Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.O[C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:9]([CH2:23][CH2:24][CH3:25])[N:8]=1.[C:26](#N)[CH3:27]>>[CH2:23]([C:9]1[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]([CH:26]=[CH2:27])[N:8]=1)[CH2:24][CH3:25]
Reactant: CC#N
Reactant: CCCc1nc(O)c(C(=O)OCC)cc1C(=O)OCC
Solvent: O=P(Cl)(Cl)Cl
Product: C=Cc1nc(CCC)c(C(=O)OCC)cc1C(=O)OCC
Temperature: 90 °C
Reaction time: 3 h

Procedure:
Phosphoryl trichloride (7.95 mL) was added to a solution of diethyl 2-hydroxy-6-propylpyridine-3,5-dicarboxylate (12.0 g) in acetonitrile (120 mL) at room temperature. The mixture was stirred at 90° C. under a dry atmosphere with calcium chloride tube for 3 hours. After cooling to room temperature, the mixture was quenched with aqueous saturated sodium hydrogen carbonate solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with brine and water, dried over anhydrous magnesium sulfate and concentrated in vacuo. A mixture of the residue, triethylamine (11.8 mL), potassium trifluoro(vinyl)borate (8.51 g) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct (2.42 g) in ethanol (130 mL) was stirred at 90° C. overnight under nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was passed through a silica gel-pad (hexane/ethyl acetate) to give the title compound (10.3 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])=O.[NH4+]>C(O)C.O.[C].[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CCC=Cc1ccccn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)CCCCc1ccccn1
Yield: 94.1 %

Procedure:
Ethyl 5-(2-pyridyl)-4-pentenoate (1.7 g, 8.2 mmol) was dissolved in ethanol (20 ml), and 10% palladium-carbon (0.22 g) and a solution of ammonium formate (3.1 g, 49.0 mmol) in water (5 ml) were added thereto. The reaction mixture was refluxed for 2 hrs. Palladium-carbon was filtered off, and the reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (1.6 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:16]C)[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.B(Br)(Br)Br.O.[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([OH:16])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc(OC)cc(Cl)c2[nH]1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cc2cc(O)cc(Cl)c2[nH]1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 71.1 %

Procedure:
To a solution of ethyl 7-chloro-5-methoxyindole-2-carboxylate (82 mg, 0.323 mmol) in dichloromethane (5 ml) at −78° C. was added boron tribromide (1.07 ml of a 1.0M solution in DCM, 1.07 mmol) and the reaction stirred at −78° C. for 30 minutes then allowed to warm to ambient temperature overnight. Water was carefully added and the pH adjusted to pH 6–7 by addition of 2M sodium hydroxide. The mixture was extracted with ethyl acetate (2×50 ml), and the organic solution washed with brine, dried (MgSO4), filtered and evaporated to give ethyl 7-chloro-5-hydroxyindole-2-carboxylate (55 mg, 71%) as an orange solid.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]([C:14]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])=[CH:19][C:15]=1[C:16](Cl)=[O:17])#[N:13].O>CN(C)C=O>[C:12]([C:14]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[Cl:31])=[CH:19][C:15]=1[C:16]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])=[O:17])#[N:13]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: N#Cc1ccc(Oc2ccc(Cl)cc2Cl)cc1C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Oc2ccc(Cl)cc2Cl)cc1C(=O)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The N-potassium salt of phthalimide (0.025 mole) dissolved in dimethylformamide (50 ml) and 2-cyano-5-(2,4-dichlorophenoxy)benzoyl chloride (0.025 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture is stirred at room temperature for a period of about 8 hours. After this time the mixture is poured into water (150 ml) and is extracted twice with toluene. The toluene extracts are combined and stripped of solvent leaving a solid residue. This residue is recrystallized to yield the desired product N-[2-cyano-5-(2,4-dichlorophenoxy)benzoyl]phthalimide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1>O1CCOCC1.CCOCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: COc1ccc(N)cc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1ccc(Nc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 0.17 h
Yield: 58.5 %

