400 mesh; eluting with 2.5% methanol in dichloromethane) to afford the title compound as yellow solid. Yield: 90 mg (16.3%). MP 279-279.8° C. 1H NMR (400 MHz, CDCl3): δ 10.18 (s, 1H), 8.14 (d, J=8.8 Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 6.20 (s, 1H), 4.78 (bs, 1H), 4.12 (s, 3H), 4.02 (s, 3H), 3.70 (d, J=12.0 Hz, 2H) 3.11 (d, J=10 Hz, 2H), 2.18 (s, 3H), 1.40 (bs, 6H).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:16]([OH:18])=O)=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][N:25]=1>>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[N:25]=[CH:26][C:27]([NH:30][C:16]([C:9]2[O:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:11][C:10]=2[C:12]([F:13])([F:14])[F:15])=[O:18])=[CH:28][N:29]=1
Reactant: O=C(O)c1oc(-c2ccccc2)nc1C(F)(F)F
Reactant: COCCN(C)c1ncc(N)cn1
Product: COCCN(C)c1ncc(NC(=O)c2oc(-c3ccccc3)nc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 1 above, 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide was prepared from 2-phenyl-4-trifluoromethyl-oxazole-5-carboxylic acid and N-(2-Methoxy-ethyl)-N-methyl-pyrimidine-2,5-diamine. LCMS calcd for C19H18F3N5O3 (m/e) 421, obsd 422 (M+H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:14]([C:16]2[NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)=[O:15])[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9]C.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[C:5]([C:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[O:15])[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[OH:9]
Reactant: COc1cc(C(=O)c2nc3ccccc3[nH]2)cc([N+](=O)[O-])c1OC
Agent: Cl
Solvent: c1ccncc1
Product: O=C(c1cc(O)c(O)c([N+](=O)[O-])c1)c1nc2ccccc2[nH]1
Temperature: 0 °C

Procedure:
1.0 g of 2-benzimidazolyl (3,4-dimethoxy- 5-nitrophenyl) ketone and 8.0 g of pyridine hydrochloride are held at 200° for 60 minutes. The dark solution is poured while still warm into ice-water and extracted three times with 100 ml of ethyl acetate each time. The organic phase is washed with water, dried over sodium sulfate and evaporated. After recrystallization from ethyl acetate/hexane, there is obtained 2-benzimidazolyl (3,4-dihydroxy- 5-nitrophenyl) ketone in the form of yellow crystals of m.p. 249°-250°.
Reaction SMILES: CO.[CH3:3][O:4][C:5]1[CH:14]=[C:13]([O:15][CH:16]([CH2:18][CH3:19])[CH3:17])[CH:12]=[C:11]2[C:6]=1[C:7](=O)[CH2:8][C:9]([CH3:21])([CH3:20])[O:10]2.[BH4-].[Na+]>O1CCCC1>[CH3:3][O:4][C:5]1[CH:14]=[C:13]([O:15][CH:16]([CH2:18][CH3:19])[CH3:17])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([CH3:20])([CH3:21])[O:10]2
Reactant: CCC(C)Oc1cc(OC)c2c(c1)OC(C)(C)CC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(C)Oc1cc(OC)c2c(c1)OC(C)(C)C=C2
Reaction time: 2 h
Yield: 85 %

Procedure:
In a mixture of 60 ml of tetrahydrofuran and 40 ml of methanol 5.6 g (20 millimoles) of 5-methoxy-7-sec. butoxy-2,2-dimethyl-4-chromanone are dissolved, whereupon 1.5 g (40 millimoles) of sodium tetrahydroborate are added in small portions and the reaction mixture is heated to boiling for 2 hours. The reaction mixture is worked up according to Example 31. The product is purified by column chromatography. Thus 4.4 g of the desired compound are obtained in the form of a light yellow oil, yield 85%.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[CH3:9][O:10][C:11]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[CH:13][N:12]=1>>[CH3:9][O:10][C:11]1[CH:16]=[C:15]([C:2]2[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=2)[CH:14]=[CH:13][N:12]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Product: COc1cc(-c2ccc(C)nn2)ccn1
Yield: 45.5 %

Procedure:
3-Chloro-6-methylpyridazine (343 mg, 2.67 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (470 mg, 2.0 mmol) were reacted according to Example 31 (step a) to provide the title compound (183 mg, 45%) as a cream solid: 1H NMR (500 MHz, CDCl3) δ 8.31 (d, J=5.3 Hz, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.59 (dd, J=5.3, 1.5 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 7.38 (s, 1H), 4.00 (s, 3H), 2.79 (s, 3H).
Reaction SMILES: C(C1C=[C:5]([NH:9][C:10]2[N:15]=[C:14]([O:16][C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])[C:13]([F:25])=[C:12]([CH3:26])[C:11]=2[F:27])C=CC=1)#N.IC.[H-].[Na+].[C:32](#[N:34])[CH3:33]>>[C:32]([C:33]1[CH:10]=[C:11]([CH2:5][NH:9][C:10]2[N:15]=[C:14]([O:16][C:17]3[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=3)[C:20]#[N:21])[C:13]([F:25])=[C:12]([CH3:26])[C:11]=2[F:27])[CH:12]=[CH:13][CH:14]=1)#[N:34]
Reactant: Cc1c(F)c(Nc2cccc(C#N)c2)nc(Oc2cccc(C#N)c2)c1F
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: Cc1c(F)c(NCc2cccc(C#N)c2)nc(Oc2cccc(C#N)c2)c1F
Reaction time: 18 h

