Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[CH2:6]([O:12][CH:13]1[NH:17][C:16](=[O:18])[CH:15]=[CH:14]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCCCCC.O1CCCC1>[C:19]1([S:25]([N:17]2[CH:13]([O:12][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:14]=[CH:15][C:16]2=[O:18])(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCCCCCOC1C=CC(=O)N1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCOC1C=CC(=O)N1S(=O)(=O)c1ccccc1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 31.9 %

Procedure:
39.37 cm3 of a 1.4M solution of n-butyllithium in n-hexane is added to a solution of 10.1 g of 1,5-dihydro-5-n-hexyloxy-2H-pyrrol-2-one obtained at stage A in 170 cm3 of tetrahydrofuran cooled to -30° C. The temperature is maintained at -30° C. while agitating for 15 minutes, then is reduced to -35° C. and a solution of 9.73 g of benzenesulphonyl chloride in 70 cm3 of tetrahydrofuran is added, while maintaining the temperature at between -35° C. and -53° C. The temperature is allowed to return to the ambient, the solvent is evaporated under reduced pressure, and the residue is chromatographed on silica (eluent: ethyl acetate-n-hexane, 1-2). 5.68 g of the expected product is obtained.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][CH:17]=[C:16]([F:23])[C:15]=1[OH:24].[C:25]([O:29][C:30](=[O:36])[NH:31][C@@H:32]([CH3:35])[CH2:33]O)([CH3:28])([CH3:27])[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:25]([O:29][C:30](=[O:36])[NH:31][C@@H:32]([CH3:33])[CH2:35][O:24][C:15]1[C:16]([F:23])=[CH:17][CH:18]=[C:19]([N+:20]([O-:22])=[O:21])[C:14]=1[F:13])([CH3:28])([CH3:27])[CH3:26]
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(F)c(O)c1F
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](COc1c(F)ccc([N+](=O)[O-])c1F)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
Diethylazodicarboxylate (349 μL, 2.22 mmol) in THF (1 mL) was added slowly to a solution of 2,6-difluoro-3-nitrophenol (260 mg, 1.48 mmol), ((S)-2-hydroxy-1-methylethyl)carbamic acid tert-butyl ester (312 mg, 1.78 mmol) and triphenylphosphine (582 mg, 2.22 mmol) in THF (10 mL) at 0° C. The solution was stirred for 30 min at 0° C., and then concentrated in vacuo. The residue was purified by flash chromatography (Si—PPC, gradient 0-30% EtOAc in cyclohexane) to afford the title compound as a pale yellow oil (340 mg, 69%). 1H NMR (CDCl3, 300 MHz): δ 7.82 (1H, ddd, J=13.0, 9.5, 5.3 Hz), 7.04 (1H, app. td, J=9.4, 2.1 Hz), 4.75 (1H, br s), 4.24-4.12 (2H, m), 4.00 (1H, br s), 1.44 (9H, s), 1.34 (3H, d, J=6.9 Hz)
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[NH:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:5]=1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.Cl[CH2:23][C:24](OCC)=[O:25].O>CN(C)C=O>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[C:5]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)=[C:4]3[NH:3][C:24](=[O:25])[CH2:23][N:8]3[N:7]=2)=[CH:10][CH:11]=1
Reactant: Nc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: CCOC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1Cn2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2N1
Reaction time: 0.5 h
Yield: 10.1 %

Procedure:
To a suspension of sodium hydride (288 mg) in N,N-dimethylformamide (20 ml) was added dropwise a solution of 5-amino-3-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole (1.524 g) in N,N-dimethylformamide (5 ml) with ice cooling. The mixture was stirred for 30 minutes and to the mixture was added a solution of ethyl chloroacetate (883 mg) in N,N-dimethylformamide (5 ml). After stirring of the mixture for 1 hour at ambient temperature, the reaction mixture was poured into water and the separated oil was extracted with dichloromethane. The extract was washed with brine, dried and concentrated in vacuo. The residue was dissolved in a solution of sodium (138 mg) in ethanol (5 ml) and the solution was refluxed for 1 hour. The reaction mixture was cooled, poured into water and neutralized with diluted hydrochloric acid. The separated oil was extracted with dichloromethane and the extract was washed with brine, dried and concentrated in vacuo. The residue was crystallized from ethanol to yield 2,3-dihydro-6-(4-fluorophenyl)-2-oxo-7-(pyridin-4-yl)-1H-imidazo[1,2-b]pyrazole (178 mg).
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]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[CH2:33][OH:34].C(O)(C(F)(F)F)=O>>[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]([CH:20]([N:28]4[CH2:32][CH2:31][CH2:30][C@H:29]4[CH2:33][OH:34])[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1
Reactant: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Reactant: OC[C@@H]1CCCN1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(C)N4CCC[C@H]4CO)cc3)cc12

