Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[C:4]([CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C.[OH-].[Na+].Cl>CS(C)=O.CO>[CH3:11][C:6]1[CH:5]=[C:4]([CH3:12])[N:3]=[C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:19]=2)[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: COC(=O)CCc1ccc(N)cc1
Reactant: Cc1cc(C)c([N+](=O)[O-])c(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C)c([N+](=O)[O-])c(Nc2ccc(CCC(=O)O)cc2)n1
Temperature: 140 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
To a solution of 2-chloro-4,6-dimethyl-3-nitropyridine (17.9 g, 96 mmol) and methyl 3-(4-aminophenyl)propanoate (19 g, 96 mmol) in DMSO (100 mL) was added N,N-diisopropylethylamine (26 g, 200 mmol), and the reaction mixture was heated at 140° C. overnight. The reaction mixture was partitioned between water (400 mL) and ethyl acetate/toluene (v/v, 2:1, 300 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate/toluene (v/v, 2:1, 200 mL). The combined organic extracts were washed with brine (200 mL), dried (Na2SO4), and concentrated. To a solution of residual oil in methanol (100 mL) was added 2 N aqueous NaOH (150 mL, 300 mmol) and the resulting mixture was stirred at room temperature for 2 h. The volatile component was removed under reduced pressure and the residue was washed with ethyl acetate (200 mL). The aqueous phase was acidified with 2N hydrochloric acid (200 mL, 400 mmol) and extracted with ethyl acetate (3×200 mL). The extracts were washed with brine (200 mL), dried (Na2SO4), and concentrated to give 23.2 g (77%) of the title compound as pale brown solids.
Reaction SMILES: [CH2:1]([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[CH:14][S:13][C:12]=2[CH:16]=1.CI>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[C:14]([CH3:1])[S:13][C:12]=2[CH:16]=1
Reactant: [Li]CCCC
Reactant: COc1ccc2ccsc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc2cc(C)sc2c1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A 2.5 M solution of n-butyllithium in hexanes (20 ml, 50 mmole) was added under argon to a solution of 6-methoxybenzo[b]thiophene 1a (3.68 g, 22.4 mmole) in THF (150 ml) at −75°. After stirring at −75° for a further 30 minutes, the cooling bath was exchanged and the reaction warmed to −10° C. prior to addition of CH3I (4.2 ml, 9.58 g, 67 mmole). The resultant mixture was stirred at 0° C. for an additional 30 minutes, then allowed to gradually warm to room temperature before diluting with saturated NaHCO3 (150 ml). The layers were separated and the aqueous phase was extracted with EtOAc (2×100 ml). The combined organic extracts were dried over Na2SO4 and concentrated, in vacuo, to give 4.2 g of an amber oil which was purified by silica gel chromatography. Elution with hexane: Et2O (98:2) and evaporation of the appropriate fractions gave 3.639 (91%) of a colourless oil. 1H NMR (DMSO-d6) δ 7.57 (1H, d, J=8.7 Hz), 7.43 (1H, d, J=2.4 Hz), 6.99 (1H, s), 6.92 (1H, dd, J=2.4, 8.7 Hz), 3.78 (3H, s), 2.50 (3H, s). Anal. Calcd. for C10H10OS: C, 67.38; H, 5.66; S, 17.99. Found: C, 67.42; H, 5.74; S, 17.87.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].CO>O1CCCC1.C(N(CC)CC)C>[CH2:28]([Sn:23]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:24][CH2:25][CH2:26][CH3:27])[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1cccc(-c2cccnc2)c1
Agent: [Li]C(C)(C)C
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(-c2cccnc2)c1
Temperature: 25 °C
Yield: 82 %

Procedure:
A cooled (−78° C.) solution of 3-(3-bromophenyl)pyridine (7.50 g, 32 mmol) in tetrahydrofuran (120 ml) was treated with a cooled (−78° C.) solution of tert-butyllithium (41 ml of a 1.7M solution in hexanes, 70 mmol). After 5 minutes tri-n-butyltin chloride (9.6 ml) was added and the mixture was allowed to warm to room temperature over 1 h. Methanol (7.5 ml) and triethylamine (7.5 ml) were added and the solvent evaporated. The residue was partitioned between ethyl acetate and saturated sodium hydrogencarbonate solution, the organics washed with brine, dried and evaporated to give a yellow oil. This oil was purified by silica gel flash column chromatography eluting with isohexane/ethyl acetate/triethylamine (99:1:0.5 through to 80:20:0.5) to afford 3-[3-(tri-n-butylstannanyl)phenyl]pyridine (11.7 g, 82%) as a colourless oil. 1H NMR (360 MHz, CDCl3) δH 0.86-0.93 (3H, m), 1.06-1.12 (2H, m), 1.28-1.40 (2H, m), 1.54-1.56 (2H, m), 7.34-7.39 (2H, m), 7.48-7.52 (2H, m), 7.62-7.65 (1H, m), 7.83-7.88 (1H, m), 8.57-8.60 (1H, m), 8.85 (1H, s).
Reaction SMILES: [SH:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][CH2:13][C:14]([F:18])=[C:15]([F:17])[F:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:18][CH:14]([CH:15]([F:17])[F:16])[CH:13]=[CH:12][S:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: FC(F)=C(F)CCBr
Reactant: Sc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)C(F)C=CSc1nc2ccccc2o1
Reaction time: 2 h
Yield: 103.2 %

