Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:8]2[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=[C:7]2[N:6]=[C:5]([C:16]2[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=2)[CH:4]=1.[F:25][CH2:26][CH2:27][CH2:28]O>>[F:25][CH2:26][CH2:27][CH2:28][NH:20][C:19]1[CH:21]=[CH:22][C:16]([C:5]2[CH:4]=[C:3]([C:2]([F:1])([F:23])[F:24])[N:8]3[C:9]4[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=4[N:11]=[C:7]3[N:6]=2)=[CH:17][CH:18]=1
Reactant: OCCCF
Reactant: Nc1ccc(-c2cc(C(F)(F)F)n3c(n2)nc2ccccc23)cc1
Product: FCCCNc1ccc(-c2cc(C(F)(F)F)n3c(n2)nc2ccccc23)cc1

Procedure:
The title compound was prepared using General Procedure S from 4-(4-(trifluoromethyl)benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)aniline and 3-fluoropropan-1-ol on a 0.03 mmol scale. N-(3-Fluoropropyl)-4-(4-(trifluoromethyl)benzo[4,5]imidazo[1,2-a]pyrimidin-2-yl)aniline (T693) was obtained as a orange solid (3.9 mg, 33%). 1H NMR (400 MHz, DMSO-d6): δ 8.25 (d, J=8.8, 2H), 8.07 (s, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.57 (t, J=7.6 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 6.81 (t, J=5.2 Hz, 1H), 6.76 (d, J=8.8 Hz, 2H), 4.64 (t, J=5.6 Hz, 1H), 4.53 (t, J=5.6 Hz, 1H), 3.28 (m, 2H), 1.97 (m, 2H); MS (ESI) m/z [M+H]+389.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12.[C:26]([N:34]=[C:35]=[S:36])(=O)[C:27]1C=CC=C[CH:28]=1.C([O-])([O-])=O.[K+].[K+].BrC(C)C=O>CC(C)=O>[CH:14]1([N:13]([CH:17]2[CH2:19][CH2:18]2)[C:11]([C:9]2[N:8]([CH2:20][CH3:21])[C:6]3=[N:7][C:2]([NH:1][C:35]4[S:36][C:27]([CH3:28])=[CH:26][N:34]=4)=[C:3]4[N:24]=[CH:23][N:22]([CH3:25])[C:4]4=[C:5]3[CH:10]=2)=[O:12])[CH2:16][CH2:15]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Reactant: O=C(N=C=S)c1ccccc1
Agent: CC(Br)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncc(C)s3)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
4-Amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 1J, 86.3 mg, 0.255 mmol) was dissolved in acetone and benzoyl isothiocyanate (37.8 μL, 0.281 mmol) was added. The reaction was stirred at room temperature for 2 h. The solvent was removed in vacuo. The residue was taken up in ethanol (1500 μL) and K2CO3 (49.3 mg, 0.357 mmol) was added. The reaction mixture was warmed to 60° C. for 3 h. 2-Bromopropanal (45.4 mg, 0.332 mmol) was added. After 3 h, additional 2-bromopropanal (˜100 mg) was added. Stirred at 60° C. for 16 h. Additional 2-bromopropanal was added and the reaction mixture was stirred at 60° C. 3 h. The ethanol was removed by concentration in vacuo. The crude residue was purified by flash chromatography using an Isco 12 g column eluting with 2-10% MeOH/CH2Cl2). Additional purification was accomplished via preparative HPLC. N,N-dicyclopropyl-6-ethyl-1-methyl-4-(5-methylthiazol-2-ylamino)-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (20 mg, 17.47% yield) was isolated as a white solid.
