Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[CH:13]=[CH:12][C:11](=[O:17])[N:10]([CH2:18][CH:19]=[CH2:20])[C:9]=2[N:8]=1)(=O)=O.O.[CH3:24][N:25](C=O)C>[C-]#N.[C-]#N.[Zn+2].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].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[O:17]=[C:11]1[N:10]([CH2:18][CH:19]=[CH2:20])[C:9]2[N:8]=[C:7]([C:24]#[N:25])[CH:16]=[CH:15][C:14]=2[CH:13]=[CH:12]1
Reactant: C=CCn1c(=O)ccc2ccc(OS(=O)(=O)C(F)(F)F)nc21
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: C=CCn1c(=O)ccc2ccc(C#N)nc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a degassed solution of 7-oxo-8-(2-propen-1-yl)-7,8-dihydro-1,8-naphthyridin-2-yl trifluoromethanesulfonate (697 mg, 2.087 mmol) in DMF (10 ml) was added Zn(CN)2, (147 mg, 1.252 mmol) Pd2(dba)3 (48 mg, 0.052 mmol), and 1,1′-bis(diphenylphosphino)ferrocene (58 mg, 0.104 mmol). The reaction was then heated at 50° C. for 1 h and then at 70° C. for a further 1 h and at 100° C. for a further 1 h. More Zn(CN)2, (147 mg, 1.252 mmol) Pd2(dba)3 (48 mg, 0.052 mmol), and 1,1′-bis(diphenylphosphino)ferrocene (58 mg, 0.104 mmol) was then added and the reaction was heated at 100° C. for a further 1 h. The reaction was then cooled and treated with water (200 ml). The reaction was then extracted with DCM (3×200 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using an ethyl acetate/hexane gradient to provide the desired compound (374 mg, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:29]3[CH:30]=[C:31](OC(=O)C=C)[CH:32]=[CH:33][CH:34]=3)=[C:7]([CH2:13][C:14]([NH:16][C:17]3[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][C:20]([F:27])=[CH:19][C:18]=3[OH:28])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][C:3]=1[CH3:40]>C1COCC1.C(O)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:29]3[CH:30]=[C:31](/[CH:6]=[CH:7]/[C:8]([OH:12])=[O:9])[CH:32]=[CH:33][CH:34]=3)=[C:7]([CH2:13][C:14]([NH:16][C:17]3[C:22]([C:23]([F:26])([F:24])[F:25])=[CH:21][C:20]([F:27])=[CH:19][C:18]=3[OH:28])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][C:3]=1[CH3:40]
Reactant: C=CC(=O)Oc1cccc(-c2c(CC(=O)Nc3c(O)cc(F)cc3C(F)(F)F)c(=O)oc3cc(Cl)c(C)cc23)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2c(-c3cccc(/C=C/C(=O)O)c3)c(CC(=O)Nc3c(O)cc(F)cc3C(F)(F)F)c(=O)oc2cc1Cl
Reaction time: 5 h
Yield: 52 %

