Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)=[O:7].[OH-].[Na+].Cl>>[C:11]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:12]=[CH:13][C:8]([C:6]([NH:5][CH2:4][C:3]([OH:20])=[O:2])=[O:7])=[CH:9][CH:10]=1
Reactant: COC(=O)CNC(=O)c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 90.1 %

Procedure:
[(Biphenyl-4-carbonyl)amino]acetic acid methyl ester (6.58 g, 25 mmol, 1.0 eq., from step (a) above) was added to the flask followed by aqueous sodium hydroxide (1 M, 84 mL, 50 mmol, 2.0 eq). The mixture was heated to 50° C. using an oil bath for 5 hours. The solution was then stirred overnight (16 hours) at room temperature. On cooling, a white precipitate formed. The mixture was cooled further to 5° C. using an ice/water bath. Concentrated hydrochloric acid (8 mL) was added very slowly to the cooled solution, ensuring that the temperature did not rise above 10° C. The mixture was stirred for 15 minutes and was then filtered. The white solid was air dried for 30 minutes and then dried in vacuo at 40° C. for 16 hours to give an off-white solid (5.75 g, 93%).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([NH:15][C@@H:16]([CH3:30])[C:17]([N:19]3[CH2:24][CH2:23][CH:22]([O:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:21][CH2:20]3)=[O:18])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.S(=O)(=O)(O)O.[OH-].[Na+].C(=O)([O-])O.[Na+].[CH2:43](O)[CH3:44]>[Cl-].[Na+].O.ClCCl>[ClH:1].[CH2:43]([C@H:26]([O:25][CH:22]1[CH2:21][CH2:20][N:19]([C:17](=[O:18])[CH:16]([NH:15][C:13]([C:9]2[CH:8]=[C:7]3[C:12](=[CH:11][CH:10]=2)[C:3]([NH2:2])=[N:4][CH:5]=[CH:6]3)=[O:14])[CH3:30])[CH2:24][CH2:23]1)[C:27]([OH:29])=[O:28])[CH3:44]
Reactant: C[C@H](NC(=O)c1ccc2c(N)nccc2c1)C(=O)N1CCC(OCC(=O)O)CC1
Reactant: CCO
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: CC[C@H](OC1CCN(C(=O)C(C)NC(=O)c2ccc3c(N)nccc3c2)CC1)C(=O)O

Procedure:
To a stirred solution of 394 mg of (S)-[[1-(2-[[(1-amino-6-isoquinolinyl)carbonyl]amino]-1-oxopropyl)piperidin-4-yl]oxy]acetic acid hydrochloride in 10 mL of ethanol at 0° C. was added 0.55 mL of sulfuric acid (95-98%). The reaction mixture was allowed to warm to room temperature and after 2 hours 5 mL of 2N aqueous sodium hydroxide, 20 mL of brine, 20 mL of 5% aqueous sodium hydrogencarbonate and 40 mL of dichloromethane was added. The organic layer was separated and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried (sodium sulfate) and concentrated. Purification using column chromatography (silica gel, dichloromethane:ethanol =9:1) and lyophilisation (t-butanol/hydrochloric acid) yielded 265 mg of the title compound.
Reaction SMILES: ClCCN1CCOCC1.CS([O:14][CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)(=O)=O.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([C:37]2[N:46]=[C:45]([NH:47][C:48]3[CH:52]=[C:51]([CH3:53])[NH:50][N:49]=3)[C:44]3[C:39](=[CH:40][C:41](OC4CCCCN4C([O-])=O)=[CH:42][CH:43]=3)[N:38]=2)[OH:36])=[CH:31][CH:30]=1.Cl.O1CCOCC1>>[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([C:37]2[N:46]=[C:45]([NH:47][C:48]3[CH:52]=[C:51]([CH3:53])[NH:50][N:49]=3)[C:44]3[C:39](=[CH:40][C:41]([O:14][CH:15]4[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]4)=[CH:42][CH:43]=3)[N:38]=2)[OH:36])=[CH:31][CH:30]=1
Reactant: Cc1cc(Nc2nc(C(O)c3ccc(F)cc3)nc3cc(OC4CCCCN4C(=O)[O-])ccc23)n[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: Cl
Agent: ClCCN1CCOCC1
Solvent: C1COCCO1
Product: Cc1cc(Nc2nc(C(O)c3ccc(F)cc3)nc3cc(OC4CCNCC4)ccc23)n[nH]1
Reaction time: 20 h
Yield: 21 %

