Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12]([Li])CCC.CI>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1
Reactant: [Li]CCCC
Reactant: O=C(O)Cc1ccc(Cl)cc1
Solvent: CI
Solvent: C1CCOC1
Product: CC(C(=O)O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Under a nitrogen atmosphere, to a mixture of (4-chlorophenyl)acetic acid (13.6 g) in THF (140 mL) was added n-butyllithium (1.6 M hexane solution, 100 mL) at −60° C. to −70° C., and the mixture was allowed to warm to 0° C. A mixture of methyl iodide (4.96 mL) in THF (40 mL) was added to the reaction mixture at 0° C.-10° C., and the mixture was stirred at room temperature for 12 hr. The reaction mixture was extracted with 1N aqueous sodium hydroxide solution (2×100 mL), and the extract was acidified with 3N hydrochloric acid (100 mL). The mixture was extracted with ethyl acetate (3×100 mL), the extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (13.3 g).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10].[O:17]([C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[C:9](/[C:11](=[CH:28]\[C:27]1[CH:30]=[CH:31][C:24]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:25][CH:26]=1)/[C:12]([O:14][CH2:15][CH3:16])=[O:13])#[N:10]
Reactant: CCOC(=O)CC#N
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)/C(C#N)=C/c1ccc(Oc2ccccc2)cc1
Reaction time: 1 h

Procedure:
Potassium phosphate (0.751 g, 3.54 mmol) was added to a solution of ethyl 2-cyanoacetate (2.00 g, 17.68 mmol) and 4-phenoxybenzaldehyde (3.50 g, 17.68 mmol) in ethanol (50 mL). After 1 h at room temperature, the mixture was quenched with water (20 mL). The ethanol solvent was evaporated in vacuo. The residue was taken up in ethyl acetate (150 mL), washed with brine (2×10 mL), dried (MgSO4) and concentrated. Silica gel chromatography, loading with toluene and eluting with 5 to 20% ethyl acetate in hexanes, gave (E)-ethyl 2-cyano-3-(4-phenoxyphenyl)acrylate as tan liquid. 1H NMR (500 MHz, CDCl3) δ ppm 8.19 (1H, s), 7.92-8.05 (2H, m), 7.37-7.48 (2H, m), 7.24 (1H, t, J=7.42 Hz), 7.10 (2H, δ, J=7.70 Hz), 6.98-7.07 (2H, m), 4.38 (2H, q, J=7.15 Hz), 1.40 (3H, δ, J=7.15 Hz); MS (ES+) m/z: 294 (M+H); LC retention time: 4.405 min (analytical HPLC Method B).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[N:5][N:6]=1.[CH2:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10].O>N1C=CC=CC=1>[CH2:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:1][C:2]2[S:3][CH:4]=[N:5][N:6]=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nncs1
Solvent: c1ccncc1
Solvent: O
Product: CCCCc1ccc(S(=O)(=O)Nc2nncs2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.9 %

