Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:15])[CH:12]=2)[CH2:7][N:6]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:4].[C:23]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][C:30]3[CH:31]=[CH:32][C:27]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:28][CH:29]=3)[CH:12]=2)[CH2:7][N:6]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:4]
Reactant: COC(=O)C1Cc2cc(O)ccc2CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: COC(=O)C1Cc2cc(Oc3ccc(C(C)(C)C)cc3)ccc2CN1C(=O)OC(C)(C)C
Yield: 49.2 %

Procedure:
6-Hydroxy-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester (0.5 g, 1.62 mmol) in DCM (15 mL) was treated with copper acetate (0.59 g, 3.3 mmol), 4-tert-butylphenylboronic acid (0.87 g, 4.8 mmol), and TEA (1.0 mL, 7.9 mmol) by the general procedure G. The crude product was purified by flash column chromatography on silica gel using Hexanes:EtOAc (70:30) to give 0.35 g of 6-(4-tert-butyl-phenoxy)-3,4-dihydro-1H-isoquinoline-2,3-dicarboxylic acid 2-tert-butyl ester 3-methyl ester which was deprotected using general procedure N to give 6-(4-tert-butyl-phenoxy)-1,2,3,4-tetrahydro-isoquinoline-(3S)-carboxylic acid methyl ester hydrochloride salt (0.27 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([CH3:31])([S:27]([CH3:30])(=[O:29])=[O:28])[C:17]([NH:19][O:20]C2CCCCO2)=[O:18])=[CH:10][CH:9]=1.Cl.CO>C(Cl)Cl>[OH:20][NH:19][C:17](=[O:18])[C:16]([CH3:31])([S:27]([CH3:30])(=[O:28])=[O:29])[CH2:15][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[OH:1])=[CH:13][CH:12]=1
Reactant: CC(CCc1ccc(-c2ccccc2O)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CC(CCc1ccc(-c2ccccc2O)cc1)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-(2′-Hydroxybiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (19.6 mg, 0.044 mmol) was dissolved in methylene chloride (1 mL) at ambient temperature. To this solution was added HCl (4M in 1,4-dioxane, 0.33 mL, 1.32 mmol) and the solution was stirred at RT for 5 minutes. Methanol (100 uL) was added followed by silica gel and the mixture was concentrated to dryness. The crude material was purified via silica gel chromatography and eluted with methylene chloride/methanol to afford N-hydroxy-4-(2′-hydroxybiphenyl-4-yl)-2-methyl-2-(methylsulfonyl)butanamide as a solid. 6.5 mg
Reaction SMILES: [CH3:1][C@H:2]([NH:10][CH3:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-:13].[Na+].[Na+].C(=O)(O)[O-]>>[CH3:1][C@H:2]([NH:10][CH3:11])[C@@H:3]([OH:13])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CN[C@@H](C)Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: CN[C@@H](C)[C@@H](O)c1ccccc1
Reaction time: 0.5 h

Procedure:
96-well microtitre plates were coated overnight at room temperature with monoclonal anti-methamphetamine antibody (East Coast Biologicals, USA) at 5 :g/ml, 100 :l/well, in 50 mM sodium carbonate/bicarbonate buffer, pH 9.6. The plate was washed 3 times with wash buffer and blocked in the same buffer for 30 minutes. 3-fold dilutions in assay buffer of the enzyme-drug conjugate (100 :l/well) were added. After 30 minutes incubation at room temperature, the plate was washed 3 times and the substrate solution added as described before. FIG. 4 shows the titration profile obtained with this conjugate. The conjugate retained both enzyme activity and the ability to bind to immobilised anti-methamphetamine antibody allowing its use in drug capture competitive enzyme immunoassay.
Reaction SMILES: BrBr.[NH2:3][C:4]1[CH:5]=[C:6]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=2)[C:7]([F:11])=[CH:8][C:9]=1[Cl:10].[S-:23][C:24]#[N:25].[Na+].O>C(O)(=O)C>[NH2:25][C:24]1[S:23][C:5]2[C:6]([C:12]3[C:17]([Cl:18])=[CH:16][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][N:13]=3)=[C:7]([F:11])[CH:8]=[C:9]([Cl:10])[C:4]=2[N:3]=1
Reactant: N#C[S-]
Reactant: Nc1cc(-c2ncc(C(F)(F)F)cc2Cl)c(F)cc1Cl
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc2c(Cl)cc(F)c(-c3ncc(C(F)(F)F)cc3Cl)c2s1
Temperature: 25 °C
Reaction time: 10 h
Yield: 13 %

