Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[S:26][C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=5)=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.Cl>>[NH:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[S:26][C:25]([C:27]5[CH:34]=[CH:33][C:30]([CH2:31][NH:7][CH2:6][C:2]6[S:1][CH:5]=[CH:4][CH:3]=6)=[CH:29][CH:28]=5)=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Reactant: NCc1cccs1
Agent: Cl
Product: c1csc(CNCc2ccc(-c3cc4ncnc(Nc5ccc6[nH]ccc6c5)c4s3)cc2)c1

Procedure:
The title compound was prepared from C-thiophen-2-yl-methylamine and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. The product was converted to the mesylate salt analogous to example 17 being converted to the HCl salt. M. P.111-121° C.; LC-MS: 468 (MH+); HPLC RT: 4.44 minutes.
Reaction SMILES: FC(F)(F)C(O)=O.[OH:8][C:9]1[CH:36]=[CH:35][C:34]([O:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18]C(C)(C)C)=[O:17])=[O:12]>>[OH:8][C:9]1[CH:36]=[CH:35][C:34]([O:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([OH:18])=[O:17])=[O:12]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(Oc2ccccc2)ccc1O
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(Oc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.9 %

Procedure:
Trifluoroacetic acid (2.0 mL) was added to the obtained tert-butyl 2-(2-hydroxy-5-phenoxybenzamido)-4-phenylbenzoate (0.017 g), followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The solid substance was collected by filtration to obtain 0.012 g of 2-(2-hydroxy-5-phenoxybenzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].[OH:19][C:20]1([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(=O)(O)[O-].[Na+].CN(C)C=O>O1CCCC1>[CH3:32][C:29]1[CH:28]=[CH:27][C:26]([C:20]2([OH:19])[CH2:25][CH2:24][N:23]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:22][CH2:21]2)=[CH:31][CH:30]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: Cc1ccc(C2(O)CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1ccc(C2(O)CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)cc1
Temperature: 100 °C
Yield: 23 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2,8 g), 4-hydroxy-4-(4-methylphenyl)piperidine (2.1 g) and sodium bicarbonate (0.94 g) i mixture of dimethylformamide (60 cc) and tetrahydrofuran (50 cc). The mixture is heated for 5 hours at a temperature of about 100° C. then cooled to a temperature of about 20° C. Stirring is maintained for 15 hours at this temperature. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and methanol (95-5 vol) as eluant, 2-{3-[4-(4-methylphenyl)-4-hydroxypiperidino ]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (1 g) is obtained, in the form of 1,1-dioxide (1 g) is obtained, in the form of the hydrochloride of m.p. 218° C.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH2:7][CH3:8])[C:3]=1[C:9]#[N:10].[Cl-].[Cl:12][C:13](Cl)=[N+:14]([CH3:16])[CH3:15]>ClCCl>[C:9]([C:3]1[C:4]([CH2:7][CH3:8])=[N:5][S:6][C:2]=1[N:1]=[C:13]([Cl:12])[N:14]([CH3:16])[CH3:15])#[N:10]
Reactant: CCc1nsc(N)c1C#N
Reactant: C[N+](C)=C(Cl)Cl
Agent: [Cl-]
Solvent: ClCCl
Product: CCc1nsc(N=C(Cl)N(C)C)c1C#N
Yield: 16.6 %

