Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.Cl.[NH2:5][C:6]1([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[C:20]4=[N:21][C:22]([C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([N:31]6[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]6)[CH:26]=5)=[CH:23][CH:24]=[C:19]4[N:18]=[C:17]3[C:38]3[C:39]([NH2:44])=[N:40][CH:41]=[CH:42][CH:43]=3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7]1.C(N(CC)CC)C.[CH3:52][S:53](Cl)(=[O:55])=[O:54]>C(Cl)Cl.CCOC(C)=O>[NH2:5][C:6]1([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:20]4=[N:21][C:22]([C:25]5[CH:26]=[C:27]([N:31]6[CH2:32][CH2:33][CH:34]([NH:37][S:53]([CH3:52])(=[O:55])=[O:54])[CH2:35][CH2:36]6)[CH:28]=[CH:29][CH:30]=5)=[CH:23][CH:24]=[C:19]4[N:18]=[C:17]3[C:38]3[C:39]([NH2:44])=[N:40][CH:41]=[CH:42][CH:43]=3)=[CH:14][CH:15]=2)[CH2:7][CH2:8][CH2:9]1
Reactant: Nc1ncccc1-c1nc2ccc(-c3cccc(N4CCC(N)CC4)c3)nc2n1-c1ccc(C2(N)CCC2)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NC1CCN(c2cccc(-c3ccc4nc(-c5cccnc5N)n(-c5ccc(C6(N)CCC6)cc5)c4n3)c2)CC1
Yield: 53.9 %

Procedure:
A solution of 3-{3-[4-(1-aminocyclobutyl)phenyl]-5-[3-(4-aminopiperidin-1-yl)phenyl]-3H-imidazo[4,5-b]pyridin-2-yl}pyridin-2-amine tetrahydrochloride (49 mg, 0.0731 mmol) in CH2Cl2 (2 mL) was added triethylamine (0.061 mL, 0.439 mmol), then methanesulfonyl chloride (0.006 mL, 0.0804 mmol) at 0° C. and stirred at r.t for 3.5 hours. The mixture was diluted with AcOEt, washed with 0.5N NaOH, brine, dried over Na2SO4, then filtrated. The filtrate was concentrated and the residue was purified by preparative thin-layer chromatography (CH2Cl2/MeOH=5:1) to afford desired product (24 mg, 54%) as pale yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)CC)C.[Cl:14][CH2:15][C:16](Cl)=[O:17]>C1C=CC=CC=1>[Cl:14][CH2:15][C:16]([N:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: C1=CCNCC1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CC=CCC1
Reaction time: 0.25 h

Procedure:
A solution of 1,2,5,6-tetrahydropyridine (41.5 grams; 0.5 mol) and triethylamine (50 grams) in benzene (1 l.) was placed into a 2 l. glass reaction flask equipped with a mechanical stirrer, reflux condenser and addition funnel. Chloroacetyl chloride (56.5 grams; 0.5 mol) was slowly added, with stirring, over a period of about 15 minutes. After the addition was completed stirring was continued for an additional period of about 15 minutes. After this time the reaction mixture was cooled and filtered to remove the triethylamine hydrochloride which had formed. The remaining benzene solution was stripped of solvent to yield a dark colored oil. The oil was then distilled under reduced pressure, to yield 1-(α-chloroacetyl)-1,2,5,6-tetrahydropyridine as a pale yellow oil having a boiling point of 88° to 91° C. at 0.35 mm Hg. pressure, an index of refraction of 1.5224 at 25° C. and having the following elemental analysis as calculated for C7H10ClNO.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.Br[CH2:13][C:14](OCC)=[O:15].[CH2:19]([OH:21])[CH3:20]>>[CH2:19]([O:21][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH:7]([CH:13]=[C:14]=[O:15])[C:2]1([CH3:11])[CH3:1])[CH3:20]
Reactant: CCO
Reactant: CCOC(=O)CBr
Reactant: CC1(C)CC(O)CC(C)(C)N1
Product: CCON1C(C)(C)CC(O)C(C=C=O)C1(C)C

