Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1)=[C:11]2[CH2:25][CH2:26][NH2:27])([CH3:7])[CH3:6])[CH3:2].N(C1C=CC(C(C)(C)C(OCC)=O)=CC=1)N.S([O-])([O-])(=O)=O.[Mg+2].[N:51]1[CH:56]=[CH:55][CH:54]=[C:53]([CH2:57][CH2:58][CH2:59][CH:60]=O)[CH:52]=1.[BH4-].[Na+]>CO>[CH2:1]([O:3][C:4](=[O:28])[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:18]=[C:19]([CH3:24])[CH:20]=[C:21]([CH3:23])[CH:22]=1)=[C:11]2[CH2:25][CH2:26][NH:27][CH2:60][CH2:59][CH2:58][CH2:57][C:53]1[CH:52]=[N:51][CH:56]=[CH:55][CH:54]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: O=CCCCc1cccnc1
Reactant: CCOC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN)c2c1
Agent: CCOC(=O)C(C)(C)c1ccc(NN)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Solvent: CO
Product: CCOC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCNCCCCc3cccnc3)c2c1
Reaction time: 0.71 h

Procedure:
A dry flask containing 3.00 g (7.93 mmol) of 2-[3-(2-aminoethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid ethyl ester (prepared essentially as described in EXAMPLE 1 from ethyl 2-(4-hydrazinophenyl)-2-methylpropionate), 4.76 g (39.7 mmol) of anhydrous magnesium sulfate, and a magnetic stirring bar was fitted with a septum and needle adapter leading to a Firestone valve. The flask was thoroughly purged with nitrogen, and the mixture was cooled in an ice-methanol bath at -10° to -5° C. and stirred vigorously as a solution of 1.32 g (8.88 mmol) of 4-(pyridin-3-yl)butyraldehyde in 15 mL of dry CDCl3 was added gradually by syringe over 10-15 minutes. The resulting mixture was stirred under nitrogen at -10° to -5° C. for 40-45 minutes. Then the septum was removed just long enough to add 390 mg (10.3 mmol) of sodium borohydride. The mixture was stirred under nitrogen at -10° to -5° C. as 10 mL of dry methanol was added dropwise by syringe over several minutes. After 30 minutes, the mixture was removed from the cooling bath and partitioned between 90 mL of ethyl acetate and 90 mL of water. The organic layer was washed with 2×30 mL of brine, then dried over anhydrous sodium sulfate. The filtered solution was concentrated in vacuo, and the residue was flash chromatographed of silica gel (gradient elution with 0-10% methanol in methylene chloride). Fractions containing product and a small amount of unreacted starting material were combined and concentrated to give 3.00 g of light beige, stiff foam, used directly in the next step without further purification or characterization.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:21]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)=[CH:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1>[Pt]>[C:5]1([S:8]([NH:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:21]([C:28]4[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=4)[CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:18]=3)[CH2:13]2)(=[O:10])=[O:9])[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: O=C(O)CCC=C(c1cccnc1)c1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Agent: [Pt]
Product: O=C(O)CCCC(c1cccnc1)c1ccc2c(c1)CC(NS(=O)(=O)c1ccccc1)C2

Procedure:
Prepared from 5-(2-(4-chlorobenzenesulphonylamino)indan-5-yl)-5-(3-pyridyl)pent-4-enoic acid analogously to Example 19 by catalytic hydrogenation in the presence of platinum as catalyst.
Reaction SMILES: Br.[CH3:2][C@H:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.CS(O[CH2:13][CH2:14][C:15]1[O:16][C:17]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=3)=[CH:20][C:18]=2[CH:19]=1)(=O)=O>>[CH3:2][C@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH2:13][CH2:14][C:15]1[O:16][C:17]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]([CH:27]=[CH:28][CH:29]=3)[C:30]#[N:31])=[CH:20][C:18]=2[CH:19]=1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3cccc(C#N)c3)ccc2o1
Reactant: C[C@H]1CCCN1
Agent: Br
Product: C[C@H]1CCCN1CCc1cc2cc(-c3cccc(C#N)c3)ccc2o1

Procedure:
(2S)-2-Methylpyrrolidine hydrobromide and the product from Example 112D are processed as described in Example 1D to provide the titled compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])[C:5]([Cl:25])=[CH:4][N:3]=1.[NH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1>O1CCOCC1>[Cl:25][C:5]1[C:6]([CH:8]([S:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[F:16])=[CH:7][C:2]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]2)=[N:3][CH:4]=1
Reactant: Fc1ccc(F)c(C(Sc2ccc(Cl)cc2)c2cc(Cl)ncc2Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(C(Sc3ccc(Cl)cc3)c3cc(F)ccc3F)c(Cl)cn2)CC1
Temperature: 25 °C
Yield: 12.9 %

