Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:13]3[CH:21]=[C:20]4[C:16]([CH:17]=[N:18][NH:19]4)=[CH:15][C:14]=3[CH3:22])[CH:8]=[C:9](F)[CH:10]=2)[N:5]=[N:4][C:3]=1[C:23]([NH2:25])=[O:24].CCN(C(C)C)C(C)C.[NH:35]1[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]1>CC(N(C)C)=O>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:13]3[CH:21]=[C:20]4[C:16]([CH:17]=[N:18][NH:19]4)=[CH:15][C:14]=3[CH3:22])[CH:8]=[C:9]([N:35]3[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]3)[CH:10]=2)[N:5]=[N:4][C:3]=1[C:23]([NH2:25])=[O:24]
Reactant: Cc1cc2cn[nH]c2cc1-c1cc(F)cc2c(N)c(C(N)=O)nnc12
Reactant: OC1CCNCC1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2cn[nH]c2cc1-c1cc(N2CCC(O)CC2)cc2c(N)c(C(N)=O)nnc12
Temperature: 140 °C
Yield: 24.4 %

Procedure:
The mixture of 4-amino-6-fluoro-8-(5-methyl-1H-indazol-6-yl)cinnoline-3-carboxamide (200 mg, 0.59 mmol), DIPEA (1000 mg), piperidin-4-ol (573 mg) and DMA (4 mL) was heated at 140° C. in a microwave under N2 for 3 h. The mixture was cooled, concentrated and purified directly with prep-HPLC to give the title compound as solid (60 mg, yield=24%). 1H NMR (400 MHz, DMSO-d6): δ 12.93 (1H, s), 8.27 (1H, s), 8.02 (1H, s), 7.60 (1H, s), 7.48-7.47 (3H, m), 7.35 (1H, s), 4.74 (1H, d, J=4.4 Hz), 3.89-3.86 (2H, m), 3.75-3.72 (m, 1H), 3.17-3.12 (2H, m), 2.00 (3H, s), 1.87-1.84 (2H, m), 1.53-1.49 (2H, m); LC-MS (5-95% ACN in H2O gradient with 0.02% NH4OAc, tR 2.809 minutes); ESI+APCI m/z [M+H]+ 418.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.[N:20]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:21]=[O:22]>>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][CH2:23][NH:20][C:21]([NH:1][C:2]1[S:3][C:4]([C:8]2[CH:9]=[CH:10][C:11]([S:14](=[O:15])(=[O:16])[N:17]([CH3:18])[CH3:19])=[CH:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1)=[O:22])[CH3:29]
Reactant: Cc1nc(N)sc1-c1ccc(S(=O)(=O)N(C)C)cc1
Reactant: CCOC(=O)CCN=C=O
Product: CCOC(=O)CCNC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N(C)C)cc2)s1

Procedure:
Using 4-(2-amino-4-methyl-thiazol-5-yl)-N,N-dimethyl-benzenesulfonamide (Example 24a) (0.083 g, 0.28 mmol) and replacing ethyl isocyanatoacetate with ethyl 3-isocyanatopropionate (0.05 ml, 0.34 mmol) in the above reaction affords the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:18])[C:4]=1[CH3:19].[C-:20]#[N:21].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([CH3:17])[C:11]=1[CH2:10][O:9][C:5]1[C:4]([CH3:19])=[C:3]([CH2:2][C:20]#[N:21])[CH:8]=[CH:7][CH:6]=1
Reactant: Cc1cccc(C)c1COc1cccc(CBr)c1C
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1COc1cccc(CC#N)c1C

Procedure:
The solution of 1-(bromomethyl)-3-(2,6-dimethylbenzyloxy)-2-methylbenzene (Step D, 4.28 g, 13.41 mmol) and NaCN (0.789 g, 16.10 mmol) in dry DMF (20 ml) was heated at 120° C. for 3 hours then cooled and diluted with EtOAc (50 ml). The organic layer was washed with water (30 ml), brine, dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex: ethyl acetate 4:1) to give the title compound.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][CH2:6]Br)[CH3:2].[Mg].[CH2:9]([N:16]1[C@H:20]2[CH2:21][S:22][C:23](=[O:24])[C@H:19]2[N:18]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:17]1=[O:32])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S(=O)(=O)(O)O>CCOCC.C1C=CC=CC=1.II>[CH2:9]([N:16]1[C@H:20]2[CH2:21][S:22][C:23]([OH:24])([CH2:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])[C@H:19]2[N:18]([CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:17]1=[O:32])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C1SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Reactant: CCOCCCBr
Agent: II
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOCCCC1(O)SC[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Yield: 100.5 %