Procedure:
A mixture of 15.7 parts of 2,2,6,6-tetramethylpiperidin-4-ol and 8.3 parts of ethyl bromoacetate in 50 parts of ethyl alcohol was heated at reflux for 48 hours. The cooled reaction mixture was filtered to remove 2,2,6,6-tetramethylpiperidin-4-ol hydrobromide and the solvent removed by distillation in vacuo. The residue was triturated with 40°-60°C petroleum ether to remove the unreacted 2,2,6,6-tetramethylpiperidin-4-ol. The filtrate was then distilled under reduced pressure to yield pure 1-ethoxy-carbonylmethyl-2,2,6,6-tetramethylpiperidin-4-ol as a colourless liquid (of boiling point 116°C at 0.2 mm) which slowly solidified on standing (melting point 42°-42.5°C). This material gave the following elemental analysis by weight:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH2:12](O)[CH2:13][CH2:14][OH:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[OH:15][CH2:14][CH2:13][CH2:12][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: CNC(=O)c1ccc(O)cn1
Reactant: OCCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(OCCCO)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.4 %

Procedure:
To a mixture of 5-hydroxy-N-methylpyridine-2-carboxamide (400 mg, 3.0 mmol), 1,3-propanediol (230 mg, 3.0 mmol), triphenylphosphine (786 mg, 3.0 mmol) and N,N-dimethylformamide (4.5 ml, 60 mmol) was added diisopropyl azodicarboxylate (606 mg, 3.0 mmol) while stirring at ambient temperature. After 18 hours, the solvent was removed under reduced pressure and the resulting residue was taken up in ethyl acetate (40 mL) and filtered. The filtrate was concentrated and purified by column chromatography over silica gel using methanol/ethyl acetate (3-4%) to give 488 mg (80%) of 5-(3-hydroxypropoxy)-N-methylpyridine-2-carboxamide as a colorless gum. MS [M+H] 211.2, 1H NMR (CDCl3) δ (ppm) 8.19 (d, J=3.0 Hz, 1H), 8.13 (d, J=8.7 Hz, 1H), 7.83 (b, 1H), 7.28 (m, 1H), 4.21 (t, J=6.3 Hz, 2H), 3.88 (m, 2H), 3.02 (d, J=5.1 Hz), 2.08 (m, 2H).
Reaction SMILES: CS(C)=O.FC(F)(F)[C:7](OC(=O)C(F)(F)F)=[O:8].[O:18]([C:25]1[N:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N1C=CC=CC=1CO.C(N(CC)CC)C>C(Cl)Cl>[O:18]([C:25]1[N:30]=[C:29]([CH:7]=[O:8])[CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: c1ccc(Oc2ccccn2)cc1
Agent: OCc1ccccn1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=Cc1cccc(Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 141 %

Procedure:
A solution containing 21.0 ml of dry DMSO in 150 ml of dry CH2Cl2 under an atmosphere of nitrogen was cooled to -75° (internal). To this reaction mixture was then added 31.0 g of trifluoroactic anhydride at such a rate to maintain the temperature below -60° (internal). After the addition was complete the reaction mixture was stirred at -75° for 20 min. To the resulting mixture was added a solution containing 29.25 g of 6-phenoxypyridine-2-pyridinemethanol in 150 ml CH2Cl2. During this addition the internal temperature was not allowed to rise above -60° C. After stirring this reaction mixture for 1 hr. at -75° C., 90 ml of triethylamine was added. The cooling bath was removed and the reaction mixture was allowed to warm to room temperature. The reaction mixture was diluted with 1 L of ether and washed four times with H2O. After drying over anhydrous Na 2 SO4, removal of the solvents afforded 29.31 g of dark oil. This material was treated with decolorizing carbon and recrystallized from hexane-ethyl acetate to afford 21.50 g of the desired crystalline aldehyde.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:11]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[CH:22][CH:21]=3)[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1.C(=O)([O-])[O-:30].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[C:3]2[N:11]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH2:28])=[O:30])=[CH:22][CH:21]=3)[C:4]=2[C:5](=[O:8])[NH:6][CH:7]=1
Reactant: N#CCc1ccc(-c2nn(-c3c(F)cccc3F)c3c(Cl)c[nH]c(=O)c23)cc1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)Cc1ccc(-c2nn(-c3c(F)cccc3F)c3c(Cl)c[nH]c(=O)c23)cc1
Reaction time: 8 h
Yield: 74.7 %