Procedure:
((2S)-1-(1-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethyl)pyrrolidin-2-yl)methanol was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone (from Example 171) and (S)-pyrrolidin-2-ylmethanol (commercially available) following the procedures described for Example 182. 1H NMR (Acetone-d6) TFA Salt: δ 8.83 (s, 1H), 8.80 (s, 1H), 8.43 (d, 1H), 7.36-7.53 (m, 6H), 4.68 (m, 1H), 3.69 (m, 2H), 3.19-3.21 (m, 4H), 2.55 (m, 4H), 1.75-1.78 (m, 6H), 1.74 (d, 3H). LRMS [M+H]=441.2
Reaction SMILES: C([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([N:15]2[CH2:20][CH2:19][C:18]3([CH2:29][C:28](=[O:30])[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([Cl:31])[CH:26]=4)[O:21]3)[CH2:17][CH2:16]2)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=O)CCC.O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:31][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[O:21][C:18]1([CH2:19][CH2:20][N:15]([C:13]3[CH:12]=[CH:11][N:10]=[C:9]([C@H:7]([OH:6])[CH3:8])[N:14]=3)[CH2:16][CH2:17]1)[CH2:29][C:28]2=[O:30]
Reactant: CCCC(=O)O[C@H](C)c1nccc(N2CCC3(CC2)CC(=O)c2cc(Cl)ccc2O3)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)c1nccc(N2CCC3(CC2)CC(=O)c2cc(Cl)ccc2O3)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 18 %

Procedure:
A mixture of (R)-1′-[2-(1-butyryloxy-ethyl)-pyrimidin-4-yl]-6-chloro-spiro[chroman-2,4′-piperidin]-4-one (prepared according to the method of Example 78, Step B, 270 mg, 0.61 mmol) and lithium hydroxide hydrate (80 mg, 1.83 mmol) in a 3:1:1 mixture of tetrahydrofuran/methanol/water (5 mL) was stirred at room temperature for 1.5 h. The organic solvents were evaporated and the residue was extracted with chloroform (4×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (ethyl acetate) to give 41 mg (18%) of the title compound as a reddish foam. 1H NMR (CDCl3, 300 MHz) δ 8.19 (d, 1H), 7.82 (d, 1H), 7.44 (dd, 1H), 6.96 (d, 1H), 6.40 (d, 1H), 4.65 (q, 1H), 4.20 (app s, 2H), 3.42-3.32 (c, 2H), 2.73 (s, 2H), 2.14 (d, 2H), 1.67 (td, 2H), 1.48 (d, 3H); MS (APCI) 374, 376 (MH+); [α]D+12.6 (c, 0.5, MeOH).
Reaction SMILES: [Cl-:1].[Cl-].C([Al+2])CCCCCCC.[CH2:12]([Al:20](CCCCCCCC)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].CCCCCC>CCCCCC.CCCCCCC>[Cl-:1].[CH2:21]([Al+:20][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCC[Al](CCCCCCCC)CCCCCCCC
Agent: CCCCCCCC[Al+2]
Agent: [Cl-]
Solvent: CCCCCCC
Solvent: CCCCCC
Product: CCCCCCCC[Al+]CCCCCCCC

Procedure:
A 1 weight percent solution of dioctyl aluminum chloride in hexane/heptane was prepared by mixing octyl aluminum dichloride (2.11 g, 0.01 mol), a 25.3 weight percent solution of trioctyl aluminum (14.5 g, 0.01 mol) and hexane (561 g) together under an atmosphere of argon.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.[CH2:7]([O:14][C:15](Cl)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:7]([O:14][C:15]([N:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC1CCNC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(O)C1