Procedure:
To a stirred solution of 2-amino-1,3,4-thiadiazole (2.0 g, 19.7 mmol) in pyridine (30 mL) under argon at −20° C. was added p-butylbenzenesulfonyl chloride (4.89 g, 21 mmol) over 10 min. The reaction mixture was stirred at room temperature for 16 hours. Water (300 mL) was added to quench the reaction. The mixture was extracted with CH2Cl2 and the organic extracts washed with 2N HCl (2×150 mL), brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluted with methanol:DCM 1:33 to give the product (3.46 g, 11.6 mmol, 59% yield) as a solid, mp 120-121° C.; 1H NMR (300 MHz, CDCl3) δ 0.91 (t, 3H, J=7 Hz), 1.29-1.37 (m, 2H), 1.56-1.61 (m, 2H), 2.65 (t, 2H, J=7 Hz), 7.27 (d, 2H, J=8 Hz), 7.84 (d, 2H, J=8 Hz), 8.25 (s, 1H); 13C NMR (75 MHz, CDCl3) 13.9, 22.3, 33.2, 33.6, 126.5, 129.1, 138.1, 142.7, 148.6, 167.4; MS (Q-TOF) Calcd for C12H16N3O2S2 298.0684. found 298.0695 (M+H)+. Calcd for C12H15N3NaO2S2 320.0503. found 320.0361 (M+Na)+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:56]=[C:55]([O:57][CH3:58])[CH:54]=[C:53]([O:59][CH3:60])[C:13]=1[CH:14]=[CH:15][CH:16]([S:26]([CH:29]([CH:39]=[CH:40][C:41]1[C:46]([O:47][CH3:48])=[CH:45][C:44]([O:49][CH3:50])=[CH:43][C:42]=1[O:51][CH3:52])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([NH2:38])[CH:31]=1)(=[O:28])=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([NH2:25])[CH:18]=1>O1CCCC1>[CH3:60][O:59][C:53]1[CH:54]=[C:55]([O:57][CH3:58])[CH:56]=[C:12]([O:11][CH3:10])[C:13]=1/[CH:14]=[CH:15]/[CH:16]([S:26]([CH:29](/[CH:39]=[CH:40]/[C:41]1[C:42]([O:51][CH3:52])=[CH:43][C:44]([O:49][CH3:50])=[CH:45][C:46]=1[O:47][CH3:48])[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[C:32]([NH:38][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:31]=1)(=[O:28])=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([NH:25][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:18]=1
Reactant: COc1cc(OC)c(C=CC(c2ccc(OC)c(N)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Product: COc1cc(OC)c(/C=C/C(c2ccc(OC)c(NC(=O)c3ccccc3)c2)S(=O)(=O)C(/C=C/c2c(OC)cc(OC)cc2OC)c2ccc(OC)c(NC(=O)c3ccccc3)c2)c(OC)c1
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of benzoyl chloride (10 mmol) in tetrahydrofuran (40 mL) was added dropwise a solution of 2,4,6-trimethoxystyryl-3-amino-4-methoxybenzyl-sulfone (10 mmol) in tetrahydrofuran. The solution was stirred overnight and the completion of the reaction was monitored by TLC. The solvent was removed and the residue was taken up in dichloromethane and washed with water. The organic layer was dried over anhydrous sodium sulfate and evaporated to give (E)-2,4,6-trimethoxystyryl-3-benzamido-4-methoxybenzylsulfone in 76% yield. m.p. 163-166° C. NMR (DMSO-d6) δ 3.82 (s, 3H), 3.83 (s, 6H), 3.86 (s, 3H), 4.2 (s, 2H), 6.14 (s, 2H), 7.10-7.18 (d, 1H vinylic), 7.00-7.86 (m, aromatic), 8.90 (s, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[CH:18][C:19]=2[CH3:20])=[CH:10][CH:9]=1)[NH2:6].[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:26]=1[C:27](Cl)=[O:28].CCN(C(C)C)C(C)C>ClCCl>[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:22])[N:16]([CH3:21])[CH:17]=[CH:18][C:19]=2[CH3:20])=[CH:12][CH:13]=1)[NH:6][C:27]([C:26]1[C:25]([Cl:24])=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:34])=[O:28]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)ccn(C)c2=O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2c(C)ccn(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Reaction time: 0.08 h
Yield: 48.6 %

Procedure:
To a suspension of 4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester hydrochloride salt (34 mg, 0.1 mmol) and 2,6-dichlorobenzoyl chloride (25 mg, 0.12 mmol) in dichloromethane (2 mL) was added DIEA (174 μL, 1.0 mmol) at room temperature. After 5 min, a clear solution was obtained which was stirred for 72 h. Then, the mixture was concentrated, the residue was dissolved in ethyl acetate (25 mL), was washed with 0.5 N HCl (25 mL), saturated NaHCO3 solution (25 mL), brine solution (15 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration gave crude product, which was purified by silica gel chromatography using a Biotage (40s) column, to afford 23 mg (49% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,4-dimethyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester as an amorphous white solid. ES-HRMS m/e calcd for C24H22Cl2N2O4 (M+Na) 495.0850, found 495.0859.
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[C:8]([N:11]1[CH2:15][CH2:14][CH2:13][O:12]1)(=[NH:10])[NH2:9].S([O-])([O-])(=O)=O.[Na+].[Na+].[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:25]=1[N:31]=[C:32]=[O:33].[N-]=C=O.[ClH:37]>O1CCCC1.CO.C(OCC)(=O)C>[ClH:37].[CH3:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[C:25]=1[NH:31][C:32]([NH:10][C:8]([N:11]1[CH2:15][CH2:14][CH2:13][O:12]1)=[NH:9])=[O:33]
Reactant: Cc1cccc(C)c1N=C=O
Reactant: N=C(N)N1CCCO1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cccc(C)c1NC(=O)NC(=N)N1CCCO1