Procedure:
2-Mercaptobenzoxazole (2 g), 4-bromo-1,1,2-trifluorobut-1-ene (2.75 g) and potassium carbonate (1 g) were stirred together in 40 ml of acetone and heated to reflux. After 2 hours the reaction mixture was allowed to cool, filtered to remove insoluble potassium salts and the filterate was evaporated under reduced pressure to yield 3.54 g of a brown oil which was used in step b without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[C:14]=3[N:13]=[C:12](Cl)[C:11]=2[CH:10]=[CH:9]1>C(CN)O.O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[C:14]=3[N:13]=[C:12]([NH:13][CH2:14][CH2:15][OH:21])[C:11]=2[CH:10]=[CH:9]1
Reactant: Cc1ccccc1-n1ccc2c(Cl)nc3c(OCC(F)(F)C(F)(F)F)cccc3c21
Solvent: O
Solvent: NCCO
Product: Cc1ccccc1-n1ccc2c(NCCO)nc3c(OCC(F)(F)C(F)(F)F)cccc3c21
Temperature: 180 °C
Reaction time: 15 h
Yield: 171.9 %

Procedure:
1-(2-Methylphenyl)-4-chloro-6-β,β,γ,γ,γ-pentafluoropropyloxypyrrolo[3,2-c]quinoline(600 mg, 1.4 mmol) was dissolved in ethanolamine(5.0 ml), then stirred at 180° C. for 15 hours in the pressure tube. The reaction mixture was dissolved in water, extracted with dichloromethane, and the organic layer was washed with water for 3 times. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography(ethyl acetate:hexane=1:1) to obtain 560 mg of desired compound as solid in 89% of yield.
Reaction SMILES: F[C:2](F)([CH2:6][NH:7][CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=CC=C(OC3CCC4(CCCCC4)CC3)C=2)[CH:10]=1)C(O)=O.[NH3:32].[CH2:33]([OH:35])C>>[CH3:33][O:35][C:11]1[CH:10]=[C:9]2[C:18](=[CH:17][CH:16]=1)[N:32]=[C:6]([CH3:2])[N:7]=[CH:8]2
Reactant: CCO
Reactant: O=C(O)C(F)(F)CNCc1ccc2cc(OC3CCC4(CCCCC4)CC3)ccc2c1
Reactant: N
Product: COc1ccc2nc(C)ncc2c1
Temperature: -78 °C

Procedure:
N-(2-Formyl-4-methoxyphenyl)acetamide (2, 2.50 g, 12.9 mmol) was dissolved in Ethanol (300 mL, 5000 mmol) and cooled to at −78° C. in a high pressure reactor. A solution of NH3 saturated in ethanol was added. The reaction mixture was then heated at 135° C. for 2 hours. Cooled to 23° C., and solvent was removed to give a crude product, which was then purified via chromatography (SiO2, 120 g, 0-20% MeOH/DCM; 1.87 g, 83%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.91 (s, 3H) 3.97 (s, 3H) 7.15 (d, J=2.51 Hz, 1H) 7.56 (dd, J=9.04, 2.51 Hz, 1H) 7.93 (d, J=9.04 Hz, 1H) 9.27 (s, 1H). MS (ESI, M+1): 175.10.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]2[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=2)[NH2:13])[CH:5]=1)[CH3:2].[C:17]([O:21][C:22]([NH:24][C:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=S)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl.C(OCC)(=O)C>[C:31]([O:30][C:28]([NH:27][C:25]([NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])=[N:13][C:12]1[CH:14]=[CH:15][CH:16]=[C:10]([C:6]2[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[CH:8][N:7]=2)[CH:11]=1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: CCOc1ccnc(-c2cccc(N)c2)c1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOc1ccnc(-c2cccc(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Reaction time: 2 h
Yield: 70.8 %

