Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:16])=[C:4]([C:13]([Cl:15])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([Cl:9])=[O:8].[CH3:17][O:18][CH2:19][C:20](Cl)=[O:21]>CC(N(C)C)=O>[CH3:17][O:18][CH2:19][C:20]([NH:1][C:2]1[C:10]([I:11])=[C:6]([C:7]([Cl:9])=[O:8])[C:5]([I:12])=[C:4]([C:3]=1[I:16])[C:13]([Cl:15])=[O:14])=[O:21]
Reactant: Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I
Reactant: COCC(=O)Cl
Solvent: CC(=O)N(C)C
Product: COCC(=O)Nc1c(I)c(C(=O)Cl)c(I)c(C(=O)Cl)c1I

Procedure:
5-amino-2,4,6-triiodoisophthalic acid dichloride of formula (2) is used as a starting material. The compound of formula (2) is reacted with methoxyacetyl chloride in dimethylacetamide solvent to produce 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid dichloride of formula (3) which is then used without an additional purification procedure for the next step. The compound of formula (3) is reacted with 2,3-dihydroxypropylamine in dimethylacetamide solvent in the presence of triethylamine to form 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-dihydroxypropyl)amide chloride of formula (4), as shown in the following reaction scheme 6.
Reaction SMILES: ClC1C=CC(C(C(C)C)C([O:11][CH2:12][C:13]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])([OH:20])[CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=O)=CC=1.[OH-].[K+]>CO>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:13]([OH:20])([CH2:12][OH:11])[CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: CC(C)C(C(=O)OCC(O)(Cn1ccnc1)c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: OCC(O)(Cn1ccnc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (+)-3-[2-(4-chlorophenyl)isovaleroyloxy]-2-(2,4-dichlorophenyl)-1-(imidazol-1-yl)-2-propanol (2.89 g; M.P., 145°-146.5° C.) in methanol (40 ml) was added a 20% aqueous potassium hydroxide solution (6 ml), and the mixture was stirred at room temperature for 3 hours. The solvent was removed in vacuo, and the oily residue was dissolved in 6N hydrochloric acid (30 ml). The acidic aqueous solution was washed with chloroform (20 ml×2) and then neutralized with a 28% aqueous ammonia solution. The resulting crystals were collected by filtration to give (+)-2-(2,4-dichlorophenyl)-1-(imidazol-1-yl)-2,3-propanediol. Yield, 1.51 g; 81%. M.P., 143° C. [α]D19, -113.1° (C=1.0, MeOH).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([O-])=O.[H][H]>C1COCC1.[Ni]>[N:9]1([CH2:8][CH2:7][C:6]2[CH:5]=[C:4]([NH2:1])[CH:17]=[CH:16][CH:15]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=[N+]([O-])c1cccc(CCN2CCCCC2)c1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: Nc1cccc(CCN2CCCCC2)c1

Procedure:
To a solution of 0.2 g (0.85 mmol, 1.0 eq.) of 1-(3-nitrophenethyl)piperidine (I-25) in 15 mL of THF was added ˜30 mg of Raney Nickel. The reaction mixture was stirred under 1 atm. of hydrogen at room temperature for 16 h. The reaction mixture was then filtered through Celite® and the solvent was removed in vacuo to provide 3-(2-(piperidin-1-yl)ethyl)benzenamine (I-26).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([O:11]C)[C:6]([O:9]C)=[CH:7][CH:8]=1)[CH3:2].C(O)(=O)C.Br.O>CCOCC>[CH2:1]([C:3]1[CH:4]=[C:5]([OH:11])[C:6](=[CH:7][CH:8]=1)[OH:9])[CH3:2]
Reactant: CCc1ccc(OC)c(OC)c1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCc1ccc(O)c(O)c1
Yield: 89 %

