Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([N+:26]([O-:28])=[O:27])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:30]=[C:31]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1)[NH2:32]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:12]2[O:13][N:32]=[C:31]([C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[N:30]=2)[CH:15]=[C:16]([N+:26]([O-:28])=[O:27])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=NO)c1ccncc1
Reactant: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c([N+](=O)[O-])c1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(-c2nc(-c3ccncc3)no2)cc(OCc2ccccc2)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 3,4-dibenzyloxy-5-nitrobenzoic acid (0.5 g, 1.32 mmol) in dimethylformamide (5 mL) at room temperature was added 1,1-carbonyldiimidazole (0.246 g, 1.52 mmol) in one portion. After stirring for one hour, N′-hydroxypyridine-4-carboximidamide (0.208 g, 1.52 mmol) was added in one portion and the resulting mixture was stirred at room temperature overnight. The mixture was then stirred at 110° C. for three hours and then allowed to cool to room temperature. The mixture was poured onto ice-water (100 mL) and extracted with 20% isopropanol/dichloromethane. The organic extracts were washed with water and brine, then dried (Na2SO4), filtered and evaporated to leave a solid residue that was recrystallised from ethanol. 4-[5-(3,4-Bis-benzyloxy-5-nitro-phenyl)-[1,2,4]oxadiazol-3-yl]-pyridine was obtained as a beige solid (0.395 g, 62%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([OH:10])=[O:9].C(N(CC)CC)C.[C:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)#[C:19][CH2:20][CH3:21]>O1CCOCC1.O.C(OCC)(=O)C>[CH2:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[C:8]([OH:10])=[O:9])(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:19]#[C:20][CH3:21]
Reactant: N[C@@H]1CCCC[C@H]1C(=O)O
Reactant: CCC#COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC#CCOc1ccc(S(=O)(=O)N[C@@H]2CCCC[C@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a room temperature solution of 1.5 g (10.2 mmol) of trans-2-amino-1-cyclohexylcarboxylic acid in 75 ml of dioxane:H2O (1:1) containing 2.55 ml (18.3 mmol) of triethylamine was added 3.0 g (11.2 mmol) of 4-butynyloxybenzenesulfonyl chloride. The mixture was stirred at 25° C. for 18 h. The resulting mixture was diluted with ethyl acetate and washed with 1N aqueous hydrochloric acid (3×). The organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo to afford (1R,2R)-2-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)cyclohexanecarboxylic acid as a white solid. Electrospray Mass Spec 352.2 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:16][C:17]1[C:18]([C:27]([F:30])([F:29])[F:28])=[N:19][N:20]([CH2:23][C:24](O)=[O:25])[C:21]=1[CH3:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CC(N(C)C)=O.CCOC(C)=O>[Cl:16][C:17]1[C:18]([C:27]([F:29])([F:28])[F:30])=[N:19][N:20]([CH2:23][C:24]([N:10]2[CH2:9][CH2:8][C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:15][CH:14]=3)([OH:13])[CH2:12][CH2:11]2)=[O:25])[C:21]=1[CH3:22]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Reactant: OC1(Cc2ccc(F)cc2)CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)N1CCC(O)(Cc2ccc(F)cc2)CC1
Reaction time: 5 h
Yield: 80.4 %

