Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[N:10]2[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2].[Cl:16]N1C(=O)CCC1=O.FC(F)(F)C(O)=O.C(OCC)(=O)C>C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[C:1]([C:6]1[N:10]2[C:11]([CH2:15][Cl:16])=[CH:12][CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cnc2cccc(C)n12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc2cccc(CCl)n12
Temperature: 25 °C
Reaction time: 14 h
Yield: 69.6 %

Procedure:
To a solution prepared by dissolving 430 mg (2.06 mM) of 3-carbethoxy-5-methylimidazo[1,2-a]pyridine in 10 ml of ethyl acetate was added 330 mg (2.67 mM) of N-chlorosuccinimide. Then, 1.03 ml (1.03 mM) of 1N-tri-fluoroacetic acid-ethyl acetate was added dropwise at room temperature. The mixture was stirred under argon gas at room temperature for 14 hours. After the reaction, the reaction mixture was poured in 30 ml of saturated aqueous NaHCO3 solution with ice-cooling and the mixture was extracted with 20 ml of ethyl acetate. The organic layer was washed with 30 ml of saturated aqueous NaCl solution and dried over MgSO4. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluent: ethyl acetate) to provide 350 mg (yield 71.2%) of the title compound as yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[NH:20][C:5]2=[N:6][C:7]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[Cl:30].C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C>[Cl:30][C:24]1[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][N:20]1[C:5]2=[N:6][C:7]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[C:4]2[N:3]=[C:2]1[CH3:1]
Reactant: COC(=O)c1cc(N2CCOCC2)nc2[nH]c(C)nc12
Reactant: Clc1cccc(CBr)c1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)nc2c1nc(C)n2Cc1cccc(Cl)c1Cl
Temperature: 25 °C
Yield: 78 %

Procedure:
A mixture of methyl 2-methyl-5-morpholino-3H-imidazo[4,5-b]pyridine-7-carboxylate (200 mg, 0.72 mmol), 1-(bromomethyl)-2,3-dichlorobenzene), prepared as described in Example 3, step f, (259 mg, 1.08 mmol and Na2CO3 (229 mg, 2.16 mmol) in DMF (10 mL) was stirred at 80° C. for 16 h. The reaction mixture was cooled to room temperature and poured into water (100 mL). It was extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (100 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with MeOH/DCM=1/60 to afford the desired product as a black solid (243 mg, 78%); LC/MS: MS (ES+) m/e 435 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 2.46 (s, 3H), 3.40 (t, J=4.2 Hz, 4H), 3.67 (t, J=4.2 Hz, 4H), 3.92 (s, 3H), 5.50 (s, 2H), 6.60 (d, J=7.8 Hz, 1H), 7.06 (s, 1H), 7.27 (t, J=7.8 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:21]([O-])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)=[N:7][CH:6]=[CH:5]2.O.O.[Sn](Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>CCO>[NH2:21][C:3]1[C:2]([CH3:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[C:8]2[NH:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1
Reactant: Cc1ccc2c(Nc3ccc(C#N)cc3)nccc2c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(Nc3ccc(C#N)cc3)nccc2c1N
Temperature: 70 °C
Reaction time: 17 h
Yield: 70.5 %

Procedure:
A mixture of 4-(6-methyl-5-nitroisoquinolin-1-ylamino)benzonitrile (0.47 g, 1.5 mmol), tin(II) chloride dihydrate (1.8 g, 7.7 mmol) and absolute EtOH (50 mL) was stirred under N2 at 70° C. for 17 h. The crude reaction mixture was poured onto ˜100 mL ice. The resulting solution was treated with solid Na2CO3 to pH 10. The milky yellow suspension was extracted with EtOAc (3×150 mL). The combined EtOAc extracts were washed with saturated NaCl (100 mL), dried over Na2SO4, filtered and concentrated in vacuo to give 510 mg as a red solid. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (40 g), eluting with a gradient of 1% to 5% MeOH in CH2Cl2, to provide 4-(5-amino-6-methylisoquinolin-1-ylamino)benzonitrile (0.29 g, 68% yield) as a red solid. MS (ESI, pos. ion) m/z: 275 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH2:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][NH2:19])[CH3:12].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][NH:19][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:12]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCN1CCCC1CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCN1CCCC1CNC(=O)c1ccc(F)cc1
Reaction time: 20 h