Procedure:
A mixture of 10.0 g (60.2 mM) of 4-ethylveratrole, 38.4 g (639 mM) of acetic acid and 115.0 g (668 mM) of 47% hydrobromic acid was heated under reflux for 4 hours with stirring After cooling to the room temperature, 100 ml of water was added and the resultant mixture was extractbd three times with each 110 ml of ether. The ether extract was successively washed with 110 ml of water, 150 g of 5% aqueous sodium thiosulfate solution and further twice with each 110 ml of water. The resulting ether solution was dried with anhydrous sodium sulfate, filtered, concentrated and distilled under vacuum to obtain 7.4 g (53.6 mM) of 4-ethylcatechol as a light yellow liquid having a boiling point of 111°-112 ° C./4 mmHg.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][O:8][C:7]2[CH:10]=[CH:11][C:12]([C:14](C)=[O:15])=[CH:13][C:6]=2[O:5]1.[SH-].[Na+].Cl.[O-:20]Cl.[Na+]>>[CH3:1][O:2][CH2:3][CH:4]1[CH2:9][O:8][C:7]2[CH:10]=[CH:11][C:12]([C:14]([OH:15])=[O:20])=[CH:13][C:6]=2[O:5]1
Reactant: COCC1COc2ccc(C(C)=O)cc2O1
Reactant: [O-]Cl
Agent: Cl
Agent: [Na+]
Agent: [SH-]
Product: COCC1COc2ccc(C(=O)O)cc2O1
Temperature: 65 °C

Procedure:
To 13% (v/v) NaOCl (140 ml, purchased from Fluka) solution was added the titled compound of Example 2 (12.85 g, 0.0578 mol), followed by stirring. After being refluxed for 30 min while maintaining the temperature of 65° C., the reaction mixture was cooled down to a room temperature, stirred for 30 min and filtered to obtain a filtrate. To the said filtrate was added 10 ml of 25% (w/v) sodium hydrosulfide, and then, concentrated hydrochloric acid was added to adjust the pH by 3-4. The reaction mixture was filtered to give a solid, which was then washed and recrystallized with a mixture of water and ethanol (40:60, v/v) to prepare the titled compound (6.262 g, 48%, m.p. 119-123° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[CH3:40][C:41]1([CH2:46][CH2:47][C:48](O)=[O:49])[O:45][CH2:44][CH2:43][O:42]1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:40][C:41]1([CH2:46][CH2:47][C:48]([NH:1][C:2]2[CH:3]=[N:4][C:5]3[C:10]([C:11]=2[NH:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:49])[O:45][CH2:44][CH2:43][O:42]1
Reactant: CC(C)(C)OC(=O)NNc1c(N)cnc2ccccc12
Reactant: CC1(CCC(=O)O)OCCO1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NNc1c(NC(=O)CCC2(C)OCCO2)cnc2ccccc12
Temperature: 0 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of tert-butyl N′-(3-aminoquinolin-4-yl)hydrazinecarboxylate (4.50 g, 16.4 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (3.93 g, 20.5 mmol), 4-methylmorpholine (2.29 mL, 20.5 mmol), and 4-dimethylaminopyridine (0.100 g, 0.82 mmol) in pyridine (120 mL) was chilled to 0° C. under an atmosphere of nitrogen. The mixture was treated drop-wise with a solution of 3-(2-methyl-[1,3]dioxolan-2-yl)-propionic acid (3.28 g, 20.5 mmol) in pyridine (30 mL). The reaction mixture was allowed to slowly come to ambient temperature. After 18 h, the reaction mixture was concentrated under reduced pressure to give a dark red oil. The oil was dissolved in chloroform (150 mL) and washed with 5% Na2CO3 aqueous solution (2×50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to yield 6.83 g of crude tert-butyl 2-(3-{[3-(2-methyl-1,3-dioxolan-2-yl)propanoyl]amino}quinolin-4-yl)hydrazinecarboxylate as a dark red oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][CH3:10])[CH:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[C:13](=[O:30])[CH:14]([CH2:19][C:20]2[N:25]=[C:24]([NH:26][CH3:27])[C:23]([C:28]#[N:29])=[CH:22][CH:21]=2)[CH2:15][C:16]=1[O:17]C.Cl>CC(C)=O>[CH3:11][C:4]1[CH:5]=[C:6]([C:8]#[C:9][CH3:10])[CH:7]=[C:2]([CH3:1])[C:3]=1[CH:12]1[C:16](=[O:17])[CH2:15][CH:14]([CH2:19][C:20]2[N:25]=[C:24]([NH:26][CH3:27])[C:23]([C:28]#[N:29])=[CH:22][CH:21]=2)[C:13]1=[O:30]
Reactant: CC#Cc1cc(C)c(C2=C(OC)CC(Cc3ccc(C#N)c(NC)n3)C2=O)c(C)c1
Agent: Cl
Solvent: CC(C)=O
Product: CC#Cc1cc(C)c(C2C(=O)CC(Cc3ccc(C#N)c(NC)n3)C2=O)c(C)c1
Temperature: 60 °C
Yield: 85.5 %

