Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C([O:31][CH2:32][C:33](Cl)=[O:34])(=O)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C@@H:19]([NH:21][C:32](=[O:31])[CH2:33][OH:34])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(=O)OCC(=O)Cl
Reactant: C[C@@H](N)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Product: C[C@H](NC(=O)CO)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
Prepared as described in Example 7 using (1S,2R)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-phenylpropan-2-amine (1a, 149 mg, 0.41 mmol) and 2-chloro-2-oxoethyl acetate (49 μL, 0.45 mmol). Yield 125 mg (72%).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:18]=[C:19]([O:29][CH3:30])[C:20]=3[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]([O:16]C)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH-].[K+]>CO>[C:1]12([C:11]3[CH:12]=[C:13]([CH:18]=[C:19]([O:29][CH3:30])[C:20]=3[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]([OH:16])=[O:15])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: COC(=O)c1cc(OC)c(OCc2ccccc2)c(C23CC4CC(CC(C4)C2)C3)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)O)cc(C23CC4CC(CC(C4)C2)C3)c1OCc1ccccc1

Procedure:
18.32 g (58 mM) of the phenol obtained in Example 11(a) are treated with benzyl bromide under the conditions described in Example 5(a). After the same treatment, followed by chromatography on silica in the hexane/ether (90/10) eluent, there are isolated 15.26 g (59.6%) of methyl 3-(1-adamantyl)-4-benzyloxy-5-methoxybenzoate. 15.22 g (37.5 mM) of this ester in 150 ml of methanol are treated with 6.3 g of potassium hydroxide and are heated at reflux overnight. After the same treatment as in Example1(d), there are isolated 13.7 g (93.2%) of the expected derivative, of melting point 229° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][NH:17]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:40][C:41](O)=[O:42])[CH:26]=[CH:27][C:28]=1[NH:29][C:30]([NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39])=[O:31]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:41](=[O:42])[CH2:40][C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])=[O:31])=[C:23]([O:22][CH3:21])[CH:24]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)c1ccc(OC[C@@H]2CCCN2)c(OC)c1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OC[C@@H]2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To a stirred solution of ethyl (S)-3-methoxy-4-(2-pyrrolidinylmethoxy)benzoate (424 mg, 1.52 mmol) in DMF (8 mL) was added pentafluorphenyl ester of 3-methoxy-4-[N′-(2-methylphenyl) ureido]phenylacetic acid (728 mg, 1.52 mmol) and Et3 N (0.26 mL, 1.87 mmol). And the resulting mixture was stirred at room temp overnight. The mixture was diluted with EtOAc, washed with 1 N HCl, sat. NaHCO3, brine, and dried over MgSO4. The solvent was evaporated off in vacuo and the residue was purified by column chromatography on silica-gel with CHCl3-MeOH (50:1, v/v) as eluent to give 830 mg (95%) ethyl (S)-3-methoxy-4-[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenyl acetyl]-2-pyrrolidinyl methoxy]benzoate as an amorphous solid. 1H-NMR (CDCl3) δ 1.38 (t, 3 H, J=7.3 Hz), 1.88–2.20 (m, 4 H, m), 2.24 (m, 3 H), 3.44–3.50 (m, 1 H), 3.53–3.58 (m, 7 H), 3.82 (s, 3 H), 4.09–4.17 (m, 1 H), 4.22–4.25 (m, 1 H), 4.35 (q, 2 H, J=7.3 Hz), 4.38–4.49 (m, 1 H), 6.71–6.78 (m, 1 H), 6.99 (d, 1 H, J=8.3 Hz), 7.04–7.07 (m, 1H), 7.16–7.19 (m, 2 H), 7.49–7.66 (m, 3 H), 8.06 (d, 1 H, J=8.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH:22]=O)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[F:33][C:34]1([F:38])[CH2:37][NH:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][N:36]3[CH2:37][C:34]([F:38])([F:33])[CH2:35]3)[C:11](=[O:26])[C@:10]([CH2:28][C:29]([OH:31])=[O:30])([CH3:27])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](C=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: FC1(F)CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: CC[C@@H](CN1CC(F)(F)C1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
To a solution of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)acetic acid (99 mg, 0.215 mmol; Example 210, Step A) in 1,2-dichloroethane (3 mL) was added 3,3-difluoroazetidine hydrochloride (55.7 mg, 0.430 mmol) followed by sodium triacetoxyborohydride (91 mg, 0.430 mmol). After stirring overnight, the mixture was quenched with water. The mixture was extracted with ethyl acetate (2×). The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4 and concentrated. The residue was purified by reverse phase preparatory HPLC (column: Gemini-NX C18 5 um column; Phenomonex, Torrance, Calif.; eluent: 0 to 100% MeCN +0.1% TFA in water +0.1% TFA, over 20 minutes). Fractions containing the product were transferred to a separatory funnel and sat. aq. NaHCO3 and dichloromethane were added. The aqueous layer was back extracted with dichloromethane. The combined organic layers were washed with sat. aq. NaCl solution, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated to afford the title compound.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[C:6]2[N:7]=1.Cl.C([OH:16])C>>[OH:16][C:3]1[N:4]=[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=[C:6]2[N:7]=1
Reactant: CCO
Reactant: CSc1nc2cccccc-2n1
Agent: Cl
Product: Oc1nc2cccccc-2n1
Temperature: 25 °C