Procedure:
At about 20° C., a solution of 37 g (234 mmol) of bromine in 10 ml of glacial acetic acid was added over a period of 10 minutes to a solution of 38 g (117 mmol) of 2-(3-amino-4-chloro-6-fluorophenyl)-3-chloro-5-trifluoromethylpyridine and 38 g (468 mmol) of sodium thiocyanate in 500 ml of glacial acetic acid. The reaction mixture was subsequently stirred at room temperature for 10 hours and then poured into 2 l of water. The product was then extracted with 3×500 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate and (finally concentrated. The crude product was purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate =4:1→1:1). Yield: 13%; m.p.: 230-235° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7](Cl)[C:6]=12.[NH3:16].O>CC(O)C>[Br:1][C:2]1[N:3]=[C:4]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[N:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH2:16])[C:6]=12
Reactant: Clc1nccn2c(C3CCC3)nc(Br)c12
Reactant: N
Solvent: CC(C)O
Solvent: O
Product: Nc1nccn2c(C3CCC3)nc(Br)c12
Temperature: 100 °C

Procedure:
A suspension of 1-bromo-8-chloro-3-cyclobutylimidazo[1,5-a]pyrazine (341 mg, 1.2 mmol) in IPA (3 mL) was saturated with NH3(g) at 0° C. for 3 min. The tube was sealed and heated at 100° C. for 17 h. H2O (10 mL) was added and the mixture was extracted with EtOAc (3×30 mL). The organic phase was washed with brine and concentrated under reduced pressure to provide the title compound as a white solid; 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J=4.8 Hz, 1H), 6.97 (d, J=5.2 Hz, 1H), 5.65 (br, 2H), 3.70 (qud, J=0.8 Hz, 8.4 Hz, 1H), 2.55-2.35 (m, 4H), 2.18-1.93 (m, 2H); MS (ES+): m/z 267.1 (100), 269.1 (100) [MH+]; HPLC: tR=1.70 min (OpenLynx, polar—5 min).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][S:6][CH2:7][CH:8]1[CH2:13][CH2:12][C:11]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)(=[O:24])=[O:23])([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])[CH2:10][CH2:9]1)C.[OH-].[Li+].Cl>CO.O>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([S:22]([C:11]2([C:14]3[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=3[F:21])[CH2:10][CH2:9][CH:8]([CH2:7][S:6][CH2:5][C:4]([OH:32])=[O:3])[CH2:13][CH2:12]2)(=[O:24])=[O:23])=[CH:26][CH:27]=1
Reactant: CCOC(=O)CSCC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CSCC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 772 %

Procedure:
The product from Example 69 (15 mg, 0.003 mmol) was dissolved in methanol (1 mL) and lithium hydroxide (1 mg, 0.015 mmol) added. The reaction was stirred at room temperature overnight, diluted with water, acidified with 2 M aqueous hydrochloric acid and extracted with ethyl acetate (x3). The organic extracts were washed with water and brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica eluting with iso-hexane/ethyl acetate (1:1) to give a white solid (11 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)=[CH:5][CH:4]=1.C([Li])CCC.[CH2:20]([CH:22]([CH2:25][CH3:26])[CH:23]=[O:24])[CH3:21]>C1COCC1>[CH2:20]([CH:22]([CH2:25][CH3:26])[CH:23]([C:12]1[N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:14][CH:13]=2)[N:9]=[CH:10][N:11]=1)[OH:24])[CH3:21]
Reactant: CCC(C=O)CC
Reactant: COc1ccc(Cn2cncn2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(CC)C(O)c1ncnn1Cc1ccc(OC)cc1
Temperature: 25 °C
Yield: 114.1 %

