Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C@@H:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH3:19])[CH:13]=2)[CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.[Li]C(C)(C)C.CN([CH:28]=[O:29])C>CCOCC>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C@H:9]([NH:8][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[CH:28]=[O:29])[CH2:10][CH3:11])=[CH:13][C:14]=1[CH3:19]
Reactant: CC[C@@H](Nc1cccc(Br)c1)c1ccc(Cl)c(C)c1
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CC[C@@H](Nc1cccc(C=O)c1)c1ccc(Cl)c(C)c1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of INT 6 (5.00 g, 14.8 mmol) in Et2O (148 mL) at −78° C. was added tBuLi (1.7 M in pentane, 34.7 mL, 59.0 mmol) dropwise. The mixture was stirred at −78° C. for 40 minutes and DMF (2.5 mL) was added. The reaction mixture was stirred at −78° C. for an additional 30 minutes. The mixture was quenched with saturated aqueous NH4Cl and extracted with Et2O (2×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (heptane/EtOAc) to afford INT 7.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[CH2:11][C:10]([C:21]([F:27])([F:26])[C:22]([F:25])([F:24])[F:23])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:28]([N:35]1[CH2:40][CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>>[C:28]([N:35]1[CH2:36][CH:37]=[C:38]([C:2]2[CH:3]=[C:4]([N:8]3[CH:12]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=4[F:20])[CH2:11][C:10]([C:21]([F:26])([F:27])[C:22]([F:25])([F:23])[F:24])=[N:9]3)[CH:5]=[CH:6][CH:7]=2)[CH2:39][CH2:40]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]
Reactant: Fc1ccc(C2CC(C(F)(F)C(F)(F)F)=NN2c2cccc(Br)c2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: CC(C)(C)OC(=O)N1CC=C(c2cccc(N3N=C(C(F)(F)C(F)(F)F)CC3c3ccc(F)cc3F)c2)CC1

Procedure:
The titled compound was prepared in accordance with the same procedures as in Example 204, except for using 1-(3-bromo-phenyl)-5-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole prepared in Step 4 of Preparation 14; and using 1-BOC-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine instead of 3-(methylthio)phenylboronic acid.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][CH:12]3[C:22]4[C:15](=[CH:16][CH:17]=[C:18]([CH:23]=O)[C:19]2=4)[NH:14][CH2:13]3)[N:9]([CH3:25])[CH2:8]1)=[O:5])[CH3:2].[NH2:28]OS(O)(=O)=O.N>O>[C:23]([C:18]1[C:19]2=[C:22]3[C:15]([NH:14][CH2:13][CH:12]3[CH2:11][C@@H:10]3[C@@H:20]2[CH2:21][C@H:7]([NH:6][C:4](=[O:5])[N:3]([CH2:1][CH3:2])[CH2:26][CH3:27])[CH2:8][N:9]3[CH3:25])=[CH:16][CH:17]=1)#[N:28]
Reactant: NOS(=O)(=O)O
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(C=O)ccc4c3C(CN4)C[C@H]2N(C)C1
Agent: N
Solvent: O
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(C#N)ccc4c3C(CN4)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 26 %

Procedure:
A suspension of 500 mg of 1,1-diethyl-3-(2,3-dihydro-12-formyl-6-methyl-8α-ergolinyl)urea and 460 mg of hydroxylamine-O-sulfonic acid in 5 ml of water is stirred for 20 hours at room temperature. The reaction mixture is poured on ice, set to be alkaline with 25% strength ammonia solution, and extracted with dichloromethane. The organic phase is dried (Na2SO4), concentrated, the residue chromatographed on silica gel with dichloromethane/methanol=95/5 as the eluting agent, and crystallized from ethyl acetate/pentane. Yield 26% of theory.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:6]([CH3:9])[C:7]=1[NH2:8].[C:16](OC)(OC)(OC)[CH3:17].N>C(O)(=O)C>[CH3:16][C:17]1[NH:8][C:7]2[C:6]([CH3:9])=[CH:5][C:4]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:3][C:2]=2[N:1]=1
Reactant: COC(C)(OC)OC
Reactant: Cc1cc(-c2ccccc2)cc(N)c1N
Agent: N
Solvent: CC(=O)O
Product: Cc1nc2cc(-c3ccccc3)cc(C)c2[nH]1
Temperature: 110 °C
Reaction time: 18 h
Yield: 96.3 %

Procedure:
[step 4] 3,4-Diamino-5-methylbiphenyl (150 mg, 0.64 mmol) obtained in step 3 was suspended in acetic acid (4 mL), trimethyl ortho acetate (0.14 mL, 0.76 mmol) was added, and the mixture was stirred at 110° C. for 18 hr. Under ice-cooling, 28% aqueous ammonia solution (5 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (137 mg, 96%).
Reaction SMILES: [Br:1][C:2]1[C:3]([S:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH:5]=O.Cl.[NH2:19][OH:20]>C(O)(C)C.O>[Br:1][C:2]1[C:3]([S:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH:5]=[N:19][OH:20]
Reactant: CC(C)(C)Sc1c(Br)cc([N+](=O)[O-])cc1C=O
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CC(C)(C)Sc1c(Br)cc([N+](=O)[O-])cc1C=NO
Yield: 150.1 %

Procedure:
A solution of 3-bromo-2-tert-butylsulfanyl-5-nitro-benzaldehyde (1.2 g, 3.8 mmol) and hydroxylamine hydrochloride (1.2 g, 7.7 mmol) in isopropanol (36 mL) and water (8 mL) was heated to 90° C. for 16 h. The reaction mixture was cooled and concentrated to remove isopropanol. Water was added to the residue, followed by saturated sodium bicarbonate solution until the pH was ˜8.0. The residue was extracted with dichloromethane (2×30 mL). The combined organic fractions were dried with sodium sulfate, filtered, and concentrated to afford 1.9 g of the crude title compound which was used without further purification.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[C:11]([NH:16][C:17](=[O:34])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1)[CH:10]=2)=[O:5])C.O.[OH-].[Li+]>O1CCCC1CO.O>[F:33][C:30]([F:31])([F:32])[C:27]1[CH:28]=[CH:29][C:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[C:17]([NH:16][C:11]2[CH:10]=[C:9]3[C:14]([CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)=[CH:13][CH:12]=2)=[O:34])=[N:25][CH:26]=1
Reactant: CCOC(=O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cn3)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: OCC1CCCO1
Solvent: O
Product: O=C(O)c1cnc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cn3)ccc2c1

Procedure:
7-[2-(5-Trifluoromethyl-pyridin-2-yl)-benzoylamino]-quinoline-3-carboxylic acid ethyl ester (180 mg, 0.387 mmol) was dissolved in 5 ml of a 3:1:1 mixture of tetrahydrofuran-methanol-water, and lithium hydroxide monohydrate (50 mg, 1.16 mmol) was added. After 18 h at reflux, the volatiles were removed under vacuum and water was added to the mixture, which was acidified with 1N HCl, extracted with ethyl acetate. The combined organic layers were dried (magnesium sulfate), filtered and concentrated under vacuum to provide the title compound.
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:17][CH:16]=[CH:15][C:14]=2[CH:18]=1>CN(C=O)C.O>[CH:1]1([O:5][CH2:9][C:10]2[CH:11]=[CH:12][C:13]3[O:17][CH:16]=[CH:15][C:14]=3[CH:18]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCC1
Reactant: BrCc1ccc2occc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1cc2cc(COC3CCC3)ccc2o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of cyclobutanol (1.0 mL, 14.0 mmol) and sodium hydride (0.5 g, 14.0 mmol) in DMF (20 mL) was stirred at 0° C. for 30 minutes. 5-(Bromomethyl)benzofuran (2.9 g, 14.0 mmol) was the added and resultant reaction mixture was slowly warmed to room temperature and left stirring over night. Reaction mixture was diluted to 100 mL with water. The solution was extracted with Et2O (20 mL×3); the combined extracts were washed with 1N NaOH solution, water and brine, dried, and concentrated under reduced pressure to yield the desired product after purification on silica (4/1 hexane/ethyl acetate). 1H NMR (400 MHz, CDCl3) δ 7.58 (d, 2H), 7.42 (d, 1H), 7.27 (d, 1H), 6.78 (s, 1H), 4.54 (s, 2H) 4.03 (m, 1H), 2.21 (m, 2H), 1.94 (m, 2H), 1.76 (m, 1H), 1.52 (m, 1H).
Reaction SMILES: I[N:2]1[C:7]([OH:8])=[C:6]2[CH:9]=[CH:10][N:11]=[C:5]2[N:4]=[CH:3]1.[C:12]([C:14]1[CH:33]=[CH:32][C:17]([C:18]([NH:20][C@H:21]([C:28]([O:30][CH3:31])=[O:29])[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:19])=[CH:16][CH:15]=1)#[CH:13]>>[OH:8][C:7]1[N:2]([C:13]#[C:12][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:20][C@H:21]([C:28]([O:30][CH3:31])=[O:29])[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[O:19])=[CH:32][CH:33]=2)[CH:3]=[N:4][C:5]2=[N:11][CH:10]=[CH:9][C:6]=12
Reactant: C#Cc1ccc(C(=O)N[C@@H](CCC(=O)OC)C(=O)OC)cc1
Reactant: Oc1c2ccnc-2ncn1I
Product: COC(=O)CC[C@H](NC(=O)c1ccc(C#Cn2cnc3nccc-3c2O)cc1)C(=O)OC

