Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C@@H:14]3[CH2:18][CH2:17][CH2:16][O:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1.C(N(C(C)C)C(C)C)C>CCCCO>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][CH2:23][C@@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]2)=[C:4]2[C:10]([NH:11][C:12]([C@@H:14]3[CH2:18][CH2:17][CH2:16][O:15]3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)[C@@H]1CCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)[C@@H]4CCCO4)c23)C1
Temperature: 160 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
A mixture of (S)-N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)tetrahydrofuran-2-carboxamide (195 mg, 0.594 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (357 mg, 1.78 mmol), and N-ethyl-N-isopropylpropan-2-amine (207 μL, 1.19 mmol) in n-BuOH (5 mL) were purged under N2 and stirred at 160° C. in a sealed tube for 16 hours. The solvent was then removed in vacuo, and the residue obtained was purified by C-18 reverse phase column chromatography (Biotage Flash 25M+; C-18) on Biotage SP4 unit eluting with a gradient of 15-90% CH3CN/water (25 CV) to provide tert-butyl (R)-1-(5-bromo-3-((S)-tetrahydrofuran-2-carboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (150 mg, 0.295 mmol, 49.6% yield) as a solid. LCMS (APCI+) m/z 508.1, 510.1 (M+H)+; Retention time=3.85 minutes (Method 2).
Reaction SMILES: [CH:1]1([C:5]2[NH:13][C:12]3[C:11](=[O:14])[NH:10]/[C:9](=[N:15]\[NH2:16])/[N:8]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:7]=3[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:22](OCC)(OCC)(OCC)[CH3:23]>>[CH:1]1([C:5]2[NH:13][C:12]3[C:11](=[O:14])[N:10]4[C:22]([CH3:23])=[N:16][N:15]=[C:9]4[N:8]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:7]=3[N:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]c(C3CCC3)nc21
Reactant: CCOC(C)(OCC)OCC
Product: CCCCCn1c2nc(C3CCC3)[nH]c2c(=O)n2c(C)nnc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 10.6 %

Procedure:
(2E)-8-cyclobutyl-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (100 mg, 0.0003 mol) was mixed with triethyl orthoacetate (10 mL, 0.05 mol) and then stirred at 100° C. overnight. After cooling to room temperature, the mixture was concentrated and purified by preparative LCMS to yield the desired product (10 mg, 9.2%). 1HNMR (300 MHz, CD3OD): δ 4.35 (m, 2H), 3.72 (m, 1H), 2.84 (s, 3H), 2.44 (m, 4H), 2.05 (m, 2H), 1.90 (m, 2H), 1.40 (m, 4H), 0.92 (m, 3H). LCMS calculated for C16H23N6O(M+H): 315.2; found: 315.2.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.C(Cl)CCl.CCN(CC)CC.[CH3:21][C:22](O)([CH3:24])[CH3:23]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[O:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][C:22]([CH3:24])([CH3:23])[CH3:21])=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(O)C1CCOCC1
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)C1CCOCC1
Temperature: 40 °C
Reaction time: 18 h

Procedure:
Tetrahydro-2H-pyran-4-carboxylic acid (10 g, 77 mmol) and EDC (17.68 g, 92 mmol) were added to a flask, followed by DCM (200 ml). To the resulting suspension was added Et3N (16 ml, 115 mmol), tBuOH (16.1 ml, 169 mmol) and DMAP (9.39 g, 77 mmol). The reaction mixture was stirred at 40° C. for 18 hr. The reaction mixture was diluted with DCM (100 Ml) and washed with 1N NaOH (1×100 Ml) followed by 1M citric acid solution (1×100 Ml). The organic layer was dried over sodium sulfate, filtered and concentrated to afford tert-butyl tetrahydro-2H-pyran-4-carboxylate. 1H NMR (500 MHz, CDCl3) δ 3.90 (dt, 2H), 3.37 (dt, 2H), 2.38 (septet, 1H), 1.77-1.67 (m, 4H), 1.40 (s, 9H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:14]([CH3:15])=[CH:13][C:12]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])=[CH:11][C:10]2=[O:26])[CH:6]=[CH:7][CH:8]=1.[CH3:27][NH:28][CH3:29]>CO>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[CH2:17][O:16][C:12]1[CH:13]=[C:14]([CH3:15])[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][N:28]([CH3:29])[CH3:27])[CH:4]=2)[C:10](=[O:26])[CH:11]=1