Procedure:
Add 5.05 g (31.8 mmol) of p-fluorobenzoyl chloride drop-wise to a 0° C. solution of 4.08 g (31.8 mmol) of 1-ethyl-2-(aminomethyl)pyrrolidine and 3.85 (35.0 mmol) of sodium carbonate in 50 mL of water. Stir the resultant solution at 0° C. for about 30 minutes, then at room temperature for about 20 hr. Extract the resultant solution with methylene chloride (2×100 mL). Dry the combined extracts with Na2SO4 and evaporate the solvent to give the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:18][CH3:19])=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11](O)=[C:6]2[CH:5]=[N:4]1)[CH3:2].C(Cl)(=O)C([Cl:23])=O>ClCCl.C1(C)C=CC=CC=1>[Cl:23][C:11]1[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:9]([CH2:18][CH3:19])[N:8]=[C:7]2[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][C:6]=12
Reactant: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1O
Reactant: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1c(CC)nc2c(cnn2CC)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
Ethyl 1,6-diethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (0.10 g, 0.38 mmol, 1 equivalent, e.g. which can be as prepared in Intermediate 2C) was dissolved in dichloromethane (1.5 ml). Oxalyl chloride (0.07 ml, 0.10 g, 0.76 mmol, 2.0 equivalents) was added in one portion to the stirred solution. The reaction mixture, a solution, was stirred at room temperature for 2 hours, then was heated to 39° C. and stirred for 22.5 hours at this temperature, and then allowed to cool. The reaction mixture was diluted with toluene and then the solvent was removed in vacuo to give a brown oil which solidified on standing at room temperature to yield the title compound as a brown solid (0.086 g, about 80% theory yield). HPLC (5 min generic solvent gradient): TRET about 3.43. Mass Spectrum: Found: MH+ 282.1.
Reaction SMILES: [C:1]12([NH:11][C:12](=[O:30])[C:13]3[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([O:22]C(=O)C)=[C:15]([O:26]C(=O)C)[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.S(=O)(=O)(O)O.O>CO>[C:1]12([NH:11][C:12](=[O:30])[C:13]3[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([OH:22])=[C:15]([OH:26])[CH:14]=3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: CC(=O)Oc1cc(C(=O)NC23CC4CC(CC(C4)C2)C3)cc([N+](=O)[O-])c1OC(C)=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: O=C(NC12CC3CC(CC(C3)C1)C2)c1cc(O)c(O)c([N+](=O)[O-])c1
Yield: 88.8 %

Procedure:
A solution containing 1.2 g of the product obtained in Example 43 and a catalytic amount of sulfuric acid in 10 ml of methanol was refluxed for 3 h. 20 ml of water was added and on cooling 0.85 g (89.5%) of the desired product was crystallized, m.p. 207°614 208° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C([O:32][CH2:33][C:34](Cl)=[O:35])(=O)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[C@@H:19]([NH:21][C:33](=[O:32])[CH2:34][OH:35])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: C[C@H](N)[C@@H](Cc1ccccc1)Oc1ccc2c(cnn2-c2ccc(F)cc2)c1
Product: C[C@H](NC(=O)CO)[C@@H](Cc1ccccc1)Oc1ccc2c(cnn2-c2ccc(F)cc2)c1

Procedure:
Prepared as described in Example 64 using (2S,3R)-3-[1-(4-fluorophenyl)indazol-5-yl]oxy-4-phenyl-butan-2-amine (60 mg, 0.16 mmol) and acetoxyacetyl chloride (0.069 mL, 0.64 mmol). Yield 60 mg (87%).
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([N:13]([CH3:42])[C:14]([N:16]([CH3:41])[C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29](OC3C=CC([N+]([O-])=O)=CC=3)=[O:30])[CH2:18]2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1>>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([N:13]([CH3:42])[C:14]([N:16]([C@H:17]2[C@H:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:20][N:19]([C:29]([N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[O:30])[CH2:18]2)[CH3:41])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:43])[F:44])[CH:8]=1
Reactant: C1COCCN1
Reactant: CN(C(=O)N(C)[C@@H]1CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CN(C(=O)N(C)[C@@H]1CN(C(=O)N2CCOCC2)C[C@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
By reaction and purification in the same manner as in the method described in Example 420 and using the compound obtained in Example 362 and morpholine, the title compound was obtained.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)([O-])=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=1[CH2:21][CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:4]2[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:8][CH:9]=2)=[CH:16][C:15]=1[CH2:21][CH3:22]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Reactant: CCc1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCc1cc(Oc2cccc([N+](=O)[O-])c2)ccc1Cl
Temperature: 100 °C
Yield: 78.5 %