Procedure:
Intermediate compound (R,S)-tert-butyl 4-(2-(4-fluorophenyl)(hydroxy)methyl)-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-7-yloxy)piperidine-1-carboxylate was obtained (105 mg) following the procedure described in Example 38 for the synthesis of (R,S)-(4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)-7-(2-morpholinoethoxy)quinazolin-2-yl)methanol, substituting 4-(2-chloroethyl)morpholine in Example 38 with tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate. To the crude tert-butyl 4-(2-(((4-fluorophenyl)(hydroxy)methyl)-4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-7-yloxy)piperidine-1-carboxylate (100 mg, 18.2 mmol) in a flask at 0° C. was added 4N HCl/dioxane (5 mL). After stirring for 20 h, the solvent was removed and the residue was shaken with DCM and aq sodium bicarbonate. The solvents were removed, and the remaining residue was extracted with MeOH/DCM. The extracts were concentrated and the residue was chromatographed on reverse phase HPLC to afford (4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)-7-(piperidin-4-yloxy)quinazolin-2-yl)methanol as a white solid (32 mg, 21%). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.54 (m, 2H) 1.89 (s, 13H) 1.89 (s., 3H) 1.98 (m, 2H) 2.68 (m, 2H) 2.99 (m, 2H) 4.66 (m, 4H) 5.62 (s, 1H) 5.76 (s, 1H) 6.36 (b., 1H) 7.08-7.18 (m, 4H) 7.52 (m, 2H) 8.45 (m., 1H), 10.29 (bs, 1H). LC-MS (ESI) m/z 449 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[F:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[O:10][C:4]=2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: O=C1Nc2ccc(F)cc2Oc2sc3ccccc3c21
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CN1CCN(C2=Nc3ccc(F)cc3Oc3sc4ccccc4c32)CC1

Procedure:
In the same manner as in Example 80 and using 8-fluoro-[1]benzothieno[2,3-b][1,5]benzoxazepin-12(11H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 8-fluoro-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzoxazepine is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][CH3:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].CC([O-])(C)C.[K+].CCOC(C)=O>COCCOC>[C:14]([O:18][C:19]([N:21]1[CH2:27][CH2:26][CH2:25][N:24]([C:2]2[CH:3]=[C:4]([CH2:12][CH3:13])[CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CCc1cc(Br)c2ncccc2c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)c2ncccc2c1
Temperature: 60 °C
Yield: 53.2 %

Procedure:
A mixture of 8-bromo-6-ethylquinoline (1.3 g, 5.51 mmol, 1.04 equiv) and 1-(tert-butoxycarbonyl)homopiperazine (1.06 g, 1.0 equiv) in 5.5 mL of DME was degassed with compressed nitrogen gas for 5 minutes. To the mixture was added t-BuOK (0.83 g, 1.4 equiv). After degassing for another 2 minutes, allylchloro[1,3-(2,6-di-isopropylphenyl)imidazol-2-ylidene]palladium (II) (61 mg, 0.02 equiv) was added and the resulting mixture was heated at 60° C. overnight and cooled down to room temperature. EtOAc (˜70 mL) was added and the mixture was filtered through celite. The filtrate was washed with saturated aqueous NaHCO3 (70 mL) and brine (70 mL), dried over magnesium sulfate and concentrated. The residue was purified by silica gel flash column chromatography using 5% to 20% EtOAc in hexane to afford the title compound (1.0 g). MS (ES) m/z 356.2 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[C@@:10]([C:14](O)=[O:15])([CH2:11]2)[C@@H:9]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>>[CH2:1]([N:8]1[CH2:13][CH:12]2[C@@:10]([C:14]([Cl:25])=[O:15])([CH2:11]2)[C@@H:9]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)[C@@]12CC1CN(Cc1ccccc1)[C@H]2c1ccccc1
Product: O=C(Cl)[C@@]12CC1CN(Cc1ccccc1)[C@H]2c1ccccc1

