Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[O-]CC.[Na+].[C:10]([CH:12]([C:28](OCC)=[O:29])[CH2:13][CH2:14][CH2:15][S:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1)#[N:11].C(O)(=O)C>C(O)C>[NH2:4][C:3]1[NH:5][C:28](=[O:29])[C:12]([CH2:13][CH2:14][CH2:15][S:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=2)=[C:10]([NH2:11])[N:2]=1
Reactant: CCOC(=O)c1ccc(SCCCC(C#N)C(=O)OCC)cc1
Reactant: N=C(N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(SCCCc2c(N)nc(N)[nH]c2=O)cc1
Yield: 95.6 %

Procedure:
Dry guanidine hydrochloride (3.43 g, 35.9 mmoles) was added to a solution of sodium ethoxide 53.5 mmoles) in ethanol (25 mL), and the mixture was treated with 1B (6.00 g, 17.9 mmoles) as a solution in ethanol (25 mL) and refluxed for 5 hours. After cooling, the pH was adjusted to 7.0 with acetic acid, and the mixture was evaporated to a viscous residue in vacuo. The residue was treated with water (70 mL) and was filtered to give an off white solid, which was washed with 3 volumes (30 mL) of water and 3 volumes (30 mL) of ether and was dried in vacuo to give crude product title compound, 1C, (5.96 g, 95%) as a white solid. NMR (DMSO-d6) δ1.3 (t, 3H, CH3 of ester), 1.65 (m, 2H, CH2 --CH2 --CH2), 2.3 (t, 2H, CH2 --CH2 --CH2 --S), 2.95 (m, 2H, CH2 --S), 4.3 (q, 2H, CH2 of ester), 5.7 (br s, 2H, NH2), 5.95 (br s, 2H, NH2), 7.3 (d, 2H) (benzoate H's ortho to sulfur), 7.85 (d, 1H, 7.95 (d, 1H), 9.8 (br s, 1H, ring NH). The aromatic region of the NMR spectrum indicated slight impurities; compound 1C was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=[CH:10][N:11](C)C)=[CH:4][C:3]=1[CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19].O.[NH2:22]N>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][NH:11][N:22]=2)=[CH:4][C:3]=1[CH2:15][NH:16][C:17](=[O:20])[O:18][CH3:19]
Reactant: COC(=O)NCc1cc(C(=O)C=CN(C)C)ccc1Cl
Reactant: NN
Solvent: CO
Solvent: O
Product: COC(=O)NCc1cc(-c2cc[nH]n2)ccc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of methyl N-[[2-chloro-5-[3-(dimethylamino)-1-oxo-2-propen-1-yl]phenyl]methyl]carbamate (i.e. the product of Step A) (4.14 g, 13.9 mmol) in methanol (80 mL) was added hydrazine hydrate (0.771 g, 15.4 mmol). The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was filtered and the solid collected was dried under reduced pressure to provide the title compound, a compound of the present invention, as a solid (3.26 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:4][C:3]1=[O:14].O=C1N(C(OCC2C=CC=CC=2)=O)[C@H](C(O)=O)CN1.[H-].[Na+].FC(F)(F)S(O[CH2:42][CH:43]([F:45])[F:44])(=O)=O>CN(C)C=O>[F:44][CH:43]([F:45])[CH2:42][N:4]1[CH:5]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[CH2:6][N:2]([CH3:1])[C:3]1=[O:14]
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Reactant: CN1CC(C(=O)OC(C)(C)C)NC1=O
Agent: O=C(O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC(C(=O)OC(C)(C)C)N(CC(F)F)C1=O
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
To a solution of 1,1-dimethylethyl 1-methyl-2-oxo-4-imidazolidinecarboxylate (200 mg, 0.999 mmol) (prepared as described in step (i) of Example 49 from 5-(1,1-dimethylethyl)1-(phenylmethyl)3-methyl-2-oxo-1,5-imidazolidinedicarboxylate, itself prepared as described in step (ii) of Example 13, starting originally from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) in N,N-dimethylformamide (10 ml) at −35° C. under argon was added sodium hydride (39.9 mg, 0.999 mmol). The mixture was stirred for 15 minutes, 2,2-difluoroethyl trifluoromethanesulfonate (428 mg, 1.998 mmol) was added and the reaction mixture was stirred at −35° C. for 30 minutes then slowly warmed to −15° C. After 1 hour the reaction mixture was quenched with water (10 ml), warmed to room temperature and