Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:4][S:3][CH2:2]1.[CH3:13][C@@H:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.C1C(CCCCC(O)=O)SSC1>[CH2:1]1[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[S:4][S:3][CH2:2]1.[CH3:13][C@@H:14]([NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)CCCCC1CCSS1
Agent: C[C@@H](N)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(O)CCCC[C@@H]1CCSS1
Yield: 101.6 %

Procedure:
A further 51.6 g (250 mmol) racemic alpha-lipoic acid were dissolved in the toluene/alpha-lipoic acid solution from B) and reacted at 40° C. with 47.3 g (390 mol) R-(+)-alpha-methylbenzylamine and worked up as described above under A). 83.2 g (254 mmol) R-alpha-lipoic acid-R-(+)-alpha-methylbenzylamine salt were obtained.
Reaction SMILES: [CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[C:10]([OH:18])(=[O:17])[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].C(OCC)(=O)C>CO>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3].[C:10]([O-:18])(=[O:17])[CH2:11][CH2:12][CH2:13][C:14]([O-:16])=[O:15]
Reactant: O=C(O)CCCC(=O)O
Agent: CN(C)C(=N)NC(=N)N
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C([O-])CCCC(=O)[O-]
Yield: 65.9 %

Procedure:
10.0 g of the metformin free-base and 3.98 g of glutaric acid were stirred in 100 ml of methyl alcohol at a temperature of 40° C., and then ethyl acetate was added thereto. The produced crystal was filtered and dried in hot air, thus obtaining 5.15 g (yield: 43.8%) of metformin glutarate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.BrBr.[Cl-].[Al+3].[Cl-].[Cl-].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: Fc1ccccc1
Reactant: N#CCc1ccc(F)cc1
Agent: BrBr
Agent: Cl
Agent: [Al+3]
Product: N#CC(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
70 Parts of 4-fluorobenzeneacetonitrile were heated at 120° C. and there were added dropwise 83 parts of bromine and stirring was continued for 30 minutes. The resulting reaction mixture was added dropwise to a stirred mixture (room temperature) of 85 parts of aluminium chloride and 200 parts of fluorobenzene (exothermic reaction: temperature rises to 50° C.). After stirring for 30 minutes at 50° C., the reaction mixture was poured onto a mixture of crushed ice and 75 parts of hydrochloric acid solution. The product was extracted with methylbenzene. The extract was dried and evaporated. The residue was crystallized twice from 2-propanol, yielding 51 parts of 4-fluoro-α-(4-fluorophenyl)benzeneacetonitrile, mp. 63.5° C. (intermediate 13).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)[CH:5]=[N:6][CH:7]=1.Cl.[NH2:19][CH2:20][CH:21]1[CH2:23][CH2:22]1.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH:19][CH2:20][CH:21]2[CH2:23][CH2:22]2)=[O:13])[CH:5]=[N:6][CH:7]=1
Reactant: O=C(O)c1cccnc1Oc1cncc(Cl)c1
Reactant: NCC1CC1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCC1CC1)c1cccnc1Oc1cncc(Cl)c1
Yield: 61 %

Procedure:
To a stirred solution of 2-(5-chloro-pyridin-3-yloxy)-nicotinic acid (0.200 grams, 0.88 mmole), aminomethylcyclopropane hydrochloride (0.094 grams, 0.88 mmole), triethylamine (0.089 grams, 0.88 mmole) and 1-hydroxybenzotriazole hydrate (0.119 grams, 0.88 mmole) in dry dimethylformamide (3 ml) was added 1-(3-dimethylamino)-propyl)-3-ethylcarbodiimide hydrochloride (0.164 grams, 0.96 mmole) and stirred over night. The mixture was poured into 100 ml water and extracted with ethyl acetate. The combined organics were washed with 1 N NaOH, water and brine, dried over MgSO4, filtered and concentrated to give an oil that was purified by chromatography on silica gel eluting with 2.5% methanollmethylene chloride. Recrystalization from ethyl acetate/hexane gave a white solid (0.163 g). M.P. 105-107° C.; Anal. calcd. for C15H14N3O2Cl: C, 59.31;H, 4.65; N, 13.83. Found: C, 59.41;H, 4.68; N, 13.44.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[C:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:24]=[CH:25][CH:26]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>O1CCOCC1.O.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[O:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[N:5]1[CH:6]=[C:2]([C:25]2[CH:24]=[C:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:22]=[CH:21][CH:26]=2)[CH:3]=[N:4]1
Reactant: Brc1cnn(C2CCCCO2)c1
Reactant: CCOC(=O)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Cc1cccc(-c2cnn(C3CCCCO3)c2)c1
Temperature: 80 °C
Reaction time: 14 h

