Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([OH:43])=O)=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[Cl-].[N:49]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[CH:52]=[C:51]([CH2:59][NH3+:60])[CH:50]=1>>[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:60][CH2:59][C:51]4[CH:50]=[N:49][C:58]5[C:53]([CH:52]=4)=[CH:54][CH:55]=[CH:56][CH:57]=5)=[O:43])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1
Reactant: [NH3+]Cc1cnc2ccccc2c1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Agent: [Cl-]
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cnc2ccccc2c1
Yield: 50 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with quinolin-3-ylmethanaminium chloride, the title compound was obtained as a colorless solid in 50% yield: 1H NMR (300 MHz, CDCl3) δ 8.91 (s, 1H), 8.15-8.08 (m, 2H), 7.81 (d, J=8.2 Hz, 1H), 7.74-7.66 (m, 1H), 7.58-7.51 (m, 1H), 7.30-7.22 (m, 2H), 7.07-6.98 (m, 2H), 6.22 (t, J=5.6 Hz, 1H), 6.09 (s, 1 H), 4.74 (d, J=5.6 Hz, 2H), 4.42 (s, 2H), 3.83-3.74 (m, 2H), 3.47-3.38 (m, 2H), 2.50 (s, 3H); MS (ES+) m/z 475.2 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH2:27][NH:28][CH3:29]>O1CCOCC1>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][N:28]([CH2:27][C:21]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:20]=2[Cl:19])[CH3:29])=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: CNCc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(CC(=O)c1ccc(Br)cc1)Cc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-bromo-1-(4-bromophenyl)ethanone (9.3 g, 33.45 mmol, 1.00 equiv) in dioxane (100 mL), triethylamine (5.0 g, 1.50 equiv), and (2,4-dichlorophenyl)-N-methylmethanamine (6.4 g, 33.68 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at 25° C. The solids were filtered out. The filtrate was used for next step directly.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[N:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=1>ClCCl>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:48][C:45]5[CH:46]=[CH:47][N:42]=[CH:43][CH:44]=5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccncc1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)Nc2ccncc2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 2 h
Yield: 17.4 %

Procedure:
A mixture of 0.050 g (0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl-amino)-3-methoxy-benzoic acid (I-22), 0.048 g (0.12 mmole) of N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridine-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide, 0.037 g (0.28 mmole) of ethyldiisopropyl amine, 0.016 g (0.17 mmole) of pyridine-4-ylamine and 0.5 ml of dichloromethane was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 0.5 ml of methanol, and then precipitated by the addition of water. The residue was washed three times with water and then purified by chromatography on reverse phase silica gel, eluting with acetonitrile-water to give 0.01 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-pyridin-4-yl-benzamide (I-129).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[S:10][C:9]([C:11]([NH2:13])=[O:12])=[CH:8][CH:7]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[NH2:1][CH2:4][CH2:5][C:6]1[S:10][C:9]([C:11]([NH2:13])=[O:12])=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=NCCc1ccc(C(N)=O)s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: NCCc1ccc(C(N)=O)s1

Procedure:
2-(2-Thienyl)ethyl p-toluenesulphonate (J.A.C.S. 95, 1973, 1247), acetyl chloride and aluminium chloride were reacted in methylene chloride to give 2-[(5-acetyl-2-thienyl)ethyl]p-toluenesulphonate (melting point 111°-112°, from ethanol). This was converted with sodium azide in dimethyl sulphoxide into 5-(2-azidoethyl)-2-thienyl methyl ketone. Oxidation with sodium hypobromite yielded 5-(2-azidoethyl)-2-thiophenecarboxylic acid of melting point 53°-55° C. Treatment of this acid with thionyl chloride gave the corresponding acid chloride which was reacted with ammonia to give 5-(2-azidoethyl)-2-thiophenecarboxamide (melting point 104°-105°, from ethanol). Reaction of this amide with triphenylphosphine and hydrolysis (J. Org. Chem. 40, 1975, 1659) gave 5-(2-aminoethyl)-2-thiophenecarboxamide of melting point 134°-136° (from acetonitrile).
Reaction SMILES: [Mg].C1C2C3C=CC=CC=3OC=2C=CC=1.C(Br)C=C.C[Si](C)(Cl)Cl.[C:24]1([CH2:30][CH2:31][C:32](=[O:36])[CH2:33][CH2:34][CH3:35])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>C1COCC1>[OH:36][C:32]([CH2:31][CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH2:33][CH2:34][CH3:35])[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]
Reactant: CCCC(=O)CCc1ccccc1
Reactant: CCOC(=O)CCl
Agent: C[Si](C)(Cl)Cl
Agent: [Mg]
Solvent: C=CCBr
Solvent: C1CCOC1
Solvent: c1ccc2c(c1)oc1ccccc12
Product: CCCC(O)(CCc1ccccc1)CC(=O)OCC
Reaction time: 0.3 h