Procedure:
To a 20 mL vial equipped with a magnetic stirring bar was added 78 mg of 4-(4-Fluoro-benzyl)-piperidin-4-ol (0.37 mmol, 1.0 equiv.), 100 mg of (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (0.41 mmol, 1.1 equiv), and 207 mg of (Benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (0.40 mmol, 1.1 equiv.). The reagents were dissolved in 3 mL of DMA and to the resultant solution was added 0.26 mL of DIPEA (1.5 mmol, 4.1 equiv). The reaction solution was stirred for 5 h and then poured into 50 mL of EtOAc. The organic phase was washed with saturated aq. NaCl (5×10 mL), 1% aq NaOH (1×10 mL), and 0.1 N HCl (1×10 mL). The organic phase was then dried over MgSO4 and concentrated in vacuo to afford a yellow oil, which was purified by preparative HPLC to afford 129 mg of 2-(4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(4-fluoro-benzyl)-4-hydroxy-piperidin-1-yl]-ethanone (80% yield): MS (ES) M+H expected=414.2, found 414.2. 1H NMR (CDCl3, 400 MHz, 23° C.) δ 7.10-7.14 (m, 2H), 6.99-7.03 (m, 2H), 5.00 (d, J=15.6 Hz, 1H), 4.86 (d, J=15.6 Hz, 1H), 4.32-4.35 (m, 1H), 3.64-6.68 (m, 1H), 3.42-3.50 (m, 1H), 2.96-3.03 (m, 1H), 2.74 (s, 2H), 2.26 (s, 3H), 1.55-1.61 (m, 4H), 1.23 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][CH2:21][O:22][CH3:23]>CN1C(=O)CCC1>[CH3:23][O:22][CH2:21][CH2:20][O:12][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[CH:11][C:2]([CH3:1])=[N:3]2)=[CH:8][CH:7]=1
Reactant: Cc1ccc2ccc(O)cc2n1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COCCOc1ccc2ccc(C)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
To a stirred mixture of 2-methylquinolin-7-ol (300 mg, 1.88 mmol), Cs2CO3 (1.84 g, 5.65 mmol) and NMP (10 mL) was added 1-bromo-2-methoxyethane (0.786 g, 5.65 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction was partitioned between ether and water. The aqueous layer was extracted with ether. The combined organic layers were washed with water and brine, dried and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (2:1 to 1:2 hexanes/EtOAc) to give 7-(2-methoxyethoxy)-2-methylquinoline (235 mg, 57%).
Reaction SMILES: [CH2:1]([C@@:8]([C:38]([OH:40])=[O:39])([CH2:17][CH2:18][C:19]([NH:21][CH:22]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:29][CH:28]=1)[C:23]([O:25][CH3:26])=[O:24])=[O:20])[NH:9]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.O>ClCCl>[CH2:1]([C@@:8]([C:38]([OH:40])=[O:39])([CH2:17][CH2:18][C:19]([NH:21][CH:22]([C:27]1[CH:28]=[CH:29][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=1)[C:23]([O:25][CH3:26])=[O:24])=[O:20])[NH2:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(C(NC(=O)CC[C@](Cc2ccccc2)(NC(=O)OC(C)(C)C)C(=O)O)C(=O)OC)cc1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1ccc(C(NC(=O)CC[C@@](N)(Cc2ccccc2)C(=O)O)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 127.8 %

Procedure:
To a solution of methyl (2RS)-2-{N-[α-benzyl-N-(tert-butoxycarbonyl)-L-γ-glutamyl]amino}-2-[p-(methoxycarbonylmethyl)phenyl]acetate (1.35 g, 2.4 mmol) in 5 ml of dichloromethane was added 5 ml of TFA and 0.5 ml of water. After stirring for 1 hour at room temperature the solution was evaporated to dryness and the resulting solid was azeotroped with toluene to give methyl (2RS)-2-[N-(α-benzyl-L-γ-glutamyl)-amino]-2-[p-(methoxycarbonylmethyl)phenyl]acetate (1.4 g) as a gummy solid;
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>O1CCCC1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:22])=[O:3])=[CH:8][CH:9]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)COc1ccc(OCc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(OCc2ccc(F)cc2)cc1
Temperature: 50 °C
Yield: 82.8 %

