Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([F:35])[C:29]=1[NH:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH2:6][NH:7][C:8](=[O:26])[CH:9]=[CH:10][C:11]1[C:12]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=1)#[CH:2].CO>[Pd]>[C:1]([C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([F:35])[C:29]=1[NH:30][S:31]([CH3:34])(=[O:32])=[O:33])[CH2:6][NH:7][C:8](=[O:26])[CH2:9][CH2:10][C:11]1[C:12]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)=[N:13][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:15][CH:16]=1)#[CH:2]
Reactant: C#Cc1cc(CNC(=O)C=Cc2ccc(C(F)(F)F)nc2N2CCCC2)cc(F)c1NS(C)(=O)=O
Agent: [Pd]
Solvent: CO
Product: C#Cc1cc(CNC(=O)CCc2ccc(C(F)(F)F)nc2N2CCCC2)cc(F)c1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 100.9 %

Procedure:
To a suspension of N-(3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-acrylamide (15 mg, 0.029 mmol) in 5% Pd/C (5 mg) was added CH3OH (1.0 ml). The mixture was purged three times with hydrogen gas (50 psi) and then shaken for 40 min at room temperature. The reaction mixture was filtered over celite pad and concentrated under reduced pressure. The crude residue was chromatographed to yield the N-(3-ethynyl-5-fluoro-4-methanesulfonylamino-benzyl)-3-(2-pyrrolidin-1-yl-6-trifluoromethyl-pyridin-3-yl)-propionamide (15 mg, 98%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[N:3]=1.CC1(C)C(C)(C)OB([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:29][CH:28]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>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].O>[CH:13]1([O:12][C:4]2[N:3]=[C:2]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=3)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: FC(F)(F)c1cc(Cl)nc(OC2CCCC2)n1
Reactant: COC(=O)Cc1ccc(CB2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)Cc1ccc(Cc2cc(C(F)(F)F)nc(OC3CCCC3)n2)cc1
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 61.5 %

Procedure:
A 20-mL sealed tube, with stirrer bar, was charged with 4-chloro-2-(cyclopentyloxy)-6-(trifluoromethyl)pyrimidine (0.400 g, 1.50 mol), methyl 2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate (0.478 g, 1.65 mmol), Pd(dppf)Cl2 (0.122 g, 0.15 mmol), and powdered Na2CO3 (0.477 g, 4.50 mmol). Dioxane (8 mL) and water (4 mL) were added. The resulting mixture was stirred under Ar at 90° C. for 2.5 h. After this time, the mixture was cooled to room temperature and filtered through celite washing with ethyl acetate until the filtrate was colorless. The aqueous layer was separated and the organic layer was washed with saturated sodium chloride (2×10 mL) then dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica using hexane/ethyl acetate (10:0 to 3:1) as eluent to afford the title compound (0.40 g, 67%) as a yellow oil. MW=394.39. 1H NMR (CDCl3, 300 MHz) δ 7.25 (s, 4H), 7.14 (s, 1H), 5.46 (septet, J=3.0 Hz, 1H), 4.08 (s, 2H), 3.69 (s, 3H), 3.62 (s, 2H), 2.04-1.73 (m, 6H), 1.72-1.56 (m, 2H); ESI MS m/z 327 [M-C5H9+2H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Cl:10][CH2:11][C:12](Cl)=[O:13]>C(Cl)Cl.N1C=CC=CC=1>[Cl:10][CH2:11][C:12]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9])=[O:13]
Reactant: Nc1cc(Cl)ccc1O
Reactant: O=C(Cl)CCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(CCl)Nc1cc(Cl)ccc1O
Reaction time: 18 h
Yield: 55 %