Procedure:
EX-8A) To a solution of 1,3-dinitrobenzene (16.8 g, 0.1 mol) and 4-chloro-3-ethylphenol (15.6 g, 0.1 mol) in 200 mL of dimethylsulfoxide was added cesium carbonate (65 g, 0.2 mol). The reaction mixture was heated at 100° C. under nitrogen overnight then cooled to room temperature. The reaction mixture was filtered through celite then rinsed with diethyl ether and a small amount of water. The filtrate was extracted several times with diethyl ether. The organic layers were combined, washed with water and brine, dried over MgSO4, and concentrated in vacuo to give 21.8 g (78%) of the desired 3-(4-chloro-3-ethylphenoxy)-1-nitrobenzene product as a dark orange oil, which was greater than 90% pure by reverse phase HPLC analysis. HRMS calcd. for C14H12ClNO3: 295.0849 [M+NH4]+, found 295.0862.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([Br:13])[CH:3]=1.[CH2:14]([O:16][C:17](=[O:29])[CH2:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([SH:27])=[CH:22][C:21]=1[CH3:28])[CH3:15].C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN1C(=O)CCC1>[CH2:14]([O:16][C:17](=[O:29])[CH2:18][O:19][C:20]1[CH:25]=[C:24]([CH3:26])[C:23]([S:27][C:2]2[CH:7]=[C:6]([O:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([Br:13])[CH:3]=2)=[CH:22][C:21]=1[CH3:28])[CH3:15]
Reactant: CCOC(=O)COc1cc(C)c(S)cc1C
Reactant: CC(C)COc1cc(Br)cc(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1cc(C)c(Sc2cc(Br)cc(OCC(C)C)c2)cc1C
Temperature: 140 °C
Reaction time: 1 h

Procedure:
1,3-Dibromo-5-isobutoxy-benzene (1.66 g; 5.4 mmol), (4-Mercapto-2,5-dimethyl-phenoxy)-acetic acid ethyl ester (1.0 g; 4.1 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.11 g; 0.12 mmol), and 1,1′-bis-(diphenylphosphineo)ferrocene (0.14 g; 0.25 mmol) were added to a dry reaction flask under an atmosphere of nitrogen. Triethylamine (2.3 mL) and NMP (10 mL) was added, and the reaction mixture was stirred in a microwave oven for 1 h at 140° C. A 5% aqueous citric acid solution (150 mL) was added to the reaction mixture, which was extracted with ethyl acetate (4×100 mL). The pooled organic phases were dried and evaporated in vacuo. The crude reaction product was purified by flash chromatography (heptane: ethyl acetate (10:1→1:1). Yield: 1.3 g; 67%. HPLC-MS: m/z: 467.0 (M+); Rt: 3.10 min
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N+]([O-])=O)[CH:6]=1.[CH3:25][P:26]([O:30]CC)[O:27][CH2:28][CH3:29]>C(#N)C>[CH3:25][P:26]([C:7]1[CH:6]=[C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([C:21]([F:24])([F:23])[F:22])=[CH:20][C:2]=2[Cl:1])[CH:10]=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12])(=[O:30])[O:27][CH2:28][CH3:29]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Reactant: CCOP(C)OCC
Solvent: CC#N
Product: CCOP(C)(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-(2-chloro-4-trifluoromethylphenoxy)-1,2-dinitrobenzene (0.9 g, 2.48 mmol), diethyl methylphosphonite (0.5 g, 3.72 mmol) and acetonitrile (3 ml) is stirred at room temperature overnight. The reaction mixture is concentrated to dryness, and the residue is purified by preparative thin layer chromatography (silica gel, eluting with 50% ethyl acetate/hexane) to give ethyl P-methyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinate.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]([CH:19]=O)=[O:18].Cl>C(O)(=O)C.C1(C)C=CC=CC=1>[C:11]([C:7]1[C:6](=[O:15])[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][C:9](=[CH:16][C:17](=[O:18])[CH3:19])[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: CC(=O)C=O
Agent: Cl
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(=O)C=C1C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C1
Yield: 2.9 %

