Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[C:10]([C:14]3[CH:19]=[CH:18][N:17]4[C:20]([C:23]5[CH:24]=[C:25]([NH:29][C:30]([NH:32][CH2:33][C:34]([F:37])([F:36])[F:35])=[O:31])[CH:26]=[CH:27][CH:28]=5)=[CH:21][N:22]=[C:16]4[CH:15]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:3][CH2:2]1.[C:38](Cl)(=[O:40])[CH3:39].CCN(CC)CC>CN(C=O)C>[C:38]([N:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:9]=[C:10]([C:14]3[CH:19]=[CH:18][N:17]4[C:20]([C:23]5[CH:24]=[C:25]([NH:29][C:30]([NH:32][CH2:33][C:34]([F:35])([F:36])[F:37])=[O:31])[CH:26]=[CH:27][CH:28]=5)=[CH:21][N:22]=[C:16]4[CH:15]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:3][CH2:2]1)(=[O:40])[CH3:39]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cccc(OC5CCNCC5)c4)ccn23)c1
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(Oc2cccc(-c3ccn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(3-{7-[3-(Piperidin-4-yloxy)-phenyl]-imidazo[1,2-a]pyridine-3-yl}-phenyl)-3-(2,2,2-trifluoro-ethyl)-urea (50 mg, 98 μmol in DMF(10 ml) was added acetyl chloride (6.3 μl, 82 μmol) and Et3N (14 μl). The reaction was stirred at room temperature for 3 h, then partitioned between EtOAc and H2O. The aqueous layer was again extracted with EtOAc, the organics combined, dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by preparative HPLC to give the title compound (17.5 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=2[Cl:16])=[N:6][CH:5]=[C:4](Cl)[N:3]=1.[NH3:18]>C(O)C>[NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[C:10]([Cl:15])[C:9]=2[Cl:16])=[N:6][CH:5]=[C:4]([NH2:18])[N:3]=1
Reactant: N
Reactant: Nc1nc(Cl)cnc1-c1cc(Cl)cc(Cl)c1Cl
Solvent: CCO
Product: Nc1cnc(-c2cc(Cl)cc(Cl)c2Cl)c(N)n1
Temperature: 180 °C

Procedure:
A suspension of 2-amino-6-chloro-3-(2,3,5-trichlorophenyl)pyrazine (0.3 g, 9.71×10−4 mole) in absolute ethanol (4 ml) and 0.880 aqueous ammonia (8.24 ml) was stirred and heated in an autoclave at 180° C. for 44 hrs The cooled mixture was evaporated in vacuo, and the residue extracted with chloroform (3×30 ml). The combined chloroform extracts were dried over anhydrous magnesium sulphate, filtered and the filtrate evaporated down in vacuo. The residue was purified by ‘flash chromatography’ using chloroform to 98:2 chloroform:methanol as the eluent. The product was triturated with 40-60° C. petroleum ether, filtered and dried in vacuo. Yield 0.155 g (56%), M.p. 178-180° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1[NH:22][NH2:23])[C:15](OC)=[O:16].O>C1(C)C=CC=CC=1>[Cl:11][C:12]1[CH:13]=[C:14]([CH2:15][OH:16])[CH:19]=[CH:20][C:21]=1[NH:22][NH2:23]
Reactant: COC(=O)c1ccc(NN)c(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: NNc1ccc(CO)cc1Cl
Temperature: -73 °C
Reaction time: 0.5 h

Procedure:
Diisobutylaluminium hydride (1M in toluene, 190 ml) is added dropwise, under a nitrogen atmosphere and at −73° C., to a solution of methyl 3-chloro-4-hydrazino-benzoate (9.5 g, 47 mmol) in 1 l of toluene in such a way that the temperature does not rise above −70° C. The reaction mixture is stirred at −73° C. for 30 min and then warmed to −5° C. Following hydrolysis with 500 ml of water, the precipitate is filtered off and washed with ethyl acetate (5×500 ml). The organic phase is evaporated, after which the residue is taken up in a little ethyl acetate and precipitated with petroleum ether/diethyl ether and filtered off. The solid which is obtained in this way is purified chromatographically on silica gel using cyclohexane/ethyl acetate. Yield: 2.9 g
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:15]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:16][O:17][C:18]=2[CH2:19][OH:20])=[CH:8][N:7]=1)=[O:5])C.[F:28][C:29]([F:33])([F:32])[CH2:30][NH2:31]>>[F:28][C:29]([F:33])([F:32])[CH2:30][NH:31][C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[C:15]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)=[N:16][O:17][C:18]=2[CH2:19][OH:20])=[CH:8][N:7]=1)=[O:5]
Reactant: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Reactant: NCC(F)(F)F
Product: O=C(NCC(F)(F)F)c1ccc(OCc2c(-c3ccc(F)cc3)noc2CO)cn1
Yield: 81 %