Reactant: CNC
Reactant: Cc1cc(OCc2ccc(F)cc2F)cc(=O)n1-c1cccc(CCl)c1
Solvent: CO
Product: Cc1cc(OCc2ccc(F)cc2F)cc(=O)n1-c1cccc(CN(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
1-[3-(chloromethyl)phenyl]-4-[(2,4-difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one (from step 1 of the synthesis of EXAMPLE 293) (0.500 g, 1.330 mmol) was suspended in a stock solution of N,N-dimethylamine in methanol (2.0 mL, 2.0 M) and stirred overnight at room temperature. Reaction was concentrated and the residue partitioned between H2O (25 mL) and ethyl acetate (25 mL). The aqueous layer was further extracted with ethyl acetate (2×30 mL), and the combined organics were washed with brine (30 mL), dried over MgSO4, and concentrated to afford an off-white solid (0.508 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[CH3:23][C:24]1[N:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][CH:25]=1>CO>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([N:1]=[CH:30][C:28]4[CH:27]=[CH:26][CH:25]=[C:24]([CH3:23])[N:29]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cccc(C=O)n1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cccc(C=Nc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)n1

Procedure:
Analogously to Example 32, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1 H-pyrazolo[3,4-d]pyrimidine and 180 mg of acetic acid are dissolved in 26 ml of methanol and reacted with 182 mg (1.5 mmol) of 6-methyl-pyridine-2-carbaldehyde to form 4-(3-chloro-phenylamino)-3-[(6-methyl-pyrid-2-yl)-methyleneamino)-1H-pyrazolo-[3,4-d]pyrimidine. Reduction of the above intermediate in 15 ml of DMEU with 8 ml (8 mmol) of DIBAL-H, analogous working-up and digestion in ethyl acetate yield 4-(3-chloro-phenylamino)-3-[(6-methyl-pyrid-2-yl)-methylamino]-1H-pyrazolo[3,4-d]pyrimidine; m.p: 231-233° C.; HPLC: tRet(grad20-100)=6.6; MS: (M)+=365.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:45](=[O:55])[N:46]([CH2:51][CH2:52][CH2:53][CH3:54])[CH2:47][CH2:48][CH2:49][CH3:50])=[N:4][N:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:13][C:12]=2[C:33]([N:35]2[CH2:44][CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:36]2)=[O:34])[C:6]=1[CH2:7][C:8](O)=[O:9].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:68]1([S:71]([NH2:74])(=[O:73])=[O:72])[CH2:70][CH2:69]1.C1CCN2C(=NCCC2)CC1>C1COCC1.CCOC(C)=O>[CH2:51]([N:46]([CH2:47][CH2:48][CH2:49][CH3:50])[C:45]([C:3]1[C:2]([Cl:1])=[C:6]([CH2:7][C:8]([NH:74][S:71]([CH:68]2[CH2:70][CH2:69]2)(=[O:73])=[O:72])=[O:9])[N:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:32])[NH:18][S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])=[CH:13][C:12]=2[C:33]([N:35]2[CH2:44][CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:36]2)=[O:34])[N:4]=1)=[O:55])[CH2:52][CH2:53][CH3:54]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(CC(=O)O)c1Cl
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)NS(=O)(=O)c3ccc4ccccc4c3)cc2C(=O)N2CCc3ccccc3C2)c(CC(=O)NS(=O)(=O)C2CC2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.2 %

Procedure:
To a solution of 2-(4-chloro-3-(dibutylcarbamoyl)-1-(4-(naphthalen-2-ylsulfonylcarbamoyl)-2-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)phenyl)-1H-pyrazol-5-yl)acetic acid (Example 171, 24 mg, 0.031 mmol) in THF (625 μL) was added CDI (16 mg, 0.10 mmol). The resulting solution was heated at reflux for 30 min and then cooled to room temperature. Cyclopropanesulfonamide (14 mg, 0.12 mmol) was then added followed by DBU (24 μL, 0.16 mmol), and the resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with EtOAc, washed with 1N aq. HCl solution (2×) and extracted with EtOAc (3×). The combined organic extracts were washed with sat. aq. NaCl solution, dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (5 mg, 16%) as a white solid after lyophilization. 