Procedure:
To a solution of 1-(4-methoxybenzyl)-1H-1,2,4-triazole (2.12 g, 11.2 mmol) in THF (120 mL) at −78° C. was added a solution of n-butyllithium (2.5 M in hexanes, 4.9 mL, 12.3 mmol) over a period of 20 min. The solution was stirred at −78° C. for 2h and 45 min. Then 2-ethylbutyraldehyde (0.65 mL, 5.3 mmol) was added. After 1.5 h the reaction mixture was warmed to room temperature, quenched with saturated aqueous ammonium chloride, extracted with EtOAc and dried over Na2SO4. After removal of the solvents, the product was purified by recrystallization from EtOAc/hexanes to give 1.75 g (54%) of 2-ethyl-1-[1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl]butan-1-ol as a white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]([CH:15]([CH2:21][CH3:22])[CH:16]([CH3:20])[C:17](O)=[O:18])=O)=[CH:11][C:10]=1[OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:27][NH2:28]>C(O)(=O)C>[CH2:1]([NH:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]2[CH:15]([CH2:21][CH3:22])[CH:16]([CH3:20])[C:17](=[O:18])[NH:27][N:28]=2)=[CH:11][C:10]=1[OH:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCC(C(=O)c1ccc(NCc2ccccc2)c(O)c1)C(C)C(=O)O
Solvent: O
Solvent: CC(=O)O
Product: CCC1C(c2ccc(NCc3ccccc3)c(O)c2)=NNC(=O)C1C

Procedure:
3.00 g (8.79 mmol) 3-(4-benzylamino-3-hydroxy-benzoyl)-2-methyl-pentanoic acid, 6.31 mL (126.00 mmol) hydrazine hydrate and 25 mL glacial acetic acid are stirred for 3 h at 110° C. The reaction mixture is concentrated by rotary evaporation i. V. and the residue is separated through RP (xBridge, MeOH/H2O/TFA).
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[N:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[N:28]=[CH:27][N:26]=[C:25]([NH2:29])[CH:24]=2)[CH:18]=1>ClCCl.CN(C)C=O>[N:29]([C:25]1[CH:24]=[C:23]([C:19]2[CH:18]=[N:17][CH:22]=[CH:21][CH:20]=2)[N:28]=[CH:27][N:26]=1)=[C:1]=[S:2]
Reactant: Nc1cc(-c2cccnc2)ncn1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: S=C=Nc1cc(-c2cccnc2)ncn1
Temperature: 60 °C

Procedure:
To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.682 g, 2.94 mmol) in dichloromethane/N,N-dimethylformamide at room temperature was added 6-(pyridin-3-yl)pyrimidin-4-amine (0.337 g, 1.957 mmol). The mixture was heated at 60° C. for 18 hours. LC/MS showed the desired product peak as the major peak. The deep orange mixture was purified by silica gel chromatography (1-40% ethyl acetate-hexanes) to afford 4-isothiocyanato-6-methoxypyrimidine (0.12 g, 0.56 mmol, 28.6% yield) as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11](=[O:27])[NH:12][C:13]1[C:14]([CH3:26])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[C:20]([Cl:25])[CH:19]=1)[CH3:9].[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)[CH3:29]>>[CH2:28]([O:30][C:31](=[O:48])[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:26])[C:13]=3[NH:12][C:11]([O:10][C@@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:27])=[CH:19][C:20]=2[Cl:25])=[CH:35][CH:34]=1)[CH3:29]
Reactant: Cc1noc(-c2ccc(Br)c(Cl)c2)c1NC(=O)O[C@H](C)c1ccccc1Cl
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@H](C)c3ccccc3Cl)cc2Cl)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-3-chloro-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide (2′-chloro-4′-{4-[(R)-1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 36, Step 7.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=[O:13])=[CH:4][CH2:3]1.[CH2:16]=[CH:17][CH:18]=[CH2:19]>>[CH3:1][C:2]1([CH3:15])[CH2:3][CH:4]2[C:5]([C:12]([OH:14])=[O:13])([CH2:16][CH:17]=[CH:18][CH2:19]2)[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CC1(C)CC=C(C(=O)O)c2ccccc21
Reactant: C=CC=C
Product: CC1(C)CC2CC=CCC2(C(=O)O)c2ccccc21
Yield: 32 %