Procedure:
Ethyl (2E)-3-{(3-[7-chloro-3-(2-{[4-fluoro-2-hydroxy-6-(trifluoromethyl)phenyl]amino}-2-oxoethyl)-6-methyl-2-oxo-2H-chromen-4-yl]phenyl}acrylate obtained in Reference Example 22 (0.31 g) was dissolved in a mixture of THF (5 ml) and ethanol (5 ml), and 2N aqueous sodium hydroxide solution (1.5 ml) was added thereto. After stirring for 5 hours, the reaction mixture was concentrated. To the residue was added 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated to obtain the title compound as crystals (0.155 g, 52%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)=[CH:24][N:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C2C(=CC=CC=2)C=CC=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25](/[CH:28]=[CH:29]\[C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)=[CH:24][N:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C#Cc4ccc(F)cc4)cn3)c2CC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(/C=C\c4ccc(F)cc4)cn3)c2CC1
Reaction time: 36 h
Yield: 63.1 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-[5-(4-fluorophenylethynyl)-pyridin-2-ylmethylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.0 g, 1.9 mmol), Lindlar catalyst (240 mg), and quinoline (0.8 mL) in methanol (30 mL). Degas, purge with nitrogen, and stir under a balloon of hydrogen for 36 h. Filter the mixture and wash the catalyst with additional methanol. Concentrate the filtrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (8:1) to give (Z)-3-tert-butoxycarbonyl-7-chloro-6-{5-[2-(4-fluoro-phenyl)-vinyl]-pyridin-2-ylmethylthio}-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a clear oil (630 mg, 63%). MS (APCI+) m/z: 525 (M+H)+, 425 (M+H-Boc)+. Use a method similar to the General Procedure 1-4 to give the title compound as a pale yellow solid. MS (APCI+) m/z: 425 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([N+:11]([O-])=O)=[CH:4][N:3]=1.[H][H]>CCOC(C)=O>[Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([NH2:11])=[CH:4][N:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Product: Nc1cnc(Cl)c(N)c1
Reaction time: 3 h
Yield: 65 %

Procedure:
A tablespoonful of Raney nickel catalyst in water was washed first with 95% EtOH and then with EtOAc; it was added to a solution of 2-chloro-3,5-dinitropyridine (4.00 g, 0.0196 mol) in EtOAc (150 ml) and the mixture was hydrogenated at an initial hydrogen pressure of 47.5 p.s.i. for 3 hours. The mixture was filtered through celite and the filtrate was concentrated. The residue was crystallized from CH2Cl2 -pentane to give 1.83 g of the titled product.
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:8](Cl)([Cl:11])([Cl:10])=[S:9]>>[C:1]1([P:8]([Cl:11])([Cl:10])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=P(Cl)(Cl)Cl
Reactant: Oc1ccccc1
Product: S=P(Cl)(Cl)c1ccccc1

Procedure:
Phenol is treated with an excess of thiophosphoryl chloride (at reflux) to yield phenyl thiophosphoryl dichloride ##STR16## and this product was condensed with p-nitroaniline and hydrogenated as set out in Example 1. The corresponding polymer is obtained by polycondensation with isophthaloyl chloride as in Example 2. The inherent viscosity was 0.9 dl/g.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[CH2:12](I)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH2:12][CH3:13]
Reactant: Cc1ccc([N+](=O)[O-])cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc([N+](=O)[O-])ccc1C
Yield: 74.5 %

Procedure:
A mixture of 2-methyl-5-nitrophenol (450 mg, 2.94 mmol), ethyl iodide (356 μl, 4.41 mmol) and potassium carbonate (609 mg, 4.41 mmol) in 15 mL of acetone was heated at reflux for 2 days. The reaction mixture was filtrated, concentrated under vacuum, and the residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate and concentrated under vacuum to provide the title compound (397 mg) which was directly used in the next step.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:23]([CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:22]([Cl:30])[CH:21]=[CH:20][C:4]=1[O:5][C@H:6]1[CH2:9][C@H:8]([CH2:10][N:11](C)[C:12](=O)OC(C)(C)C)[CH2:7]1>O1CCOCC1>[Cl:2][C:3]1[C:23]([CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:22]([Cl:30])[CH:21]=[CH:20][C:4]=1[O:5][C@H:6]1[CH2:9][C@H:8]([CH2:10][NH:11][CH3:12])[CH2:7]1
Reactant: CN(C[C@H]1C[C@H](Oc2ccc(Cl)c(CN3CCCC3)c2Cl)C1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CNC[C@H]1C[C@H](Oc2ccc(Cl)c(CN3CCCC3)c2Cl)C1
Reaction time: 20 h

