Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:25])[C:11]2[C:16]([CH3:17])=[CH:15][C:14]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[CH:13][C:12]=2[OH:24])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32](I)[CH3:33]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:25])[C:11]2[C:16]([CH3:17])=[CH:15][C:14]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)=[CH:13][C:12]=2[O:24][CH2:32][CH3:33])=[CH:4][CH:3]=1
Reactant: Cc1cc(N2CCOCC2)cc(O)c1C(=O)NCc1ccc(Cl)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cc(N2CCOCC2)cc(C)c1C(=O)NCc1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
To a solution of N-[(4-chlorophenyl)-methyl]-2-hydroxy-6-methyl-4-morpholin-4-yl-benzamide (0.2 g, 0.56 mmol) in acetone (5 ml) are added potassium carbonate (0.092 g, 0.66 mmol) and ethyl iodide (0.066 ml, 0.83 mmol). The reaction mixture is stirred at 50° C. for 1 h. Additional ethyl iodide (0.22 ml, 2.77 mmol) is added and heating is continued for another 2 h. Additional ethyl iodide (0.22 ml, 2.77 mmol) is then added and the reaction mixture is stirred for 15 h. After completion of reaction, the solution is filtered through a pad of celite and concentrated to obtain the crude product, which is purified by column chromatography (silica gel, 15% ethyl acetate/hexan) yielding N-[(4-chlorophenyl)-methyl]-2-ethoxy-6-methyl-4-morpholin-4-yl-benzamide (example 11) (0.12 g, 0.3 mmol, 56%). [M+H]+ 389.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:18])[CH:11]=[C:12]([C:15]([OH:17])=[O:16])O[CH:14]=2)=[CH:5][CH:4]=1.[CH3:21][NH2:22].Cl>>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[C:10](=[O:18])[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[N:22]([CH3:21])[CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(COc2coc(C(=O)O)cc2=O)cc1
Reactant: CN
Agent: Cl
Product: COc1ccc(COc2cn(C)c(C(=O)O)cc2=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.9 %

Procedure:
A mixture of 5-((4-methoxybenzyl)oxy)-4-oxo-4H-pyran-2-carboxylic acid (1.4627 g, 5.30 mmol) and methanamine (11.0 ml, 22.00 mmol) was stirred at room temperature for 20 h, The reaction was concentrated under reduced pressure, and the residue was dissolved in 15 mL of de-ionized water. The aqueous solution was cooled in an ice bath and treated dropwise with 2N hydrochloric acid (3.0 ml, 6.00 mmol). The resulting yellow solid was filtered, washed with water and acetone, and dried to give 5-((4-methoxybenzyl)oxy)-1-methyl-4-oxo-1,4-dihydropyridine-2-carboxylic acid (1.21 g, 4.18 mmol, 79% yield). LCMS: (M+H)+: 290.1.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[S:10][CH:11]([CH3:19])[CH2:12][CH2:13][C:14]([O:16]CC)=O.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:1][C:2]=1[S:10][CH:11]([CH3:19])[CH2:12][CH2:13][C:14]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=[O:16]
Reactant: C1COCCN1
Reactant: CCOC(=O)CCC(C)Sc1nc2ccccc2[nH]1
Product: CC(CCC(=O)N1CCOCC1)Sc1nc2ccccc2[nH]1
Yield: 57.6 %

Procedure:
0.56 g of ethyl 4-(2-benzimidazolylthio)valerate and 0.53 g of morpholine were heated at 100° C. for 20 hours. The reaction mixture was applied without treatment to a silica gel column for purification (methanol:methylene chloride=1:10), and 0.37 g of the title compound was obtained as solid (yield: 58%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[C:19]3[C:18]4[CH:17]=[C:16]([C:20]5[CH:21]=[N:22][C:23]([O:29][CH3:30])=[C:24]([N+:26]([O-])=O)[CH:25]=5)[CH:15]=[CH:14][C:13]=4[N:12]=[CH:11][C:10]=3[N:9]([CH3:31])[C:8]2=[O:32])[C:4]([CH3:33])=[N:3]1.[H][H]>C1COCC1.CO.[Pd]>[NH2:26][C:24]1[CH:25]=[C:20]([C:16]2[CH:15]=[CH:14][C:13]3[N:12]=[CH:11][C:10]4[N:9]([CH3:31])[C:8](=[O:32])[N:7]([C:5]5[C:4]([CH3:33])=[N:3][N:2]([CH3:1])[CH:6]=5)[C:19]=4[C:18]=3[CH:17]=2)[CH:21]=[N:22][C:23]=1[O:29][CH3:30]
Reactant: [H][H]
Reactant: COc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1N

