Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH3:10])[CH:3]=1.C([Li])CCC.C[O:17][B:18](OC)[O:19]C>C1(C)C=CC=CC=1.C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:18]([OH:19])[OH:17])=[CH:3][C:4]=1[O:9][CH3:10]
Reactant: COB(OC)OC
Reactant: COc1cc(Br)ccc1Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1cc(B(O)O)ccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To 4-bromo-1-chloro-2-methoxybenzene (2.2 g, 9.9 mmol) in toluene/THF (16/6 mL) at −78° C. was added n-butyl lithium (8.7 mL, 1.6 M in hexane, 14 mmol) dropwise. The reaction was stirred at −78° C. for 30 min, then trimethylborate (2.2 mL, 19.8 mmol) was added. The reaction was allowed to warm to rt and stirred overnight and then quenched with 1 M HCl (15 mL). The organic layer was separated and dried over sodium sulfate. The solvent was removed and the crude product was purified by flash column chromatography to give 25A (1.2 g, 65% yield) as a white solid. 1H NMR (400 MHz, CDOD3) δ ppm 3.87 (m, 3H) 7.11 (d, J=7.83 Hz, 1H) 7.20 (s, 1H) 7.29 (d, J=7.83 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[C:5]([NH2:6])=[CH:4][C:3]([C:2]([CH3:9])([CH3:8])[CH3:1])=[N:26]2)=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Product: CC(C)(C)c1cc(N)n(-c2ccc(OCc3ccccc3)cc2)n1

Procedure:
The title compound was prepared from 4,4-dimethyl-3-oxopentane nitrile and 4-benzyloxyphenylhydrazine hydrochloride, using the same method as that described for preparation 7, as a pale pink powder in quantitative yield.
Reaction SMILES: [CH2:1]([C:9]1[S:13][C:12]2[S:14][C:15]([CH:17]=[O:18])=[CH:16][C:11]=2[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:19]([CH:24]([CH2:27]O)[CH2:25][OH:26])[CH2:20][CH2:21][CH2:22][CH3:23].C1(C)C(S(O)(=O)=O)=CC=CC=1.O>C1(C)C=CC=CC=1>[CH2:1]([C:9]1[S:13][C:12]2[S:14][C:15]([C@H:17]3[O:26][CH2:25][C@H:24]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:27][O:18]3)=[CH:16][C:11]=2[CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1cc2cc(C=O)sc2s1
Reactant: CCCCCC(CO)CO
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCc1cc2cc([C@H]3OC[C@H](CCCCC)CO3)sc2s1

Procedure:
20.4 g of 5-n-octylthieno[2,3-b]thiophene-2-carbaldehyde (obtainable from 2-n-octylthieno[2,3-b]thiophene by Vilsmeyer formylation with phosphorus oxychloride/dimethylformamide) and 9.5 g of 2-n-pentylpropane-1,3-diol are dissolved in 150 ml of toluene, a pinch of toluenesulfonic acid is added, and the mixture is heated under a water separator until water is no longer separated off. The acid is washed out with sodium bicarbonate solution, the organic phase is dried over sodium sulfate, and the toluene is distilled off. The pure trans-2-(5-n-octylthieno[2,3-b]thien-2-yl)-5-n-pentyl-1,3-dioxane is obtained by repeated recrystallization from ethanol (17.5 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[N+:19]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([CH3:18])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Agent: [Pd]
Product: Cc1cc(N)c(NC(=O)OC(C)(C)C)cc1C(F)(F)F
Yield: 86.8 %

Procedure:
Prepared from (4-methyl-2-nitro-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A18) (4.68 g, 14.6 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a white solid (3.68 g, 87%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)=O.C([NH:18][C:19]([NH2:21])=[NH:20])(=O)C>C(#N)C>[NH2:21][C:19]1[NH:18][CH:2]=[C:3]([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[N:20]=1
Reactant: COC(=O)c1ccc(C(=O)CBr)cc1
Reactant: CC(=O)NC(=N)N
Solvent: CC#N
Product: COC(=O)c1ccc(-c2c[nH]c(N)n2)cc1

