Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:26]=1[OH:32]>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:26]2[CH:27]=[CH:28][C:29]([CH3:31])=[CH:30][C:25]=2[Cl:24])=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: Cc1ccc(O)c(Cl)c1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccc(C)cc2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 2-chloro-4-methylphenol: 1H-NMR (CDCl3) δ 8.53 (1H, d, J=2.6 Hz), 8.20 (1H, d, J=7.4 Hz), 8.11 (1H, d, J=2.6 Hz), 8.01 (2H, d, J=8.4 Hz), 7.45 (2H, d, J=8.4 Hz), 7.37–7.31 (1H, m), 7.23–7.17 (2H, m), 5.39 (1H, dq, J=7.4, 6.9 Hz), 3.90 (3H, s), 2.40 (3H, s), 1.60 (3H, d, J=6.9 Hz); MS (ESI) m/z 459 (M+H)+, 457 (M−H)−.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][CH:16]=[CH:17][CH:18]=[C:13]4[N:12]([CH2:19][CH3:20])[C:11]3=[O:21])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:23]1[N:27]([CH2:28]OCC[Si](C)(C)C)[C:26]2[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=2[N:24]=1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[CH2:19]([N:12]1[C:13]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[N:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[N:1]([C:23]2[N:27]([CH3:28])[C:26]4[CH:36]=[CH:37][CH:38]=[CH:39][C:25]=4[N:24]=2)[CH2:2][CH2:3]3)[C:11]1=[O:21])[CH3:20]
Reactant: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Reactant: CCn1c(=O)n(-c2ccc3c(c2)CCN3)c2ncccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCn1c(=O)n(-c2ccc3c(c2)CCN3c2nc3ccccc3n2C)c2ncccc21
Temperature: 120 °C
Reaction time: 10 h
Yield: 8.2 %

Procedure:
A mixture of 3-(2,3-dihydro-1H-indol-5-yl)-1-ethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (100 mg) and 2-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (101 mg) in NMP (2 mL) was stirred at 120° C. for 10 h, treated with saturated NaHCO3 solution and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was dissolved in DMF (2 mL), and then iodomethane (0.022 mL) and Cs2CO3 (0.176 g) were added. The mixture was stirred at room temperature for 3 h, treated with water and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was suspended in CH3CN and the precipitate was filtered off. The residue was purified by prep. HPLC, and then chromatographed on silica gel eluting with AcOEt/Hexane. Crystallization from AcOEt/Hexane gave the title compound (12 mg).
Reaction SMILES: C[O:2][C:3](=O)/[CH:4]=[CH:5]/[C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]=1[N+:17]([O-])=O.C(O)C>[Pd].O1CCCC1>[O:2]=[C:3]1[CH2:4][CH2:5][C:6]2[C:7](=[CH:8][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=2)[NH:17]1
Reactant: CCOC(=O)c1ccc(/C=C/C(=O)OC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1ccc2c(c1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
To a mixture of 1.8 g of ethyl 4-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]-3-nitrobenzoate, 32 ml of ethanol and 32 ml of tetrahydrofuran was added 640 mg of 10% palladium/carbon under an argon atmosphere, followed by 2 hours of stirring at room temperature under a hydrogen atmosphere. The reaction solution was filtrated through celite and the organic solvent in the filtrate was removed under reduced pressure. To the residue were added 50 ml of methanol and 2 drops of concentrated hydrochloric acid, followed by 30 minutes of stirring at 60° C. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and water and chloroform were added to the residue, followed by an analytical operation. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by evaporation. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain 1.16 g of ethyl 2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate as a white solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.BrC1C=CC(N(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:30][N:31]1[C:35]([Sn](CCCC)(CCCC)CCCC)=[CH:34][CH:33]=[C:32]1[C:49]1[CH:67]=[CH:66][C:52]([N:53]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:51][CH:50]=1.CN1C=CC=C1[Sn](CCCC)(CCCC)CCCC>>[C:54]1([N:53]([C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[C:52]2[CH:66]=[CH:67][C:49]([C:32]3[N:31]([CH3:30])[C:35]([C:2]4[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=4)=[CH:34][CH:33]=3)=[CH:50][CH:51]=2)[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(-c2ccc(N(c3ccccc3)c3ccccc3)cc2)n1C
Reactant: O=Cc1ccc(Br)cc1
Agent: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Product: Cn1c(-c2ccc(C=O)cc2)ccc1-c1ccc(N(c2ccccc2)c2ccccc2)cc1