Procedure:
A solution of 1-(1,3-dimethyl-1H-pyrazol-4-yl)-8-(6-methoxy-5-nitro-pyridin-3-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Example 66, 50 mg, 0.112 mmol) in 5 ml THF and 5 ml MeOH was stirred in presence of palladium 10% on charcoal under 1.1 bar of hydrogen for 5 h at rt. The reaction mixture was filtered over Celite and the catalyst was washed with MeOH/THF. The filtrate was evaporated and the crude product was purified by Prep.HPLC (H2O (0.1% TFA)/CH3CN 95:5 to 50:50). The fractions containing products were collected together, basified with NaHCO3, concentrated and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and evaporated to give the title compound as a light yellow solid. (HPLC: tR 2.29 min (Method A); M+H=416 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.94 (s, 1H), 8.12-8.10 (m, 1H), 8.08-8.05 (m, 1H), 7.76-7.72 (m, 1H), 7.47-7.45 (m, 1H), 7.43-7.41 (m, 1H), 7.00-6.97 (m, 11-1), 5.11 (s, br, 2H), 3.92 (s, 3H), 3.89 (s, 3H), 3.57 (s, 3H), 1.94 (s, 3H))
Reaction SMILES: [C:1]([CH2:9][C:10]#[N:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH:13]1[CH2:18]SC(O)C[S:14]1.C(NCC)C>C(O)C>[NH2:11][C:10]1[S:14][CH:13]=[CH:18][C:9]=1[C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: OC1CSC(O)CS1
Solvent: CCNCC
Solvent: CCO
Product: Nc1sccc1C(=O)c1ccccc1
Reaction time: 2 h