Procedure:
To racemic Intermediate 39, one enantiomer being (1S,2S)-3-benzyl-2-phenyl-3-aza-bicyclo[3.1.0]hexane-1-carboxylic acid (0.16 g, 0.56 mmol) was added thionyl chloride (2 mL) dropwise with stirring. The homogeneous solution was refluxed gently for 2 hours. The solvent was removed at reduced pressure to yield the title compound (0.17 g, quantitative yield) as an oil, which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:52]=[CH:53][CH:54]=1)[O:5][C:6]1([CH2:50][OH:51])[CH2:11][CH2:10][CH2:9][CH:8]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:19]=[C:18]3[C:43]2[CH:48]=[CH:47][N:46]=[C:45]([CH3:49])[CH:44]=2)=[O:14])[CH2:7]1.[SiH](CC)(CC)CC>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:52]=[CH:53][CH:54]=1)[O:5][C:6]1([CH2:50][OH:51])[CH2:11][CH2:10][CH2:9][CH:8]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[C:18]3[C:43]2[CH:48]=[CH:47][N:46]=[C:45]([CH3:49])[CH:44]=2)=[O:14])[CH2:7]1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(CO)(Oc5cccc(F)c5)C4)cc23)ccn1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2n[nH]c3ccc(C(=O)NC4CCCC(CO)(Oc5cccc(F)c5)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
N-(3-(3-fluorophenoxy)-3-(hydroxymethyl)cyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide was stirred in neat TFA at room temperature for 10 minutes, and then Et3SiH (5 equiv.) was added. The reaction mixture was stirred at room temperature for 5 minutes, and then concentrated. The product was obtained after purification by reverse phase HPLC. The diastereomers were separated and enantiomers were separated on chiral column (AD) on a HPLC.
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[C:43]([O:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[CH:42][C:41]2[C:40]3[C:35](=[CH:36][C:37]([O:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])=[C:38]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])[CH:39]=3)[C:34]3[C:29](=[CH:30][C:31]([O:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH3:78])=[C:32]([O:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])[CH:33]=3)[C:28]=2[CH:27]=1)(=[O:8])[O:5]CC)C.C[Si](Br)(C)C>C(Cl)Cl>[CH2:45]([O:44][C:43]1[C:26]([O:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][P:4](=[O:3])([OH:8])[OH:5])=[CH:27][C:28]2[C:29]3[C:34]([C:35]4[C:40]([C:41]=2[CH:42]=1)=[CH:39][C:38]([O:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH3:57])=[C:37]([O:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[CH:36]=4)=[CH:33][C:32]([O:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[C:31]([O:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH3:78])[CH:30]=3)[CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: CCCCCCOc1cc2c3cc(OCCCCCC)c(OCCCCCC)cc3c3cc(OCCCCCCCCCCCCCCCCP(=O)(OCC)OCC)c(OCCCCCC)cc3c2cc1OCCCCCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: CCCCCCOc1cc2c3cc(OCCCCCC)c(OCCCCCC)cc3c3cc(OCCCCCCCCCCCCCCCCP(=O)(O)O)c(OCCCCCC)cc3c2cc1OCCCCCC
Temperature: 25 °C
Reaction time: 27 h
Yield: 100.6 %

Procedure:
In 15 mL of methylene chloride, 2.0 g (1.8 mmol) of [16-(3,6,7,10,11-pentakishexyloxytriphenylene-2-yloxy)-hexadecyl]-phosphonic acid diethylester was dissolved, and 1.2 mL of trimethylsilylbromide was added to the solution under argon. Then, the solution was stirred at ambient temperature. After 27 hours, the solvent and excess trimethylsilylbromide were evaporated, and the residue was dissolved in 100 mL of ethanol. The solution was stirred at ambient temperature for 48 hours, and then the solvent was evaporated. As a result, 1.9 g of a white solid was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)=[CH:4][C:3]=1[N+:24]([O-])=O.Cl>C(O)C.O.[Fe]>[NH2:24][C:3]1[CH:4]=[C:5]([CH:8]2[C:17]([CH3:18])([CH3:19])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([O:22][CH3:23])=[O:21])[CH:14]=3)[NH:9]2)[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(Cl)c([N+](=O)[O-])c1)N2
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(Cl)c(N)c1)N2
Temperature: 25 °C
Yield: 15.4 %