Procedure:
The compound of the present example was synthesized by the same method as described in example 1, except that 1.85 parts of 4-bromo-benzaldehyde was used to substitute 4-bromo-N,N-diphenylaniline, and 6.63 parts of 4-(1-methyl-5-(tributylstannyl)-1H-pyrrole-2-yl)-N,N-diphenylaniline (13) was used to substitute 1-methyl-2-(tributylstannyl)-1H-pyrrole, wherein 4-(1-methyl-5-(tributylstannyl)-1H-pyrrole-2-yl)-N,N-diphenylaniline (13) was synthesized according to the method illustrated in Armaroli, N.; Balzani, V. Angew. Chem. Int. Ed. 2007, 46, 52.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14]3[CH2:18][C:17]4([CH2:23][CH2:22][CH:21]([C:24]#[N:25])[CH2:20][CH2:19]4)[O:16][N:15]=3)=[CH:12][N:11]=[C:10]3[N:26]([CH2:30][CH3:31])[N:27]=[C:28](C)[C:9]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:32]=[N+:33]=[N-:34].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:1]1([NH:7][C:8]2[C:9]3[CH:28]=[N:27][N:26]([CH2:30][CH3:31])[C:10]=3[N:11]=[CH:12][C:13]=2[C:14]2[CH2:18][C:17]3([CH2:23][CH2:22][CH:21]([C:24]4[NH:34][N:33]=[N:32][N:25]=4)[CH2:20][CH2:19]3)[O:16][N:15]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [N-]=[N+]=[N-]
Reactant: CCn1nc(C)c2c(NC3CCCCC3)c(C3=NOC4(CCC(C#N)CC4)C3)cnc21
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(CCC(c5nnn[nH]5)CC4)C3)cnc21

Procedure:
3-[4-(Cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-1-oxa-2-azaspiro[4.5]dec-2-ene-8-carbonitrile (0.00098 mole) (example 40), sodium azide (0.00147 mole) and triethyl amine hydrochloride (0.00147 mol) is taken in toluene. The reaction mixture is refluxed overnight. Toluene is removed and water is added. The extraction is done with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure to give crude compound, which is purified by column chromatography
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[C:26]([O:32][CH3:33])=[N:27][CH:28]=[C:29]([Cl:31])[CH:30]=1>>[Cl:31][C:29]1[CH:30]=[C:25]([C:20]2([OH:23])[CH2:21][CH2:22][N:17]([CH2:16][C:13]34[CH2:15][CH:6]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=53)[C:5]3[C:14]4=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:18][CH2:19]2)[C:26]([O:32][CH3:33])=[N:27][CH:28]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: COc1ncc(Cl)cc1Br
Product: COc1ncc(Cl)cc1C1(O)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 25 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 3-bromo-5-chloro-2-methoxypyridine, the title compound was formed in 25% yield as a white solid, mp 195°-200 C, (dec). free base: 1H NMR (CDCl3, 250 MHz) 7.99 (d, J=2.4 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 7.20 (m, 4H), 6.93 (m, 4H), 4.27 (s, 1H), 3.99 (s, 3H), 3.58 (s, 1H), 3.47 (s, 2H), 2.82 (m, 4H), 2.60 (d, J=0.8 Hz, 2H), 2.00 (m, 4H) MS (CI, CH4) m/z 447 (M+1,100), 475 (M+29,18), 429 (34), 449 (36) hydrochloride salt:
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:20]1([NH2:27])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCOCC.[ClH:33]>CO>[ClH:1].[ClH:33].[CH:20]1([NH:27][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1cccnc1
Reactant: NC1CCCCCC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=C(Nc1nc2cccc(NC3CCCCCC3)n2n1)c1cccnc1
Yield: 42 %