Procedure:
By allowing 3-iodo-4-hydroxypyrrolo[2,3-d]pyrimidine to react with dimethyl N-(4-ethynylbenzoyl)-L-glutamate in the manner described in Example 2, there is obtained dimethyl N-[4-(4-hydroxypyrrolo[2,3-d]pyrimidin-3-ylethynyl)benzoyl]-L-glutamate which is purified by chromatography over silica, m.p. 160 ° C. (dec.). 1NMR (d6 -DMSO)δ1.98-2.15 (m, 2H), 2.45 (t, J=7.5 Hz, 2H) 3.57 (s, 3H), 3.64 (s, 3H), 4.40-4.45 (m, 1H), 7.51 ((d, J=2.5 Hz, 1H), 7.55 (d, J=8.2 Hz, 2 H), 7.87 (s, 1H), 7.90 (d, J=8.2 Hz, 1 H), 11.97 ((d, J=3.7 Hz, 1 H), 12.31 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.CC1(C)O[C:18](=[O:19])[CH2:17][C:15](=[O:16])[O:14]1>O>[OH:11][C:8]1[C:9]([OH:10])=[C:2]2[C:3]([CH:4]=[C:17]([C:15]([OH:16])=[O:14])[C:18](=[O:19])[O:1]2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(O)c(O)c1O
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: O
Product: O=C(O)c1cc2ccc(O)c(O)c2oc1=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
2,3,4-trihydroxybenzaldehyde (106.7 mg, 0.69 mmol) and Meldrum's acid (100 mg, 0.69 mmol) were combined in H2O (1 mL). The solution was stirred at 75° C. for 2 h. After cooling to room temperature, the precipitate was filtered and dried at suction to give 114.1 mg of 7,8-dihydroxy-3-carboxy-coumarin in a 74% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]#[N:9].C[O:11][C:12](OC)(N(C)C)[CH3:13]>CN(C=O)C>[CH2:1]([C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]#[N:9])[C:12]([CH3:13])=[O:11]
Reactant: COC(C)(OC)N(C)C
Reactant: Cc1ccncc1C#N
Solvent: CN(C)C=O
Product: CC(=O)Cc1ccncc1C#N
Yield: 68.7 %

Procedure:
A solution of 4-methyl-3-cyanopyridine (4 g, 33.9 mmol) and N,N-dimethylacetamide dimethylacetal (5.4 g, 40.6 mmol) in dry DMF (20 ml) was stirred at 130° for 7 h. The volatiles were removed in vacuo to afford a dark oil which solidified on standing. This material was chromatographed (SiO2; 50% EtOAc/Hexane—100% EtOAc) affording the title compound as an off-yellow solid (3.73 g, 69%). δH (CDCl3) 8.87 (1H, s), 8.74 (1H, d, J 5.2 Hz), 7.28 (1H, d, J 5,2 Hz), 4.00 (2H, s) and 2.36 (3H, s); m/z (ES+, 70V) 161 (MH+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]1[N:17]=[C:16]([NH:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=[CH:14][CH:13]=1.[OH2:24]>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([CH2:11][C:12]1[N:17]=[C:16]([NH:18][CH2:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=[CH:14][CH:13]=1)=[O:24]
Reactant: CC(C)(C)CNc1cccc(CSc2nc3ccccc3[nH]2)n1
Reactant: O
Product: CC(C)(C)CNc1cccc(CS(=O)c2nc3ccccc3[nH]2)n1