Procedure:
As described for example 31, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-pyridine-2-carboxylic acid ethyl ester (75 mg, 0.2 mmol) was converted, using 2,2,2-trifluoroethylamine instead of 1,1,1-trifluoro-isopropylamine, to the title compound (70 mg, 81%), which was obtained as a colourless gum. MS: m/e=426.2 [M+H]+.
Reaction SMILES: Br[C:2](Br)=[CH:3][C@@H:4]([O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1)[C@@:5]([O:11][CH3:12])([CH3:10])[CH2:6][CH2:7][CH2:8][CH3:9].[Mg].CCCCCC>C1COCC1>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[O:13][C@@H:4]([C@@:5]([O:11][CH3:12])([CH3:10])[CH2:6][CH2:7][CH2:8][CH3:9])[C:3]#[CH:2]
Reactant: CCCC[C@@](C)(OC)[C@@H](C=C(Br)Br)OC1CCCCO1
Agent: [Mg]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C#C[C@@H](OC1CCCCO1)[C@@](C)(CCCC)OC

Procedure:
A solution of (3R,4R)l,l-dibromo-3-tetrahydro-pyranyloxy-4-methoxy-4-methyl-l-octene (240 mg; 0.58 mmol) in THF (2 ml) is added dropwise to a refluxing mixture of activated magnesium turnings (activated with I2, 183 mg, 0.75 mmol) in THF (1 ml). The mixture is refluxed for 1 h, hexane (5 ml) is added and the suspension is filtered through a short path of silica gel. The filter cake is washed with ether and the solvent is removed in vacuo. The alkyne (3R,4R)3-tetrahydropyranyloxy-4-methoxy-4-methyl-l-octyne is purified by column chromatography on silica gel, eluting with 5% EtOAc in petroleum ether, to afford (3R,4R)3-tetrahydropyranyloxy-4-methoxy-4-methyl-l-octyne.
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].CN(N=O)/C(/N)=N/[N+]([O-])=O.[OH-].[K+].[N+:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1)([O-:18])=[O:17]>CCOCC>[N+:1](=[CH:3][C:23]([C:22]1[CH:21]=[CH:20][C:19]([N+:16]([O-:18])=[O:17])=[CH:27][CH:26]=1)=[O:24])=[N-:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C=[N+]=[N-]
Agent: CN(N=O)/C(N)=N/[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: [N-]=[N+]=CC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
The ethereal diazomethane solution [prepared by adding 12.5 g n-methyl-n-nitro-n-nitroso guanidine to potassium hydroxide (50%, 20 ml) and ether (200 ml) at 0°, stirring for 1 hr, and decanting the ether layer; 65% presumed yield] is treated with TEA (7.7 ml) at 0°, then dropwise with p-nitrobenzoyl chloride (10.21 ml) in ether (25 ml). After stirring for 19 hrs, the reaction is filtered through celite and concentrated to give the title compound.
Reaction SMILES: [I:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([O:9]C)=O)[CH:3]=1.[NH3:11]>CO>[I:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([NH2:11])=[O:9])[CH:3]=1
Reactant: COC(=O)c1cc(I)[nH]n1
Reactant: N
Solvent: CO
Product: NC(=O)c1cc(I)[nH]n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of methyl 5-iodo-1H-pyrazole-3-carboxylate (compound 260.3, 900 mg, 3.57 mmol) in methanol (5 mL). Ammonia (25% aq.) (15 mL) was added and the resulting solution was stirred overnight at 60° C., then cooled and concentrated under reduced pressure to obtain the title compound as a white solid (0.8 g, 95%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:14](=[O:17])[CH2:15]Cl)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][O:26][C:22]=2[CH:21]=1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:14](=[O:17])[CH2:15][N:30]3[CH2:29][CH2:28][CH:27]([C:24]4[C:23]5[CH:33]=[CH:34][C:20]([F:19])=[CH:21][C:22]=5[O:26][N:25]=4)[CH2:32][CH2:31]3)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)N1CCc2c(sc(C)c2C(=O)CCl)C1
Agent: Cl
Product: CC(=O)N1CCc2c(sc(C)c2C(=O)CN2CCC(c3noc4cc(F)ccc34)CC2)C1
Yield: 53.7 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.0 g of 6-acetyl-3-chloroacetyl-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine and 0.95 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.9 g of 6-acetyl-3-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)-1-oxoethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 92°-94° C. as 3/2oxalate 1/2hydrate thereof.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[F:10].Br[CH2:13][C:14]([O:16]C)=[O:15].O>CS(C)=O.CO>[Cl:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[F:10])[O:11][CH2:13][C:14]([OH:16])=[O:15]
Reactant: Oc1ccc(F)c(Cl)c1
Reactant: COC(=O)CBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Solvent: O
Product: O=C(O)COc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
To a stirring solution of finely ground KOH (1.2 g, 20.4 mmol) in DMSO (6 mL) was added 3-chloro-4-fluorophenol (1.0 g, 6.8 mmol). The mixture was stirred for 10 minutes at RT, then cooled to 0° C. Methyl bromoacetate (1.25 g, 8.2 mmol) was added, and the reaction was slowly warmed to RT and stirred overnight. H2O (10 mL) and MeOH (10 mL) were added to the mixture, and the reaction was stirred for 1 h. After removing MeOH under reduced pressure, H2O (100 mL) and Et2O (50 mL) were added, and the layers were separated. The aqueous phase was acidified to pH 2 with an aqueous concentrated HCl solution and extracted with CH2Cl2 (200 mL). The organic layer was dried over MgSO4, filtered, concentrated, and dried to give 2-(3-chloro-4-fluorophenoxy)acetic acid as a white solid (1.1 g, 79%). 1H NMR (400 MHz, CDCl3) δ 7.10 (t, J=8.8 Hz, 1H), 7.01-6.98 (m, 1H), 6.84-6.80 (m, 1H), 4.68 (s, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:5][CH3:6])[OH:4])[CH3:2].[CH2:7]=O.[CH2:9]([NH:12][CH2:13][CH:14]=[CH2:15])[CH:10]=[CH2:11]>>[CH2:1]([N:3]([CH2:5][CH3:6])[O:4][CH2:7][N:12]([CH2:13][CH:14]=[CH2:15])[CH2:9][CH:10]=[CH2:11])[CH3:2]
Reactant: C=O
Reactant: C=CCNCC=C
Reactant: CCN(O)CC
Product: C=CCN(CC=C)CON(CC)CC