Procedure:
A solution of 500 mg of [4-(4-fluoro-benzyloxy)-phenoxy]-acetic acid ethyl ester in 10 ml of tetrahydrofurane was treated with 3.3 ml of sodium hydroxide solution (1 N). The mixture was heated at 50° C. for 2 h, then it was cooled to room temperature and 3.3 ml of hydrochloric acid (1 N) were added. While the tetrahydrofurane was evaporated under reduced pressure, the acid precipitated and, thereafter, was collected on a filter funnel. After washing with water and drying under reduced pressure, 376 mg of [4-(4-fluoro-benzyloxy)-phenoxy]-acetic acid was obtained, which was directly used for the further transformation.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]([CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH2:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C([O:30][C:31](=O)[C:32]([F:35])([F:34])[F:33])C>CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C@@H:14]([C:16]([OH:18])=[O:17])[NH:15][C:31](=[O:30])[C:32]([F:35])([F:34])[F:33])=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 130 h

Procedure:
112.5 g (0.41 mmol) of O-benzyltyrosine is suspended in 1 liter of dry methanol and combined at room temperature with 58.9 ml (0.42 mol) of triethylamine. After adding 67 ml (0.53 mol) of trifluoroacetic acid ethyl ester, the mixture is stirred at room temperature for 130 hours under exclusion of moisture. The mixture is separated from unreacted starting material and volatile components are removed by shaking with ethyl acetate/aqueous hydrochloric acid. The ethyl acetate phase is decolorized with activated carbon. Evaporation of the solvents yields 120.7 g (80% of theory) of colorless crystals. Melting point: 149°-150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][CH3:16])[C:9]2=[O:17])=[N:5][N:4]=1.[C:18]1(C)C(S(O)(=O)=O)=CC=C[CH:23]=1>C(O)C>[CH3:1][O:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][CH2:18][CH3:23])[CH2:12][CH2:11][N:10]([CH2:15][CH3:16])[C:9]2=[O:17])=[N:5][N:4]=1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: CCN1CCC(O)N(c2nnc(OC)s2)C1=O
Solvent: CCO
Product: CCOC1CCN(CC)C(=O)N1c1nnc(OC)s1

Procedure:
Tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-ethyl-6-hydroxy-2(1H)-pyrimidinone (7 grams), ethyl alcohol (50 ml) and toluenesulfonic acid (0.2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is then heated at reflux for a period of about 24 hours. After this time the mixture is stripped of unreacted alcohol under reduced pressure to yield a solid product. This product is then recrystallized to yield the desired product tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-ethyl-6-ethoxy-2(1H)-pyrimidinone.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([O:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([NH:16][C:17]([C@H:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)=[O:18])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>C(#N)C>[C:25]1([S:31]([N:21]2[CH2:22][CH2:23][CH2:24][C@H:19]([C:17]([NH:16][C@H:13]3[CH2:12][CH2:11][C@H:10]([O:9][C:6]4[CH:5]=[CH:4][N:3]=[CH:8][CH:7]=4)[CH2:15][CH2:14]3)=[O:18])[CH2:20]2)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(N[C@H]1CC[C@H](Oc2ccncc2)CC1)[C@H]1CCCNC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(N[C@H]1CC[C@H](Oc2ccncc2)CC1)[C@H]1CCCN(S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (3S)—N-[trans-4-(pyridin-4-yloxy)cyclohexyl]piperidine-3-carboxamide dihydrochloride (28 mg, purity: 40%, 0.03 mmol), benzenesulfonyl chloride (6.3 mg, 0.036 mmol), triethylamine (16 μL, 0.12 mmol) in acetonitrile (1 mL) was stirred at r.t. overnight. the mixture was purified with prep. HPLC. 5.9 mg (45%) of final product was obtained. LCMS: m/z 444.1 (M+H)+; 466.1 (M+Na)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:10]([C:11](=[O:20])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)=[O:5])[CH3:2]>Cl.C(O)(C)C>[ClH:19].[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:10]([C:11](=[O:20])[NH:12][C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)[C@H]1CNC[C@@H]1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound 39b (1.6 g; 4.03 mmol) is dissolved in 6N HCl in isopropanol (12.5 ml) and the reaction mixture is stirred for 2 h at 25° C. The reaction mixture is evaporated to dryness and the crude product is crystallized twice from diethylether to yield an off-white solid. Yield: 1.44 g (107.2%), ESI-MS: m/z=297 [M+H]+, Cl-Pattern
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH2:8][CH:9]1[CH2:14][N:13]2[CH2:15][CH2:16][NH:17][CH2:18][CH:12]2[CH2:11][NH:10]1)([CH3:7])[CH3:6])([CH3:4])[CH3:3].C(N(CC)CC)C.[C:26](Cl)(=[O:28])[CH3:27]>ClCCl>[C:26]([N:17]1[CH2:16][CH2:15][N:13]2[CH2:14][CH:9]([CH2:8][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([CH3:6])[CH3:7])[NH:10][CH2:11][CH:12]2[CH2:18]1)(=[O:28])[CH3:27]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)CC1CN2CCNCC2CN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN2CC(C[Si](C)(C)C(C)(C)C)NCC2C1