Procedure:
To a suspension of 3-(4-ethoxypyridin-2-yl)aniline (258 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (399 mg) and diisopropylethyl-amine (0.482 ml) in dichloromethane (12 ml) was added 1-methyl-2-chloropyridinium iodide (400 mg), and the mixture was stirred for 2 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 25 g, n-hexane:ethyl acetate=3:1) to give N,N′-bis(tert-butoxycarbonyl) -N″-(3-(4-ethoxypyridin-2-yl)phenyl)guanidine (389 mg).
Reaction SMILES: Cl[C:2]([C:11]1[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:18])=[N:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10].ClC(Cl)Cl.[C-:23]#[N:24].[K+]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.O>[Cl:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([Cl:17])[C:11]=1[C:2](=[N:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:10])[C:23]#[N:24]
Reactant: [C-]#N
Reactant: Cc1ccccc1N=C(Cl)c1c(Cl)cccc1Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccccc1N=C(C#N)c1c(Cl)cccc1Cl
Reaction time: 0.5 h

Procedure:
To a stirred solution of 7.45 parts of N-[chloro(2,6-dichlorophenyl)methylene]-2-methylbenzenamine in 150 parts of trichloromethane is added a solution of 4.88 parts of potassium cyanide and 8.5 parts of N,N,N-triethylbenzenemethanaminium chloride in 8 parts of water while stirring vigorously. Stirring is continued for 30 minutes at room temperature. The organic phase is separated, washed twice with water, dried, filtered and evaporated. The residue is dissolved in petroleumether and the solution is decanted from some insoluble tar. The petroleumether is evaporated in vacuo. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 17.5 parts of petroleumether, yielding 2.8 parts of 2,6-dichloro-α-[(2-methylphenyl)imino]benzeneacetonitrile; mp. 55° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N=CC1C=CC=CC=1O)C1C=CC=CC=1>>[CH2:12]([N:19]=[CH:4][C:3]1[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:2]=1[OH:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(O)c(C=O)c1
Reactant: NCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccccc1C=NCc1ccccc1
Product: COc1ccc(O)c(C=NCc2ccccc2)c1

Procedure:
This compound was prepared from 2.7 g of 2-hydroxy-5-methoxy-benzaldehyde, 2.3 mL of benzylamine and 0.03 g of p-toluenesulphonic acid using the procedure described for 64a. Yield: 4:3 g (oil).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[CH3:24][O:25][C:26]([CH:28]1[CH2:32][CH2:31][N:30]([C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]1[C:41]1[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=1)=[O:27].[CH2:48](N(CC)CC)C.CN(C1C=CC=CN=1)C>O1CCCC1>[CH2:24]([O:25][C:26]([CH:28]1[CH2:32][CH2:31][N:30]([C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:29]1[C:41]1[CH:42]=[CH:43][C:44]([NH:47][C:21](=[O:23])[CH2:20][C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:45][CH:46]=1)=[O:27])[CH3:48]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: COC(=O)C1CCN(C(=O)c2ccccc2)C1c1ccc(N)cc1
Reactant: CCN(CC)CC
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C(=O)c2ccccc2)C1c1ccc(NC(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Reaction time: 0.17 h