Procedure:
30 g of 3-pyrrolidinol was dissolved in 500 ml of chloroform, to which 53 ml of triethylamine was added, followed by gradually dropping 52 ml of benzyloxycarbonyl chloride at room temperature. After completion of the reaction, the reaction solution was poured into water and extracted with chloroform. The solvent was distilled off under reduced pressure and the resultant residue was purified by column chromatography (eluting solvent: hexane-ethyl acetate) to obtain 70.67 g of the intended compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27]N(C=O)C.[H-].[Na+].CI>O>[CH3:27][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:12]1
Reactant: CN(C)C=O
Reactant: c1ccc(CN(CCc2c[nH]c3ccccc23)Cc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cn1cc(CCN(Cc2ccccc2)Cc2ccccc2)c2ccccc21
Reaction time: 0.25 h

Procedure:
N,N-dibenzyl-tryptamine (1.72 g) was added to an anhydrous DMF solution containing 0.24 g of NaH (60% nujol) and the mixture was stirred for 15 minutes. Methyl iodide (0.31 ml) was added and the mixture was stirred for one hour. Water was added and the solvent was evaporated off. The residue to which water was added was extracted with IPE, the extract was washed with water and the brine and dried over magnesium sulfate. The crude product was purified by column chromatography on silica gel. Eluates with ethyl acetate/hexane (1/9) afforded 1.58 g of the oily title compound.
Reaction SMILES: [CH3:1][C:2]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:3][C:4]([CH3:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5].[C:26](=O)([O-:28])[O-:27].[K+].[K+].C(=O)=O.O>C1C=CC=CC=1>[CH3:1][C:2]([C:19]1[CH:24]=[C:23]([C:26]([OH:28])=[O:27])[C:22]([OH:25])=[CH:21][CH:20]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:3][C:4]([CH3:5])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:12]
Reactant: CC(C)(CC(C)(c1ccccc1)c1ccc(O)cc1)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(CC(C)(c1ccccc1)c1ccc(O)c(C(=O)O)c1)c1ccccc1
Temperature: 180 °C
Reaction time: 5 h
Yield: 84.9 %

Procedure:
33.0 g (0.1 mole) of p-(1,3-dimethyl-1,3-diphenylbutyl)phenol and 100 g of anhydrous potassium carbonate were placed in an autoclave and thereto, carbon dioxide gas was introduced at a pressure of 40 Kg/cm2. Then, the mixture was shaken at 180° C. for 5 hours. After cooling to room temperature, the pressure in the autoclave was returned to atmospheric pressure and then, 200 ml of water and 400 ml of benzene were added to the reaction product in the autoclave, followed by heating them in order to dissolve the reaction product in these solvents. The organic phase separated out was taken out of the autoclave and shaken with a dilute hydrochloric acid solution to convert the potassium salt into the corresponding free acid. Then, it was washed with water, dried and then, concentrated in order to remove the benzene. Thus, white needle crystal was separated out. The crystal was filtered off to obtain 31.8 g of 5-(1,3-dimethyl-1,3-diphenylbutyl)salicylic acid (yield: 85%, mp: 153°-155° C.).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[I:28]I.[OH-].[K+].OS([O-])=O.[Na+]>O1CCCC1.O.N1C=CC=CC=1>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=4)=[O:19])=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([I:28])=[CH:4][N:3]=1
Reactant: Nc1nccc2scc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)c12
Reactant: II
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncc(I)c2scc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)c12
Temperature: 50 °C