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[NH2:19][C@H:20]([C:31]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:43][CH:44]([CH3:46])[CH3:45])=[O:40])[C:35]([CH3:38])([CH3:37])[CH3:36])=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:19][C@H:20]([C:31]([NH:33][C@H:34]([C:39]([NH:41][C@H:42]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:43][CH:44]([CH3:45])[CH3:46])=[O:40])[C:35]([CH3:37])([CH3:38])[CH3:36])=[O:32])[CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)=[O:5]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
Z-Pro (2.18 g, 8.3 mmol) and Trp-Tle-Leu-OEt (prepared by catalytic hydrogenation of Z-Trp-Tle-Leu-OEt over palladium on charcoal) (3.47 g, 7.6 mmol), and NMM (0.92 mL) are dissolved in 35 mL DMF, cooled to 0° C., and treated with TBTU (2.66 g, 8.3 mmol). The reaction is stirred at 0° C. for 1 hour then removed from the ice bath and stirred at room temperature for 2 hours. The mixture is poured into 350 mL of a saturated solution of sodium bicarbonate which is then extracted with 350 mL of ethyl acetate. The combined organic extracts are washed with 350 mL of 1 M KHSO4, water and brine, and then dried over sodium sulfate. The solvents are removed and the residue chromatographed on silica gel (1.5% MeOH in chloroform) to give Z-Pro-Trp-Tle-Leu-OEt (Seq ID No: 7) (4.7 g). FABMS M+1 690
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:31]=[CH:30][C:10]([C:11]([NH:13][CH:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)[C:15](O)=[O:16])=[O:12])=[CH:9][CH:8]=1.[CH3:34][NH2:35]>>[CH3:34][NH:35][C:15](=[O:16])[CH:14]([NH:13][C:11](=[O:12])[C:10]1[CH:30]=[CH:31][C:7]([O:6][CH2:5][CH2:4][CH2:3][C:2]([F:33])([F:32])[F:1])=[CH:8][CH:9]=1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1
Reactant: CN
Reactant: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O)c1ccc(OCCCC(F)(F)F)cc1
Product: CNC(=O)C(Cc1ccc(OC(F)(F)F)cc1)NC(=O)c1ccc(OCCCC(F)(F)F)cc1

Procedure:
A reaction similar to that described in Example 32 (32c) was conducted using 2-{[4-(4,4,4-trifluorobutoxy)benzoyl]amino}-3-[4-(trifluoromethoxy)phenyl]propanoic acid (360 mg) prepared in Example 82 (82a) and methylamine (450 μL, 2 M methanol solution) to give 270 mg of the title compound (white powder).
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:13]CC)(=O)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[N:16]([CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=1)=[N+:17]=[N-:18]>C(O)C>[CH2:10]([O:9][C:7]([C:6]1[N:18]=[N:17][N:16]([CH2:19][C:20]2[CH:21]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=2)[C:5]=1[OH:13])=[O:8])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: [N-]=[N+]=NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1O
Temperature: 25 °C
Reaction time: 7 h

Procedure:
Combine a solution of sodium ethoxide (5.5 mL, 21 wt % in ethanol) and diethyl malonate (2.50 mL, 16.5 mmol) in ethanol (26 mL) with a solution of 1-azidomethyl-3,5-bis-trifluoromethyl-benzene (4.40 g, 16.3 mmol) in ethanol (6 mL) and heat to 80° C. After 7 h, cool to RT and concentrate the mixture in vacuo. Dissolve the viscous oil in H2O (20 mL) and add aqueous 1N HCl until the solution reaches pH 2–3. Collect the white precipitate by filtration and dry under reduced pressure to give the title compound. MS (ES) 384.0 (M+H)+, MS (ES−) 382.1 (M−H); 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.92 (s, 2H), 5.41 (s, 2H), 4.15 (q, 2H, J=7.3 Hz), 1.22 (t, 3H, J=7.3 Hz).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[NH:13]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:13]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: C1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CCN2CCCCCC2)cc1
Temperature: 25 °C
Yield: 84.3 %

Procedure:
1-(2-Bromo-ethyl)-4-nitro-benzene (10 g, 43.47 mmol) is added under argon to a mixture of azepane (4.9 ml, 43.47 mmol) and potassium carbonate (6 g, 43.47 mmol) in 100 ml of DMF. After stirring over night at room temperature, the mixture is filtered and evaporated under high vacuum. The residue is dissolved in ethyl acetate, washed with water and brine and dried over sodium sulfate. Evaporation gave 9.1 g (84%) of a yellow oil.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:34]=[CH:33][C:26]([CH2:27][CH2:28][PH:29](=[O:32])[O:30][CH3:31])=[CH:25][CH:24]=1)=[O:22])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:10]=1[NH:20][C:21]([C:23]1[CH:24]=[CH:25][C:26]([CH2:27][CH2:28][PH:29](=[O:32])[O:30][CH3:31])=[CH:33][CH:34]=1)=[O:22]