1H NMR (CD3OD, 2:1 mixture of amide rotamers) δ 8.74 (s, 1H), 8.16-7.96 (m, 6H), 7.81-7.64 (m, 3H), 7.28-7.05 (m, 3.5H), 6.91 (d, J=7.5 Hz, 0.5H), 4.71-4.33 (m, 1.5H), 4.12-2.55 (m, 11.5H), 1.53-0.84 (m, 15H), 0.76 (t, J=7.4 Hz, 2H), 0.67 (t, J=7.4 Hz, 1H); MS(ESI+) m/z 887.5 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH2:10])=[O:9])[CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>CC(N(C)C)=O>[C:8]([C:4]1[CH:3]=[C:2]([O:18][C:15]2[CH:16]=[CH:17][C:12]([NH2:11])=[CH:13][CH:14]=2)[CH:7]=[CH:6][N:5]=1)(=[O:9])[NH2:10]
Reactant: NC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1
Solvent: CC(=O)N(C)C
Product: NC(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
Entry 14: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 using DMAC in place of DMF to give 4-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C4, 2-methoxy-5-(trifluoromethyl)aniline was reacted with phosgene followed by 4-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([C:10](=O)[C:11]1[CH:16]=[C:15](C)[CH:14]=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19])=[CH:6][N:7](C)C)[CH3:2].Cl.[CH2:24]([O:26][C:27](=[O:31])[CH2:28][NH:29]N)[CH3:25].[C:32](O)(=O)C>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[N:7][N:29]([CH2:28][C:27]([O:26][CH2:24][CH3:25])=[O:31])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([CH3:32])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19])=[O:22])[CH3:2]
Reactant: CCOC(=O)CNN
Reactant: CC(=O)O
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(C)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cn1ncc(C(=O)OCC)c1-c1ccc(C)cc1[N+](=O)[O-]
Yield: 50 %

Procedure:
The above crude 3-dimethylamino-2-(5-methyl-2-nitro-benzoyl)-acrylic acid ethyl ester j (3.06 g, 10 mmol) and the hydrazino-acetic acid ethyl ester hydro chloride (1.64 g, 10 mmol) were refluxed in absolute ethanol containing catalytic amount of acetic acid for 8 h. The reaction mixture was cooled and concentrated in vacuo. The residue was purified by column chromatography to provide pure compound 1 (1.81 g, 50% yield for two steps): LC MS (Method B): 362 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:11]=1[CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]([C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:24]([O:26][CH3:27])=[O:25])[C:16](=[O:32])[CH:15]=1.CN1CCOCC1.Cl[C:46]([O:48][CH3:49])=[O:47]>CC(N(C)C)=O>[F:37][C:35]1[CH:34]=[CH:33][C:11]([CH2:12][O:13][C:14]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:24]([O:26][CH3:27])=[O:25])[C:16](=[O:32])[CH:15]=2)=[C:10]([CH2:9][NH:8][C:46]([O:48][CH3:49])=[O:47])[CH:36]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3CN)cc2=O)c1
Reactant: COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: COC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2cc(C(=O)OC)ccc2C)c(=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of methyl 3-[4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate trifluoroacetate (from Step 2) (0.50 g, 0.95 mmol) in DMA (4 mL) was added 4-methylmorpholine (0.21 mL, 1.9 mmol) and methyl chloroformate (0.08 mL, 1.0 mmol). Reaction was stirred at RT for 1 h. Solvent removed by distillation. Crude product purified by preparatory HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHCO3 (30 mL) and extracted in DCM (3×25 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated to a white solid, dried in vacuo (0.36 g, 81%). 1H NMR (CD3OD/400 MHz) δ8.03 (m, 1H), 7.77 (s, 1H), 7.53 (d, 1H, J=7.6 Hz), 7.47 (m, 1H), 7.12 (m, 1H), 7.03 (m, 1H), 6.21 (s, 1H), 6.08 (s, 1H), 5.18 (s, 2H), 4.38 (s, 2H), 3.89 (s, 3H), 3.65 (s, 3H), 2.12 (s, 3H), 1.89 (s, 3H). ESHRMS m/z 469.1767 (M+H calculated for C25H26FN2O6 requires 469.1769).