Procedure:
To 2.9 g. (36.0 mmol) of fifty percent (w/w) sodium hydroxide suspended in tetrahydrofuran (50 ml.) is added 6.0 g. (18.0 mmol) of N-amidinoisooxazolidine sulfate and the mixture stirred for one hour. Five (5.0) grams of anhydrous sodium sulfate are added and the mixture stirred for an additional hour. To this mixture are added 5.4 g. (36.0 mmol) of 2,6-dimethylphenylisocyanate and the mixture stirred for three hours. Thin layer chromotography (ethyl acetate) showed no starting isocyanate so the tetrahydrofuran is removed under vacuum. The residue is partitioned between water and chloroform. The layers are separated and the aqueous layer extracted with chloroform (1×100 ml.). The combined chloroform extracts are dried over anhydrous magnesium sulfate, filtered and concentrated to give an oil which is dissolved in methanol and acidified (pH=1) with methanolic hydrochloric acid. The methanol is removed to give an oil which is triturated with diethyl ether to give a solid which is crystallized from tetrahydrofuran/hexane to give N-[(2,6-dimethylphenylcarbamoyl)amidino] isooxazolidine hydrochloride, m.p. 147°-8° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[O:15])=[C:12]([C:22]([CH3:25])([CH3:24])[CH3:23])[O:11][N:10]=1.[BH4-].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:13]([CH:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[OH:15])=[C:12]([C:22]([CH3:25])([CH3:24])[CH3:23])[O:11][N:10]=1
Reactant: CC(C)(C)c1onc(-c2ccc(Cl)cc2Cl)c1C(=O)c1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1onc(-c2ccc(Cl)cc2Cl)c1C(O)c1cccnc1
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of 92 mg (0.24 mmol) of 3-(2,4-dichlorophenyl)-5-(1,1-dimethylethyl)-4-[(3-pyridyl)carbonyl]isoxazole in 5 mL of ethanol at 0° C. was added 20 mg (0.53 mmol) of sodium borohydride. After 2 hr, the reaction mixture was poured into water, and the product was extracted several times with ethyl acetate. The combined ethyl acetate fractions were washed with saturated sodium chloride and dried over magnesium sulfate. The drying agent was filtered off, and the ethyl acetate was removed by rotoevaporation. The crude product was purified by prep TLC to yield 68 mg (0.18 mmol) 3-(2,4-dichlorophenyl)-5-(1,1-dimethylethyl)-4-[(3-pyridyl)hydroxy-methyl]isoxazole. 1H NMR (CDCl3): δ 1.52 (s, 9), 6.14 (br s, 1), 6.86 (d, 1), 7.38 (m, 1), 8.27 (br s, 1) and 8.33 ppm (m, 1). MS m/z: 377.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-])=O)=[N:9]2)=[CH:4][CH:3]=1>C(O)C.[Pt].ClCCl>[NH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1[CH2:11][C:12](=[O:13])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]=1
Reactant: O=C1CC(c2ccccc2[N+](=O)[O-])=NN1c1ccc(Cl)cc1
Agent: [Pt]
Solvent: ClCCl
Solvent: CCO
Product: Nc1ccccc1C1=NN(c2ccc(Cl)cc2)C(=O)C1

