Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](Cl)=[O:42])=[CH:36][CH:35]=1.O>ClCCl>[C:1]1([CH2:7][CH2:8][N:9]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[C:41](=[O:42])[CH2:40][C:37]2[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(NCCc2ccccc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CC(=O)N(CCc2ccccc2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of commercially available tert-butyl 4-oxo-1-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 2-phenylethylamine (0.143 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HCl (0.1 N, 1×15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-(2-phenylethyl)amino-piperidine carboxylate. Yield: 221 mg. To a solution of tert-butyl 4-(2-phenylethyl)amino-piperidine carboxylate (50 mg, 0.16 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HCl (0.2 N, 2×15 ml), NaOH (0.2 N, 2×15 ml), and water (10 ml), dried (Na2SO4), filtered and concentrated to give N-(2-phenylethyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was used without any further purification. N-(2-Phenylethyl)-N-(1-(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2×15 ml), dried (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3×6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 52 mg; 13C-NMR (CD3OD, rotamers): δ 27.1, 28.5, 34.9, 36.6, 40.2, 40.4, 44.1, 44.2, 44.4, 53.3, 54.2, 54.6, 114.0, 114.1, 126.2, 126.6, 127.2, 127.4, 128.3, 128.6, 128.79, 128.82, 129.7, 138.5, 139.5, 158.96, 159.0, 172.7, 173.1
Reaction SMILES: [Br:1][CH2:2][CH:3]([CH:7]([CH3:9])[CH3:8])[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:15][C:16](=[CH2:18])[CH3:17].C(=O)([O-])O.[Na+]>ClCCl>[C:16]([O:5][C:4](=[O:6])[CH:3]([CH2:2][Br:1])[CH:7]([CH3:9])[CH3:8])([CH3:18])([CH3:17])[CH3:15]
Reactant: C=C(C)C
Reactant: CC(C)C(CBr)C(=O)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C(CBr)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
To a solution of 2-bromomethyl-3-methyl-butyric acid (52.1 g, 0.267 mol) in dichloromethane (150 ml) was added concentrated sulphuric acid (2.85 ml) and isobutylene (150 ml). The mixture was stirred in a Parr vessel at room temperature for 24 hours. The mixture was slowly added to a saturated solution of sodium hydrogencarbonate (300 ml) and extracted with dichloromethane (50 ml). The organic layer was washed with brine (100 ml), separated, dried over magnesium sulphate, filtered and the solvent removed in vacuo to afford the title compound as a pale yellow oil (66.4 g, 99%).
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]([CH3:11])([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)[CH3:5].[OH-].[K+]>O.C(O)C>[CH3:11][C:4]([C:6]1[CH:10]=[CH:9][S:8][CH:7]=1)([CH3:5])[C:3]([OH:12])=[O:2]
Reactant: COC(=O)C(C)(C)c1ccsc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C(=O)O)c1ccsc1

Procedure:
The 2 -methyl-2-(3-thienyl)propionic acid methyl ester obtained in the foregoing Example 7 was added to a water:ethanol (1:4) solution (200 ml) of potassium hydroxide (18.5 g). Then the mixture was refluxed under heating for one hour and concentrated under reduced pressure, followed by a further addition of water thereto. Then the mixture was washed with dichloromethane (100 ml). The aqueous layer was acidified with diluted hydrochloric acid and the liberated carboxylic acid was extracted with dichloromethane (200 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent was removed by a water pump. The residue was recrystallized from hexane to obtain 2-methyl-2-(3-thienyl)propionic acid with mp. 78°-80.5° C.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3](=[O:31])/[CH:4]=[CH:5]/[C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:10]=1[CH3:11].[ClH:33].CCOCC>C(O)C.[Pd]=O>[ClH:33].[ClH:33].[CH3:32][N:2]([CH3:1])[C:3](=[O:31])[CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH3:11]
Reactant: Cc1c(/C=C/C(=O)N(C)C)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=[Pd]
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: Cc1[nH]cnc1CCC(=O)N(C)C
Reaction time: 72 h