Procedure:
To a cooled (0° C.) solution of 2-amino-4-chlorophenol (30 g, 209 mmol) in DCM (200 mL) and pyridine (17 mL) was added a solution of chloroacetyl chloride in DCM (23.6 g, 230 mmol in 75 mL). The mixture was allowed to reach rt slowly and was subsequently stirred for 18 h. The precipitate was filtered, washed with DCM, and dried overnight at 50° C. to give crude 2-chloro-N-(5-chloro-2-hydroxyphenyl)acetamide (intermediate 56) (26 g, 55%), as a brown solid which was used in the next step without any further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:32]=1[CH2:33]Br>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][CH2:33][C:32]3[C:31]([Cl:30])=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:39])=[CH:18][CH:19]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Reactant: Clc1cccc(Cl)c1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Clc1cccc(Cl)c1CNc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
A mixture of 4-(4-benzyl-morpholin-2-yl)-phenylamine (0.82 g; 3.06 mmol), DIPEA (1.57 mL; 9.17 mmol) and 2,6-dichlorobenzyl bromide (0.88 g; 3.67 mmol) in MeOH (25 mL). was stirred at RT, overnight. The resulting mixture was partitioned between 5% aqueous NaHCO3 and EtOAc. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to afford [4-(4-benzyl-morpholin-2-yl)-phenyl]-(2,6-dichloro-benzyl)-amine (1.25 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:32])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](=[O:31])[CH3:30])=[CH:20][CH:19]=1)#[N:2].[BH4-].[Na+].C(Cl)(Cl)Cl>O1CCCC1.CO>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:32])[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]([OH:31])[CH3:30])=[CH:22][CH:23]=1)#[N:2]
Reactant: CC(=O)CCCCOc1ccc(C(=O)Nc2ccccc2Sc2ccccc2C#N)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(O)CCCCOc1ccc(C(=O)Nc2ccccc2Sc2ccccc2C#N)cc1
Reaction time: 1 h
Yield: 94.2 %

Procedure:
In 30 ml of tetrahydrofuran was suspended 3.33 g of N-[2-(2-cyanophenylthio)phenyl]-4-(5-oxohexyloxy)benz-amide (prepared in accordance with Reference Example 6, Step 2) followed by addition of a solution of 0.31 g of sodium borohydride in methanol, and the mixture was stirred for 1 hour. To the reaction mixture was added chloroform and the mixture was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate-n-hexane to give 3.15 g of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:16][CH:17]2[CH2:19][CH2:18]2)[C@H:11]([C:13]([OH:15])=O)[CH3:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:20]([NH2:22])[CH3:21]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]([CH2:16][CH:17]2[CH2:19][CH2:18]2)[C@H:11]([C:13]([NH:22][CH2:20][CH3:21])=[O:15])[CH3:12])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C[C@@H](C(=O)O)N(CC1CC1)c1ccc(C#N)c(Cl)c1
Reactant: CCN
Product: CCNC(=O)[C@H](C)N(CC1CC1)c1ccc(C#N)c(Cl)c1

Procedure:
Synthesized in a manner similar to example 3 using N-(3-chloro-4-cyanophenyl)-N-(cyclopropylmethyl)alanine and ethylamine: MS (ES) m/z 306 (M+1).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[S:11][CH:12]=1)(=O)=O.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:24][O:23][C:15]1[CH:14]=[C:13]([C:10]2[S:11][CH:12]=[C:8]([CH2:7][CH2:6][N:25]3[CH2:30][CH2:29][N:28]([CH2:6][CH2:7][C:8]4[N:9]=[C:10]([C:13]5[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=5)[S:11][CH:12]=4)[CH2:27][CH2:26]3)[N:9]=2)[CH:18]=[C:17]([O:19][CH3:20])[C:16]=1[O:21][CH3:22]
Reactant: C1CNCCN1
Reactant: COc1cc(-c2nc(CCOS(C)(=O)=O)cs2)cc(OC)c1OC
Product: COc1cc(-c2nc(CCN3CCN(CCc4csc(-c5cc(OC)c(OC)c(OC)c5)n4)CC3)cs2)cc(OC)c1OC