Procedure:
To a solution of (4-(7-chloro-1-(2,6-difluorophenyl)-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetonitrile (134.5 mg) obtained in Example 116 and potassium carbonate (94 mg) in DMSO (2 mL) was added 30% aqueous hydrogen peroxide (139 μL) at room temperature. The reaction mixture was stirred overnight, and poured into water. The precipitated crystals were collected by filtration, and purified by HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)), to the obtained fraction was added saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified to give the title compound (105 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[CH:4]=O.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[CH2:20][CH2:21][C:22]#[N:23]>>[F:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[N:1]=[C:22]([NH2:23])[C:21]([CH2:20][C:13]1[C:14]([O:18][CH3:19])=[CH:15][CH:16]=[CH:17][C:12]=1[F:11])=[CH:4]2
Reactant: COc1cccc(F)c1CCC#N
Reactant: Nc1ccc(F)cc1C=O
Product: COc1cccc(F)c1Cc1cc2cc(F)ccc2nc1N

Procedure:
The title compound was synthesized according to EXAMPLE 11 from 2-amino-5-fluorobenzaldehyde and 3-(2-fluoro-6-methoxyphenyl)propionitrile. Reaction temperature 100° C.
Reaction SMILES: [F:1][C:2]1[CH:44]=[CH:43][C:5]([O:6][C:7]2[C:8]([NH:23][C:24]3[S:28][N:27]=[C:26]([CH2:29][CH:30]4[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)[N:25]=3)=[N:9][CH:10]=[C:11]([S:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]4[CH:20]=[CH:21][S:22][C:15]=34)[CH:12]=2)=[CH:4][CH:3]=1.CO.C(Cl)[Cl:48].[ClH:50]>O1CCOCC1>[ClH:48].[ClH:50].[ClH:48].[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[C:8]([NH:23][C:24]3[S:28][N:27]=[C:26]([CH2:29][CH:30]4[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]4)[N:25]=3)=[N:9][CH:10]=[C:11]([S:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]4[CH:20]=[CH:21][S:22][C:15]=34)[CH:12]=2)=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2nsc(Nc3ncc(Sc4ccnc5ccsc45)cc3Oc3ccc(F)cc3)n2)CC1
Reactant: ClCCl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Fc1ccc(Oc2cc(Sc3ccnc4ccsc34)cnc2Nc2nc(CC3CCNCC3)ns2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
A 10 mL round-bottomed flask was charged with tert-butyl 4-((5-(3-(4-fluorophenoxy)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)methyl)piperidine-1-carboxylate (52.2 mg, 0.0802 mmol) and a 1:1 mix of methanol and CH2Cl2 (4 mL). 4N HCl in dioxane (2 mL) was added and the reaction stirred at room temperature for 10 minutes. The solvent was removed to afford crude 3-(4-fluorophenoxy)-N-(3-(piperidin-4-ylmethyl)-1,2,4-thiadiazol-5-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine trihydrochloride (52.9 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][O:34][CH2:35][C:36]([O:38]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:37])[C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:20]([O:22][CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(OC(C)C)(C)C>FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:33][O:34][CH2:35][C:36]([OH:38])=[O:37])[C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:20]([O:22][CH2:23][C:24]([OH:26])=[O:25])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)OCC(=O)OC(C)(C)C)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: C=CC1=C(C(=O)OCC(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Yield: 81.3 %

