Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]1[S:6][C:7]([CH:10]=O)=[CH:8][N:9]=1)[C:2]#[CH:3].[C:12](#[N:16])[CH2:13][C:14]#[N:15]>O.C(O)C>[CH2:1]([O:4][C:5]1[S:6][C:7]([CH:10]=[C:13]([C:12]#[N:16])[C:14]#[N:15])=[CH:8][N:9]=1)[C:2]#[CH:3]
Reactant: C#CCOc1ncc(C=O)s1
Reactant: N#CCC#N
Solvent: CCO
Solvent: O
Product: C#CCOc1ncc(C=C(C#N)C#N)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
1.4 g of 2-(2-propynyloxy)-1,3-thiazole-5-carbaldehyde was dissolved in a mixture of 6 ml of water and 14 ml of ethanol, and 0.56 g of malononitrile was added dropwise. The mixture was stirred at room temperature for 3 hours. Thereafter, the reaction mixture was filtered, and the resulting cake was washed with 5 ml of ethanol two times and dried under reduced pressure to obtain 1.55 g of {[2-(2-propynyloxy)-1,3-thiazol-5-yl]methylidene}malononitrile.
Reaction SMILES: Cl.[C:2]([CH2:4][C:5]1([N:16]2[CH:20]=[C:19]([C:21]3[CH:26]=[N:25][N:24]4[C:27]([C:30]5[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][C:37]([NH:39][CH2:40][C:41]([F:44])([F:43])[F:42])=[O:38])[CH:31]=5)=[CH:28][N:29]=[C:23]4[CH:22]=3)[CH:18]=[N:17]2)[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)#[N:3].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C(Cl)Cl>[C:2]([CH2:4][C:5]1([N:16]2[CH:20]=[C:19]([C:21]3[CH:26]=[N:25][N:24]4[C:27]([C:30]5[CH:31]=[C:32]([NH:36][C:37]([NH:39][CH2:40][C:41]([F:43])([F:44])[F:42])=[O:38])[CH:33]=[CH:34][CH:35]=5)=[CH:28][N:29]=[C:23]4[CH:22]=3)[CH:18]=[N:17]2)[CH2:6][NH:7][CH2:8]1)#[N:3]
Reactant: CC(C)(C)OC(=O)N1CC(CC#N)(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
HCl in 1,4-dioxane (4.0 N, 2 mL) was added to a mixture of tert-butyl 3-(cyanomethyl)-3-(4-{3-[3-({[(2,2,2-trifluoro ethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)azetidine-1-carboxylate (0.55 g, 0.92 mmol) in methylene chloride (10.0 mL). The reaction mixture was stirred at r.t. for 1 h. The mixture was adjusted to pH=8 with aqueous Na2CO3, and extracted with ethyl acetate (3×40 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with MeOH (with 5% NH3.H2O) in DCM (0-15%) to afford the desired product. LCMS (M+H)+: m/z=496.1.