Procedure:
The compound from Example 42 (8.5 g, 36.7 mmol) and butadiene were reacted in a Diels-Alder condensation as previously described to give after silica gel chromatography the title compound (3 g, 32% yield).
Reaction SMILES: [CH3:1][C@:2]1([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[N:14][C:15]([NH:18][NH2:19])=[CH:16][CH:17]=2)[C:8]([F:11])([F:10])[F:9])[CH2:3]1.[CH:28]([O:31][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]2[C:41]=1[N:40]=[C:39]([CH:42]=O)[CH:38]=[CH:37]2)([CH3:30])[CH3:29]>C(O)C>[CH3:1][C@:2]1([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:6][CH2:5][N:4]([C@@H:7]([C:12]2[CH:13]=[N:14][C:15]([NH:18]/[N:19]=[CH:42]/[C:39]3[CH:38]=[CH:37][C:36]4[C:41](=[C:32]([O:31][CH:28]([CH3:30])[CH3:29])[CH:33]=[CH:34][CH:35]=4)[N:40]=3)=[CH:16][CH:17]=2)[C:8]([F:9])([F:10])[F:11])[CH2:3]1
Reactant: CC(C)Oc1cccc2ccc(C=O)nc12
Reactant: CC(C)(C)OC(=O)N[C@@]1(C)CCN([C@@H](c2ccc(NN)nc2)C(F)(F)F)C1
Solvent: CCO
Product: CC(C)Oc1cccc2ccc(/C=N/Nc3ccc([C@H](N4CC[C@](C)(NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(6-hydrazinylpyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (1.30 g, 3.34 mmol) in Ethanol (25 mL) was added 8-isopropoxyquinoline-2-carbaldehyde (0.719 g, 3.34 mmol) and stirred at ambient temperature overnight. The reaction was concentrated and the residue purified by chromatography (C18, 300 g, 10% MeCN/water to 95% MeCN/water over 25 column volumes) to give tert-butyl (S)-3-methyl-1-((S)-2,2,2-trifluoro-1-(6-((E)-2-((8-isopropoxyquinolin-2-yl)methylene)hydrazinyl)pyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (1.33 g, 2.27 mmol, 67.9% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:19]1(I)[CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1>[CH2:17]([O:16][C:14]([C:11]1([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: IC1CCCC1
Solvent: C1CCOC1
Product: CCOC(=O)C1(C2CCCC2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -75 °C
Reaction time: 2 h

Procedure:
A solution of 5 g ethyl 1-tert-butoxycarbonylpiperidine-4-carboxylate in 50 mL THF was added at −75° C. drop wise over 50 min. The yellow solution was stirred at −75° C. for 2 h. A solution of 4.5 g cyclopentyliodide in 20 mL THF was added drop wise over 45 min. The reaction was stirred at −75° C. for 1 h. The reaction was allowed to warm to room temperature over the weekend. The reaction was cooled to 0° C., quenched with 150 mL 10% citric acid solution. The aqueous layer was separated and extracted once with 150 mL ethyl acetate. The organic layers were washed with 100 mL brine, dried over Na2SO4, filtered and concentrated under vacuum. The crude product (yellow viscous oil, 7.75 g) was purified over silica chromatography eluting with a gradient formed from heptane and TBME to yield after evaporation of the product containing fractions 5.54 g (88%) of the title compound as colourless viscous oil. MS ISP (m/e): 326.3 [(M+H)+].
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[S:9])[C:5]([CH3:8])=[CH:6]O.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH2:14]>CO.O.Cl>[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH:14][CH:6]=[C:5]([CH3:8])[C:4]([O:3][CH3:2])=[S:9]
Reactant: COc1ccc(N)cc1Cl
Reactant: COC(=S)C(C)=CO
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=S)C(C)=CNc1ccc(OC)c(Cl)c1