Procedure:
The title compound (100 mg) was prepared by the method of Example 85 using 1.52 g (4.65 mmole) of 6-[(1H-benzimidazol-2-ylthio)methyl]-N-(2,2-dimethylpropyl)-2-pyridinamine (see Example 106) instead of 6-[(1H-benzimidazol-2-ylthio)methyl]-2-pyridinamine. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis. Analysis. Calc'd. for C18H22N4SO*¼ H2O: C, 62.31; H, 6.48; N, 16.15; S, 9.24. Found: C, 62.19; H, 6.47; N, 15.76; S, 9.09.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[N:16]3)[O:11][C:10]2=[O:21])[CH:5]=[CH:6][C:7]=1I.C([Sn](CCCC)(CCCC)[C:27]1[O:31][N:30]=[C:29]([CH3:32])[CH:28]=1)CCC>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][N:15]3[CH:19]=[C:18]([CH3:20])[N:17]=[N:16]3)[O:11][C:10]2=[O:21])[CH:5]=[CH:6][C:7]=1[C:27]1[O:31][N:30]=[C:29]([CH3:32])[CH:28]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)no1
Reactant: Cc1cn(C[C@H]2CN(c3ccc(I)c(F)c3)C(=O)O2)nn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: Cc1cn(C[C@H]2CN(c3ccc(-c4cc(C)no4)c(F)c3)C(=O)O2)nn1
Temperature: 100 °C
Yield: 88.3 %

Procedure:
(5R)-3-(3-Fluoro-4-iodophenyl)-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (Intermediate 2, 2.08 g, 5.20 mmol) was dissolved in anhydrous 1,4-dioxane (10 ml) and degassed and placed under argon. Bis(triphenylphospine)palladium(II) chloride (0.145 g, 0.210 mmol) was added followed by dropwise addition of 5-(tributylstannyl)-3-methylisoxazole (2.41 g, 6.50 mmol) (Sakamoto, T. et al., Tetrahedron, 47, 28, 5111–5118) in 1,4-dioxane (2 ml). The reaction was degassed and heated at 100° C. for 48 hours. The solvent was removed under vacuum and the residue was dissolved in acetonitrile and washed with hexanes. The acetonitrile layer was concentrated to give a yellow solid (1.64 g) that was adsorbed onto silica gel and purified by flash chromatography using 10–20% acetone/dichloromethane. Relevant fractions were concentrated to give an off-white solid (1.50 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Br[CH:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12].N1C=CC=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: Nc1ccc(Cl)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)C(Nc1ccc(Cl)cc1)C(=O)OCC
Reaction time: 8 h
Yield: 34.8 %

Procedure:
p-Chloroaniline (2 g) was dissolved in dry benzene (20 ml), and diethyl bromomalonate (3.8 g) and then dry pyridine (1.3 ml) were added. The mixture was refluxed with stirring overnight. The solvent was distilled off under reduced pressure, and then water was added. The mixture was extracted with chloroform twice. The chloroform layers were washed with water twice and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue (3.34 g) was purified by silica gel column chromatography using benzene as an eluent to give 1.56 g (yield 35%) of diethyl p-chloroanilinomalonate having the following NMR data.
Reaction SMILES: N1C=CC=CC=1.[Br:7][CH2:8][C:9](Br)=[O:10].[C:12]1([C:18]([OH:21])([CH3:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[Br:7][CH2:8][C:9]([O:21][C:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:20])[CH3:19])=[O:10]
Reactant: O=C(Br)CBr
Reactant: CC(C)(O)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(OC(=O)CBr)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
Pyridine (3.84 mL, 47.7 mmol) followed by bromoacetyl bromide (4.16 mL, 47.7 mmol) was added to a solution of 2-phenylpropan-2-ol (5.00 g, 36.7 mmol) in dichloromethane (100 mL) at 0° C., warmed to r.t. and stirred overnight. The reaction mixture was washed with water (3×100 mL), saturated aqueous sodium bicarbonate (3×100 mL), water (2×100 mL), dried (Na2SO4) and concentrated. The crude residue was purified by silica gel flash column chromatography (neutralized with TEA, heptanes) to afford the title compound (2.8 g (non-optimized), 30%) as a colorless oil. 1H NMR (300 MHz, ((CD3)2CO) δ: 7.44 (d, J=7.2 Hz, 2H), 7.34 (t, J=7.2 Hz, 2H), 7.25 (t, J=7.2 Hz, 1H), 4.01 (s, 2H), 1.78 (s, 6H).
Reaction SMILES: [N:1]([O-])=O.[Na+].[Cl:5][C:6]1[N:11]=[CH:10][N:9]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:7]=1[NH2:20]>C(O)(=O)C.C(Cl)Cl>[Cl:5][C:6]1[C:7]2[N:20]=[N:1][N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[C:8]=2[N:9]=[CH:10][N:11]=1
Reactant: O=N[O-]
Reactant: Cc1ccccc1Nc1ncnc(Cl)c1N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1ccccc1-n1nnc2c(Cl)ncnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.6 %

