Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1)[CH2:7][CH:6]([NH2:18])[CH2:5]2.ON1C2C=CC=NC=2N=N1.[C:29]1([C:39](O)=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.C(N(C(C)C)CC)(C)C.[ClH:51].CN(C)CCCN=C=NCC>CN(C)C=O.C(Cl)(Cl)Cl>[ClH:51].[ClH:51].[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1)[CH2:7][CH:6]([NH:18][C:39]([C:29]1[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31][CH:30]=1)=[O:40])[CH2:5]2
Reactant: NC1Cc2cc(Br)ccc2N(Cc2c[nH]cn2)C1
Reactant: O=C(O)c1cccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ncccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: O=C(NC1Cc2cc(Br)ccc2N(Cc2c[nH]cn2)C1)c1cccc2ccccc12
Reaction time: 18 h

Procedure:
To a solution of 6-Bromo-1,2,3,4-tetrahydro-1-(1H-imidazol-4-ylmethyl)-3-quinolinamine (30 mg, 0.072 mmol) in dimethyl formamide (1 mL) were sequentially added 1-hydroxyazabenzotriazole (19 mg, 0.15 mmol), 1-naphthoic acid (25 mg, 0.15 mmol), diisopropylethyl amine (0.7 mL, 0.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28 mg, 0.15 mmol). After 18 hours, the mixture was diluted with chloroform (10 mL) and washed with saturated NaHCO3 solution (10 mL). The organic layer was separated, dried and concentrated. Purification by silica gel flash column chromatography eluting with 50% ethyl acetate in hexanes followed by 1:9 methanol in chloroform afforded two fractions. More polar fraction 2 (14 mg) was the desired product and the less polar fraction 1 (35 mg) was diacylated product. Fraction 1 was dissolved in methanol (1 mL) and treated with NaOH solution (1 N, 0.2 mL). After 30 minutes, the mixture was concentrated and mixed with fraction 2 obtained above. The resulting mixture was dissolved in chloroform (10 mL) and washed with water (10 mL). The organic layer was dried (MgSO4), concentrated and purified by silica gel flash column eluting with 5% methanol in chloroform to afford the free base of the title compound (20 mg, 60%). The solid was dissolved in chloroform and HCl gas was bubbled for 30 seconds. The mixture was then concentrated in vacuo to afford the title compund (23 mg). MS: (M+H)+=461, 463 (1:1 ratio), 1 Br pattern.
Reaction SMILES: C([Li])CCC.[Cl-].[CH3:7][O:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[CH:37]([CH3:46])[C:38]([C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)=O.O>O1CCCC1>[Cl:29][C:30]1[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=1[CH:37]([CH3:46])/[C:38](/[C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1)=[CH:7]\[O:8][CH3:9]
Reactant: CC(C(=O)c1cccnc1)c1ccc(Cl)cc1Cl
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CO/C=C(/c1cccnc1)C(C)c1ccc(Cl)cc1Cl
Reaction time: 3 h

Procedure:
135 ml of n-butyllithium (1.6M in n-hexane) are added dropwise at 0° C. under argon to a suspension of 73.9 g (0.215 mol) of methoxymethyltriphenylphosphonium chloride in 500 ml of anhydrous tetrahydrofuran in such a manner that the temperature does not exceed 5° C. After stirring at 0° C. for 30 minutes a solution of 50 g (0.178 mol) of 2-(2,4-dichlorophenyl)-1-(3-pyridyl)-1-propanone in 100 ml of dry tetrahydrofuran is added dropwise at -75° C. within 30 minutes. The mixture is stirred at this temperature for 3 hours and 100 ml of water are then added dropwise at 0° C. The tetrahydrofuran is distilled off under reduced pressure and the residue is extracted with ethyl acetate. After distilling off the ethyl acetate the oily residue is chromatographed on silica gel with dichloromethane/ethyl acetate (95:5 vol%) as the eluent. There is thus obtained with the 1st fraction (E)- 3-(2,4-dichloro-α-methoxy methylene-β-methylphenethyl)-pyridine as beige crystals, m.p. 67-68° C., and with the 2nd fraction (Z)-3-(2,4-dichloro-α-methoxymethylene-β-methylphenethyl)-pyri dine as a yellowish oil in the ratio of about 1:1 in a total amount of 44.4 g.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:8][CH2:7]1.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[C:36]([NH:2][CH2:3][CH2:4][N:5]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH:6]1[CH2:7][CH2:8][N:9]([C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])[CH2:10][CH2:11]1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: C=CCOC(=O)N1CCC(N(CCN)CCc2ccc(Cl)cc2)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)N1CCC(N(CCNC(=O)c2ccccc2)CCc2ccc(Cl)cc2)CC1
Temperature: -15 °C
Reaction time: 2 h