Procedure:
Sodium (7.65 g.) was dissolved in anhydrous methanol (450 ml.) and the solution evaporated to dryness. The resulting sodium methoxide was suspended in anhydrous diethyl ether (300 ml.). The suspension was stirred at 0° and methyl methylthioacetate (40 g.) was added dropwise. The mixture was stirred at 0° for 1 hour and then treated dropwise with methyl formate (21 g.). The mixture was stirred at 0° for 1 hour and then stirred overnight at room temperature. The resulting suspension of solid was extracted with water (300 ml.) and the aqueous extract adjusted to 333 ml. with water. This aqueous extract containing methyl-3-hydroxy-2-methylthioacrylate, sodium salt (0.33 mole) was added to a stirred solution of 3-chloro-4-methoxyaniline (52 g.) in a mixture of water (800 ml.) and 11.6 N hydrochloric acid (33 ml.) at 0°. The mixture was stirred for 30 minutes and the product collected by filtration to give the novel intermediate compound methyl 3-(3-chloro-4-methoxyanilino)-2-methylthioacrylate, m.p. 110°-112°. This acrylate (77.6 g.) was added to diphenyl ether (200 ml.) stirred at 250° under nitrogen. After stirring at 250° for 15 minutes the mixture was cooled. The resulting precipitate was collected by filtration to give the novel intermediate compound 7-chloro-6-methoxy-3-methylthio-4-quinolone, m.p. 288°-290° (dec.) Examination by thin layer chromatography showed the presence of a minor amount of the corresponding 5-chloro isomer.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:22]([CH:23]=[CH:24][CH:25]=O)=[CH:21][C:20]=1[O:29][CH3:30].[O:31]1[CH2:35][C:34](=[O:36])[NH:33][C:32]1=[O:37]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=2)=[N:4][C:3]=1[CH2:17][O:18][C:19]1[CH:28]=[CH:27][C:22]([CH2:23][CH2:24][CH2:25][CH:35]2[O:31][C:32](=[O:37])[NH:33][C:34]2=[O:36])=[CH:21][C:20]=1[O:29][CH3:30]
Reactant: O=C1COC(=O)N1
Reactant: COc1cc(C=CC=O)ccc1OCc1nc(-c2ccc3ccccc3c2)oc1C
Product: COc1cc(CCCC2OC(=O)NC2=O)ccc1OCc1nc(-c2ccc3ccccc3c2)oc1C

Procedure:
In substantially the same manner as in Working Example 11, 4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]-3-methoxycinnamaldehyde was condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic hydrogenation to yield 5-[3-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]-3-methoxyphenyl]propyl]-2,4-oxazolidinedione. The product was recrystallized from chloroform-methanol-ether to give colorless prisms, m.p.173-174° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[NH2:11][CH2:12][CH2:13][OH:14]>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([NH:11][CH2:12][CH2:13][OH:14])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: NCCO
Product: Nc1ccc(NCCO)nc1
Yield: 64.4 %