Procedure:
4-(2-Methanesulfonyloxyethyl)-2-(3,4,5-trimethoxy-phenyl)thiazole (164 mg) and piperazine (17 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [C:1]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][O:25][P:26]([OH:29])([OH:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(O)(=O)CCC/C=C\CC=CCC=CCC=CCC=CCC>>[C:1]([NH:22][C@H:23]([C:30]([OH:32])=[O:31])[CH2:24][O:25][P:26]([OH:29])([OH:28])=[O:27])(=[O:21])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH:8]=[CH:9][CH2:10][CH:11]=[CH:12][CH2:13][CH:14]=[CH:15][CH2:16][CH:17]=[CH:18][CH2:19][CH3:20]
Reactant: CCCCCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](COP(=O)(O)O)C(=O)O
Agent: CCC=CCC=CCC=CCC=CC/C=C\CCCC(=O)O
Product: CCC=CCC=CCC=CCC=CC/C=C\CCCC(=O)N[C@@H](COP(=O)(O)O)C(=O)O

Procedure:
This compound was prepared as described above for (6) using 0.5 mmol (151 mg) of cis-5,8,11,14,17-eicosapentaenoic acid; yield 84 mg, (36%); Rf 0.05-0.10 (system B); 1H-NMR (CD3SOCD3, 200 MHz) δ0.9-1.0 (t, 3H, ω-CH3); 1.5-1.6 (t, 2H, CH2); 2.0-2.2 (m, 6H, CH2CO and 2 CH2CH═CH); 2.7-2.9 (br s, 8H, 4HC═CH—CH2—CH═CH); 3.9-4.0 (br s, 2H, CH2OP); 4.34.4 (m, 1H, NH CHCO); 5.2-5.4 (br s, 10H, 5 HC═CH); 8.2-8.4 (m, 3H, NH and 2POH)
Reaction SMILES: [N:1]1([CH:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:23](Cl)(=[O:25])[CH3:24]>C(O)(=O)C>[N:1]1([CH:6]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:23](=[O:25])[CH3:24])=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(C(c2ccccc2)n2ccnc2)cc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(c2ccccc2)n2ccnc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 95 %

Procedure:
(a-4) A mixture of 1.45 parts of 4-[(1H-imidazol-1-yl)phenylmethyl]-2-nitrobenzenamine, 0.78 parts of acetyl chloride and 25 parts of acetic acid was stirred over weekend at room temperature. The methanol layer was removed in vacuo and the residue was taken up in water and dichloromethane. After treatment with ammonium hydroxide, the dichloromethane layer was dried, filtered and evaporated, yielding 1.6 parts (95%) of N-[4-[(1H-imidazol-1-yl)phenylmethyl]-2-nitrophenyl]-acetamide as a residue (int. 127).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:19]([O:21]CC=C)=[O:20])=[C:8]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[CH:13][N:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C(CCCC)C([O-])=O)C.[K+:56].C(OCC)C>ClCCl.C(OCC)(=O)C>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:19]([O-:21])=[O:20])=[C:8]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[CH:13][N:12]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[K+:56]
Reactant: C=CCOC(=O)C1=C(c2ncc3sccn23)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Agent: CCCCC(CC)C(=O)[O-]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3ncc4sccn34)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
To a solution of 40 mg of allyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(imidazo[5,1-b]thiazol-5-yl)-1-methyl-1-carbapen-2-em-3-carboxylate in 0.8 ml of dichloromethane and 0.8 ml of ethyl acetate were added under the atmosphere of argon 3.4 mg of triphenylphosphine, 29 mg of potassium 2-ethylhexanoate, 6.4 mg of tetrakis-triphenylphosphine palladium (0), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into diethyl ether, and the resulting precipitate was collected by filtration, and purified by column chromatography on COSMOSEAL 40C18-PREP (water:methanol=20:1) to give 13 mg of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]([CH3:20])([CH3:19])[CH:5]([C:13]1[S:14][C:15]([Br:18])=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[OH-].[K+]>CO.CS(C)=O>[Br:18][C:15]1[S:14][C:13]([CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[C:4]([CH3:20])([CH3:19])[C:3]([OH:21])=[O:2])=[CH:17][CH:16]=1
Reactant: COC(=O)C(C)(C)C(c1cccc(F)c1)c1ccc(Br)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: CC(C)(C(=O)O)C(c1cccc(F)c1)c1ccc(Br)s1
Temperature: 75 °C
Yield: 85.9 %