Procedure:
A mixture of 4-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole (5 g, 21.6 mmol), ethyl [3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetate (6.5 g, 22.7 mmol), sodium carbonate (7 g, 64.8 mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.513 g, 0.648 mmol) in dioxane (60 mL) and water (30 mL) was stirred at 80° C. for 14 hours. After allowing to cool to room temperature, ethyl acetate and water were added to the mixture, and the resultant mixture was filtered. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford ethyl {3-[1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]phenyl}acetate as an oil.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O>>[CH3:19][O:18][C:11]1[C:10]([CH:2]2[N:1]([CH2:28][C:27]3[CH:30]=[CH:31][CH:32]=[C:25]([C:21]4[S:20][CH:24]=[CH:23][N:22]=4)[CH:26]=3)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]2)=[C:15]([O:16][CH3:17])[CH:14]=[CH:13][N:12]=1
Reactant: O=Cc1cccc(-c2nccs2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)ccnc1OC
Product: COc1ccnc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2nccs2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,4-dimethoxypyridin-3-yl)pentanoate with commercially available 3-(thiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.68 min.; [M+H]+: 409.86 g/mol.
Reaction SMILES: N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[CH:31][CH:30]=[CH:29]2)=[CH:24][CH:23]=1.[C:33]([O:37][C:38]([NH:40][NH2:41])=[O:39])([CH3:36])([CH3:35])[CH3:34]>[Cu](I)I.CN(C=O)C>[C:33]([O:37][C:38]([N:40]([C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[CH:31][CH:30]=[CH:29]2)=[CH:24][CH:23]=1)[NH2:41])=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NN
Reactant: Ic1ccc(-n2cccc2)cc1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(N)c1ccc(-n2cccc2)cc1
Temperature: 80 °C
Reaction time: 21 h

Procedure:
Copper iodide (18 mg, 0.05 eq, 0.09 mmol), 1,10-phenanthroline (67 mg, 0.2 eq, 0.37 mmol) and caesium carbonate (0.85 g, 1.4 eq, 2.6 mmol) were mixed in a RB flask, placed under vacuum and purged with N2 (g). 1-(4-iodo-phenyl)-1H-pyrrole (0.5 g, 1.0 eq, 1.86 mmol), hydrazine carboxylic acid tert-butyl ester (0.3 g, 1.2 eq, 2.23 mmol) and DMF (25 ml) were added to the mixture which was then heated to 80° C. with stirring under an inert atmosphere for 21 hours. The reaction mixture was allowed to cool and was then filtered through a silica pad, which was then washed with ethyl acetate. The filtrate was then concentrated to dryness in vacuo. The resultant residue was purified by column chromatography using heptane/ethyl acetate (3:1) as eluent to yield the title compound as an off white-solid (0.32 g, 1.16 mmol, 62%). LCMS: [M+H]+=274, 94% purity
Reaction SMILES: [CH:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].N1C=CC=CC=1.[CH2:24]([O:30][C:31](Cl)=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CC(N(C)C)=O>[CH2:24]([O:30][C:31]([NH:15][C:14]1[CH:16]=[CH:17][N:10]([C@@H:1]2[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]2[OH:3])[C:11](=[O:12])[N:13]=1)=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: Nc1ccn(C2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Reactant: CCCCCCOC(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: CCCCCCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.5 %

