Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:28][CH2:27][C:26]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)([NH2:29])[CH2:25][CH2:24]3)=[O:22])[C:9]=2[CH3:36])=[CH:4][CH:3]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([N:23]3[CH2:24][CH2:25][C:26]([NH:29][C:37](=[O:39])[CH3:38])([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:27][CH2:28]3)=[O:22])[C:9]=2[CH3:36])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C(=O)N2CCC(N)(c3ccccc3)CC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)NC1(c2ccccc2)CCN(C(=O)c2nn(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)c2C)CC1
Yield: 71 %

Procedure:
1-{[5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-amine (1 eq, 35.3 mg, 0.066 mmol) was stirred in a mixture of acetic anhydride (2 mL) and pyridine (2 mL) for 16 h. The reaction was concentrated in vacuo. The crude reaction material was then purified by silica gel column chromatography using 0-100% ethyl acetate/hexane to yield pure N-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-yl)acetamide (27 mg, 71%). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.01 (s, 3H) 2.05-2.19 (m, 2H) 2.21 (s, 3H) 2.34 (d, J=14.60 Hz, 1H) 2.66 (d, J=13.85 Hz, 1H) 3.15-3.34 (m, 1H) 3.52 (t, J=11.68 Hz, 1H) 4.26 (d, J=13.75 Hz, 1H) 4.54 (d, J=13.75 Hz, 1H) 6.10 (s, 1H) 7.03-7.11 (m, 2H) 7.14-7.19 (m, 1H) 7.19-7.41 (m, 8H) 7.44 (d, J=2.17 Hz, 1H).
Reaction SMILES: [CH:1]([C:4]1[C:13]([CH:14]([CH3:16])[CH3:15])=[N:12][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]=1)([CH3:3])[CH3:2].[OH2:17]>C(O)(=O)C>[CH:1]([C:4]1[C:13]([CH:14]([CH3:16])[CH3:15])=[N:12][C:11]2[CH2:10][CH2:9][CH2:8][C:7](=[O:17])[C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(nc1C(C)C)CCCC2
Reactant: O
Solvent: CC(=O)O
Product: CC(C)c1nc2c(nc1C(C)C)C(=O)CCC2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
1.5 g of 5,6,7,8-tetrahydro-2,3-diisopropylquinoxaline was dissolved in 10 ml of acetic acid, followed by the dropwise addition of a solution of 1.0 g of chromic acid anhydride in acetic acid (6 ml)/water (1 ml). The obtained mixture was stirred at 80° C. for 2 hours, cooled by allowing to stand, and poured into water, followed by the extraction with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate, and concentrated in a vacuum. The obtained residue was purified by silica gel chromatography (developer: 10% ethyl acetate/hexane) to give 0.6 g of the title compound as a brown solid.
Reaction SMILES: [CH3:1][N:2]1[CH:11]2[C:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH2:19]1[O:27][C:26]2[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=2[O:20]1.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:24]4[CH:23]=[CH:22][C:21]5[O:20][CH2:19][O:27][C:26]=5[CH:25]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: CN1C(=O)CCC2(C)c3ccc(Br)cc3CCC12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc5c(c4)OCO5)cc3CC[C@@H]12
Yield: 57.2 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)- 10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a, 5,6,10b-octahydrobenzo[f]quinolin-3-one 200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 3,4-methylenedioxyphenyl boronic acid (131 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 130 mg (57%) of the title compound as an amorphous solid. mp 146°-152° FDMS: m/e=349. α[D]589 =+67.92 (c=1.06, chloroform).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C@H:16]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][N:26]([CH3:28])[CH3:27])[CH2:21][CH2:20]1)=[O:18])C)(C)(C)C>ClCCl>[CH3:27][N:26]([CH2:25][CH:22]1[CH2:23][CH2:24][N:19]([C:17](=[O:18])[C@H:16]([NH:14][CH3:13])[CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:20][CH2:21]1)[CH3:28]
Reactant: CN(C)CC1CCN(C(=O)[C@@H](Cc2ccccc2)N(C)C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccccc1)C(=O)N1CCC(CN(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
At 0° C., trifluoroacetic acid (20 ml) was added to a solution of N-[(1R)-1-benzyl-2-(4-((dimethylamino)methyl)piperidin-1-yl)-2-oxoethyl]-N-methylcarbamic acid tert-butyl ester (1.22 g, 3.02 mmol) in dichloromethane (20 ml). The reaction mixture was stirred for 1 h at 0° C. The solvents were removed in vacuo. The residue was dissolved in dichloromethane (70 ml) and the solvent was removed in vacuo. The latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (100 g), using dichloromethane/methanol/25% aqueous ammonia (100:10:1), to give 659 mg of (2R)-1-(4-((dimethylamino)methyl)piperidin-1-yl)-2-(methylamino)-3-phenylpropan-1-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[C:12]([C:17]([O:19][CH3:20])=[O:18])[C:13](=[O:16])[NH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:14]2[C:13](=[O:16])[C:12]([C:17]([O:19][CH3:20])=[O:18])=[CH:11][C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)=[N:15]2)=[CH:24][CH:23]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(Cc2ccc(Cl)cc2)c1=O
Yield: 97.6 %

Procedure:
Following the procedure of Example 1(6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-chlorobenzyl chloride were reacted to yield the title compound as yellow needles (yield: 97.6%).