Procedure:
To a Grignard reagent solution prepared from 3-ethoxypropyl bromide (41.7 g), magnesium metal (shoot, 11.2 g) and iodine (0.2 g) in 110 ml of anhydrous ether and 30 ml of anhydrous benzene, a solution of cis-1,3-dibenzyl-hexahydrothieno[3,4-d]imidazole-2,4-dione ([α]D20 + 91°, 60.0 g) in 700 ml of anhydrous benzene is added with stirring for two and half hours at 25° to 40°C. The mixture is stirred and refluxed at 68° to 73° C for 5 hours. The reaction mixture is decomposed by the addition of 3N sulfuric acid (280 g) below 20°C. The organic layer is washed with water and concentrated in vacuo to give the residual oil of 76 g of cis-1,3-dibenzyl-4-hydroxy-4-(3-ethoxypropyl)-hexahydrothieno[3,4-d]imidazol-2-one. [α]D20 + 17° (C = 1 in CHCl3). IR (Nujol) 3350 cm-1 (OH); 1690 cm-1 (C = O).
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:4].COC(C1NN=C(OC[C:38]2[C:39]([C:44]3[CH:49]=CC=CC=3)=[N:40][O:41][C:42]=2C)C=1)=O.NC1CCOCC1>>[O:41]1[CH2:49][CH2:44][CH:39]([NH:40][C:3]([C:5]2[N:6]([CH3:26])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)=[N:14][O:15][C:16]=3[CH2:17][OH:18])[CH:9]=2)=[O:4])[CH2:38][CH2:42]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2CO)nn1C
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Agent: NC1CCOCC1
Product: Cn1nc(OCc2c(-c3ccc(F)cc3)noc2CO)cc1C(=O)NC1CCOCC1
Yield: 67 %

Procedure:
As described for example 1b, 5-[3-(4-fluoro-phenyl)-5-hydroxymethyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (150 mg, 0.42 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester, was converted, using 4-aminotetrahydropyran instead of morpholine, to the title compound (120 mg, 67%) which was obtained as a white solid. MS: m/e=429.1 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[CH3:29][N:30]([CH3:37])[CH2:31]/[CH:32]=[CH:33]/[C:34](O)=[O:35]>>[NH2:13][C:9]1[N:10]=[CH:11][N:12]=[C:7]([O:6][C:5]2[CH:27]=[CH:28][C:2]([NH:1][C:34](=[O:35])/[CH:33]=[CH:32]/[CH2:31][N:30]([CH3:37])[CH3:29])=[CH:3][CH:4]=2)[C:8]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1
Reactant: CN(C)C/C=C/C(=O)O
Reactant: Nc1ccc(Oc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)cc1
Product: CN(C)C/C=C/C(=O)Nc1ccc(Oc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)cc1
Yield: 29 %

Procedure:
(E)-N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide was prepared from 6-(4-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine and (E)-4-(dimethylamino)but-2-enoic acid using Method E (29% yield). HPLC: 99%, RT=3.448 min. MS: m/z=482 [M+H]+, RT=3.40 min. 1H-NMR (DMSO-d6) δ 10.30 (s, 1H), 8.02 (s, 1H), 7.62 (d, 2H), 7.43-7.38 (m, 4H), 7.15 (tt, 1H), 7.10-7.01 (m, 6H), 6.73 (m, 1H), 6.49 (broad s, 2H), 6.44 (d, 1H), 3.93 (m, 2H), 2.80 (s, 6H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]#[N:11].[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O>CCCCCCC.CCOC(C)=O>[C:13]1([CH3:12])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]#[N:11]
Reactant: N#CCNc1cnccc1I
Reactant: Cc1ccccc1B(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccccc1-c1ccncc1NCC#N