Procedure:
To a stirred solution of 6-[[3-(2,6-dimethyl-4-prop-1-ynyl-phenyl)-4-methoxy-2-oxo-cyclopent-3-en-1-yl]methyl]-2-(methylamino)pyridine-3-carbonitrile (34 mg, 0.085 mmol) in acetone (1 ml) was added 2M aqueous HCl (1 ml). The reaction was heated at 60°C. for 5 hours and then allowed to cool to room temperature. The reaction was concentrated under reduced pressure and then 2M aqueous K2CO3 solution (2 ml) added to the residue. The pH was adjusted to about 5.5 with saturated NH4Cl solution and then extracted with dichloromethane (3×10 ml). The combined organics were dried over MgSO4, filtered and evaporated to dryness under reduced pressure to give the desired compound (28 mg, 85%) as a brown gum. 1H NMR (400 MHz, CDCl3) 7.71 (d, 1H), 7.09 (s, 2H), 6.63 (d, 1H), 5.60 (br, 1H), 2.96-3.36 (m, 7H), 2.37-2.45 (m, 1H), 2.13 (s, 6H), 2.02 (s, 3H).
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:12]([O:18][C:19](=[O:21])[CH3:20])[C@@H:11]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:10][C@H:5]1OC(=O)C)=[N+:2]=[N-:3].[OH:27][C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1>C(Cl)Cl>[N:1]([C@@H:4]1[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:12]([O:18][C:19](=[O:21])[CH3:20])[C@@H:11]([CH2:22][O:23][C:24](=[O:26])[CH3:25])[O:10][CH:5]1[S:34][C:31]1[CH:32]=[CH:33][C:28]([OH:27])=[CH:29][CH:30]=1)=[N+:2]=[N-:3]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Oc1ccc(S)cc1
Solvent: ClCCl
Product: CC(=O)OC[C@H]1OC(Sc2ccc(O)cc2)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 45 °C
Yield: 89.5 %

Procedure:
To a solution of 2-azido glucose tetraacetate 57 (0.222 g, 0.59 mmol) in 6.6 mL of CH2Cl2 is added 4-hydroxythiophenol (0.146 g, 1.15 mmol) followed by boron trifluoride diethyl ether complex (15.9 mL, 18.4 g. 141 mmol). The reaction mixture is heated at 45° C. for 12 h and then quenched by the addition of 2 mL of H2O. The reaction mixture is diluted with 25 mL of CH2Cl2, washed with H2O (10 mL), saturated NaCl (10 mL), dried over Na2SO4, filtered, and concentrated to afford 0.232 g of crude 2-azido-1,2-dideoxy-1-(4-hydroxyphenylthio)-3,4,6-tri-O-acetyl-α,β-D-glucopyranose 58 as a yellow oil, a mixture of anomers which is then taken on to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].[I:12]Cl>C(Cl)(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:12])=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10]
Reactant: ClI
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: ClC(Cl)Cl
Product: Nc1ccc(I)cc1S(N)(=O)=O
Temperature: 25 °C
Yield: 54.1 %