Procedure:
A mixture of palladium acetate (37 mg, 0.165 mmol) and BINAP (154 mg, 0.248 mmol) in 5 mL dioxane was stirred for 10 min under Ar atmosphere. To this mixture was added 1-bromo-4-nitrobenzene (1.11 g, 5.5 mmol), 4-methoxyaniline (745 mg, 6.07 mmol), CsCO3 (2.5 g, 7.73 mmol), and 10 mL of dioxane. The mixture was heated at reflux for 15 h and cooled and diluted with ether (80 mL). The solid was removed through filtration and the filtrate was concentrated. The residue was chromatographed (hexane/EtOAc) to afford 4-methoxy-N-(4-nitrophenyl)aniline as a yellow solid (786 mg, 58%). MS (ESI) m/z 245 (M+H+).
Reaction SMILES: [CH3:1][O:2][P:3]([C:7]1[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:10]=[CH:11][C:12]=1[OH:13])(=[O:6])[O:4][CH3:5].I[CH3:22].[OH-].[Na+]>CN(C=O)C>[CH3:1][O:2][P:3]([C:7]1[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:22])(=[O:6])[O:4][CH3:5]
Reactant: CI
Reactant: COP(=O)(OC)c1cc(-c2ccc(C)cc2)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(C)cc2)cc1P(=O)(OC)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
A mixture of 4-hydroxy-4′-methylbiphenyl-3-yl-phosphonic acid dimethyl ester (500 mg, 1.7 mmol), iodomethane (342 mg, 2.4 mmol) and 10 M aqueous NaOH (190 μL, 1.9 mmol) in DMF (10 mL) was stirred at r.t. overnight. After dilution with H2O, the mixture was extracted with EtOAc. Chromatography over silica gel and elution with EtOAc with 5% of MeOH gave 330 mg (63%) of title compound as a white solid.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12]3[CH:20]=[C:19]([NH:21][CH2:22][C:23]4[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=4[F:30])[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:7][CH:6]=2)[CH2:2]1.C[C:32](N(C)C)=[O:33].C(O)(C(F)(F)F)=O>CN(C=O)C>[F:30][C:24]1[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:23]=1[CH2:22][NH:21][C:19]1[C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:11][C:8]2[CH:9]=[CH:10][C:5]([CH:3]3[CH2:4][N:1]([CH:32]=[O:33])[CH2:2]3)=[CH:6][CH:7]=2)[CH:20]=1
Reactant: NC(=O)c1cnc(Nc2ccc(C3CNC3)cc2)cc1NCc1cc(F)ccc1F
Reactant: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cnc(Nc2ccc(C3CN(C=O)C3)cc2)cc1NCc1cc(F)ccc1F

Procedure:
Compound 6-(4-(azetidin-3-yl)phenylamino)-4-(2,5-difluorobenzylamino)nicotinamide (Example 213) (35 mg, 0.08 mmol) was stirred in 4 mL DMF with DMA (300 μL) at 120° C. in a sealed tube for three days. The mixture was acidified with 0.5 mL TFA and subjected to reverse phase preparative HPLC to isolate the title compound (15 mg). MS found for C23H21F2N5O2 as (M+H)+ 438.4. UV: λ=259 nm. 1H NMR: (CD3OD) δ 8.17 (1H, s), 8.02 (1H, s), 7.44 (2H, dt, J=8.0; 1.6 Hz), 7.21 (1H, m), 7.15-7.04 (3H, m), 5.85 (1H, s), 4.67 (1H, m), 4.51 (2H, s), 4.46 (1H, m), 4.27 (1H, m), 4.04 (2H, m) ppm.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH3:13][N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19][CH2:20][NH2:21].[Na]>ClCCl>[CH3:13][N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19][CH2:20][NH:21][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: CN1CCCC1CCN
Reactant: O=Cc1ccc2ccccc2c1
Agent: [Na]
Solvent: ClCCl
Product: CN1CCCC1CCNCc1ccc2ccccc2c1

Procedure:
Experimental condition analogous to Example 1, from 2-naphthalencarboxaldehyde 0.15 g (1 mmol), 2-(1-methyl-pyrrolidin-2-yl)-ethylamine 0.14 g (1.1 mmol), and sodium triacethoxyborohydride 0.31 g (1.5 mmol), in 10 mL dichloromethane. The crude material is 110 mg pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:27])[N:13]([S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=4)(=[O:18])=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C1CCCCC=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:27])[N:13]([S:16]([C:19]4[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=4)(=[O:18])=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: COc1cccc(S(=O)(=O)N2c3cc(F)ccc3-c3ccccc3C2C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CC1c2ccccc2-c2ccc(F)cc2N1S(=O)(=O)c1cccc(O)c1
Yield: 22.9 %

