Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:13]=[CH:12]3)=[CH2:8])[CH:2]=1.[H][H]>CO.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:13]=[CH:12]3)[CH3:8])[CH:2]=1
Reactant: [H][H]
Reactant: C=C(c1cccnc1)c1ccc2cc(C(=O)OC)ccc2c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc2cc(C(C)c3cccnc3)ccc2c1
Yield: 20 %

Procedure:
130 mg of Pd/C (10%) are added to 0.25 g (0.86 mmol) of methyl 6-[1-(3-pyridyl)ethenyl]-2-naphthoate in 25 ml of absolute methanol, and hydrogenation is carried out under atmospheric pressure (hydrogen uptake: 40 ml). The catalyst is then removed by filtration, and the solution is evaporated and chromatographed on silica gel using ethyl acetate. 50 mg (20%) of methyl 6-[1-(3-pyridyl)ethyl]-2-naphthoate are obtained as an oil. RF (ethyl acetate): 0.34.
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].[Cl:17][C:18]1[CH:23]=[CH:22]C([Mg]Br)=[CH:20][CH:19]=1.[Cl-].[NH4+].O>CCOCC>[Cl:17][C:18]1[CH:23]=[CH:22][C:5]([CH:4]([N:2]([CH3:3])[CH3:1])[CH:7]2[CH2:16][CH2:15][C:10]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:9][CH2:8]2)=[CH:20][CH:19]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CN(C)C(c1ccc(Cl)cc1)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 4 (22.43 g, 100 mmol) in absolute ether (100 ml) was added dropwise to a 1 M solution of 4-chlorophenylmagnesium bromide in ether (200 ml, 200 mmol) under argon and while cooling with ice, and the mixture was stirred at RT for 20 hours. The reaction mixture was worked up by adding saturated ammonium chloride solution (100 ml) and water (100 ml) while cooling with ice, and extracting the mixture with diethyl ether (3×100 ml). The organic phase was washed with water and saturated sodium chloride solution, dried and concentrated.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:22])[N:4]([CH3:21])[C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[CH:9][C:8]([CH3:19])=[C:7]([CH3:20])[CH:6]=2.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C1C=CC=CC=1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:1][C:2]2[C:3](=[O:22])[N:4]([CH3:21])[C:5]3[C:10]([C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][C:8]([CH3:19])=[C:7]([CH3:20])[CH:6]=3)=[O:32])=[CH:26][CH:25]=1
Reactant: Cc1cc2c(-c3ccccc3Cl)c(N)c(=O)n(C)c2cc1C
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: c1ccccc1
Product: Cc1cc2c(-c3ccccc3Cl)c(NC(=O)Nc3ccc(Cl)cc3)c(=O)n(C)c2cc1C
Yield: 80.8 %

Procedure:
A mixture of 3-amino-4-(2-chlorophenyl)-1,6,7-tri-methyl-2(1H)-quinolone (156 mg), 4-chlorophenyl isocyanate (115 mg) and benzene (4 ml) was refluxed for 1.5 hours and then distilled to remove the solvent. The remaining crystals as collected by filtration were washed with isopropyl ether to obtain N-(4-chlorophenyl)-N'-[4-(2-chlorophenyl) -1,2-dihydro-1,6,7-trimethyl-2-oxo-3-quinolyl]urea (188 mg, 80.7%). Recrystallization from acetone - hexane gave colorless needles. mp 207°-209° C.
Reaction SMILES: [OH:1][C@H:2]([C:18]1[CH:27]=[CH:26][C:21]2[C:22](=[O:25])[O:23][CH2:24][C:20]=2[C:19]=1[CH3:28])[CH2:3][N:4]1[CH:10]2[CH:8]([CH2:9]2)[N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1.[C:29]([OH:35])([C:31]([F:34])([F:33])[F:32])=[O:30]>C(Cl)Cl>[OH:35][C:29]([C:31]([F:34])([F:33])[F:32])=[O:30].[CH:10]12[CH2:9][CH:8]1[NH:7][CH2:6][CH2:5][N:4]2[CH2:3][C@@H:2]([C:18]1[CH:27]=[CH:26][C:21]2[C:22](=[O:25])[O:23][CH2:24][C:20]=2[C:19]=1[CH3:28])[OH:1]
Reactant: Cc1c([C@@H](O)CN2CCN(C(=O)OC(C)(C)C)C3CC32)ccc2c1COC2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c([C@@H](O)CN2CCNC3CC32)ccc2c1COC2=O