Procedure:
A 1,4-dioxane (2.2 ml) solution of the 2,5-dichloro-4-[(4-chlorophenylthio)-(2,5-difluorophenyl)methyl]pyridine (300 mg, 0.48 mmol) obtained in Example 54 and t-butyl 4-aminopiperidine-1-carboxylate (600 mg) was stirred at 120° C. for 5 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was purified by silica gel chromatography (hexane:ethyl acetate=3:1) to give the title compound (36 mg, 9%) as an oil.
Reaction SMILES: B(Br)(Br)Br.[CH:5]1([CH2:11][C:12]2[N:16]=[C:15]([CH:17]=[CH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[C:21]([O:27]C)[CH:20]=3)[O:14][N:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>ClCCl>[CH:5]1([CH2:11][C:12]2[N:16]=[C:15]([CH:17]=[CH:18][C:19]3[CH:20]=[C:21]([OH:27])[C:22]([OH:25])=[CH:23][CH:24]=3)[O:14][N:13]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: COc1ccc(C=Cc2nc(CC3CCCCC3)no2)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(C=Cc2nc(CC3CCCCC3)no2)cc1O
Reaction time: 0.62 h

Procedure:
To a cooled solution of 0.14 mL of 1M boron tribromide (1.5 mmol) in 2 mL dichloromethane, 0.216 g (0.658 mmol) of 3-cyclohexylmethyl-5-[2-(3,4-dimethoxy-phenyl)-vinyl]-[1,2,4]oxadiazole (compound of Example 45) dissolved in 1 mL of dichloromethane was added over a period of 15-20 min at −45° C. to −40° C. The reaction mixture was stirred at −45° C. to −40° C. for 30-45 min and allowed to attain 25° C. to 30° C. slowly, over a period of 1 h. The reaction mixture was further stirred at 25° C. to 30° C. for 4-5 h. After the completion of the reaction, the reaction mixture was quenched with 10 mL of chilled 5% sodium bicarbonate solution, below 20° C. (pH: 8-9). 10 mL of ethyl acetate was added to the reaction mass to dissolve the solid and stirred for 10-15 min. The organic layer was separated and the aqueous layer was washed with 10 mL of 10% sodium chloride solution. The organic layer was collected and distilled to obtain a crude residue, which was purified by column chromatography (silica gel, chloroform-methanol) to yield the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:26][C:27]#[N:28]>CN(C=O)C>[C:27]([CH2:26][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:16])[C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)#[N:28]
Reactant: Cc1ccc(C(=O)c2ccccc2O)cc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2ccccc2OCC#N)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 83.5 %

Procedure:
To a stirred solution of 2'-hydroxy-4-methylbenzophenone (9 g), potassium iodide (8.46 g) and potassium carbonate (8.79 g) in DMF (200 ml) was added chloroacetonitrile (3.85 g) and the mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated to dryness. After the addition of water, the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to dryness. The residue was purified by column chromatography on silica gel to give pale brown syrup (8.9 g, 84%).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([NH2:12])[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:13][CH:14]([C:20](=O)[CH3:21])[C:15](OCC)=[O:16]>CC(O)=O>[F:13][C:14]1[C:20]([CH3:21])=[N:12][C:10]2[N:9]([N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:11]=2)[C:15]=1[OH:16]
Reactant: Nc1cc(-c2ccccc2)n[nH]1
Reactant: CCOC(=O)C(F)C(C)=O
Solvent: CC(=O)O
Product: Cc1nc2cc(-c3ccccc3)nn2c(O)c1F
Temperature: 100 °C
Yield: 64 %

Procedure:
To a solution of 3-phenyl-1H-pyrazol-5-amine x131 (52 mmol, 1 eq, 8.3 g) in 50 ml of AcOH, is added ethyl 2-fluoro-3-oxobutanoate x132 (57 mmol, 1.2 eq, 8.5 g). The mixture is heated at 100° C. for 0.5 hour. After cooling to room temperature, the resulting product is filtered, washed with EtOH and dried to afford 8.1 g of 6-fluoro-5-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-7-ol x133.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([O:19][CH3:20])[C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=O.[OH-].[Na+]>C(#N)C>[CH3:20][O:19][C:13]1[C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:8]2[CH2:7][CH2:6][NH:5][CH2:11][CH2:10][C:9]=2[CH:12]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCN(C(=O)C(F)(F)F)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: COc1cc2c(cc1[N+](=O)[O-])CCNCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.6 %