Procedure:
4M HCl in dioxane (3.5 mL) was added to a solution of example 376, tert-Butyl ({trans-3-[2,4-dichloro-3-(pyrrolidin-1-ylmethyl)phenoxy]cyclobutyl}methyl)methylcarbamate (1.65 g, 3.72 mmol) in 2 mL of dioxane. The mixture was stirred for 20 h and evaporated to dryness. Water (5 mL) was added to the residue, and the solution was subjected to extraction with CHCl3 (2×5 mL). The organic layers were discarded. Saturated K2CO3 (5 mL) was added to the water layer. The water solution was subjected to extraction with CHCl3 (3×10 mL). The combined extracts were dried with Na2SO4 and evaporated; the residue was dried in vacuo to give the title compound (850 mg, 67%) as a yellow oil. LC/MS data: 343.1, 344.1, 345.1 (M+H) (calculated for C17H24Cl2N2O 343.3). 1H NMR-data (DMSO-d6): 7.33 (d, 1H, J=9 Hz, Ar—H); 6.86 (d, 1H, J=9.0 Hz, Ar—H); 4.79-4.88 (m, 1H), 3.81 (s, 2H, CH2); 2.57 (d, 2H, J=7.3 Hz, CH2); 2.50-2.55 (m, 4H); 2.33-2.45 (m, 1H); 2.28 (s, 3H, NCH3); 2.21-2.27 (m, 2H); 2.10-2.19 (m, 2H); 1.60-1.68 (m, 4H).
Reaction SMILES: [CH3:1]CCCCCC.ClCCl.C[Zn]C.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1>ClCCl.CCCCCCC.O.Cl[Ti](Cl)(C)C.[Ti](Cl)(Cl)(Cl)Cl>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:26])([CH3:1])[C:22]([F:24])([F:25])[F:23])=[CH:17][CH:16]=1
Reactant: CCCCCCC
Reactant: O=C(c1ccc(Br)cc1)C(F)(F)F
Agent: C[Ti](C)(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C[Zn]C
Solvent: ClCCl
Solvent: O
Product: CC(O)(c1ccc(Br)cc1)C(F)(F)F
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
A suspension of dichloro(dimethyl)titanium in a heptane/dichloromethane mixture was first prepared as follows: 100 ml (100 mmol) of a 1 M solution of titanium tetrachloride in dichloromethane were cooled to −30° C., 100 ml (100 mmol) of a 1 M solution of dimethylzinc in heptane were added dropwise and the mixture was stirred at −30° C. for a further 30 min. Subsequently, this suspension was cooled to −40° C. and a solution of 10 g (39.5 mmol) of 1-(4-bromophenyl)-2,2,2-trifluoroethanone in 50 ml of dichloromethane was added. The mixture was stirred at −40° C. for a further 5 min, then the temperature was allowed to come to RT and the mixture was stirred at RT for a further 2 h. While cooling with ice, 50 ml of water were slowly added dropwise and then the mixture was diluted with a further 300 ml of water. The mixture was extracted twice with dichloromethane, the combined dichloromethane phases were washed once with water, dried over anhydrous magnesium sulphate and filtered, and the solvent was removed on a rotary evaporator. The residue was purified by column chromatography on silica gel (eluent: 85:15 cyclohexane/ethyl acetate). 10.5 g (100% of theory) of the title compound were obtained, which, according to 1H NMR, still contained residues of solvent.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[C:10]3[N:11]([C:22]([CH2:25][CH3:26])=[CH:23][CH:24]=3)[N:12]=[C:13]([C:19]([OH:21])=O)[C:14]=2[S:15]([CH3:18])(=[O:17])=[O:16])[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:25]([C:22]1[N:11]2[N:12]=[C:13]([C:19]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:21])[C:14]([S:15]([CH3:18])(=[O:17])=[O:16])=[C:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[C:1]#[N:2])[C:10]2=[CH:24][CH:23]=1)[CH3:26]
Reactant: C1CCNC1
Reactant: CCc1ccc2c(-c3cccc(C#N)c3)c(S(C)(=O)=O)c(C(=O)O)nn12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCc1ccc2c(-c3cccc(C#N)c3)c(S(C)(=O)=O)c(C(=O)N3CCCC3)nn12
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.8 %