Procedure:
A solution of tert-butoxycarbonylmethyl 7-[2-(2-aminothiazol-4-yl)-2-benzhydryloxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (3.0 g) in trifluoroacetic acid (10 ml) and anisole (5 ml) was stirred at 25° to 30° C. for an hour. The reaction mixture was poured into diisopropyl ether (150 ml), and the precipitates were collected by filtration and dissolved in 5% aqueous sodium bicarbonate (50 ml). The aqueous solution was washed with ethyl acetate and then adjusted to pH 2.3 with 10% hydrochloric acid. The precipitated substance was collected by filtration and washed with water to give carboxymethyl 7-[2-(2-aminothiazol-4-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (1.7 g).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[OH:12])[CH:2]([CH3:4])[CH3:3].[C:13](O)(=[O:15])[CH3:14].CC([O-])=O.[Na+]>B(F)(F)F>[OH:11][C:8]1[CH:7]=[C:6]([OH:12])[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][C:9]=1[C:13](=[O:15])[CH3:14]
Reactant: CC(C)Cc1ccc(O)cc1O
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Product: CC(=O)c1cc(CC(C)C)c(O)cc1O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
4-Isobutyl-benzene-1,3-diol (1 eq)was taken up in BF3.Oet2 (6 eq) and aceticacid (2 eq) was added. The solution was heated for 16 hours at 90° C. than allowed to cool to room temperature. The solution was added drop wise to 10% NaOAc (aq) and allowed to stand for 4 hours, before being extracted twice with diethyl ether. The organic phases were combined and washed with sat. NaHCO3 (aq), then dried over magnesium sulfate, filtered and concentrated in vacuo to give 1-(2,4-dihydroxy-5-isobutyl-phenyl)-ethanone, which was used without additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:10]C(O)=O)=[C:4]([CH:14]=O)[CH:3]=1.C([O-])(=O)C.[Na+].[OH-].[Na+]>C(OC(=O)C)(=O)C.C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[O:9][CH:10]=[CH:8][C:6]=2[CH:7]=1
Reactant: Cc1cc(Cl)cc(C=O)c1OCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: Cc1cc(Cl)cc2ccoc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 15.4 %

Procedure:
A solution of [(4-chloro-2-formyl-6-methylphenyl)oxy]acetic acid (4.69 mmol) in acetic anhydride (20 mL) was treated with sodium acetate (14.07 mmol). The resulting solution was heated to reflux and stirred for three days. The brown reaction solution was allowed to cool to room temperature, and was diluted with toluene (10 mL). The solution was then treated with 1N aq NaOH (10 mL) and was stirred at room temperature for 20 min. The solution was then further diluted with water (50 mL) and was extracted using ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting brown residue was purified by flash chromatography (hexanes) to provide the title compound as a clear oil (120 mg, 15% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.07 (d, J=2.27 Hz, 1H) 7.55 (d, J=1.77 Hz, 1H) 7.20 (d, J=1.01 Hz, 1H) 6.94 (d, J=2.27 Hz, 1H) 2.47 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:13][C:14]1[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[CH:17][C:15]=1[NH2:16].Cl>CC(O)CCC.C(O)(C)C>[ClH:1].[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:16][C:15]3[CH:17]=[C:18]([OH:22])[C:19]([CH3:21])=[CH:20][C:14]=3[F:13])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1cc(F)c(N)cc1O
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: Cl
Solvent: CCCC(C)O
Solvent: CC(C)O
Product: Cc1cc(F)c(Nc2ccnc3cc(Cl)ccc23)cc1O
Yield: 88.4 %

Procedure:
A solution of 4,7-dichloroquinoline (198 mg, 1 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (1 69 mg, 1.2 mmol), (prepared as described for the starting material in Example 1), in 2-pentanol (5 ml) containing 5M hydrochloric acid in isopropanol (0.5 ml) was heated at reflux for 2 hours. The volatiles were removed by evaporation and the residue was triturated with ether. The solid was collected by filtration, washed with isopropanol, followed by ether and dried under vacuum to give 7-chloro-4-(2-fluoro-5-hydroxy-4-methylanilino)quinoline hydrochloride (300 mg, 88%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:12]([C:14]1[CH:19]=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=1)[CH3:13])([CH3:4])([CH3:3])[CH3:2].[NH2:37][C:38]1[C:43]([I:44])=[CH:42][NH:41][C:40](=[O:45])[N:39]=1.CO.CN(C)CCN(C)C>CC([O-])=O.CC([O-])=O.[Cu+2].O>[C:1]([O:5][C:6](=[O:36])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:14]1[CH:15]=[CH:16][C:17]([N:41]2[CH:42]=[C:43]([I:44])[C:38]([NH2:37])=[N:39][C:40]2=[O:45])=[CH:18][CH:19]=1)[CH3:13])[C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1nc(=O)[nH]cc1I
Reactant: CC(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)CCN(C)C
Solvent: CO
Solvent: O
Product: CC(c1ccc(-n2cc(I)c(N)nc2=O)cc1)N(CCCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.9 %