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[O:22]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=O)=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1.O>C1COCC1>[O:22]1[C:27]2[CH:28]=[CH:29][C:30]([C:32]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[CH:9][C:10]#[N:11])=[CH:31][C:26]=2[O:25][CH2:24][CH2:23]1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(C(=O)c2ccc3c(c2)OCCO3)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=CC#N)c2ccc3c(c2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
To a solution of cyanomethylphosphonic acid diethyl ester (2.4 mL, 15.0 mmol) in anhydrous THF (20 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 15.0 mL, 15.0 mmol) at 0° C. and stirred for 30 min at room temperature followed by addition of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-methoxy-phenyl)-methanone (2.02 g crude, 7.5 mmol) in THF (15 mL) and refluxed for 30 min. The reaction mixture was poured into water (50 if L), extracted with CH2Cl2 (2×50 mL). The combined organic phases were washed with brine (50 mL), dried over MgSO4, and purified via flash column chromatography (EtOAc, Hexane) to give 3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-3-(4-methoxy-phenyl)-acrylonitrile as a yellow solid (1.44 g, 66% yield): mp, 112-114° C.; 1H NMR (DMSO-d6) δ 3.79 and 3.83 (2s, 3H, OCH3), 4.25-4.33 (m, 4H, CH2CH2), 6.07 and 6.08 (2s, 1H, CH), 6.77-7.32 (m, 7H, Ar); 13C NMR (DMSO-d6) δ 55.2, 55.3, 64.0, 64.0, 64.2, 64.3, 92.7, 93.0, 113.9, 114.1, 117.0, 117.2, 118.0, 118.6, 118.7, 121.9, 122.5, 129.1, 130.0, 130.1, 130.4, 130.8, 131.4, 143.1, 143.2, 144.7, 145.5, 160.3, 160.7, 160.8, 161.1. Anal. Calcd for C18H15NO3+0.1H2O: C, 73.26; H, 5.19; N, 4.75. Found: C, 72.96; H, 5.22; N, 4.67.
Reaction SMILES: [Cl:1][C:2]1[CH:49]=[CH:48][CH:47]=[CH:46][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]([CH:28]=[N:29][NH:30][C:31](=O)[CH2:32][CH2:33][N:34]1[C:42](=[O:43])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]1=[O:44])C(=O)CCN1C(=O)C2C(=CC=CC=2)C1=O)=[O:5].FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:49]=[CH:48][CH:47]=[CH:46][C:3]=1[C:4](=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH:28]=[N:29][N:30]=[C:31]1[CH2:32][CH2:33][N:34]1[C:42](=[O:43])[C:41]2=[CH:40][CH:39]=[CH:38][CH:37]=[C:36]2[C:35]1=[O:44]
Reactant: O=C(CCN1C(=O)c2ccccc2C1=O)NN=CN(C(=O)CCN1C(=O)c2ccccc2C1=O)c1ccccc1C(=O)c1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1Cl)c1ccccc1-n1cnnc1CCN1C(=O)c2ccccc2C1=O

Procedure:
The 1,3-dioxo-2-isoindolinepropionic acid, [[N-[2-(o-chlorobenzoyl)phenyl]-1,3-dioxo-2-isoindolinepropionamido]methylene]hydrazide from Preparation 5A is mixed with toluene (165 ml.), treated with trifluoroacetic acid (0.732 ml.) and warmed, under nitrogen, at 100°-110° C. for 1.5 hours. The mixture is concentrated in vacuo and the residue is mixed with cold, dilute sodium bicarbonate and extracted with chloroform. The extract is washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on silica gel (200 g.) with 2% methanol-98% chloroform. The product thus obtained is crystallized to give 2'-chloro-2-[3-(2-phthalimidoethyl)-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [OH-:1].[Na+].ClCl.C[C:6]([C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH:11]=[CH:10][C:9]=1[O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:7]>O>[F:23][C:22]([F:25])([F:24])[CH2:21][O:20][C:9]1[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:13][C:8]=1[C:6]([OH:7])=[O:1]
Reactant: [OH-]
Reactant: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Agent: ClCl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F
Temperature: 50 °C
Yield: 94.5 %

Procedure:
To a solution of 7.3 moles (292 g.) of sodium hydroxide in 600 ml. of water is added ice to make the total volume of 1.75 liters. Chlorine gas is passed into the solution while maintaining the temperature below 10° C. until it is neutral to litmus, and 2.19 moles (87.6 g.) of sodium hydroxide dissolved in 200 ml. of water is added. The combined solution is warmed to 50° C., and 0.73 mole (230 g.) of 2,5-bis(2,2,2-trifluoroethoxy)acetophenone is added slowly. The reaction mixture is stirred while heating until an exotherm begins about 75° C. and is thereafter maintained at about 80° C. by cooling. The mixture is stirred for about 16 hours at about 80° to 90° C. while monitoring the extent of the reaction by thin-layer chromatography. The excess hypochlorite is then destroyed by adding 75 g. of sodium bisulfite in 250 ml. of water, and the mixture is cooled to about 25° C. and carefully acidified with 10 percent hydrochloric acid. The light yellow solid product is collected by filtration, washed with water, and dried. A 94.5 percent yield of 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid, m.p 120° to 122° C., is obtained.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.Cl.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]1[N:38]=[C:37]([CH:39]2[CH2:44][CH2:43][NH2+:42][CH2:41][CH2:40]2)[O:36][N:35]=1>ClCCl>[C:2]1([C:1]([N:42]2[CH2:43][CH2:44][CH:39]([C:37]3[O:36][N:35]=[C:34]([C:30]4[S:29][CH:33]=[CH:32][CH:31]=4)[N:38]=3)[CH2:40][CH2:41]2)=[O:9])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1
Reactant: c1csc(-c2noc(C3CC[NH2+]CC3)n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCC(c2nc(-c3cccs3)no2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.5 %

Procedure:
67.40 mg (1 eq.) of benzoic acid, 106 mg (1 eq.) of EDCI and 165 μl (2 eq.) of triethylamine were dissolved in 2 ml of dichloromethane. 150 mg (1 eq.) of 4-(3-thiophen-2-yl[1,2,4]oxadiazol-5-yl)piperidinium hydrochloride dissolved in 2 ml of dichloromethane and 165 μl (2 eq.) of triethylamine were added to the reaction medium, which was stirred at room temperature overnight. The reaction medium was evaporated under reduced pressure and the residue was chromatographed on a thick layer (eluent: CH2Cl2/MeOH (98/2: v/v)) to give 98 mg (52%) of the expected product.
Reaction SMILES: [C:1]([N:4]([CH2:8][CH2:9][OH:10])[CH2:5][CH2:6][OH:7])(=[O:3])[CH3:2].C(N(CC)CC)C.Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[C:1]([N:4]1[CH2:8][CH2:9][O:10][C:19](=[O:21])[O:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(=O)N(CCO)CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCOC(=O)OCC1

Procedure:
The procedure of Example 1 was followed using N-acetyl diethanolamine (12.3 g, 83.9 mmol), triethylamine (24.0 mL, 167.8 mmol), dry THF (600 mL) and triphosgene (8.3 g, 28.8 mmol). The filtrate was concentrated yielding only oligomeric compounds.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[CH3:14][C:15]1[N:20]=[C:19]([CH:21]=O)[CH:18]=[CH:17][CH:16]=1.N1CCCCC1>C(O)C>[OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[CH:21][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:14])[N:20]=1)[C:7](=[O:13])[NH:8]2
Reactant: O=C1Cc2c(CCO)cccc2N1
Reactant: Cc1cccc(C=O)n1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cccc(C=C2C(=O)Nc3cccc(CCO)c32)n1
Temperature: 100 °C

Procedure:
A mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (89 mg, 0.5 mmol), 6-methyl-2-pyridine-carbaldehyde (61 mg, 0.5 mmol) and piperidine (0.1 mL) in 1.0 mL of ethanol was heated at 100° C. for 1 hour and cooled to room temperature. The precipitate was filtered and recrystallized from ethyl acetate and hexanes to give 4-(2-hydroxy-ethyl)-3-(6-methyl-pyridin-2-ylmethylene)-1,3-dihydro-indol-2-one as a yellow solid.
Reaction SMILES: C1(C)C=CC(S(O[C@@H:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH3:12])(=O)=O)=CC=1.[CH3:23][NH2:24]>C(O)C>[CH3:23][NH:24][C@H:11]([CH2:13]/[CH:14]=[CH:15]/[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)O[C@H](C)C/C=C/c2cccnc2)cc1
Reactant: CN
Solvent: CCO
Product: CN[C@@H](C)C/C=C/c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24 %