Procedure:
A solution of (E)-N,N-dimethyl-3-[5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl]-2-propenamide (6.0 g) in ethanol (100 ml) was hydrogenated at room temperature and pressure over 10% palladium oxide on carbon (dry, 2.0 g, pre-reduced in ethanol (25 ml)) for 48 h. The catalyst was filtered off (Hyflo), replaced with fresh palladium oxide (2.0 g) and hydrogenation continued for 72 h. The catalyst was filtered off (Hyflo) and the filtrate evaporated in vacuo to yield a yellow oil. This was dissolved in ethanol (15 ml) and acidified with ethanolic hydrogen chloride (to pH1). Dry ether (500 ml) was added and the resulting precipitate was filtered off to give the title compound (1.72 g) as a white powder, m.p. 142°-144°.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:31])[CH:6]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[NH:30])[NH2:29])=[CH:24][CH:23]=1)[C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[C:10]([O:16][CH2:17][CH2:18][OH:19])=[CH:9][C:8]=1[F:20])[CH3:3].CN(C=O)C.C(N(CC)CC)C.[C:44]1([N:50]=[C:51]=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C1COCC1>[CH2:2]([O:4][C:5](=[O:31])[CH:6]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([NH2:29])=[N:30][C:51](=[O:52])[NH:50][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:24][CH:23]=1)[C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[C:10]([O:16][CH2:17][CH2:18][OH:19])=[CH:9][C:8]=1[F:20])[CH3:3]
Reactant: O=C=Nc1ccccc1
Reactant: CCOC(=O)C(Nc1ccc(C(=N)N)cc1)c1cc(OCC)c(OCCO)cc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(Nc1ccc(C(N)=NC(=O)Nc2ccccc2)cc1)c1cc(OCC)c(OCCO)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
The (RS)-(4-carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester hydrochloride (456 mg) described in example 1.6 was dissolved in THF (3 ml). DMF (3 ml), triethylamine (106 mg) and phenylisocyanate (131 mg) were added and the mixture was stirred for 3 h at room temperature. The reaction mixture was concentrated and purified by column chromatography (hexane/ethyl acetate) to give 380 mg of (RS)-[4-(Amino-phenylcarbamoylimino-methyl)-phenylamino]-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester as a colorless foam. MS: 539 ([M+H]+).
Reaction SMILES: Br[CH2:2][C:3]1([CH2:26][OH:27])[O:7][N:6]=[C:5]([C:8]2[C:9]([NH:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:10]3[CH:16]=[N:15][N:14]([CH2:17][CH3:18])[C:11]3=[N:12][CH:13]=2)[CH2:4]1.O.[OH-].[K+]>C(O)C>[CH:20]1([NH:19][C:9]2[C:10]3[CH:16]=[N:15][N:14]([CH2:17][CH3:18])[C:11]=3[N:12]=[CH:13][C:8]=2[C:5]2[CH2:4][C:3]3([CH2:26][O:27][CH2:2]3)[O:7][N:6]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCn1ncc2c(NC3CCCCC3)c(C3=NOC(CO)(CBr)C3)cnc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCn1ncc2c(NC3CCCCC3)c(C3=NOC4(COC4)C3)cnc21
Yield: 28 %

Procedure:
{5-(Bromomethyl)-3-[4-(cyclohexylamino)-1-ethyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-4,5-dihydroisoxazol-5-yl}methanol (110 mg, 0.00025 mole) (example 20) was dissolved in ethanol (10 ml). Water (2 ml) was added followed by potassium hydroxide (20 mg, 0.00050 mole). The reaction mixture was stirred at refluxing temperature overnight. The solvent was removed under reduced pressure. Water was added and the mixture was extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulphate and concentrated in vacuo. The crude product obtained was purified by column chromatography.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[Cu][C:14]#[N:15]>COCCOC.CCCCCC.CCOC(C)=O.O>[C:14]([C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1)#[N:15]
Reactant: COC(=O)c1ccc(Br)cc1F
Reactant: N#C[Cu]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C#N)cc1F
Temperature: 25 °C
Yield: 75.3 %