Procedure:
To a solution of 4.0 g of arabinofuranosylcytosine dissolved in 50 ml of dimethylacetamide, there are added 3.0 g of pyridine and 4.06 g of n-hexylchloroformate. The reaction is carried out by stirring the mixture at room temperature for 3 hours. After the reaction is over, dimethylacetamide is evaporated under reduced pressure. The residue is diluted with 100 ml of cold water and the mixture is stirred under ice-cooling for one hour. The precipitated solids are filtrated and dried. The resultant white powders are washed with ethyl ether to obtain 2.9 g of N4 -hexyloxycarbonyl-1-β-D-arabinofuranosylcytosine (Yield:47%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([CH3:10])[C:8]=1[NH2:9])[CH3:2].[OH-].[K+].Br[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].Cl>CS(C)=O>[CH3:10][C:7]1[CH:6]=[C:5]([O:11][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:4]=[C:3]([CH2:1][CH3:2])[C:8]=1[NH2:9]
Reactant: CCOC(=O)CCCCBr
Reactant: CCc1cc(O)cc(C)c1N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOC(=O)CCCCOc1cc(C)c(N)c(CC)c1
Temperature: 15 °C
Yield: 71.4 %

Procedure:
500 ml of dimethyl sulfoxide (DMSO) are introduced at room temperature and, while stirring vigorously, 52.1 g (338.6 mmol) of the 3-ethyl-4-amino-5-methylphenol prepared in stage 2 are added in small portions. The mixture is cooled to 15° C. Then 33.5 g (507.9 mmol) of aqueous 85% strength potassium hydroxide solution are added dropwise so that the reaction temperature does not exceed 20° C. Then 82.7 ml (507.9 mmol) of ethyl 5-bromovalerate are added dropwise over the course of 70 minutes, maintaining the reaction temperature at 25° C. After a homogeneous solution has formed it is added to a mixture of 130 ml of 4M hydrochloric acid and ice and stirred well. The aqueous mixture is washed with diethyl ether. The aqueous phase is then made alkaline with 2M NaOH and extracted with diethyl ether, and the ether phase is washed twice with water and then with saturated brine, dried over sodium sulfate and concentrated. 67.5 g of a viscous oil are obtained and purified by vacuum distillation. Yield 31.7 g (33.7% of theory), boiling point 151°-152° C./10-2Torr.
Reaction SMILES: S(Cl)(Cl)=O.C(O[C:8]([C:10]1[C:11]([NH:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[CH:22]3)=[N:12][C:13]([S:16][CH3:17])=[N:14][CH:15]=1)=[O:9])C.[CH3:28][NH:29][CH2:30][CH2:31][OH:32].[OH-].[Na+]>CO.O.CN(C)C=O.C(Cl)Cl>[OH:32][CH2:31][CH2:30][N:29]([CH3:28])[C:8]([C:10]1[C:11]([NH:18][C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[NH:24][N:23]=[CH:22]3)=[N:12][C:13]([S:16][CH3:17])=[N:14][CH:15]=1)=[O:9]
Reactant: CNCCO
Reactant: CCOC(=O)c1cnc(SC)nc1Nc1ccc2[nH]ncc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ncc(C(=O)N(C)CCO)c(Nc2ccc3[nH]ncc3c2)n1
Reaction time: 0.08 h
Yield: 45 %

Procedure:
To the solution of methylene chloride (120 ml) was added N,N-dimethylformamide (1.1 ml) and thionyl chloride (1.2 ml) and refluxed for 2 hr. The solution was added 4-(1H-5-indazolylamino)-2-methylthio-5-pyrimidinecarboxylic acid ethyl ester (3 g) prepared from preparation example 3, and refluxed for 10 hr. The reaction mixture was cooled and slowly added 2-(methylamino)ethanol (4 ml) at 0˜5° C. and stirred for 1 hr. The reaction mixture was added methanol (80 ml), stirred 5 min. and then filtered for removing impurity. The filtrate was concentration by evaporation under pressure and it was obtained a solid product. The solid product in methanol: H2O=1:1 was added aq. 3N NaOH (3 ml), stirred for 1 hr, filtered and washed with H2O. The desired compound (1.61 g. 45%) was obtained by recrystallization with methylene chloride:isopropyl ether=1:4.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][N:10](C)[CH2:9][C@H:8]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C@@H:7]2[CH2:12][CH2:11][N:10]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:9][C@H:8]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:20][CH:21]=1
Reactant: CCOC(=O)Cl
Reactant: CN1CC[C@@H](Oc2ccc(Cl)cc2)[C@H](c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)N1CC[C@@H](Oc2ccc(Cl)cc2)[C@H](c2ccccc2)C1
Reaction time: 64 h