Procedure:
To a solution of the (3R,9aS or 9aR)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]methyl}octahydro-2H-pyrazino[1,2-a]pyrazine (D86, 217 mg) in 9 mL of dichloromethane was added triethylamine (212 μL ) and it was brought to −10 ° C. A solution of acetyl chloride (54 μL) in 2 mL of dichloromethane was added dropwise. After 15 min the reaction was quenched by addition of MeOH. The crude was purified by flash chromatography (silica, CH2Cl2 to CH2Cl2: (0.5 M NH3 in MeOH) 95:5). The sample thus obtained was dissolved in CH2Cl2 and extracted with sat. NaHCO3. The organics were dried and the solvent removed, leading to the title compound (128 mg).
Reaction SMILES: C([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:5]1)(=O)C.[ClH:24]>C(O)CCC>[ClH:24].[C:18]1([S:15]([NH:14][C:10]2[CH:9]=[CH:8][CH:7]=[C:6]3[C:11]=2[CH2:12][CH2:13][NH:4][CH2:5]3)(=[O:17])=[O:16])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)N1CCc2c(cccc2NS(=O)(=O)c2ccccc2)C1
Agent: Cl
Solvent: CCCCO
Product: O=S(=O)(Nc1cccc2c1CCNC2)c1ccccc1

Procedure:
A stirred mixture of 2-acetyl-5-phenylsulphonamido-1,2,3,4-tetrahydroisoquinoline (9.4 g), hydrochloric acid (140 ml, 3.0M) and n-butanol (14 ml) was heated under reflux for 6 hours. The solvents were evaporated under reduced pressure and the residue was recrystallised from ethanol to give 5-phenylsulphonamido-1,2,3,4-tetrahydroisoquinoline hydrochloride as a white solid (7.8 g) m.p. 209°-21° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[I:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1>CN(C=O)C.CCOC(C)=O>[I:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]=2)=[CH:17][CH:16]=1
Reactant: Clc1cnccn1
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Ic1ccc(Oc2cnccn2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A mixture of chloropyrazine (124 mg, 1.08 mmol), K2CO3 (749 mg, 5.42 mmol), and 4-iodophenol (263 mg, 1.20 mmol) in DMF (24 mL) was heated at 100° C. for 9.5 h and then stirred at rt overnight. The reaction was diluted with EtOAc and washed with H2O (40 mL). The aqueous wash was back extracted with EtOAc (20 mL). The organic extracts were combined, washed with H2O (2×40 mL), washed with brine (40 mL), dried (MgSO4), filtered, concentrated and purified by silica gel chromatography (0%-20% EtOAc in hexanes) to give 289 mg of 2-(4-iodophenoxy)pyrazine (containing 15% of 4-iodophenol) as a white semi-solid. 1H NMR (400 MHz, DMSO-d6): δ 8.57 (d, 1H), 8.41 (d, 1H), 8.21 (dd, 1H), 7.78 (d, 2H), 7.07 (d, 2H).
Reaction SMILES: C[N:2]([CH3:13])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.[NH2:14][C:15]1[C:19](C#N)=[C:18]([CH3:22])[NH:17][N:16]=1>C(O)(=O)C>[CH3:22][C:18]1[C:19]([C:15]#[N:14])=[C:13]2[N:2]=[CH:3][CH:4]=[C:5]([C:7]3[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=3)[N:16]2[N:17]=1
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: Cc1[nH]nc(N)c1C#N
Solvent: CC(=O)O
Product: Cc1nn2c(-c3cccnc3)ccnc2c1C#N