Procedure:
Slurry methyl 4-bromo-2-fluoro-benzoate (5 g, 21.5 mmol) and copper(I) cyanide (3.8 g, 42.9 mmol) in anhydrous DME (90 mL). Heat the mixture to reflux for 20 h under a nitrogen atmosphere. Cool the mixture to room temperature, dilute with hexane/EtOAc (1:1, 300 mL) and water (150 mL). Filter the mixture through Celite® washing with hexane/EtOAc (1:1) to reduce the emulsion layer. Separate the organic layer and extract the aqueous layer with hexane/EtOAc (1:1, 2×200 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1 gradient) to obtain the desired intermediate (2.9 g, 76%). GC-MS m/z: 179 (M+).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:9])[O:4][CH:5](O)[C:6]=1[Br:7].[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Al+3].[Cl-].[Cl-].[Cl-]>>[Br:1][C:2]1[C:3](=[O:9])[O:4][CH:5]([C:13]2[CH:14]=[CH:15][C:10]([CH3:16])=[CH:11][CH:12]=2)[C:6]=1[Br:7]
Reactant: O=C1OC(O)C(Br)=C1Br
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C2OC(=O)C(Br)=C2Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3,4-dibromo-5-hydroxyfuran-2(5H)-one (0.5 g, 1.939 mmol) in toluene (5 mL, 1.939 mmol) was added AlCl3 (0.310 g, 2.327 mmol) at room temperature. The mixture was stirred at room temperature overnight. The reaction was quenched with water, extracted with EtOAc (3×20 mL), dried over anhydrous MgSO4, and filtered. The filtrate was concentrated under reduced pressure to give the title compound without further purification. LCMS m/z=332.8 [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1([N:11]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([N:20]3[CH2:23][CH:22]([O:24][C:25]4[CH:26]=[CH:27][C:28]([C:31]([CH3:37])([CH3:36])[C:32](OC)=[O:33])=[N:29][CH:30]=4)[CH2:21]3)=[O:19])[CH2:13][CH2:12]2)[CH2:10][CH2:9][CH2:8]1>C1COCC1>[CH:7]1([N:11]2[CH2:17][CH2:16][CH2:15][N:14]([C:18]([N:20]3[CH2:21][CH:22]([O:24][C:25]4[CH:26]=[CH:27][C:28]([C:31]([CH3:37])([CH3:36])[CH2:32][OH:33])=[N:29][CH:30]=4)[CH2:23]3)=[O:19])[CH2:13][CH2:12]2)[CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)C(C)(C)c1ccc(OC2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccc(OC2CN(C(=O)N3CCCN(C4CCC4)CC3)C2)cn1
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
To a 0° C. solution of LiAlH4 (0.56 ml, 0.562 mmol, 1M in THF) in THF (1 ml) under a nitrogen atmosphere was added methyl 2-[5-({1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-yl}oxy)pyridin-2-yl]-2-methylpropanoate (110 mg, 62% UV purity) in THF (1 ml). TLC analysis of the reaction mixture after 30 minutes indicated complete consumption of starting material. Water (1 ml), 2M NaOH (1 ml), and water (1 ml) were cautiously added to the reaction mixture. The mixture was diluted with EtOAc (20 ml), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by FCC on silica gel [eluting with 5% methanolic ammonia (7N) in DCM] to provide the title compound as colourless oil (34.5 mg).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([C:17]([F:20])([F:19])[F:18])=[CH:12][CH:13]=2)[N:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[N:23]=2)[CH:7]=1)=[O:5].[F:30][C:31]1[CH:32]=[C:33]([Mg]Cl)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38]>C1COCC1>[Br:28][C:24]1[N:23]=[C:22]([CH2:21][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[C:11]([C:17]([F:20])([F:19])[F:18])[N:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:33]3[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:31]([F:30])[CH:32]=3)=[CH:7]2)[CH:27]=[CH:26][CH:25]=1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2nc(C(F)(F)F)ccc2c1=O
Reactant: COc1ccc([Mg]Cl)cc1F
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3nc(C(F)(F)F)ccc3c2=O)cc1F