extracted with ethyl acetate (20 ml×2). The combined organic layers were washed with sodium hydrogen carbonate saturated solution (15 ml), water (10 ml×2) and brine (15 ml). The organic layer was then dried (magnesium sulfate), filtered and evaporated. The crude residue was purified by silica gel chromatography eluting with 10-100% of ethyl acetate in isohexane to give 1,1-dimethylethyl 3-(2,2-difluoroethyl)-1-methyl-2-oxo-4-imidazolidinecarboxylate (178 mg). LC/MS [M+H]+=265. (ii) 1,1-Dimethylethyl 3-(2,2-difluoroethyl)-1-methyl-2-oxo-4-imidazolidinecarboxylate (178 mg, 0.674 mmol) was dissolved in dichloromethane (3.00 ml) and trifluoroacetic acid (1 ml) was added. The solution was stirred at room temperature for 2 hours. The solvent was evaporated and the residue co-evaporated with dichloromethane and toluene to give a crude 3-(2,2-difluoroethyl)-1-methyl-2-oxo-4-imidazolidinecarboxylic acid (assume 0.674 mmol) which was used for the next reaction. LC/MS [M+H]+=209.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:15])[C:5]2[CH:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][CH3:14])[C:6]=2[N:7]=1.ClCCl.[Br:19]Br>CC(C)=O>[NH2:1][C:2]1[N:3]=[C:4]([CH3:15])[C:5]2[CH:11]=[C:10]([Br:19])[C:9](=[O:12])[N:8]([CH2:13][CH3:14])[C:6]=2[N:7]=1
Reactant: BrBr
Reactant: CCn1c(=O)ccc2c(C)nc(N)nc21
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCn1c(=O)c(Br)cc2c(C)nc(N)nc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Amino-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (2.70 g, 13.2 mmol) was added to dichloromethane (100 mL), and then bromine (0.75 mL, 1.10 equiv.) was added slowly. This reaction mixture was stirred for 3 h at room temperature. After that, the solvent was evaporated nearly 80% volume of reaction mixture under vacuum, and then acetone was added to give 3.54 g 2-Amino-6-bromo-8-ethyl-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one as a tan solid. LC/MS: Calculated for C10H11BrN4O (283.12). Found: 285.15 (M+2). HPLC analytical purity: 97.7%.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[F:11].[C:12]1([O:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Al+3].[Cl-].[Cl-].[Cl-].Cl>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:15]2[CH:16]=[CH:17][C:12]([O:18][CH3:19])=[CH:13][CH:14]=2)=[O:7])=[CH:4][C:3]=1[F:11]
Reactant: O=C(Cl)c1ccc(Br)c(F)c1
Reactant: COc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(Br)c(F)c2)cc1
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 83.7 %

Procedure:
To a stirred solution of 4-bromo-3-fluorobenzoyl chloride (3.00 g, 12.6 mmol) and anisole (1.65 mL, 1.65 g, 15.2 mmol, 1.20 eq) in DCM (30 mL) at −5° C. was added, portion-wise, over 5 minutes, AlCl3 (2.54 g, 19.0 mmol, 1.50 eq) as a powder. The reaction was stirred at −5° C. for 2 h. The reaction was poured onto a mixture of 1 N HCl (100 mL) and ice (200 g) and stirred for 1 h. The DCM layer was washed with saturated aq. NaHCO3 (100 mL) and brine (100 mL) then dried (MgSO4) and concentrated. The resulting white solid was triturated with ˜100 mL hexanes, filtered and air-dried overnight to afford 3.26 g (83%) of compound 185. 1H NMR (400 MHz, DMSO-d6): δ 3.87 (s, 3H), 7.11 (d, J=8.9 Hz, 2H), 7.45 (d, J=8.9 Hz, 1H), 7.64 (d, J=8.9 Hz, 1H), 7.78 (d, J=8.9 Hz, 2H), 7.91 (t, J=7.1 Hz, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:10]=[C:11]([C:15]2([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[CH2:20][CH2:19][C:18](=[O:21])[CH:17]=[CH:16]2)[CH:12]=[CH:13][CH:14]=1.C(O[CH2:34][N:35]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:36][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[CH2:41]([N:35]1[CH2:36][CH:17]2[CH:16]([C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([F:8])[CH:10]=3)[CH2:20][CH2:19][C:18]2=[O:21])[CH2:34]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CC(c2cccc(F)c2)(c2cccc(F)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC(c2cccc(F)c2)(c2cccc(F)c2)C2CN(Cc3ccccc3)CC12