Procedure:
A mixture of (2R)-(4E)-5-(3-pyridyl)-4-penten-2-ol p-toluenesulfonate (9.00 g, 28.35 mmol), methylamine (200 mL, 40% solution in water), and ethyl alcohol (10 mL) was stirred at ambient temperature for 18 h. The resulting solution was extracted with chloroform (3×100 mL). The combined chloroform extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. The crude product was purified by column chromatography over aluminum oxide, eluting with ethyl acetate-methanol (7:3, v/v). Selected fractions were combined and concentrated by rotary evaporation, producing an oil. Further purification by vacuum distillation furnished 1.20 g (24.0%) of a colorless oil, by 90-100° C. at 0.5 mm Hg.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]([CH3:24])[C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29]>>[CH2:1]([O:8][C:9]1[C:10]([C:33]2[CH:34]=[CH:35][C:30]([CH:28]=[O:29])=[CH:31][CH:32]=2)=[CH:11][C:12]([CH2:13][N:14]([CH3:24])[C:15](=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:25][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CCCCCCCC(=O)N(C)Cc1ccc(OCc2ccccc2)c(Br)c1
Product: CCCCCCCC(=O)N(C)Cc1ccc(OCc2ccccc2)c(-c2ccc(C=O)cc2)c1
Yield: 81.1 %

Procedure:
In a manner similar to that of Example 1(e), by reacting 13.6 g (31 mmol) of N-(4-benzyloxy-3-bromo benzyl)-N-methyloctanamide and 6.1 g (40 mmol) of 4-formylbenzene boronic acid, 11.5 g (69%) of the expected product are obtained in the form of a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[C:8]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[CH:9][N:10]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]5[CH:32]=[N:31][CH:30]=[CH:29][N:28]=5)[CH:22]=4)=[CH:15][CH:14]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:8]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:9][N:10]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]5[CH:32]=[N:31][CH:30]=[CH:29][N:28]=5)[CH:22]=4)=[CH:17][CH:18]=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cccc(-c4cnccn4)c3)cc2)cc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)CCc1cn(Cc2ccc(OCc3cccc(-c4cnccn4)c3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
A mixture of ethyl 3-[4-phenyl-1-[4-[3-(2-pyrazinyl)benzyloxy]benzyl]-3-pyrrolyl]propionate (647 mg), 1N aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature overnight, and 1N hydrochloric acid (2.5 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The colorless crystals obtained were collected by filtration to yield 3-[4-phenyl-1-[4-[3-(2-pyrazinyl)benzyloxy]benzyl]-3-pyrrolyl]propionic acid (470 mg, yield: 77%). This was recrystallized from ethyl acetate-hexane. Melting point: 91–92° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([OH:1])[CH:11]=[CH:10]2
Reactant: Oc1ccc2ccccc2n1
Reactant: BrBr
Solvent: CC(=O)O
Product: Oc1ccc2cc(Br)ccc2n1

Procedure:
2-Hydroxyquinoline (ex. Aldrich) was treated with bromine in acetic acid to give 6-bromo-2-hydroxyquinoline (Paolo and Gianlorenzo, Chem. Abs., 63, 5602C, 1965). The latter was treated with phosphorous oxychloride and phosphorous pentachloride at 90° to give 6-bromo-2-chloroquinoline. The latter was converted to the title compound by analogy with compound 33.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20](OS(C)(=O)=O)[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].O>CN(C=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20]([O:10][C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
Sodium hydride (554 mg, 13.84 mmol) is added to a solution of 4-fluorophenol (1.60 g, 14.20 mmol) in DMF (20 ml) and the mixture is stirred at room temperature for 2 minutes. 3-Methanesulphonyloxy-pyrrolidine-1-carboxylic acid tert-butyl ester is added and the mixture heated at 60° C. for 18 hours. Water (50 ml) is then added and the resulting product is extracted using diethyl ether (3×30 ml). The organic extracts are dried (using MgSO4), filtered and evaporated to give a white solid, which is purified using column chromatography over silica gel (ethyl acetate/isohexane 1:9 v/v) to give the title compound.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][OH:17])[CH2:10][C@H:9]1[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)=[O:7].C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][O:17][S:46]([CH3:45])(=[O:48])=[O:47])[CH2:10][C@H:9]1[CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCCO)C[C@H]1Cc1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc3ccccc3c2)C1
Reaction time: 2 h
Yield: 78.2 %