Procedure:
In a round bottom flask charged with stirring bar, tert-butyl (±)5-[(2R)-2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]-2,5-diazabicyclo[4.1.0]heptane-2-carboxylate (502 mg, 1.292 mmol) was dissolved in DCM (5 mL) and was treated with TFA (2 mL, 26.0 mmol) at room temperature for 3 hours. Then solvent was removed on rotavapor. Residue was re-dissolved in small amount of DCM and evaporated to take out remained TFA. Then it was dried on high vacuum pump for 4 hours to remove extra TFA. Without further purification, crude product was used to make ROMK inhibitors. LC/MS: (M+1)+=289.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:68][CH:69]=[CH2:70].FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1.C(OCC)(=O)C>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:70][CH:69]=[CH2:68])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([O:55][Si:56]([C:59]([CH3:60])([CH3:61])[CH3:62])([CH3:58])[CH3:57])[CH2:5][C:4]1=[O:63])[CH3:2]
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=CCOC1CCC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CC(O[Si](C)(C)C(C)(C)C)C2C)C(OC)CC3C)CC1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 47 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (2.1 g) (STEP 11B) in 24 ml 33% methylene chloride in cyclohexane, was added allyl trichloroacetimidate (938 mg neat) and the reaction mixture was allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (41 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 24 hours, the reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate, water and brine. The organic layer was dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:5))+1% methanol) gave the title compound (1.03 g). 1H NMR consistent with the desired structure.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.S1(CCCC1)(=O)=O.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([NH:18][C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Brc1c[nH]c2ncccc12
Reactant: Nc1ccccc1
Solvent: O=S1(=O)CCCC1
Product: c1ccc(Nc2c[nH]c3ncccc23)cc1
Temperature: 180 °C

Procedure:
To 10 mg of 3-bromo-1H-pyrrolo[2,3-b]pyridine 582 was added 0.4 mL of sulfolane and aniline (2-3 equiv). The vial was scaled and heated at 180° C. for 10 minutes. After cooling, the desired compound was isolated by preparative HPLC/MS.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].C(O)(=O)C.[C:10]([NH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][C:15]=1[I:22])(=[O:12])[CH3:11]>O.C(O)C>[C:10]([NH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[N:1][NH:2][C:3]([NH2:5])=[S:4])=[CH:16][C:15]=1[I:22])(=[O:12])[CH3:11]
Reactant: NNC(N)=S
Reactant: CC(=O)Nc1ccc(C=O)cc1I
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C=NNC(N)=S)cc1I
Reaction time: 0.75 h

Procedure:
A solution of 0.728 g (0.008 mole) of thiosemicarbazide (Aldrich T3,340-5) in 25 mL of water containing 1.6 mL of glacial acetic acid was added to a solution of 2.319 (0.008 mole) of 4-acetamido-3-iodobenzaldehyde (33) in 40 mL of absolute ethanol (heating was required to make this dissolve) at 80°. The mixture was stirred at this temperature for 45 minutes. A white precipitate developed in the solution which was filtered after cooling the reaction mixture to give 2.55 (88%) of 34 as white crystals, mp 241-43° (dec.). Infrared (IR) and NMR analysis gave the following results:
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])=[CH:23][CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[Br:37][C:38]1[CH:39]=[C:40]([CH2:44][NH2:45])[CH:41]=[N:42][CH:43]=1.C(N(CC)CC)C.CS(C)=O>C(#N)C>[Br:37][C:38]1[CH:39]=[C:40]([CH2:44][NH:45][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:22]=[CH:23][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[O:33][CH3:34])=[CH:25][CH:26]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])[CH:41]=[N:42][CH:43]=1
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1
Reactant: NCc1cncc(Br)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cncc(Br)c4)n3Cc3ccccc32)cc1
Yield: 44.7 %

Procedure:
A solution of 2,2,2-trichloro-1-{10-[(2′-methoxy-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone (0.288 g, 0.534 mmol), (5-bromopyridin-3-yl)methylamine of Step C (0.20 g, 1.07 mmol), triethylamine (0.043 g, 0.588 mmol), dimethylsulfoxide (0.190 mL, 2.67 mmol), and acetonitrile (5 mL) was heated for 17 hours at an oil bath temperature of 81° C. The solvent was removed under reduced pressure and the resulting residue taken up in dichloromethane. The organics were washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to a yellow solid. The solid was triturated with hexane, diethyl ether, and ethyl acetate, collected by filtration, and dried under reduced pressure to give the title compound (0.145 g) as an off white solid, m.p 180-184° C.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][C@H:9]([OH:28])[CH2:10][CH2:11][C@@H:12]2[C@@H:16]([CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[C@@H:15]([OH:26])[CH2:14][C@H:13]2[OH:27])=[CH:5][CH:6]=1.C([O-])([O-])=O.[K+].[K+].I[CH:36]([CH3:38])[CH3:37].O>CN(C=O)C.C(OCC)(=O)C>[OH:27][C@@H:13]1[CH2:14][C@H:15]([OH:26])[C@H:16]([CH2:17]/[CH:18]=[CH:19]\[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH:36]([CH3:38])[CH3:37])=[O:24])[C@H:12]1[CH2:11][CH2:10][C@@H:9]([OH:28])[CH2:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: CC(C)I
Reactant: O=C(O)CCC/C=C\C[C@@H]1[C@@H](CC[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)OC(=O)CCC/C=C\C[C@@H]1[C@@H](CC[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
A solution of crude Latanoprost acid (1.3 g from Example 29) in DMF (13 mL) was treated with K2CO3 (1.38 g, 1.0 mmol) and 2-iodopropane (1.13 g, 6.6 mmol). This mixture was then stirred at 80° C. for 2 hr under an atmosphere of nitrogen (TLC monitoring). Water (40 mL) and ethyl acetate (40 mL) were added and the mixture was stirred for 10 min. The aqueous layer was separated and extracted with ethyl acetate (40 mL), and the combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 1.1 g of crude Latanoprost. The crude Latanoprost could be purified by column chromatography and then concentrated under reduced pressure to provide 0.7 g of Latanoprost (60.3% yield, 2 steps; HPLC (Phenomenex Luna 5 μm silica) analysis of the product showed that no isomer was detectable).
Reaction SMILES: O.[S:2]([C:6]1[CH:11]=[CH:10][C:9]([N:12]=[C:13]=[S:14])=[CH:8][CH:7]=1)([OH:5])(=[O:4])=[O:3].[Na:15].C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O.C[N:30](C)CC=C>O>[S:2]([C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13]([NH2:30])=[S:14])=[CH:10][CH:11]=1)([OH:5])(=[O:3])=[O:4].[Na:15]
Reactant: C=CCN(C)C
Reactant: O=S(=O)(O)c1ccc(N=C=S)cc1
Agent: O=C1c2ccccc2C(=O)C1(O)O
Agent: [Na]
Solvent: O
Product: NC(=S)Nc1ccc(S(=O)(=O)O)cc1
Temperature: 53 °C

Procedure:
A Solid sodium 4-sulfophenylisothiocyanate monohydrate (2.55g; 10 mmol) was added to a solution of poly-L-lysine (15-30 K) (Sigma Chemical Company) (1.0 g) in a mixture of water (20 ml) and N,N-dimethyl-N-allylamine buffer (pH 9.5; 15 ml). The resulting mixture was heated under nitrogen at 53° C. for 3 hours, when a ninhydrin test was negative. The cooled mixture was filtered and the filtrate concentrated to give a grey solid residue. The solid residue was redissolved in water and passed through a column of Amberlite IR 120(Na) and then concentrated. The crude product was purified by gel filtration (Sephadex LH20; water) and freeze dried to give sodium 4-sulfophenylthiourea terminated poly-L-lysine BRI2995 as a white fluffy solid (1.25 g).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][Cl:18])[CH2:10][C@H:9]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=1)=[O:7].[CH:37]1([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[ClH:18].[ClH:18].[ClH:18].[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]#[C:16][CH2:17][N:46]2[CH2:47][CH2:48][N:43]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[CH2:44][CH2:45]2)[CH2:10][C@H:9]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=1)=[O:7]
Reactant: Cc1ccc(C[C@@H]2CN(CC#CCCl)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: C1CCC(N2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C[C@@H]2CN(CC#CCN3CCN(C4CCCCC4)CC3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Product: Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 226.9 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(4-chloro-2-butynyl)piperazine (200 mg), 1-cyclohexylpiperazine (63 mg) and powdered potassium carbonate (210 mg) in dry N,N-dimethylformamide (2 ml) was stirred for 12 hours at room temperature. Additional 1-cyclohexylpiperazine (25 mg) was added and after 2 hours the reaction mixture was poured into water (20 ml) and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the resulting residue was purified by column chromatography on silica gel using a mixture of dichloromethane and methanol (30:1). The obtained product was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate solution (0.6 ml) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[4-(4-cyclohexylpiperazin-1-yl)-2-butynyl]piperazine trihydrochloride (220 mg).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]1([C:11]2([C:18]3[CH:27]=[C:26]([O:28][CH2:29][C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=4)[CH:25]=[CH:24][C:19]=3[C:20]([NH:22][NH2:23])=[O:21])[CH2:16][CH:15]3[CH2:17][CH:12]2[CH2:13][CH2:14]3)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[C:5]1([C:11]2([C:18]3[CH:27]=[C:26]([O:28][CH2:29][C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=4)[CH:25]=[CH:24][C:19]=3[C:20]3[O:21][C:1](=[O:2])[NH:23][N:22]=3)[CH2:16][CH:15]3[CH2:17][CH:12]2[CH2:13][CH2:14]3)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(Cl)Cl
Reactant: NNC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=c1[nH]nc(-c2ccc(OCc3ccc4ccccc4n3)cc2C2(c3ccccc3)CC3CCC2C3)o1
Reaction time: 0.75 h