Procedure:
To 3-[(6-(3-cyanophenyl)amino-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzonitrile (0.10 g, 0.28 mmol) in acetonitrile (10 mL) was added iodomethane (0.20 g, 1.4 mmol) and sodium hydride (0.055 g, 1.4 mmol). After stirring for 18 hours the reaction was partitioned with water and ethyl acetate. The organic layer was separated, dried (Na2SO4), and the solvent was removed in vacuo. Chromatography of the residue on silica gel with ethyl acetate/hexane (1/3) as eluent gave 3-[(6-(3-cyanophenyl)methylamino-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzonitrile; NMR (CDCl3) 7.4 (m,5), 7.25 (m,1), 7.1 (m,2), 3.25 (s,3), 2.3 (s,3) ppm.
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]([Cl:10])=[C:6](Cl)[C:5]([Cl:12])=[N:4]1)[CH3:2].[CH2:13]([O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][NH2:21])[CH2:14][CH3:15]>C(O)C>[CH2:1]([N:3]1[C:8](=[O:9])[C:7]([Cl:10])=[C:6]([NH:21][CH2:20][C:19]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:17]([O:16][CH2:13][CH2:14][CH3:15])[CH:18]=2)[C:5]([Cl:12])=[N:4]1)[CH3:2]
Reactant: CCn1nc(Cl)c(Cl)c(Cl)c1=O
Reactant: CCCOc1cc(CN)ccc1OC
Solvent: CCO
Product: CCCOc1cc(CNc2c(Cl)nn(CC)c(=O)c2Cl)ccc1OC
Reaction time: 3.5 h

Procedure:
A mixture comprising 455 mg of 2-ethyl-4,5,6-trichloro-3(2H)pyridazinone, 1.20 g of 3-n-propoxy-4-methoxybenzylamine and 20 ml of ethanol, was refluxed under stirring for 3.5 hours. Ethanol was distilled off under reduced pressure, and water was poured into the residue thereby obtained. The mixture was extracted with ethyl acetate. The extract was washed with dilute hydrochloric acid and water in this order and dried over sodium sulfate. Then, the solvent was distilled off to obtain a light brown viscous oily substance. The product was purified by silica gel column chromatography by using a solvent mixture of benzene-ethyl acetate (15:1 v/v) as the eluent, to obtain 277 mg of the above identified compound. The physical properties and the spectrum data of NMR and MS of the compound completely agreed to those of the compound prepared by the method (1).
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH2:28])=[O:27].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([NH:22][C:23]4[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=4)[C:26]([NH2:28])=[O:27])=[O:18])=[CH:13][CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: NC(=O)c1cccc(N)c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of the 4-adamantan-1-yl-phenoxy acetic acid (114.6 mg, 0.40 mmol) and 3-amino benzamide (81.7 mg, 0.60 mmol) ware dissolved in DMF (4.0 mL), and were added EDCHCl (115.1 mg, 0.60 mmol), HOBt (81.1 mg, 0.60 mmol) and DIPEA (0.15 mL, 0.60 mmol). The reaction mixture was stirred overnight and then partitioned between Ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (n-Hexane:Ethyl acetate:MeOH=9:3:1) gave 3-[2-(4-Adamantan-1-yl-phenoxy)acetyl-amino]-benzamide as a white solid (145.0 mg, 89.6% yield).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[C:19]([C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][C:26](=[O:30])[NH:27]2)=[CH:23][CH:22]=1)=[O:20]>C1COCC1>[O:30]=[C:26]1[CH2:25][C:24]2[C:28](=[CH:29][C:21]([C:19]([C:18]3[CH:17]=[C:16]([NH:15][C:8]([C:7]4[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][CH:6]=4)=[O:10])[CH:33]=[CH:32][CH:31]=3)=[O:20])=[CH:22][CH:23]=2)[NH:27]1
Reactant: CCn1nccc1C(=O)O
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: CCn1nccc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 3 h
Yield: 67.4 %

Procedure:
A dry flask was charged with 2-Ethyl-2H-pyrazole-3-carboxylic acid (0.111 g, 0.792 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (8 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.200 g, 0.793 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and subsequently vacuum filtered. The solid was washed with 0° C. THF (˜5 mL) and collected to afford the 2-Ethyl-2H-pyrazole-3-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.200 g, 0.534 mmol, 68%).