Procedure:
2,2,2-Trifluoro-1-(7-methoxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone (7.0 g, 0.022 mol) was dissolved in acetonitrile (150 mL). A 50% aqueous solution (70 mL) of sodium hydroxide was added at 0° C. After 10 minutes the reaction mixture allowed to warm to room temperature and stirred for 3 hours. The reaction mixture was partitioned between saturated Na2CO3 and dichloromethane, extracted, dried (MgSO4), filtered, and concentrated, to provide 7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (4.43 g, 89%). 1H-NMR (CDCl3) δ 7.67 (s, 1H), 6.82 (s, 1H), 3.93 (s, 3H), 2.75-3.05 (m, 8H), 1.90 (br s, 1H); LC/MS (ESI+): 223.03 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[O:27]=[C:28]1[NH:33][CH2:32][CH2:31][NH:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:30]2[CH2:31][CH2:32][NH:33][C:28](=[O:27])[CH2:29]2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: O=C1CNCCN1
Product: O=C1CN(C(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)c(Cl)c2)CCN1

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 3-oxopiperazine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-oxopiperazine-1-carbonyl)benzamide. MS (Q1) 470 (M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].O.[F:11][C:12]([F:20])([F:19])[C:13]([C:15]([F:18])([F:17])[F:16])=[O:14].[OH-].[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:8]=[C:7]([C:13]([OH:14])([C:15]([F:18])([F:17])[F:16])[C:12]([F:20])([F:19])[F:11])[CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4]
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: Cc1cccc(C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Temperature: 100 °C
Yield: 42 %

Procedure:
At room temperature, 24.4 g of 2,6-dimethylaniline and 50.0 g of hexafluoroacetone hydrate were mixed, and 0.5 g of p-toluenesulfonic acid monohydrate was added. The reaction solution was stirred and heated to 100° C. After the loss of the starting material was confirmed through TLC, ethyl acetate and an aqueous solution of 1N sodium hydroxide were added to the reaction solution, and phase separation was carried out. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was washed by addition of hexane. The suspension was filtered, and thus obtained filtered residue was dried under reduced pressure at room temperature to give 24.3 g (yield 69%) of the title compound as a powder form.
Reaction SMILES: [Na].O[CH:3]=[C:4]1[CH2:8][CH2:7][O:6][C:5]1=[O:9].[C:10]1([CH2:16][CH2:17][NH2:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([CH2:16][CH2:17][NH:18][CH:3]=[C:4]2[CH2:8][CH2:7][O:6][C:5]2=[O:9])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1OCCC1=CO
Reactant: NCCc1ccccc1
Agent: [Na]
Product: O=C1OCCC1=CNCCc1ccccc1
Yield: 74.9 %

Procedure:
Using 3-hydroxymethylenedihydrofuran-2-one sodium salt (50 mmol) and 2-phenylethylamine (55 mmol) and proceeding according to the abovementioned method A1, 3-(2-phenylethylamino)methylenedihydrofuran-2-one (8.14 g, efficiency: 75%) is produced in the form of a white powder.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8]Cl)[N:3]=[CH:2]1.[C:10]1([CH2:16][CH2:17][CH2:18][SH:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Na]>C(O)C>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][S:19][CH2:18][CH2:17][CH2:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=[CH:2]1
Reactant: SCCCc1ccccc1
Reactant: ClCCCc1c[nH]cn1
Agent: [Na]
Solvent: CCO
Product: c1ccc(CCCSCCCc2c[nH]cn2)cc1