Procedure:
Allyl 4-((2-aminoethyl)(4-chlorophenethyl)amino)piperidine-1-carboxylate hydrochloride obtained in Step 2 was suspended in dichloromethane (4 mL/mmol), the suspension was cooled to −15° C. and DIPEA (2.2 equiv) followed by benzoyl chloride (1.05 equiv) were added dropwise over 5 minutes. The cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature. After 2 h TLC revealed no presence of starting material. The reaction mixture was diluted with EtOAc (10 mL/mmol of starting material), washed with 1 M NaOH (2×), water (2×) and brine (2×) and dried over anhydrous MgSO4. After filtration of the drying agent the solvent was stripped off and the crude product was purified by column chromatography.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](SC)=[N:18][C:19](=[S:36])[N:20]([CH2:22][C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([O:28]C(C)(C)C)=[O:27])[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=[O:42]>ClCCl>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[O:42])[NH:18][C:19](=[S:36])[N:20]([CH2:22][C:23]4[CH:24]=[C:25]([CH:33]=[CH:34][CH:35]=4)[C:26]([OH:28])=[O:27])[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CSc1nc(=S)n(Cc2cccc(C(=O)OC(C)(C)C)c2)cc1C1c2ccccc2C=Cc2ccccc21
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=S)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of the product from step (vi) (0.5 g) in dichloromethane (12 ml) was treated with trifluoracetic acid (9 ml) and stirred at room temperature for 3.5 hours. The mixture was evaporated and the residue dissolved in ethanol (50 ml) and 2M HCl. The mixture was heated at reflux at 4 hours. The mixture was evaporated and the residue treated with water, filtered and dried (MgSO4). Purified by chromatography eluting with 5% methanol in dichloromethane. Yield 0.27 g.
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[O:14][C:13]2[C:12]([NH2:15])=[N:11][N:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9]=2[CH:8]=1)=[O:6])[CH2:2][CH3:3].C(N(C(C)C)CC)(C)C.[N+:30]([C:33]1[CH:41]=[CH:40][CH:39]=[CH:38][C:34]=1[C:35](Cl)=[O:36])([O-:32])=[O:31]>O1CCCC1>[CH2:1]([O:4][C:5]([C:7]1[O:14][C:13]2[C:12]([NH:15][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][CH:40]=[CH:41][C:33]=3[N+:30]([O-:32])=[O:31])=[N:11][N:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:9]=2[CH:8]=1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCOC(=O)c1cc2c(o1)c(N)nn2C(=O)OCC
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCOC(=O)c1cc2c(o1)c(NC(=O)c1ccccc1[N+](=O)[O-])nn2C(=O)OCC
Reaction time: 0.17 h
Yield: 74.1 %

Procedure:
To a solution of 3-amino-furo[3,2-c]pyrazole-1,5-dicarboxylic acid 1-ethyl ester 5-propyl ester (500 mg, 1.606 mmol) and diisopropylethylamine (DIEA, 0.824 mL, 4.818 mmol) in tetrahydrofuran (THF, 20 mL) at 0° C., 2-nitro-benzoyl chloride (0.318 mL, 2.409 mmol) was added. The reaction mixture was kept at the same temperature for 10 minutes then allowed to reach room temperature and let react overnight. The solvent was removed under vacuum, the residue was dissolved in dichloromethane (DCM) and washed with a 10% solution of acetic acid (AcOH), water, saturated NaHCO3 and brine. The crude was purified on silica gel (eluant dichloromethane/methanol 96/4) yielding 512 mg (69%) of the title compound.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1>C(#N)C.CN(C)C=O>[OH:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3]([NH:2][CH3:1])=[O:4])=[CH:7][CH:8]=1
Reactant: CN=C=O
Reactant: Nc1ccc(O)cc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CNC(=O)Nc1ccc(O)cc1
Reaction time: 12 h
Yield: 51.8 %