Procedure:
A mixture of 10.26 g of trans-4-(4-chlorophenoxy)-1-methyl-3-phenylpiperidine of Example 26, 7.05 g of anhydrous potassium carbonate, 75 ml of dry benzene and 5.53 g of ethyl chloroformate is refluxed for 18 hours under nitrogen. The mixture is then partitioned between distilled water and hexane. The organic phase is washed with water, the combined aqueous extracts are extracted with hexane, the combined organic extracts are washed with saturated aqueous NaCl solution, dried over anhydrous MgSO4, and concentrated in vacuo to afford an oil which almost completely crystallizes after standing for about 64 hours. The colorless solid is triturated with hexane, filtered and washed well with hexane to afford trans-4-(4-chlorophenoxy)-1-ethoxycarbonyl-3-phenylpiperidine, m.p. s 80°, 81.5°-84° C.
Reaction SMILES: NC1C=CC=CC=1.C(OC([O:14][C@@H:15]([C@H:17]1[C:32](=[O:33])[N:19]2[C:20]([C:26]([O:28]CC=C)=[O:27])=[C:21]([CH2:24]O)[C@H:22]([CH3:23])[C@H:18]12)[CH3:16])=O)C=C.C(OC([N:40]([CH2:45][C:46]1[S:50][C:49]2=[CH:51][N:52]=[CH:53][N:48]2[C:47]=1[CH3:54])[S:41]([NH2:44])(=[O:43])=[O:42])=O)C=C>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].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:14][C@@H:15]([C@H:17]1[C:32](=[O:33])[N:19]2[C:20]([C:26]([O-:28])=[O:27])=[C:21]([CH2:24][N:52]3[CH:51]=[C:49]4[S:50][C:46]([CH2:45][NH:40][S:41]([NH2:44])(=[O:42])=[O:43])=[C:47]([CH3:54])[N+:48]4=[CH:53]3)[C@H:22]([CH3:23])[C@H:18]12)[CH3:16]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Reactant: C=CCOC(=O)N(Cc1sc2cncn2c1C)S(N)(=O)=O
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Nc1ccccc1
Product: Cc1c(CNS(N)(=O)=O)sc2cn(CC3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)c[n+]12
Yield: 10 %

Procedure:
The same procedure as in Example 1 was repeated except that in a deprotective reaction, two catalysts, i.e., 23.4 mg of tris(dibenzylideneacetone)dipalladium and 59.1 mg of tetrakis(triphenylphosphine)palladium were used, 0.14 ml of aniline was used as a trapping agent, and 110.3 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 196 mg of 2-[N-allyloxycarbonyl-N-(aminosulfonyl)amino]methyl-3-methylimidazo[5,1-b]thiazole were used, thereby obtaining 14.2 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH3:33])[NH2:27])[CH3:22].Cl>C(O)CCC>[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[N:3]=[CH:4][C:5]3[CH:10]=[CH:9][N:8]([C:11]4[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=4)[C:6]=3[N:7]=2)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH3:33])[CH3:22]
Reactant: CCOc1ccc(N)cc1OCC
Reactant: CS(=O)(=O)c1ccc(-n2ccc3cnc(Cl)nc32)cc1
Agent: Cl
Solvent: CCCCO
Product: CCOc1ccc(Nc2ncc3ccn(-c4ccc(S(C)(=O)=O)cc4)c3n2)cc1OCC
Temperature: 140 °C