Procedure:
At room temperature, methyl 4-bromoacetylbenzoate (1.37 g) and acetylguanidine (1.62 g) were suspended in acetonitrile, followed by heating under reflux for 16 hours. The solvent was then distilled off under reduced pressure. Water was added to the residue. The insoluble matter so precipitated was collected by filtration, followed by washing with ethanol, whereby methyl 4-[2-aminoimidazol-4-yl]benzoate was obtained. The resulting product was dissolved in a mixed solvent of dioxane (10 ml) and 1N hydrochloric acid (10 ml), followed by heating under reflux for 8 hours. The residue obtained by distilling off the solvent was solidified by tetrahydrofuran and then collected by filtration, whereby the title compound (500 mg, 39%) was obtained.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[CH:31]([CH3:33])[CH3:32]>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([O:22][CH2:30][CH:31]([CH3:33])[CH3:32])=[C:6]([C:12]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:13]=2[CH2:14][CH2:15][C:16]3=[O:21])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CC(C)CBr
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC(C)C)c1OC(F)F
Temperature: 80 °C
Yield: 21.3 %

Procedure:
To a stirring solution of 4-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.25 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.75 mmol) and isobutylbromide (102 mg, 0.75 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-30% ethyl acetate in pet ether) to afford title compound as a solid (20 mg, 21.2%).
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH3:16][C:17]1[CH:44]=[C:43]2[C:20]([CH2:21][CH2:22][C:23]3[C:24]2=[N:25][O:26][C:27]=3[C:28]2[C:32]([C:33]([F:36])([F:35])[F:34])=[C:31]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[O:30][N:29]=2)=[CH:19][C:18]=1O.CCCCCC>N1C=CC=CC=1>[F:13][C:10]([F:11])([F:12])[S:7]([O:6][C:18]1[CH:19]=[C:20]2[C:43](=[CH:44][C:17]=1[CH3:16])[C:24]1=[N:25][O:26][C:27]([C:28]3[C:32]([C:33]([F:34])([F:35])[F:36])=[C:31]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[O:30][N:29]=3)=[C:23]1[CH2:22][CH2:21]2)(=[O:8])=[O:9]
Reactant: Cc1cc2c(cc1O)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCCCCC
Solvent: c1ccncc1
Product: Cc1cc2c(cc1OS(=O)(=O)C(F)(F)F)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 0 °C
Yield: 77.1 %

Procedure:
Trifluoromethanesulfonic anhydride (0.074 mL, 0.440 mmol) was added to a solution of 8-methyl-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-ol (Preparation 64C, 0.121 g, 0.293 mmol) in pyridine (5 mL) at 0° C. over a period of 5 min. The reaction mixture was stirred at 0° C. for ten minutes and then at room temperature overnight. The reaction mixture was concentrated, and the yellowish-brown residue was partitioned between ethyl acetate (10 mL) and water (10 mL). The ethyl acetate layer was washed sequentially with 1N aqueous HCl (10 mL), saturated aqueous NaHCO3 (10 mL), and brine (10 mL). The organic layer was collected, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography eluting with a mixture of 15% ethyl acetate:85% hexane to yield 8-methyl-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl trifluoromethanesulfonate as a tan solid (0.123 g, 0.226 mmol, 77%). The product had an HPLC ret. time=4.52 min (condition B). LC/MS M+1=545.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[N:11]3[N:17]=[CH:18][C:19]([C:20]([OH:22])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[C:26]([S:30]([NH2:33])(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[S:30]([C:26]1[CH:25]=[C:24]([NH:23][C:20]([C:19]2[CH:18]=[N:17][N:11]3[C:12]([CH:14]4[CH2:16][CH2:15]4)=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[N:9][C:10]=23)=[O:22])[CH:29]=[CH:28][CH:27]=1)(=[O:31])(=[O:32])[NH2:33]
Reactant: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C4CC4)cc(-c4ccc(Cl)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.28) and 3-amino-benzenesulfonamide according to general procedure II. Pale-yellow solid. MS (ISP) 468.5 [(M+H)+].
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH3:22])[CH:13]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:29]1([S:35]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C=O)C>[C:29]1([S:35]([N:38]2[CH2:43][CH2:42][N:41]([CH2:2][CH2:3][O:4][C:5]3[CH:6]=[C:7]([NH:11][C:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]=[C:14]([CH3:22])[CH:13]=4)[CH:8]=[CH:9][CH:10]=3)[CH2:40][CH2:39]2)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=S(=O)(c1ccccc1)N1CCNCC1
Reactant: Cc1cc(Nc2cccc(OCCCl)c2)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cccc(OCCN3CCN(S(=O)(=O)c4ccccc4)CC3)c2)c2ccccc2n1
Temperature: 90 °C
Yield: 5.9 %