Procedure:
Phosgene (751 μL of a −20% w/v solution in toluene, 1.42 mmol) was added dropwise via syringe to a stirred solution of 4d (365 mg, 0.79 mmol) in methylene chloride (20 mL) at −78° C. After approximately 45 minutes, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with methylene chloride. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC on YMC Pack Pro C18 stationary phase (gradient elution; 0-75% acetonitrile/water as eluent, 0.1% TFA as modifier). Lyophilization of the purified fractions afforded the title compound 4e, m/z (ES) 490 (MH)+.
Reaction SMILES: NCC[N:4]1C(=O)/[C:7](=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)/[S:6][C:5]1=[O:20].[CH2:21]([N:23]([CH2:26]C)[CH2:24][CH3:25])C.[CH2:28]=[O:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:26][N:23]([CH3:21])[CH2:24][CH2:25][N:4]1[C:28](=[O:29])/[C:7](=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)/[S:6][C:5]1=[O:20]
Reactant: CCOc1ccc(/C=C2\SC(=O)N(CCN)C2=O)cc1
Reactant: C=O
Reactant: CCN(CC)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCOc1ccc(/C=C2\SC(=O)N(CCN(C)C)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
To a solution of compound 76 (122 mg, 0.30 mmol) in 4 mL of 1,2-dichloroethane was added triethylamine (84 μL, 0.60 mmol), aqueous formaldehyde (37%, 24 μL, 0.30 mmol) and sodium triacetoxyborohydride (254 mg, 1.20 mmol). The reaction mixture was allowed to stir overnight at room temperature. The reaction was quenched by adding sat'd aqueous NaHCO3 and stirred at room temperature for 20 min. The reaction mixture was partitioned between ethyl acetate and sat'd aqueous NaHCO3, the organic layer was washed with brine, collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography using dichloromethane/methanol/NH4OH (ratio: 92/7/1) to afford compound 24a (76.2%, 73 mg) as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].CN(C=O)C.C(Cl)(=O)C([Cl:23])=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][C:12]([Cl:23])=[O:14])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: N#Cc1cc(CCC(=O)O)ccc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc(CCC(=O)Cl)ccc1F
Reaction time: 2 h
Yield: 100 %