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 80 mg of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid methoxy-methyl-amide, 2 mL of THF was treated with 3-fluoro-4-methoxyphenyl magnesium chloride (0.5 M in THF, 1.3 mL, 2 equiv) at rt for 2 h. The reaction was quenched by slow addition of saturated aqueous ammonium chloride. The mixture was subjected to HPLC and then preparative TLC purification to give 1-(6-Bromo-pyridin-2-ylmethyl)-3-(3-fluoro-4-methoxy-benzoyl)-7-trifluoromethyl-1H-[1,8]naphthyridin-4-one. LCMS (ES) M+H 536.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4](I)[C:3]=1[OH:10].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[CH:20])=[CH:15][CH:14]=1.O>CN(C=O)C.C(NCC)C.[Cu]I>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]2[O:10][C:19]([C:16]3[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=3)=[CH:20][C:4]=2[CH:5]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: Oc1c(Cl)cc(Cl)cc1I
Agent: [Cu]I
Solvent: O
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COc1ccc(-c2cc3cc(Cl)cc(Cl)c3o2)cc1
Reaction time: 1 h
Yield: 39.6 %

Procedure:
A solution of 2,4-Dichloro-6-iodo-phenol [2040-83-7] (2.0 g, 6.9 mmol), 4-Methoxyphenylacetylene (0.91 g, 6.9 mmol), PdCl2P(PH3)2 (0.15 g), and CuI (50 mg) in DMF/Diethylamine (20 ml) was heated to 60° C. After 1 hr, the reaction was cooled and poured into water which was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated to give a solid which was triturated with MeOH, filtered to give 85 as a solid (0.80 g, 42%): Mp=172-174° C.; 1H NMR (CDCl3) δ 7.82 (d, 2 H, J=8.1 Hz), 7.41 (d, 1 H, J=1.8 Hz), 7.24 (d, 1 H, J=1.9 Hz), 7.00 (d, 2 H, J=8.8 Hz), 6.84 (s, 3 H), 3.87 (s, 3 H); MS 293/295 [M+H]+
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][C@H:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:35]=[CH:34][C:33]([C:36]([OH:38])=O)=[C:32]([F:39])[CH:31]=1)[CH3:22])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.[Br:47][C:48]1[CH:66]=[N:65][C:51]2[O:52][C:53]([CH3:64])([CH3:63])[C:54](=[O:62])[N:55]([CH:56]3[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]3)[C:50]=2[CH:49]=1>>[Br:47][C:48]1[CH:66]=[N:65][C:51]2[O:52][C:53]([CH3:63])([CH3:64])[C:54](=[O:62])[N:55]([CH:56]3[CH2:57][CH2:58][N:59]([C:36]([C:33]4[CH:34]=[CH:35][C:30]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=5[O:23][C@H:21]([CH3:22])[CH2:20][CH2:19][OH:18])=[CH:31][C:32]=4[F:39])=[O:38])[CH2:60][CH2:61]3)[C:50]=2[CH:49]=1
Reactant: C[C@H](CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)Oc1ccccc1-c1ccc(C(=O)O)c(F)c1
Reactant: CC1(C)Oc2ncc(Br)cc2N(C2CCNCC2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CCO)Oc1ccccc1-c1ccc(C(=O)N2CCC(N3C(=O)C(C)(C)Oc4ncc(Br)cc43)CC2)c(F)c1

Procedure:
In accordance with the methods of Examples 13-4 and 5-5, the compound of Example 5-3 was used instead of the compound of Example 13-3, and the compound of Example 52-2 was used instead of the compound of Reference Example 3 to afford 7-bromo-1-{1-[(3-fluoro-2′-{[(1R)-3-hydroxy-1-methylpropyl]oxy}biphenyl-4-yl)carbonyl]piperidin-4-yl}-3,3-dimethyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:12][N:13]([CH:15](OC)OC)[CH3:14]>CN(C=O)C>[CH3:12][N:13]([CH3:15])/[CH:14]=[CH:10]/[C:9](=[O:11])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)CCc1ccccc1
Solvent: CN(C)C=O
Product: CN(C)/C=C/C(=O)CCc1ccccc1
Yield: 36.9 %

Procedure:
A solution of 4-phenylbutan-2-one (3.96 g, 20 mmol) and DMF-DMA (2.4 g, 20 mmol) in DMF (10 mL) was stirred at 100° C. overnight. The reaction mixture was cooled, concentrated, and purified by silica gel column (PE/EA=4:1˜2:1) to give the title compound (1.5 g, 37%) as a yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5](Cl)=[O:6])[CH:3]=1.[CH:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>[Fe](Cl)Cl>[C:4]1([C:5]([C:2]2[CH:10]=[CH:9][CH:8]=[CH:4][CH:3]=2)=[O:6])[CH:8]=[CH:9][CH:10]=[C:2]([C:1]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])[CH:3]=1
Reactant: c1ccccc1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Agent: Cl[Fe]Cl
Product: O=C(c1ccccc1)c1cccc(C(=O)c2ccccc2)c1

Procedure:
To a mechanically stirred, 600 mL autoclave is added 1 mole of isophthaloyl dichloride, 10 moles of benzene and 2% iron chloride, based on the amount of isophthaloyl dichloride. The reactor is closed and the temperature of the reaction zone is elevated to 200° C. The reaction goes to completion in approximately 4 to5 hours with a quantitative yield of 1,3-phenylene-bis(phenyl methanone). The maximum pressure experienced during the reaction was 300 psig.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([O:24][CH:25]([CH3:27])[CH3:26])[C:21]=1[O:22][CH3:23])[C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[C:10]([CH3:18])[CH:9]=1)=[O:6]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([O:24][CH:25]([CH3:27])[CH3:26])[C:21]=1[O:22][CH3:23])[C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[C:10]([CH3:18])[CH:9]=1)=[O:6]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(OC)c(OC(C)C)c2)cc1C
Solvent: CO
Product: COc1c(Cl)cc(C(=O)Nc2ccc(C(=O)O)c(C)c2)cc1OC(C)C
Temperature: 40 °C
Reaction time: 18 h
Yield: 6.1 %

Procedure:
4-(3-Chloro-5-isopropoxy-4-methoxybenzamido)-2-methylbenzoic acid (AAA-075) (94 mg, 57%) was prepared from methyl 4-(3-chloro-5-isopropoxy-4-methoxybenzamido)-2-methylbenzoate (7) (167 mg, 4.10 mmol) using a procedure essentially the same as in step (ii) for AAA-001 except that MeOH was added dropwise until a solution formed and the mixture was stirred at 40° C. for 18 h: m/z 378 [M+H]+ (ES+), 376 [M−H]− (ES−). 1H NMR (400 MHz, DMSO-d6) δ:12.63 (1H, br s), 10.34 (1H, s), 7.86 (1H, d), 7.75-7.63 (3H, m), 7.57 (1H, d), 4.77 (1H, sep), 3.83 (3H, s), 2.53 (3H, s), 1.34 (6H, d).
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[CH:7][N:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39](O)=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[N:5]=1)([CH3:3])[CH3:2].[CH:47]1([S:50]([NH2:53])(=[O:52])=[O:51])[CH2:49][CH2:48]1.ClC1C(OC)=CC=C2C=1N=C(C1SC=C(C(C)C)N=1)C=C2OC1CC2C(C(=O)N(C)CCCCC=CC3C(C(NS(C4CC4)(=O)=O)=O)(NC2=O)C3)C1>>[CH:1]([C:4]1[CH:8]=[CH:7][N:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:37][CH:36]4[CH:22]([C:23](=[O:43])[N:24]([CH3:42])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][CH:31]5[C:33]([C:39]([NH:53][S:50]([CH:47]6[CH2:49][CH2:48]6)(=[O:52])=[O:51])=[O:40])([NH:34][C:35]4=[O:38])[CH2:32]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-n3ccc(C(C)C)n3)nc2c1C
Agent: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3nc(C(C)C)cs3)nc2c1Cl
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-n3ccc(C(C)C)n3)nc2c1C

Procedure:
The title compound was prepared from 17-[2-(3-isopropylpyrazol-1-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (65) and cyclopropylsulfonamide following the procedure reported for the preparation of N-[17-[8-chloro-2-(4-isopropylthiazole-2-yl)-7-methoxyquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]-octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (56): m/z=733 (M+H)+. 1H NMR (CDCl3): 0.80-1.50 (m, 12H), 1.65-1.78 (m, 1H), 1.79-2.05 (m, 4H), 2.15-2.31 (m, 1H), 2.32-2.48 (m, 2H), 2.49-2.63 (m, 5H), 2.84-2.96 (m, 2H), 3.03 (s, 3H), 3.05-3.14 (m, 1H), 3.33-3.42 (m, 2H), 3.61-3.70 (m, 1H), 3.96 (s, 3H), 4.60 (t, J=12.3 Hz, 1H), 5.04 (t, J=10.6 Hz, 1H), 5.26-5.46 (m, 1H), 5.61-5.69 (m, 1H), 6.32 (d, J=2.5 Hz, 1H), 6.37 (br s, 1H), 7.13 (d, J=9.0 Hz, 1H), 7.30 (s, 1H), 7.95 (d, J=9.0 Hz, 1H), 8.68 (d, J=2.5 Hz, 1H), 10.88 (br s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:11]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.FC1C=C([B:27]2[O:31][C:30]([CH3:33])([CH3:32])[C:29]([CH3:35])([CH3:34])[O:28]2)C=CC=1NC1OC2C=CC=CC=2N=1>>[CH3:34][C:29]1([CH3:35])[C:30]([CH3:33])([CH3:32])[O:31][B:27]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]3[O:10][C:11]4[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:12]=4[N:13]=3)=[CH:4][CH:3]=2)[O:28]1
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4o3)c(F)c2)OC1(C)C
Reactant: Cc1cc(C)c2oc(Nc3ccc(Br)cc3)nc2c1
Product: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1

Procedure:
N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5,7-dimethyl-1,3-benzoxazol-2-amine was prepared from N2-(4-bromophenyl)-5,7-dimethyl-1,3-benzoxazol-2-amine (1.215 g, 3.831 mmol) in a manner similar to that used for the preparation of N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazol-2-amine. The compound was formed as a tan powder (0.880 g, 63%). RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) Rt=14.48 min, 81%; m/z 365 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[C:13](=[O:15])=[O:14].C(OCC)C>O1CCCC1>[CH3:1][O:2][C:3]1[S:4][C:5]([C:13]([OH:15])=[O:14])=[CH:6][CH:7]=1
Reactant: COc1cccs1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Methoxythiophene (4.0 ml) was dissolved in tetrahydrofuran (50 ml), and the mixture was cooled to -78° C. n-Butyllithium (1.6M in hexane, 31 ml) was slowly added dropwise, and the mixture was stirred at the same temperature for 1 hour. The mixture was poured into a mixture of dry ice and diethyl ether, and warmed to room temperature with stirring. The solvent was distilled off, and the residue was acidified with 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-methoxy-2-thiophenecarboxylic acid (5.62 g).