Procedure:
Magnesium (9.1 g, 0.374 mole) was suspended in THF (99 mL) containing dibenzofuran (1.4109 g) as an internal standard substance and allyl bromide (0.28 g) was added at 31° C. in a thin stream. Thereto was added 2.5 mL of a mixed solution (143 mL) of dimethyldichlorosilane (1.84 g, 14.2 mmole), 1-phenyl-3-hexanone (47.1 g, 0.267 mole), ethyl chloroacetate (34.8 g, 0.284 mole), allyl bromide (0.28 g, 2.3 mmole) and THF (49 mL) at 30° C. in a thin stream. After 18 min, exothermic heat was observed and the internal temperature rose to 32.5° C. After 34 min from the addition in a thin stream, the remaining mixed solution was added at an internal temperature of 32-36° C. over 3 hr in a thin stream. Thereafter, ethyl chloroacetate (10.2 g, 83.2 mmole) was added at an internal temperature of 32-35° C. over 1 hr in a thin stream and thermally insulated at an internal temperature of 36° C. for 1 hr. The title compound in the reaction mixture was analyzed and a reaction mixture containing the title compound (52.5 g, yield 74.3%) was obtained (quantitative analysis by HPLC). The NMR data were the same as in Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=[O:19])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])[CH3:2].[F:21][C:22]([Si](C)(C)C)([F:27])[C:23]([F:26])([F:25])[F:24].[F-].Cl>C1COCC1.O>[CH2:1]([O:3][C:4](=[O:20])[C:5]([OH:19])([C:22]([F:27])([F:21])[C:23]([F:26])([F:25])[F:24])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])[CH3:2]
Reactant: C[Si](C)(C)C(F)(F)C(F)(F)F
Reactant: CCOC(=O)C(=O)CC(C)(C)c1cccc(F)c1OC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(CC(C)(C)c1cccc(F)c1OC)C(F)(F)C(F)(F)F
Temperature: -25 °C
Reaction time: 4.5 h
Yield: 115.9 %

Procedure:
1.0 g (3.54 mmol) of ethyl-4-(3-fluoro-2-methoxyphenyl)-2-oxo-4-methyl-valerate and 0.98 g (5.1 mmol) of (pentafluoroethyl)-trimethylsilane in 7 ml of THF are mixed with 65 mg (0.7 mmol) of tetramethylammonum fluoride at −40° C. The reaction mixture is heated to −25° C. and stirred at this temperature. After 4.5 hours, 1 ml of 2N hydrochloric acid is added, and the reaction mixture is added to water. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. 1.65 g of ethyl-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)valerate is obtained as a crude product. The ester is mixed in 80 ml of diethyl ether at 0° C. with 300 mg (8 mmol) of lithium aluminum hydride and stirred for 3.5 more hours at room temperature. A little water is carefully added to the batch at 0° C., and it is stirred vigorously for 15 more minutes. It is filtered by Cellite, and the precipitate is rewashed thoroughly with ethyl acetate. The filtrate is dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-15%), 800 mg of 4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-(pentafluoroethyl)pentane-1,2-diol is obtained. 1.8 ml (13 mmol) of triethylamine and, in portions over 10 minutes, 1.6 g (10 mmol) of pyridine SO3 complex are added to 800 mg (2.2 mmol) of diol in 25 ml of dichloromethane and 8.9 ml of DMSO. It is stirred for 2.5 hours, and saturated ammonium chloride solution is added. The mixture is stirred for another 15 minutes, the phases are separated, and it is extracted with dichloromethane. It is washed with water and dried on sodium sulfate. The solvent is removed in a vacuum, and the desired aldehyde is obtained quantitatively.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-])=O)[N:4]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:16]=2)[N:3]=1.[NH4+].[Cl-]>CO.[Zn]>[CH3:21][C:17]1[N:16]=[C:15]([CH2:14][N:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[C:9]([NH2:11])[C:10]=3[CH:2]=[N:3]2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cccc(Cn2nc(I)c3c([N+](=O)[O-])cccc32)n1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: Cc1cccc(Cn2ncc3c(N)cccc32)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
A solution of 3-iodo-1-((6-methylpyridin-2-yl)methyl)-4-nitro-1H-indazole (Example 89, Steps A-B; 1.00 g, 2.54 mmol) in MeOH (25 mL) was cooled to 0° C. Zinc dust (0.829 g, 12.7 mmol) was added and the mixture was stirred for 10 minutes. Saturated aqueous NH4Cl was added (25 mL) and the mixture was stirred vigorously for 2 hours at 0° C. and then warmed to ambient temperature and stirred for an additional 2 hours. Additional saturated aqueous NH4Cl was added (12.5 mL) and the mixture was stirred at ambient temperature for an additional 2 hours. The mixture was diluted with MeOH and filtered. To the filtrate was added saturated aqueous NH4OAc and the mixture was concentrated to remove bulk MeOH. The mixture was then extracted with EtOAc and the combined organic extracts were washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography (2 to 20% IPA/CHCl3) to afford 0.428 g (70%) of the desired product as an orange solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2].C([Li])CCC.F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1>O1CCCC1>[CH:1]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1ccccn1
Reactant: Fc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(c1ccccn1)c1ccccn1
Temperature: -80 °C
Yield: 80 %