Procedure:
The procedure of Example I is repeated using 26.74 g of diethylhydroxylamine, 10.81 g of aqueous formaldehyde (37%) solution and 29.15 g of diallylamine, to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]2[CH:6]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:4]=2[CH:3]=1.Cl[C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=1)=[O:27].C(N(CC)CC)C>C(Cl)Cl>[C:14]([O:13][C:11]([N:9]1[CH2:10][C:4]2[CH:3]=[C:2]([NH:1][C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])[CH:24]=[CH:23][C:5]=2[CH:6]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH2:7][CH2:8]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)CC1CCN(C(=O)OC(C)(C)C)Cc2cc(N)ccc21
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC1CCN(C(=O)OC(C)(C)C)Cc2cc(NC(=O)OCc3ccc([N+](=O)[O-])cc3)ccc21
Reaction time: 5 h

Procedure:
To a stirring solution of methyl 2-{8-amino-2-[(tert-butyl)oxycarbonyl]-1H,3H,4H,5H-benzo[e]azepin-5-yl}acetate (1 eq) in methylene chloride (0.1 M) was added 4-nitrobenzyl chloroformate (1.1 eq) and triethylamine (5 eq) at room temperature. After stirring for 5 hr, the reaction mixture was diluted with methylene chloride. The organic phase was washed with saturated sodium bicarbonate, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (20% EtOAc/Hexane). EI-MS m/z 514 (M+H)+.
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([CH3:16])[C@@H:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)[OH:5].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:32]3[C:27](=[CH:28][C:29](I)=[CH:30][CH:31]=3)[CH:26]=[N:25]2)=[CH:20][CH:19]=1.[C:34](=O)([O-])[O-:35].[Cs+].[Cs+]>C(#N)CCC.[Cu]I>[ClH:1].[F:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[C:32]3[C:27](=[CH:28][C:29]([O:5][C@H:4]([C:6]4[CH:15]=[CH:14][C:13]5[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=5)[CH:7]=4)[C@@H:3]([NH2:2])[CH3:16])=[CH:30][CH:31]=3)[CH:26]=[N:25]2)=[CH:22][CH:23]=1.[C:13]([O:35][CH3:34])([CH3:12])([CH3:8])[CH3:14].[ClH:1]
Reactant: O=C([O-])[O-]
Reactant: C[C@H](N)[C@H](O)c1ccc2ccccc2c1
Reactant: Fc1ccc(-n2ncc3cc(I)ccc32)cc1
Agent: [Cu]I
Agent: Cl
Agent: [Cs+]
Solvent: CCCC#N
Product: COC(C)(C)C
Product: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc2ccccc2c1

