Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]3=[C:11]([C:22](OC)=[O:23])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[Cl-].[Ca+2].[Cl-].[Cl-].[NH4+]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]3=[C:11]([CH2:22][OH:23])[C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1c2c(nc3ccccc13)CCN(C(=O)OC(C)(C)C)C2
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2nc3ccccc3c(CO)c2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.1 %

Procedure:
Methyl 2-t-butoxycarbonyl-1,2,3,4-tetrahydro-benzo[b][1,6]-naphthyridine-10-carboxylate (1.14 g, 3.05 mmol) was dissolved in ethanol (3 ml), followed by adding thereto sodium tetrahydroborate (138.4 mg, 3.66 mmol) and then a solution of calcium chloride (338.5 mg, 3.05 mmol) in ethanol (3 ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 4 hours and then at 60° C. for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the desired compound (442 mg, 46%) as a yellow oil.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH:8]([N:10]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]([NH:19][CH:20]([C:29]([O:31]CC)=[O:30])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11]1=[O:34])[CH3:9])=[O:7])C>C(O)C>[C:6]([CH:8]([N:10]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]([NH:19][CH:20]([C:29]([OH:31])=[O:30])[CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11]1=[O:34])[CH3:9])([OH:7])=[O:5]
Reactant: CCOC(=O)C(CCc1ccccc1)NC1CCCCCCN(C(C)C(=O)OCC)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C(=O)O)N1CCCCCCC(NC(CCc2ccccc2)C(=O)O)C1=O

Procedure:
The diastereomerically pure benzyl ester products of Example 3 are separately treated with excess lN NaOH in 50% ethanol at room temperature for 18 hours. Work-up according to Example 1 affords, after lyophilization, the title diastereomerically pure diacids. These same diacid products can also be prepared by saponification of the diethyl ester products of Example 4.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1>C(O)CCC>[NH2:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][NH:16][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:20][CH:21]=1
Reactant: NCCc1ccc(N)cc1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CCCCO
Product: COc1cc2ncnc(NCCc3ccc(N)cc3)c2cc1OC
Temperature: 25 °C
Yield: 79.5 %

Procedure:
A solution of 4-chloro-6,7-dimethoxy-quinazoline (2 g, 8.92 mmol) and 4-(2-amino-ethyl)-phenyl amine (1.3 g, 9.82 mmol) in 1-butanol (20 mL) was heated at 80° C. overnight. After the solution was cooled to room temperature, the solvent was removed and the residue was purified by silica gel column chromatography (eluted by 5% methanol in CH2Cl2) to get the title compound (2.3 g, 68%). 1H-NMR (300 MHz CDCl3) δ 8.57 (s, 1H), 7.19 (s, 1H), 7.48 (d, 2H, J=8.1 Hz), 6.66 (d, 3H, J=7.8 Hz), 5.36 (t, 1H, NH), 4.00 (s, 3H), 3.93 (s, 1H), 3.85 (q, 2H, J=6.6 Hz), 3.62 (s, 1H), 2.92 (t, 2H, J=6.6 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:31][C:12]3([CH2:17][CH2:16][N:15]([C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH3:29])[CH:20]=4)[CH2:14][CH2:13]3)[CH2:11][C:10](=[O:32])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[O:31][C:12]3([CH2:17][CH2:16][N:15]([C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH3:29])[CH:20]=4)=[O:30])[CH2:14][CH2:13]3)[CH2:11][CH:10]([OH:32])[CH:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CC(=O)C=C(c2cncc(F)c2)O3)ccc1OC(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(C(=O)N2CCC3(CC2)CC(O)C=C(c2cncc(F)c2)O3)ccc1OC(C)C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
To a solution of 10-(5-fluoro-3-pyridyl)-3-(4-isopropoxy-3-methyl-benzoyl)-11-oxa-3-azaspiro[5.5]undec-9-en-8-one (273 mg, 0.62 mmol) in methanol (7.8 mL) was slowly added sodium borohydride (25 mg, 0.65 mmol) The reaction mixture was allowed to stir for 30 minutes. A solution of saturated aqueous ammonium chloride (50 mL) was added. After brief stirring, the mixture was concentrated to half volume and was extracted with dichloromethane (3×75 mL). The organic layers were combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified on silica gel utilizing a gradient of 60-100% ethyl acetate in hexanes to yield [10-(5-fluoro-3-pyridyl)-8-hydroxy-11-oxa-3-azaspiro[5.5]undec-9-en-3-yl]-(4-isopropoxy-3-methyl-phenyl)methanone (256 mg) as a colorless oil. ESI-MS m/z calc. 440.2, found 441.3 (M+1)+; Retention time: 1.73 minutes (3 min run).
Reaction SMILES: Cl[C:2]1[N:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]=[N:16][N:17]([CH3:28])[C:18]2[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[C:4](=[O:8])[N:5]([CH3:7])[N:6]=1.[CH3:29][O-:30].[Na+]>C1COCC1.O>[CH3:29][O:30][C:2]1[N:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]=[N:16][N:17]([CH3:28])[C:18]2[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[C:4](=[O:8])[N:5]([CH3:7])[N:6]=1
Reactant: C[O-]
Reactant: CN(N=Cc1ccccc1-n1c(Cl)nn(C)c1=O)c1ncccc1C(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1nn(C)c(=O)n1-c1ccccc1C=NN(C)c1ncccc1C(F)(F)F
Temperature: 25 °C