Procedure:
58.0 g (540 mmol) of 2-ethylpyridin were dissolved in 550 ml tetrahydrofurane and cooled to −80° C. 200 ml (540 mmol) of butyl lithium (2.7 M in heptane) were added over a period of thirty minutes. After stirring at −20° C. for two hours 26.3 g (270 mmol) of 2-fluoropyridine were added. The mixture was stirred under reflux for thirty minutes, then cooled and poured on 500 ml ice. The layers were separated and the aqueous layer was extracted with 200 ml dichloromethane. The combined organic layers were dried with sodium sulphate and concentrated under reduced pressure. The oily residue was distilled under reduced pressure to yield 39.8 g (80%) of yellow oil that was used in the next synthesis without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([C:26]([OH:28])=O)=[CH:22][C:20]=3[N:21]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].C(Cl)CCl.[NH4+:37]>CN(C1C=CN=CC=1)C>[CH3:32][C:2]([CH3:1])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][C:23]([C:26]([NH2:37])=[O:28])=[CH:22][C:20]=3[N:21]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1nc2cc(C(=O)O)ccc2o1
Reactant: [NH4+]
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1nc2cc(C(N)=O)ccc2o1
Yield: 7 %

Procedure:
2-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzooxazole-5-carboxylic acid (150 mg, 0.343 mmol), DMAP (125 mg, 1.03 mmol) and EDC (99 mg, 0.514 mmol) and aqueous ammonium hydrroxide (1.0 mL, 30%) is reacted analogous to Example 2 to give the title product (10 mg, 7%). MS (ES) m/e: 437.3 (M+1).
Reaction SMILES: CN(CCO[C:7](=O)[O:8][CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])C.[Mg].[Al]>>[CH3:13][N:11]([CH2:10][CH2:9][O:8][CH2:7][CH2:10][N:11]([CH3:13])[CH3:12])[CH3:12]
Reactant: CN(C)CCOC(=O)OCCN(C)C
Agent: [Al]
Agent: [Mg]
Product: CN(C)CCOCCN(C)C

Procedure:
A process for preparing bis[2-(N,N-dimethylamino)ethyl]ether which comprises (i) contacting 2-(N,N-dimethylamino)ethanol with diethyl carbonate under conditions effective to produce bis[2-(N,N-dimethylamino)ethyl]carbonate, and (ii) contacting bis[2-(N,N-dimethylamino)ethyl]-carbonate with a magnesium:aluminum mixed metal oxide catalyst under conditions effective to produce bis[2-(N,N-dimethylamino)ethyl]ether.
Reaction SMILES: [ClH:1].[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:20]2[NH:29][C:23]3=[N:24][CH:25]=[C:26](N)[CH:27]=[C:22]3[CH:21]=2)[CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:8][CH:7]=1)(=[O:5])=[O:4].N([O-])=O.[Na+].[OH-].[Na+]>Cl.O.[Cu]Cl>[Cl:1][C:26]1[CH:27]=[C:22]2[CH:21]=[C:20]([CH:12]([C:9]3[CH:10]=[CH:11][C:6]([S:3]([CH3:2])(=[O:5])=[O:4])=[CH:7][CH:8]=3)[CH2:13][CH:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[NH:29][C:23]2=[N:24][CH:25]=1
Reactant: Cl
Reactant: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2cc3cc(N)cnc3[nH]2)cc1
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)c2cc3cc(Cl)cnc3[nH]2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 11.4 %