Procedure:
The starting material is prepared thus: 2 g if 1-(p-chlorophenyl)-3-(o-nitrophenyl)-4,5-dihydropyrazol-5-one are catalytically hodrogenated in 100 ml of ethanol over 200 mg of 5% platinum on carbon at room temperature and 3 atmospheres. Since the product crystallizes from the mixture as it is formed, the mixture is diluted with dichloromethane to dissolve said crystalline product. It is filtered, the filtrate evaporated, and the dried residue recrystallized from ethanol, affording the 3-(o-aminophenyl)-1-(p-chlorophenyl)-4,5-dihydropyrazol-5-one melting at 199°-201°.
Reaction SMILES: [CH3:1][N:2]([S:22]([C:25]1[S:26][CH:27]=[CH:28][CH:29]=1)(=[O:24])=[O:23])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][C:14]([CH2:17][CH2:18][C:19](O)=[O:20])=[CH:15][N:16]=1)=[CH:8]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:42][S:43]([NH2:46])(=[O:45])=[O:44].C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:42][S:43]([NH:46][C:19](=[O:20])[CH2:18][CH2:17][C:14]1[S:13][C:12]([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[S:22]([C:25]2[S:26][CH:27]=[CH:28][CH:29]=2)(=[O:23])=[O:24])=[N:16][CH:15]=1)(=[O:45])=[O:44]
Reactant: CN(c1cccc2cc(-c3ncc(CCC(=O)O)s3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CN(c1cccc2cc(-c3ncc(CCC(=O)NS(C)(=O)=O)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A mixture of 3-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-1,3-thiazol-5-yl)propanoic acid (0.3.0 g), 1,1′-carbonylbis-1H-imidazole (0.27 g) and tetrahydrofuran (10 mL) was heated under reflux for 2 hr. The reaction mixture was cooled to room temperature, methanesulfonamide (0.32 g) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.50 mL) were added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated and 10% aqueous citric acid solution was added. The resulting crystals were collected by filtration, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (0.21 g, yield 60%) was obtained as yellow crystals from a fraction eluted with tetrahydrofuran-hexane (3:1, volume ratio). The crystals were recrystallized from ethyl acetate. melting point 217-218° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH:15]=[C:14]([OH:16])[C:13](=[O:17])[CH:12]=[C:11]3[CH3:18])[C:4]=2[N:3]=[CH:2]1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:21]=1[CH2:22]Br>CN(C=O)C>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:21]=1[CH2:22][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH:15]=[C:14]([OH:16])[C:13](=[O:17])[CH:12]=[C:11]3[CH3:18])[C:4]=2[N:3]=[CH:2]1
Reactant: Fc1cccc(Cl)c1CBr
Reactant: Cc1cc(=O)c(O)cn1-c1cccc2[nH]cnc12
Solvent: CN(C)C=O
Product: Cc1cc(=O)c(O)cn1-c1cccc2c1ncn2Cc1c(F)cccc1Cl
Temperature: 100 °C
Reaction time: 3 h

Procedure:
1-(1H-Benzimidazol-4-yl)-5-hydroxy-2-methylpyridin-4(1H)-one (30 mg, 0.124 mmol) and 2-chloro-6-fluorobenzyl bromide (20 μl, 0.146 mmol) were combined in DMF (0.5 ml) then heated to 100° C. After 3 h LC/MS indicated the reaction was incomplete. The mixture was cooled to RT and 10 μL of 2-chloro-6-fluorobenzyl bromide was added. The mixture was heated to 100° C. After 1 hr the mixture was cooled to RT and purified directly by preparative reversed-phase HPLC (20×150 mm Waters Sunfire (0.1% TFA), 5-40% ACN/water over 20 min at 20 mL/min). Fractions containing the product were pooled then applied to a Phenomenex Strata-X—C ion exchange column. The column was washed with H2O and MeOH (discard) then with 10% concentrated NH4OH in MeOH (collect). The collected fraction was concentrated to give 1-[1-(2-Chloro-6-fluorobenzyl)-1H-benzimidazol-4-yl]-5-hydroxy-2-methylpyridin-4(1H)-one as an off-white solid. 1H NMR (500 MHz, d6-DMSO) δ 8.43 (s, 1 H), 7.66 (d, J=8.3 Hz, 1 H), 7.52-7.29 (m, 6 H), 6.24 (s, 1 H), 5.70 (s, 2 H), 1.90 (s, 3 H). HRMS (ESI) Calc (M+H)=384.0910. Found 384.0913.
Reaction SMILES: [OH:1][C:2]([CH3:16])([CH3:15])[CH2:3][C:4](=O)[C:5](=[C:11]([CH3:13])[CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7].O.[NH2:18][NH2:19]>C(O)(=O)C>[CH3:12][C:11]1([CH3:13])[NH:19][N:18]=[C:4]([CH2:3][C:2]([OH:1])([CH3:16])[CH3:15])[CH:5]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(C(=O)CC(C)(C)O)=C(C)C
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1C(CC(C)(C)O)=NNC1(C)C
Temperature: 180 °C
Yield: 98 %