Procedure:
The subtitle compound was prepared analogous to the method described in Example 19 (step 19a). (1R,2S)-2-amino-1-(naphthalen-2-yl)propan-1-ol hydrochloride (238 mg, 1.00 mmol), 1-(4-fluorophenyl)-5-iodo-1H-indazole (406 mg, 1.20 mmol), Cesium carbonate (979 mg, 3.00 mmol) and copper(I) iodide (38.1 mg, 0.20 mmol) in Butyronitrile (3 mL) was heated for 19 h at +125° C. in a sealed reaction tube flushed with Argon. After final purification by HPLC the obtained material was isolated as a brownish coloured hydrochloride salt from tert-butylmethylether/HCl.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].O[CH2:8][P:9]([CH2:12]O)[CH2:10]O.[C:14]1(F)C(=O)NC(=O)[NH:16][C:15]=1[C:22]([OH:24])=[O:23]>O>[C:4]([CH:2]([NH:1][CH2:12][P:9]([CH2:8][NH:16][CH:15]([CH3:14])[C:22]([OH:24])=[O:23])[CH2:10][NH:1][CH:2]([C:4]([OH:6])=[O:5])[CH3:3])[CH3:3])([OH:6])=[O:5]
Reactant: C[C@H](N)C(=O)O
Reactant: OCP(CO)CO
Reactant: O=C(O)c1[nH]c(=O)[nH]c(=O)c1F
Solvent: O
Product: CC(NCP(CNC(C)C(=O)O)CNC(C)C(=O)O)C(=O)O
Reaction time: 1 h
Yield: 95 %

Procedure:
As shown in Scheme II, alanine (2.15 g, 24.19 mmol) in 25 mL of distilled water was added to tris(hydroxymethyl)phosphine (1.00 g, 8.06 mmol) in water (15 mL) at 25° C. The reaction was stirred under dry nitrogen for one hour. The solvent was removed in vacuo to obtain a solid. The residue was washed in methanol (3×15 mL) and dried in vacuo to yield the analytically pure compound (THPAL) in 95% yield (2.58 g) as a white solid; ESI/MS calcd for C12H24N3O6P [M+H]+ 337.31, found 338.20; Anal. (calcd) for C12H24N3O6P: C, 42.73, H, 7.17. N 12.46. Found: C, 43.21, H, 7.54, N, 11.76; 1H NMR (D2O, 300 MHz): δ 1.37 (d, 9H, —CH(CH3), 3.47 (d, 6H, P—(CH2)), 3.65 (q, 3H, —CH(CH3); 13C NMR (D2O, 75 MHz): δ 14.84 (s, —CH(CH3), 42.65 (d, P—CH2, 1JP—C=12.83 Hz), 59.36 (d, CH(CH3),3JP—C=5.30 Hz), 174.09 (s, —COOH); 31P{1H} NMR (D2O, 121.5 MHz): −39.50 (s).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:11]1([CH3:24])[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[S:19]([O:22][NH2:23])(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][C:13]1[CH:14]=[C:15]([CH3:17])[CH:16]=[C:11]([CH3:24])[C:12]=1[S:19]([O-:22])(=[O:21])=[O:20].[NH2:23][N+:6]1[CH:7]=[CH:8][C:3]([C:2]([F:10])([F:9])[F:1])=[CH:4][CH:5]=1
Reactant: FC(F)(F)c1ccncc1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: N[n+]1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-trifluoromethylpyridine (2.23 g, 15.2 mmol) in CH2Cl2 (66 ml.) at 0° C., O-(mesitylsulfonyl)hydroxylamine (3.27 g, 15.2 mmol) was added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was filtered to afford the desired product with quantitative yield.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]([C:13]1[CH:18](CCl)[C:17]([CH3:25])([C:21]([O:23][CH3:24])=[O:22])[CH2:16][NH:15][C:14]=1[CH3:26])=[O:12].[CH2:27](OCC)C>O1CCCC1>[CH3:24][O:23][C:21]([CH:17]1[CH:25]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:18][C:13]([C:11]([O:10][CH3:9])=[O:12])=[C:14]([CH3:26])[N:15]=[C:16]1[CH3:27])=[O:22]
Reactant: COC(=O)C1=C(C)NCC(C)(C(=O)OC)C1CCl
Reactant: CCOCC
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)N=C(C)C(C(=O)OC)C(c2ccccc2)C1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 92 %