Procedure:
In the manner of Example VI, 7.6 g of 5-amino-4 -cyano-3-ethylisothiazole and 8.1 g of N-(dichloromethylene) -N,N-dimethylammonium chloride were allowed to react in 100 ml of dichloromethane. The volatile materials were evaporated under reduced pressure. The residue was recrystallized twice from cyclohexane to give 2.0 g of N'-(4-cyano-3-ethyl-5-isothiazolyl)-N,N-dimethylchloroformamidine, mp 95°-97°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[O:15][C:16]1[C:21]([CH2:22][OH:23])=[CH:20][CH:19]=[CH:18][N:17]=1.CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:23][CH2:22][C:21]1[C:16]([O:15][C:3]2[CH:4]=[CH:5][C:6]3[N:7]([CH2:11][CH:12]4[CH2:13][CH2:14]4)[N:8]=[N:9][C:10]=3[C:2]=2[Br:1])=[N:17][CH:18]=[CH:19][CH:20]=1)(=[O:34])=[O:33]
Reactant: OCc1cccnc1Oc1ccc2c(nnn2CC2CC2)c1Br
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cccnc1Oc1ccc2c(nnn2CC2CC2)c1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(2-{[4-bromo-1-(cyclopropylmethyl)-1H-1,2,3-benzotriazol-5-yl]oxy}pyridin-3-yl)methanol (195) (1 g, 2.62 mmol, 1.0 equiv.) and Et3N (1.1 ml, 7.85 mmol, 3.0 equiv.) in DCM (13 ml) were cooled to 0° C., followed by MsCl (265 ul, 3.40 mmol, 1.3 equiv.), then stirred @ 0° C. for 1 hour. The reaction mixture then quenched with NaHCO3(sat) and extracted with DCM (2×40 ml). The combined DCM layer was washed with brine and dried over Na2SO4, filtered and concentrated down solvent. LRMS m/z (M+H) 486.8 and 488.8 found, 487.0 and 489.0 required.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[CH:12]1([C:18](Cl)=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([C:18]2[NH:11][S:8](=[O:9])(=[O:10])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: Nc1ccccc1S(N)(=O)=O
Product: O=S1(=O)NC(C2CCCCC2)=Nc2ccccc21

Procedure:
2-Aminobenzenesulfonamide was transformed by Method E (using cyclohexanecarbonyl chloride).
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C:9]1=[O:17]>CCOCC>[N:8]1([C:6]([NH2:5])=[O:7])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C:9]1=[O:17]
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCOCC
Product: NC(=O)N1C(=O)Cc2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.5 %

Procedure:
Chlorosulfonyl isocyanate (1.20 g, 8.4 mmoles) was added to a mixture of 2-oxindole (0.94 g, 7.1 mmole) in ether (30 ml) and the reaction stirred at room temperature for 20 hours. The ether was removed under vacuum and the residue treated with water (10 ml) and 1N HCl (10 ml). Ethyl acetate (125 ml) was added and the mixture stirred for one hour. The ethyl acetate phase was separated, washed with 1N HCl (1×50 ml), brine (2×100 ml) and dried (MgSO4). Concentration afforded 0.97 g (77%) of crude product. Recrystallization from ethanol gave 0.18 g; m.p. 178°-180° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([S:11]([O:14][C:15]3[CH:16]=[C:17]([CH:23]=[C:24]([CH3:26])[CH:25]=3)[O:18][CH2:19][CH2:20][CH2:21][OH:22])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:47]1[C:51](=[O:52])[C:50]2=[CH:53][CH:54]=[CH:55][CH:56]=[C:49]2[C:48]1=[O:57].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[CH:1]1[C:10]2[C:5](=[C:6]([S:11]([O:14][C:15]3[CH:16]=[C:17]([CH:23]=[C:24]([CH3:26])[CH:25]=3)[O:18][CH2:19][CH2:20][CH2:21][O:22][N:47]3[C:48](=[O:57])[C:49]4=[CH:56][CH:55]=[CH:54][CH:53]=[C:50]4[C:51]3=[O:52])(=[O:12])=[O:13])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cccc3cnccc23)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(OCCCON2C(=O)c3ccccc3C2=O)cc(OS(=O)(=O)c2cccc3cnccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a solution of 3-[3-(5-isoquinolinylsulfonyloxy)-5-methylphenoxy]propanol (560 mg, 1.5 mmol), as prepared in the preceding step, triphenylphosphine (520 mg, 2.0 mmol), and N-hydroxyphthalimide (245 mg, 1.5 mmol) in tetrahydrofuran (15 mL) at 0° C. was added diethyl azodicarboxylate (350 mg, 2.0 mmol). The reaction mixture was stirred at room temperature overnight. Water (50 mL) was added, and the reaction mixture was extracted into ethyl acetate (3×50 mL). The ethyl acetate solution was washed with brine (2×50 mL) and dried over Na2SO4. After removing the solvent, the residue was purified by flash column chromatography (4:1 dichloromethane/ethyl acetate) to give the title compound as a colorless foam (580 mg, 75%). 1H-NMR (300 MHz, CDCl3) δ9.42 (s, 1H), 8.81 (d, J=6.1 Hz, 1H), 8.56 (d, J=6.1 Hz, 1H), 8.34 (d, J=7.1 Hz, 1H), 8.31 (d, J=7.2 Hz, 1H), 7.84 (m, 2H), 7.77 (m, 2H), 7.68 (t, J=7.7 Hz, 1H), 6.59 (s, 1H), 6.33 (s, 1H), 6.21 (s, 1H), 4.31 (t, J=6.1 Hz, 2H), 4.00 (t, J=6.1 Hz, 2H), 2.17 (s, 3H), 2.11 (m, 2H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=O.Cl.[NH2:12][OH:13].O.[OH-].[NH4+]>C(O)C>[CH3:1][C:2]([NH:12][OH:13])=[C:4]1[CH:5]=[CH:6][C:7](=[O:10])[CH:8]=[CH:9]1
Reactant: NO
Reactant: CC(=O)c1ccc(O)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(NO)=C1C=CC(=O)C=C1
Yield: 99.9 %