Procedure:
A solution of 1-(4-(4-aminothieno[3,2-c]pyridin-3-yl)phenyl)-3-(3-fluorophenyl)urea (example 49 in WO2005/10009) (12.2 g, 32.2 mmol) and pyridine (75 mL) in tetrahydrofuran (250 mL) was treated with iodine (36.8 g, 145 mmol) at room temperature. The reaction mixture was heated to 50° C. for 3.5 hours, then cooled to room temperature and treated with 20% aqueous KOH (18.1 g) followed by a 10% aqueous NaHSO3 solution (134 g) added in portions. The resulting mixture was heated to 60° C., diluted with water (366 mL), cooled to room temperature, and filtered. The wet cake was dried to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[C:10](Cl)[N:9]=[C:8]([NH2:13])[N:7]=1.[CH2:19]1[C:23]2([CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH2:22][C@@H:21]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:20]1[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].C([O-])(O)=O.[Na+]>O1CCOCC1>[NH2:13][C:8]1[N:9]=[C:10]([N:26]2[CH2:25][CH2:24][C:23]3([CH2:19][N:20]([C:34]([O:36][CH2:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[O:35])[C@H:21]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:22]3)[CH2:28][CH2:27]2)[CH:11]=[C:6]([O:5][CH2:4][C:3]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:2]=2[Br:1])[N:7]=1
Reactant: Nc1nc(Cl)cc(OCc2ccc(Cl)cc2Br)n1
Reactant: CCOC(=O)[C@@H]1CC2(CCNCC2)CN1C(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(OCc4ccc(Cl)cc4Br)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 4-((2-bromo-4-chlorobenzyl)oxy)-6-chloropyrimidin-2-amine (300 mg, 1.1 mmol), (S)-2-benzyl 3-ethyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (400 mg, 1.2 mmol), and NaHCO3 (550 mg, 7 mmol) in dioxane (5 mL) was heated to 100° C. for 12 h. The reaction was cooled to RT, concentrated in vacuo, and extracted with EtOAc. The combined organic layers were washed with brine, water, dried over Na2SO4, and concentrated in vacuo. Purification on normal phase silica gel (EtOAc/petroleum ether) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((2-bromo-4-chlorobenzyl)oxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](C1N=C2N(CC3C=C4C(=CC=3)N=CC=C4)N=NC2=NC=1)=[CH2:5])[CH3:2].Br[C:27]1[N:32]=[C:31]2[N:33]([CH:36]([C:38]3[CH:39]=[C:40]4[C:45](=[CH:46][C:47]=3[F:48])[N:44]=[CH:43][CH:42]=[CH:41]4)[CH3:37])[N:34]=[N:35][C:30]2=[N:29][CH:28]=1>>[CH2:4]([O:3][C:1]([C:27]1[N:32]=[C:31]2[N:33]([CH:36]([C:38]3[CH:39]=[C:40]4[C:45](=[CH:46][C:47]=3[F:48])[N:44]=[CH:43][CH:42]=[CH:41]4)[CH3:37])[N:34]=[N:35][C:30]2=[N:29][CH:28]=1)=[CH2:2])[CH3:5]
Reactant: C=C(OCC)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: CC(c1cc2cccnc2cc1F)n1nnc2ncc(Br)nc21
Product: C=C(OCC)c1cnc2nnn(C(C)c3cc4cccnc4cc3F)c2n1

Procedure:
The title compound was prepared in analogy to the synthesis of compound 52.3 from 6-(1-(6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)ethyl)-7-fluoroquinoline. 1H-NMR (400 MHz, CDCl3) δ ppm 9.17 (9.17 (s, 1H), 8.90 (m, 1H), 8.10 (d, 1H), 7.89 (d, 1H), 7.78 (d, 1H), 7.39 (dd, 1H), 6.82 (q, 1H), 5.56 (d, 1H), 4.56 (d, 1H), 4.04 (q, 2H), 2.30 (d, 3H), 1.48 (t, 3H). LCMS (method B): [MH]+=365, tR=2.55 min.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[N:12]([CH2:13][C:14]([C:16]3[CH:17]=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[O:15])[C@H:11]([C:23]([F:26])([F:25])[F:24])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[CH:7]=1.Cl.[C@H:28]12[CH2:34][C@H:31]([NH:32][CH2:33]1)[CH2:30][O:29]2.C(N(CC)CC)C>>[CH3:22][C:19]1[N:18]=[CH:17][C:16]([C:14](=[O:15])[CH2:13][N:12]2[C:4]3=[N:3][C:2]([N:32]4[CH2:33][C@@H:28]5[CH2:34][C@H:31]4[CH2:30][O:29]5)=[CH:7][C:6](=[O:8])[N:5]3[CH2:9][CH2:10][C@H:11]2[C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=1
Reactant: C1O[C@@H]2CN[C@H]1C2
Reactant: Cc1ccc(C(=O)CN2c3nc(Cl)cc(=O)n3CC[C@H]2C(F)(F)F)cn1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)CN2c3nc(N4C[C@@H]5C[C@H]4CO5)cc(=O)n3CC[C@H]2C(F)(F)F)cn1