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-ylamino)-acetonitrile and 2-methylphenylboronic acid (CAS RN 16419-60-6) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light brown solid (48%). MS (ESI): m/z=224.12 [M+H]+.
Reaction SMILES: [C:1]1([C:7]([N:9]=[C:10]=[S:11])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:19]=[C:18]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:14]=1[NH2:15].C1(C)C=CC=CC=1>C(O)C>[C:7]([NH:9][C:10]([NH:15][C:14]1[CH:16]=[CH:17][C:18]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:19][C:13]=1[Cl:12])=[S:11])(=[O:8])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: O=C(N=C=S)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccccc4)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
Commercially available 1-benzenecarbonyl isothiocyanate (50 μl) was dissolved in ethanol (1 ml) to prepare a solution. 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (36 mg, yield 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[CH:6]([N:16]3[CH2:21][CH2:20][N:19]([C:22](SC)=[N:23][C:24]#[N:25])[CH2:18][CH2:17]3)[C:7]3[N:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][N:10]([CH3:11])[C:4]=2[CH:3]=1.[NH2:30][CH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[CH:6]([N:16]3[CH2:21][CH2:20][N:19]([C:22](=[N:30][CH2:31][C:32]4[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=4)[NH:23][C:24]#[N:25])[CH2:18][CH2:17]3)[C:7]3[N:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][N:10]([CH3:11])[C:4]=2[CH:3]=1
Reactant: CSC(=NC#N)N1CCN(C2c3ccc(Cl)cc3N(C)Cc3cccnc32)CC1
Reactant: NCc1ccncc1
Product: CN1Cc2cccnc2C(N2CCN(C(=NCc3ccncc3)NC#N)CC2)c2ccc(Cl)cc21
Temperature: 0 °C

Procedure:
Methyl 4-(8-chloro-6,11-dihydro-6-methyl-5H-pyrido[3,2-c][1]benzazepin-11-yl)-N-cyano-1-piperazinecarboximidothioate (105 mg) and 4-aminomethyl-pyridine (0.45 ml) were heated at 80° C. in a sealed vial allowing escape of gases. Ice-water was then added, and the resulting tan solid was chromatographed on silica gel to afford the desired product, 107 mg; HRMS, FAB: calcd. 487.2125; found 487.2141.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)=O.[CH3:19][C:20](=[O:23])[CH:21]=[CH2:22].[OH-].[K+]>CO.O>[O:23]=[C:20]1[CH2:21][CH2:22][C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH:1]=[CH:19]1
Reactant: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C=CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2

Procedure:
A solution of 0.98 g (3.96 mmol) benzyl 4-formylpiperidine-1-carboxylate (prepared by the method from Eur. J. Med. Chem. 1991, 26, 625) and 0.28 g (4.0 mmol) 3-buten-2-one in a mixture of 1 ml methanol and 1 ml water was added dropwise to a boiling solution of 0.015 g (0.27 mmol) potassium hydroxide in 1 ml methanol. After 1 hour heating with reflux the cooled mixture was poured into 50 ml water, and it was extracted with tert.-butylmethylether. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The title compound was obtained from the remaining oil by HPLC on silica gel with hexane/acetone 4:1.
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH:3]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:4]([N:6]1[CH2:10][C@@H:9]2[C@@H:11]([NH:14]C(=O)OC(C)(C)C)[CH2:12][CH2:13][C@@H:8]2[CH2:7]1)=[O:5].[ClH:29].O1CCOCC1>CCOCC>[ClH:29].[NH2:14][C@@H:11]1[C@@H:9]2[C@@H:8]([CH2:7][N:6]([C:4](=[O:5])[CH:3]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:2]([CH3:28])[CH3:1])[CH2:10]2)[CH2:13][CH2:12]1
Reactant: CC(C)C(C(=O)N1C[C@H]2CC[C@H](NC(=O)OC(C)(C)C)[C@H]2C1)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)C(C(=O)N1C[C@H]2CC[C@H](N)[C@H]2C1)c1ccccc1
Reaction time: 2 h