Procedure:
To a stirred mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(3-hydroxypropyl)-2-(2-naphthylmethyl)piperazine (1.1 g) and triethylamine (425 mg) in dichloromethane (10 ml) was added dropwise methanesulfonyl chloride (252 mg) at ice-bath temperature. After 2 hours, the reaction mixture was washed with water and then dried over magnesium sulfate. After evaporation of the solvent, the resulting residue was chromatographed on silica gel using ethyl acetate as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(2-naphthylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (988 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[N:13][C:12]2[N:11]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23](O)=[O:24])=[N:21][CH:22]=3)[C:10]3[CH2:9][CH2:8][N:7]4[CH2:26][CH2:27][CH2:28][CH:6]4[C:5]=3[C:4]=2[CH:3]=1.C(Cl)(=O)C(Cl)=O.C[N:36](C=O)C>C(Cl)Cl>[CH3:1][C:2]1[CH:14]=[N:13][C:12]2[N:11]([CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([NH2:36])=[O:24])=[N:21][CH:22]=3)[C:10]3[CH2:9][CH2:8][N:7]4[CH2:26][CH2:27][CH2:28][CH:6]4[C:5]=3[C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: Cc1cnc2c(c1)c1c(n2CCc2ccc(C(=O)O)nc2)CCN2CCCC12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1cnc2c(c1)c1c(n2CCc2ccc(C(N)=O)nc2)CCN2CCCC12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-[2-(9-Methyl-1,2,3,4,5,10c-hexahydro-3a,6,7-triaza-cyclopenta[c]fluoren-6-yl)-ethyl]-pyridine-2-carboxylic acid (400 mg, 1.063 mmol) was dissolved in 15 mL DCM and cooled at 0° C. Oxalyl chloride (669 mg, 5.315 mmol) and catalytic amount of DMF was added and the reaction mixture was stirred at RT for 1 h. The reaction was monitored by LCMS. The reaction mixture was concentrated and aqueous ammonia was added at 0° C. The reaction mixture was warmed to RT and stirred for 1 h. The reaction mixture was concentrated to obtain the crude product that was purified by reverse phase chromatography to obtain 2.5 mg of 5-[2-(9-methyl-1,2,3,4,5,10c-hexahydro-3a,6,7-triaza-cyclopenta[c]fluoren-6-yl)-ethyl]-pyridine-2-carboxylic acid amide as the TFA salt. 1H NMR TFA:—CD3OD: 8.2 (s, 2H), 7.95 (d, 1H), 7.8 (s, 1H), 7.6 (d, 1H), 5.0 (t, 1H), 4.6 (m, 2H), 3.62 (m, 1H), 3.5 (m, 2H), 3.3 (m, 3H), 2.8 (d, 1H), 2.63 (m, 2H), 2.4 (s, 3H), 2.2 (m, 2H), 2.1 (m, 1H). Separation by chiral HPLC provides enantiomers II-243a-b.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[N:10]=[CH:9][C:8]=1[CH2:26][C:27]([NH2:29])=[O:28].[C:33](OC(=O)C)(=[O:35])[CH3:34].O>N1C=CC=CC=1>[C:33]([NH:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[N:10]=[CH:9][C:8]=1[CH2:26][C:27]([NH2:29])=[O:28])(=[O:35])[CH3:34]
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCOCC3)cc2)cc1NCc1cccc(N)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1cccc(CNc2cc(Nc3ccc(N4CCOCC4)cc3)ncc2CC(N)=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.8 %