Procedure:
480 mg (1.24 mmol) of (8S)-2-chloro-9-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 201.94 mg (1.49 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride and 313.97 mg (3.10 mmol) of triethylamine were used in the reaction. After purification by chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient A/B: t 0 min 30% B, t 35 min 60% B, t 40 min 60% B), 335 mg of (8S)-9-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one were obtained, corresponding to the following characteristics:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]2[C:8]([C:18](=O)[C:19]([O:21][CH3:22])=[O:20])=[C:9]([C:13](OCC)=[O:14])[C:10]([O:11][CH3:12])=[C:4]2[C:3]1=[O:24].C(OC(NCC(N(CC(OC)OC)C)=O)=O)C1C=CC=CC=1.C(O)(=O)C.[NH2:51][NH2:52]>C(O)(=O)C>[CH3:12][O:11][C:10]1[C:9]2[C:13](=[O:14])[NH:52][N:51]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:8]=2[N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[C:3](=[O:24])[C:4]=12
Reactant: NN
Reactant: CCOC(=O)c1c(OC)c2n(c1C(=O)C(=O)OC)CCN(C)C2=O
Agent: COC(CN(C)C(=O)CNC(=O)OCc1ccccc1)OC
Solvent: CC(=O)O
Product: COC(=O)c1n[nH]c(=O)c2c(OC)c3n(c12)CCN(C)C3=O
Temperature: 160 °C

Procedure:
A solution of ethyl 2-methyl-8-(methoxy)-6-[methoxy(oxo)acetyl]-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (1.28 g, 3.78 mmol; prepared in a manner similar to that described in Example 62, step 5 to 8, starting with 1-methylpiperazin-2-one (Example 7, step 1 to 3) and hydrazine acetate (1.05 g, 11.36 mmol) in glacial acetic acid (8 mL) was heated at 160° C. in an microwave oven for 20 minutes. The mixture was concentrated under vacuum. The residue was partitioned between chloroform and brine. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The residue was triturated in a 4:1 mixture of ethanol and diethyl ether. The precipitate was filtered to afford the title compound. ES MS M+1=321
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:16][N:17]1[C:21]2=[N:22][CH:23]=[C:24]([CH:26]=[CH2:27])[CH:25]=[C:20]2[CH:19]=[CH:18]1.[OH-].[K+]>CN1C(=O)CCC1>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:27][CH2:26][C:24]3[CH:25]=[C:20]4[CH:19]=[CH:18][N:17]([CH3:16])[C:21]4=[N:22][CH:23]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1cnc2c(ccn2C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2cnc3c(ccn3C)c2)CCN(C)C1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, 1-methyl-5-vinyl-1H-pyrrolo[2,3-b]pyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[C:14](=[O:26])[N:15]([CH3:25])[C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][C:19]([CH3:24])=[CH:18][CH:17]=2)=O)C>C1(C)C=CC=CC=1.O>[CH:1]1([NH:7][C:11]([C:13]2[C:14](=[O:26])[N:15]([CH3:25])[C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][C:19]([CH3:24])=[CH:18][CH:17]=3)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(O)c2cc(C)ccc2n(C)c1=O
Reactant: NC1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)c(O)c(C(=O)NC1CCCCC1)c(=O)n2C
Yield: 96.9 %