Reaction SMILES: [CH:1]1([C:4](=[O:9])[CH2:5][CH2:6][NH:7][CH3:8])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].C(O[C:20](=[O:22])[CH3:21])(=O)C>>[CH:1]1([C:4](=[O:9])[CH2:5][CH2:6][N:7]([CH3:8])[C:20](=[O:22])[CH3:21])[CH2:3][CH2:2]1
Reactant: CC(=O)OC(C)=O
Reactant: CNCCC(=O)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)N(C)CCC(=O)C1CC1
Temperature: 25 °C

Procedure:
A crude solution of 1-cyclopropyl-3-methylamino-1-propanone was cooled to 8°-10° C. and 8.2 g. (0.06 mole) of potassium carbonate was added, followed by 50 g. (0.5 mole) of acetic anhydride. The mixture was stirred until it warmed to room temperature. The benzene layer was separated, dried over magnesium sulfate, concentrated, and the residual oil distilled at 99°-150° C./0.1 mm. The distillate weighed 65 g. It was calculated to contain 80% of 1-cyclopropyl-3-(N-methylacetamido)-1-propanone by the nuclear magnetic resonance spectrum.
Reaction SMILES: [Na].[NH2:2][C:3]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=[CH:4][C:5]#[N:6].[C:15](=O)([O:19]CC)[O:16][CH2:17][CH3:18].Cl>C(O)C.O.C(OCC)(=O)C>[C:5]([CH:4]=[C:3]([NH:2][C:15](=[O:19])[O:16][CH2:17][CH3:18])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])#[N:6]
Reactant: CCOC(=O)OCC
Reactant: N#CC=C(N)c1ccc(Cl)cc1Cl
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)NC(=CC#N)c1ccc(Cl)cc1Cl

Procedure:
4.85 g (211 mmol) of sodium are dissolved in ethanol (260 ml), 30.0 g (141 mmol) of 3-amino-3-(2,4-dichlorophenyl)acrylonitrile and 36.59 g (310 mmol) of diethyl carbonate are added, and the reaction solution is stirred under reflux for 4 h. Ethyl acetate and water are added to the reaction mixture, and the pH is adjusted to pH=5 with concentrated hydrochloric acid. The organic phase is separated off, dried over magnesium sulphate and concentrated in a rotary evaporator. The residue is chromatographed on silica gel (mobile phase cyclohexane/ethyl acetate 7:1 to 1:1); the product has Rf=0.5 in cyclohexane/ethyl acetate 1:1. 17.1 g (43% of theory) of the product are obtained.