Procedure:
A mixture of 4-(3-cyanophenyl)-7-ethyl-3-(methylsulfonyl)pyrrolo[1,2-b]pyridazine-2-carboxylic acid (40.0 mg), pyrrolidine (10.8 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31.1 mg), and 1-hydroxybenzotriazole (21.9 mg) in N,N-dimethylformamide (1 mL) was stirred for 6 hour at room temperature. The mixture was partitioned between ethyl acetate (20 mL) and 1N hydrochloric acid (10 mL). The organic layer was washed with water (10 mL) three times, saturated sodium bicarbonate (10 mL), and brine, dried, and evaporated to give 3-[7-ethyl-3-(methylsulfonyl)-2-(1-pyrrolidinylcarbonyl)pyrrolo[1,2-b]pyridazin-4-yl]benzonitrile as an yellow solid (35.6 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[N+:14]([O-])=O)[C:9]#[N:10].CO.[H][H]>[Pd].O1CCOCC1>[NH2:14][C:13]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[NH:5][CH2:4][C:3]1[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=1[Cl:1]
Reactant: N#Cc1ccc([N+](=O)[O-])c(NCc2ccccc2Cl)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: N#Cc1ccc(N)c(NCc2ccccc2Cl)c1
Yield: 83.8 %

Procedure:
Fifty milligrams of 10% palladium on carbon were added to a mixed solution of 261 mg of 3-[N-(2-chlorobenzyl)amino]-4-nitrobenznitrile, 15 ml of methanol and 3 ml of 1,4-dioxane to conduct the catalytic reduction in a hydrogen atmosphere at 3 atm. After the completion of the reaction, the reaction solution was filtered through celite, and the filtrate was distilled off under reduced pressure. The resulting solid material was washed with ether, and was collected through filtration to give 196 mg of 4-amino-3-[N-(2-chlorobenzyl)amino]benznitrile.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](C(O)=O)=[CH:13][N:12]=[C:11]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N:25](CC)CC.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.O>C1COCC1>[CH2:1]([O:8][C:9]1[C:14]([NH2:25])=[CH:13][N:12]=[C:11]([N:18]2[CH:22]=[CH:21][CH:20]=[N:19]2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1cnc(-n2cccn2)nc1OCc1ccccc1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: Nc1cnc(-n2cccn2)nc1OCc1ccccc1
Temperature: 66 °C
Yield: 40 %

Procedure:
4-(benzyloxy)-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 2-e, (200 mg, 0.68 mmol) was dissolved in THF (20 ml) and treated with Et3N (204 mg, 2.02 mmol) and DPPA (204 mg, 0.74 mmol). The mixture was heated at 66° C. for 12 hours. Then water was added and the resulting mixture was continued to stir at reflux for 2 h. After that the mixture was concentrated under vacuum. The residue was diluted with aq. K2CO3 followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under vacuum. The residue was purified on silica gel column with the eluent of dichloromethane/methanol=50/1 (Rf=0.7) to provide compound 2-f (72 mg, 40%).
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[S:29](Cl)(=[O:31])=[O:30].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[N:12]([S:29]([C:20]4[CH:21]=[CH:22][C:23]5[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=5)[CH:19]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: C1=C(c2c[nH]c3ccncc23)CC2CCCN2C1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccc2ccccc2c1)n1cc(C2=CCN3CCCC3C2)c2cnccc21