Procedure:
To a solution of 2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-ylamine hydrochloride (454 mg, 1.05 mmol) in concentrated hydrochloric acid (6 mL) at 0° C. was added a solution of sodium nitrite (360 mg, 5.25 mmol) in water (3 mL) dropwise. After stirring for 10 min at 0° C., a solution of copper (I) chloride (310 mg, 3.15 mmol) in concentrated hydrochloric acid (3 mL) was added. After stirring for another 10 min at 60° C., the mixture was treated with 20% sodium hydroxide solution (pH 8), extracted with dichloromethane, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using a Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) to afford 5-chloro-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (50 mg, 11%): LC/MS m/e calcd for C21H23ClN2O3S [M+H]+ 419.95, observed 419.3; 1H NMR (400 MHz, CD3OD) δ ppm 8.06 (s, 1H), 7.87-7.92 (m, 3H), 7.60 (d, J=8.1 Hz, 2H), 6.39 (s, 1H), 4.43 (t, J=8.0 Hz, 1H), 3.85-3.92 (m, 2H), 3.21-3.29 (m, 2H), 3.09 (s, 3H), 2.18-2.26 (m, 1H), 1.98-2.06 (m, 1H), 1.62-1.75 (m, 2H), 1.30-1.51 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:9]=1[NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:4].N#N.[Cl:23][C:24]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>ClC(Cl)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][C:9]=1[N:10]([C:11]([CH3:14])([CH3:12])[CH3:13])[C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:24]=1[Cl:23])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1NC(C)(C)C
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: N#N
Solvent: CC(Cl)Cl
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)c1ccc(Cl)cc1Cl)C(C)(C)C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
To a solution of 3-tert-Butylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester (100 mg, 0.35 mmol) in dichloroethane (10 ml) in an atmosphere of N2 was added 2,4-dichloro-benzoyl chloride (79 mg, 0.38 mmol). The reaction mixture was stirred for 16 h at reflux. Then, the solvents were removed and the residue was purified by flash chromatography (9:1 Hexane/EtOAc) to obtain 112 mg (69%) of 3-[tert-Butyl-(2,4-dichloro-benzoyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): 7.50 ppm (m, 2H, Haro) 7.44-7.34 ppm (m, 3H, Haro); 7.27 ppm (s, 1H, Haro); 7.18 ppm (dl, 1H, Haro); 7.14 ppm (d, 1H, Haro); 7.00 ppm (dd, 1H, Haro); 3.93 ppm (s, 3H); 1.56 ppm (s, 9H).
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[N:8][CH:7]=1)=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:14]>N1C=CC=CC=1>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:5]2[S:14][CH:1]=[N:3][N:4]=2)[CH:7]=1
Reactant: O=CNNC(=O)c1cccnc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: c1cncc(-c2nncs2)c1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a solution of 22 g of N'-formylnicotinic acid hydrazide in 150 ml of pyridine are added, in portions, 28 g of phosphorus pentasulfide. During this addition the temperature rises to 65° C. After 5 minutes the mixture is heated to 110° C. and stirred for 2 hours at this temperature. The pyridine is then distilled off in a water jet vacuum. The residue is taken up in chloroform and the solution is extracted with a 5% sodium hydroxide solution and water. The organic phase is dried and the solvent is removed by evaporation, affording 2-(3-pyridyl)-1,3,4-thiadiazole as a pale yellow powder with a melting point of 78°-79° C.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH:7]=[CH:8][N:9]=1.[H-].[Na+].Cl[CH2:24][C:25]1[N:26]=[C:27](/[CH:30]=[CH:31]/[C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=2[F:39])[O:28][CH:29]=1>>[F:38][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([F:39])[C:32]=1/[CH:31]=[CH:30]/[C:27]1[O:28][CH:29]=[C:25]([CH2:24][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][CH2:11][CH2:10][N:6]3[CH:7]=[CH:8][N:9]=[C:5]3[CH2:4][CH2:3][S:2][CH3:1])=[CH:15][CH:16]=2)[N:26]=1
Reactant: CSCCc1nccn1CCCCc1ccc(O)cc1
Reactant: Fc1cccc(F)c1/C=C/c1nc(CCl)co1
Agent: [H-]
Agent: [Na+]
Product: CSCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3c(F)cccc3F)n2)cc1
Yield: 72.4 %