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (3 cc) is added to a solution of 4,4-bis(3-fluorophenyl)cyclohexenone (90.3 g) and N-butoxymethyl-N-(trimethylsilylmethyl)benzylamine (123 cc) in dry dichloromethane (1000 cc). The reaction mixture is brought to reflux, then stirred for 2 hours while allowing the temperature to return to 25° C. and for a further 15 minutes after the addition of potassium carbonate (60 g). After filtration and concentration to dryness under reduced pressure (2.7 kPa), the crystallized residue is stirred vigorously with isopropyl ether, drained, washed and recrystallized in cyclohexane (300 cc). The crystals are drained, washed with cyclohexane (2×15 cc) and dried to give (3aRS,7aRS)-2-benzyl-7,7-bis(3-fluorophenyl)perhydro-4-isoindolone (92 g) in the form of white crystals. M.p. 124° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([O:12][C:13]1[CH:14]=[CH:15][C:16]3[N:20]=[C:19]([CH2:21][O:22][C:23]4[CH:36]=[CH:35][C:26]([CH2:27][CH:28]5[S:32][C:31](=[O:33])[NH:30][C:29]5=[O:34])=[CH:25][CH:24]=4)[N:18]([CH3:37])[C:17]=3[CH:38]=1)[CH:8]=[CH:7]2.[C:39]1([S:45]([N:48]=[C:49]=[O:50])(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1>[C:39]1([S:45]([NH:48][C:49]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]4[CH:14]=[CH:15][C:16]5[N:20]=[C:19]([CH2:21][O:22][C:23]6[CH:24]=[CH:25][C:26]([CH2:27][CH:28]7[S:32][C:31](=[O:33])[NH:30][C:29]7=[O:34])=[CH:35][CH:36]=6)[N:18]([CH3:37])[C:17]=5[CH:38]=4)[CH:10]=3)[CH:5]=[CH:4][CH:3]=2)=[O:50])(=[O:46])=[O:47])[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc4cccc(N)c4c3)cc21
Solvent: C1CCOC1
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc4cccc(NC(=O)NS(=O)(=O)c5ccccc5)c4c3)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.2 %

Procedure:
To a solution of 5-[4-[6-(8-aminonaphthalen-2-yloxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.4 g) in anhydrous tetrahydrofuran (8 ml) was added benzenesulfonyl isocyanate (0.22 g) and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=3:1 as the eluant. The product was recrystallized from n-hexane to afford the title compound (55 mg, mp 199-205° C.).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](I)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].C([Sn](CCCC)(CCCC)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)CCC>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCCNC(=O)c1nnc2c(I)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3ccccn3)cccc2c1N
Yield: 39 %

Procedure:
Using method C, 4-amino-8-iodo-N-propyl-cinnoline-3-carboxamide (178 mg, 0.500 mmol) and 2-(tributylstannyl)pyridine (220 mg, 0.600 mmol) were reacted to afford the title compound (60 mg, 39% yield) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.79 (m, 1H), 8.52 (br, 1H), 8.26-8.21 (m, 1H), 8.14-8.09 (m, 1H), 8.05-7.98 (m, 1H), 7.88-7.75 (m, 2H), 7.34 (m, 1H), 3.47 (apparent quartet, J=7.0 Hz, 2H), 1.68 (apparent sextet, J=7.0 Hz, 2H), 1.01 (t, J=7.0 Hz, 3H). MS APCI, m/z=308 (M+H). HPLC 1.53 min.