Procedure:
A mixture of benzoylacetonitrile (1.45 g, 10 mmole), 2,5-dihydroxy-1,4-dithiane (0.76 g, 5 mmole) and diethylamine (0.73 g=1.04 mL, 10 mmole) in 4 mL absolute ethanol was heated in a teflon-sealed pressure tube for 4 hours at 50° C. with frequent stirring on a vortex mixer. By 2 hours starting materials had dissolved and shortly thereafter product began to crystallize. After refrigerating the tube overnight, the product was filtered off and washed with a little methanol to give bright yellow crystals. Yield 1.3 g, 64% 1H NMR (CDCl3) δ: 6.14 (d, 1H, H-5), 6.88 (d, 1H, H-4), 6.95 (br s, 2H, NH2), 7.5-7.7 (m, 5H, C6H5).
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:35][S:36]([C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1)(=[O:38])=[O:37]>C(#N)C.O.Cl>[C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[N:19]([CH2:43][C:42]3[CH:41]=[CH:40][C:39]([S:36]([CH3:35])(=[O:38])=[O:37])=[CH:46][CH:45]=3)[CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2cc[nH]c2c(=O)n1C
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2ccn(Cc3ccc(S(C)(=O)=O)cc3)c2c(=O)n1C
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
A suspension of methyl 2-(tert-butoxy)-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (17 mg, 0.044 mmol) in Acetonitrile (0.4 mL) was treated with Cs2CO3 (57.9 mg, 0.178 mmol), 4-methylsulfonylbenzyl bromide (44.3 mg, 0.089 mmol), and stirred at 70° C. for 1.5 hours. The reaction was cooled to rt, diluted with water and 1N HCl, extracted with EtOAc, washed with Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography (0-100% EtOAc/Hexane) gave methyl 2-(tert-butoxy)-2-(6-methyl-1-(4-(methylsulfonyl)benzyl)-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (22 mg, 0.040 mmol, 90% yield) as yellow oil. The ester intermediate was dissolved in Methanol (0.5 mL) and Tetrahydrofuran (THF) (0.5 mL), treated with 2M LiOH (0.120 mL, 0.24 mmol), and stirred at 60° C. for 2 hours. The reaction was concentrated and purified with reverse phase HPLC (20-100% MeCN/H2O-0.1% TFA) to give title compound (9.3 mg, 0.017 mmol, 37.6 yield) as off white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 1.00 (s, 9H), 2.44 (s, 3H), 3.02 (s, 3H), 3.64 (s, 3H), 5.47 (s, 1H), 5.81 (d, J=15.7 Hz, 1H), 6.02 (d, J=15.6 Hz, 1H), 6.10 (d, J=2.8 Hz, 1H), 7.05 (d, J=2.9 Hz, 1H), 7.29 (d, J=8.1 Hz, 2H), 7.32-7.43 (m, 3H), 7.47-7.58 (m, 1H), 7.89 (d, J=8.4 Hz, 2H). LCMS (m/z) ES+=537 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[C@@H:6]2[CH2:7][N:8]([C:10]3[N:15]=[C:14]([C:16]4[O:20][C:19]([C:21]5[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=5)=[N:18][N:17]=4)[C:13]([N:37]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[N:12][CH:11]=3)[CH2:9][C@@H:5]2[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH2:59]([S:61](Cl)(=[O:63])=[O:62])[CH3:60]>C(Cl)Cl>[CH2:59]([S:61]([NH:1][CH:2]1[C@@H:6]2[CH2:7][N:8]([C:10]3[N:15]=[C:14]([C:16]4[O:20][C:19]([C:21]5[CH:26]=[CH:25][C:24]([CH2:27][N:28]([CH3:36])[C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=5)=[N:18][N:17]=4)[C:13]([N:37]([C:38]([O:40][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:39])[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[N:12][CH:11]=3)[CH2:9][C@@H:5]2[CH2:4][CH2:3]1)(=[O:63])=[O:62])[CH3:60]
Reactant: CN(Cc1ccc(-c2nnc(-c3nc(N4C[C@@H]5CCC(N)[C@@H]5C4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)cc1)C(=O)OC(C)(C)C
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)NC1CC[C@H]2CN(c3cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c4nnc(-c5ccc(CN(C)C(=O)OC(C)(C)C)cc5)o4)n3)C[C@@H]12
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
To a solution of tert-butyl N-[[4-[5-[6-[(3aR,6aS)-6-amino-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-3-[bis(tert-butoxycarbonyl)amino]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (150 mg, 0.22 mmol) and triethylamine (24 mg, 33 μL, 0.23 mmol) in DCM (1 mL) at 0° C. was added ethanesulfonyl chloride (29 mg, 21 μL, 0.22 mmol). The reaction mixture was stirred for 30 min. The solvent was evaporated and the crude material was purified via silica gel column chromatography using 10 to 70% EtOAc in DCM to obtain tert-butyl N-[[4-[5-[6-[(3aR,6aS)-6-(ethylsulfonylamino)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]-3-[bis(tert-butoxycarbonyl)amino]pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]phenyl]methyl]-N-methyl-carbamate (110 mg, 650%). LC/MS m/z 799.5 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH2:18][CH3:19])[C:15]([C:20](O)=[O:21])=[C:11]2[O:12][C:13]=1[CH3:14].[CH:23]1([CH2:26][NH:27][CH2:28][CH2:29][CH3:30])[CH2:25][CH2:24]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH:23]1([CH2:26][N:27]([CH2:28][CH2:29][CH3:30])[C:20]([C:15]2[C:16]([CH2:18][CH3:19])=[N:17][N:10]3[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])=[C:13]([CH3:14])[O:12][C:11]=23)=[O:21])[CH2:25][CH2:24]1
Reactant: CCc1nn2c(-c3ccc(Cl)cc3Cl)c(C)oc2c1C(=O)O
Reactant: CCCNCC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCN(CC1CC1)C(=O)c1c(CC)nn2c(-c3ccc(Cl)cc3Cl)c(C)oc12
Temperature: 50 °C