Procedure:
A solution of 2-aminobenzenesulfonamide (25.0 g, 145.2 mmol) in chloroform (275 mL) at 0° C. was treated with a solution of iodine monochloride (24.75 g, 152.4 mmol) in chloroform (50 mL) dropwise over 1 h. After addition, the solution was allowed to slowly warm to 25° C. over 18 h. The precipitate was collected by filtration and washed with chloroform (3×), saturated sodium bicarbonate solution (1×), and water (4×). After air drying, these procedures afforded the title compound (23.4 g, 55%) as a red solid. 1H NMR (300 MHz, DMSO-d6): δ 6.65 (d, J=8.46 Hz, 1 H) 7.35 (s, 2 H) 7.48 (dd, J=8.82, 2.21 Hz, 1 H) 7.76 (d, J=2.21 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](Br)[C:3]=1[CH:4]=[O:5].[N:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([C:14]2[CH:15]=[CH:16][N:11]=[CH:12][CH:13]=2)[C:3]=1[CH:4]=[O:5]
Reactant: OB(O)c1ccncc1
Reactant: O=Cc1c(Cl)cccc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: O=Cc1c(Cl)cccc1-c1ccncc1
Yield: 50.5 %

Procedure:
2-Chloro-6-bromobenzaldehyde (200 mg, 0.91 mmol), pyridine-4-boronic acid (125 mg, 1.0 mmol), dichlorobis(triphenylphosphine)palladium (II) (5 mol %, 30 mg), acetonitrile (2 mL) and aqueous sodium carbonate (2 molar solution, 2 mL) were combined in a microwave vial and sealed with a crimp seal. The mixture was microwaved at 150° C. for 5 min. The crude reaction mixture was then poured over Celite and washed with acetonitrile. The mixture was concentrated under reduced pressure and taken up in ethyl acetate. This organic solution was successively washed with water and brine, then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel, eluting with 98:2 methylene chloride:methanol to provide 2-chloro-6-(4-pyridyl)benzaldehyde (100 mg, 51% yield). NMR (300 MHz, CDCl3): 10.3 (s, 1H), 8.65 (m, 2H), 7.55 (m, 2H), 7.2 ppm (m, 3H).
Reaction SMILES: [ClH:1].[CH3:2][C@H:3]1[CH2:8][CH2:7][NH:6][CH2:5][C@H:4]1[OH:9].C(N(CC)CC)C.C(O)(=O)C.C(OC([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][CH:36]=O)[C:30](=[O:38])[CH:29]1[CH3:39])=O)(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[ClH:1].[ClH:1].[OH:9][C@H:4]1[C@@H:3]([CH3:2])[CH2:8][CH2:7][N:6]([CH2:36][CH2:35][CH2:34][N:31]2[CH2:32][CH2:33][NH:28][CH:29]([CH3:39])[C:30]2=[O:38])[CH2:5]1
Reactant: CC1C(=O)N(CCC=O)CCN1C(=O)OC(C)(C)C
Reactant: C[C@H]1CCNC[C@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1NCCN(CCCN2CC[C@H](C)[C@H](O)C2)C1=O
Reaction time: 2 h
Yield: 194.8 %