Procedure:
The title compound was prepared from 3-fluoro-5-[(3-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (350 mg, 0.91 mmol), cyclohexene (1.85 mL, 18 mmol), and 1.0 M solution of boron tribromide in dichloromethane (5.5 mL) according to the procedure and in the same manner as described in Example 105, step e. The volatile components were removed in vacuo and the crude residue was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butyl ether in hexane, to afford the desired compound (77 mg, 30%) as a solid, m.p. 164-167° C.;
Reaction SMILES: IC.[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[CH:5]=[CH:4]1.[C:15](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:15][O:13][C:12]([C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[CH:4][NH:3]2)=[CH:7][CH:8]=1)=[O:14]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc2cc[nH]c2c1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Iodomethane (0.75 mL, 12.0 mmol) was added to a suspension of indole-6-carboxylic acid (1.68 g, 10.5 mmol) and potassium carbonate (2.16 g, 15.7 mmol) in DMF (30 mL) under argon. The reaction was stirred at room temperature for 19 hr. The reaction was quenched with sat. NH4Cl and extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (0-60% EtOAc:Hexane). ESI-MS m/z 176 (MH)+.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1)(O)[OH:4].[H][H]>[Pd].C(O)C>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([CH:3]([OH:4])[C:2]([F:1])([F:15])[F:16])=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(C(O)(O)C(F)(F)F)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C(O)C(F)(F)F)cc1
Yield: 100 %

Procedure:
A mixture of 2,2,2-trifluoro-1-(4-nitro-phenyl)-ethane-1,1-diol (1.1 g, 4.6 mmol), palladium on carbon (100 mg, 10%), and ethanol (50 ml) was treated with hydrogen gas on a Parr shaker (50 psi) for 1 hour. The mixture was filtered through celite under suction and the filtrate was concentrated under reduced pressure to afford 1-(4-amino-phenyl)-2,2,2-trifluoro-ethanol (100% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]1[C:17]([OH:19])=O.[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]1[C:17]([NH:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:39])[CH3:40])[CH:31]=2)[CH2:26][CH2:25]1)=[O:19]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CC1=C(C(=O)O)C(c2ccc(F)cc2F)CC(=O)N1
Product: CC1=C(C(=O)NCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)C(c2ccc(F)cc2F)CC(=O)N1

Procedure:
Prepared by Procedure AC and Scheme AM using 4-(2,4-difluorophenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridinecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 553.0 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[NH:10][C:11]([NH:13][C:14](=[NH:17])[NH:15][CH3:16])=[O:12].[CH3:18]N(C=O)C.CC(N(C)C)=O>C(#N)C>[CH3:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH3:2])[C:4]=1[N:10]1[CH:16]=[N:15][C:14]([NH:17][CH3:18])=[N:13][C:11]1=[O:12]
Reactant: CN(C)C=O
Reactant: CNC(=N)NC(=O)Nc1c(C)cccc1C
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: CNc1ncn(-c2c(C)cccc2C)c(=O)n1
Temperature: 105 °C

Procedure:
About 200 mg of 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride was introduced in a gas chromatograph hypo vial and dissolved in 1 ml of acetonitrile. To the solution was added 0.2 ml of DMF DMA reagent. The vial was sealed with crimper and heated at 105° C. for 15 minutes in an oven. Seven vials were made. The contents of the vials were then put into a long-neck round bottom flask and evaporated to dryness by a flask evaporator. The solid mass was dissolved in a mixture of 30 ml of CHCl3 and 20 ml of water and shaken vigorously in a 60 ml separatory funnel. The aqueous layer was discarded and 20 ml of water was added and shaken. The CHCl3 layer was then taken and about 10 g of anhydrous Na2SO4 was added, the CHCl3 solution was decanted into a flask and evaporated to dryness. The solid material was dissolved in 2-pentanone (about 80 ml) at 70° C. The solution was concentrated and crystallized upon cooling. The crystals were collected and dried in a desiccator with P2O5 with vacuum for one hour.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:18]=1.Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][CH:15]=[C:16]([O:17][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:9]=3[CH2:8][CH2:7][C:6]=2[CH:18]=1
Reactant: O=C1c2ccc(Cl)cc2CCc2c(O)cccc21
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C1c2ccc(Cl)cc2CCc2c(OCCN3CCOCC3)cccc21