Procedure:
To a solution of methyl 2-(4-chloro-3-nitrophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (2.82 g, 7.53 mmol) in ethanol/water (30 mL/7.5 mL) was added 0.5 mL of concentrated hydrochloric acid solution and iron powder (4.21 g, 75.3 mmol). The resultant mixture was stirred and heated to reflux for 4 h. LC-MS showed the reaction was complete. The reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated and the residue was purified by column chromatography on silica gel to afford 400 mg of methyl 2-(3-amino-4-chlorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a solid. Yield: 15%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9]Cl)[CH:5]=[CH:6][CH:7]=1.[C:11]1([CH:17]([NH:20][C:21]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][CH:27]=[CH:26]3)=[O:22])[CH2:18][CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][CH2:9][N:28]1[C:29]2[C:25](=[CH:24][C:23]([C:21]([NH:20][CH:17]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:18][CH3:19])=[O:22])=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: CCC(NC(=O)c1ccc2[nH]ccc2c1)c1ccccc1
Reactant: ClCCc1cccc(Cl)c1
Product: CCC(NC(=O)c1ccc2c(ccn2CCc2cccc(Cl)c2)c1)c1ccccc1

Procedure:
The title compound was prepared following the same general protocol as described in Step 1 of Example 21, using 2-(3-chlorophenyl)ethyl chloride and N-(1-phenylpropyl)-1H-indole-5-carboxamide. LC-MS 417 (M+H).
Reaction SMILES: Cl.C([O:5][C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][C:18](=[O:25])[CH:19]([CH3:24])[CH2:20][CH2:21][CH2:22][CH3:23])[CH:9]=[CH:10][C:11]=1[O:12]C(=O)C)(=O)C>>[OH:5][C:6]1[CH:7]=[C:8]([CH:16]=[CH:17][C:18](=[O:25])[CH:19]([CH3:24])[CH2:20][CH2:21][CH2:22][CH3:23])[CH:9]=[CH:10][C:11]=1[OH:12]
Reactant: CCCCC(C)C(=O)C=Cc1ccc(OC(C)=O)c(OC(C)=O)c1
Agent: Cl
Product: CCCCC(C)C(=O)C=Cc1ccc(O)c(O)c1
Yield: 93.7 %

Procedure:
A hydrochloric acid-acidified aqueous solution obtained by following the same procedure as in Example 27 using 1.0 g of 1-(3,4-diacetoxyphenyl)-4-methyl-1-octen-3-one, was extracted twice each time with 20 ml of ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide 0.7 g of oily 1-(3,4-dihydroxyphenyl)-4-methyl-1-octen-3-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH2:10](Br)[C:11]#[CH:12].C(N(C(C)C)C(C)C)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:12]([NH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])[C:11]#[CH:10]
Reactant: C#CCBr
Reactant: N#Cc1cccc(N)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CCNc1cccc(C#N)c1

Procedure:
11.8 g (0.1 mol) of 3-aminobenzonitrile and 12.3 ml (0.11 mol) of propargyl bromide (80% in toluene) are stirred in 250 ml toluene and 19.2 ml (0.11 mol) of N-ethyl-diisopropylamine for 18 hours at 90° C. After cooling the mixture is diluted with ethyl acetate and washed with water. The combined organic extracts are dried and concentrated by evaporation. The residue is chromatographed on silica gel, eluting with dichloromethane/ethanol in the ratio 98:2.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:13]2[N:12](C)[C:11](=O)[NH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH:2]=[CH2:3]>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([NH2:10])[C:13]=1[NH:12][CH3:11])[CH:2]=[CH2:3]
Reactant: C=CCOc1cccc2[nH]c(=O)n(C)c12
Solvent: Cc1ccccc1
Product: C=CCOc1cccc(N)c1NC

Procedure:
4-Allyloxy-3-methyl-benzimidazol-2-one, which has a melting point of 167°-168°, is obtained analogously to Example 10c) from 5.4 g of 1-allyloxy-2-methylamino-3-aminobenzene and 6.1 g N,N'-carbonyldiimidazole in 100 ml of toluene, after working up and subsequently recrystallising from toluene.
Reaction SMILES: [CH2:1]([C:8]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:9]=1[NH2:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:18][CH2:19][NH2:20].Cl[CH2:22][CH2:23]N.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC.C(Cl)Cl>[ClH:15].[Cl:15][C:12]1[CH:13]=[CH:14][C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:9]([N:10]2[CH2:23][CH2:22][NH:20][CH2:19][CH2:18]2)[CH:11]=1
Reactant: NCCCl
Reactant: Nc1cc(Cl)ccc1Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCCCO
Product: Clc1ccc(Cc2ccccc2)c(N2CCNCC2)c1

Procedure:
18.18 g of 2-benzyl-5-chloroaniline, 14.90 g of bis-(2-chloroethylamine)hydrochloride in 65 ml of n-butanol and repeated additions of 5.78 g of anhydrous potassium carbonate are reacted according to the method described in Ex. 1. The hydrochloride is formed in methylene chloride and a precipitate forms by adding ethyl ether; it is then filtered, washed repeatedly with ethyl ether and dried to give 17 g of hygroscopic product. 8.4 g (25%) of a whitish solid, m.p. 256°-258° C., chromatographically pure and elemental analysis correct are isolated by recrystallization from ethanol.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:19]=[CH:18][C:6]([CH2:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][N:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1>C(O)(=O)C.CO.[Pt](=O)=O>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[CH2:9][CH:10]([C:11]([O:13][CH3:14])=[O:12])[CH2:15][CH2:16][NH:17]2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1ccnc(Cc2ccc(C(F)(F)F)cc2)c1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)C1CCNC(Cc2ccc(C(F)(F)F)cc2)C1
Reaction time: 6 h
Yield: 80.9 %

Procedure:
Methyl 2-(4-(trifluoromethyl)benzyl)isonicotinate (11.5 g, 38.95 mmol) was dissolved in acetic acid (200 mL) and methanol (100 mL). Platinum(IV) oxide (0.177 g, 0.78 mmol) was added and the mixture hydrogenated in a Büchi hydrogenator at room temperature and 7 bar for 6 h. The catalyst was filtered off. Fresh platinum(IV) oxide (0.18 g, 0.78 mmol) was added and hydrogenation continued at 9 bar for 7 h. The catalyst was filtered off, the solvent was evaporated and the residue partitioned between ethyl acetate and Na2CO3 (aq). The organic layer was dried over MgSO4, filtered through celite and the solvent evaporated. Methyl 2-(4-(trifluoromethyl)benzyl)piperidine-4-carboxylate (9.5 g, 81%) was isolated.
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]([CH3:32])([CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]4[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=4)[N:19]=3)=[CH:16][N:17]=2)[CH2:9][CH2:8]1)[CH3:6])C.[OH-].[Na+].Cl>CO.O1CCCC1>[CH3:32][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([NH:24][C:25]4[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][N:26]=4)[N:19]=3)=[CH:16][N:17]=2)[CH2:9][CH2:8]1)([CH3:6])[C:4]([OH:33])=[O:3]
Reactant: CCOC(=O)C(C)(C)C1CCN(c2ncc(-c3cccc(Nc4cc(C)ccn4)n3)s2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccnc(Nc2cccc(-c3cnc(N4CCC(C(C)(C)C(=O)O)CC4)s3)n2)c1
Reaction time: 15 h
Yield: 66.7 %