Procedure:
A solution of methyl isocyanate (6 g) in acetonitrile (10 ml) was added dropwise to a solution of 4-aminophenol (10.9 g) in N,N-dimethylformamide (50 ml) at 10° C. to 20° C. The mixture was stirred at 25° C. to 35° C. for 12 hours and evaporated under reduced pressure. Water (100 ml) was added to the resulting syrup and the mixture was stirred for 30 minutes. The mixture became thick in the course of stirring. The solid substance was collected by filtration, washed with cold water and recrystallized from aqueous alcohol to give 8.6 g of N-(4-hydroxyphenyl)-N'-methylurea of melting point 169°-171° C.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[OH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](OCC)=[O:24].Cl>O.O1CCCC1>[OH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:2][OH:3])=[O:24]
Reactant: CCOC(=O)CCCCCC(c1ccccc1)c1c(O)ccc2ccccc12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCCCCC(c1ccccc1)c1c(O)ccc2ccccc12)NO
Reaction time: 4 h
Yield: 38.4 %

Procedure:
Hydroxylamine hydrochloride (1.4 g) was dissolved in water (14 ml) followed by addition of sodium hydroxide (93%, 2 g) and water (7 ml). To this mixture was added a solution of ethyl 7-(2-hydroxy-1-naphthyl)-7-phenylheptanoate (1.08 g) in tetrahydrofuran (3 ml) and the mixture was stirred for 4 hours. This reaction mixture was neutralized with 1N-HCl and extracted with ethyl acetate. The organic layer was washed, dried, and concentrated, and the residue was purified using a silica gel column (chloroform-methanol) to provide the title compound (0.4 g).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]([C:13]3[C:14]([F:34])=[C:15]([NH:20][S:21]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.CS(C)=O.[C-:39]#[N:40].[K+]>O>[C:39]([C:2]1[C:3]2[C:10]([C:11]([C:13]3[C:14]([F:34])=[C:15]([NH:20][S:21]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)(=[O:22])=[O:23])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1)#[N:40]
Reactant: [C-]#N
Reactant: O=C(c1c(F)ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F)c1c[nH]c2ncnc(Cl)c12
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ncnc2[nH]cc(C(=O)c3c(F)ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)c3F)c12
Temperature: 150 °C
Yield: 13.1 %

Procedure:
To N-[3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1016, 62 mg, 0.12 mmol), 1.00 mL of dimethyl sulfoxide is added, followed by potassium cyanide (39.0 mg, 0.60 mmol). The reaction is heated at 150° C. in an oil bath for 4 hours, then at 150° C. overnight. The reaction is poured into water and extracted with ethyl acetate. The organic layer is concentrated under vacuum and purified by silica gel column chromatography, eluting with a gradient of 10-60% ethyl acetate in hexanes. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-1023, 8 mg). MS (ESI) [M+H+]+=508.1.
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH:10]([NH:12][CH2:13][C:14]#[CH:15])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:17].C(N([CH:30]([CH3:32])C)CC)(C)C.ClCCl.C(=O)([O-])[O-:37].[K+].[K+]>O1CCOCC1>[C:16]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]([N:12]([CH2:13][C:14]#[CH:15])[C:30](=[O:37])[CH3:32])[CH2:11][CH:2]1[CH3:1])(=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C#CCNC1CC(C)N(C(=O)c2ccccc2)c2ccccc21
Reactant: O=C([O-])[O-]
Reactant: CCN(C(C)C)C(C)C
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: C#CCN(C(C)=O)C1CC(C)N(C(=O)c2ccccc2)c2ccccc21
Yield: 58.8 %