Procedure:
For the synthesis of the title compound, 0.44 g (1.69 mmol) of 8-chloro-1-hydroxy-10,11-dihydrodibenzo[a,d]cyclohepten-5-one, 0.345 g (1.86 mmol) of 4-(2-chloroethyl)morpholine hydrochloride and 0.93 g (6.75 mmol) of K2CO3 in 15 ml of acetonitrile are reacted by method Q. C21H21ClNO3 (Mr=371.87); GC 29.7 min
Reaction SMILES: Cl.[CH2:2]([N:4]1[C:16]2[CH:15]=[CH:14][C:13]([CH2:17][N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([C:24](=[NH:27])OC)[CH2:19]3)=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[CH:28]([NH:30][NH2:31])=O>N1C=CC=CC=1.O>[N:30]1[NH:31][C:24]([CH:20]2[CH2:21][CH2:22][CH2:23][N:18]([CH2:17][C:13]3[CH:14]=[CH:15][C:16]4[N:4]([CH2:2][CH3:3])[C:5]5[C:10]([C:11]=4[CH:12]=3)=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH2:19]2)=[N:27][CH:28]=1
Reactant: NNC=O
Reactant: CCn1c2ccccc2c2cc(CN3CCCC(C(=N)OC)C3)ccc21
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCn1c2ccccc2c2cc(CN3CCCC(c4ncn[nH]4)C3)ccc21
Temperature: 110 °C
Reaction time: 8 h
Yield: 0.8 %

Procedure:
A 100-mL round-bottomed flask was charged with a solution of methyl 1-((9-ethyl-9H-carbazol-3-yl)methyl)piperidine-3-carbimidate hydrochloride (1.44 g, 3.94 mmol, 1.00 equiv, 1.44%) in pyridine (20 mL) and formohydrazide (0.249 g, 4.07 mmol, 1.03 equiv, 0.249%). The resulting solution was stirred overnight at 110° C. in an oil bath. Upon completion, the resulting solution was cooled down to room temperature and diluted with water. This mixture was then extracted with ethyl acetate (3×30 mL). Combined organic layers were dried over anhydrous sodium sulfate. After filtration, organic later was concentrated on a rotary evaporator to give a residue that was purified by a silica gel column chromatography eluted with ethyl acetate/hexane (1:10) affording 3-((3-(2H-1,2,4-triazol-3-yl)piperidin-1-yl)methyl)-9-ethyl-9H-carbazole as white solid (0.011 g, 1%). LCMS: [M+H]+: 360. 1H NMR (CDCl3, 300 MHz) δ 11.55 (s, 1H), 8.10 (m, 3H), 7.68 (d, 1H), 7.50 (t, 1H), 7.38 (m, 2H), 7.25 (t, 1H), 4.35 (t, 3H), 3.76 (d, 2H), 3.50 (d, 1H), 2.66 (s, 1H), 2.32 (d, 1H), 2.12 (d, 1H), 2.01 (d, 1H), 1.84 (d, 1H), 1.55 (d, 1H), 1.39 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[N+:32]([C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)([O-:34])=[O:33]>O1CCCC1>[CH:18]1([CH2:17][CH:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][S:41]([C:38]3[CH:37]=[CH:36][C:35]([N+:32]([O-:34])=[O:33])=[CH:40][CH:39]=3)(=[O:42])=[O:43])=[CH:7][CH:6]=2)[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 47.4 %

Procedure:
A solution of 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (63.0 mg, 0.20 mmol) in tetrahydrofuran (10 mL) was treated with N,N-diisopropylethylamine (0.04 mL, 0.24 mmol) and 4-nitro-benzene sulfonyl chloride (49.0 mg, 0.20 mmol). The reaction mixture was stirred at 25° C. for 21 h. At this time, the reaction was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(4-nitro-benzenesulfonylamino)-phenyl]-N-thiazol-2-yl-propionamide (47.5 mg, 47.5%) as a yellow solid: mp 120-125° C.; FAB-HRMS m/e calcd for C23H24N4O5S2 (M+H)+ 501.1266, found 501.1264.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][NH:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][CH3:16].C(=O)([O-])[O-].[Na+].[Na+].CCOCC.[Cl:28][CH2:29][C:30](Cl)=[O:31]>O>[Cl:28][CH2:29][C:30]([N:7]([CH2:6][CH:2]1[O:3][CH2:4][CH2:5][O:1]1)[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][CH3:16])=[O:31]
Reactant: O=C(Cl)CCl
Reactant: CCc1cccc(C)c1NCC1OCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CCc1cccc(C)c1N(CC1OCCO1)C(=O)CCl
Reaction time: 0.25 h