Procedure:
To a suspension of (3S,4S)-4-methyl-piperidin-3-ol hydrochloride (intermediate 26; 0.04 g, 0.3 mmol) in dichloromethane (1 ml) was added triethylamine (0.04 ml, 0.3 mmol) and acetic acid (0.03 ml, 0.5 mmol) followed by a solution of crude 2-methyl-3-oxo-4-(3-oxo-propyl)piperazine-1-carboxylic acid tert-butyl ester (intermediate 14c; 0.08 g, 0.3 mmol) in dichloromethane (1 ml). Sodium triacetoxyborohydride (0.07 g, 0.4 mmol) was then added and the mixture stirred for 2 h, after which time the mixture was washed with saturated aq. sodium hydrogencarbonate solution, dried (Na2SO4) and concentrated. The crude residue was then treated with HCl in dioxane (2 ml, 4N) and stirred for 30 minutes after which time the reaction was concentrated to afford crude 1-[3-((3S,4S)-3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride as a white powder (0.1 g). To a solution of crude 1-[3-((3S,4S)-3-hydroxy-4-methyl-piperidin-1-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride (0.03 g, 0.1 mmol) in N,N-dimethylformamide (0.8 ml) was added 3,4-dichlorocinnamic acid (0.02 g, 0.1 mmol), triethylamine (0.05 ml, 0.4 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (0.04 g, 0.1 mmol) and the reaction shaken for 1 h, after which time the reaction mixture was directly purified by preparative HPLC. This afforded the titled product as a colorless gum. MS (ISP)=468.1 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)=[CH:16][CH:15]=2)[N:12]=[C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])[CH2:10]1.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH2:21][CH2:22][N:23]([S:39]([CH:36]4[CH2:38][CH2:37]4)(=[O:41])=[O:40])[CH2:24][CH:25]=3)=[CH:18][CH:19]=2)[N:12]=[C:11]([C:26]([C:32]([F:35])([F:33])[F:34])([C:28]([F:29])([F:30])[F:31])[OH:27])[CH2:10]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: OC(C1=NN(c2ccc(C3=CCNCC3)cc2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(C1CC1)N1CC=C(c2ccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
5-(2-Chloro-phenyl)-1-[4-(1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (20.0 mg, 0.04 mmol) prepared in Example 427, cyclopropanesulfonyl chloride (6.0 uL, 0.06 mmol), and triethylamine (26.0 uL, 0.19 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/1) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[C:5]([CH3:11])=[CH:4][C:3]=1[N+:12]([O-])=O.C([O-])=O.[NH4+]>CO.[Pd]>[NH2:12][C:3]1[CH:4]=[C:5]([CH3:11])[C:6]2[N:7]=[CH:8][NH:9][C:10]=2[C:2]=1[CH3:1]
Reactant: Cc1cc([N+](=O)[O-])c(C)c2[nH]cnc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(N)c(C)c2[nH]cnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4,7-dimethyl-5-nitrobenzimidazole (1.17 g) in methanol (150 mL) is added Pd/C (10%, 0.16 g) and ammonium formate (1.31 g). The mixture is stirred at room temperature overnight, then filtered on Celite, with methanol wash of the solids. The filtrate is rotary evaporated and the residue partitioned between water and ethyl acetate. The organic layer is washed with saturated ammonium chloride, dried over magnesium sulfate, filtered and rotary evaporated to afford 5-amino-4,7-dimethylbenzimidazole as a foamy reddish solid.
Reaction SMILES: O.FC(F)(F)C(O)=O.C([O:11][CH:12](OCC)[CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])C>C(Cl)(Cl)Cl>[O:24]=[C:15]1[C:16]2[C:17](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:19])[N:14]1[CH2:13][CH:12]=[O:11]
Reactant: CCOC(CN1C(=O)c2ccccc2C1=O)OCC
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=CCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.8 %

Procedure:
Water (50 mL) and trifluoroacetic acid (50 mL) were added to a solution of phthalimidoacetaldehyde diethyl acetal (30.0 g, 114 mmol) in chloroform (200 mL), and the reaction mixture was stirred at room temperature for 48 hours. The aqueous layer was separated, adjusted to pH 7 with the addition of sodium carbonate, and extracted with several portions of dichloromethane. The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 14.2 g of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetaldehyde as a white solid.
Reaction SMILES: C(COC)OC.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[N:27]=[CH:26][C:25](Br)=[CH:24][N:23]=2)=[O:21])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[N:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.[F-].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[N:27]=[CH:26][C:25]([C:32]3[CH:33]=[CH:34][N:29]=[CH:30][CH:31]=3)=[CH:24][N:23]=2)=[O:21])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ncc(Br)cn2)CC1
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ncc(-c3ccncc3)cn2)CC1