Procedure:
A solution was prepared by adding 13.6 g (0.1 mol) of 4-hydroxyacetophenone, 7.6 g (0.11 mol) of hydroxylamine hydrochloride, and 10 g of water to 40 mL of ethanol. To the solution was added 5.0 g of 30% ammonium hydroxide which was then heated at reflux for 2 h. The ethanol was removed on a rotary evaporator to yield a yellow oil. An extractive work-up afforded 15.1 g (99%) of 4-hydroxyacetophenone oxime.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.Cl.[NH2:17][OH:18].C(N(CC)CC)C>C(O)C>[OH:18][N:17]=[C:12]([C:11]1[CH:10]=[CH:9][C:8]([C:2]2([OH:1])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)=[CH:15][CH:14]=1)[NH2:13]
Reactant: N#Cc1ccc(C2(O)CCOCC2)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=NO)c1ccc(C2(O)CCOCC2)cc1
Temperature: 25 °C
Yield: 119.6 %

Procedure:
A solution of 4-(4-hydroxytetrahydro-2H-pyran-4-yl)benzonitrile (Step 1, 200 mg, 0.984 mmol), hydroxylamine hydrochloride (150 mg, 2.17 mmol) and triethylamine (219 mg, 2.17 mmol) in ethanol (5 mL) was stirred and heated at reflux for 4 h. After being cooled to rt, the reaction mixture as such was subjected to preparative HPLC, affording the pure title compound (278 mg, 99%): 1H NMR (500 MHz, DMSO-d6) δ 9.71 (broad, 1H), 9.58 (s, 1H), 7.62 (d, 2H), 7.48 (d, 2H), 7.22 (broad, 1H), 5.78 (s, 2H), 5.07 (s, 1H), 3.80-3.75 (m, 2H), 3.72-3.68 (m, 2H), 2.00-1.93 (m, 2H), 1.53-1.49 (m, 2H); ES-MS m/z 237 (MH)+; HPLC RT (Method F) 0.72 min.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[C:6]([C:9]1[N:24]=[CH:23][C:12]2[N:13]([CH:20]([CH3:22])[CH3:21])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][CH:17]=[CH:16][CH:15]=3)([OH:8])=[O:7].CC1(C)CCCC(C)(C)N1.CI>C1COCC1>[C:6]([C:9]1[N:24]=[CH:23][C:12]2[N:13]([CH:20]([CH3:21])[CH3:22])[C:14]3[C:19]([C:11]=2[C:10]=1[CH2:1][CH3:2])=[CH:18][CH:17]=[CH:16][CH:15]=3)([OH:8])=[O:7]
Reactant: [Li]CCCC
Reactant: CC(C)n1c2ccccc2c2cc(C(=O)O)ncc21
Agent: CC1(C)CCCC(C)(C)N1
Solvent: CI
Solvent: C1CCOC1
Product: CCc1c(C(=O)O)ncc2c1c1ccccc1n2C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.6 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 3.2 ml, 8 mmol) and 3-carboxy-9-isopropyl-9H-pyrido[3,4-b]indole (Method 2; 504 mg, 2 mmol) were added to a solution of 2,2,6,6-tetramethyl piperidine (1.01 ml, 6 mmol) in THF (15 ml) at −50° C. The mixture was allowed to stir for 30 minutes warming to 0° C. Methyl iodide (0.15 ml, 2.4 mmol) was then added in a single portion and the mixture was left at 0° C. for a further 30 minutes and at room temperature for a further 16 hours. The mixture was concentrated in vacuo and the residue was dissolved in DCM. The solution was washed with 1 M HCl and then with water. The organic phase was separated, dried and concentrated in vacuo. The crude product was purified by preparative HPLC eluting over a gradient of 20-90% MeCN in water (0.1% TFA). The product was obtained as a yellow solid (190 mg) after evaporation of the appropriate fractions. NMR (300 MHz) 9.16 (s, 1H), 8.39 (d, 1H), 8.01 (d, 1H), 7.72 (t, 1H), 7.43 (t, 1H), 5.39 (m, 1H), 3.60 (q, 2H), 1.67 (d, 6H), 1.38 (t, 3H).
Reaction SMILES: [CH2:1]([CH:3]([C:6](=O)[CH3:7])[CH2:4]O)[CH3:2].[Na].[C:10]([CH2:12][C:13]([NH2:15])=[O:14])#[N:11].C([O-])(=O)C.[NH2+]1CCCCC1>O.C(O)(=O)C>[C:10]([C:12]1[C:13](=[O:14])[NH:15][C:1]([CH3:2])=[C:3]([CH2:6][CH3:7])[CH:4]=1)#[N:11]
Reactant: N#CCC(N)=O
Reactant: CCC(CO)C(C)=O
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Agent: [Na]
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc(C#N)c(=O)[nH]c1C
Temperature: 25 °C