Procedure:
A mixture of 3.50 g. of 3-dimethylamino-1-(3-pyridyl)-2-propen-1-one, 25 L ml. of glacial acetic acid and 2.44 g. of 3-amino-5-methylpyrazole-4-carbonitrile is refluxed 6 hours. The solvent is removed in vacuo. The residue is dissolved in dichloromethane and the solution washed with saturated sodium bicarbonate solution. The dichloromethane layer is dried over anhydrous sodium sulfate and pased through a column of hydrous magnesium silicate. The eluent is concentrated and hexane added to give 2.60 g. of the product of the example, m.p. 245°-246° C.
Reaction SMILES: N.[Na].[C:3]1([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)=[O:9])[S:7][CH:6]=[CH:5][CH:4]=1.[CH3:20]I>C(OCC)C>[C:3]1([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:20])[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)=[O:9])[S:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1ccc(C(=O)c2cccs2)cc1
Reactant: CI
Agent: N
Agent: [Na]
Solvent: CCOCC
Product: CC(C(=O)O)c1ccc(C(=O)c2cccs2)cc1
Reaction time: 0.5 h

Procedure:
To 400 parts of liquid ammonia are added a trace of ferric chloride and 3 parts of sodium. The mixture is stirred for 30 minutes, after which 14.8 parts of 2-[p-(2-thenoyl)phenyl]acetic acid are added slowly during 30 minutes, and the mixture is further stirred for 45 minutes. 13.6 parts of methyl iodide are added dropwise and the reaction mixture is stirred for 2h. 30 400 parts of diethyl ether are then added and the mixture is stirred overnight. The ammonia is evaporated and the resulting solution is acidified with diluted hydrochloric acid. The ethereal layer is separated and extracted with 10% sodium hydroxide solution. The extract is washed with ether, acidified and extracted with ether. The ethereal solution is dried on sodium sulfate and the ether is evaporated in vacuo. The residue is triturated in petroleumether, filtered off and crystallized twice from acetonitrile, first at -20° C and then at 0° C, yielding p-(2-thenoyl)hydratropic acid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:11][CH:10]=[C:9]([C:12]3[CH:13]=[C:14]([S:18]([NH:21][CH3:22])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=3)[C:4]=2[N:5]=[C:6](Cl)[N:7]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH2:35])[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32]>>[NH2:1][C:2]1[C:3]2[S:11][CH:10]=[C:9]([C:12]3[CH:13]=[C:14]([S:18]([NH:21][CH3:22])(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=3)[C:4]=2[N:5]=[C:6]([NH:35][C:27]2[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=2)[N:7]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: CNS(=O)(=O)c1cccc(-c2csc3c(N)nc(Cl)nc23)c1
Product: CNS(=O)(=O)c1cccc(-c2csc3c(N)nc(Nc4cc(OC)c(OC)c(OC)c4)nc23)c1
Yield: 77.4 %