Procedure:
Sodium nitrite (0.323 g, 4.69 mmol) was added to 6-chloro-N4-o-tolylpyrimidine-4,5-diamine (Intermediate AP5)(1 g, 4.26 mmol) in acetic acid (50% Aq) (25 mL)and DCM (25 mL) at room temperature. The resulting solution was stirred at room temperature for 15 minutes. The reaction mixture was separated and the organic phase was washed with water (10 mL), dried (MgSO4) and evaporated to give crude 7-chloro-3-o-tolyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (0.980 g, 94%) that was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si](C=[N+]=[N-])(C)C>C1COCC1.CO>[CH3:12][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([I:11])=[CH:10][C:2]=1[OH:1]
Reactant: O=C(O)c1ccc(I)cc1O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(I)cc1O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 2-hydroxy-4-iodo-benzoic acid (4.0 g, 0.015 mol) in THF (25 ml) and MeOH (25 ml) is treated by the dropwise addition of (trimethylsilyl)-diazomethane (2.0M in Et2O, 15 ml) and stirred at room temperature for 2.5 hours. Volatiles are removed in vacuo and the crude residue diluted into EtOAc. The organic phase is sequentially washed with saturated aqueous NaHCO3 (3×), saturated aqueous NaCl (1×), and H2O (1×). The organic phase is dried over MgSO4, filtered, and concentrated. The crude product is purified with silica gel column chromatography (0-80% ethyl acetate in hexanes gradient) to afford 2-hydroxy-4-iodo-benzoic acid methyl ester: ESMS m/z 279.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:15][CH3:16])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C(N(CC)CC)C.[CH3:24][OH:25].C1(N=C=NC2CCCCC2)CCCCC1>C(=S)=S>[CH2:15]([N:6]1[C:5]2[CH:4]=[CH:3][C:2]([N:1]=[C:24]=[O:25])=[CH:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH3:16]
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: S=C=S
Product: CCn1c2ccccc2c2cc(N=C=O)ccc21
Reaction time: 4 h

Procedure:
38.6 g of 3-amino-9-ethylcarbazole and 27.9 ml of triethylamine were added to 300 ml of methanol, and, while cooling with ice, 15.2 g of carbon disulfide was added dropwise thereto. After conducting reaction at room temperature for 3 hours, 41.3 g of dicyclohexylcarbodiimide was added thereto, followed by reacting at room temperature for 4 hours. Crystals thus precipitated were collected by filtration, heat-refluxed in 500 ml of ethyl acetate, and cooled to precipitate and then filter off solids. The filtrate was concentrated to obtain the desired product (29 g).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:24]([CH3:25])[C:13]2=[N:14][CH:15]=[C:16]([CH:18](O)[C:19]([F:22])([F:21])[F:20])[CH:17]=[C:12]2[N:11]=1)[CH3:2].C1(C)C=CC=CC=1.S(Cl)([Cl:35])=O.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[Cl:35][CH:18]([C:16]1[CH:17]=[C:12]2[N:11]=[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[S:3][CH2:1][CH3:2])[N:24]([CH3:25])[C:13]2=[N:14][CH:15]=1)[C:19]([F:22])([F:21])[F:20]
Reactant: CCSc1ccccc1-c1nc2cc(C(O)C(F)(F)F)cnc2n1C
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCSc1ccccc1-c1nc2cc(C(Cl)C(F)(F)F)cnc2n1C
Temperature: 50 °C

Procedure:
To a mixture of 1-[2-(2-ethylsulfanyl-phenyl)-3-methyl-3H-imidazo[4,5-b]pyridin-6-yl]-2,2,2-trifluoro-ethanol (98 mg), toluene (10 ml), and pyridine (50 μl), thionyl chloride (1 ml) was added. The mixture was stirred with heating at 50° C. for 5 hours, and then saturated aqueous sodium hydrogen carbonate solution was poured, and extracted with ethyl acetate. The combined organic layer was dried over sodium, sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 66 mg of 6-(1-chloro-2,2,2-trifluoro-ethyl)-2-(2-ethylsulfanyl-phenyl)-3-methyl-3H-imidazo[4,5-b]pyridine (hereinafter referred to as Present Compound 266).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1.[CH2:10](I)[CH3:11]>C(#N)C>[CH2:10]([N:7]1[CH2:8][CH:9]=[C:4]([CH2:3][O:2][CH3:1])[CH2:5][CH2:6]1)[CH3:11]
Reactant: CCI
Reactant: COCc1ccncc1
Solvent: CC#N
Product: CCN1CC=C(COC)CC1