Procedure:
Accordingly to the method described in J. Heterocyclic Chem., 24, 351 (1987), a mixture 2-ethyl-3-oxobutanol, sodium salt (37.5 g, 0.275 mol), cyanoacetamide (25.2 g, 0.30 mol), aqueous piperidinium acetate (22 mL) [prepared from glacial acetic acid (4.2 mL), water (10 mL) and piperidine (7.2 mL)] in water (775 ml) was refluxed for four hours. Glacial acetic acid (30 ml) was added cautiously (much foaming) as the product precipitated. Upon cooling to room temperature, the product was collected by filtration, washed with cold water and air dried to yield 22.3 g (50%), m.p. 237°-240° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[S:7][C:6]([N:8]=[C:9]=[O:10])=[N:5][N:4]=1.[CH3:11][NH:12][CH2:13][CH:14]=[O:15]>C1C=CC=CC=1>[CH3:11][N:12]([CH2:13][CH:14]=[O:15])[C:9]([NH:8][C:6]1[S:7][C:3]([CH2:2][Cl:1])=[N:4][N:5]=1)=[O:10]
Reactant: CNCC=O
Reactant: O=C=Nc1nnc(CCl)s1
Solvent: c1ccccc1
Product: CN(CC=O)C(=O)Nc1nnc(CCl)s1

Procedure:
A mixture of 5-chloromethyl-1,3,4-thiadiazol-2-yl isocyanate dimer (9.5 grams), the dimethyl acetal of 2-methylaminoacetaldehyde (5.8 grams) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. This product is recrystallized to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-chloromethyl-1,3,4-thiadiazol-2-yl)ureido]-acetaldehyde.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[O:10][C:9]2([CH3:20])[CH3:19])[CH:6]=[N:5][CH:4]=1.S(Cl)([Cl:23])=O>>[Cl:23][CH2:2][C:3]1[N:7]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[O:10][C:9]2([CH3:20])[CH3:19])[CH:6]=[N:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1CO
Product: CC1(C)OC(=O)c2ccccc2C1n1cncc1CCl

Procedure:
A solution of 4-(5-hydroxymethyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one (0.300 g, 1.1 mmol) (Example 6d) in thionyl chloride (3 mL) is refluxed overnight. The volatiles are removed in vacuo to give 4-(5-chloromethyl-imidazol-1-yl)-3,3-dimethyl-isochroman-1-one, which is redissolved in methanol (10 mL). The solution is injected in an H-Cube™ using a Pd on carbon cartridge at 0.5 mL/min, 100 bar H2 and 50° C. The solution eluting from the cartridge is collected and concentrated in vacuo. The residue is purified by semi-preparative reverse phase HPLC to give 3,3-dimethyl-4-(5-methyl-imidazol-1-yl)-isochroman-1-one as a white solid; MS (ESI) m/z 257.0 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 1.34 (s, 3 H), 1.58 (s, 3 H), 2.38 (br. s, 3 H), 5.18 (br. s, 1 H), 6.92 (s, 1 H), 7.17 (br. s, 1 H), 7.35 (br. s, 1 H), 7.58 (t, J=7.6 Hz, 1 H), 7.62-7.68 (m, 1 H), 8.26 (d, J=7.8 Hz, 1 H).
Reaction SMILES: C(/N=[CH:6]/[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([Cl:14])[C:8]=1[CH2:15][CH3:16])CCC.C(OCC)(=[O:19])C.CCCCCCC>>[Cl:14][C:9]1[C:8]([CH2:15][CH3:16])=[C:7]([C:12]([F:13])=[CH:11][CH:10]=1)[CH:6]=[O:19]
Reactant: CCOC(C)=O
Reactant: CCCC/N=C/c1c(F)ccc(Cl)c1CC
Solvent: CCCCCCC
Product: CCc1c(Cl)ccc(F)c1C=O