Procedure:
To a solution of 3-(5-bromo-thiophen-2-yl)-3-(3-fluoro-phenyl)-2,2-dimethyl-propionic acid methyl ester (419 mg, 1.128 mmol) in MeOH (4 ml) and DMSO (2 ml) was added a 40% aqueous solution of potassium hydroxide (4 ml). The reaction mixture was heated at 75° C. for 6 hours. After removal of methanol, the solution was adjusted to pH 2 and was extracted with ethyl ether. The ether layer was washed, dried and evaporated to give 3-(5-bromo-thiophen-2-yl)-3-(3-fluoro-phenyl)-2,2-dimethyl-propionic acid (1a) as a white glass (346.2 mg, 86% yield). 1H NMR (400 MHz, CDCl3): δ 1.06 (s, 3H), 1.15 (s, 3H), 3.21 (s, 1H), 6.75 (d, 1H, J=3.8 Hz), 6.82 (d, 1H, J=3.8 Hz), 6.87 (td, 1H, J=8.1, 2.6 Hz), 7.02 (m, 1H), 7.10 (br d, J=8.1 Hz), 7.20 (m, 1H). HPLC Rt: 3.695 min.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][N:5]([C:7]2[C:12]([F:13])=[CH:11][C:10]([N+:14]([O-])=O)=[CH:9][C:8]=2[F:17])[CH:6]=1.ClC1N=CN(C2C(F)=CC(N)=CC=2F)C=1>[Pd].CCO>[F:13][C:12]1[CH:11]=[C:10]([CH:9]=[C:8]([F:17])[C:7]=1[N:5]1[CH:6]=[CH:2][N:3]=[CH:4]1)[NH2:14]
Reactant: O=[N+]([O-])c1cc(F)c(-n2cnc(Cl)c2)c(F)c1
Agent: [Pd]
Agent: Nc1cc(F)c(-n2cnc(Cl)c2)c(F)c1
Solvent: CCO
Product: Nc1cc(F)c(-n2ccnc2)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 116.9 %

Procedure:
Step J (2): 10% Palladium on carbon (0.500 g) was added under an atmosphere of nitrogen to a solution of 4-chloro-1-(2,6-difluoro-4-nitrophenyl)-1H-imidazole (1.9 g, 7.32 mmol) in EtOH (30 mL). The flask was repeated evacuated and flushed with hydrogen gas (double balloon). The resulting mixture was allowed to warm to rt and left to stir for 1.5 h under the hydrogen atmosphere. Purged with nitrogen gas. Filtered the crude reaction mixture through a short plug of diatomaceous earth (Celite®). Rinsed reaction vessel and plug with methanol. Concentrated filtrate in vacuo. Dried residue on high vacuum overnight to afford a 1:1 mixture of 4-(4-chloro-1H-imidazol-1-yl)-3,5-difluoroaniline and 3,5-difluoro-4-(1H-imidazol-1-yl)aniline (1.67 g, ˜99% yield). LC-MS (M+H)+ 230.1 and 196.2.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]3)=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CO.[ClH:28].CCOC(C)=O>C1COCC1>[ClH:28].[ClH:28].[N:13]1([C:10]2[CH:11]=[N:12][C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)=[N:8][CH:9]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc(N3CCOCC3)nc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: c1nc(N2CCOCC2)ncc1N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 4-[2-(morpholin-4-yl)pyrimidin-5-yl]piperazine-1-carboxylate (1.42 g) was mixed with MeOH (20 ml) and THF (20 ml), and a 4M hydrogen chloride/EtOAc (10 ml) was added thereto, followed by stirring at room temperature overnight and then stirring for 30 minutes under ice-cooling. The precipitated solid was collected by filtration and washed with EtOAc to obtain 4-[5-(piperazin-1-yl)pyrimidin-2-yl]morpholine dihydrochloride (1.15 g).
Reaction SMILES: O=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:5]=2[N:4]=[CH:3]1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[S:10][C:5]2=[N:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cc2[nH]c(=O)cnc2s1
Product: COC(=O)c1cc2nc(Cl)cnc2s1
Yield: 78.5 %