Procedure:
500 mg of the product of Step B were added to 3 ml of acetic acid and 121 mg of hydrazine hydrate and the temperature rose spontaneously to 40° C. The acetic acid was distilled by heating the mixture up to 180° C. during which the majority of the acetic acid was removed. The mixture was cooled and water was added thereto. The mixture was extracted with chloroform and the organic phase was dried over magnesium sulfate and evaporated to dryness to obtain 520 mg of ethyl 4,5-dihydro-5,5-dimethyl-3-(2-hydroxy-2-methylpropyl)-[1H]-pyrazole-4-carboxylate in the form of a liquid.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[NH:14][N:15]=2)(=O)=O)C=CC=CC=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26](/[CH:29]=[CH:30]\[C:31]#[N:32])=[N:27][CH:28]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:30]=[C:31]([NH2:32])[N:15]3[N:14]=[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[N:12]=[C:11]3[CH:10]=2)=[N:27][CH:28]=1
Reactant: N#C/C=C\c1ccc(Cl)cn1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccccn2)n1)c1ccccc1
Product: Nc1cc(-c2ccc(Cl)cn2)cc2nc(-c3ccccn3)nn12

Procedure:
The title compound, MS m/e (%):323 (M+H+,100), was prepared in accordance with the general method of example 1 from 2-(5-benzenesulfonylmethyl-2H-[1,2,4]triazol-3-yl)-pyridine and (E)/(Z)-3-(5-chloro-pyridin-2-yl)-acrylonitrile.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:7]2[CH2:8][CH2:9][CH:10]([C:12](O)=[O:13])[CH2:11][C:6]2=[N:5][N:4]=1.C(Cl)(C(Cl)=O)=O.Cl.ClC1C(CN)=[N:27]C=CN=1.CCN(C(C)C)C(C)C>C1COCC1.CN(C=O)C>[F:1][C:2]([F:16])([F:15])[C:3]1[N:7]2[CH2:8][CH2:9][CH:10]([C:12]([NH2:27])=[O:13])[CH2:11][C:6]2=[N:5][N:4]=1
Reactant: NCc1nccnc1Cl
Reactant: O=C(O)C1CCn2c(nnc2C(F)(F)F)C1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)C1CCn2c(nnc2C(F)(F)F)C1
Reaction time: 1 h
Yield: 49.3 %

Procedure:
To a solution of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxylic acid (1.63 g, 6.93 mmol) in THF (35 mL) was added dropwise (COCl)2 (4.4 g, 34.66 mmol) and 0.1 mL of DMF at 0° C., the mixture was stirred at this temperature for 1 hours and then the solvent was removed. The resulting residue was dissolved in THF (35 mL), (3-chloropyrazin-2-yl)methanamine hydrochloride (1.37 g, 7.63 mmol) and DIEA (2.68 g, 20.79 mmol) was added, the mixture was stirred at 60° C. for 1 h. Remove the solvent in vacuo and the residue was extracted with DCM and the combined organic layer was washed with water, brine and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo and the residue was purified by silica gel column chromatography (DCM/THF=100/20) to afford N4(3-chloropyrazin-2-yl)methyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-7-carboxamide (0.8 g, yield 32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][CH:10]=2)=[CH:5][CH:4]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.COC1C=CC(C2OC3C=CC=CC=3C=2C(=O)C2C=CC(C)=CC=2)=CC=1>C(Cl)Cl>[C:18]([C:10]1[O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(-c2coc3ccccc23)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: COc1ccc(-c2oc3ccccc3c2C(=O)c2ccc(C)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2c(C(=O)c3ccccc3)oc3ccccc23)cc1

Procedure:
Acylation of 3-p-methoxyphenylbenzofuran with benzoyl chloride and stannic chloride in methylene chloride as described in Example 1 for the preparation of 2-p-methoxyphenyl-3-p-methylbenzoylbenzofuran gives 2-benzoyl-3-p-methoxyphenylbenzofuran.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]2)[N:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CC#N.O>[CH3:9][NH:8][C:6]1[N:7]=[C:2]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[N:3]=[C:4]([NH:10][C@@H:11]2[CH2:12][CH2:13][C@H:14]([C:17]([OH:19])=[O:18])[CH2:15][CH2:16]2)[N:5]=1
Reactant: CNc1nc(Cl)nc(N[C@H]2CC[C@@H](C(=O)O)CC2)n1
Reactant: C1CCNCC1
Solvent: CC#N
Solvent: O
Product: CNc1nc(N[C@H]2CC[C@@H](C(=O)O)CC2)nc(N2CCCCC2)n1
Temperature: 80 °C