Procedure:
Cyclohexylamine (2.85 mL, 24.95 mmol) was added to a solution of Compound 17 (3.26 g, 12.47 mmol) in toluene (50 mL) and refluxed for 4 h. The solution was cooled and the solvent was evaporated under vacuum. The residue obtained was suspended in water, briefly sonicated, and filtered. The crude product was recrystallized by ether to yield 3.8 g (97%) of white solids. M.P. 218° C. 1H NMR (DMSO-d6): δ 1.28 (m, 1H), 1.36 (m, 4H), 1.55 (m, 1H), 1.68 (m, 2H), 1.87 (m, 2H), 2.40 (s, 3H), 3.59 (s, 3H), 3.87 (m, 1H), 7.51 (d, J=8.7 Hz, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.86 (s, 1H), 10.49 (s, 1H). EIMS m/z 315 (M+1), 337 (M+23).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][N:7]=[C:8]=[O:9])=[C:4]([F:12])[CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([NH2:24])[C:17](=[CH:22][CH:23]=1)[C:18](OC)=[O:19].C[O-].[Na+].C(O)=O>C1(C)C(C)=CC=CC=1.CO>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][N:7]2[C:18](=[O:19])[C:17]3[C:16](=[CH:15][C:14]([Cl:13])=[CH:23][CH:22]=3)[NH:24][C:8]2=[O:9])=[C:4]([F:12])[CH:3]=1
Reactant: O=C=NCc1ccc(Br)cc1F
Reactant: COC(=O)c1ccc(Cl)cc1N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=CO
Solvent: Cc1ccccc1C
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)n1Cc1ccc(Br)cc1F
Temperature: 110 °C
Reaction time: 2 h
Yield: 86.2 %

Procedure:
A solution of 4-bromo-2-fluorobenzyl isocyanate (46.0 g, 0.20 mol) in xylene (100 ml) is metered, at room temperature, into a solution of methyl 4-chloroanthranilate (37.1 g, 0.20 mol) in xylene (250 ml). After the addition has ended, the batch is stirred at 110° C. for 2 hours. 3.60 ml of a 30% solution of methanolic sodium methylate (0.020 mol) are metered in and the mixture is stirred at 90° C. for 2 hours, during which process methanol is distilled off. 1.8 ml of 85% formic acid (0.040 mol) are subsequently added, and the mixture is stirred at 90° C. for a further hour. After cooling, the product is filtered off with suction, washed with 3×50 ml of xylene, 3×50 ml of ethanol and 3×100 ml of water, and dried. 66.1 g of 3-(4-bromo-2-fluorobenzyl)-7-chloro-2,4(1H,3H)-quinazolinedione (yield: 86.2% of theory) of melting point 288 ° to 289° C. (lit. >280° C.) are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=O)=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].[NH2:34]C1C=CC(C#N)=CN=1>>[C:20]([C:19]1[CH:23]=[CH:24][C:16]([NH:15][C:13](=[O:14])[CH2:12][CH2:11][CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[F:1])[C:7](=[O:33])[N:8]2[CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)=[N:17][CH:18]=1)#[N:34]
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Reactant: N#Cc1ccc(N)nc1
Product: N#Cc1ccc(NC(=O)CCC2c3c(F)cccc3C(=O)N2Cc2ccc(F)cc2)nc1

Procedure:
The product of Example 11, Part D (113 mg, 0.34 mmol) and 2-amino-5-cyanopyridine (41 mg, 0.34 mmol) were converted to the title compound in a manner analogous to the method described in Example 27 (61 mg, 41%). 1H NMR (400 MHz, CDCl3) δ 8.48 (broad s, 1H); 8.24 (d, J=8.6 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.82 (broad s, 1H), 7.70 (d, J=7.6 Hz, 1H); 7.49-7.45 (m, 1H), 7.33 (m, 2H), 7.23 (t, J=8.6 Hz, 1H); 7.04 (t, J=8.5 Hz, 2H); 5.24 (d, J=15 Hz, 1H), 4.72 (m, 1H), 4.28 (d, J=15 Hz, 1H), 2.61-2.56 (m, 1H); 2.53-2.46 (m, 1H); 2.00-1.95 (m, 2H). MS: m/z (MH+) 433.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1.[CH2:11](I)[CH3:12]>CN(C)C=O.O>[CH2:11]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1)[CH3:12]
Reactant: Cc1ccc(O)cn1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 16.6 g sodium hydride in 500 ml dry dimethylformamide (DMF) under nitrogen at 0° C. is added 90 g 5-hydroxy-2-methylpyridine at such a rate that the temperature remains between 0°-5° C. When gas evolution ceases, 73.8 ml ethyl iodide in 100 ml DMF is added dropwise. After stirring at room temperature overnight, the mixture is diluted with water and extracted with ether. The ether extracts are washed with brine, dried and concentrated. This oil is distilled to give 62.5 g of 5-ethoxy-2-methylpyridine, bp 89°-91° C. at 12 mm.