Procedure:
A stirred solution of [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid (1.35 g, prepared as described in Example 52B of International Patent Application Publication No. WO 96/22966) in anhydrous tetrahydrofuran (60 ml), at 20° C. and under an atmosphere of argon, was treated with benzotriazol-lyloxytris(dimethylamino)phosphonium hexafluorophosphate (2.04 g). After stirring for 10 minutes the mixture was treated with 2-(4-amino-phenyl)-1-benzoyl-pyrrolidine-3-carboxylic acid methyl ester (1.5 g, Reference Example 14) then with triethylamine (1.77 ml) and dimethylaminopyridine (0.051 g). The resulting mixture was stirred at 20° C. for 60 hours then evaporated (40° C. and 2.7 kPa). The residue was dissolved in ethyl acetate (150 ml) and the solution was washed with water (100 ml), then with aqueous potassium bicarbonate solution (100 ml, 10%), then with water (50 ml), then dried over magnesium sulphate and then evaporated under reduced pressure (40° C., 2.7 kPa). The residue was subjected to flash chromatography on silica (200 g, 0.045-0.020 mm particle size) eluting with a mixture of cyclohexane and ethyl acetate (30:70, v/v) affording the title compound (0.33 g) as an off-white powder. MS [DCI (reactant gas, ammonia)]: 621 [M+H]+.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.C[O:14][C:15](=O)[C@H:16]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(O)=O>C1COCC1>[C:18]([NH:17][C@@H:16]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:15](=[O:14])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COP(C)(=O)OC
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)OC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
A solution of dimethyl methylphosphonate (3.06 mL, 28.27 mmol, 8.0 eq) in anhydrous THF (30 mL) was cooled to −78° C. and 2.5 N n-BuLi (2.66 mL, 28.60 mmol, 8.0 eq) was added dropwise. After addition, the solution was stirred at −78° C. for 30 min and then a solution of compound 1 (1.00 g, 3.53 mmol, 1.0 eq) in anhydrous THF (20 mL) was added slowly. The resulting mixture was stirred at −78° C. for 1 h and then at ambient temperature for 1 h. The solution was acidified with 10% AcOH (20 mL), extracted with EtOAc (3×50 mL). The extract was washed with 10% NaHCO3, brine, dried over anhydrous MgSO4 and evaporation of the solvent gave a crude residue, which was subjected to column chromatography on silica gel elution with 100% EtOAc afforded dimethyl [(3S)-3-[(N-benzoyl)amino]-2-oxo-4-phenyl-butyl]phosphonate 2 as a pale yellow oil (0.876 g, 66%): Rf 0.34 (EtOAc); 1H NMR (300 MHz, CDCl3) δH 3.10 (2H, m, —CH2Ph), 3.34 (2H, m, —CH2—), 3.69 and 3.73 (6H, 2xs, 2xOMe), 5.10 (1H, m, —CH—) and 7.18-7.82 (10H, m, Ar—H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Br:12][C:13]1[CH:18]=[C:17]([CH2:19]Br)[CH:16]=[CH:15][C:14]=1[S:21]([CH3:24])(=[O:23])=[O:22].C(OCC)(=O)C>CN(C=O)C>[ClH:11].[Br:12][C:13]1[CH:18]=[C:17]([CH:16]=[CH:15][C:14]=1[S:21]([CH3:24])(=[O:23])=[O:22])[CH2:19][N:10]1[CH:9]=[C:8]([Cl:11])[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:2]1=[NH:1]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1Br
Reactant: NC(=O)c1cc(Cl)cnc1N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(Cn2cc(Cl)cc(C(N)=O)c2=N)cc1Br
Product: Cl
Temperature: 25 °C
Yield: 49 %

Procedure:
A solution of 2-amino-5-chloronicotinamide (300 mg) and 2-bromo-4-(bromomethyl)-1-(methylsulfonyl)benzene (860 mg) in DMF (5 ml) was stirred at 100° C. for 6 hr. The mixture was allowed to cool to room temperature, ethyl acetate was added, and the precipitated crystals were collected by filtration. The obtained crystals were dissolved in 1N sodium hydroxide solution, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=9:1→-ethyl acetate:methanol=9:1). The obtained yellow solid was dissolved in methanol, 4N hydrogen chloride-ethyl acetate solution was added, and the precipitated crystals were collected by filtration, and recrystallized to give the title compound (195 mg).
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH3:40])([CH3:39])[C:36]([NH2:38])=[O:37])[N:34]=2)[N:31]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[ClH:25].[ClH:25].[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([CH3:40])([CH3:39])[C:36]([NH2:38])=[O:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CC(C)(C(N)=O)c1cn2nc(Cl)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C(N)=O)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Product: Cl
Yield: 137.1 %

Procedure:
1.29 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 0.478 g of 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl]-2-methylpropionamide were stirred at 190-200° C. for 70 minutes. After cooling, aqueous sodium bicarbonate was added, followed by.,extraction with ethyl acetate. The extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (90:10:1). The desired fraction was collected; the residue was dissolved in 10 ml of ethyl acetate; 1.5 ml of a 4 N hydrogen chloride solution in ethyl acetate was added, followed by concentration under reduced pressure. Ethyl acetate was added to the residue; the resulting powder was collected by filtration, washed with ethyl acetate and dried to yield 0.823 g of the title compound.
Reaction SMILES: [S:1]1[C:5]2[CH2:6][NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:41])=[C:27]([CH:40]=1)[C:28]([NH:30][C:31]1[N:36]=[CH:35][C:34]([C:37](Cl)=[O:38])=[CH:33][CH:32]=1)=[O:29]>ClCCl>[S:1]1[C:5]2[CH2:6][N:7]([C:37]([C:34]3[CH:33]=[CH:32][C:31]([NH:30][C:28](=[O:29])[C:27]4[CH:40]=[C:23]([F:22])[CH:24]=[CH:25][C:26]=4[CH3:41])=[N:36][CH:35]=3)=[O:38])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=[CH:2]1
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Reactant: c1ccc2c(c1)Cc1ccsc1CN2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3sccc3Cc3ccccc32)cn1