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[CH:36]=O.N1CCCCC1>CO>[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2/[CH:36]=[C:7]1\[O:8][C:4]2[C:3]([CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=2[C:6]\1=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccc(Cl)cc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) obtained in Example A16, Step 1 in methanol (1.2 mL) was added with 5-chloro-1H-indole-3-carboxaldehyde (0.0515 g, 0.287 mmol) and piperidine (0.00244 g, 0.0287 mmol), and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, and added with methanol (4 mL), and the solid was suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-({2-[(5-chloro-1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0730 g, 49%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][CH2:8][C:9]1[CH:10]=[C:11]([OH:16])[CH:12]=[C:13]([OH:15])[CH:14]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20](F)[CH:19]=1.Cl>CN(C=O)C.C(OCC)C.O>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[C:20]([O:15][C:13]2[CH:14]=[C:9]([CH2:8][OH:7])[CH:10]=[C:11]([OH:16])[CH:12]=2)[CH:19]=1
Reactant: OCc1cc(O)cc(O)c1
Reactant: N#Cc1ccc(Cl)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: N#Cc1ccc(Cl)cc1Oc1cc(O)cc(CO)c1
Temperature: 120 °C
Yield: 9 %

Procedure:
To a stirred solution of cesium carbonate (11.62 g) in dry DMF (70 ml) was added 5-(hydroxymethyl)-1,3-benzenediol (5 g) followed by 4-chloro-2-fluorobenzonitrile (5 g). The mixture was then stirred and heated at 120° C. for 3 h. The cooled mixture was then poured into water (200 ml) and made acidic by the addition of 2M aqueous hydrochloric acid The products were extracted into ethyl acetate (3×150 ml), and the combined extracts were washed with 10% aqueous potassium carbonate solution (100 ml). The organic extract was collected, dried (MgSO4) and concentrated to dryness. Diethyl ether was added to the residue and the mixture filtered. The filtrate was concentrated to dryness and the residue purified by chromatography (silica, 70% diethyl ether/isohexane) to afford, after trituration with diethyl ether, the sub-title compound (800 mg).
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1.[OH-].[Na+].Cl>O1CCCC1.O>[C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:15])=[O:2])=[CH:5][C:6]=1[N+:12]([O-:14])=[O:13])#[N:11]
Reactant: COC(=O)c1ccc(C#N)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Cyano-3-nitro-benzoic acid methyl ester (13.4 g, 61.6 mmol) was dissolved in tetrahydrofuran (74 ml) and aqueous sodium hydroxide (1M) (73.9 ml) was added. The reaction mixture was stirred at 25° C. for 4 hours. Then the reaction mixture was diluted with water (700 ml) and acidified with aqueous hydrochloric acid (1M). The mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. 4-Cyano-3-nitro-benzoic acid (12.0 g) was used in the next step without further purification. 1H-NMR (400 MHz, DMSO-d6): 13.00 (bs, 1H), 8.79 (s, 1H), 8.40 (d, 1H), 8.30 (d, 1H) ppm.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.Cl[C:14]1[C:15](=[O:33])[N:16]([CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[C:17](=[O:25])[C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CC#N>[C:19]1([C:18]2[C:17](=[O:25])[N:16]([CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[C:15](=[O:33])[C:14]=2[NH:8][C:7]2[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C1C(Cl)=C(c2ccccc2)C(=O)N1Cc1cccnc1
Solvent: O
Solvent: CC#N
Product: O=C1C(Nc2ccc(OC(F)(F)F)cc2)=C(c2ccccc2)C(=O)N1Cc1cccnc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 44.5 %

Procedure:
4-(Trifluoromethoxy)aniline (0.94 mmol, 177 mg) dissolved in dry CH3CN (2 mL) was added to crude 3-chloro-4-phenyl-1-(pyridin-3-ylmethyl)-1H-pyrrole-2,5-dione (0.47 mmol, 140 mg) and the reaction mixture was sequentially subjected to microwave heating single node 140° C. for 20 min, 140° C. for 120 min, and 140° C. for 120 min. 0.3 mL Water was added and the reaction mixture was purified using HPLC (57% 0.1M ammonium acetate buffer: 43% CH3CN→100% CH3CN, 20 mL/min) to give 92 mg (45%) of the title compound. 1H NMR (400 MHz, CD3CN) δ 8.63 (d, 1H), 8.52 (dd, 1H), 7.95 (bs, 1H), 7.80-7.74 (m, 1H), 7.37-7.32 (m, 1H), 7.19-7.08 (m, 3H), 7.01-6.95 (m, 2H), 6.94-6.88 (m, 2H), 6.84-7.78 (m, 2H), 4.77 (s, 2H).