Procedure:
To a stirred solution of 3-(2,4-dichloro-phenyl)-6-ethyl-2methyl-pyrazolo[5,1-b]oxazole-7-carboxylic acid (Intermediate IA) (37 mg, 0.11 mmol, 1 eq.) in DMF (0.8 ml) is successively added cyclopropylmethyl-propylamine (0.017 ml, 0.12 mmol, 1.1 eq.), DIPEA (0.038 ml, 0.22 mmol, 2 eq.) and HATU (46 mg, 0.12 mmol, 1.1 eq.) at RT. The reaction mixture is heated at 50° C. for 2 h then poured into EtOAc and washed with K2CO3 2M in water (2×). The organic layer is dried over Na2SO4, filtered and concentrated to dryness and the resulting crude residue is purified by column chromatography (SiO2; gradient elution iso-hexane/EtOAc 6:1 to 1:1) to yield the title compound as a yellow oil. MS: m/z 434.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.90 (1H, d), 7.73 (1H, d), 7.65 (1H, dd), 3.46 (2H, t), 3.30 (2H, s), 2.70 (2H, q), 2.34 (3H, s), 1.60 (2H, m), 1.11 (3H, t), 1.02 (1H, m), 0.63 (3H, m), 0.48 (2H, m), 0.20 (2H, m).
Reaction SMILES: [C:1]([NH:7][C:8](=[O:30])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:29])OC(C)=C)[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:31][O:32][CH2:33][CH2:34][NH2:35].CN1CCCC1>O1CCOCC1.CC#N.O>[CH3:31][O:32][CH2:33][CH2:34][NH:35][C:24](=[O:29])[NH:23][C:19]1[CH:18]=[C:17]([O:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4])=[O:30])=[N:15][CH:14]=2)[CH:22]=[CH:21][N:20]=1
Reactant: COCCN
Reactant: C=C(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Agent: CN1CCCC1
Solvent: CC#N
Solvent: O
Solvent: C1COCCO1
Product: COCCNC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.3 %

Procedure:
A mixture of Example C2 (0.120 g, 0.290 mmol), 2-methoxyethylamine (0.1 mL, 1.15 mmol) and N-methylpyrrolidine (0.012 g, 0.145 mmol) in dioxane (5 mL) was heated at 80° C. overnight, cooled to RT, and concentrated to dryness. The residue was dissolved in DCM and stirred with sat'd NaHCO3. The aqueous layer was back-extracted with DCM (3×) and the organic phases combined, dried (Na2SO4) and concentrated to afford a light brown oil. The crude residue was purified via silica gel chromatography (MeOH/DCM) to afford a white solid, which was dissolved in MeCN/H2O, frozen and lypholized overnight to afford N-((5-((2-(3-(2-methoxyethyl)ureido)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)pivalamide as a white solid (54 mg, 43%). 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 10.44 (s, 1H), 9.14 (s, 1H), 8.24 (d, J=2.9 Hz, 1H), 8.07-8.06 (m, 2H), 7.96 (s, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H), 6.97 (d, J=2.3 Hz, 1H), 6.57 (dd, J=5.9, 2.4 Hz, 1H), 3.35-3.34 (m, 2H), 3.28-3.22 (m, 2H), 3.24 (s, 3H), 1.21 (s, 9H); MS (ESI) m/z: 431.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>N1C=CC=CC=1>[CH3:13][S:14]([NH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][N:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1ccnc(N)c1
Solvent: c1ccncc1
Product: CCOC(=O)c1ccnc(NS(C)(=O)=O)c1
Reaction time: 3 h
Yield: 88 %