Procedure:
To a solution of (2-methyl-4-prop-2-ynylamino-3,4-dihydro-2H-quinolin-1-yl)-phenyl-methanone (0.06 g), diisopropyl ethyl amine (0.038 g) in dioxane (5 ml), anhydride acetic (0.2 g) was added under stirring. The mixture was heated under reflux over the night. After cooling dichloromethane and an aqueous solution of potassium carbonate were added. The organic layer was separated, and then dried over sodium sulfate. Organic solvent was removed under reduce pressure to give the crude compound (0.15 g). Purification by chromatography was performed with dichloromethane/methanol (99/1) as eluent to give the desired title compound (0.04 g, 58.8% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][Mg]Cl>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:9])[CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: C[Mg]Cl
Reactant: O=Cc1ccnc(Br)c1
Solvent: C1CCOC1
Product: CC(O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a chilled (−78° C.) solution of 2-bromopyridine-4-carboxaldehyde (10.0 g, 53.8 mmol) in THF (100 mL) is added a 3 M solution of methylmagnesium chloride in THF (18 mL, 54 mmol) over a 10 minute period. After 1 hour, the solution is allowed to warm gradually to room temperature over a 3 hour period. The reaction is quenched by the slow addition of saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (2×200 mL). The combined organic layers are washed with brine, dried over sodium sulfate, and concentrated to afford an oil. The crude material is purified by silica gel chromatography eluting with a gradient of 10-45% EtOAc in hexanes to afford 1-(2-bromopyridin-4-yl)-ethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32].N1C=CC=CC=1>C(Cl)Cl>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([NH:1][C:2]1[CH:3]=[C:4]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(N)cc3ccoc23)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2cc(NS(=O)(=O)c3ccccc3Cl)cc3ccoc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
tert-Butyl 4-(5-amino-1-benzofuran-7-yl)piperazine-1-carboxylate (0.59 g, 1.87 mmol; Intermediate 10) was dissolved in DCM. 2-Chlorobenzenesulfonyl chloride (0.59 g, 2.8 mmol) was added followed by pyridine (0.45 mL, 5.6 mmol). The reaction mixture was stirred at room temperature overnight. Filtration through a silica plug afforded 0.66 g (72%) of the title product. HPLC purity 92%, RT=2.56 min (System A; 10-97% MeCN over 3 min). 1H NMR (400 MHz, CDCl3) δ ppm 1.48 (s, 9H) 3.07-3.21 (m, 4H) 3.51-3.65 (m, 4H) 6.51 (d, J=2.0 Hz, 1H) 6.62 (d, J=2.3 Hz, 1H) 6.93 (d, J=2.0 Hz, 1H) 7.00 (s, 1H) 7.18-7.31 (m, 2H) 7.36-7.47 (m, 1H) 7.47-7.57 (m, 2H) 7.90 (dd, J=7.9, 1.6 Hz, 1H). MS (ESI+) m/z 492.2 (M+H)+.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH:24]([O:27][C:28]1[N:33]=[C:32]2[S:34][C:35]([NH2:37])=[N:36][C:31]2=[CH:30][CH:29]=1)([CH3:26])[CH3:25].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14]([NH:37][C:35]3[S:34][C:32]4[C:31]([N:36]=3)=[CH:30][CH:29]=[C:28]([O:27][CH:24]([CH3:26])[CH3:25])[N:33]=4)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CC(C)Oc1ccc2nc(N)sc2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)Oc1ccc2nc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)sc2n1
Yield: 38.9 %

Procedure:
The compound of example A82 was obtained by similar method described in example A75 using (4-cyclopropanesulfonyl-phenyl)-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Preparation 14) (0.100 g,0.29 mmol), 5-iso-propoxy-thiazolo[5,4-b]pyridin-2-ylamine (0.067 g, 0.32 mmol), HOBt (0.047 g, 0.35 mmol), and EDCI (0.067 g, 0.35 mmol), N-methyl morpholine (0.065 g, 0.58 mmol) in DMF (5 mL) to provide the title compound (0.060 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12]Cl)[N:6]=[CH:5]2.Cl.[C@H:15]12[CH2:21][C@H:18]([NH:19][CH2:20]1)[CH2:17][O:16]2.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH2:12][N:19]1[CH2:20][C@@H:15]3[CH2:21][C@H:18]1[CH2:17][O:16]3)[N:6]=[CH:5]2
Reactant: ClCCn1ncc2cc(Br)ccc21
Reactant: C1O[C@@H]2CN[C@H]1C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2c(cnn2CCN2C[C@@H]3C[C@H]2CO3)c1
Temperature: 90 °C
Reaction time: 19 h
Yield: 38.9 %