Procedure:
5 mmol of 3-(1H-imidazol-4-yl)propyl chloride are introduced into a solution of 6 mmol of 3-phenylpropanethiol and 10 mmol of sodium in 30 ml of ethanol and the mixture is brought to reflux for 3 h. The suspension is evaporated under vacuum until dryness, potassium carbonate is added and the mixture is stirred in methanol/water. The residual semi-solid oil is brought to boiling in ethanol with active charcoal, filtered and recrystallized in the hydrogenmaleate form from ethanol/diethyl ether.
Reaction SMILES: [CH2:1]([N:3]([CH2:6]C)[CH2:4][CH3:5])C.Cl.[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[CH:19]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)C1CNC1.C=O.C(O)(=O)C.[BH4-].C(O)(=O)C.[Na+].[OH-].[Na+]>CO>[CH3:6][N:3]1[CH2:1][CH:5]([CH:19]([C:10]2[CH:11]=[CH:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:9]=2)[O:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:4]1
Reactant: c1ccc(OC(c2ccc3ccccc3c2)C2CNC2)cc1
Reactant: CCN(CC)CC
Agent: C=O
Agent: Cl
Agent: [BH4-]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CC(C(Oc2ccccc2)c2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
Triethylamine (0.2 mL, 1.4 mmol) was added to 3-(naphthalen-2-yl(phenoxy)methyl)azetidine hydrochloride (0.3 g, 0.92 mmol) dissolved in the methanol solution (20 mL), and stirred at room temperature for 1 hour. Formaldehyde (37% aqueous solution, 0.32 mL, 3.7 mmol), acetic acid (0.21 mL, 3.7 mmol) and sodium acetate borohydride (0.78 g, 3.7 mmol) were added in this order to the reaction mixture, and heated to reflux for one day. The temperature was reduced to room temperature, and 1N caustic soda solution (10 mL) was added thereto, followed by stirring for 30 minutes. The reaction mixture was extracted with methylene chloride, and the organic layer was washed with distilled water once, and then dried over anhydrous magnesium sulfate. The solvent was removed by reduced pressure evaporation to obtain a light yellow oily liquid, which was purified by flash chromatography (methylene chloride:methanol=9:1) to obtain a light yellow oily liquid (0.17 g).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:20]1[S:24][N:23]=[CH:22][N:21]=1)[S:7]([C:10]1[CH:19]=[CH:18][C:13]2[NH:14][C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][C:39]=2[C@@H:41](O)[CH3:42])[CH:34]=[CH:33][N:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O>C1COCC1>[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][C:39]=2[C@H:41]([N:14]2[C:13]3[CH:18]=[CH:19][C:10]([S:7]([NH:6][C:20]4[S:24][N:23]=[CH:22][N:21]=4)(=[O:8])=[O:9])=[CH:11][C:12]=3[O:16][C:15]2=[O:17])[CH3:42])[CH:34]=[CH:33][N:32]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3[nH]c(=O)oc3c2)c(OC)c1
Reactant: C[C@H](O)c1cccc2ccncc12
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](c1cccc2ccncc12)n1c(=O)oc2cc(S(=O)(=O)Nc3ncns3)ccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of N-(2,4-dimethoxybenzyl)-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (100 mg, 0.214 mmol) and (S)-1-(isoquinolin-8-yl)ethanol (74.3 mg, 0.429 mmol) in THF (1072 μl) at 0° C. was treated with PS-triphenylphosphine (112 mg, 0.429 mmol) (0.233 g resin-bound PPh3, 1.84 mmol PPh3/g of resin), and (E)-di-tert-butyl diazene-1,2-dicarboxylate (99 mg, 0.429 mmol). Reaction mixtured was monitored at 0° C. After stirring at 0° C. for 2 h, the reaction was filtered and concentrated in vacuo. Residue was dissolved in 1 mL of DCM and treated with 0.25 mL of TFA. After stirring at RT for 30 minutes, the solvent and TFA were removed in vacuo. Purified by reverse phase chromatography (10-95% MeCN in water w/0.1% TFA, C18 column) to yield 14-7. 1H NMR δ (ppm)(CH3OH-d4): 9.86 (1H, s), 8.61 (1H, d, J=6.42 Hz), 8.47 (2H, dd, J=14.05, 6.52 Hz), 8.32-8.24 (2H, m), 8.14 (1H, s), 7.64-7.57 (2H, m), 7.29 (1H, d, J=8.39 Hz), 6.64-6.55 (1H, m), 2.15 (3H, d, J=7.05 Hz). HRMS [M+H]C20H15N5O4S2 calc'd 454.0638. Found 454.0633.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:11]\[NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)/[CH2:9][CH3:10])=[C:4](F)[CH:3]=1.BrC1C=CC(/C(=N/NC2C=CC=CC=2)/CC)=C(F)C=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:8]([CH2:9][CH3:10])=[N:11][N:12]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC/C(=N/Nc1ccccc1)c1ccc(Br)cc1F
Agent: CC/C(=N\Nc1ccccc1)c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nn(-c2ccccc2)c2cc(Br)ccc12
Temperature: 100 °C
Reaction time: 48 h