Procedure:
The title compound of Step B (0.38 g, 0.93 mmol) was dissolved in THF (10 mL) and then sodium methoxide (25% in methanol, 0.56 mL) was added dropwise. The mixture was heated at reflux for 1 h, cooled to room temperature and then diluted with water and extracted three times with ethyl acetate. The combined organic phases were washed with saturated aqueous NaCl, dried (MgSO4), filtered and concentrated to an oil which was purified by flash column chromatography on silica gel to afford 0.27 g of the title compound of Step C, a compound of the invention, as a pale yellow solid melting at 185-187° C. 1H NMR (300 MHz, CDCl3): δ 8.41 (dd,1H, J=5, 1.5 Hz), 8.12 (dd,1H, J=8, 1.5 Hz), 8.01 (dd,1H, J=8, 1.5Hz), 7.42 (m,3H), 7.23 (d,1H J=8 Hz), 15 7.02 (dd,1H, J=8, 5Hz), 3.93 (s,3H), 3.56 (s,3H), 3.48 (s,3H).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>C1C=CC=CC=1>[C:1]1([C:7]#[C:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]([Cl:18])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)/C=C/CCC#Cc1ccccc1
Solvent: c1ccccc1
Product: O=C(Cl)/C=C/CCC#Cc1ccccc1

Procedure:
7-Phenylhept-2E-en-6-ynoic acid (2 g) was dissolved in benzene (20 ml), thionyl chloride (2.5 ml) was added, and the mixture was refluxed under a nitrogen atmosphere for 45 minutes. Benzene and excess thionyl chloride were removed under reduced pressure and the residue was treated with benzene (2×4 ml), followed by evaporation, to leave a residue of 7-phenylhept-2E-en-6-ynoyl chloride. The acid chloride was dissolved in ether (20 ml), and triethylamine (1.5 ml) and isobutylamine (3 ml) were added. The mixture was stirred at room temperature for 2 hours then cooled to 0° C. The mixture was filtered and the filtrate was subjected to chromatography on silica (60 g), eluting with 100% hexane grading to 100% ether, to yield N-isobutyl-7-phenylhept-2E-en-6-ynamide mp 86°-8° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:15]O>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc([N+](=O)[O-])ccc1F
Temperature: 70 °C