Procedure:
The target compound of Example 26 (33 mg, 77% yield) was prepared in the same manner as Step 9 of Example 1 using 3-(4-amino-2-chlorothieno[3,2-d]pyrimidin-7-yl)-N-methylbenzenesulfonamide (30 mg, 0.085 mmol) and 3,4,5-trimethoxybenzenamine (31 mg, 0.170 mmol).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C:26]2=[CH:25][CH2:24][C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2].CC(O)=[O:34]>>[C:1]([O:4][C@@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@H:7]([CH2:8][CH2:9][C@@H:10]3[C:26]2=[CH:25][C:24](=[O:34])[C@@:23]2([CH3:31])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:22])[CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC[C@]12C
Reactant: CC(=O)O
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)C3=CC(=O)[C@]12C
Temperature: 50 °C
Yield: 50 %

Procedure:
CrO3 (17.0 g, 170 mmol) was added to a solution of compound 1.8a (17 g, 39.5 mmol) in AcOH (270 mL). The resulting mixture was heated at 50° C. for 24-36 h. Upon complete disappearance of the starting material by TLC, the solvent was evaporated under vacuum and the crude material was dissolved in ethyl acetate (400 mL) and water (200 mL). The two phases were separated and the organic layer was washed twice with water (2×100 mL) and then once with saturated brine solution (100 mL). The organic phase was dried over anhydrous Na2SO4 (40 g) and filtered. The filtrate was concentrated under vacuum and the resulting solid was purified by column chromatography [49 mm (W)×600 mm (L), 60-120 mesh silica, 120 g], eluting with ethyl acetate/hexane (1:5) [10 mL fractions, 3 mL/min elution, monitored by TLC and detected with UV light (254 nm) lamp]. The product-containing fractions were combined and concentrated under vacuum to afford compound 1.9a (8.8 g, 50% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.Cl.[CH2:8]1[CH2:12]O[CH2:10][CH2:9]1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:10]([C:3]1[S:4][C:5]([C:2]2[CH:6]=[CH:5][S:4][CH:3]=2)=[CH:6][CH:2]=1)[CH2:9][CH2:8][CH2:12][CH2:12][CH2:8][CH2:9][CH2:10][CH2:3][CH2:2][CH2:6][CH3:5]
Reactant: C1CCOC1
Reactant: Brc1ccsc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Product: CCCCCCCCCCCCc1ccc(-c2ccsc2)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
Separately, diphenylphosphinoferroceneparadium dichloride (hereinafter referred to as “Pd(dppf)Cl2”) (1.7 g, 2.11 mmol, 0.01 eq) and 3-bromothiophene (41.0 g, 253 mmol, 1.2 eq) were placed in a three-necked flask, and the atmosphere in the flask was replaced by Ar. Dehydrated THF (200 ml) was added to the contents of the flask, and the mixture was cooled to 0° C. The Grignard reagent prepared above was added dropwise thereto, and the mixture was stirred for 30 min. The reaction solution was brought to room temperature and was stirred for 6 hr. A 1 N aqueous HCl solution (20 ml) was added thereto, and the mixture was stirred for 15 min. THF was removed by evaporation, and the residue was extracted with diethyl ether, followed by washing with water until pH=7. The extract was dehydrated over Na2SO4, and the solvent was removed by evaporation, and the residue was purified by chromatography on silica gel and was recrystallized from ethanol to give an objective substance 5′ dodecyl-3,2′-bithiophene as a light yellow solid (about 38.5 g, yield about 54%). An NMR spectrum of the compound thus obtained was measured at room temperature with an NMR spectrometer (model JNM-LA400W, manufactured by Japan Electric Optical Laboratory). 1H-NMR (d6-DMSO, TMS/ppm): 0.86 (t, 3H, J=6.83 Hz), 1.26 (m, 18H), 1.64 (m, 2H), 2.77 (t, 2H, J=7.32 Hz), 6.75 (d, 1H, J=3.42 Hz), 7.11 (d, 1H J=3.42 Hz), 7.32 (dd, 1H, J=0.97 Hz, J=5.12 Hz), 7.53 (m, 2H).