Procedure:
A solution of methyl 2-oxo-1,2-dihydrothieno[3,2-b]pyrazine-6-carboxylate 21 (0.35 g, 1.665 mmol) in phosphorus oxychloride (10 mL, 107 mmol) was stirred at 105° C. for 5 h. Evaporated to dryness. Dissolved in EtOAc and washed with NaHCO3 solution, brine, dried and evaporated to give crude methyl 2-chlorothieno[3,2-b]pyrazine-6-carboxylate 22 (299 mg, 79%). NMR (400 MHz, CDCl3) 4.02 (s, 3H), 8.11 (s, 1H), 8.61 (s, 1H). (m/z)=229 and 231 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.[NH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.CC(C)([O-])C.[Na+].CCOC(C)=O.CCCCCCC>C1(C)C=CC=CC=1.[Cl-].[Na+].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.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH2:10]([O:9][C:4]1[CH:3]=[C:2]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:7]=[C:6]([Br:8])[CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1cc(Br)cc(OCc2ccccc2)c1
Reactant: Nc1cccnc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: Brc1cc(Nc2cccnc2)cc(OCc2ccccc2)c1
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 40.5 %

Procedure:
An oven-dried flask was charged with (±)-BINAP (1.05 g, 1.68 mmol), Pd2(dba)3 CHCl3-complex (580 mg, 0.56 mmol) and then flushed with argon. Degassed toluene (28 mL) was added and the solution was stirred for 10 min. The catalyst solution was added to a mixture of 3,5-dibromo-1-benzyloxybenzene (38.3 g, 112 mmol), 3-aminopyridine (5.27 g, 56.0 mmol) and sodium tert-butoxide (7.54 g, 78.4 mmol) in degassed toluene (250 mL) and the mixture was heated to 80-90° C. for 24 h (conversion not complete). The reaction mixture was cooled to room temperature and brine (500 mL) was added. The mixture was extracted with ethyl acetate (500 mL) and the layers were separated. The organic layer was washed with brine (2×300 mL), dried (Na2SO4) and concentrated to give the crude product. FC (SiO2, AcOEt/heptane 2:1) gave 8.06 g (41%) of (3-benzyloxy-5-bromo-phenyl)-pyridin-3-yl-amine as yellow solid. 3,5-Dibromo-1-benzyloxybenzene was recovered, repurified and reused.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])[CH:3]([CH3:5])[CH3:4].C([O-])([O-])=O.[Na+].[Na+].[C:20](Cl)([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21]>O.O1CCOCC1>[CH:35]1[C:36]2[CH:24]([CH2:23][O:22][C:20]([NH:1][C@@H:2]([CH:3]([CH3:5])[CH3:4])[C:6]([NH:8][C@@H:9]([CH3:10])[C:11]([OH:13])=[O:12])=[O:7])=[O:21])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
H-Val-Ala-OH 11 (1.0 g, 5.313 mmol, 1.0 eq.) and Na2CO3 (1.42 g, 13.282 mmol, 2.5 eq.) were solubilised in distilled H2O (40 mL) and the mixture was cooled to 0° C. before dioxane (40 mL) was added. Partial precipitation of the amino acid salt occurred. A solution of Fmoc-Cl (1.44 g, 5.579 mmol, 1.05 eq.) dissolved in dioxane (40 mL) was added dropwise with vigorous stirring over 10 minutes. The resulting mixture was stirred at 0° C. for 2 hours before the ice bath was removed and the stirring maintained for 16 hours. The solvent was evaporated under reduced pressure and the solid remaining dissolved in water (450 mL). The pH was adjusted to 2 with 1N HCl (25 mL) and the aqueous layer was subsequently extracted with EtOAc (3×250 mL). The combined organics were washed with brine (100 mL), dried over MgSO4, filtered and the volatiles removed under reduced pressure to afford pure HO-Ala-Val-Fmoc 12 as a white solid (2.06 g, 94%). LC/MS (2.758 min (ES+)), m/z: 411.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.47 (br s, 1H), 8.20 (d, 1H, J=6.7 Hz), 7.89 (d, 2H, J=7.5 Hz), 7.75 (t, 2H, J=6.8 Hz), 7.43-7.38 (m, 3H), 7.34-7.30 (m, 2H), 4.31-4.16 (m, 4H), 3.88 (dd, 1H, J=8.8, 7.2 Hz), 1.98 (m, 1H), 1.26 (d, 3H, J=7.3 Hz), 0.89 (d, 3H, J=6.8 Hz), 0.86 (d, 3H, J=6.8 Hz).
Reaction SMILES: [Cl:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[N:8]2)=[N:3]1.C1C(=O)N([I:18])C(=O)C1>>[Cl:1][N:2]1[C:10]([I:18])=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[N:8]2)=[N:3]1
Reactant: Cln1cc2ncccc2n1
Reactant: O=C1CCC(=O)N1I
Product: Cln1nc2cccnc2c1I