Procedure:
3-(3-Cyano-4-fluorophenyl)-propionic acid (Int. A7) was dissolved in dichloromethane (30 ml) containing 0.1 ml DMF and oxalyl chloride (0.79 g, 6.2 mmol) added dropwise over 5 min. The reaction mixture was stirred for 2 h then concentrated in vacuo to yield the title compound as an oil (1.3 g, 100%). 1H-NMR (CDCl3) δ 3.02 (2H, t), 3.21 (2H, t), 7.13 (1H, t), 7.45 (2H, m).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2
Reactant: Oc1cnc2ccccc2c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cnc4ccccc4c3)c2cc1OC
Temperature: 140 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (243 mg), 3-hydroxyquinoline (100 mg), and 4-dimethylaminopyridine (348 mg) were dissolved in o-dichlorobenzene (13 ml) to prepare a solution which was stirred at 140° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (213 mg, yield 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:25])[C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[N:13][C:12]=2[O:20][CH2:21][CH:22]([F:24])[F:23])[CH:5]=[C:6]([F:8])[CH:7]=1.CSC1C2C(=CC(Br)=CC=2Br)NC=1SC>[Ni].[H][H]>[NH2:17][C:15]1[CH:14]=[N:13][C:12]([O:20][CH2:21][CH:22]([F:23])[F:24])=[C:11]([CH:16]=1)[C:10]([NH:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:25]
Reactant: O=C(Nc1cc(F)cc(Cl)c1)c1cc([N+](=O)[O-])cnc1OCC(F)F
Reactant: [H][H]
Agent: [Ni]
Agent: CSc1[nH]c2cc(Br)cc(Br)c2c1SC
Product: Nc1cnc(OCC(F)F)c(C(=O)Nc2cc(F)cc(Cl)c2)c1

Procedure:
Prepared analogously to example 6d with N-(3-chloro-5-fluoro-phenyl)-2-(2,2-difluoroethoxy)-5-nitro-nicotinamide (230 mg; 0.61 mmol); Ra-Ni/H2 (50 mg; 3 bar) in 8 mL. Yield: quantitative; MS: [M+H]+=346 (Cl isotope pattern); HPLC: Rt=2.1 min (Method MC-6)
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[CH:4]=[CH:3]1.ClC(Cl)(Cl)C(=N)O[C:12]([CH3:15])([CH3:14])[CH3:13].B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:12]([O:7][CH:5]1[CH2:6][C:2](=[O:1])[CH:3]=[CH:4]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C1C=CC(O)C1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC1C=CC(=O)C1
Temperature: 6.5 °C
Reaction time: 2 h
Yield: 19.7 %

Procedure:
A solution of 4-hydroxy-2-cyclopentenone (1.15 g, 11.7 mmol) in methylene chloride is cooled to 3° C. and treated sequentially with tert-butyl trichloroacetimidate (4.2 mL, 23.7 mmol) and boron trifluoride diethyl etherate (0.15 mL). The reaction mixture is stirred at 3-10° C. for 2 hours and then allowed to warm to room temperature and stirred for 22 hours. The reaction mixture is then treated with sodium bicarbonate (250 mg) and filtered. The filtrate is concentrated under vacuum and the residue is purified by chromatography (silica gel, 39 g, 20% ethyl acetate/hexane, 600 mL) to provide the title compound (355 mg, 40%) as a yellow oil; 1H NMR (CDCl3)δ7.44 (dd, 1H, J=18 Hz), 6.2 (d, 1H, J=5.4 Hz), 4.8 (m, 1H), 2.68 (dd, 1H, J=5.8, 18 Hz), 2.25 (d, 1H, J=18 Hz), 1.27 (s, 9H); IR (neat) νmax 2976, 2936, 1721, 1368, 1352, 1188, 1103, 1161 cm-1 ; MS (CI) m/e (% relative intensity) 155 (M+H+, 22), 99 (100).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[CH3:7][C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:22]([NH2:23])=[N:21][NH:20][C:17]3=[CH:18][N:19]=2)=[CH:10][CH:9]=1>N1C=CC=CC=1>[CH:1]1([C:4]([N:20]2[C:17]3=[CH:18][N:19]=[C:14]([C:11]4[CH:12]=[N:13][C:8]([CH3:7])=[CH:9][CH:10]=4)[CH:15]=[C:16]3[C:22]([NH:23][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])=[N:21]2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1ccc(-c2cc3c(N)n[nH]c3cn2)cn1
Solvent: c1ccncc1
Product: Cc1ccc(-c2cc3c(NC(=O)C4CC4)nn(C(=O)C4CC4)c3cn2)cn1

Procedure:
Cyclopropanecarbonyl chloride (186 mg, 1.776 mmol) was added to a stirred solution of 5-(6-methylpyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-ylamine (200 mg, 0.888 mmol) in anhydrous pyridine (5 mL) and the reaction was heated under reflux for 16 hours. The solvent was removed in vacuo, and the residue chromatographed on silica gel using 10% v/v methanol in dichloromethane as eluent to afford the title compound as a solid.