Procedure:
To a solution of ethyl 2-aminoisonicotinate (1 g, 6.02 mmol) in dry pyridine (20 ml), methanesulfonyl chloride (0.938 ml, 12.04 mmol) was added at room temperature, and the resulting solution was stirred for 3 hours. Pyridine was evaporated and the residue was triturated with water (20 ml). The solid was collected by filtration and dried affording ethyl 2-(methylsulfonamido)isonicotinate as a light brown powder (1.3 g, 5.32 mmol, 88% yield, MS/ESI+ 245.2 [MH]+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[O:4].Br[CH2:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[CH2:20]Br)[CH:13]=[CH:12][CH:11]=1.[H-].[Na+]>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([N:5]1[CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:19]=2[C:18](=[CH:17][CH:16]=[CH:15]3)[CH2:20]1)=[O:4]
Reactant: BrCc1cccc2cccc(CBr)c12
Reactant: NC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(N1Cc2cccc3cccc(c23)C1)C(F)(F)F

Procedure:
Trifluoroacetamide (10 mmol) is reacted with 1,8-bis(bromomethyl)naphthalene (10 mmol) and sodium hydride (10 mmol) in DMF according to the procedure of Wright et al (Biochim. Biophys. Acta 1990, 1040, 95-101) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]2[O:20][CH2:21][CH2:22][C:23]=2[C:24]([O:26]CC)=O)=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C.CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:24](=[O:26])[C:23]3[CH2:22][CH2:21][O:20][C:19]=3[NH:18][C:16]2=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C1=C(NC(=O)Nc2cc(C(=O)OC(C)C)c(Cl)cc2F)OCC1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCO3)c(F)cc1Cl

Procedure:
using isopropyl 2-chloro-4-fluoro-5-{3-[3-(ethoxycarbonyl)-4,5-dihydro-furan-2-yl]ureido}-benzoate with sodium isopropylate in an isopropanol/dimethylformamide mixture there is obtained isopropyl 2-chloro-4-fluoro-5-{1,2,5,6-tetrahydro-2,4-dioxo-furo[2,3-d]pyrimidin-3(4H)-yl}-benzoate, m.p. 213°-215° C.,
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:17]=1)[C:14](O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH4+:26].[OH-].Cl>C(Cl)Cl.C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:17]=1)[C:14]([NH2:26])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(OCc2ccccc2)cc1C(=O)O
Reactant: [NH4+]
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(OCc2ccccc2)cc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a stirred solution of 5-(benzyloxy)-2-methoxybenzoic acid (8, 1.16 g. 4.5 mmol) in CH2Cl2 (25 mL) at room temperature was added oxalyl chloride (1.5 mL, 17.9 mmol). The reaction mixture was stirred at room temperature for 2 h. It was concentrated to dryness to provide the crude acid chloride as a brown-yellow waxy solid. The crude acid chloride was dissolved in THF (10 mL) and was added dropwise to a stirred mixture of concentrated NH4OH (20 mL) and THF (10 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 1 h and was adjusted to pH 8 with 2 N HCl. The precipitate was collected, washed with water, and dried in vacuo to afford the title compound (0.73 g, 63%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.88 (d, J=3.3 Hz, 1H), 7.82 (br s, 1H), 7.47-7.43 (m, 2H), 7.40-7.37 (m, 2H), 7.33-7.30 (m, 1H), 7.10 (dd, J=9.0, 3.3 Hz, 1H), 6.94 (d, J=9.0 Hz, 1H), 5.75 (br s, 1H), 5.08 (s, 2H), 3.94 (s, 3H); ESI MS m/z 258 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:15]=[C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=[CH:12][C:11]=1[N+:29]([O-])=O)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>[Pd].C1(C)C=CC=CC=1.CO>[NH2:29][C:11]1[CH:12]=[CH:13][C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:15][C:10]=1[N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2-c2ccccc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2-c2ccccc2)ccc1N
Yield: 89.5 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-methyl-N-[2-nitro-5-(2-phenylphenoxy)phenyl]carbamate (8.3 g), palladium on carbon (10%, 0.66 g) and toluene/methanol=7/3 (100 ml) and the reaction mixture was purified to give the title compound (6.9 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[C:4](=[O:18])[CH:3]=1.Br[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[OH:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][N:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:3][C:4]2=[O:18])=[CH:11][CH:12]=1
Reactant: BrCc1cccnc1
Reactant: O=c1cc(O)ccn1CCc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1cc(OCc2cccnc2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 500 mg (2.04 mmol) 4-hydroxy-1-[2-(4-hydroxymethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 2b) in 20 mL DMF is added 0.62 g (2.45 mmol) 3-bromomethyl-pyridine and 0.85 g (6.12 mmol) potassium carbonate. The reaction mixture is stirred overnight at RT, diluted with 60 mL of EtOAc and is washed twice with water. The organic phase is dried over MgSO4, filtered and the solvent is evaporated. The residue is purified via reverse HPLC chromatography (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([CH:11]=O)=[C:8]([CH3:13])[C:6]=2[N:7]=1.[CH3:20][N:21]([CH3:30])[C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23]>>[CH3:20][N:21]([CH3:30])[C:22]([N:24]1[CH2:25][CH2:26][N:27]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)=[N:3][C:2]([Cl:1])=[N:7][C:6]=3[C:8]=2[CH3:13])[CH2:28][CH2:29]1)=[O:23]
Reactant: CN(C)C(=O)N1CCNCC1
Reactant: Cc1c(C=O)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(CN2CCN(C(=O)N(C)C)CC2)sc2c(N3CCOCC3)nc(Cl)nc12