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B4), 296 mg; 1.08 mmol; 1.0 eq.) and cycloheptylamine (1.0 mL). The parent compound was dissolved in MeOH and Et2O/HCl was added. The precipitate obtained was filtered, washed with Et2O and dried under reduced pressure at 40° C. to give the title compound as a white powder (178 mg, 42%). HPLC, Rt: 2.98 min. (purity 99.7%). LC/MS, M+(ESI): 351.4, M−(ESI): 349.4. CHN analysis: [C19H22N6O.2.0 HCl.1.5H20] Corrected: C, 50.67%; H, 6.04%; N, 18.66%. Found: C, 50.69%; H, 5.97%; N, 18.61%.
Reaction SMILES: FC1C=CC(C(Cl)=O)=CC=1.C[O:12][C:13](=[O:46])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@H:27]([N:34]([C:42](=[O:44])[CH3:43])[C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[CH2:26][C@@H:25]2[CH3:45])=[O:23])=[CH:18][CH:17]=1.[Li+].[OH-]>C1COCC1.CO>[C:42]([N:34]([C:35]1[CH:36]=[CH:37][C:38]([Cl:41])=[CH:39][CH:40]=1)[C@H:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:24]([C:22]([C:19]2[CH:20]=[CH:21][C:16]([CH:15]=[CH:14][C:13]([OH:46])=[O:12])=[CH:17][CH:18]=2)=[O:23])[C@@H:25]([CH3:45])[CH2:26]1)(=[O:44])[CH3:43]
Reactant: COC(=O)C=Cc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: O=C(Cl)c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(C=CC(=O)O)cc2)c2ccccc21
Yield: 94.1 %

Procedure:
(2S,4R)-3-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-acrylic acid was prepared following general procedure C, substituting 3-(4-chlorocarbonyl-phenyl)-acrylic acid methyl ester for 4-fluorobenzoyl chloride. The ester was hydrolyzed as follows. To a solution of (2S,4R)-3-(4-{4-[acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-acrylic acid methyl ester (112 mg, 0.239 mmol) in THF/MeOH (2 ml, 2 ml) was added LiOH (4 ml: 1.0 M in H2O). Upon consumption of the starting unit (1 hour), the mixture was neutralized with aq. HCl (1.0 M), partioned with EtOAc (10 ml) and separated. The organic layer was separated and concentrated whereby the resulting oil was subjected to silica gel chromatography (2% MeOH in EtOAc to 10% MeOH in EtOAc) to afford the title compound (110 mg, 99%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][C@H:10]([N:17]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:11][O:12]2)(=O)=O.CCCC[Sn]([C:47]1[CH:52]=[CH:51][CH:50]=[N:49][CH:48]=1)(CCCC)CCCC.O>O1CCOCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH2:18]([N:17]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C@H:10]1[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[C:47]2[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=2)[O:12][CH2:11]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: O=S(=O)(Oc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CO2)C(F)(F)F
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(CN(Cc2ccccc2)[C@@H]2COc3cccc(-c4cccnc4)c3C2)cc1
Reaction time: 1 h
Yield: 36.9 %

Procedure:
Palladium-tetrakis(triphenylphosphine) (48 mg, 0.042 mmol) and (3S)-3-(dibenzylamino) -3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate (200 mg, 0.42 mmol) in dioxane (4 mL) were added to 3-(tri-N-butylstannyl)pyridine (232 mg, 0.63 mmol) under an atmosphere of argon and the resulting reaction mixture was irradiated in a microwave at 120-140° C. for 1.5 h. More palladium-tetrakis(triphenylphosphine) (48 mg, 0.042 mmol) was added and the irradiation was continued at 140° C. for 1 h. Water (20 mL) was added and the mixture was extracted with ethyl acetate. The organic phases was dried over sodium sulfate, the solvent was evaporated in vacuo and the residue purified by column chromatography, using a gradient of ethyl acetate in heptanes as the eluent, gave 63 mg (74%) of the title compound: MS (ES) m/z 407[M+H+].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(C(C)C)C(C)C)C>C1COCC1>[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: CN1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 42.8 %

Procedure:
A mixture of 1-chloro-4-nitro benzene (3 g, 19 mmol), 1-methyl piperazine (2.28 g, 22.8 mmol) and ethyl-diisopropylamine (2 ml) in THF (20 ml) was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure to give a residue, which was then partitioned between dichloromethane and water. The organic layer was separated and evaporated under reduced pressure to give crude compound, which was purified by column chromatography over silica gel, using ethyl acetate as eluent, to yield 1-methyl-4-(4-nitro-phenyl)-piperazine (1.8 g, 44%) as solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.O.O.O.C([O-])(=[O:22])C.[Na+].[Cl-].[OH-].[Na+]>C(O)C.O>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:22]
Reactant: CC(=O)[O-]
Reactant: BrCCCCCCOCCc1ccccn1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OCCCCCCOCCc1ccccn1
Yield: 70.3 %