Procedure:
To a suspension of 2-chloro-7-(4-methanesulfonyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidine (30.0 mg, 0.093 mmol) in BuOH (1.5 mL) is added 3,4-diethoxyaniline (41.0 mg, 0.220 mmol) and concentrated aqueous HCl (37%, 23.0 μL, 0.232 mmol). The reaction mixture is heated to 140° C. for 24 h, cooled to rt, and concentrated under reduce pressure. The residue is purified by reverse phase prep-HPLC (Waters) to afford the title compound (1) as a yellow solid. HPLC: tR=1.61 min (Method A); MS-ES: (M+H)+=453.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[C:9]3[CH:16]=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:17][C:18]1[C:27]2[CH:26]=[CH:25][C:24]([CH3:28])=[C:23]([NH2:29])[C:22]=2[CH:21]=[CH:20][N:19]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[N:11]1[C:10]2[NH:14][CH:15]=[CH:16][C:9]=2[C:8]([C:7]2[C:2]([NH:29][C:23]3[C:22]4[CH:21]=[CH:20][N:19]=[C:18]([Cl:17])[C:27]=4[CH:26]=[CH:25][C:24]=3[CH3:28])=[N:3][CH:4]=[CH:5][CH:6]=2)=[N:13][CH:12]=1
Reactant: Cc1ccc2c(Cl)nccc2c1N
Reactant: Fc1ncccc1-c1ncnc2[nH]ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2c(Cl)nccc2c1Nc1ncccc1-c1ncnc2[nH]ccc12
Temperature: 22 °C
Reaction time: 4 h
Yield: 72.9 %

Procedure:
A mixture of 4-(2-fluoropyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (2.17 g, 10.1 mmol) and 1-chloro-6-methylisoquinolin-5-amine (1.95 g, 10.1 mmol) in THF (4 mL) was sonicated for 3 min until throughly mixed. Lithium bis(trimethylsilyl)amide (7.63 g, 45.6 mmol) (1 N in THF from Aldrich) was added in a stream and the resulting dark brown solution was stirred at 22° C. for 4 h. The reaction was quenched with NaHCO3 (aq., sat.) while cooled in an ice bath. The reaction mixture was then partitioned between EtOAc and NaHCO3 (aq., sat). The aqueous layer was washed with EtOAc twice. The organic layers were combined and concentrated in vacuo. The light brown solid residue was triturated with EtOAc (˜50 mL) to give a yellow solid. This solid was collected by filtration and washed with EtOAc twice and then dried in a vacuum oven (45° C.) over the weekend to give N-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyridin-2-yl)-1-chloro-6-methylisoquinolin-5-amine as a yellow solid (2.85 g, 73% yield). MS (ESI, pos. ion) m/z: 387 [M+H]+
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:8][CH:7]=1)(=[NH:4])[CH2:2][CH3:3].Br.Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=1)=O>>[CH2:2]([C:1]1[N:5]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:8][CH:7]=2)[CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[N:4]=1)[CH3:3]
Reactant: CCC(=N)Nc1ccc(CCNC(=O)OC(C)(C)C)cc1
Reactant: Cc1cccc(C(=O)CBr)n1
Agent: Br
Product: CCc1nc(-c2cccc(C)n2)cn1-c1ccc(CCNC(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 4 of Example 26 from tert-butyl 2-[4-(propanimidoylamino)phenyl]ethylcarbamate and 2-bromo-1-(6-methylpyridin-2-yl)ethanone hydrobromide (J. Med. Pharm. Chem., 1961, 3, 561). MS (ESI) m/z 407 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)=O.[F:20][C:21]([F:29])([F:28])[C:22](=[O:27])[CH2:23][C:24](=O)[CH3:25]>C(O)(=O)C.S(=O)(=O)(O)O>[Cl:19][C:14]1[CH:13]=[C:12]([C:10]2[C:23]([C:22](=[O:27])[C:21]([F:29])([F:28])[F:20])=[C:24]([CH3:25])[N:1]=[C:2]3[S:6][C:5]4[CH2:7][CH2:8][CH2:9][C:4]=4[C:3]=23)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Nc1sc2c(c1C(=O)c1ccc(Cl)c(Cl)c1)CCC2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1nc2sc3c(c2c(-c2ccc(Cl)c(Cl)c2)c1C(=O)C(F)(F)F)CCC3
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 13.1 %