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[N:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[C:11](Cl)[N:10]=1>O1CCCC1.[C].[Pd]>[N:10]1[CH:11]=[CH:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:14][CH:9]=1
Reactant: CCOC(=O)c1cc(Cl)nc(Cl)n1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccncn1
Reaction time: 6 h
Yield: 86605.9 %

Procedure:
Triethylamine (48.03 g, 0.475 mmol) was added to a solution of ethyl 2,6-dichloropyrimidine-4-carboxylate (38.60 g, 0.175 mmol) in tetrahydrofuran (700 ml). 5% Palladium-carbon was added and the mixture was stirred under a hydrogen atmosphere for 6 hrs. The solid in the reaction system was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give ethyl pyrimidine-4-carboxylate (23.06 g, 87%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][C:14](=O)[NH:15][CH2:16][CH2:17][NH:18][C:19](=O)[CH3:20])=[O:5])[CH3:2].B>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[CH:9][NH:8][C:7]=1[CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH2:17][NH:18][CH2:19][CH3:20])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)c[nH]c1CCC(=O)NCCNC(C)=O
Agent: B
Solvent: C1CCOC1
Product: CCNCCNCCCc1[nH]cc(C)c1C(=O)OCC
Yield: 31.1 %

Procedure:
2-[2-Acetylamino-ethylcarbamoyl)-ethyl]-4-methyl-1H-pyrrole-3-carboxyl is acid ethyl ester 62b (600 mg, 1.94 mmol) was dissolved in 4 ml of tetrahydrofuran under stirring, and added with a solution of borane in tetrahydrofuran (7.79 ml, 1 mol/L, 7.79 mmol) to the solution in an ice-water bath under an argon atmosphere. Upon completion of the addition, the reaction mixture was heated to reflux for 2 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was quenched with hydrochloric acid, stirred for 30 minutes at room temperature, adjusted to about pH 12 with aqueous sodium hydroxide solution (10%) and extracted with ethyl acetate (30 ml×3). The combined organic extracts were washed with saturated brine (30 ml), dried over anhydrous magnesium sulfate, filtered to remove the drying agent and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound 2-[3-(2-ethylamino-ethylamino)-propyl]-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester 62c (170 mg, yield 31%) as a white solid.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[C:24]([O:26][CH3:27])=[O:25])=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=O)(C)(C)C>Cl.CO>[CH3:27][O:26][C:24](=[O:25])[C:23]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[C:14]1[CH:15]=[N:16][C:17]2[NH:8][CH2:9][CH2:10][CH2:11][C:12]=2[CH:13]=1
Reactant: COC(=O)c1ccncc1-c1cnc2c(c1)CCCN2C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccncc1-c1cnc2c(c1)CCCN2
Temperature: 30 °C
Reaction time: 16 h
Yield: 72.2 %

Procedure:
6-(4-Methoxycarbonyl-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester (400 mg, 1.1 mmol) is dissolved in 1.25 M HCl in MeOH (200 mL). The mixture is stirred at 30° C. for 16 hrs. The solvent is removed and the pH of the residue is adjusted to 9˜10 using saturated aqueous NaHCO3 solution. The mixture is then extracted with DCM and the organic layer is dried over Na2SO4, filtered and concentrated to give 214 mg of 3-(5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-isonicotinic acid methyl ester which is used in the next step without further purification.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.BrCC1CCCCO1.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:29]=2[C:30]2([C:49]4[C:40](=[CH:41][C:42]5[O:47][CH2:46][CH2:45][O:44][C:43]=5[CH:48]=4)[O:39][CH2:38]2)[C:31](=[O:37])[NH:32]3)[CH:19]=1>>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:3][N:32]1[C:33]2[C:29](=[C:28]([C:20]3[CH:19]=[N:18][C:27]4[C:22]([CH:21]=3)=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:36]=[CH:35][CH:34]=2)[C:30]2([C:49]3[C:40](=[CH:41][C:42]4[O:47][CH2:46][CH2:45][O:44][C:43]=4[CH:48]=3)[O:39][CH2:38]2)[C:31]1=[O:37]