Procedure:
Phenyl magnesium bromide (2.68 mL) in diethylether (3.0M) was added dropwise to 1.00 gram of dimethyl-2,5-dimethyl-4-chloromethyl-1,4-dihydropyridine-3,5-dicarboxylate 11a (3.66 mm) [See; e.g., E. Benary, Chem. Ber., 44, 489 (1911)] in dry tetrahydrofuran under an argon atmosphere at -78° C. Stirring was continued at -78° for 15 minutes followed by warming to -10° C. for 1 hour. The excess Grignard reagent was quenched with saturated aqueous ammonium chloride. Extraction with ethyl acetate (3×75 mL), washing the organic portion with saturated aqueous NaCl, drying (MgSO4), filtering, and evaporation gave crude product. Crystallization from toluene/hexane (1/1) gave 1.10 gr (92%) of pure dimethyl-4-phenyl-4,5-dihydro-2,7-dimethylazepine-3,6-dicarboxylate (11).
Reaction SMILES: C[Si]([Br:5])(C)C.[Cl:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([Cl:25])[C:14]=1[C:15]1[S:16][C:17]2[C:18](Cl)=[N:19][CH:20]=[CH:21][C:22]=2[N:23]=1)[C:10]#[N:11].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>C(#N)CC>[Br:5][C:18]1[C:17]2[S:16][C:15]([C:14]3[C:7]([Cl:6])=[CH:8][C:9]([C:10]#[N:11])=[CH:12][C:13]=3[Cl:25])=[N:23][C:22]=2[CH:21]=[CH:20][N:19]=1
Reactant: N#Cc1cc(Cl)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Reactant: C[Si](C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC#N
Solvent: ClCCl
Product: N#Cc1cc(Cl)c(-c2nc3ccnc(Br)c3s2)c(Cl)c1
Temperature: 90 °C
Yield: 96.1 %

Procedure:
Trimethylsilylbromide (0.23 mL, 1.74 mmol) was added to a stirred solution of 3,5-dichloro-4-(4-chloro-thiazolo[5,4-c]pyridine-2-yl)-benzonitrile (295 mg, 0.87 mmol) in propionitrile (11 mL) and the mixture heated at 90° C. for 48 hours. The reaction mixture was allowed to cool and poured onto a mixture of saturated aqueous potassium carbonate solution and ice. DCM was added and the organic phase was separated, dried over Na2SO4 and concentrated to dryness under reduced pressure to give the desired compound as a white solid (322 mg, 96% yield). 1H NMR (300 MHz, CDCl3): δ 8.53 (d, J=5.5 Hz, 1H), 8.03-8.00 (m, 1H), 7.80 (s, 2H). LCMS (Method D): RT=4.04 min, m/z: 386 [M+H+].
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][Br:26])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:26][CH2:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][CH2:17][CH2:16][CH:8]([NH2:7])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NC(CCCc1ccccc1CBr)Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(CCCc1ccccc1CBr)Cc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 30j (680 mg, 1.58 mmol) in DCM (20 mL) was added CF3COOH (1.79 g, 15.8 mmol). The solution was left to stir at rt until TLC analysis indicated the total consumption of the SM. Then the solvent was removed to get the crude desired product as yellow oil, which was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=1.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)[CH:16]=1
Reactant: Nc1c(C(=O)c2cccc(O)c2)cnn1-c1ccc(F)cc1
Reactant: OCc1ccccn1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Nc1c(C(=O)c2cccc(OCc3ccccn3)c2)cnn1-c1ccc(F)cc1
Reaction time: 16 h