Procedure:
3-Chloro-2-ethyl-6-fluoro-benzaldehyde was prepared from butyl-[1-(3-chloro-2-ethyl-6-fluoro-phenyl)-meth-(E)-ylidene]-amine by flash chromatography (silica gel, ethyl acetate/heptane gradient): yellow oil; 1H-NMR (CDCl3): 1.21 (3H, t, CH3), 3.16 (2H, q, CH2), 6.99 (1H, dd, ArH), 7.55 (1H, dd, ArH), 10.45 (1H, s, CH═O).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[CH:6])[CH3:2].[Li]CCCC.[CH:15](=[O:19])[CH:16]([CH3:18])[CH3:17]>C1COCC1>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[C:5]#[C:6][CH:15]([OH:19])[CH:16]([CH3:18])[CH3:17])[CH3:2]
Reactant: C#CC(OCC)OCC
Reactant: CC(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(C#CC(O)C(C)C)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3,3-Diethoxy-propyne (1.82 g, 14.2 mmol) in THF (40 ml) was cooled to −78 C under N2. A solution of n-BuLi (2.0M in cyclohexane, 9.2 mL, 18.46 mmol) was added. After 30 min, Isobutyraldehyde (1.33 g, 18.46 mmol) in THF (10 ml) was added. After 3 h, the reaction was quenched by dilution with 1N HCl, warmed to room temperature and extracted into EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated to give product, 3.18 g (100%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].F[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=1.CC(C)([O-])C.[K+]>CS(C)=O>[Br:1][C:2]1[C:3]([CH3:9])=[C:4]([NH:5][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][N:12]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccnc(F)c1
Reactant: Cc1c(N)cccc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccnc(Nc2cccc(Br)c2C)c1
Temperature: 190 °C
Yield: 33.6 %

Procedure:
A mixture of 3-bromo-2-methylaniline (200 mg, 1.075 mmol), 2-fluoro-4-methylpyridine (155 mg, 1.397 mmol) and potassium tert-butoxide (193 mg, 1.72 mmol) in DMSO (4 mL) was heated in a sealed tube via microwave irradiation at 190° C. for 40 min. The mixture was partitioned between EtOAc and water, and the organic phase was washed with brine, dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from hexane to 85:15 hexane-EtOAc) to provide N-(3-bromo-2-methylphenyl)-4-methylpyridin-2-amine as a yellow solid (100 mg, 34%). 1H NMR (400 MHz, chloroform-d) δ 8.05 (1H, d, J=5.3 Hz), 7.38 (2H, d, J=8.1 Hz), 7.06 (1H, t, J=8.0 Hz), 6.58 (1H, d, J=5.3 Hz), 6.40 (1H, s), 6.23 (1H, br. s.), 2.37 (3H, s), 2.23 (3H, s). Mass spectrum m/z 277, 279 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]=[CH:10][C:11]([C:13]1[N:14]=[C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:36])[CH2:25][N:26]3[C:30]([CH3:31])=[CH:29][C:28]([C:32]([F:35])([F:34])[F:33])=[N:27]3)[CH2:20][CH2:19]2)[S:16][CH:17]=1)=O.Cl.[CH3:38][O:39][NH2:40]>CO>[CH3:38][O:39][N:40]=[C:11]([C:13]1[N:14]=[C:15]([CH:18]2[CH2:23][CH2:22][N:21]([C:24](=[O:36])[CH2:25][N:26]3[C:30]([CH3:31])=[CH:29][C:28]([C:32]([F:33])([F:34])[F:35])=[N:27]3)[CH2:20][CH2:19]2)[S:16][CH:17]=1)[CH:10]=[CH:9][C:3]1[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=1[F:8]
Reactant: CON
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)C=Cc3c(F)cccc3F)cs2)CC1
Agent: Cl
Solvent: CO
Product: CON=C(C=Cc1c(F)cccc1F)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Temperature: 60 °C