Procedure:
Using 4-[4-[2-[2-(methylsulfanyl)ethyl]-1H-imidazol-1-yl]butyl]phenol (300 mg), 65% sodium hydride (63.1 mg) and 4-chloromethyl-2-[(E)-2-(2,6-difluorophenyl)ethenyl]-1,3-oxazole (290 mg), the same reaction as Example 11-(i) was carried out to yield the titled compound (381 mg) as a colorless amorphous form.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][C:25](O)=[O:26].C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][C:25]([N:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[CH2:9][CH2:10]1)=[O:26]
Reactant: COc1ccc(CC(=O)O)c(OC)c1
Reactant: Cc1ccccc1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1ccc(CC(=O)N2CCN(c3ccccc3C)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(2-methylphenyl)piperazine (.087 g, 0.41 mmol) and 2,4-dimethoxyphenylacetic acid (0.096 g, 0.49 mmol) were dissolved in 20 DMF (5 ml) and treated with EDC (0.091 g, 0.47 mmol) and HBT (0.071 g, 0.52 mmol). Triethylamine was added to the stirred mixture to bring the pH (moistened E. Merck colorpHast indicator) to ca. 9. The mixture was stirred at ambient temperature for 18 hours, then concentrated in vacuo. The residue was taken up in ethyl acetate, and the ethyl acetate layer was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and the filtrate was concentrated to dryness in vacuo. The residue was chromatographed on silica gel eluted with 1.5% methanol in methylene chloride. The combined product fractions were evaporated to dryness in vacuo to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[CH:11]1(N=C=NC2CCCCC2)CCCC[CH2:12]1.CCO>CN(C=O)C.CN(C)C1C=CN=CC=1>[CH2:11]([O:9][C:8](=[O:10])[C:7]1[C:2]([Cl:1])=[CH:3][CH:4]=[N:5][CH:6]=1)[CH3:12]
Reactant: O=C(O)c1cnccc1Cl
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.8 %

Procedure:
To a solution of 4-chloro-nicotinic acid (2.5 g, 15.9 mmol) in DMF (26 mL)), were added Dicyclo-hexylcarbodiimide (DCC) (7.75 g, 37.5 mmol), 4-dimethylaminopyridine (DMAP) (0.286 g, 2.1 mmol) and EtOH (2.6 mL, 46.8 mmol). The reaction mixture was stirred at room temperature for 4 h. The mixture was then distilled (0.1 mmHg) to afford 1.5 g (51%) of 4-chloro-nicotinic acid ethyl ester as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]2[NH:9][N:10]=[CH:11][C:3]=12.C(=O)([O-])[O-].[Na+].[Na+].O>C(#N)C.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>[Cl:8][C:6]1[N:5]=[C:4]2[NH:9][N:10]=[CH:11][C:3]2=[CH:2][N:7]=1
Reactant: Clc1nc(Cl)c2cn[nH]c2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Clc1ncc2cn[nH]c2n1
Temperature: 80 °C

Procedure:
4,6-Dichloro pyrazolo[3,4-d]pyrimidine intermediate 27 and an aryl boronic acid or pinacol ester (1 eq) are suspended in acetonitrile, and sodium carbonate (3 eq, 80 mg) in solution with water. Bis(triphenylphosphine)palladium(II) chloride (0.05 eq) is added. The reaction mixture is heated in microwave at about 80° C. for about 5 min. Water is added to the mixture, and the precipitated product is filtered and purified by column chromatography to yield the 4-aryl, 6-chloro pyrazolo[3,4-d]pyrimidine product 31. Substituents R1′ and R2′ may be R1 and R2 as defined, or protected forms or precursors thereof.