Procedure:
5-Amino-1-(4-fluorophenyl)-4-[3-hydroxybenzoyl]pyrazole, from Example 10, step 2, (0.5 g, 1.68 mmol), 2-pyridylcarbinol (0.81 mL, 8.41 mmol), triphenylphospine (1.81 g, 6.9 mmol), and diethylazodicarboxylate (1.09 mL, 6.9 mmol)) were combined in toluene (50 mL). The reaction mixture was stirred for 16 hours then quenched with a saturated aqueous solution of NH4Cl and extracted three times with ethyl acetate. The product was then extracted from the ethyl acetate into a 10% aqueous solution of HCl. The aqueous layer was then neutralized with NaOH and extracted with ethyl acetate. The organic extracts were dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by column chromatography on silica gel using 1:1 hexane/ethyl acetate to give 0.165 g of 5-amino-1-(4-fluorophenyl)-4-[3-(pyridin-2-ylmethoxy)benzoyl]pyrazole (mpt. 176.1-177.3° C.).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Br:11][C:12]1[CH:27]=[C:15]2[N:16]=[C:17]([CH3:26])[C:18]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:19]([Cl:20])[N:14]2[N:13]=1.C1(C2[O:36]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1>[Br:11][C:12]1[CH:27]=[C:15]2[N:16]=[C:17]([CH3:26])[C:18]([CH:21]([OH:36])[C:22]([O:24][CH3:25])=[O:23])=[C:19]([Cl:20])[N:14]2[N:13]=1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: COC(=O)Cc1c(C)nc2cc(Br)nn2c1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(O)c1c(C)nc2cc(Br)nn2c1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a stirred solution of KHMDS (0.5 M in toluene, 2.83 mL, 1.413 mmol) in THF (6 mL) at −78° C. was added a solution of methyl 2-(2-bromo-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (300 mg, 0.942 mmol) in THF (6 mL) dropwise over 20 min. The mixture was stirred at −78° C. for 30 min. A solution of 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (369 mg, 1.413 mmol) in THF (6 mL) was added over 15 min and the reaction mixture was stirred for additional 60 min at −78° C. The reaction mixture was quenched with saturated NH4Cl aqueous solution (4 mL). The reaction mixture was allowed to warm to room temperature and then diluted with ethyl acetate (100 mL). The organic phase was washed with water and brine and dried with sodium sulfate. The solvent was evaporated. Purification by silica gel chromatography provided the title compound (85 mg, 27%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.63 (3H, s), 3.84 (3H, s), 5.74 (1H, s), 6.71 (1H, s).
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH2:13][NH:12][CH2:11][CH2:10]3)[CH2:5][C@H:4]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[O:3]1.N1([CH:35]=[O:36])C2C=CC=CC=2N=N1>C1COCC1>[O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH2:13][N:12]([CH:35]=[O:36])[CH2:11][CH2:10]3)[CH2:5][C@H:4]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[O:3]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc3c(c2)CCNC3)C(=O)O1
Reactant: O=Cn1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc3c(c2)CCN(C=O)C3)C(=O)O1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 98.2 %

Procedure:
A solution of 1,1-dimethylethyl [[(5S)-2-oxo-3-[1,2,3,4-tetrahydro-6-isoquinolinyl]-5-oxazolidinyl]methyl]carbamate (Step 2, 292 mg, 0.841 mmol) in dry THF (16.8 mL) is treated with 1H-benzotriazol-1-carboxaldehyde (148 mg, 1.01 mmol), and the resulting suspension is stirred at ambient temperature for 1.25 hrs and is then concentrated to remove THF. The residue is rediluted with CH2Cl2 (25 mL), washed with 1N aqueous NaOH (2×10 mL) and brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure to give the crude product which is then chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with MeOH/CH2Cl2 (2.5/97.5). Those fractions with an Rf=0.60 by TLC (MeOH/CHCl3, 10/90) are pooled and concentrated to give 310 mg (98%) of the title compound as an amorphous, glassy solid. MS (ESI+) for C19H25N3O5 m/z 376 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]=[S:13].[CH3:14][CH:15]([CH2:18][CH3:19])[CH2:16][NH2:17].Cl[CH2:21][C:22](O)=[O:23]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:17]([CH2:16][CH:15]([CH3:14])[CH2:18][CH3:19])[C:22](=[O:23])[CH2:21][S:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: O=C(O)CCl
Reactant: CCC(C)CN
Product: CCC(C)CN1C(=O)CSC1=Nc1ccc([N+](=O)[O-])cc1C

Procedure:
2-Methyl-4-nitrophenyl isothiocyanate was reacted with 2-methyl-1-butylamine followed by chloroacetic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-(2-methylbutyl)-1,3-thiazolidin4-one.