Procedure:
tert-Butyl(3aR,4S,6aS)-2-(3-methyl-2-phenylbutanoyl)octahydrocyclopenta[c]pyrrol-4-ylcarbamate (39 mg, 0.101 mmol) from Step C was combined with 4 M HCl in dioxane (5 mL, 20.00 mmol) in ether (5 mL). After about 2 hours, the solvent was removed in vacuo to give 1-((3aR,4S,6aS)-4-aminohexahydrocyclopenta[c]pyrrol-2(1H)-yl)-3-methyl-2-phenylbutan-1-one hydrochloric acid salt which was used in the next step without additional purification: MS (ESI+) m/z 287 (M+H)+.
Reaction SMILES: C1CC=CCC=1.[CH3:7][N:8]1[C:12]([CH2:13][N:14]2[CH2:19][CH2:18][N:17](C(OCC3C=CC=CC=3)=O)[CH2:16][C:15]2=[O:30])=[N:11][CH:10]=[N:9]1>[Pd].C(O)C>[CH3:7][N:8]1[C:12]([CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]2=[O:30])=[N:11][CH:10]=[N:9]1
Reactant: Cn1ncnc1CN1CCN(C(=O)OCc2ccccc2)CC1=O
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CCO
Product: Cn1ncnc1CN1CCNCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.3 %

Procedure:
A slurry of palladium on carbon (10%, 1.7 g) and 1,4-cyclohexadiene (4.1 g, 51 mmol) in ethanol (10 mL) was added to a solution of phenylmethyl 4-[(1-methyl-1H-1,2,4-triazol-5-yl)methyl]-3-oxo-1-piperazinecarboxylate (Description 140, 1.7 g, 5.2 mmol) in ethanol (40 mL) and the mixture was stirred at room temperature for 2 hours. The mixture was filtered through Celite™ and the solvent was evaporated under reduced pressure, The residue was recrystallized from propan-2-ol to give the title compound (500 mg, 49%). m/z (ES+) 196 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].C[O-].[Na+].O/[N:14]=[C:15](\Cl)/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[CH3:1][O:2][C:3]([C:4]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:14][O:8][C:5]=1[CH2:6][CH3:7])=[O:9]
Reactant: CCC(=O)CC(=O)OC
Reactant: O/N=C(\Cl)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1onc(-c2ccccc2)c1C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-oxo-pentanoic acid methyl ester (19.3 g, 0.15 mol) in methanol (30 mL) was added a solution of sodium methoxide (8.1 g, 0.15 mol) in methanol (30 mL) dropwise under ice-bath cooling keeping the temperature below 30° C. The reaction mixture was then stirred at room temperature for 30 min. Then a solution of (E)- and/or (Z)-N-hydroxy-benzenecarboximidoyl chloride (21.7 g, 0.14 mol, in Example 1a) in methanol (78 mL) was added to this mixture under ice-bath cooling keeping the temperature below 0° C. After adding, the ice-bath was removed and stirring was continued overnight at room temperature. The resulting mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The aqueous phase was further extracted with ethyl acetate. The combined organic extracts were then dried over sodium sulphate and concentrated to give the title compound as a yellow oil which was used in the next reaction without further purification. MS: m/e=232.1 [M+H]+.
Reaction SMILES: [2H][C:2]1[C:7]([2H])=[C:6]([NH2:9])[C:5]([NH2:10])=[C:4]([2H])[C:3]=1[2H].[NH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=O)=[CH:16][CH:15]=1>O.C(=O)([O-])[O-].[K+].[K+]>[NH2:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]2[NH:9][C:6]3[CH:7]=[CH:2][CH:3]=[CH:4][C:5]=3[N:10]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: [2H]c1c([2H])c([2H])c(N)c(N)c1[2H]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1ccc(-c2nc3ccccc3[nH]2)cc1
Temperature: 195 °C
Yield: 88.2 %

Procedure:
This intermediate was prepared according to the procedure given in E. Acalade et al., J. Org. Chem. 52:5009-15 (1987). A mixture of 3.21 g (0.0247 moles) of O-phenylenediamine, 3.93 g (0.0287 moles) of 4-aminobenzoic acid and 42 g of polyphosphoric acid was heated to 195° C. for 5 hours. After cooling to room temperature, the reaction mixture was diluted with 180 mL of water and basified to pH 8 with solid potassium carbonate. The resulting precipitate was collected, washed with water and dried to give 4.56 g of product.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.Cl.Cl[CH2:25][CH2:26][S:27][C:28]1[N:29]([CH3:33])[CH:30]=[CH:31][N:32]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:25][CH2:26][S:27][C:28]4[N:29]([CH3:33])[CH:30]=[CH:31][N:32]=4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1
Reactant: Cn1ccnc1SCCCl
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCSc1nccn1C
Temperature: 90 °C
Yield: 18.1 %