Procedure:
A mixture of 2-[2[(6-bromohexyl)oxy]ethyl]pyridine (9.0 g), sodium acetate trihydrate (34.24 g), trictylpropylammonium chloride (1.9 g) and water (25 ml) was stirred under reflux for 2 h. 2N sodium hydroxide solution (50 ml) and ethanol (50 ml) were added to the cooled mixture which was further stirred for 10 min at room temperature. The ethanol was evaporated in vacuo and the residue diluted with brine (150 ml) and extracted with ether (2×100 ml). The combined organic extracts were washed successively with water (150 ml), brine (100 ml), dried and evaporated in vacuo to give a yellow oil. Purification by FCC eluting with ether gave the title compound as a colourless oil (4.94 g), t.l.c. (ether) Rf 0.31.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]3[C:16]4[N:17]([CH2:25][CH2:26][N:27]=4)[C:18]([NH2:24])=[N:19][C:20]=3[C:21]=2[O:22][CH3:23])[CH2:4][CH2:3]1.[NH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][N:31]=1>>[NH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:24][C:18]2[N:17]3[CH2:25][CH2:26][N:27]=[C:16]3[C:15]3[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:5]4[CH2:6][CH2:7][S:2](=[O:1])(=[O:28])[CH2:3][CH2:4]4)=[C:21]([O:22][CH3:23])[C:20]=3[N:19]=2)=[O:35])=[CH:32][N:31]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: COc1c(OCCCN2CCS(=O)(=O)CC2)ccc2c1N=C(N)N1CCN=C21
Product: COc1c(OCCCN2CCS(=O)(=O)CC2)ccc2c1N=C(NC(=O)c1ccc(N)nc1)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 16, Step 2 was used to prepare the title compound from 8-[3-(1,1-dioxidothiomorpholin-4-yl)propoxy]-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-amine (Step 1) and 6-aminonicotinic acid. High vacuum drying gave the title compound (135 mg, 69%): HPLC MS RT=1.16 min, MH+=528.1; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.24-2.29 (2H, m), 3.43-3.49 (2H, m), 3.60-3.62 (4H, m), 3.82 (4H, bs), 3.99 (3H, s), 4.23-4.27 (2H, m), 4.33 (2H, t), 4.48-4.54 (2H, m), 7.05 (1H, d), 7.44 (1H, d), 8.04 (1H, d), 8.47 (1H, dd), 8.77 (1H, d).
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:12][CH2:13][CH:14]([OH:17])[CH2:15]O.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]([CH:5]1[CH2:6][CH2:7][C:8]2([O:17][CH:14]([CH2:13][Cl:12])[CH2:15][O:11]2)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OCC(O)CCl
Reactant: CC(C)(C)C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)C1CCC2(CC1)OCC(CCl)O2
Yield: 99 %

Procedure:
97.0 g (0.597 mol) of 4-t-butylcyclohexanone and 134.7 g (1.184 mol) of 3-chloro-1,2-propanediol are dissolved in 1100 ml of toluene in the presence of 11.5 g (0.060 mol) of PTSA. The mixture is brought to reflux for 6 hours while removing the water formed using a Dean-Stark trap. The reaction mixture is brought to room temperature and washed twice with 1500 ml of an aqueous solution containing 5% of NaHCO3. The organic phase is dried over MgSO4 and concentrated under vacuum. The residual oil is used directly in the following step (yield: 99%; NMR analysis)
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[CH:9]=[C:8]([CH3:20])[N:7]=1)=[O:5])C.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27]#[N:28])[N:26]=1>>[C:27]([C:25]1[N:26]=[C:22]([NH:21][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([F:19])[CH:15]=[C:16]([F:18])[CH:17]=3)[CH:9]=[C:8]([CH3:20])[N:7]=2)=[O:5])[S:23][CH:24]=1)#[N:28]
Reactant: CCOC(=O)c1cc(-c2cc(F)cc(F)c2)cc(C)n1
Reactant: N#Cc1csc(N)n1
Product: Cc1cc(-c2cc(F)cc(F)c2)cc(C(=O)Nc2nc(C#N)cs2)n1

Procedure:
The title compound, was prepared from 4-(3,5-Difluorophenyl)-6-methyl-pyridine-2-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 2-Amino-4-thiazolecarbonitrile instead of 3-chloroaniline to yield the final compound as a off-white solid, MS (ISP): m/e=356.9 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.OC[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N+:34]([O-:36])=[O:35]>C(Cl)Cl>[Br:24][CH2:20][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N+:34]([O-:36])=[O:35]
Reactant: O=[N+]([O-])c1ccccc1CCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1CCBr
Reaction time: 8 h
Yield: 80.8 %