Procedure:
To a solution of 2-fluoro-5-nitrobenzoic acid (5 g, 27.0 mmol) in methanol (135 mL) was added HCl (2.66 mL, 32.4 mmol, 12.2 M), and the mixture was heated with an oil bath at 70° C. for 24 hours. The solvent was evaporated, and the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, and concentrated to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.63 (dd, J=3.0, 6.2, 1H), 8.58-8.50 (m, 1H), 7.74-7.61 (m, 1H), 3.92 (s, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:27])([CH2:24][CH2:25][CH3:26])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH2:28]([O:35][C:36]1[CH:37]=[CH:38][C:39]([CH3:45])=[C:40]([CH:44]=1)[C:41](O)=[O:42])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:36]1[CH:37]=[CH:38][C:39]([CH3:45])=[C:40]([C:41]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:27])([CH2:24][CH2:25][CH3:26])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)=[O:42])[CH:44]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CCCC1(C)C(=O)N(C2CCNCC2)N=C1c1ccc(OC)c(OC)c1
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)O
Agent: Cl
Product: CCCC1(C)C(=O)N(C2CCN(C(=O)c3cc(OCc4ccccc4)ccc3C)CC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4-methyl-2-piperidin-4-yl-4-propyl-2,4-dihydro-3H-pyrazol-3-one (compound B8) and 5-(benzyloxy)-2-methylbenzoic acid (compound F1) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by a second chromatography (silica gel and cyclohexane/EA=6:4) to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28]C)[C:23]4=[O:30])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[CH:13][N:14]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[C:23]4=[O:30])=[CH:20][CH:21]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: COc1cccn(-c2ccc(-n3cnc(CNC(=O)c4ccc(Cl)s4)c3)cc2)c1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(NCc1cn(-c2ccc(-n3cccc(O)c3=O)cc2)cn1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
To a solution of 5-chloro-N-((1-(4-(3-methoxy-2-oxopyridin-1(2H)-yl)phenyl)-1H-imidazol-4-yl)methyl)thiophene-2-carboxamide (75 mg, 0.14 mmol) in CH2Cl2 (4 mL), BBr3 (0.365 mL, 3.8 mmol) was added. The mixture was stirred at room temperature for 1 h. It was concentrated in vacuo. The residue was purified by HPLC to give the titled compound (40 mg). MS 427.0 and 429.0 (M+H, Cl pattern).
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([CH:42]=[CH:43][C:44]=1[CH3:45])[CH2:7][O:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])=[CH:17][CH:16]=2)[CH2:13][CH2:12][N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10]1)=[O:3].[CH3:46][O:47][CH2:48][CH2:49][NH2:50]>>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][O:25][CH2:24][CH2:23][CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([CH:14]2[CH2:13][CH2:12][N:11]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:10][CH:9]2[O:8][CH2:7][C:6]2[CH:42]=[CH:43][C:44]([CH3:45])=[C:4]([C:2](=[O:3])[NH:50][CH2:49][CH2:48][O:47][CH3:46])[CH:5]=2)=[CH:16][CH:17]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(C)c(C(=O)Cl)c2)cc1
Reactant: COCCN
Product: COCCNC(=O)c1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C

Procedure:
Analogously to Example 127a, 0.222 g of tert-butyl 3-(3-chlorocarbonyl-4-methylbenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate (Example 127b) and 0.053 g of 2-methoxyethylamine are reacted. The title compound is obtained as a colourless oil. Rf=0.14 (1:2 EtOAc-heptane); Rt=5.54.
Reaction SMILES: [N:1]1[C:2]([CH2:10][CH2:11][O:12][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:19]3=[O:43])=[CH:15][CH:14]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.FC(F)(F)C(O)=O>C(Cl)Cl>[N:1]1[C:2]([CH2:10][CH2:11][O:12][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:43])=[CH:15][CH:14]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C1SC(Cc2ccc(OCCc3cn4ccccc4n3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NC(=O)C(Cc2ccc(OCCc3cn4ccccc4n3)cc2)S1