Procedure:
Into a 1000-mL 3-necked round-bottom flask, was placed a solution of (Z)-1-(1-(4-bromo-2-fluorophenyl)propylidene)-2-phenylhydrazine and (E)-1-(1-(4-bromo-2-fluorophenyl)propylidene)-2-phenylhydrazine (44.3 g, 138.01 mmol, 1.00 equiv) in N,N-dimethylformamide (400 mL), potassium carbonate (83 g, 601.45 mmol, 4.40 equiv). The resulting solution was stirred for 2 days at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with water (500 mL). The resulting solution was extracted with ethyl acetate (2×300 mL) and the organic layers combined. The resulting mixture was washed with water (2×300 mL) and brine (1×300 mL). The resulting mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50) to yield 6-bromo-3-ethyl-1-phenyl-1H-indazole as a yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:28])=[CH:24][C:25]=4[F:27])[N:20]([CH3:29])[N:19]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])[CH3:5].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([Cl:28])=[CH:24][C:25]=4[F:27])[N:20]([CH3:29])[N:19]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])[CH3:5]
Reactant: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)cc(F)c34)nc12
Solvent: NCCN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC[C@H](C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(Cl)cc(F)c34)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55.9 %

Procedure:
In a 25 mL round-bottom flask, 2-(6-chloro-4-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide (40 mg, 0.073 mmol) and TFA (0.60 ml, 7.8 mmol) were combined with dichloromethane (2 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (2 mL) and ethylenediamine (0.40 ml, 5.9 mmol) was added. The reaction mixture was stirred at room temperature for 18 h then concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (dichloromethane/heptane) to afford 17 mg (55%) of 2-(6-chloro-4-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as an off-white solid. MS: [M+H]+=417; 1H NMR (300 MHz, DMSO-d6) δ: 12.68 (br. s., 1H), 9.00 (s, 1H), 8.44 (s, 1H), 8.32 (d, J=8.7 Hz, 1H), 7.89 (d, J=1.5 Hz, 1H), 7.27 (dd, J=10.6, 1.5 Hz, 1H), 4.31 (dt, J=13.5, 7.0 Hz, 1H), 4.19 (s, 3H), 3.45 (dd, J=9.3, 5.8 Hz, 3H), 3.36 (dd, J=9.8, 5.3 Hz, 1H), 3.20 (s, 3H), 1.22 (d, J=6.8 Hz, 3H).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:5][CH2:4]1.CO.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].[OH-].[Na+]>C1(C)C=CC=CC=1>[N:3]1([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:8][CH2:7][CH:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH2:5][CH2:4]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1CC(C2CCNCC2)CCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(OCc1ccccc1)N1CCC(C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.6 %

Procedure:
4,4′-Bipiperidine dihydrochloride (2.95 g) was mixed with MeOH (25 ml), and a mixture of benzyl chloroformate (2.2 g) and toluene (5 ml) was added dropwise thereto over 1 hour while keeping the solution neutral by adding a 6M aqueous NaOH solution at the same time. The reaction mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. CHCl3, and a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain benzyl 4,4′-bipiperidine-1-carboxylate (1.5 g).
Reaction SMILES: C([O:8][NH:9][C:10](=[O:40])[CH2:11][C@H:12]([C:17](=[O:39])[NH:18][C@H:19]1[CH2:36][CH:35]2[CH2:37][N:28]([CH:29]3[CH:34]2[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:20]1=[O:38])[CH2:13][CH:14]([CH3:16])[CH3:15])C1C=CC=CC=1>C(O)C.CO.CCOCC.[Pd]>[OH:8][NH:9][C:10](=[O:40])[CH2:11][C@H:12]([C:17](=[O:39])[NH:18][C@H:19]1[CH2:36][CH:35]2[CH2:37][N:28]([CH:29]3[CH:34]2[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][NH:21][C:20]1=[O:38])[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)C[C@H](CC(=O)NOCc1ccccc1)C(=O)N[C@H]1CC2CN(CCCCCCNC1=O)C1CCCCC21
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Solvent: CO
Product: CC(C)C[C@H](CC(=O)NO)C(=O)N[C@H]1CC2CN(CCCCCCNC1=O)C1CCCCC21
Yield: 90.9 %

Procedure:
(3R,10S)-N-benzyloxy-5-methyl-3-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadecan-10-ylcarbamoyl)hexanamide (75 mg, 0.135 mmol) was hydrogenated at 1 atm H2 pressure in absolute ethanol (5 mL) in the presence of 10% Pd-C (35 mg) for 2 hours. Argon gas was bubbled into the reaction mixture for 10 minutes and the reaction mixture was filtered through a cone of celite. The catalyst on celite was further washed with 5 mL of ethanol. The combined filtrate was evaporated to dryness to afford a solid residue. The solid was stirred in 10 mL of 5% MeOH in ether at 0° C. for 30 mins and filtered to yield 57 mg (91%) of (3R,10S)-N-hydroxy-5-methyl-3-(9-oxo-1,8-diaza-tricyclo[10.6.1.013,18 ]nonadecan-10-ylcarbamoyl) hexanamide, as an off-white powder, MS: 465 (M+H)+.