Procedure:
To a stirred solution of 50 mg (0.16 mmol) (2-amino-5,6-dihydro-4H-cyclopenta[b]thiophen-3-yl)-(3,4-dichloro-phenyl)-methanone in 2 ml acetic acid was added 0.020 ml (0.17 mmol) of 1,1,1-trifluoro-pentane-2,4-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 10:1) afforded 9 mg (14%) 1-[4-(3,4-dichloro-phenyl)-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]-2,2,2-trifluoro-ethanone as a yellow solid. ES-MS m/e (%): 430 (M+H+, 100).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:17]2[CH2:16][CH2:15][N:14]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[OH:6][C:7]1[C:17]2[CH2:16][CH2:15][N:14]([C:18](=[O:23])[C:19]([F:22])([F:20])[F:21])[CH2:13][CH2:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: COc1cccc2c1CCN(C(=O)C(F)(F)F)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(N1CCc2cccc(O)c2CC1)C(F)(F)F
Temperature: 25 °C
Yield: 93.8 %

Procedure:
To a 1M solution of BBr3 (1.1 L, 1.6 equiv.), cooled at 0° C. with an ice-water bath, add 6-methoxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (187 g, 0.684 mol) in DCM (200 mL) over 1 h., while maintaining the temperature between 0° C. and 10° C. Warm the reaction mixture to ambient temperature and stir until HPLC indicates completion of the reaction (about 2 h.). Cool the solution to 0° C. and transfer it via cannula into an ice/water solution (1.2 L), thereby precipitating the product as a white solid. Add EtOAc (2 L) to dissolve most of the precipitate, separate the layers and concentrate the organic layer in vacuo. Extract the aqueous layer three times with EtOAc (2×2 L, 1×1 L). Wash the combined organic layers with water (2 L), and then brine (2 L), dry over Na2SO4, filter and concentrate in vacuo to give the desired intermediate as a light yellow solid (166.3 g, 94%). Use the product for the next step without further purification. Prepare an analytical sample by chromatography on silica gel eluting with 40% diethyl ether in hexane: mp 183.0-185.2° C. 1H NMR (300 MHz, DMSO-d6), δ 9.39 (s, 1H), 6.94-6.88 (m, 1H), 6.72-6.68 (m, 1H), 6.61-6.57 (m, 1H), 3.67-3.32 (m, 4H), 2.99-2.86 (m, 4H); 13C NMR (300 MHz, DMSO-d6), 154.50, 141.47, 141.18, 126.77, 126.64, 125.77, 125.33, 120.38, 120.32, 118.49, 114.67, 113.64, 113.47, 47.31, 47.27, 47.00, 46.96, 45.83, 45.49, 36.17, 34.93, 26.46, 25.18, 20.66, 14.00; MS (ES+) m/z 260 (M+H)+; Anal. Calc'd. for C12H12F3NO2: C, 55.60; H, 4.67; N, 5.40. Found: C, 55.51; H, 4.71; N, 5.29.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1.[CH2:14]([Sn:18](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH3:17]>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([Sn:18]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:14][CH2:15][CH2:16][CH3:17])=[N:8][CH:9]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1ccc(Br)nc1
Agent: [Li]CCCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Temperature: 25 °C
Yield: 58.4 %

Procedure:
n-Butyllithium (12.8 ml, 2.5M in hexanes, 32.6 mmol) was added dropwise to a cooled (−78° C.) solution of 2-bromo5-methylpyridine (5.0 g, 29.1 mmol), and the solution stirred for an hour. Tri-n-butyltin chloride (9.5 ml, 34.9 mmol) was then added and the reaction allowed to warm to room temperature, and stirred for 18 hours. The reaction mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel using an elution gradient of pentane:ethyl acetate (100:0 to 90:10) to give the title compound, (6.5 g, 58%) as a yellow oil.