Reaction SMILES: [NH:1]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:13][C:14]([CH3:20])([CH3:19])[CH2:15][C:16](Cl)=[O:17]>>[CH3:13][C:14]([CH3:20])([CH3:19])[CH2:15][C:16]([N:1]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:17]
Reactant: C1COCCOCCOCCN1
Reactant: CC(C)(C)CC(=O)Cl
Product: CC(C)(C)CC(=O)N1CCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1-aza-4,7,10-trioxacyclododecane and 3,3-dimethylbutyryl chloride.
Reaction SMILES: CO.Cl.C(OCC)(=O)C.[CH2:10]([O:17][C:18]([NH:20][C@H:21]1[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=[O:28])[CH2:23][C@H:22]1[O:34][CH3:35])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl:36][CH2:37]C(Cl)=O>C(Cl)Cl.C(OCC)(=O)C>[Cl:36][CH2:37][C:27]([N:24]1[CH2:25][CH2:26][C@H:21]([NH:20][C:18](=[O:19])[O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C@H:22]([O:34][CH3:35])[CH2:23]1)=[O:28]
Reactant: CO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCOC(C)=O
Product: CO[C@@H]1CN(C(=O)CCl)CC[C@@H]1NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanol (10 ml), ethyl acetate (10 ml) and a 4 N hydrochloric acid/ethyl acetate solution (30 mL) were added to tert-butyl cis(±)-4-{[(benzyloxy)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained in Example (40a) (1.88 g, 5.16 mmol), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, azeotropically dehydrated by adding toluene, and dissolved in methylene chloride (100 ml), followed by adding diisopropylethylamine (2.1 g). Chloroacetyl chloride (640 mg, 5.68 mmol) was dissolved in methylene chloride (50 ml), and the solution was added dropwise at 0° C. Following the dropwise addition, the mixture was stirred at 0° C. to room temperature overnight. The reaction solution was washed with water and aqueous sodium bicarbonate, concentrated under reduced pressure, and then azeotropically dehydrated by adding toluene to obtain the title compound. Half of the resulting compound was used for the next reaction without purification.
Reaction SMILES: Cl[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[CH3:14])=[N:5][S:4][N:3]=1.[BH4-].[Li+]>C1COCC1>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[CH:2]=[N:3][S:4][N:5]=2)=[C:8]([CH3:14])[CH:9]=1
Reactant: Cc1cc(Cl)ccc1-c1nsnc1Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1-c1cnsn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 3-chloro-4-(4-chloro-2-methylphenyl)-1,2,5-thiadiazole (0.503 g, 2.05 mmol) in THF (5.0 mL) was added 2 M lithium borohydride in THF (2.05 mL, 4.10 mmol). The reaction was stirred at ambient temperature for 15 min then was quenched with water and extracted into EtOAc. The organic phase was dried (Na2SO4) and reduced in vacuo. The residue was purified by flash chromatography (eluting with CH2Cl2/hexanes gradient, 1–15% CH2Cl2). 3-(4-Chloro-2-methylphenyl)-1,2,5-thiadiazole was isolated as a solid. 1H NMR (CDCl3, 400 MHz) δ 2.49 (s, 3H), 7.30 (d, J=8.2 Hz, 2H), 7.34 (s, 1H), 7.53 (d, J=8.2 Hz, 1H), 8.71 (s, 1H); MS m/z=211.4.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]3[S:22][N:21]=[CH:20][N:19]=3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3]1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][C:35](O)=[O:36])[CH:28]=[CH:27]2.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CC#N.CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][C:35]([N:7]1[CH2:6][CH2:5][N:4]([C:8]3[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]4[S:22][N:21]=[CH:20][N:19]=4)(=[O:16])=[O:15])=[CH:10][CH:9]=3)[CH2:3][CH:2]1[CH3:1])=[O:36])[CH:28]=[CH:27]2
Reactant: CC1CN(c2ccc(S(=O)(=O)Nc3ncns3)cc2)CCN1
Reactant: O=C(O)CCn1ccc2cc(Cl)ccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: CC1CN(c2ccc(S(=O)(=O)Nc3ncns3)cc2)CCN1C(=O)CCn1ccc2cc(Cl)ccc21

Procedure:
Synthesized according to general procedure 9, method A. The reaction was set up with 4-(3-methylpiperazin-1-yl)-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide, (35 mg, 0.10 mmol) 3-(5-chloro-1H-indol-1-yl)propanoic acid (25 mg, 0.10 mmol), BOP reagent (46 mg, 0.10 mmol), triethylamine (14 μL, 0.10 mmol), and DMF (300 μL). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=545.0; tR=3.25 min.
Reaction SMILES: [CH3:1][C:2]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH3:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1
Reactant: Cc1c([N+](=O)[O-])ccc2c1cnn2C1CCCCO1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1c(N)ccc2c1cnn2C1CCCCO1
Yield: 101.7 %

Procedure:
To a solution of 4-methyl-5-nitro-1-tetrahydro-2H-pyran-2-yl-1H-indazole (1.06 g, 4.06 mmol) in ethanol (20 ml) were added 10% Pd—C (200 mg) and ammonium formate (1.28 g, 20.3 mmol), and the resulting mixture was heated under reflux for 1 hour. After the solid was removed by filtration using Celite, water, ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution were added to the residue. The resulting mixture was extracted with ethyl acetate, and the extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby 4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine (955 mg, 100%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[N:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([O:29][CH3:30])[N:22]=2)[C:3]=1[C:4](OC1C=CC([N+]([O-])=O)=CC=1)=[O:5].[CH3:31][S:32]([NH2:35])(=[O:34])=[O:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3]([C:4]([NH:35][S:32]([CH3:31])(=[O:34])=[O:33])=[O:5])=[C:16]([CH:17]=[CH:18][CH:19]=1)[O:20][C:21]1[N:26]=[C:25]([O:27][CH3:28])[N:24]=[C:23]([O:29][CH3:30])[N:22]=1
Reactant: COc1nc(OC)nc(Oc2cccc(Cl)c2C(=O)Oc2ccc([N+](=O)[O-])cc2)n1
Reactant: CS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1nc(OC)nc(Oc2cccc(Cl)c2C(=O)NS(C)(=O)=O)n1

Procedure:
This compound is prepared in a manner analogous to that of Example 1, Step I, using equimolar amounts of 4-nitrophenyl 2-chloro-6-(4,6-dimethoxy-1,3,5-triazin-2-yloxy)benzoate, methanesulfonamide, and potassium carbonate in acetonitrile to yield 2-[3-chloro-2-(methylsulfonylaminocarbonyl)phenoxy]-4,6-dimethoxy-1,3,5-triazine, Compound 38 of Table 1.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([NH:10][C@H:11]([CH2:13][CH3:14])[CH3:12])[N:7]=[C:6]([C:15](=[O:17])[CH3:16])[CH:5]=1.[OH-].[Li+].Cl>C1COCC1>[C:15]([C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([NH:10][C@H:11]([CH2:13][CH3:14])[CH3:12])[N:7]=1)[C:3]([OH:18])=[O:2])(=[O:17])[CH3:16]
Reactant: CC[C@H](C)Nc1cc(C(=O)OC)cc(C(C)=O)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC[C@H](C)Nc1cc(C(=O)O)cc(C(C)=O)n1
Yield: 96 %

Procedure:
Dissolve 2-acetyl-(S)-6-sec-butylamino-isonicotinic acid methyl ester (60 mg, 0.24 mmol) in THF (3 mL). Slowly add 1 N lithium hydroxide (0.3 mL) and stir overnight at room temperature. Acidify the mixture to about pH=6 by 5 N HCl and concentrate to near dryness. Dilute with ethyl acetate (15 mL) and wash the organic layer with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give the title compound as a solid (96%).