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 0.94 g of 5-[4-{2-(imidazo[1,2-a]pyridin-2-yl)ethoxy}benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 27), 4 ml of methylene chloride and 1 ml of trifluoroacetic acid were used, to give the title compound as a crude product. This product was purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate and subsequently a 1:2 by volume mixture of ethyl acetate and tetrahydrofuran, as the eluents, to give 287 mg of the title compound, melting at 205.9°-207.0° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:16].Cl[CH2:18][C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:16][CH2:18][C:19]#[N:20]
Reactant: N#CCCl
Reactant: Oc1ccc(Oc2cccc(Cl)c2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCOc1ccc(Oc2cccc(Cl)c2)cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
A mixture of 14.99 g of 2-chloro-4-(3-chlorophenoxy)phenol, 4.44 g of chloro acetonitrile and 8.94 g of potassium carbonate in 150 ml dimethylformamide was stirred at a temperature of 70° to 80° C. in an oil bath for 5 hours. The reaction mixture was cooled to room temperature, poured into water and extracted twice with 100 ml of ethyl acetate. The extracts were combined together, washed twice with 200 ml of water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 14.0 g of [2-Chloro-4-(3-chlorophenoxy)phenoxy]acetonitrile as a crude product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[C:12]([O:14]CC)=O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[Cl:18][C:19]1[N:24]=[C:23]([NH:25][CH3:26])[C:22]([NH2:27])=[CH:21][N:20]=1>C(O)C.C(O)(=O)C.ClCCl>[Cl:18][C:19]1[N:20]=[CH:21][C:22]2[N:27]=[C:11]([C:5]3[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:12](=[O:14])[N:25]([CH3:26])[C:23]=2[N:24]=1
Reactant: CNc1nc(Cl)ncc1N
Reactant: CCOC(=O)C(=O)c1cc(OC)cc(OC)c1
Solvent: CCO
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(OC)cc(-c2nc3cnc(Cl)nc3n(C)c2=O)c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 55.4 %

Procedure:
A mixture of ethyl 2-(3,5-dimethoxyphenyl)-2-oxoacetate (1 g, 4.2 mmol) and 2-chloro-N4-methylpyrimidine-4,5-diamine (600 mg, 3.8 mmol) in ethanol (100 mL) and acetic acid (2.5 mL) was stirred at 80° C. for 48 h and cooled to RT (5° C.). The mixture was diluted with dichloromethane and washed with brine. The organic layer was directly concentrated and purified by chromatography on silica gel to give the title compound (700 mg, 50%). MS (ES+) C15H13ClN4O3 requires: 332, 334. found: 333, 335 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1)[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=1)=[O:7].[C:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=1)(=[O:34])[CH3:33].C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>ClCCl>[C:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39]([N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:4]=3)[C@H:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=3)[CH2:10]2)=[O:40])=[CH:37][CH:36]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: Cc1ccc(C[C@@H]2CNCCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(C(=O)N2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc(C)c(C)c3)C2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.7 %

Procedure:
To a mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (0.25 g) and 4-acetylbenzoic acid (0.09 g) in dichloromethane (8 ml) was added triethylamine (0.2 ml) at room temperature. 2-Chloro-1-methylpyridinium iodide (0.17 g) was added, and the mixture was stirred at room temperature for 2.5 hours. The resulting mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was washed with aqueous sodium bicarbonate solution and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography using ethyl acetate--n-hexane (1:1) as an eluent to afford (2R)-4-(4-acetylbenzoyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)piperazine (0.31 g).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[CH:26]=[CH:25][C:12]([O:13][CH2:14][CH:15]([OH:24])[CH2:16][CH2:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[C:1]1([CH2:7][CH2:8][C:9]2[CH:26]=[CH:25][C:12]([O:13][CH2:14][CH:15]([OH:24])[CH2:16][CH2:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC(CCc1cccnc1)COc1ccc(/C=C/c2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: OC(CCc1cccnc1)COc1ccc(CCc2ccccc2)cc1
Yield: 90.1 %

Procedure:
A solution of (±)-(E)-1-(4-(2-phenylethenyl)phenoxy)-4-(3-pyridyl)-2-butanol (0.32 g, Example 61) was dissolved in dry ethanol (50 ml) and hydrogenated for 24 hours at 3 atmospheres using palladium on carbon (10%, 0.1 g) as catalyst. The reaction mixture was filtered through Celite® and the residue washed with ethanol. The filtrate and washings were combined and concentrated under reduced pressure. The residue was purified by column chromatography over silica eluting with dichloromethane:methanol (95:5) to give the title compound as a white solid (0.29 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][C:15]=3[CH3:21])=[CH:7][C:6]=2[C:5]2[CH:22]=[CH:23][C:24]([CH3:26])=[CH:25][C:4]=2[N:3]=1.Br[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH3:26][C:24]1[CH:23]=[CH:22][C:5]2=[C:6]3[C:11](=[C:2]([NH2:1])[N:3]=[C:4]2[CH:25]=1)[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:16][C:15]=1[CH3:21])=[CH:7]3
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3C)cc12
Reactant: BrCCN1CCOCC1
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCN4CCOCC4)cc3C)cc12