Procedure:
3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-Azaindole (10 mg, 0.0418 mmol), 2-naphthalenesulfonyl chloride (20 mg, 0.088 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:2]=12.C(Cl)(=O)C([Cl:16])=O>CN(C)C=O.C(Cl)Cl>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]([Cl:16])=[O:12])[CH:8]=[CH:9][C:2]=12
Reactant: O=C(O)c1ccc2nonc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2nonc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
To a solution of 0.84 g (5.0 mmoles) benzofurazan-5-carboxylic acid and 1 drop dimethylformamide in 20 ml methylene chloride cooled in an ice-bath was added 0.70 g (5.5 mmoles) oxalyl chloride. The solution was warmed to room temperature, stirred for 3 hours, and the solvent was removed in vacuo. The residual oil was extracted with 3×15 ml warm hexane. The combined extract was evaporated to dryness, the resulting solid was stirred under 2 ml cold hexane, the hexane was decanted, and the solid was dried to give 0.895 g (98%) crude benzofurazan-5-carbonyl chloride.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][S:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20]OS(C)(=O)=O)(=[O:8])=[O:7].C(O)C>O>[CH3:5][S:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][N:1]=[N+:2]=[N-:3])(=[O:8])=[O:7]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCOCCOCCOCCOS(C)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)OCCOCCOCCOCCN=[N+]=[N-]
Yield: 47.1 %

Procedure:
Sodium azide (1.0 g) is added to a solution of tetraethyleneglycol dimethanesulphonate (5.25 g, 15 mmol), obtained according to A. W. Chwabacher et al. (J. Org. Chem. 1998, 65(5), 1717), in 18 mL of 95° ethanol. The reaction mixture is taken to reflux for 24 hours. Then the solvent is evaporated off, the reaction crude is added to 100 mL of salt water and extracted with ether (3×100 mL). The organic phase is dried over MgSO4, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on a silica column using a gradient of AcOEt in hexane (1/1 to 3/1) as eluents. 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl mono-methanesulphonate 47 (2.10 g, 47%) is obtained, which is used directly in the following stage.
Reaction SMILES: [H-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])([CH3:6])([CH3:5])[CH3:4].[CH3:14][O:15][CH2:16][CH2:17][O:18][CH2:19]Cl>O1CCCC1>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])([CH3:6])([CH3:4])[CH3:5]
Reactant: COCCOCCl
Reactant: CC(C)(C)c1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCOc1ccccc1C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
In dry tetrahydrofuran (25 mL) was suspended 4.80 g (120 mmol) of 60% sodium hydride, and a dry tetrahydrofuran (80 mL) solution containing 15.0 g (100 mmol) of 2-tert-butylphenol was added dropwise to this suspension at 0° C. After stirring the mixture at 0° C. for 10 minutes, a dry tetrahydrofuran (80 mL) solution containing 14.9 g (119 mmol) of 2-methoxyethoxymethyl chloride was added dropwise to the mixture. The reaction mixture was stirred in an ice bath for 4 hours and 30 minutes, and allowed to stand at room temperature overnight. To the reaction mixture were further added 1.20 g (30 mmol) of 60% sodium hydride and 3.8 g (30 mmol) of 2-methoxyethoxymethyl chloride at 0° C., and the mixture was stirred at 0° C. for 7 hours. The reaction mixture was poured into ice-cold water (250 mL), and extracted with ethyl acetate. The organic layers were combined, washed with 2N aqueous sodium hydroxide solution and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (eluted with hexane:ethyl acetate=20:1) to obtain 19.7 g (82.8 mmol, Yield: 82.8%) of tert-butyl-2-[(2-methoxyethoxy)methoxy]benzene.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C:12]2[C:21]3[CH2:20][CH:19]([OH:22])[CH2:18][CH2:17][C:16]=3[CH:15]=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>COCCOC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)C>[C:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([NH:11][C:12]2[C:21]3[CH2:20][CH:19]([OH:22])[CH2:18][CH2:17][C:16]=3[CH:15]=[CH:14][CH:13]=2)=[O:10])[CH:3]=1
Reactant: O=C(Cc1cccc(Br)c1)Nc1cccc2c1CC(O)CC2
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: O=C(Cc1cccc(-c2ccccc2)c1)Nc1cccc2c1CC(O)CC2
Temperature: 25 °C
Yield: 26.2 %