Procedure:
Cu(OAc)2 (6.02 g, 33.13 mmol, 1.1 eq.) was added to a mixture of [3-(tert-butoxycarbonyl-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-amino)-propyl]-carbamic acid tert-butyl ester (15.18 g, 30.12 mmol, 1 eq.), 4-amino-5-iodo-1H-pyrimidin-2-one (7.85 g, 33.13 mmol, 1.1 eq.), MeOH (400 mL) and H2O (100 mL), followed by N,N,N′,N′-tetramethyl-ethane-1,2-diamine (7.69 g, 66.26 mmol, 2.2 eq.). The Mixture was stirred at RT under air for 48 h (weekend) before concentrated to a volume ca. 130 mL. The residue was diluted with CH2Cl2 (200 mL). The CH2Cl2 extract was washed with brine and concentrated. The crude product was purified by flash chromatography (CH2Cl2:MeOH:NH4OH/35:1:0.01) to afford [3-({1-[4-(4-amino-5-iodo-2-oxo-2H-pyrimidin-1-yl)-phenyl]-ethyl}-tert-butoxycarbonyl-amino)-propyl]-carbamic acid tert-butyl ester (16.06 g, 87%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9].[F:23]C1C=CC(S(Cl)(=O)=O)=CC=1>>[F:23][C:6]1[CH:5]=[CH:4][C:3]([S:8]([NH:11][C@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])=[CH:2][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: O=C(O)[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1F
Product: O=C(O)[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccc(F)cc1

Procedure:
Following the 14a synthetic method, using 4-fluorobenzenesulfonyl chloride (97.31 mg, 0.5 mmol) instead of 2-fluorobenzenesulfonyl chloride gave 16a as a colorless oil; (108.48 mg, 67.1%). [α]D25: −19.1 (c=0.41, CHCl3); 1H-NMR (300 MHz, CDCl3): δ 7.77-7.73 (m, 2H), 7.24-7.21 (m, 7H), 6.92 (d, J=9 Hz, 1H), 4.21-4.14 (m, 1H), 3.15-2.90 (m, 2H); 13C NMR (300 MHz, acetone-d6): δ 171.55, 166.28, 162.95, 137.53, 136.53, 129.74, 129.62, 129.39, 128.24, 126.68, 115.93, 115.63, 57.29, 38.49; HRMS (ESI): calcd for: C15H14FNO4S [M+Na]+=346.0520, obsd [M+Na]+=346.0513.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])[CH2:9][C:10]([OH:12])=O)=[O:6])[CH3:3].CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[Cl:39][C:40]1[C:41]2[CH2:53][CH2:52][NH:51][CH2:50][C:42]=2[N:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[N:45]=1>C1COCC1.CCOCC>[CH3:22][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])[CH2:9][C:10]([N:51]1[CH2:52][CH2:53][C:41]2[C:40]([Cl:39])=[N:45][C:44]([C:46]([F:49])([F:48])[F:47])=[N:43][C:42]=2[CH2:50]1)=[O:12])=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)ccc1F
Reactant: FC(F)(F)c1nc(Cl)c2c(n1)CNCC2
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCc2c(Cl)nc(C(F)(F)F)nc2C1)Cc1cc(F)ccc1F
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
A mixture of 60 mg (0.20 mmol) of (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]4-(2,5-difluorophenyl)butanoic acid and 0.033 mL (0.30 mmol) of N-methylmorpholine in 0.6 mL of THF was cooled to −15° C. and 0.031 mL of isobutyl chloroformate was added. After 10 min, 1.0 mL of ether was added. The mixture was transferred to a syringe and filtered through a syringe filter into a mixture of 35 mg (0.20 mmol) of amine hydrochloride from Step A and 0.033 mL (0.30 mmol) of N-methylmorpholine in 0.5 mL of THF at 0° C. The reaction mixture was warmed to ambient temperature. After 30 min, the reaction was judged to be complete by TLC. The mixture was filtered using a syringe filter, washing with ether, and concentrated under nitrogen. The solid was partitioned between ethyl acetate and water. The organics were washed with brine, dried over magnesium sulfate and concentrated to give a yellow oil. Purification by flash chromatography (5 g silica gel cartridge, 10 to 35% ethyl acetate/hexane step gradient) gave 62 mg (58%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]3[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:5]=3[C:4]=2[CH:3]=1.I[C:26]1[CH:27]=[N:28][CH:29]=[CH:30][C:31]=1[CH3:32].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([S:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:12])[C:6]3[CH2:20][CH2:21][N:22]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][C:31]=4[CH3:32])[C:23](=[O:24])[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccncc1I
Reactant: O=C1NCCc2c1c1cc(F)ccc1n2S(=O)(=O)c1ccccc1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2c(c3cc(F)ccc3n2S(=O)(=O)c2ccccc2)C1=O
Yield: 10.5 %