Procedure:
8-Methyl-2-(2-methyl-4-(2-morpholinoethoxy)phenethyl)benzo[f][1,7]naphthyridin-5-amine was prepared following an analogous procedure to the preparation described for Example 139, but using 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol (from Example 50) and 4-(2-bromoethyl)morpholine. 1H NMR (Acetone-d6): δ 8.73 (d, 2H), 8.26 (d, 1H), 7.44 (s, 1H), 7.17 (d, 1H), 7.05 (d, 1H), 6.76 (s, 1H), 6.67 (d, 1), 4.04-4.08 (m, 3H), 3.60-3.62 (m, 4H), 3.30 (s, 1H), 3.16 (t, 2H), 3.04 (t, 2H), 2.71 (t, 2H), 2.50-2.52 (m, 2H), 2.47 (s, 3H), 2.28 (s, 3H). LRMS [M+H]=457.3
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[CH3:32][N:33]([CH3:47])[CH2:34][CH2:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43]([NH2:46])(=[O:45])=[O:44])=[CH:39][CH:38]=1>>[CH3:32][N:33]([CH3:47])[CH2:34][CH2:35][O:36][C:37]1[CH:38]=[CH:39][C:40]([S:43]([NH:46][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([N:4]3[C:5]([CH3:13])=[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:2]([CH3:1])=[N:3]3)=[CH:19][CH:18]=2)=[O:24])(=[O:45])=[O:44])=[CH:41][CH:42]=1
Reactant: CN(C)CCOc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(OCCN(C)C)cc3)cc2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 4-[2-(dimethylamino)ethoxy]benzenesulfonamide: 1H-NMR [CDCl3/CD3OD(4:1)] δ δ 7.87-7.84 (2H, m), 7.48-7.26 (9H, m), 7.01-6.98 (2H, m), 4.19-4.15 (2H, m), 3.46-3.41 (2H, m), 2.92-2.82 (4H, m), 2.45 (6H, s), 2.32 (3H, s), 2.27 (3H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:18][N:6]2[C:7](=[O:17])[CH:8]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[N:10]=[C:5]2[NH:4][CH2:3]1.[H-].[Na+].CS(O[CH2:27][CH2:28][O:29][CH3:30])(=O)=O>CN(C=O)C>[CH3:30][O:29][CH2:28][CH2:27][N:4]1[C:5]2=[N:10][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:8][C:7](=[O:17])[N:6]2[CH2:18][C:2]([CH3:19])([CH3:1])[CH2:3]1
Reactant: CC1(C)CNc2nc(N3CCOCC3)cc(=O)n2C1
Reactant: COCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCN1CC(C)(C)Cn2c1nc(N1CCOCC1)cc2=O
Reaction time: 0.5 h
Yield: 37.3 %

Procedure:
0.22 g of 7,7-dimethyl-2-(morpholin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]-pyrimidin-4-one are solubilized in anhydrous DMF. 0.7 g of 60% NaH are added and stirred for 30 mins. 0.24 g of 2-methoxyethyl methanesulfonate are added and the mixture is heated with reflux for 3 h. After returning to RT, the mixture is poured into a water/ice/AcOEt mixture. The organic phase is decanted, washed with a solution saturated with NaCl and then dried with magnesium sulfate. The solvents are evaporated. The crude is purified by flash chromatography on silica gel (CH2Cl2/MeOH, 95/5). 0.1 g (yield=39%) of 9-(2-methoxyethyl)-7,7-dimethyl-2-(morpholin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one are obtained as a white powder including the following characteristics: