Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([N:13]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)[CH2:16][O:15][C:14]2=[O:26])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:27]C1C=C(C=C(F)C=1F)C=O>>[O:26]=[C:14]1[N:13]([C:11]([O:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[O:12])[C@@H:17]([C:18]2[CH:23]=[C:22]([F:27])[C:21]([F:24])=[C:20]([F:25])[CH:19]=2)[CH2:16][O:15]1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: O=C1OCC(c2ccc(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1
Product: O=C1OC[C@H](c2cc(F)c(F)c(F)c2)N1C(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
Following the procedure for the synthesis of 4-(3,4-difluorophenyl)-2-oxo-oxazolidine-3-carboxylic acid-4-nitro-phenyl ester, 3,4,5-triflourobenzaldehyde yielded the desired product. 1H NMR (400 MHz, CDCl3) δ 8.27 (d, 2H, J=9.0 Hz), 7.31 (d, 2H, J=9.0 Hz), 7.11-7.02 (m, 2H), 5.37 (dd, 1H, J=4.1, 9.0 Hz), 4.81 (apparent t, 1H, J=9.0 Hz), 4.33 (dd, 1H, J=4.1, 9.0 Hz); Anal. Calc. for C16H9F3N2O6: C, 50.27; H, 2.37; N, 7.33. Found: C, 50.56; H, 2.50; N, 7.49.
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[CH:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[C:16](Br)[CH:15]=1>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:20][C:19]1[CH:18]=[CH:17][C:16]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:15][CH:14]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: Clc1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(-c2ccccc2)cc1

Procedure:
6 mol of a 26% strength by weight phenylmagnesium chloride/THF solution are added dropwise in the course of 4 hours to a boiling solution of 6 mol of 1,4-bromochlorobenzene and 100 mg of Pd(dppf)Cl2 *CH2Cl2 in 600 g of tetrahydrofuran (THF). After completion of the addition, the reaction mixture is refluxed for a further 5 hours. After hydrolysis with 3600 g of 8% strength by weight sulfuric acid, phase separation and subsequent removal of the solvent by distillation, crude 4-chlorobiphenyl is obtained, which is purified by fractional distillation in vacuo. Yield 1080 g (96%), purity of the product □ 99.7% (a/a GC).
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([NH:22][CH:23]1[CH2:26][N:25]([S:27]([O-:30])(=[O:29])=[O:28])[C:24]1=[O:31])=[O:21])(OCC1C=CC=CC=1)=[O:2].[Na+:32].[C:33]([OH:36])(=O)C>CO.[H][H].[Pd]>[O:36]=[C:33]1[NH:25][CH2:24][CH2:23][N:22]1[C:1]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([NH:22][CH:23]1[CH2:26][N:25]([S:27]([O-:30])(=[O:29])=[O:28])[C:24]1=[O:31])=[O:21])=[O:2].[Na+:32]
Reactant: O=C(Cc1ccccc1CNC(=O)OCc1ccccc1)NC1CN(S(=O)(=O)[O-])C1=O
Reactant: CC(=O)O
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Solvent: CO
Product: O=C(Cc1ccccc1CNC(=O)N1CCNC1=O)NC1CN(S(=O)(=O)[O-])C1=O
Reaction time: 1.5 h

Procedure:
In 70 ml of 30% methanol is dissolved 0.30 g of the sodium 3-[2-(2-carbobenzoxyaminomethylphenyl)acetamido]-2-oxoazetidine-1-sulfonate obtained in Example 80 followed by addition of 0.68 ml of 6% acetic acid and 75 mg of palladium black. The mixture is stirred in hydrogen gas streams at room temperature for 90 minutes, after which the catalyst is filtered off. The filtrate is concentrated under reduced pressure, followed by addition of 30 ml of tetrahydrofuran. Then, under ice-cooling, 0.15 g of 1-chlorocarbonylimidazolid-2-one is added to the above tetrahydrofuran solution. The mixture is stirred for 90 minutes (its pH being maintained at 8.5 with a 1% aqueous solution of sodium hydrogen carbonate). The reaction mixture is adjusted to pH 6.5 wih phosphoric acid, and the tetrahydrofuran is distilled off under reduced pressure. The residue is purified on an Amberlite XAD-II column to provide 0.24 g of sodium 3-[2[2-(2-oxoimidazolidin-1 -yl)carbonylaminomethylphenyl]acetamido]-2-oxoazetidine-1-sulfonate.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26](OCC)=[O:27])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH2:26][OH:27])[N:25]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OCc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture comprising 2.6 g of ethyl 2-tritylaminothiazole-4-carboxylate and 10 ml of tetrahydrofuran was added dropwise under ice-cooling to a mixture comprising 0.24 g of lithium aluminum hydride and 30 ml of tetrahydrofuran, under a stream of nitrogen. After completion of the dropwise addition, the resulting mixture was stirred at room temperature for 3 hours, and then with heating under reflux for one hour. Ethyl acetate and then water were added to the reaction mixture under ice-cooling, the organic layer was separated off, and the aqueous layer was re-extracted with ethyl acetate. The combined ethyl acetate extract was washed with saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography, using as eluent a 1:1 by volume mixture of benzene and ethyl acetate. The product was recrystallized from a mixture of ethyl acetate, acetone and n-hexane. giving the desired compound as a pale yellow powder.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[N:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[O:41]=[C:42]([N:59]1[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]1)[CH2:43][NH:44][C:45]([C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:49][CH:48]=1)=[O:46]>CN(C=O)C.O>[Cl:10][C:11]1[N:16]=[CH:15][C:14]([C:17]([N:62]2[CH2:61][CH2:60][N:59]([C:42](=[O:41])[CH2:43][NH:44][C:45]([C:47]3[CH:52]=[CH:51][C:50]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=4)=[CH:49][CH:48]=3)=[O:46])[CH2:64][CH2:63]2)=[O:19])=[CH:13][CH:12]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccc(Cl)nc2)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 33.9 %

Procedure:
DIPEA (179.7 mg, 0.24 mL, 1.39 mmol) was added to a stirred solution of 6-chloro-pyridine-3-carboxylic acid (48.6 mg, 0.37 mmol) in DMF (3 mL). HOBT (45.9 mg, 0.34 mmol) and EDCI (148.1 mg, 0.77 mmol) were then added at room temperature. After 2 minutes, Biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (120 mg, 0.37 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 90% EtOAc in Hexane as eluent) to afford 58 mg (40.8% yield) of biphenyl-4-carboxylic acid {2-[4-(6-chloro-pyridine-3-carbonyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 95.92, 1H NMR (DMSO-d6): δ 8.7-8.6 (t, 1H), 8.5 (d, 1H), 8.0-7.9 (m, 3H), 7.84-7.7 (q, 4H), 7.68-7.6 (d, 1H), 7.54-7.46 (t, 2H), 7.46-7.36 (m, 1H), 4.2 (bs, 2H), 3.8-3.4 (m, 8H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:20][CH3:21])[CH:17]=2)[C:12]1=[O:22])(=[O:3])[CH3:2].[CH3:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][Br:27]>>[Br-:27].[C:1]([C:4]1[CH:5]=[N+:6]([CH2:23][C:24]2[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=2[CH3:26])[CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:20][CH3:21])[CH:17]=2)[C:12]1=[O:22])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)CC(Cc1ccncc1C(C)=O)C2=O
Reactant: Cc1ccccc1CBr
Product: COc1ccc2c(c1)CC(Cc1cc[n+](Cc3ccccc3C)cc1C(C)=O)C2=O
Product: [Br-]

Procedure:
The title compound 138 is prepared according to the procedure reported in Example 38.1 with compound 113 (111 mg, 0.37 mmol) and 2-methylbenzyl bromide (84 μL, 0.63 mmol) as reactants. White solid. (Yield 145.2 mg, 81%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5](O)=[CH:6][CH:7]=1.ClC1C=CC=CC=1.C([O-])(=O)C.[K+].[N+:22]([O-])(OCCC(C)C)=O>C(OC(=O)C)(=O)C>[NH:1]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=[N:22]1
Reactant: Cc1cc(O)ccc1N
Reactant: CC(C)CCO[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: c1ccc2[nH]ncc2c1

Procedure:
4-Amino-m-cresol is suspended in acetic anhydride and chlorobenzene in the presence of potassium acetate, isoamyl nitrate is added to the suspension at 70° C. to 100° C., preferably about 80° C., and the mixture is stirred to form an indazole skeleton. The intermediate thus obtained is dissolved in hydrochloric acid-methanol, and the mixture is preferably stirred at room temperature to deacetylate the compound.
Reaction SMILES: [B-](F)(F)(F)F.CN(C(ON1C(=O)CCC1=O)=[N+](C)C)C.[F:21][C:22]1[CH:23]=[C:24]([NH:29][CH:30]([C:32]2[CH:33]=[C:34]([C:49](O)=[O:50])[CH:35]=[C:36]3[C:41]=2[O:40][C:39]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[CH:38][C:37]3=[O:48])[CH3:31])[CH:25]=[C:26]([F:28])[CH:27]=1.CCN(C(C)C)C(C)C.[NH:61]1[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1>C(Cl)Cl>[F:21][C:22]1[CH:23]=[C:24]([NH:29][CH:30]([C:32]2[CH:33]=[C:34]([C:49]([N:61]3[CH2:66][CH2:65][O:64][CH2:63][CH2:62]3)=[O:50])[CH:35]=[C:36]3[C:41]=2[O:40][C:39]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[CH:38][C:37]3=[O:48])[CH3:31])[CH:25]=[C:26]([F:28])[CH:27]=1
Reactant: C1COCCN1
Reactant: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Agent: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)N2CCOCC2)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
TSTU (84 mg, 0.28 mmol) at 25° C., was added to 8-(1-(3,5-difluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (100 mg, 0.14 mmol) and DIPEA (0.049 mL, 0.28 mmol) dissolved in DCM (1 mL). The resulting solution was stirred at 25° C. for 2 hrs. Morpholine (0.037 mL, 0.42 mmol) was then added, the resulting solution was stirred at 25° C. for 30 minutes then concentrated. The crude was diluted with 1 mL of DMA and purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 mL/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness, triturated in diethyl ether and collected by filtration to afford 8-(1-(3,5-difluorophenylamino)ethyl)-6-(morpholine-4-carbonyl)-2-morpholino-4H-chromen-4-one (63.0 mg, 90%) as a yellow solid. Mass Spectrum: M+H+ 500. NMR Spectrum: (DMSOd6) 1.53 (d, 3H), 3.11 (bs, 2H), 3.37-3.71 (m, 10H), 3.71-3.80 (m, 4H), 4.98-5.07 (m, 1H), 5.62 (s, 1H), 6.15 (dd, 2H), 6.25 (ddd, 1H), 6.97 (d, 1H), 7.51 (d, 1H), 7.82 (d, 1H).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[N:21]=[N:22][NH:23][CH:24]=1.C(OC([NH:32][CH:33]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C:44]([NH2:46])=[O:45])[CH:38]=1)[C:34](O)=[O:35])=O)(C)(C)C>>[NH:23]1[CH:24]=[C:20]([S:19][CH2:5][C:6]2[CH2:15][S:14][C@@H:9]3[CH:10]([NH:13][C:34](=[O:35])[CH:33]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C:44]([NH2:46])=[O:45])[CH:38]=4)[NH2:32])[C:11](=[O:12])[N:8]3[C:7]=2[C:16]([OH:18])=[O:17])[N:21]=[N:22]1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1cccc(NC(N)=O)c1
Reactant: Sc1c[nH]nn1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Product: NC(=O)Nc1cccc(C(N)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4c[nH]nn4)CS[C@H]23)c1

Procedure:
When 7-ACA, 4-mercapto-1,2,3-triazol, and α-t-butoxycarbonylamino-m-ureidophenylacetic acid are reacted according to the procedure of Example 5 the title compound is obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH:10]=1)=[O:8].C([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)(=O)C>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][OH:21])[CH:10]=1)=[O:8]
Reactant: CC(=O)OCCCCCBr
Reactant: O=C(Nc1nccs1)c1c[nH]c2ccccc12
Product: O=C(Nc1nccs1)c1cn(CCCCCO)c2ccccc12

Procedure:
The title compound was prepared using 1H-indole-3-carboxylic acid thiazol-2-ylamide and 5-bromopentyl acetate as R5X.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:3]=1[C:4]([C:6]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([OH:14])=[C:8]([O:15][CH3:16])[CH:7]=1)=O.[CH2:25]1[C:30](=[O:31])[O:29][CH2:28][C:26]1=O>S(=O)(=O)(O)O.C(O)(=O)C>[CH3:22][O:21][C:19]1[C:18]([O:23][CH3:24])=[CH:17][C:3]2[C:4]([C:6]3[CH:11]=[C:10]([O:12][CH3:13])[C:9]([OH:14])=[C:8]([O:15][CH3:16])[CH:7]=3)=[C:25]3[C:30](=[O:31])[O:29][CH2:28][C:26]3=[N:1][C:2]=2[CH:20]=1
Reactant: COc1cc(N)c(C(=O)c2cc(OC)c(O)c(OC)c2)cc1OC
Reactant: O=C1COC(=O)C1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1cc2nc3c(c(-c4cc(OC)c(O)c(OC)c4)c2cc1OC)C(=O)OC3
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 87.9 %

Procedure:
One drop of conc. sulfuric acid was added to a mixture of 2-amino-4,5,3',5'-tetramethoxy-4'-hydroxy-benzophenone (0.333 g), tetronic acid (tetrahydrofuran-2,4-dione)(0.11 g) and acetic acid (10 ml), and the mixture was stirred at 100° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residual oil was poured into water, neutralized with an aqueous saturated sodium bicarbonate solution and extracted with chloroform. The chloroform layer was washed with water and dried over magnesium sulfate. Evaporation of the solvent gave 6,7-dimethoxy-9-(4-hydroxy-3,5-dimethoxyphenyl)furo[3,4-b]quinoline-1(3H)-one (0.349 g, 88%) which was then recrystallized from methanol. Pale yellow needles. mp. 247°-248° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]([OH:15])=[C:7]([C:16](OCC)=[O:17])[C:6]2=[O:21])[CH2:3][CH2:2]1.[C:22]([NH:35][NH2:36])(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH:1]1([CH2:4][N:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]([OH:15])=[C:7]([C:16]([NH:36][NH:35][C:22](=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:17])[C:6]2=[O:21])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(O)c2ccccc2n(CC2CC2)c1=O
Reactant: CCCCCCCCCCCC(=O)NN
Product: CCCCCCCCCCCC(=O)NNC(=O)c1c(O)c2ccccc2n(CC2CC2)c1=O

Procedure:
Reagents: Comp 31 (0.45 mmols, 0.13 g); dodecanoyl hydrazine (0.68 mmols, 0.15 g). Yield: 0.09 g (49%), white solid, m.p.=121° C.-122° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][C:10](=[O:20])[C:11]=2[C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[N:7]=1.C(N(CC)CC)C.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]=[C:36]=[O:37]>C1(C)C=CC=CC=1>[F:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([F:19])[C:12]=1[C:11]1[C:10](=[O:20])[CH:9]=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][C:2]([NH:1][C:36]([NH:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[F:28])=[O:37])=[N:7]2
Reactant: O=C=Nc1ccccc1F
Reactant: Nc1ccc2c(-c3c(F)cccc3F)c(=O)ccn2n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2c(-c3c(F)cccc3F)c(=O)ccn2n1)Nc1ccccc1F
Reaction time: 3 h

Procedure:
2-amino-5-(2,6-difluorophenyl)-6H-pyrido[1,2-b]pyridazin-6-one (50 mg, 0.18 mmol), toluene (3 mL), triethyl amine (36 mg, 0.36 mmol), and 1-fluoro-2-isocyanatobenzene (49 mg, 0.36 mmol) were added to a flask and heated to reflux. The reaction was complete in 3 hrs and concentrated to dryness. The crude residue was purified via silica gel chromatography (CH2Cl2/EtOAc/MeOH) to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:15]=2[CH2:29][NH2:30])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.Cl[C:39](Cl)([O:41]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:15]=2[CH2:29][NH:30][C:39](=[O:41])[N:20]3[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(NCc3ccc(F)cc3)c2CN)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2CNC(=O)N3Cc2ccc(F)cc2)CC1
Temperature: 0 °C

Procedure:
A solution of 4-[2-aminomethyl-3-(4-fluoro-benzylamino)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (255 mg, 0.62 mmol) in CH2Cl2(6 ml) was cooled to 0° C. and NEt3(0.19 ml, 1.36 mmol) and triphosgen (64 mg, 0.22 mmol) were added. After stirring at 0° C. for half an hour, the reaction mixture was allowed to warm up to room temperature and was partitioned between water and ethyl acetate. The organic layer was washed with water and brine. After drying over MgSO4, the organic fraction was concentrated in vacuo and resulting brown residue was purified by flash chromatography to give 4-[1-(4-fluoro-benzyl)-2-oxo-1,2,3,4-tetrahydro-quinazolin-5-yl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid. (179 mg, 66%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:11][C:12]1[CH:20]=[CH:19][C:15]([CH2:16][NH:17][CH3:18])=[CH:14][CH:13]=1>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:17]([CH2:16][C:15]2[CH:19]=[CH:20][C:12]([F:11])=[CH:13][CH:14]=2)[CH3:18])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: CNCc1ccc(F)cc1
Product: CC(=O)N1CCC(N(C)Cc2ccc(F)cc2)CC1
Yield: 67.8 %

Procedure:
17.1 g (0.14 mol) of N-acetyl-4-piperidone and 16.9 g (0.14 mol) of N-(4-fluorobenzyl)-N-methylamine were reacted in a similar manner to Preparation 6. 25.1 g of 1-acetyl-4-(N-(4-fluorobenzyl)-N-methylamino)piperidine were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[CH:10]=[CH2:11].[CH2:12]([O:19][C:20]1[CH:25]=[C:24](I)[CH:23]=[CH:22][C:21]=1[N:27]1[S:31](=[O:33])(=[O:32])[NH:30][C:29](=[O:34])[CH2:28]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:12]([O:19][C:20]1[CH:25]=[C:24]([CH:10]([C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[CH3:11])[CH:23]=[CH:22][C:21]=1[N:27]1[S:31](=[O:33])(=[O:32])[NH:30][C:29](=[O:34])[CH2:28]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: C=Cc1c(C)cc(C)cc1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(C)c(C(C)c2ccc(N3CC(=O)NS3(=O)=O)c(OCc3ccccc3)c2)c(C)c1
Temperature: 120 °C

Procedure:
A mixture of 1,3,5-trimethyl-2-vinylbenzene (0.058 mL, 0.36 mmol), 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (80 mg, 0.18 mmol), Pd(OAc)2 (5 mg, 0.09 mmol) and triethylamine (0.13 mL, 0.9 mmol) in acetonitrile (1.5 mL) is heated in a microwave apparatus at 120° C. for 1 h. The mixture is filtered over Celite and the filtrate is evaporated to give the title compound which is used directly in the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:9][O:8]1.[CH3:16][CH2:17][OH:18]>CCOC(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:8])[CH2:9][N:1]1[CH2:2][CH2:3][CH2:4][C@H:16]([C:17]([O:8][CH2:7][CH3:9])=[O:18])[CH2:6]1
Reactant: c1ccc(C2(c3ccccn3)CO2)cc1
Reactant: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H]1CCCN(CC(O)(c2ccccc2)c2ccccn2)C1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
2-(2-pyridyl)-2-phenyl oxirane (prepared following the procedure of Example 11, Step F) (0.106 g, 0.537 mmol) and S-(-)-ethyl nipecotate (0.093 g, 0.591 mmol) in EtOH (0.90 mL) were heated at 50° C. in a sealed tube with stirring for 24 hr. The reaction mixture was dissolved in EtOAc, washed with brine, dried (Na2SO4), filtered, and concentrated to dryness to give the title compound.
Reaction SMILES: [C:1]12([C:11]3[CH:24]=[CH:23][C:14]([O:15][C:16]([CH3:22])([CH3:21])[C:17]([O:19]C)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O.[OH-].[Li+].Cl>O.C1COCC1>[C:1]12([C:11]3[CH:12]=[CH:13][C:14]([O:15][C:16]([CH3:21])([CH3:22])[C:17]([OH:19])=[O:18])=[CH:23][CH:24]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: COC(=O)C(C)(C)Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
To a solution of methyl 2-(4-(adamantan-1-yl)phenoxy)-2-methylpropanoate (1.0 g, 3.00 mmol), prepared from step 1, in H2O/THF (1:1.20 mL) was added lithium hydroxide monohydrate (0.51 g, 12.00 mmol), and stirred at room temperature overnight. The reaction mixture was adjusted to acidic solution with 1 N aqueous HCl and extracted with dichloromethane. The organic layer was washed with H2O and brine, and dried over anhydrous magnesium sulfate. The solvent was filtered and evaporated under reduced pressure to afford a crude solid, which was purified by silica gel column chromatography to give 2-(4-(adamantan-1-yl)phenoxy)-2-methylpropanoic acid as a white solid (0.92 g, 96.1% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:20]C([N-]C(C)C)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[CH:10]([CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[N-]C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2ccccc21
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1CN(C(=O)OC(C)(C)C)c2ccccc2C1=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-4-quinolinone (structure 68A of Scheme LI, where R1-2 =H) (EXAMPLE 325) (500 mg, 0.002 mol) in THF (5 mL) at -78° C. was added 2.0M LDA in THF (1.01 mL, 0.002 mol). The reaction mixture was stirred at -78° C. for 15 min and iodomethylane (126 mL, 0.002 mol) was added all at once. The temperature was raised to 0° C. and the resulting mixture stirred for 4 h. The reaction was then quenched with sat'd NH4Cl (5 mL), extracted with ethyl acetate (2×10 mL), dried (Na2SO4) and concentrated in vacuo to a solid residue that was subjected to flash column chromatography (silica gel, hexanes/ethyl acetate, 95:5) to give 117 mg (23%) of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3-methyl-4-quinolinone (structure 69A of Scheme LI, where R1-2 =H, R3 =methyl), 128 mg (23%) of 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3,3-dimethyl-4-quinolinone (structure 70A of Scheme LII, where R1-2 =H, R3-4 =methyl) and 200 mg (40%) of recovered starting material. Data for 1-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-3-methyl-4-quinolinone: 1 H NMR (400 MHz, CDCl3) 7.99 (dd, J=7.9, 1.7, 1H), 7.77 (d, J=8.4, 1H), 7.48 (ddd, J=7.3, 7.3, 1.7, 1H), 7.13 (dd, J=7.4, 1.0, 1H), 4.32 (dd, J=13.4, 4.4, 1H), 3.69 (dd, J=13.3, 9.8, 1H), 2.76 (ddd, J=9.8, 7.0, 4.4, 1H), 1.56 (s, 9H), 1.24 (d, J=7.0, 3H).