Reactant: CO[PH](=O)CCc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CO[PH](=O)CCc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl [4-({[2-[(tert-butoxycarbonyl)amino]-5-(2-thienyl)phenyl]amino}carbonyl)benzyl]methyl-phosphinate (6.69 g, 13.37 mmol) was dissolved in CH2Cl2 (48 ml), and TFA (12 ml) was added. The solution was stirred at room temperature for 3 h and evaporated. The residue was dissolved in CH2Cl2, washed with saturated NaHCO3 and brine, dried (MgSO4), and evaporated. The crude was then slurried in CH2Cl2 and triturated with a small amount of hexanes to precipitate the title compound as a colorless solid. This material was subjected to chiral SFC to provide enantiopure samples of the two enantiomeric forms. Spectral data for racemate: 1H NMR (DMSO-d6) δ 9.68 (s, 1H), 7.92 (d, J=7.9 Hz, 2H), 7.44 (d, J=1.6 Hz, 1H), 7.38 (dd, J=8.1, 2.0 Hz, 2H), 7.32 (dd, J=5.2, 0.9 Hz, 1H), 7.27 (dd, J=8.3, 2.2 Hz, 1H), 7.21 (d, J=3.6 Hz, 1H), 7.01 (dd, J=5.0, 3.6 Hz, 1H), 6.78 (d, J=8.7 Hz, 1H), 5.13 (s, 2H), 3.55 (d, J=11.0 Hz, 3H), 3.29 (d, J=18.0 Hz, 2H), 1.32 (d, J=13.7 Hz, 3H). MS: cal'd 401 (MH+), exp 401 (MH+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH2:19]([O:26][CH2:27][C:28]1([C:38]#[C:39][C:40]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)=O)[CH2:37][CH2:36][C:31]2([O:35][CH2:34][CH2:33][O:32]2)[CH2:30][CH2:29]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:19]([O:26][CH2:27][C:28]1([C:38]2[CH:39]=[C:40]([C:42]3[CH:43]=[CH:44][C:45]([CH3:48])=[CH:46][CH:47]=3)[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)[N:11]=2)[CH2:29][CH2:30][C:31]2([O:32][CH2:33][CH2:34][O:35]2)[CH2:36][CH2:37]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1ccc(C(=O)C#CC2(COCc3ccccc3)CCC3(CC2)OCCO3)cc1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1ccc(-n2nc(C3(COCc4ccccc4)CCC4(CC3)OCCO4)cc2-c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
To a solution of 4-methoxyphenylhydrazine hydrochloride (280 mg, 1.60 mmol) in ethanol (2.7 mL), triethylamine (0.447 mL, 3.20 mmol) was added dropwise, and the obtained solution was stirred at room temperature for 30 minutes. To the reaction solution, a solution of 3-(8-(benzyloxymethyl)-1,4-dioxaspiro[4.5]decan-8-yl)-1-(p-tolyl)propyn-1-one (Reference Example 89) (540 mg, 1.33 mmol) in ethanol (2.7 mL) was added dropwise, and the obtained solution was stirred at room temperature for 14 hours. Thereafter, the reaction solution was concentrated under reduced pressure. Water was added to the residue and the resultant was extracted with ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, distilled water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (458 mg, 0.872 mmol, 65%) as a white amorphous product.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].B(OB=O)=O.[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH:22]=O)[CH:20]=2)[CH:15]=[CH:14]1.C(OC)(OC)OC.C(N)CCC.Cl>C(OCC)(=O)C>[NH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH:22]=[CH:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5])[CH:20]=2)[CH:15]=[CH:14]1
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1ccc2cc[nH]c2c1
Agent: Cl
Agent: O=BOB=O
Solvent: COC(OC)OC
Solvent: CCOC(C)=O
Solvent: CCCCN
Product: CC(=O)CC(=O)C=Cc1ccc2cc[nH]c2c1
Temperature: 95 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
Ethyl acetate (7 mL), 2,4-pentanedione (9.35 mL, 90.9 mmol) and boron trioxide (5.76 g, 82.7 mmol) was placed in a 200 mL reaction vessel with a reflux condenser. To the stirring mixture at 85° C. was added dropwise a solution of 1H-indole-6-carboxaldehyde (2.00 g, 13.8 mmol) and trimethyl orthoformate (1.6 mL, 14 mmol) in 14 mL of ethyl acetate. After the reaction mixture was stirred for 30 min at 95° C., n-butylamine (6.8 mL, 69 mmol) was added dropwise with additional stirring for 2 h. The reaction mixture was cooled to 50° C. before addition of 3N HCl (32 mL). After being stirred at 50° C. for 30 min, the mixture was filtered to remove solids. The filtrate was diluted with ethyl acetate, washed with brine twice, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5 to 75/25) followed by recrystallization (hexane/ethyl acetate) to obtain the title compound as a pale yellow crystal (0.92 g, 29%).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[CH:6]=[C:5]([CH2:14][C:15]([OH:17])=[O:16])[C:4]1=[O:18])[CH3:2].Cl.[CH3:20]O>>[CH3:20][O:16][C:15](=[O:17])[CH2:14][C:5]1[C:4](=[O:18])[N:3]([CH2:1][CH3:2])[C:12]2[C:7]([CH:6]=1)=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2
Reactant: CCn1c(=O)c(CC(=O)O)cc2ccc(O)cc21
Reactant: CO
Agent: Cl
Product: CCn1c(=O)c(CC(=O)OC)cc2ccc(O)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 58 %

Procedure:
A suspension of (1-ethyl-7-hydroxy-2-oxo-1,2-dihydro-quinolin-3-yl)-acetic acid (2.9 g, 12 mmol) in methanol (30 mL) was treated with 12 N aqueous HCl (3 mL, 36 mmol) and the mixture heated to reflux. After 5 h, the resulting solution was cooled to room temperature, filtered and left standing overnight. The resulting solid was vacuum filtered, washed with ice-cold methanol and air-dried to give the title compound (1.8 g, 58% yield) as white needles.