Procedure:
To a mixed solvent of dimethoxyethane (60 ml) and methanol (120 ml) were added 1-(tert-butoxycarbonyl)-4-[(5-bromopyrimidin-2-yl)carbonyl]piperazine (2.97 g), (pyridin-4-yl)boronic acid (1.48 g), cesium fluoride (4.25 g) and tetrakis(triphenylphosphine)palladium (924 mg). After purging with argon, the reaction mixture was refluxed for 19 hours. The solvent was then distilled off under reduced pressure. The residue was purified by moderate-pressure chromatography on a silica gel column (size D, methanol methylene chloride=1:9), whereby the title compound (1.31 g) was obtained as a colorless solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([NH2:6])[CH:3]=[N:2]1.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH:12]=O>CO.C(O)(=O)C>[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][NH:6][C:4]1[CH:5]=[N:1][NH:2][CH:3]=1
Reactant: Nc1cn[nH]c1
Reactant: O=Cc1cccs1
Solvent: CO
Solvent: CC(=O)O
Product: c1csc(CNc2cn[nH]c2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 0° C. stirring mixture of 1H-pyrazol-4-amine (250 mg, 3.008 mmol) and thiophene-2-carbaldehyde (281 uL, 3.008 mmol) in methanol and acetic acid (5.0 ml, 10:1 ratio) was added 5-ethyl-2-methylpyridine borane complex (444 uL, 3.008 mmol). The ice bath was removed and the flask was attached to a bubbler to allow gas evolution and expansion. The reaction was stirred overnight at room temp. Most of the volatiles were evaporated in vacuo. With the aid of a 0° C. chilling bath, a 10 M solution of NaOH in water was carefully added. The ice bath was removed and stirring was continued for nearly 1 hour. The aqueous layer was extracted with DCM (3×), washed with brine, and dried over MgSO4 and concentrated. The obtained crude product was left under vacuum to remove the volatiles. The obtained viscous oil was diluted with DCM and evaporated under a gentle stream of nitrogen overnight. Solid crystals of the amine separated out and were washed with three aliquots of Hex:EtOAc=9:1. In this way, 391 mg (2.181 mmol; 72%) of the desired product were obtained in more than 97% purity by 1H-NMR analysis. 1H NMR (400 MHz, DMSO-d6) δ 4.21 (d, J=5.6 Hz, 1H), 4.92 (t, J=6.0 Hz, 1H), 6.94 (dd, J=5.1, 3.4 Hz, 1H), 7.10-6.99 (m, 3H), 7.36 (dd, J=5.1, 1.2 Hz, 1H), 12.05 (br s, 1H).
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]=12.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:13][CH2:14][CH2:15][C:3]=12
Reactant: CCOC(=O)c1cnc2c(c1O)CCC2
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2c(c1Cl)CCC2

Procedure:
A mixture of 2.6 g of ethyl 6,7-dihydro-4-hydroxy-5H-cyclopenta[b]pyridine-3-carboxylate [J. Heterocyclic Chem. 12, 1245 (1975)]and 100 mL of phosphorous oxychloride is refluxed for 2.5 hours. The excess phosphorous oxychloride is then removed by evaporating under reduced pressure. The residue is dissolved in chloroform and washed with ice-cold saturated sodium bicarbonate aqueous solution. The chloroform layer is separated, dried over magnesium sulfate, passed through a short silica gel column and evaporated to dryness to yield ethyl 4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[NH:9][C@H:10]([C:15]([O:17]C)=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(c1ccc(Br)cc1)c1ccc(S(C)(=O)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(c1ccc(Br)cc1)c1ccc(S(C)(=O)=O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl N-{(4-bromophenyl) [4-(methylsulfonyl)phenyl]methyl}-L-leucinate from step 2 (81 mg, 0.17 mmol) in THF (1 mL) and MeOH (0.5 mL) was added 1N LiOH (0.3 mL, 0.3 mmol). The resulting mixture was stirred at room temperature for 18 hours and then partitioned between EtOAc and water+1N HCl (0.5 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a colorless gum.