Procedure:
A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (350 mg, 0.9 mmol), (prepared as described for the starting material in Example 24), 2-(2-chloroethylthio)-1-methylimidazole hydrochloride (203 mg, 0.95 mmol) and potassium carbonate (303 mg 2.2 mmol) in NMP (20 ml) was heated at 90° C. for 2 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (100/0 increasing to 90/10) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(1-methylimidazol-2-ylthio)ethoxy)quinazoline (75 mg, 17%) as a solid. 1H NMR Spectrum: (DMSOd6) 3.46(s, 3H); 3.93(s, 3H); 4.39-4.44(m, 4H); 7.13(dd, 2H); 7.23(s, 1H); 7.31(dd, 1H); 7.49-7.60(m, 2H); 7.79(s, 1H); 8.37(s, 1H); 9.51(s, 1H) MS-ESI: 460 [MH]+
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:24])[C:13]=3[CH:12]=[CH:11][C:10]=2[NH:25][C:26](=[O:29])[CH2:27]Cl)=[O:7])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[N:41]1([CH2:47][CH2:48][OH:49])[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>O1CCCC1>[CH3:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[C:22]3[C:21](=[O:23])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14](=[O:24])[C:13]=3[CH:12]=[CH:11][C:10]=2[NH:25][C:26](=[O:29])[CH2:27][N:44]2[CH2:45][CH2:46][N:41]([CH2:47][CH2:48][OH:49])[CH2:42][CH2:43]2)=[O:7])=[CH:4][CH:3]=1
Reactant: OCCN1CCNCC1
Reactant: Cc1ccc(C(=O)Nc2c(NC(=O)CCl)ccc3c2C(=O)c2ccccc2C3=O)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2c(NC(=O)CN3CCN(CCO)CC3)ccc3c2C(=O)c2ccccc2C3=O)cc1
Reaction time: 0.12 h
Yield: 48 %

Procedure:
Compound CC-12 (0.86 g, 2 mmole) was dissolved in anhydrous tetrahydrofuran (30 ml), and to the solution was added successively with DIPEA (1 ml, 6 mmole) and 2-(piperazin-1-yl)ethanol (0.97 ml, 8 mmole) under stirring for 5 to 10 minutes. This mixture was heated under reflux for 16 hours. After the completion of the reaction, the mixture was filtered, and the filtrate was concentrated by reduced pressure concentrator (such as Vacuum Evaporator). The residue was extracted with ethyl acetate for several times. The extract was dried on magnesium sulfate, and concentrated under reduced pressure. The crude product was washed with ethyl acetate/hexane. Finally, the crude product was recrystallized in hot ethanol to obtain a kelly green compound CC-44. Mol. Wt.: 526.5830 (C30H30N4O5); Rf: 0.41 (ethyl acetate:n-hexane=1:2); Yield: 48%; Mp.: 210-211° C. (EtOH); HRMS (EI) m/z: calcd [M]+, 526.2216 (C30H30N4O5+). Found, 526.2219. 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 1.92 (t, J=6.0 Hz, 2H, —NCH2—), 2.03 (br, 4H, —CH2—), 2.39 (br, 4H, —CH2—), 2.43 (s, 3H, —CH3), 3.01 (s, 2H, —CH2N—), 3.26-3.30 (m, 2H, —CH2OH), 4.29 (t, J=5.4 Hz, 1H, —CH2OH), 7.43 (d, J=8.1 Hz, 2H, Ar—H), 7.87-7.91 (m, 2H, Ar—H), 8.07-8.19 (m, 4H, Ar—H), 8.27 (d, J=8.7 Hz, 1H, Ar—H), 8.79 (d, J=8.7 Hz, 1H, Ar—H), 10.00 (s, 1H, Ar—NH—), 10.50 (s, 1H, Ar—NH—); 13C-NMR (75 MHz, DMSO-d6) δ (ppm): 20.93, 52.32, 52.93, 58.21, 59.1, 61.69, 125.11, 126.37, 126.72, 126.98, 127.81, 128.04, 128.33, 129.24, 130.53, 130.53, 140.68, 142.70, 166.37 (NCO), 169.28 (NCO), 181.50 (CO), 183.67 (CO).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][N:6]1[C:10]2([CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)[C:9](=[O:19])[NH:8][C:7]1=[O:20]>O>[CH3:5][N:6]1[C:10]2([CH2:11][C:12]3[C:17](=[CH:16][CH:15]=[C:14]([N+:1]([O-:4])=[O:2])[CH:13]=3)[CH2:18]2)[C:9](=[O:19])[NH:8][C:7]1=[O:20]
Reactant: O=[N+]([O-])O
Reactant: CN1C(=O)NC(=O)C12Cc1ccccc1C2
Solvent: O
Product: CN1C(=O)NC(=O)C12Cc1ccc([N+](=O)[O-])cc1C2