Procedure:
5-Bromo-1-(2-chloroethyl)-1H-indazole (183 mg, 0.703 mmol) was added to a suspension of (1S,4S)-(+)-5-aza-2-oxabicyclo[2.2.1]heptane hydrochloride (286 mg, 2.11 mmol), K2CO3 (485 mg, 3.52 mmol) and KI (117 mg, 0.703 mmol) in DMF (10 mL) under N2. The resulting suspension was stirred at 90° C. for 19 h. The suspension was cooled, and H2O (10 mL) was added. The aqueous solution was extracted with EtOAc, and the combined organic extracts were washed with brine. The organic solution was dried over Na2SO4 and concentrated under reduced pressure to afford clear viscous oil. Flash chromatography on silica gel (100:0 to 0:100 hexanes/(9:0.9:0.1 CH2Cl2/MeOH/NH4OH)) gave the title compound (88 mg, 39%) as a clear oil: 1H NMR (300 MHz, CDCl3) δ 7.95-7.92 (m, 1H), 7.87-7.84 (m, 1H), 7.45 (dd, J=8.7, 1.8 Hz, 1H), 7.34 (d, J=8.7 Hz, 1H), 4.43 (t, J=6.7 Hz, 2H), 4.34 (br s, 1H), 3.92 (d, J=7.8 Hz, 1H), 3.56 (dd, J=7.8, 1.5 Hz, 1H), 3.34 (br s, 1H), 3.15-3.01 (m, 2H), 2.92 (d, J=21.9 Hz, 1H), 2.81 (dd, J=9.9, 1.5 Hz, 1H), 2.47 (br d, J=9.9 Hz, 1H), 1.79-1.60 (m, 1H).
Reaction SMILES: CCCCCC.[H-].[K+].[NH:9]1[CH:13]=[CH:12][CH:11]=[N:10]1.[C:14]([O:18][C:19](=[O:38])[NH:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([S:28]([C:31]2[CH:36]=[CH:35][C:34](N)=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:24][CH2:23]1)([CH3:17])([CH3:16])[CH3:15]>CN(C=O)C.O>[C:14]([O:18][C:19](=[O:38])[NH:20][CH2:21][CH:22]1[CH2:23][CH2:24][N:25]([S:28]([C:31]2[CH:36]=[CH:35][C:34]([N:9]3[CH:13]=[CH:12][CH:11]=[N:10]3)=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:26][CH2:27]1)([CH3:17])([CH3:15])[CH3:16]
Reactant: c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)NCC1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Agent: [H-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCC1CCN(S(=O)(=O)c2ccc(-n3cccn3)cc2)CC1
Temperature: 70 °C
Yield: 30.7 %

Procedure:
To a stirred mixture of hexane washed potassium hydride (0.08 g, 2 mmol) in 5 mL of DMF was added pyrazole (0.136 g, 2 mmol) in one portion. Stirring was continued until gas evolution ceased. A solution of [1-(4-aminobenzenesulfonyl)-piperidin-4-ylmethyl]-carbamic acid t-butyl ester (0.745 g, 2 mmol) in 5 mL DMF was added and the solution was heated at 70° C. overnight. The reaction mixture was poured into water and the solids formed collected and dried (high vac). The crude product was purified by flash chromatography (silica Merck 60, CH2Cl2—CH3OH, 19:1) to give 0.258 g of the product as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:8]2[CH2:9][C:10](=O)[C:11]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2].O.[NH2:22][NH2:23]>C(O)C.O1CCOCC1>[C:1]([C:3]1[C:8]2[CH2:9][C:10](=[N:22][NH2:23])[C:11]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:12]=3[S:13][C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:2]
Reactant: NN
Reactant: COc1ccc2c(c1)C(=O)Cc1c(C#N)cccc1S2
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: COc1ccc2c(c1)C(=NN)Cc1c(C#N)cccc1S2
Reaction time: 7.5 h
Yield: 79.4 %