Reaction SMILES: CO[C:3]([C:5]1[C:10]([NH:11][C:12](=[O:22])[CH2:13][C:14]2[C:15]([Cl:21])=[N:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Cl:21][C:15]1[C:14]([C:13]2[C:12](=[O:22])[NH:11][C:10]3=[N:9][CH:8]=[CH:7][N:6]=[C:5]3[C:3]=2[OH:4])=[CH:19][CH:18]=[C:17]([Cl:20])[N:16]=1
Reactant: COC(=O)c1nccnc1NC(=O)Cc1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1[nH]c2nccnc2c(O)c1-c1ccc(Cl)nc1Cl
Temperature: 100 °C

Procedure:
A mixture of 3-[2-(2,6-dichloro-pyrid-3-yl)-acetylamino]-pyrazine-2-carboxylic acid methyl ester (Example 1.5) (1.16 g) and potassium carbonate (0.943 g) in dry N,N-dimethylformamide (20 ml) was heated to 100° C. for 3 hours. The reaction mixture was cooled to ambient temperature and diluted with ethyl acetate. The mixture was filtered and the solid was washed with further ethyl acetate. The solid was then suspended in water and the pH of the suspension adjusted to pH 2 by addition of aqueous hydrochloric acid (2M). The aqueous phase was filtered to give Compound No. A13 of Table A as a beige solid which was washed with a small amount of water, followed by diethyl ether and allowed to dry (0.380 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.Cl.[NH:25]1[CH2:28][CH:27]([OH:29])[CH2:26]1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C>C1COCC1>[OH:29][CH:27]1[CH2:28][N:25]([C:19]([C:18]2[CH:17]=[N:16][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[CH:23][CH:22]=2)=[O:21])[CH2:26]1
Reactant: OC1CNC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CC(O)C2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) and azetidin-3-ol hydrochloride (70.7 mg, 0.65 mmol) in THF (6 mL) at 0° C. were added 1-hydroxybenzotriazole hydrate (100.8 mg, 0.65 mmol), N-ethyldiisopropylamine (281.7 μl, 1.613 mmol) and N-(3-dimethylaminopropy)-N′-ethylcarbodiimidazole hydrochloride (126.2 mg, 0.65 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=3:1 to 1:4) afforded the title compound (215 mg, 91%) as a colourless oil. MS: m/e=366.2 [M+H]+.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[Cs+].[Cs+].F[C:8]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=1)=[O:11].[F:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][C:27]=1OC>CN(C=O)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:8]([O:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][C:28]=2[O:4][CH3:1])=[C:9]([CH:20]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=1)=[O:11]
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1cc(Cl)ccc1F
Reactant: O=C([O-])[O-]
Reactant: COc1cc(O)ccc1F
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1Oc1ccc(Cl)cc1C(=O)Nc1cc[nH]c(=O)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
Cs2CO3 (879.9 mg, 2.7 mmol) was added to a solution of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-5-chlorobenzamide (72.0 mg, 0.27 mmol) and 4-fluoro-3-methoxyphenol (307.7 μl, 2.7 mmol) in DMF (1 mL) and the reaction was stirred at 100° C. for 1 hour. The reaction was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl as a modifier to yield 5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(2-oxo-1,2-dihydropyridin-4-yl)benzamide (70) (31.8 mg, 30%). ESI-MS m/z calc. 388.06. found 389.10 (M+1)+; Retention time: 1.52 minutes (3 minutes run).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:21][CH2:22][CH2:23][C@@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][NH:25]3)=[C:7]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[NH:30][C:31]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1)=[O:32].C=O.[C:41](O)(=O)C.C([BH3-])#N.[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:21][CH2:22][CH2:23][C@@H:24]3[CH2:29][CH2:28][CH2:27][CH2:26][N:25]3[CH3:41])=[C:7]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[NH:30][C:31]([C:33]1[CH:38]=[CH:37][N:36]=[CH:35][N:34]=1)=[O:32]