Procedure:
Next, to a mixture of 2-(3-bromophenyl)-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide (50.0 mg, 0.139 mmol), phenyl boronic acid (25.4 mg, 0.208 mmol), tri-o-tolylphosphine (8.45 mg, 0.028 mmol), and barium hydroxide octa-hydrate (65.7 mg, 0.208 mmol) in 12 mL of ethylene glycol dimethyl ether was added ethanol (4 ml,), water (4 mL), and palladium(II) acetate (3.12 mg, 0.014 mmol). The mixture was stirred vigorously under argon and was heated to reflux. After cooled to room temperature, water was added and the product was extracted with ethylacetate. The organic layer was washed with water then brine, dried over MgSO4, filtered, and concentrated under reduced pressure to obtain 2-biphenyl-3-yl-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide (13.0 mg, 26% yield).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([NH:19][C:20]4[S:21][C:22]5[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=5[N:24]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH2:5][CH2:4]1.[CH3:33][N:34]([CH2:36][C:37](O)=[O:38])[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:33][N:34]([CH3:35])[CH2:36][C:37]([N:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([NH:19][C:20]4[S:21][C:22]5[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:23]=5[N:24]=4)=[N:18][C:14]=3[CH:13]=2)=[O:11])[CH2:5][CH2:4]1)=[O:38]
Reactant: CN(C)CC(=O)O
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NC3CCNCC3)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)N1CCC(NC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(Cl)cc4s2)n3C)CC1
Yield: 57.7 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [1-(2-dimethylamino-acetyl)-piperidin-4-yl]-amide (52 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid piperidin-4-ylamide dihydrochloride (88 mg), dimethylamino-acetic acid (26 mg), HBTU (95 mg), and DIEA (70 uL) in DMF (1 mL). LC/MS: m/z 525.5. 1H NMR (DMSO-d6, 400 MHz): δ 8.40-8.38 (d, 1H), 8.11 (s, 1H), 7.96 (m, 1H), 7.80-7.78 (d, 1H), 7.55-7.50 (m, 2H), 7.43-7.40 (d, 1H), 4.43-4.25 (m, 2H), 4.09-4.08 (br. m, 1H), 3.68 (s, 3H), 3.67-3.65 (m, 1H), 3.57-3.50 (m, 1H), 3.22-3.17 (m, 1H), 2.93-2.82 (m, 6H), 1.96-1.89 (m, 2H), 1.59-1.46 (m, 2H), 1.30-1.25 (m, 1H) —NH proton signal was not observed.
Reaction SMILES: [N:1]1([C:6]2[CH:23]=[CH:22][C:9]([O:10][CH2:11][CH2:12][C@@H:13]3[CH2:15][C@@H:14]3[CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.CCN(C(C)C)C(C)C.[C:33]([N:37]=[C:38]=[O:39])([CH3:36])([CH3:35])[CH3:34]>CN(C=O)C>[C:33]([NH:37][C:38]([N:19]1[CH2:20][CH2:21][CH:16]([C@H:14]2[CH2:15][C@H:13]2[CH2:12][CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[N:4][N:3]=[N:2]3)=[CH:23][CH:22]=2)[CH2:17][CH2:18]1)=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: c1cc(-n2cnnn2)ccc1OCC[C@@H]1C[C@@H]1C1CCNCC1
Reactant: CC(C)(C)N=C=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)N1CCC([C@H]2C[C@H]2CCOc2ccc(-n3cnnn3)cc2)CC1
Reaction time: 0.33 h

Procedure:
To a solution of 4-((1R,2S)-2-(2-(4-(1H-tetrazol-1-yl)phenoxy)ethyl)cyclopropyl)piperidine (20 mg, 0.064 mmol) in DMF (0.7 ml) under nitrogen at RT was added DIPEA (0.022 ml, 0.128 mmol) followed by t-butyl isocyanate (drop). At 20 minutes, LC/MS showed no SM left. Quenched with formic acid (4.90 μl, 0. The fractions containing product were collected and dried via GenoVac to afford the title compound. GPR119 Human EC50: 14.7 nM