Reaction SMILES: C([O:5][C:6]([C:8]1([CH2:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])(C)(C)C.OS(O)(=O)=O>CC(O)=O>[CH2:18]([CH:15]([CH2:16][CH3:17])[CH2:14][C:8]1([C:6]([OH:7])=[O:5])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1)[CH3:19]
Reactant: CCC(CC)CC1(C(=O)OC(C)(C)C)CCCCC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCC(CC)CC1(C(=O)O)CCCCC1
Temperature: 95 °C
Reaction time: 18 h
Yield: 88.5 %

Procedure:
To a stirred solution of 1-(2-Ethyl-butyl)-cyclohexanecarboxylic acid t-butyl ester (2.0 g, 7.45 mmol) in AcOH (6 mL) 4M H2SO4 (0.6 mL, 2.4 mmol) was added dropwise at 95° C. After 18 h at this temperature, another portion of AcOH (4 mL) and 4M H2SO4 (0.6 mL, 2.4 mmol) was added and stirring at 95° C. was continued for 4 h. Then the reaction was complete according to GC. The reaction mixture was concentrated and then worked up by extraction to afford 1.4 g (88%) 1-(2-ethyl-butyl)-cyclohexanecarboxylic acid, purity 99% (GC area).
Reaction SMILES: C[O:2][C:3]1[C:4](=[O:15])[NH:5][C:6]2[CH2:14][CH2:13][CH2:12][CH2:11][C:7]=2[C:8](=[O:10])[CH:9]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[C:4](=[O:15])[NH:5][C:6]2[CH2:14][CH2:13][CH2:12][CH2:11][C:7]=2[C:8](=[O:10])[CH:9]=1
Reactant: COc1cc(=O)c2c([nH]c1=O)CCCC2
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1cc(O)c(=O)[nH]c2c1CCCC2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred suspension of 3-methoxy-6,7,8,9-tetrahydro-1H-1-benzazepine-2,5-dione (207 mg, 1.00 mol) in dry CH2Cl2 (2 mL, distilled from CaH2) under N2, there was added a solution of BBr3 in CH2Cl2 (2.0 mL, 1M, Aldrich) in one portion over 5 seconds at rt. A brown precipitate immediately formed. The reaction was allowed to stir under N2 at rt for 45 min. The reaction was added to saturated NaHCO3 (15 mL) and the resulting orange solution was allowed to stir for 15 min. The solution was extracted with CH2Cl2 (1×4 mL). The aqueous solution was acidified with concd HCl (pH 2), the resulting precipitate collected by filtration and washed to neutrality with water (6×2 mL). Crystallization from 95% EtOH yielded beige flakes (115 mg, 60%, pure by TLC, 1H NMR and C,H,N analysis); mp 237°-238° C. (dec.); 1H NMR (DMSO-d6) δ1.55 (m, 4H), 2.27 (m, 2H), 2.45 (m, 2H), 6.30 (s, 1H), 10.14 (bs, 1H), 10.84 (s, 1H). Anal. Calcd for C10H11NO3 : C, 62.17; H, 5.74; N, 7.25. Found: C, 62.23; H, 5.62; N, 7.26.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].O.O1CCOCC1.[C:16]1(=[O:31])[C:29]2[C:20](=[CH:21][C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:19](=[O:30])[CH:18]=[CH:17]1>O>[OH:30][C:19]1[C:20]2[C:29](=[CH:28][C:27]3[C:22]([CH:21]=2)=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:16]([OH:31])=[CH:17][CH:18]=1
Reactant: O=C1C=CC(=O)c2cc3ccccc3cc21
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Oc1ccc(O)c2cc3ccccc3cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.4 %

Procedure:
A solution of sodium hydrosulfite (16.70 g, 42.0 mmol, 1 molar equivalent) in a water/dioxane (3/2) (250 mL) mixture is added under nitrogen to the 1,4-anthracenedione 1a (5.00 g, 24.0 mmol, 1 molar equivalent). The resulting mixture is stirred at room temperature for 3 h. Water is added and the resulting precipitate is filtered, washed with water and dried under vacuum to give the title compound as a yellow powder (3.10 g, 61%). 1H NMR (300.13 MHz, THF-d8) (ppm) 6.53 (s, 2H) 7.34-7.40 (m, 2H) 7.96-7.99 (m, 2H) 8.65 (s, 2H) 8.70 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]([O:13]CC)=[CH2:12])=[C:9]([NH2:16])[N:8]=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH3:25])[C:18]=2[F:26])[N:6]=1)=[O:4].Cl>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[C:10]([C:11](=[O:13])[CH3:12])=[C:9]([NH2:16])[N:8]=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24][CH3:25])[C:18]=2[F:26])[N:6]=1)=[O:4]
Reactant: C=C(OCC)c1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1C(C)=O
Yield: 94.1 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-(1-ethoxy-vinyl)pyrimidine-4-carboxylic acid methyl ester (0.235 g, 0.616 mmol) was dissolved in THF (5 mL) and 2N HCl (0.616 mL, 1.231 mmol) and stirred at ambient temperature for 3 h. The reaction mixture was concentrated, triturated with water, and filtered. The product was washed with methanol and dried under vacuum to yield the title compound (0.205 g, 94% yield): 1H NMR (DMSO-d6) δ 7.7 (br s, 2H), 7.63 (dd, 1H), 7.42 (dd, 1H), 3.92 (s, 3H), 3.85 (s, 3H), 2.46 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:6][C:7]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][C:10]=2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([O:28][CH2:29][C:30]([O:32]CC)=[O:31])[CH:22]=[CH:21]3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+]>C1COCC1.O>[CH:1]1([CH2:6][C:7]([C:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][C:10]=2[C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[C:23]([O:28][CH2:29][C:30]([OH:32])=[O:31])[CH:22]=[CH:21]3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)COc1ccc2cc(-c3oc4ccccc4c3C(=O)CC3CCCC3)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc2cc(-c3oc4ccccc4c3C(=O)CC3CCCC3)ccc2c1
Yield: 58.8 %

Procedure:
Following the procedure described in Step 4 of Example 6, ethyl 2-({6-[3-(2-cyclopentylacetyl)-1-benzofuran-2-yl]-2-naphthyl}oxy)acetate (0.324 g, 0.710 mmol), was hydrolyzed with potassium hydroxide (0.120 g, 2.14 mmol) in THF (5 mL) and water (5 mL). Crystallization from acetonitrile yielded the title compound as a cream-colored solid (0.179 g), mp 177-178° C. Mass spectrum (−ESI, [M−H]−) m/z 427; 1HNMR (500 MHz, DMSO-d6): δ12.9-13.4 (br s, 1H), 8.35 (d, 1H, J=1.1 Hz), 7.95-8.05 (m, 3H), 7.8 (dd, 1H, J=8.5 and 1.8 Hz), 7.7 (d, 1H, J=7.6 Hz), 7.4-7.45 (m, 3H), 7.3 (dd, 1H, J=8.9 Hz and 2.5 Hz), 4.85 (s, 2H), 2.75 (d, 2H, J=7.0 Hz), 2.15-2.25 (m, 1H), 1.6-1.65 (m, 2H), 1.35-1.45 (m, 4H), and 0.95-1.0 ppm (m, 2H). Elemental Analysis for C27H24O5: Calculated: C, 75.68; H, 5.65; N, 0.00. Found: C, 75.38; H, 5.46; N, 0.02.