Procedure:
To a solution of 21 (250 mg, 0.67 mmol) in DMF (5 mL) were sequentially added sodium carbonate (149 mg, 1.41 mmol). and 22 (183 mg, 0.808 mmol). The reaction was placed under a N2 atmosphere and heated at 90° C. for 16 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate and washed with water and brine. The ethyl acetate extracts were dried over anhydrous magnesium sulfate and evaporated. The residue was purified via reversed phase HPLC to yield the title compound as a pale yellow solid (20 mg, 6%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)=[O:5])[CH3:2].Br[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]2)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]3)=[CH:20][CH:21]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Reactant: CCNC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCNC(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cc2)cc1
Yield: 25.9 %

Procedure:
The title compound (11 mg, 26%) was prepared as a tan solid from {4-[(ethylamino)carbonyl]phenyl}boronic acid (19 mg, 0.1 mmol), 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 9, Step 2, 36 mg, 0.1 mmol), Pd(PPh3)2Cl2 (10 mg, 0.01 mmol), 2M Na2CO3 (1 mL) and DME (1 mL) in a manner similar to Example 21, Step 3, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.80 (d, 2H, J=8.4 Hz), 7.60 (d, 2H, J=8.6 Hz), 7.54 (d, 2H, J=8.8 Hz), 6.96 (d, 2H, J=8.8 Hz), 6.09 (t, 1 H, J=5.4 Hz), 4.98-4.84 (m, 1H), 4.20 (bs, 2H), 3.85 (d, 2H, J=6.4 Hz), 3.61-3.41 (m, 2H), 2.87-2.71 (m, 2H), 2.05-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.32-1.13 (m, 11H); LRMS (ESI), m/z 425 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:11][OH:12].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]([NH:11][OH:12])=[NH:9])[CH:5]=[CH:4][N:3]=1
Reactant: N#Cc1ccnc(N)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(NO)c1ccnc(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
A stirred mixture of commercially available 2-amino-4-cyano-pyridine [CAS-No. 42182-27-4] (1.0 g, 8.39 mmol), hydroxylamine hydrochloride (1.17 g, 16.8 mmol) and sodium carbonate (0.89 g, 8.39 mol) in water (8 ml) and ethanol (16 ml) was heated under reflux conditions for 3 h. The reaction mixture was evaporated, water (10 ml) was added and the mixture stirred at room temperature for 1 h. The precipitate was collected by filtration to yield the title compound (0.87 g, 68%) as an off-white solid. MS (EI) 152.0 [(M)+]; mp 188° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:22](=[O:30])[CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>O1CCCC1.O>[CH2:7]([N:14]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:22](=[O:30])[CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)CCC(=O)Cl
Reactant: CCOC(=O)CNCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCC(=O)N(CC(=O)OCC)Cc1ccccc1
Yield: 85.6 %

Procedure:
Potassium carbonate (110.4 g, 0.97 mol) was added in one portion to a solution of ethyl 2-(benzylamino)acetate (78 g, 0.4 mol) in tetrahydrofuran (500 mL) and water (200 mL). Ethyl 4-chloro-4-oxobutanoate (72.7 g, 0.485 mol) in anhydrous tetrahydrofuran (200 mL) was then added dropwise over a period of 1 hour to the mixture. The mixture was filtered, and the filtrate was washed with ethyl acetate. After the solvent was removed by evaporation, standard extractive workup with ethyl acetate (100 mL) to afford the title product as a yellow oil (110 g; yield=80%). LC-MS: m/z=322 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].Cl[CH2:12][CH2:13][CH2:14][OH:15].C([O-])([O-])=O.[Ca+2]>O>[OH:15][CH2:14][CH2:13][CH2:12][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7]
Reactant: OCCCCl
Reactant: CNc1cccc(C#N)c1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: CN(CCCO)c1cccc(C#N)c1
Yield: 125.7 %