Procedure:
Following General procedure H, 2-chloro-5-nitropyridine (500 mg, 3.1 mmol) was reacted with 2-aminoethanol (213 mg, 3.5 mmol) followed by reduction to afford the desired product (306 mg, 65%) as a purple solid: ESI MS m/z 154 [C7H11N3O+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:9]([O-])=O.[Na+].[F:13][B-:14]([F:17])([F:16])[F:15].[Na+]>O>[F:13][B-:14]([F:17])([F:16])[F:15].[C:3]1([N+:2]#[N:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Nc1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: O
Product: N#[N+]c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
In a 400 mL beaker containing 30 mL of concentrated hydrochloric acid and 30 mL of water was dissolved 9.2 g (0.1 mole) of aniline. The mixture was cooled to about 0° C. in an ice bath and then diazotized by the addition of a solution containing 7 g (0.1 mole) of sodium nitrite in 12 mL of water. After filtering, the solution was added slowly with stirring to 17 g (0.15 mole) of sodium fluoroborate (NaBF4) dissolved in 30 mL of water at room temperature (although lower temperatures can be used). After stirring another 5 minutes a white precipitate formed which was recovered by filtration, washed with 50 mL of cold water and 50 mL of diethyl ether and dried in vacuum. The yield of benzenediazonium tetrafluoroborate was about 75% of theory. The process (including a final thermal decomposition of the product, which is not employed in this Example), is commonly referred to as the Schiemann method. Kirk-Othmer, Encyclopedia of Chemical Technology, Second Edition, Vol. 9, page 568, Interscience (1966) describes this preparation and shows the equation including the decomposition as follows: ##STR2## A reference to this method is given in U.S. Pat. No. 3,950,444, column 1, lines 29-37, the disclosure of which is hereby incorporated by reference.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5](SC)[N:4]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.Cl.[NH2:43][CH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([C:22]4[CH:23]=[N:24][N:25]([CH3:27])[CH:26]=4)[CH:17]=3)=[C:11]([CH3:28])[N:10]=2)=[CH:7][N:6]=[C:5]([NH:43][CH:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[N:4]=1
Reactant: COc1nc(SC)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Reactant: NC1CCOCC1
Agent: Cl
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1nc(NC2CCOCC2)ncc1-c1ccc(Oc2ccnc(-c3cnn(C)c3)c2)c(C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.5 %

Procedure:
A solution of Example C2 (0.200 g, 0.476 mmol) in DCM (5 mL) was treated with mCPBA (0.141 g, 0.571 mmol), stirred at RT for 3 h, treated with 4-aminotetrahydropyran hydrochloride (0.524 g, 3.81 mmol) and TEA (0.530 mL, 3.81 mmol) and stirred at RT overnight. Additional 4-aminotetrahydropyran hydrochloride (0.524 g, 3.81 mmol) and TEA (0.530 mL, 3.81 mmol) were added and the mixture stirred at RT for an additional 24 h. The mixture was concentrated to dryness, transferred to a sealed vessel with DMF (10 mL), treated with additional 4-aminotetrahydropyran hydrochloride (0.524 g, 3.81 mmol) and TEA (0.530 mL, 3.81 mmol) and heated at 60° C. overnight. The mixture was cooled to RT, the solids removed via filtration and washed with DCM. The filtrate was treated with satd. NaHCO3, extracted with DCM (3×) and the combined organics were washed with 5% LiCl (3×), then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford 4-methoxy-5-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-2-amine (125 mg, 56%). MS (ESI) m/z: 474.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]#[N:25])[N:21]=[C:20]([Cl:26])[N:19]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[NH2:28][OH:29]>CO.CCOC(C)=O>[NH2:25]/[C:24](=[N:28]\[OH:29])/[C:22]1[N:21]=[C:20]([Cl:26])[N:19]=[C:18]([N:15]2[CH2:16][CH2:17][CH:12]([NH:11][C:9]([C:3]3[NH:4][C:5]([CH3:8])=[C:6]([Cl:7])[C:2]=3[Cl:1])=[O:10])[CH2:13][CH2:14]2)[CH:23]=1
Reactant: NO
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3cc(C#N)nc(Cl)n3)CC2)c(Cl)c1Cl
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(/C(N)=N/O)nc(Cl)n3)CC2)c(Cl)c1Cl
Temperature: 80 °C
Yield: 33 %

Procedure:
3,4-Dichloro-N-[1-(2-chloro-6-cyanopyrimidin-4-yl)piperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide (Example 199, 150 mg, 0.36 mmol), hydroxylamine hydrochloride (25 mg, 0.36 mmol) and TEA (0.05 ml, 0.36 mmol) were combined in MeOH (5 ml), and the reaction was heated at 80° C. for 2 h. The reaction was diluted with EtOAc and washed with water. The aqueous portion was extracted with EtOAc, and the combined organic portions were dried (sodium sulfate), filtered and concentrated to give a pale yellow solid. The crude material was purified by preparatory HPLC, using a gradient of 35-75% acetonitrile/water (0.1% TFA) to give 53 mg of the title compound.