Reaction SMILES: C[O:2][C:3](=[O:35])[CH:4]([CH2:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]1)[CH2:5][CH2:6][NH:7][C@@H:8]1[C@@H:17]([O:18][CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:20](=[O:22])[NH2:21])=[CH:13][CH:14]=2)[C:9]1([CH2:25][CH3:26])[CH2:23][CH3:24].O.[OH-].[Na+]>CO.CC(O)=O>[C:20]([C:12]1[CH:11]=[C:10]2[C:15]([CH2:16][C@H:17]([O:18][CH3:19])[C@@H:8]([NH:7][CH2:6][CH2:5][CH:4]([CH2:27][C@H:28]3[CH2:33][CH2:32][C@H:31]([OH:34])[CH2:30][CH2:29]3)[C:3]([OH:35])=[O:2])[C:9]2([CH2:23][CH3:24])[CH2:25][CH3:26])=[CH:14][CH:13]=1)(=[O:22])[NH2:21]
Reactant: CCC1(CC)c2cc(C(N)=O)ccc2C[C@H](OC)[C@H]1NCCC(C[C@H]1CC[C@H](O)CC1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: CCC1(CC)c2cc(C(N)=O)ccc2C[C@H](OC)[C@H]1NCCC(C[C@H]1CC[C@H](O)CC1)C(=O)O
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of 4-((2S,3S)-7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-2-(trans-4-hydroxy-cyclohexylmethyl)-butyric acid methyl ester (f1) (27.4 mg, 0.045 mmol) in MeOH (0.50 mL) was added water (32 μL) and 10N NaOH (32 μL, 0.32 mmol). The mixture was heated at 50° C. After 15 h, the reaction mixture was cooled to RT, dissolved in 50% aqueous AcOH (6 mL) and purified by preparative HPLC to give the title compound (13.8 mg) as a lyophylized powder. (m/z): [M+H] calcd for C27H42N2O5 475.32. found 475.2. 1H NMR (CD3OD, 400 mHz) δ (ppm) 7.78 (d, J=1.6 Hz, 1H), 7.72 (dd, J=8.0 Hz, 1.7 Hz, 1H), 7.28 (d, J=8.2 Hz, 1H), 4.09 (m, 1H), 3.57 (dd, J=16.7, 5.9 Hz, 1H), 3.52 (s, 3H), 3.52-3.42 (m, 3H), 3.23 (m, 1H), 2.78 (m, 1H), 2.58 (m, 1H), 2.31 (m, 1H), 2.05-1.60 (m, 10H), 1.40-1.15 (m, 4H), 1.00 (m. 2H), 0.79 (t, J=7.5 Hz, 3H), 0.70 (dt, J=7.3, 1.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]([C@H:24]5[CH2:29][CH2:28][NH:27][CH2:26][C@H:25]5[F:30])[CH3:23])=[N:19][C:18]4=[O:31])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:34]([F:37])([F:36])[F:35])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:45][C:46]([NH2:48])=[O:47]>CN(C=O)C>[Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]([CH3:23])[C@H:24]5[CH2:29][CH2:28][N:27]([CH2:45][C:46]([NH2:48])=[O:47])[CH2:26][C@H:25]5[F:30])=[N:19][C:18]4=[O:31])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:34]([F:36])([F:37])[F:35])[CH:3]=1
Reactant: NC(=O)CBr
Reactant: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1)[C@H]1CCNC[C@H]1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1)[C@H]1CCN(CC(N)=O)C[C@H]1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.7 %

Procedure:
To a solution of 5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-{[(3R,4S)-3-fluoropiperidin-4-yl](methyl)amino}-1,3-thiazol-4(5H)-one (previous Example 54) (90 mg, 0.16 mmol) in DMF (2 mL) was added potassium carbonate (45 mg, 0.32 mmol) followed by 2-Bromo-acetamide (27 mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 4 hours and partitioned between water and ethyl acetate. The ethyl acetate layer was washed with brine, dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude solid. The crude solid was purified via flash chromatography (5% methanol in dichloromethane) to yield the title compound (63 mg, 64%).