Procedure:
3-methylaminobenzonitrile (17.34 g, 0.13 mol, 1.0 eq), 3-chloropropanol (49.70 g, 0.53 mol, 4.0 eq) and CaCO3 (52.50 g, 0.53 mol, 4.0 eq) are added into water (230 ml) at room temperature, the mixture is refluxed at elevated temperature for 40 h, and cooled, filtered and extracted with ethyl acetate (200 ml*3). The organic phases are combined, washed with water (100 ml*2), washed with saturated brine twice, dried over anhydrous sodium sulfate and concentrated to give a light yellow oily crude product (31.08 g). The residue could be used directly in next step without purification.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[OH:16][C:17]1[CH:18]=[C:19]([CH:26]=[CH:27][CH:28]=1)[CH2:20][CH:21]([C:23]([OH:25])=[O:24])[NH2:22]>>[C:23]([CH:21]([NH:22][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:20][C:19]1[CH:26]=[CH:27][CH:28]=[C:17]([OH:16])[CH:18]=1)([OH:25])=[O:24]
Reactant: NC(Cc1cccc(O)c1)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: O=C(O)c1cc2cc(Cl)ccc2nc1NC(Cc1cccc(O)c1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 32, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 3-hydroxy-DL-phenylalanine and crude product is separated by flash chromatography on SiO2 to provide the title compound in low yield.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@@H:4]([NH:22][C:23](=[O:32])[C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:31])[CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH3:21])[C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[CH:10][CH:9]=1.[OH-].[Li+].O>C1COCC1>[Cl:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([Cl:30])[C:24]=1[C:23]([NH:22][C@@H:4]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:9]=[CH:10][C:11]([N:14]([CH3:21])[C:15]2[N:16]=[CH:17][CH:18]=[CH:19][N:20]=2)=[CH:12][CH:13]=1)[C:3]([OH:33])=[O:2])=[O:32]
Reactant: COC(=O)[C@H](C/C=C/c1ccc(N(C)c2ncccn2)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(c1ccc(/C=C/C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1)c1ncccn1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 81.3 %

Procedure:
A solution of (S,E)-2-(2,6-dichlorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (1.28 g) in THF (45 ml) was cooled to 0° C. To the solution, 0.1N aqueous lithium hydroxide solution (40 ml) was added, and the resulting mixture was stirred at 0° C. for 40 minutes. Water (50 ml) was added to the reaction solution, and the resulting mixture was washed with ether. Aqueous layer was acidified by adding 1N hydrochloric acid in small portions thereto, and extracted twice with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated to dryness to obtain (S,E)-2-(2,6-dichlorobenzamido)-5-[4-(methyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid (1.01 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[C:5]([C:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:18])[N:14]=2)[NH:9][CH:8]=1)=[O:6].[Br:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28]Br>CN(C)C=O>[Br:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH2:28][N:9]1[C:10]2[C:15](=[N:14][C:13]([CH3:18])=[CH:12][CH:11]=2)[C:16](=[O:17])[C:7]([C:5](=[O:6])[C:4]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:2]([F:1])[CH:3]=2)=[CH:8]1
Reactant: COc1ccc(C(=O)c2c[nH]c3ccc(C)nc3c2=O)cc1F
Reactant: BrCc1cccc(Br)c1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)c3)c3ccc(C)nc3c2=O)cc1F
Yield: 38.9 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1 were used with 112 mg (0.358 mmol) of 3-(3-Fluoro-4-methoxy-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one, 107.5 mg (0.430 mmol) of 3-bromobenzyl bromide, 17.2 mg (0.430 mmol, 60% dispersion in oil), and 2 mL of N,N-dimethylformamide. The crude product was purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 67 mg of 1-(3-Bromo-benzyl)-3-(3-fluoro-4-methoxy-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one. LC-MSD, m/z for C24H18BrFN2O3 [M+H]: 481.05. LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.7 min
Reaction SMILES: [CH3:1][C:2]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)([CH3:5])[CH2:3][OH:4]>C(O)C.[Pd]>[CH3:5][C:2]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13])([CH3:1])[CH2:3][OH:4]
Reactant: CC(C)(CO)Nc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(CO)Nc1ccccc1N
Yield: 98 %