Procedure:
Using analogous reaction conditions and work up as described for the preparation of Example 1A, 8-fluoro-5-(phenylsulfonyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (I-60a: 450 mg, 1.308 mmol) was reacted with 3-iodo-4-methylpyridine (286 mg, 1.308 mmol), 1,4-dioxane (25 mL), copper iodide (25 mg, 0.13 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (58.46 mg, 0.392 mmol) and potassium phosphate (693 mg, 3.27 mmol) at 120° C. overnight to afford the crude product. Purification by column chromatography on silica gel (5% methanol in DCM) afforded 60 mg of the product (15% yield).
Reaction SMILES: FC(F)(S([O:16][S:17]([C:20]([F:32])([F:31])[C:21]([F:30])([F:29])[C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])(=[O:19])=[O:18])(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.[C:34]1([S:40]([N:43]2[C:47]3[CH:48]=[N:49][C:50]([C:53]#[N:54])=[C:51](O)[C:46]=3[C:45]3[CH:55]=[C:56]([C:59]4[CH:60]=[N:61][N:62]([CH3:64])[CH:63]=4)[CH:57]=[N:58][C:44]2=3)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1.Cl>C(Cl)Cl>[C:34]1([S:40]([N:43]2[C:47]3[CH:48]=[N:49][C:50]([C:53]#[N:54])=[C:51]([O:16][S:17]([C:20]([F:31])([F:32])[C:21]([F:30])([F:29])[C:22]([F:27])([F:28])[C:23]([F:24])([F:25])[F:26])(=[O:18])=[O:19])[C:46]=3[C:45]3[CH:55]=[C:56]([C:59]4[CH:60]=[N:61][N:62]([CH3:64])[CH:63]=4)[CH:57]=[N:58][C:44]2=3)(=[O:41])=[O:42])[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Cn1cc(-c2cnc3c(c2)c2c(O)c(C#N)ncc2n3S(=O)(=O)c2ccccc2)cn1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cn1cc(-c2cnc3c(c2)c2c(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c(C#N)ncc2n3S(=O)(=O)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.2 %

Procedure:
1,1,2,2,3,3,4,4,4-Nonafluorobutanesulfonic anhydride (0.75 g, 0.40 mL, 1.3 mmol) was added dropwise to a suspension of 9-benzenesulfonyl-5-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (106 mg, 0.25 mmol) in pyridine (0.7 mL, 8.0 mmol) and dry DCM (7 mL) at 0° C. The reaction mixture was then allowed to warm to ambient temperature and stirred for 4 h. The reaction mixture was treated with 1N hydrochloric acid (6 mL) and the phases were separated. The aqueous phase was extracted with DCM (2×10 mL), the combined organic phase was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was purified by chromatography (silica, 2 g column, Si-SPE, gradient of DCM/EtOAc) and further trituration with pentane (2 mL) to afford the title compound as a white solid (150 mg, 84%). 1H NMR (CDCl3, 400 MHz): 9.95 (s, 1H), 8.99 (d, J=2.1 Hz, 1H), 8.74 (d, J=2.1 Hz, 1H), 8.35-8.32 (m, 2H), 7.86 (d, J=0.8 Hz, 1H), 7.74-7.68 (m, 2H), 7.61-7.56 (m, 2H), 4.04 (s, 3H). LCMS (Method G): RT=4.80 min, M+H+=713.