Procedure:
4.12 g (0.02 Mol) of 2,6-di-tert-butylphenol and 4.0 g (0.022 mol) of 40% aqueous pyruvic aldehyde are dissolved in 20 ml of acetic acid. The solution is then saturated at 15°-25° C. with hydrogen chloride gas and stirred at room temperature for additional two hours. The mixture is then diluted with 200 ml of toluene, washed several times with water, dried over anhydrous sodium sulfate, and evaporated in vacuo. The oily residue is then chromatographed on silica gel with toluene. The pure fractions are recrystallized three times from methanol to give 0.15 g of the title compound as orange needles, melting at 70°-72° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([NH2:9])=[O:8].[H][H].C(O)C.[C:15]([OH:18])(=[O:17])[CH3:16]>[Pt]=O>[C:15]([OH:18])(=[O:17])[CH3:16].[C:15]([OH:18])(=[O:17])[CH3:16].[NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH:2]1[C:7]([NH2:9])=[O:8]
Reactant: NC(=O)c1cnccn1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: NC(=O)C1CNCCN1

Procedure:
One hundred twenty-five grams of pyrazinamide were hydrogenated in the presence of 2.5 L of 6:1 ethanol/acetic acid and 62.6 g of platinum oxide at 60 psi and 60° C. After hydrogen uptake ceased, the reaction mixture was filtered through a Celite® pad and concentrated in vacuo. Trituration with ethyl acetate afforded 219.57 g of the desired subtitle intermediate, m.p. 90-92° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(O)C.C(=O)([O-])[O-].C([N:21](C(C)C)CC)(C)C>C(#N)C>[N:5]1[C:4]2[S:8][CH:9]=[CH:10][C:3]=2[C:2]([NH2:21])=[N:7][CH:6]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1ncnc2sccc12
Agent: *CC(*)C
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: CCO
Product: Nc1ncnc2sccc12

Procedure:
An amine (VIII) is added to a solution of the 4-chlorothieno[2,3-d]pyrimidine (VII) in either ethanol or a mixture of acetonitrile and a base (for example an alkaline carbonate or diisopropylethylamine) in a closable bottle. The bottle is closed with a polypropylene cap, and heated overnight in a conventional oven at a temperature comprised between 40° and 120° C., preferably between 60 and 85° C. After cooling, the solvent is removed under reduced pressure, and the residue is purified by flash chromatography to provide the final thieno[2,3-d]pyrimidin-4-ylamine (I).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[N:9][N:8]([CH2:11][CH3:12])[C:7]=1[C:13]([OH:15])=O)=[O:5])[CH3:2].S(Cl)([Cl:18])=O>>[Cl:18][C:13]([C:7]1[N:8]([CH2:11][CH3:12])[N:9]=[CH:10][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:15]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cnn(CC)c1C(=O)O
Product: CCOC(=O)c1cnn(CC)c1C(=O)Cl
Yield: 100.1 %

Procedure:
2-Ethyl-2H-pyrazole-3,4-dicarboxylic acid 4-ethyl ester (example 62, step 3, 1.47 g, 6.93 mmol) and thionyl chloride (19.0 g, 11.6 ml, 159 mmol) were combined to give a light yellow solution. The reaction mixture was stirred at reflux for 5 h. Excess thionyl chloride was removed under reduced pressure, and residual thionyl chloride was removed under vacuum. The title compound (1.6 g, estimated purity 37%, 37% yield) was used without further purification in the next step. MS (m/e)=390.3 [M+H+].
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27]O)=[CH:22][CH:21]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH2:8]([C:20]1[CH:21]=[CH:22][C:23]([CH:26]=[CH2:27])=[CH:24][CH:25]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCc1ccc(CCO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C=Cc1ccc(CCCCCCCCCCCC)cc1
Temperature: 25 °C

Procedure:
A 2 l round-bottom flask which had been provided with a water separator and a reflux condenser was charged initially with 1.2 liters of toluene and then with (p-dodecylphenyl)methylcarbinol (50.082 g=0.173 mol) and p-toluenesulphonic acid monohydrate (0.679 g=3.6 mmol). The mixture was heated to reflux with constant stirring and kept at boiling until no further water separated out. Once the reaction mixture had been cooled to room temperature, the organic phase was extracted by shaking twice with 500 ml each time of water and once with 250 ml of saturated sodium chloride solution. After drying over magnesium sulphate, the solvent was drawn off on a rotary evaporator. A yellow oil was obtained. Subsequently, the two batches were combined. The crude product was purified by column chromatography on 400 g of silica gel 60 with hexane as the eluent, and a fraction size of 100 ml was selected.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21]O)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35].S(Cl)([Cl:38])=O.CN(C=O)C.C(=O)([O-])O.[Na+]>ClCCl>[Cl:38][CH2:21][C:20]1[CH:19]=[CH:18][N:17]=[C:16]2[N:23]([S:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[C:13]([C:9]3[C:7]4=[N:8][C:3]([O:2][CH3:1])=[C:4]([O:34][CH3:35])[CH:5]=[C:6]4[N:11]([CH3:12])[CH:10]=3)=[CH:14][C:15]=12
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CO)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(nc1OC)c(-c1cc3c(CCl)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Reaction time: 2 h