Procedure:
A mixture of 3-(2,6-difluorophenyl)-1-[2-[1-[2-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]-4-piperidinyl]-4-thiazolyl]-2-propen-1-one (i.e. the product of Example 2, Step A) (0.25 g, 0.48 mmol) and methoxyamine hydrochloride (0.047 g, 0.58 mmol) in methanol (10 mL) was heated overnight at 60° C. The reaction was concentrated under reduced pressure, partitioned between dichloromethane and saturated sodium bicarbonate. The mixture was eluted from a Celite® extraction tube (ChemElute® diatomaceous earth-based liquid-liquid exchange cartridge) with dichloromethane and concentrated to provide 0.26 g of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][N:4]([CH3:23])[C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:15]([NH:17][CH3:18])=[O:16])[CH:6]=1.C(=O)(O)[O-].[Na+].[Br:31]Br>C(Cl)Cl.O>[Br:31][C:6]1[C:7]([NH:11][C:12]2[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=2[CH3:22])[C:15]([NH:17][CH3:18])=[O:16])=[N:8][CH:9]=[N:10][C:5]=1[N:4]([CH2:3][C:2]([CH3:25])([CH3:24])[CH3:1])[CH3:23]
Reactant: CNC(=O)c1ccc(C)c(Nc2cc(N(C)CC(C)(C)C)ncn2)c1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1ccc(C)c(Nc2ncnc(N(C)CC(C)(C)C)c2Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.4 %

Procedure:
To a solution of 3-{6-[(2,2-dimethyl-propyl)-methyl-amino]-pyrimidin-4-ylamino}-4,N-dimethyl-benzamide (0.46 g, 1.34 mmol) in methylene chloride (10 mL), was added sat. aq. sodium bicarbonate (2 mL) and bromine (0.07 mL, 1.37 mmol). The resulting mixture was stirred at room temperature for 18 hours, and the reaction was then diluted with water (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (10 mL). The combined organic layer was dried (sodium sulfate), filtered and concentrated. The residue was purified by silica gel column chromatography using 2% methanol in DCM as eluent to afford the product (250 mg, yield 44%). MS (m/z): 420 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[NH2:29][C:30]1[S:31][CH:32]=[N:33][N:34]=1>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([NH:29][C:30]1[S:31][CH:32]=[N:33][N:34]=1)=[O:15])[CH:10]([CH3:12])[OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1nncs1
Reactant: CC(O)C(NC(=O)OC(C)(C)C)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(O)C(NC(=O)OC(C)(C)C)C(=O)Nc1nncs1
Yield: 79.3 %

Procedure:
Using the same procedure as in Example 1(i), 10 g of N-t-butoxycarbonyl-DL-threonine, 4.6 g of triethylamine, 5.0 g of ethyl chlorocarbonate and 4.6 g of 2-amino-1,3,4-thiadiazole were reacted in 150 ml of tetrahydrofuran to obtain 10.9 g (yield: 79%) of 2-(N-t-butoxycarbonyl-DL-threonylamino)-1,3,4-thiadiazole as white powder having a melting point of 165°-170° C. (dec.).
Reaction SMILES: O=[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]([F:15])([F:14])[F:13])[CH:6]=1)[CH:3]=O.[NH2:16][C:17]1[C:25]([NH2:26])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([OH:21])=[O:20]>CCO>[F:13][C:12]([F:15])([F:14])[O:11][C:7]1[CH:6]=[C:5]([C:2]2[CH:3]=[N:26][C:25]3[CH:24]=[CH:23][CH:22]=[C:18]([C:19]([OH:21])=[O:20])[C:17]=3[N:16]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: Nc1cccc(C(=O)O)c1N
Reactant: O=CC(=O)c1cccc(OC(F)(F)F)c1
Solvent: CCO
Product: O=C(O)c1cccc2ncc(-c3cccc(OC(F)(F)F)c3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
2-oxo-2-(3-(trifluoromethoxy)phenyl)acetaldehyde (1.0 g, 4.58 mmol) and 2,3-diaminobenzoic acid (634 mg, 4.17 mmol) were dissolved in EtOH (70 mL), and stirred at room temperature overnight. The volume was reduced to 30 mL, the precipitate was collected by filtration, washed with ethanol, and dried under vacuum to give 3-(3-(trifluoromethoxy)phenyl)quinoxaline-5-carboxylic acid as a gray solid (1.0 g, yield: 72% yield).