Reactant: Cc1cc(C)cc(-c2c(OCC[C@@H]3CCCCN3)c3cc(NC(=O)c4ccncn4)c(Cl)cc3[nH]c2=O)c1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C)cc(-c2c(OCC[C@@H]3CCCCN3C)c3cc(NC(=O)c4ccncn4)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of pyrimidine-4-carboxylic acid (S)-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-4-(2-piperidin-2-yl-ethoxy)-1,2-dihydroquinolin-6-yl]-amide (prepared essentially as described in EXAMPLE 2, 9 mg in 0.40 mL methanol) was added 6 mg paraformaldehyde followed by 20 mg powdered 4A molecular sieves and 0.01 mL acetic acid and the mixture stirred at room temperature for 10 minutes. At this time, 5 mg sodium cyanoborohydride was added and the stirring continued. After 2 hours, 0.5 mL tetrahydrofuran was added to ensure homogeneity and after 60 hours the reaction was quenched by the addition of water. The reaction mixture was extracted with methylene chloride and the combined organics washed with brine and dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (methylene chloride:10% ammonium hydroxide in methanol, 95:5; then 92:8) gave the title compound (6.7 mg). MASS: 546 (M+H) ##STR167##
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:5]([N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6].[CH2:24]([N:26]([CH2:31]C)[CH2:27][CH2:28][CH2:29][NH2:30])C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:24][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH:30][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:5]([N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6]
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CCN(CC)CCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(NCCCN(C)C)c1
Yield: 68 %

Procedure:
A mixture of 3-fluoro-N,N-bis(3-methylbutyl)-4-nitrobenzamide (2.5 g, 1 eq, prepared according to Example A1), 3-diethylamino-propylamine (877 mg, 1.1 eq) and potassium carbonate (2.13 g, 2 eq) in acetonitrile (80 ml) is heated under reflux for 5 hours then concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (130 ml) and water (50 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: dichloromethane/methanol 9:1) produces the expected compound in the form of a yellow oil (2.1 g mg; 68% yield).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[N:9]/[C:10]2[C:15]([CH:16]([CH3:18])[CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[CH:4][CH:3]=1.[BH3-]C#N.[Na+].CC(O)=O.CO>O>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:9][C:10]2[C:15]([CH:16]([CH3:17])[CH3:18])=[CH:14][CH:13]=[CH:12][C:11]=2[CH:19]([CH3:21])[CH3:20])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1cccc(C(C)C)c1/N=C/c1cccc(Br)n1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CC(C)c1cccc(C(C)C)c1NCc1cccc(Br)n1

Procedure:
A mixture of 25.0 g (134 mmol) of 6-bromopyridine-2-carbaldehyde, 23.8 g (134 mmol) of 2,6-diisopropylaniline and 1.15 g (6.70 mmol) of TsOH in 600 ml of toluene was refluxed for 15 min using a Soxhlet apparatus filled with CaCl2. The obtained solution was evaporated to dryness, and the residue was re-crystallized from 100 ml of methanol to give the imine product N-[(1E)-(6-bromopyridin-2-yl)methylene]-2,6-diisopropylaniline as a yellow crystalline solid (23.9 g). In argon atmosphere, a mixture of 22.4 g (65.0 mmol) of N-[(1E)-(6-bromopyridin-2-yl)methylene]-2,6-diisopropylaniline, 6.53 g (104 mmol) of NaBH3CN, 2 ml of AcOH and 430 ml of methanol was refluxed for 12 h. The obtained mixture was cooled, poured into 1000 ml of water, and then extracted with 3×200 ml of ethyl acetate. The combined extract was dried over MgSO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel 60 (40-63 μm, eluent: hexane-ethyl acetate=10:1, vol.). Yield 19.8 g (43%) of a yellow oil. Anal. calc. for C18H23BrN2: C, 62.25; H, 6.68; N, 8.07. Found: C, 62.40; H, 6.77; N, 7.96. 1H NMR (CDCl3): δ 7.50 (m, 1H, 4-H in 6-bromopyridyl), 7.38 (m, 1H, 5-H in 6-bromopyridyl), 7.28 (m, 1H, 3-H in 6-bromopyridyl), 7.01-7.11 (m, 3H, 3,4,5-H in 2,6-diisopropylphenyl), 4.16 (s, 2H, CH2N), 3.93 (br.s, 1H, NH), 3.31 (sep, J=6.9 Hz, 2H, CHMe2), 1.22 (d, J=6.9 Hz, 12H, CHMe2).