Procedure:
6.5 g (0.053 mol) of 4-methoxymethyl pyridine and 9.9 g of ethyl iodide are refluxed in 65 ml of acetonitrile for 1 hour. After the solvent has been distilled off the quaternary salt remaining is taken up in methanol and reduced with sodium borohydride analogously to Example 1 b). 7.8 g (95.2% of theory) of the title compound are obtained (b.p. 85° C./20 mbar).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH:4]([CH3:6])[CH3:5].[CH3:8][CH2:9][O:10][C:11]([C:13]([NH2:15])=[S:14])=[O:12]>>[CH2:9]([O:10][C:11]([C:13]1[S:14][CH:2]=[C:3]([CH:4]([CH3:6])[CH3:5])[N:15]=1)=[O:12])[CH3:8]
Reactant: CCOC(=O)C(N)=S
Reactant: CC(C)C(=O)CBr
Product: CCOC(=O)c1nc(C(C)C)cs1
Temperature: 25 °C
Yield: 50.2 %

Procedure:
A neat solution of 5.58 g (34 mmol) of 1-Bromo-3-methyl-butan-2-one and 4.50 g (34 mmol) of ethyl thioxamate (Aldrich) was heated at 70° C. over 18 h and then cooled to room temperature. The mixture was partitioned between sat. aqueous NaHCO3 and EtOAc, the EtOAc layer dried (MgSO4), concentrated and chromatographed over SiO2 (eluted with 2% to 40% EtOAc/hexanes) to afford 3.4 g (48% overall) of 4-isopropylthiazole-2-carboxylic acid ethyl ester as an oil: 1H NMR (500 MHz, CDCl3) δ ppm 1.32 (d, J=7 Hz, 6H), 1.42 (t, J=7.2 Hz, 3H), 3.23 (m, 1H), 4.46 (q, J=7.2 Hz, 2H), 7.18 (s, 1H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[CH:12]=[N:13][OH:14]>CN(C)C=O.C(OC)(C)(C)C>[Cl:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([Cl:1])=[N:13][OH:14]
Reactant: ON=Cc1ccccc1Cl
Reactant: O=C1CCC(=O)N1Cl
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: ON=C(Cl)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
N-Chlorosuccinimide (56.1 g) was added slowly to a 0° C. solution of the compound prepared in Example 4 (65.4 g) in N,N-dimethylformamide (1.2 L). The reaction was stirred at room temperature overnight and then diluted with ice water and methyl tert-butyl ether. The layers were separated and the aqueous phase was extracted once more with methyl tert-butyl ether. The organic phases were combined, washed with brine, dried over anhydrous magnesium sulfate and concentrated to obtain the title compound (79.5 g) having the following physical data.
Reaction SMILES: CC1SC(C([O-])=S)=CC=1.[NH2:10][C:11](=[S:22])[C:12]1[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[S:19])[S:15][C:16]=1[CH3:17].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])=O>CC(C)=O>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:25]1[N:10]=[C:11]([C:12]2[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[S:19])[S:15][C:16]=2[CH3:17])[S:22][CH:24]=1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Reactant: COc1ccccc1C(=O)CBr
Agent: Cc1ccc(C([O-])=S)s1
Solvent: CC(C)=O
Product: COC(=S)c1cc(-c2nc(-c3ccccc3OC)cs2)c(C)s1
Yield: 104.4 %

Procedure:
Methyl 4-4-(2-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate: 105 mg (0.424 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 5 mL of reagent grade acetone. 2-Bromo-2′-methoxy acetophenone (0.467 mmol; 110 mg) was added and the solution was allowed to reflux for 3 h. The solution was allowed to cool and the solution concentrated. The crude product was dissolved in 100 mL of CH2Cl2 and washed one time with 50 mL of 1N NaOH. The organic layer was obtained, dried over sodium sulfate, concentrated and purified on a 1 mm silica plate eluting with 20% ethyl acetate/hexane to afford 160 mg (95% yield) of methyl 4-[4-(2-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.