Procedure:
Reaction between 2-chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde and piperazine-1-carboxylic acid dimethylamide (Example 26) using General Procedure B-3 yielded 4-(2-chloro-7-methyl-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-piperazine-1-carboxylic acid dimethylamide.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[Li]C(C)(C)C.[CH3:19][N:20]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]1>>[OH:26][C:23]1([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[CH:7][N:8]3[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=2)[CH2:24][CH2:25][N:20]([CH3:19])[CH2:21][CH2:22]1
Reactant: CN1CCC(=O)CC1
Reactant: CC(C)n1ccc2ccc(Br)cc21
Agent: [Li]C(C)(C)C
Product: CC(C)n1ccc2ccc(C3(O)CCN(C)CC3)cc21
Temperature: -20 °C
Reaction time: 0.12 h
Yield: 44.1 %

Procedure:
1.5 ml of a solution of 6-bromo-1-isoproylindole (240 mg, 1 mmol) was cooled to −78 ° C., 1.7M tBuLi (1.47 ml, 2.5 mmol) was added and the mixture stirred for 7 mins. N-Methyl-4-piperidone (340.8 mg, 3 mmol) was then added and the mixture stirred for a further 10 mins. The reaction mixture was then warmed up to −20° C. and quenched with water and dichloromethane. The organic layer was washed with water, dried over anhydrous Na2SO4, concentrated in vacuo and the residue purified by column chromatography on silica gel, eluting with 2% 2M ammonia/methanol in dichloromethane to give the title product (120 mg, 44%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[F:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)=[CH:4][CH:3]=1.Br.Br.[C:27]12[CH2:34][NH:33][CH2:32][C:31]=1[CH2:30][NH:29][CH2:28]2.N12CCCN=C1CCCCC2>C(#N)C>[C:27]12[CH2:34][NH:33][CH2:32][C:31]=1[CH2:30][N:29]([C:15]1[C:16]([F:18])=[C:17]3[C:12]([C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9][N:8]3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:13][C:14]=1[F:20])[CH2:28]2
Reactant: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(F)c(F)cc2c1=O
Reactant: C1NCC2=C1CNC2
Agent: Br
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(-c2ccc(F)cc2)c2c(F)c(N3CC4=C(CNC4)C3)c(F)cc2c1=O
Reaction time: 8 h
Yield: 67 %

Procedure:
1-(4-Fluorophenyl)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.33 g), 3,7-diazabicyclo[3.3.0] oct-1(5)-ene dihydrobromide (0.27 g) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU, 1 ml) were dissolved in acetonitrile (10 ml) and refluxed for 4 hours. The reaction mixture was kept overnight at room temperature and the produced precipitate was filtered, washed with acetonitrile, methanol to give the title compound (0.28 g, yield 66%).