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH2:11][CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:6][C:5]1=[O:24])(=O)[CH3:2].Cl.[CH2:26]([O:28][NH2:29])[CH3:27].C(N(CC)CC)C.Cl>C(O)C.O>[CH2:26]([O:28][NH:29][C:1](=[C:4]1[C:5](=[O:24])[CH2:6][CH:7]([CH2:11][CH2:12][S:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=2)[CH2:8][C:9]1=[O:10])[CH3:2])[CH3:27]
Reactant: CC(=O)C1C(=O)CC(CCSc2ccc(C(F)(F)F)cc2)CC1=O
Reactant: CCON
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCONC(C)=C1C(=O)CC(CCSc2ccc(C(F)(F)F)cc2)CC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.1 Grams of 2-acetyl-5-[2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione was dissolved in 10 ml of ethanol, and 0.71 g of ethoxyamine hydrochloride and 0.68 g of triethylamine were added to the resulting solution which was then stirred overnight at room temperature. The reaction solution was poured into water, acidified with dilute hydrochloric acid and extracted with chloroform. Chloroform was removed and the residue was purified by column chromatography on silica gel (eluent, ethyl acetate:hexane=1:5) to obtain 1.2 g of 2-(1-ethoxyaminoethylidene)-5-[2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH:30]([CH3:32])[CH3:31])=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:40]1([CH:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:44][CH2:43][CH2:42][CH2:41]1.O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:48]3[CH2:49][CH2:50][CH:45]([N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)[CH2:46][CH2:47]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH:30]([CH3:32])[CH3:31])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)Oc1ccccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: C1CCN(C2CCNCC2)C1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)Oc1ccccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCC2)CC1
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
4,5-Bis-(4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (200 mg, 0.41 mmol) was added a solution of triethylamine (0.23 mL, 1.64 mmol) and 4-(1-pyrrolidinyl)-piperidine (0.11 g, 0.70 mmol) in methylene chloride (8 mL) at 0° C. over 15 min. After 30 min, the reaction was worked up with water. The mixture was extracted with methylene chloride and washed with water and brine. The organic extracts were dried over sodium sulfate and evaporated. Chromatography of the residue over silica gel using 1-2% methanol in methylene chloride gave [4,5-bis-(4-chloro-phenyl)-2-(2-isopropoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (0.18 g, 72%) as an off-white foam. HR-MS (ES, m/z) calculated for C34H39N4O2Cl2[(M+H)+]605.2445, observed 605.2448
Reaction SMILES: B([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)(O)O.Br[C:13]1[N:17]2[N:18]=[C:19]([NH:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][C:27]3=[O:31])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1>>[O:31]=[C:27]1[CH2:28][CH2:29][CH2:30][N:26]1[CH2:25][CH2:24][CH2:23][NH:22][C:19]1[CH:20]=[CH:21][C:16]2[N:17]([C:13]([C:4]3[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=3)=[CH:14][N:15]=2)[N:18]=1
Reactant: O=C(O)c1ccc(B(O)O)s1
Reactant: O=C1CCCN1CCCNc1ccc2ncc(Br)n2n1
Product: O=C(O)c1ccc(-c2cnc3ccc(NCCCN4CCCC4=O)nn23)s1
Yield: 64 %

Procedure:
The Suzuki coupling of 5-boronothiophene-2-carboxylic acid and 1-(3-((3-bromoimidazo[1,2-b]pyridazin-6-yl)amino)propyl)pyrrolidin-2-one using the procedure described in example 5.6.19 yielded 64% of the titled compound.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]([N:16]1[C:22]([CH3:24])([CH3:23])[C:20](=[O:21])[NH:19][C:17]1=[O:18])[N:7]1[C:13]([CH3:15])([CH3:14])[C:11](=[O:12])[NH:10][C:8]1=[O:9].C=O.[CH3:27][C:28]1(C)NC(=O)N[C:29]1=[O:34]>>[CH2:6]([N:7]1[C:13]([CH3:15])([CH3:14])[C:11](=[O:12])[N:10]([CH2:27][CH:28]2[O:34][CH2:29]2)[C:8]1=[O:9])[N:16]1[C:22]([CH3:24])([CH3:23])[C:20](=[O:21])[N:19]([CH2:1][CH:3]2[O:5][CH2:4]2)[C:17]1=[O:18].[CH2:6]([N:7]1[C:13]([CH3:15])([CH3:14])[C:11](=[O:12])[NH:10][C:8]1=[O:9])[N:16]1[C:22]([CH3:24])([CH3:23])[C:20](=[O:21])[NH:19][C:17]1=[O:18]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: ClCC1CO1
Agent: C=O
Agent: CC1(C)C(=O)NC(=O)N1CN1C(=O)NC(=O)C1(C)C
Product: CC1(C)C(=O)N(CC2CO2)C(=O)N1CN1C(=O)N(CC2CO2)C(=O)C1(C)C

Procedure:
1,1'-Methylene-bis[3-glycidyl-5,5-dimethylhydantoin] is prepared by the reaction of epichlorohydrin and 1,1'-methylene-bis[5,5-dimethylhydantoin] according to Example 1 of U.S. Pat. No. 3,592,923. 1,1'-Methylene-bis[5,5-dimethylhydantoin] is prepared by the general procedure of Example I of U.S. Pat. No. 3,793,248 using paraformaldehyde and 5,5-dimethylhydantoin.
Reaction SMILES: Cl[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][C:9]=1[O:17][CH2:18][CH3:19])[C:3](OCC)=[O:4].[NH2:20][C:21]([NH2:23])=[S:22].C(=O)([O-])O.[Na+]>C(O)C.O>[CH2:18]([O:17][C:9]1[CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=[CH:13][C:8]=1[CH:2]1[S:22][C:21](=[NH:20])[NH:23][C:3]1=[O:4])[CH3:19]
Reactant: CCOC(=O)C(Cl)c1ccc(OCC)cc1OCC
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ccc(C2SC(=N)NC2=O)c(OCC)c1
Yield: 71.5 %

Procedure:
730 mg of ethyl α-chloro-α-(2,4-diethoxyphenyl)acetate and 380 mg of thiourea, in 7 ml of ethanol, are stirred under reflux for 1 hour. After cooling, the solution is poured in 30 ml of water, neutralized with a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract is washed with water, dried (MgSO4) and distilled to remove the ethyl acetate, whereby 510 mg (74.5%) of 5-(2,4-diethoxyphenyl)-2-iminothiazolidin-4-one is obtained, m.p. 179°-181° C. (hemihydrate).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[C:10]1[NH:11][C:12]2[CH:18]=[C:17]([C:19](Cl)=[O:20])[CH:16]=[CH:15][C:13]=2[N:14]=1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[NH2:32].CCN(C(C)C)C(C)C.O>CCOC(C)=O>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[NH:32][C:19]([C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([C:4]3[C:3]([CH3:2])=[CH:8][CH:7]=[CH:6][C:5]=3[CH3:9])[NH:11][C:12]=2[CH:18]=1)=[O:20]
Reactant: Nc1ccc2ccccc2c1
Reactant: Cc1cccc(C)c1-c1nc2ccc(C(=O)Cl)cc2[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C)c1-c1nc2ccc(C(=O)Nc3ccc4ccccc4c3)cc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of 2-(2,6-dimethylphenyl)-3H-benzoimidazole-5-carbonyl chloride HCl salt (160 mg) and naphthalen-2-ylamine (72 mg) was added DIPEA (0.27 mL). The resulting solution was stirred for at room temperature for 18 h then the mixture was partioned between water and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were dried, filtered and concentrated. The residue was purified by an amino column using hexanes/ethyl acetate (1:4) as eluent and gave 2-(2,6-dimethylphenyl)-3H-benzoimidazole-5-carboxylic acid naphthalen-2-ylamide as a white solid; MS (ESI)m/z 392 (M+H).
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>N.CO>[CH3:29][O:30][C:31]1[CH:32]=[CH:33][C:34]([S:37]([N:11]2[C:12]3[C:8](=[C:7]4[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]4=[CH:14][CH:13]=3)[CH:9]=[CH:10]2)(=[O:39])=[O:38])=[CH:35][CH:36]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)n2ccc3c4c(ccc32)OCCNC4)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 30.7 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 4-Methoxybenzenesulfonyl chloride (21 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (5.5 mg). MS m/z 359 [M+H]+.