Procedure:
2-Heteroaryl pyrazolopyridines can be synthesized according to Scheme 1. 2-Chloro pyrazolopyridine 1 can be treated with NIS to yield 2-chloro-3-iodo pyrazolopyridine 2 which can be converted to 3-substituted 2-chloro pyrazolopyridine 3 under Suzuki conditions. Further Suzuki reaction of 3 with an appropriate heteroaryl boronate affords the desired 2-heteroaryl pyrazolopyridine 4.
Reaction SMILES: [Na].[CH2:2]([N:4]1[C:8]2=[N:9][C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]([C:13]([OH:15])=[O:14])[N:12]=[C:7]2[CH:6]=[N:5]1)[CH3:3].Cl[CH2:23][C:24]#[N:25]>CN(C)C=O>[CH2:2]([N:4]1[C:8]2=[N:9][C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]([C:13]([O:15][CH2:23][C:24]#[N:25])=[O:14])[N:12]=[C:7]2[CH:6]=[N:5]1)[CH3:3]
Reactant: N#CCCl
Reactant: CCn1ncc2nc(C(=O)O)c(-c3ccccc3)nc21
Agent: [Na]
Solvent: CN(C)C=O
Product: CCn1ncc2nc(C(=O)OCC#N)c(-c3ccccc3)nc21

Procedure:
5.8 g. of the sodium salt of 1-ethyl-6-phenyl-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic acid (0.02 mol.), 1.7 g. of chloroacetonitrile (0.22 mol.) and 70 ml. of dry dimethyl-formamide are heated in an autoclave at 120° for 5 hours. After vacuum removal of the solvent, the residual 1-ethyl-6-phenyl-1H-pyrazolo[3,4-b]pyrazine-5-carboxylic acid, cyano-methyl ester is treated with water, filtered off, again treated with alcohol and then recrystallized from ethanol, yield 3.9 g. (64%), m.p. 102°-103°.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]([O:14]C)=[O:13])[CH:9]=[C:8]([F:16])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]([CH:9]=[C:8]([F:16])[C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(F)c(C(=O)OC)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1c(F)cc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
To a solution of dimethyl 2-chloro-6-fluoroterephthalate (2.784 g, 11.3 mmoles) in tetrahydrofuran (20 mL) was added a solution of 1 N NaOH (12.4 mmol, 12.4 mL). The reaction mixture was stirred at room temperature for 30 min. The reaction was concentrated under reduced pressure and the residue was suspended in water (10 mL). The aqueous solution was acidified to pH 3 with 1 N HCl. The resulting white precipitate was collected by filtration, washed with water and ether, dried in high vacuum to afford 3-chloro-5-fluoro-4-(methoxycarbonyl)benzoic acid as a white solid (2.52 g, yield: 96%). 1H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.76 (dd, J=8.8, 1.3 Hz, 1H), 4.01 (s, 3H). LCMS (APCI+) [M+H]+233.0.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=O.[CH2:13]([O:15][C:16]([CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:17])[CH3:14]>O1CCCC1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=[CH:18][C:16]([O:15][CH2:13][CH3:14])=[O:17]
Reactant: Nc1cccc2c1C(=O)OC2=O
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C=C1OC(=O)c2c(N)cccc21

Procedure:
500 mg (3.1 mmol) 4-amino-isobenzofuran-1,3-dione and 1.13 g (3.1 mmol) (ethoxy-carbonylmethylene)-triphenylphosphorane are dissolved in 5 ml of tetrahydrofuran (THF) and refluxed for 3 h. Then the solvent is eliminated in vacuo. The crude product is purified by column chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (75:25).