Procedure:
To a mixed solution of 2-methyl-2-(1-{5-[6-(4-methylpyridin-2-ylamino)pyridin-2-yl]thiazol-2-yl}piperidin-4-yl)propionic acid ethyl ester (697 mg, 1.50 mmol) obtained in Step 3 in methanol (5 ml) and tetrahydrofuran (10 ml), 4N aqueous sodium hydroxide (3.7 ml, 15 mmol) was added and the mixture was stirred for 15 hours under refluxing. After concentrated, the reaction solution was neutralized with 1N hydrochloric acid (15 ml, 15 mmol), and the precipitated solid was collected by filtration, washed with water, ethyl acetate, tetrahydrofuran. After dried in vacuo, the title compound (438 mg, 67%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH2:26])[C:13](=[O:25])[NH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)([CH3:4])([CH3:3])[CH3:2].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>CC#N>[C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:26][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:13](=[O:25])[NH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)CCCCC[C@H](N)C(=O)Nc1ccc2ncccc2c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCCCC[C@H](NC(=O)c1ccccc1)C(=O)Nc1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a stirring solution of (7S)-7-amino-7-(quinolin-6-ylcarbamoyl)-heptanoic acid tert-butyl ester (8.0 g, 21.6 mmol) in dry MeCN (100 mL) and to this solution was added benzoyl chloride (2.78 mL, 23.8 mmol) and triethylamine (6.1 mL, 43.2 mmol). The solution was stirred at 0° C. for 1 h, then at RT for 2 h. The solvent was removed, and residue was dissolved in 400 mL EtOAc, and stirred with 100 mL 0.5 M NaHCO3 for 1 h. The aqueous layer was removed, and the organic layer was washed with 100 mL 0.5 M NaHCO3, then with 50 mL water. The solution was dried over anhydrous Na2SO4. The product (8.1 g) was obtained after column purification (EtOAc as eluent) in 78.8% yield as a thick oil. 1H NMR (CDCl3) δ 9.40 (1H, s), 8.80 (1H, d), 8.22 (1H, d), 8.0-7.0 (10H, m), 5.0 (1H, m), 2.2-1.2 (19H, m). MS (ESI): (MH+) 476.1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=2[C:13](Cl)=[O:14])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CS[C:22]1[NH:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13](=[O:14])[N:23]3[C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[N:26]=[C:22]23)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccccc1Nc1cccc([N+](=O)[O-])c1
Reactant: CSc1nc2ccccc2[nH]1
Product: O=c1c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c2nc3ccccc3n12
Yield: 62 %

Procedure:
the following compound was prepared from 2-(3-nitrophenylamino)-benzoyl chloride and 2-methylthiobenzimidazole: 5-(3-nitrophenyl)-benzimidazo-[2,1-b]-quinazolin-12(5H)-one ##STR14## Yield: 62% of theory, melting point 294° C.; N calculated 15.72%; N found 15.73%.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:12][CH:13]2[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15][CH2:14]2)[C:3]1=[O:21].[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32](O)=[O:33])=[CH:26]2>>[Cl:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([C:32]([NH:1][CH:2]1[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]([CH2:12][CH:13]3[CH2:14][O:15][C:16]([CH3:19])([CH3:20])[O:17][CH2:18]3)[C:3]1=[O:21])=[O:33])=[CH:26]2
Reactant: CC1(C)OCC(CN2C(=O)C(N)Cc3ccccc32)CO1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Product: CC1(C)OCC(CN2C(=O)C(NC(=O)c3cc4cc(Cl)ccc4[nH]3)Cc3ccccc32)CO1
Yield: 85 %

Procedure:
Following a standard amide coupling procedure analogous to Example 1, using 3-amino-1-[(2,2-dimethyl-1,3-dioxan-5-yl)methyl]-3,4-dihydroquinolin-2(1H)-one (Method 4) as the amine and 5-chloroindole-2-carboxylic acid as the acid afforded the title compound (85%) as a white solid.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([F:8])[CH:5]=[CH:4][N:3]=1.Cl.[CH3:10][O:11][C:12](=[O:16])[CH2:13][NH:14][CH3:15].C(N(CC)C(C)C)(C)C>CCCC(C)C>[F:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:14]([CH3:15])[CH2:13][C:12]([O:11][CH3:10])=[O:16])[N:7]=1
Reactant: Fc1ccnc(F)n1
Reactant: CNCC(=O)OC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCC(C)C
Product: COC(=O)CN(C)c1nccc(F)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2,4-difluoropyrimidine (J.Heterocyclic Chem. 1985, 22, 149) (4.48 g) in isohexane (50 ml) at 0° C. was added sarcosine methyl ester hydrochloride (5.39 g) followed by N,N-diisopropylethylamine (13.45 ml). After 5 minutes, the ice bath was removed and the reaction mixture allowed to stir at room temperature for 3 hours. The solvents were evaporated under reduced pressure and the residue purified by chromatography eluting with ethyl acetate/isohexane mixtures. The first and minor component of the mixture to be eluted was the subtitle compound. Yield 0.68 g.