Reactant: O=C1Nc2cccc(-c3cnc4ccccc4c3)c2C12COc1cc3c(cc12)OCCO3
Reactant: BrCc1ccccn1
Agent: Br
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccn2)c2cccc(-c3cnc4ccccc4c3)c2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 4′-quinolin-3-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-(pyridin-2-ylmethyl)-4′-quinolin-3-yl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (73%) as a colorless solid: mp 228-230° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 10.70 (s, 1H), 7.42-7.32 (m, 2H), 7.26 (t, J=7.8 Hz, 1H), 7.13-7.05 (m, 1H), 6.96-6.90 (m, 3H), 6.79-6.70 (m, 5H), 6.23 (s, 1H), 6.12 (s, 1H), 4.47 (d, J=9.3 Hz, 1H), 4.32 (d, J=9.3 Hz, 1H), 4.15-4.01 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.8, 155.4, 150.3, 149.6, 147.2, 144.8, 142.7, 138.2, 137.2, 136.4, 135.7, 131.2, 130.4, 129.2, 128.0, 126.9, 125.9, 122.9, 122.7, 121.8, 111.3, 109.5, 99.6, 64.6, 64.1, 46.3; MS (ES+) m/z 513.9 (M+1).
Reaction SMILES: [Cl-:1].[CH3:2][N:3]([CH3:29])[C:4]1[CH:28]=[CH:27][C:7]([CH:8]=[N:9][N+:10]2[CH:14]=[CH:13][N:12]([N:15]=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([N:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[C:11]=2[CH3:26])=[CH:6][CH:5]=1.C(O[CH:33](OCC)[N:34]([CH3:36])[CH3:35])C>C(O)CC>[Cl-:1].[CH3:25][N:23]([CH3:24])[C:20]1[CH:21]=[CH:22][C:17]([CH:16]=[N:15][N+:12]2[CH:13]=[CH:14][N:10]([N:9]=[CH:8][C:7]3[CH:6]=[CH:5][C:4]([N:3]([CH3:2])[CH3:29])=[CH:28][CH:27]=3)[C:11]=2[CH:26]=[CH:33][N:34]([CH3:36])[CH3:35])=[CH:18][CH:19]=1
Reactant: Cc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Reactant: CCOC(OCC)N(C)C
Agent: [Cl-]
Solvent: CCCO
Product: CN(C)C=Cc1n(N=Cc2ccc(N(C)C)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1

Procedure:
2.05 g of 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-methylimidazolium chloride and 7.35 g of N,N-dimethylformamide diethyl acetal are stirred at 100° for 45 minutes in 150 ml of 1-propanol. The product is precipitated by the addition of ether. The precipitate is crystallized from dichloromethane/methanol and recrystallized from ethanol. There is obtained 1,3-bis[[p-(dimethylamino)benzylidene]amino]-2-[2-(dimethylamino)vinyl]imidazolium chloride of melting point 246°-248°.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[C:11]([CH3:21])[CH:10]=1)C1C=CC=CC=1>C(O)C.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]([CH3:19])[CH3:20])=[O:17])=[C:11]([CH3:21])[CH:10]=1
Reactant: Cc1cc(OCc2ccccc2)ccc1CC(=O)N(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(O)ccc1CC(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[4-(benzyloxy)-2-methylphenyl]-N,N-dimethylacetamide (680 mg, 2.40 mmol) was dissolved in ethanol (4 ml). and palladium hydroxide on carbon (20%) (169 mg, 0.240 mmol) added. The mixture was stirred under an atmosphere of hydrogen gas at RT overnight. The mixture was filtered and the filtrate concentrated under reduced pressure to afford the title compound. LC/MS (m/z): 194 (M+H)+.