Procedure:
To stirred fuming nitric acid (100 mL) was slowly added (±)-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (4.5 g, 20.9 mmol) in portions over 30 min. The reaction mixture was diluted with H2O (200 mL) and the precipitate was collected by filtration, washed with H2O and dried in vacuo to give the title compound. MS: m/z=262 (M+1).
Reaction SMILES: [C:1]1([C:7]2[C:8](=O)[O:9][CH2:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+:23]>>[C:1]1([C:7]2[C:8](=[O:9])[NH:23][CH2:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: O=C1OCC(c2ccccc2)=C1c1ccccc1
Agent: CC(=O)[O-]
Product: O=C1NCC(c2ccccc2)=C1c1ccccc1

Procedure:
Analogous to the reaction of 3,4-diphenyl-2(5H)-furanone with ammonium acetate, forming 3,4-diphenyl-1,5-dihydro-pyrrol-2-on in Rio, G. and Sekiz, B. (see above):
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([NH:20][S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:18]=2)[NH:13][C:12]1=[O:30])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH2:31]([O:33][C:34]([CH2:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1)=[O:35])[CH3:32].O>CN(C=O)C>[CH2:31]([O:33][C:34]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([NH:41]/[C:4](=[C:11]2\[C:12](=[O:30])[NH:13][C:14]3[C:19]\2=[CH:18][C:17]([NH:20][S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:22])=[O:23])=[CH:16][CH:15]=3)/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:42][CH:43]=1)=[O:35])[CH3:32]
Reactant: CCOC(=O)Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)Nc2ccc(NS(=O)(=O)c3ccccc3)cc21)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(N/C(=C2\C(=O)Nc3ccc(NS(=O)(=O)c4ccccc4)cc32)c2ccccc2)cc1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
0.84 g (2 mmol) of 3-(1-ethoxy-1-phenyl-methylidene)-5-phenylsulphonylamino-2-indolinone and 0.39 g (2.2 mmol) of 4-ethoxycarbonylmethyl-aniline are dissolved in 10 ml of DMF. The mixture is heated to 140° C. for 5 hours. Then water is added while the mixture is cooled with ice and stirred for 1 hour at ambient temperature. The precipitate formed is suction filtered, washed with water, a little isopropanol and ether, then dried in vacuo.
Reaction SMILES: CS(O[CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:33](=[O:35])[NH2:34])=[C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH:20]=3)[C:9]=2[CH:8]=1)(=O)=O.[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37]>ClCCl>[CH2:36]([N:38]([CH2:6][C:7]1[N:12]=[CH:11][C:10]2[N:13]=[CH:14][N:15]([C:16]3[S:17][C:18]([C:33]([NH2:34])=[O:35])=[C:19]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH:20]=3)[C:9]=2[CH:8]=1)[CH2:39][CH3:40])[CH3:37]
Reactant: CS(=O)(=O)OCc1cc2c(cn1)ncn2-c1cc(OCc2ccccc2C(F)(F)F)c(C(N)=O)s1
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)Cc1cc2c(cn1)ncn2-c1cc(OCc2ccccc2C(F)(F)F)c(C(N)=O)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 58 mg of [1-(5-carbamoyl-4-{[2-(trifluoromethyl)benzyl]oxy}-2-thienyl)-1H-imidazo[4,5-c]pyridin-6-yl]methyl methanesulfonate (compound A1) in 4 ml of dichloromethane were added 146 mg of diethylamine, and the reaction mixture was stirred at room temperature for 12 h. The mixture was concentrated to dryness under vacuum and the residue was dissolved in acetonitrile/water and purified by preparative HPLC (water/acetonitrile, elution gradient 9/1 to 1/9 (v/v)). After lyophilization the title compound was obtained.