Procedure:
22 mg of 4-[(3-aminobenzyl)amino]-6-[(4-morpholinophenyl)amino]pyridine-3-carboxyamide (the compound of Example 103) was dissolved in 0.5 mL of pyridine, to which 5.4 mg of acetic anhydride was added, and stirred at room temperature for 4 hours. To the reaction mixture, water was added, stirred, and the solvent was evaporated. The residue was purified by silica gel thin layer chromatography (chloroform: methanol=10:1) to obtain 2.6 mg (11%) of 4-{[3-(acetylamino)benzyl]amino}-6-[(4-morpholinophenyl)amino]pyridine-3-carboxyamide (Example 104-1) as a white solid. Furthermore, 11.6 mg (44%) of 4-{[3-(acetylamino)benzyl]amino}-6-[acetyl(4-morpholinophenyl)amino]pyridine-3-carboxyamide (Example 104-2) was obtained as a yellowish brown oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]([CH3:13])([CH3:12])[CH2:8][C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.O[C@H:20]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C@@H:22]([CH2:23][CH2:24][C@:25]3([CH3:52])[C@@H:34]2[CH2:33][CH2:32][C@H:31]2[C@@:26]3([CH3:51])[CH2:27][CH2:28][C@@:29]3(/[CH:46]=[CH:47]/[C:48]([OH:50])=[O:49])[CH2:41][C:40](=[O:42])[C:39]([CH:43]([CH3:45])[CH3:44])=[C:30]32)[C:21]1([CH3:54])[CH3:53]>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6](=[O:14])[C:7]([CH3:13])([CH3:12])[CH2:8][C:9]([O:11][C@H:20]1[CH2:37][CH2:36][C@@:35]2([CH3:38])[C@@H:22]([CH2:23][CH2:24][C@:25]3([CH3:52])[C@@H:34]2[CH2:33][CH2:32][C@H:31]2[C@@:26]3([CH3:51])[CH2:27][CH2:28][C@@:29]3(/[CH:46]=[CH:47]/[C:48]([OH:50])=[O:49])[CH2:41][C:40](=[O:42])[C:39]([CH:43]([CH3:45])[CH3:44])=[C:30]32)[C:21]1([CH3:53])[CH3:54])=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)O)CC1=O
Reactant: CC(C)(C)OC(=O)C(C)(C)CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)O)CC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
To a solution of 4-(tert-butoxy)-3,3-dimethyl-4-oxobutanoic acid (122 mg, 0.604 mmol), DMAP (123 mg, 1.007 mmol) and EDC (193 mg, 1.007 mmol) in dichloromethane (12 mL) stirred at room temp for 30 min was added (E)-3-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)acrylic acid (100 mg, 0.201 mmol). The reaction mixture was stirred at 25° C. for 3 h. The produce was extracted with DCM (15 mL*3), the combined organic phase was washed with brine (20 mL), dried, and the solvent removed under reduced pressure to give 110 mg of residue as light yellow solid which was used in the next reaction without further purification.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:11]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([OH:24])=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2)(=[O:10])[CH3:9].[CH3:25][O:26][C:27](Cl)=[O:28]>O1CCCC1>[C:8]([C:11]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([O:24][C:27]([O:26][CH3:25])=[O:28])=[C:17]2[C:12]=1[CH:13]=[CH:14][CH:15]=[N:16]2)(=[O:10])[CH3:9]
Reactant: COC(=O)Cl
Reactant: CC(=O)c1cc([N+](=O)[O-])c(O)c2ncccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Oc1c([N+](=O)[O-])cc(C(C)=O)c2cccnc12

Procedure:
10.5 g of triethylamine are added to a solution of 23 g of 5-acetyl-7-nitro-8-hydroxyquinoline in 150 ml of tetrahydrofurane and 9.5 g of chloroformic acid methyl ester are slowly added dropwise to this mixture.