Procedure:
To the crude solution of cis-4-(4-chloro-6-(methylamino)-1,3,5-triazin-2-ylamino)cyclohexanecarboxylic acid (˜0.38 mmol) in CH3CN/H2O (1/1, 5 ml) was added piperidine (188 μL, 5 equivalents). The reaction mixture was heated at 80° C. overnight. The reaction solution was condensed and the crude was acidified and purified by RP-HPLC (Luna 5μ C8(2), 100×21 mm, 15-60% CH3CN/H2O, 0.1% TFA, 17 min) to give the product (34.9 mg). MS (ES+): m/e 335.22 [M+H]+.
Reaction SMILES: [C:1]([N:9]1[CH2:21][CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:24]I.O>CN(C=O)C>[C:1]([N:9]1[CH2:21][CH2:20][C:19]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:24])[C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=C(c1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c2c(c3ccccc31)CCN(C(=O)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.2 %

Procedure:
To a stirred solution of 2-benzoyl-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indole (3.0 g, 10.9 mmole) in dry DMF (75 mL) at 5° C. was added 60% NaH (0.52 g, 13.1 mmole). After 10 min, methyliodide (7.80 g, 55 mmole) was added and the reaction was allowed to warm to RT and stir for 12 hr. The reaction contents were poured into H2O (50 mL) and extracted with EtOAc (2×100 mL). The combined organic phases were washed sequentially with H2O and brine, then were dried over Na2SO4. Concentration under reduced pressure and purification on silica (hexanes/EtOAc, 1:1) afforded the title compound (3.14 g, 99%) as a white solid: MS (ES) m/e 291 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:11]1[CH:12]=[C:13]([C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[CH:41]=2)[CH:14]=[C:15]2[C:23]=1[NH:22][C:21]1[CH:20]=[C:19]([C:24]([N:26]3[CH2:32][CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[O:25])[CH:18]=[CH:17][C:16]2=1)(=[O:10])[NH2:9]>C(Cl)Cl>[N:26]1([C:24]([C:19]2[CH:20]=[C:21]3[C:16]([C:15]4[CH:14]=[C:13]([C:40]5[CH:45]=[CH:44][CH:43]=[C:42]([O:46][CH3:47])[CH:41]=5)[CH:12]=[C:11]([C:8]([NH2:9])=[O:10])[C:23]=4[NH:22]3)=[CH:17][CH:18]=2)=[O:25])[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: COc1cccc(-c2cc(C(N)=O)c3[nH]c4cc(C(=O)N5CCCN(C(=O)OC(C)(C)C)CC5)ccc4c3c2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cccc(-c2cc(C(N)=O)c3[nH]c4cc(C(=O)N5CCCNCC5)ccc4c3c2)c1
Reaction time: 4 h
Yield: 95 %

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of tert-butyl 4-(8-carbamoyl-6-(3-methoxyphenyl)-9H-carbazole-2-carbonyl)-1,4-diazepane-1-carboxylate (11 mg, 0.020 mmol) in DCM (5 mL). After 4 hr at RT, the solvents were removed and the residue was taken up in MeOH and applied onto a SCX cartridge. This was washed with MeOH and released 2 N NH3 in MeOH to leave 7-(1,4-diazepane-1-carbonyl)-3-(3-methoxyphenyl)-9H-carbazole-1-carboxamide (8.5 mg, 0.019 mmol, 92% yield) as a solid. MS (ESI) m/z 443.23 (M+H). 1H NMR (500 MHz, MeOD) δ ppm 8.57 (1H, s), 8.28 (1H, d, J=8.24 Hz), 8.24 (1H, s), 7.71 (1H, s), 7.34-7.44 (3H, m), 7.29 (1H, d, J=7.93 Hz), 6.94 (1H, dt, J=7.55, 2.02 Hz), 3.92 (3H, s), 3.81-3.89 (2H, m), 3.55-3.65 (2H, m), 3.10-3.18 (1H, m), 2.94-3.04 (2H, m), 2.87-2.95 (1H, m), 1.96-2.08 (1H, m), 1.77-1.89(1H, m).