Procedure:
To a solution of 4.2 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]methanol in 50 cm3 of dichloromethane, at a temperature in the region of 20° C., are added 0.747 cm3 of thionyl chloride and 0.3 cm3 of DMF. The reaction medium is stirred at this same temperature for 2 hours. Ice is added and the reaction medium is then neutralized with saturated sodium hydrogencarbonate solution. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. After purification by flash-pack chromatography (SiO2, dichloromethane/ethyl acetate 95/05 by volume as eluents), 2.64 g of 3-[4-chloromethyl-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridine are obtained with the following characteristics:
Reaction SMILES: CO[CH:3](O)[CH2:4][N:5]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([F:15])[CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:16].CC(N([C@H]1CCNC[C@H]1O)C(=O)[O-])(C)C.[C:33]([O:37][C:38](=[O:47])[NH:39][C@H:40]1[CH2:45][CH2:44][NH:43][CH2:42][C@H:41]1[OH:46])([CH3:36])([CH3:35])[CH3:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[F:15][C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[CH:7][C:6](=[O:16])[N:5]2[CH2:4][CH2:3][N:43]2[CH2:44][CH2:45][C@H:40]([NH:39][C:38](=[O:47])[O:37][C:33]([CH3:34])([CH3:35])[CH3:36])[C@H:41]([OH:46])[CH2:42]2)=[N:10][CH:11]=1
Reactant: COC(O)Cn1c(=O)ccc2ncc(F)cc21
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC[C@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)N(C(=O)[O-])[C@H]1CCNC[C@H]1O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H]1CCN(CCn2c(=O)ccc3ncc(F)cc32)C[C@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(7-Fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde methyl hemiacetal (200 mg, 0.8396 mmol) and 1,1-dimethylethyl[(3R,4S)-3-hydroxy-4-piperidinyl]carbamate (for a synthesis see WO2004058144, Example 5(c), cis-(3-hydroxy-piperidin-4-yl)-carbamic acid tert-butyl ester Enantiomer 1) (182 mg, 1 eq.) were stirred in chloroform (10 ml) plus MeOH (0.5 ml) under argon for 2 hours. Sodium triacetoxyborohydride (534 mg, 3 eq.) was added in one portion and the mixture was stirred at rt overnight, then quenched by addition of saturated aqueous sodium hydrogen cabonate (20 ml) and extracted with 20% v:v MeOH in DCM (3×200 ml). The organic extractes were combined, dried over anhydrous magnesium sulphate, filtered and evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica, eluted with 0-20% (2M ammonia in MeOH) in DCM. Appropriate fractions were combined and evaporated under reduced pressure to give title compound (247 mg) as an off-white foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH2:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([C:36](O)=[O:37])=[CH:30]2>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][CH2:16][CH:17]([NH:25][C:36]([C:31]2[NH:32][C:33]3[C:29]([CH:30]=2)=[CH:28][C:27]([Cl:26])=[CH:35][CH:34]=3)=[O:37])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCC(N)c2ccccc2Cl)CC1
Product: CC(C)(C)OC(=O)N1CCC(COCC(NC(=O)c2cc3cc(Cl)ccc3[nH]2)c2ccccc2Cl)CC1

Procedure:
Using coupling method A, 4-[2-amino-2-(2-chlorophenyl)-ethoxymethyl]piperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.8 mmol) and 5-chloroindole-2-carboxylic acid (158 mg, 1.4 mmol) afforded, after purification (SiO2: 33% EtOAc in hexane), 407 mg (92%) of the title compound.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.O[C:21]1C=CC(C(OC)=O)=CC=1.C1(CO)CCCC1>>[CH:4]1([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:18][CH:19]=2)[CH2:1][CH2:3][CH2:2][CH2:21]1
Reactant: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: OCC1CCCC1
Product: O=C(O)CNC(=O)c1ccc(OCC2CCCC2)cc1
Yield: 35 %

Procedure:
Reactions similar to those described in Example 1 (1a) and (1b) were conducted using methyl 4-hydroxybenzoate (22.8 g, 150 mmol) and cyclopentylmethanol (10.0 g, 100 mmol) to give 9.3 g of the title compound (colorless crystal, yield: 35%).