Procedure:
Triphenylphosphine (39.2 g, 0.150 mol) and carbon tetrabromide (49.5 g, 0.150 mol) were added sequentially to a solution of 2-(2-hydroxyethyl)-nitrobenzene (25.0 g, 0.150 mol) in methylene chloride (400 mL) at 0° C. The reaction was stirred overnight and quenched with saturated sodium bicarbonate solution. The methylene chloride phase was washed with saturated brine and dried over magnesium sulfate. The crude product was treated with ethyl acetate, and the precipitated triphenylphosphine oxide removed by filtration. Further purification by flash chromatography by (silica gel, 0-10% ethyl acetate in hexane gradient elution) produced the title compound (27.9 g).
Reaction SMILES: [C:1]1(CCCC([O-])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].C[O:15][C:16]([C:18]1C=CC(O)=[CH:20][CH:19]=1)=[O:17].C(OC(C1C=CC(O)=CC=1)=O)CC.C(O)C(O)C.[OH-].[Na+]>>[C:1]1([O:17][C:16](=[O:15])[CH2:18][CH2:19][CH3:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])CCCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCCOC(=O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(O)CO
Product: CCCC(=O)Oc1ccccc1
Temperature: 70 °C

Procedure:
Part II: 5.739 g of sodium 4-phenylbutyrate (Triple Crown America, Inc.), 0.125 g of methylparaben (Merck), 0.075 g of propylparaben (Merck), 83.5 g of 1,2-propandiol, and 20 g of 10% NaOH were mixed in a beaker and heated at 70° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[Al](C)C.CCCCCC.[Br:19][CH2:20][CH2:21][C:22](OC)=[O:23].Cl>C1COCC1>[Br:19][CH2:20][CH2:21][C:22]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)=[O:23]
Reactant: COC(=O)CCBr
Reactant: Nc1ccc(F)cc1
Agent: C[Al](C)C
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(CCBr)Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
5.75 ml of 4-fluoroaniline (6.65 g, 59.88 mmol, 1 equivalent) were initially charged in 65 ml of THF, 33 ml of 2 M trimethylaluminium solution in hexane (65.87 mmol, 1.1 equivalents) were added at −78° C. and the mixture was stirred for 20 min, slowly warming to RT. At −20° C., this solution was added dropwise to a solution of 6.54 ml (10 g, 59.8 mmol, 1 equivalent) of methyl 3-bromopropanoate in 65 ml of THF and then stirred at RT for 3 h. At 0° C., the reaction solution was acidified carefully with 1 N aqueous hydrochloric acid solution and extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated. This gave 12.6 g (67% of theory; purity 78%) of the title compound which was reacted further without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:20]=[CH:19][C:10]3[NH:11][C:12]([NH:14][C:15](=[O:18])[O:16][CH3:17])=[N:13][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1.C(OCC)C>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH:1][C:2]2[CH:22]=[CH:21][C:5]([O:6][C:7]3[CH:20]=[CH:19][C:10]4[NH:11][C:12]([NH:14][C:15](=[O:18])[O:16][CH3:17])=[N:13][C:9]=4[CH:8]=3)=[CH:4][CH:3]=2)=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: COC(=O)Nc1nc2cc(Oc3ccc(N)cc3)ccc2[nH]1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)Nc1nc2cc(Oc3ccc(NC(=O)Nc4cccc(Cl)c4)cc3)ccc2[nH]1
Temperature: 45 °C
Yield: 68 %

Procedure:
A mixture of methyl (5-(4aminophenoxy)-1H-benzimidazol-2-yl)carbamate (Intermediate 3) (80 mg, 0.27 mmol) and 3-chlorophenylisocyanate (49 mg, 0.32 mmol) in dry THF (2 ml) was heated to 45° C. overnight. After cooling, diethyl ether was added to form a precipitate. The solid was collected by filtration to provide the title compound (83 mg, 69%): 1H NMR (DMSO-d6) δ 11.60 (brs, 2H), 9.00 (s, 1H), 8.83 (s, 1H), 7.70 (m, 1H), 7.42 (d, 2H), 7.38 (d, 1H), 7.32–7.24 (m, 2H), 7.01 (m, 2H), 6.93 (d, 2H), 6.80 (dd, 1H) 3.75 (s, 3H); MS m/e 452 (M+1).