Procedure:
As described for Example 1, 9,10-dihydro-4-H-thieno[2,3-c][1]benzazepine in dichloromethane, in the presence of triethylamine is reacted with 6-[(5-fluoro-2-methylbenzoyl)amino]pyridine-3-carbonyl chloride to give the product as a non-crystalline yellow solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[O:15][C@H:14]([O:16][CH3:17])[C@@H:13]2[C@@H:11]1[O:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-:18].[Na+].O>C(O)CO>[CH2:1]([O:8][CH2:9][C@H:10]1[O:15][C@H:14]([O:16][CH3:17])[C@@H:13]([OH:12])[C@@H:11]1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@H]2O[C@H]12
Reactant: [F-]
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](F)[C@@H]1O
Temperature: 200 °C
Reaction time: 4 h
Yield: 32.9 %

Procedure:
Compound 35.7 (2.2 g, 9.32 mmol) was dissolved in 10 mL ethyleneglycol, and then treated with NaF (2.2 g), KHF2 (2.2 g). The mixture was stirred at 200° C. for 4 h, cooled to r.t. and then treated with water (150 mL). The aqueous mixture was extracted twice with 200 mL EtOAc. The organic extracts were combined, dried over MgSO4, filtered and concentrated down under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 20-100% EtOAc in hexane to give compound 35.8 (786 mg, 33% yield).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:14]([OH:16])=O)[CH2:13]C[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].CC[O:25]C(C)=O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1([CH2:13][OH:25])[CH2:10][CH2:11][O:16][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCC1
Reactant: CCOC(C)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(CO)CCOC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 46 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (6.57 g, 28.4 mmol) in THF (60 mL) was added LiAlH4 (2.89 g, 61.0 mol) at room temperature. After stirred for 5 h, the reaction mixture was poured into ice-water and stirred for 30 min. To the mixture was added AcOEt and stirred for 30 min. The mixture was filtered and the filtrate was extracted with AcOEt. The extraction mixture was washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (Hexane:AcOEt 1:1) to give [3-(tert-butoxycarbonylamino)oxolan-3-yl]methanol (2.82 g, 46%) as a colorless solid. 1H-NMR (400 MHz, DMSO-d6) δ1.36 (9H, s), 1.84-1.91 (1H, m), 1.93-2.02 (1H, m), 3.46 (2H, d, J=5.5 Hz), 3.59-3.62 (1H, d, J=8.6 Hz), 3.66-3.70 (3H, m), 4.83 (1H, t, J=5.5 Hz), 6.78 (1H, brs).
Reaction SMILES: C([C:3]([C:10](OCC)=O)=[CH:4][C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)#N.C(O[CH2:19][C:20]1[NH:21]C(C(OCC2C=CC=CC=2)=O)=CC=1)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:8]1[CH:9]=[C:5]([CH2:4][C:3]2[NH:21][CH:20]=[CH:19][CH:10]=2)[NH:6][CH:7]=1
Reactant: CC(=O)OCc1ccc(C(=O)OCc2ccccc2)[nH]1
Reactant: CCOC(=O)C(C#N)=Cc1ccc[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1c[nH]c(Cc2ccc[nH]2)c1

Procedure:
As illustrated in Reaction Scheme 2, Step 1, an equimolar amount or a slight excess of a 2-(2-cyano 2-ethoxycarbonyl-ethen-1-yl)pyrrole derivative, shown as a compound of formula 201, is reacted with a 2-acetoxymethyl-5-benzyloxycarbonylpyrrole derivative of formula 202 in an organic solvent, preferably toluene, in the presence of a catalytic amount of p-toluenesulfonic acid to give the dipyrromethane of formula 203. The benzyl protecting group of the dipyrromethane 203 is then removed by palladium-catalyzed hydrogenation, as shown in Step 2, to give the corresponding dipyrromethane-2-carboxylate derivative of formula 204. As shown in Step 3, compound 204 is then decarboxylated in the presence of trifluoroacetic acid (“TFA”) to form the unstable dipyrromethane of formula 205. This compound is then reacted in situ (Step 4) with ah excess amount of a 2-chloromethyl-5-(2-cyano 2-ethoxycarbonyl-ethen-1-yl)pyrrole of formula 206, in an organic solvent in the presence of a catalytic amount of tin(IV) chloride, to form the non-symmetric tripyrrane of formula 207. The ethylcyanoacrylate groups are then cleaved with alkali to give the non-symmetric tripyrrane α,α′-dialdehyde of Formula I.