Procedure:
N-(1,3-Dioxolan-2-ylmethyl)-2-ethyl-6-methylaniline (7.5 grams), sodium carbonate (5.0 grams), ether (100 ml) and water (40 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture was cooled to a temperature of about 0°C and chloroacetyl chloride (4.5 grams) was added, with stirring, over a period of about 15 minutes. After the addition was completed stirring was continued for a period of about one hour. After this time the resulting solution was washed with water and the washed solution was dried over anhydrous magnesium sulfate and stripped of solvent under reduced pressure to yield the desired product N-α-chloroacetyl-N-(1,3-dioxolan-2-ylmethyl)-2-ethyl-6-methylaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[O:10][C:9]2[C:11]([C:16]([O:18]CC)=[O:17])=[CH:12][C:13]([CH3:15])=[CH:14][C:8]=2[C:7]=1[CH3:21])=O.O.NN.[K].Cl>C(O)CO>[C:16]([C:11]1[C:9]2[O:10][C:6]([CH2:4][C:3]3[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:2]=3[Cl:1])=[C:7]([CH3:21])[C:8]=2[CH:14]=[C:13]([CH3:15])[CH:12]=1)([OH:18])=[O:17]
Reactant: CCOC(=O)c1cc(C)cc2c(C)c(C(=O)c3ccc(Cl)cc3Cl)oc12
Agent: Cl
Agent: NN
Agent: [K]
Solvent: O
Solvent: OCCO
Product: Cc1cc(C(=O)O)c2oc(Cc3ccc(Cl)cc3Cl)c(C)c2c1
Temperature: 150 °C
Reaction time: 4 h
Yield: 94.8 %

Procedure:
2-(2,4-Dichlorobenzoyl)-7-(ethoxycarbonyl)-3,5-dimethylbenzo[b]furan (0.78 g) and hydrazine monohydrate (0.70 g) were stirred in ethylene glycol (6.5 ml) at 140° C. for 2 hr. After cooling, potassium hydroroxide (0.75 g) was added and the mixture was stirred at 150° C. for 4 hr. After cooling, ice and concentrated hydrochloric acid were added and precipitate was collected by filtration. The precipitate was washed with water and diisopropyl ether and dried to give the objective compound (0.66 g) as white crystals.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:8]([C:9](N)=[O:10])[C:7](=[O:13])[NH:6][C:5]=1[CH3:14])(=[O:3])[CH3:2].S(=O)(=O)(O)[OH:16]>O>[C:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:16])=[O:10])[C:7](=[O:13])[NH:6][C:5]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CC(=O)c1cc(C(N)=O)c(=O)[nH]c1C
Solvent: O
Product: CC(=O)c1cc(C(=O)O)c(=O)[nH]c1C
Reaction time: 6 h

Procedure:
A mixture containing 34 g of 5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinamide, 50 ml of concentrated sulfuric acid and 100 ml of water was heated on a steam bath with stirring for 6 hours. The hot reaction solution was filtered and to the filtrate was added 50 ml of water. The resulting mixture was allowed to stand at room temperature overnight whereupon the product crystallized out. The separated product was collected, washed with water, dried in a vacuum oven at 90°-95° C. to yield 16.8 g of 5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinic acid, m.p. 238°-241° C. This acid was recrystallized from methanol and dried to yield 14.7 g of 5-acetyl-1,2-dihydro-6-methyl-2-oxonicotinic acid, m.p. 241°-243° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][CH:22]([F:32])[O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH:22]([F:21])[F:32])[CH:25]=2)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NCc1cccc(OC(F)F)c1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCc1cccc(OC(F)F)c1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 3-difluoromethoxy-benzylamine (46.6 mg, 0.39 mmol). The title compound was obtained as a solid (100 mg, 42% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.43 (1H, m), 8.98 (2H, s), 8.47 (1H, s), 7.39 (1H, m), 7.11 (1H, m), 7.06 (2H, m), 4.42 (2H, m), 3.32 (1H, m). MS m/z: 504.06, 506.07 [M+H]+.