Procedure:
2-(1,1-dimethyl-2-hydroxyethyl)aminonitrobenzene (10 g) in ethanol (200 ml) was hydrogenated at 50p.s.i. (345 kPa) over 5% Pd/C (0.5 g) for 2 hours. The catalyst was filtered off and the solvent removed under reduced pressure yielding the title compound as a yellow foam 8.4 g (98%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]4[N:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[N:32]C=1N1CCNCC1>>[NH:32]1[C:33]2[C:34](=[C:4]([C:2]3[N:3]=[C:4]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[C:5]4[S:10][C:9]([CH2:11][N:12]5[CH2:17][CH2:16][N:15]([C:18]6[N:23]=[CH:22][CH:21]=[CH:20][N:19]=6)[CH2:14][CH2:13]5)=[CH:8][C:6]=4[N:7]=3)[CH:5]=[CH:6][CH:8]=2)[CH:35]=[N:30]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCN(c4ncccn4)CC3)cc2n1
Product: c1cnc(N2CCN(Cc3cc4nc(-c5cccc6[nH]ncc56)nc(N5CCOCC5)c4s3)CC2)nc1

Procedure:
Prepared via 2-Chloro-4-morpholin-4-yl-6-(4-pyrimidin-2-yl-piperazin-1-ylmethyl)-thieno[3,2-d]pyrimidine, prepared from 1-(2-pyrimidyl)piperazine.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.F[C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH:22]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[O:21])=[CH:16][CH:15]=1.[C:37](C1C=CC(C(N(OC)C)=O)=CC=1)([CH3:40])([CH3:39])[CH3:38]>C1COCC1>[C:37]([C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH:22]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[O:23][Si:24]([C:27]([CH3:29])([CH3:30])[CH3:28])([CH3:25])[CH3:26])=[O:21])=[CH:16][CH:15]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)[Si](C)(C)OC(C(=O)c1ccc(F)cc1)c1ccncc1
Reactant: CON(C)C(=O)c1ccc(C(C)(C)C)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)c1ccc(C(=O)C(O[Si](C)(C)C(C)(C)C)c2ccncc2)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 51.7 %

Procedure:
To a cooled solution of diisopropylamine (183 mg, 1.81 mmol) in dry THF (0.35 mL) at -20° C. was added a solution of n-butyllithium in hexanes (0.83 mL of a 2.5M solution, 2.08 mmol). Stirred at -20° C. for 1 hr and then added a solution of 4-pyridyl-t-butydimethylsilyloxymethyl 4-fluorophenyl ketone from Step B (383 mg, 1.72 mmol) in THF (0.45 mL). Stirred at -20° C. for 45 min, resulting in a thick yellow-brown solution. A solution of 4-t-butyl-N-methoxy-N-methyl-benzamide (400 mg, 1.81 mmol) in THF (0.5 mL) was added and the solution stirred at -20° to 0° C. for 5 h. The reaction was cooled to -20° C. and quenched by the addition of a saturated ammonium chloride solution. The reaction mixture was then extracted with ethyl acetate (3 times) and the combined extracts washed successively with water (2 times) and saturated salt solution and dried over anhydrous sodium sulfate. The mixture was filtered and the solvent removed by rotoevaporation. The residue was purified by flash column chromatography on silica gel eluted with 5-10% ethyl acetate in hexanes to yield the title compound as a yellow oil (341 mg, 49% yield).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[C:13]([OH:18])[CH:12]=1>CN(C)C=O>[N+:8]([C:7]1[C:2]([NH:17][C:16]2[CH:11]=[CH:12][C:13]([OH:18])=[CH:14][CH:15]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccc(O)cc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1Nc1ccc(O)cc1
Temperature: 100 °C
Reaction time: 0.67 h
Yield: 81.3 %

Procedure:
8.17 g (50 mmol) of 2-chloro-3-nitropyridine and 16.70 g (150 mmol) of p-aminophenol were added to 50 ml of dimethylformamide and the mixture was stirred at 100° C. for 40 min. The solvent was distilled off under reduced pressure, the same treatment as that of Production Example 1 was repeated and the product was recrystallized from ethanol to obtain 9.4 g of the title compound.