Procedure:
900mg of 9-cyano-2-methoxy-10,11-dihydro-11-oxo-dibenzo-[b,f]thiepin was dissolved in the mixed solvent of 8ml of ethanol and 8ml of dioxane. To this was added 1.0g of 100% hydrazine hydrate and the resulting mixture was refluxed with stirring for 7.5 hours. After the completion of reaction, the solvent was distilled off to obtain the residue, which was washed with a small amount of ethanol, and there was obtained 750mg of 9-cyano-2-methoxy-10,11-dihydro-11-oxo-dibenzo[b,f]thiepin hydrazone as colorless needles having a melting point of 186°-187° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][NH2:11].[C:12]([C:14](C#N)=[C:15]([C:18]#[N:19])[C:16]#[N:17])#[N:13]>C(O)C>[NH2:19][C:18]1[N:10]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=2[Cl:9])[N:11]=[C:14]([C:12]#[N:13])[C:15]=1[C:16]#[N:17]
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Reactant: N#CC(C#N)=C(C#N)C#N
Solvent: CCO
Product: N#Cc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C#N
Yield: 41.7 %

Procedure:
A mixture of 2,4,6-trichlorophenylhydrazine (21.1 g) and tetracyanoethylene (13.3 g) in ethanol (100 ml) was heated at reflux for 15 minutes. The reaction mixture was cooled and the solid precipitate was filtered off and washed with diethyl ether to give 5-amino-3,4-dicyano-1-(2,4,6-trichlorophenyl)pyrazole (13 g), as a buff colored solid, m.p. 267-271° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11](=[O:20])[C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[C:14](=[O:15])[C:7]=2[CH2:6][CH2:5]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25](O)[CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:17][O:16][C:13]1[C:14](=[O:15])[C:7]2[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][O:1][C:25]3[CH:26]=[C:27]([O:31][CH3:32])[C:28]([O:29][CH3:30])=[C:23]([O:22][CH3:21])[CH:24]=3)[CH2:10][CH2:9][C:8]=2[C:11](=[O:20])[C:12]=1[O:18][CH3:19]
Reactant: COc1cc(O)cc(OC)c1OC
Reactant: COC1=C(OC)C(=O)C2=C(CCC(CCO)CC2)C1=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1=C(OC)C(=O)C2=C(CCC(CCOc3cc(OC)c(OC)c(OC)c3)CC2)C1=O
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 79.9 %

Procedure:
To a solution of 7-(2-hydroxyethyl)-2,3-dimethoxy-4,5,6,7,8,9-hexahydro-1H-benzo[a]cycloheptene-1,4-dione (165 mg), 3,4,5-trimethoxyphenol (335 mg), and triphenylphosphine (201 mg) in THF (3 ml) was added a solution of diethyl azodicarboxylate (148 mg) in THF (1 ml) at room temperature. The reaction mixture was stirred at room temperature for 25 min and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate/hexane=1/4) and with recrystallization from ethyl acetate-hexane to obtain the entitled compound (210 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.Cl>C(O)C.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1
Reactant: N#Cc1ccc(Cl)cn1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCc1ccc(Cl)cn1
Yield: 51.1 %

Procedure:
A solution of 5-chloropicolinonitrile (3.8 g, 27.43 mmol), conc.HCl (3 mL) and 10% Pd—C (1.0 g) in ethanol (100 mL) was shaken under a hydrogen atmosphere (40 psi) for 2 h. The reaction mixture was filtered, concentrated and the resulting residue taken up in satd NaHCO3 (50 mL) and extracted with CH2Cl2 (4×25 mL). The combined CH2Cl2 layers were dried (Na2SO4), filtered and concentrated to give the title compound as a yellow oil (2.0 g, 51% yield). LCMS (M+H) calcd for C6H8ClN2: 143.04. found: 143.07. 1HNMR (500 MHz, CDCl3) δ ppm: 8.56–8.51 (1H, br d), 7.66–7.60 (1H, m), 7.28–7.14 (1H, m), 3.97 (2H, s), 1.72 (2H, s).