Procedure:
First, 60 g of 2-methylthiocycloheptimidazole as synthesized according to Synthetic example 1 (c) with reference to the method disclosed in Journal of the American Chemical Society, vol. 76, pages 3352 and 3353 (1954) was added to 300 ml of concentrated hydrochloric acid (hydrogen chloride 35%), and refluxed with heating for 2 hours and 30 minutes. Then, 500 ml of ethanol was added, and after stirring at room temperature, deposited crystals were collected by filtration. The crystals were dissolved in 0.5 l of water, and pH was adjusted to around 7 with sodium bicarbonate. Deposited crystals were collected by filtration, washed with water and dried.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15]C(Cl)=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:19][C@H:20]1[CH2:43][CH2:42][C@@:41]2([CH3:44])[C@H:22]([CH2:23][CH2:24][C@@H:25]3[C@@H:40]2[CH2:39][CH2:38][C@@:37]2([CH3:45])[C@H:26]3[CH2:27][CH2:28][C@@H:29]2[C@H:30]([CH3:36])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:21]1.O>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][NH:19][C@H:20]3[CH2:43][CH2:42][C@@:41]4([CH3:44])[C@H:22]([CH2:23][CH2:24][C@@H:25]5[C@@H:40]4[CH2:39][CH2:38][C@@:37]4([CH3:45])[C@H:26]5[CH2:27][CH2:28][C@@H:29]4[C@H:30]([CH3:36])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:21]3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@@H](N)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@@H](NOCC5c6ccccc6-c6ccccc65)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 69 %

Procedure:
A solution of 9-fluorenylmethoxycarbonyl chloride (0.76 g; 2.93 mmol) in 1,4-dioxane (9 mL) was added dropwise to a suspension of (3β,5β)-3-aminocholan-24-oic acid B (1.0 g; 2.66 mmol) in 10% aq. Na2CO3 (16 mL) and 1,4-dioxane (9 mL) stirred at 0° C. After 6 h stirring at room temperature H2O (90 mL) was added, the aqueous phase washed with Et2O (2×90 mL) and then 2 M HCl (15 mL) was added (final pH: 1.5). The aqueous phase was extracted with EtOAc (2×100 mL), the organic phase dried over Na2SO4 and evaporated. The crude was purified by flash chromatography to give C as a white solid (1.2 g; 2.0 mmol). Yield 69%.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([C:17]2([C:33]([O:35]C)=[O:34])[CH2:22][CH2:21][N:20]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:19][CH2:18]2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[CH2:26]([O:25][C:23]([N:20]1[CH2:19][CH2:18][C:17]([S:14]([C:11]2[CH:10]=[CH:9][C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:13][CH:12]=2)(=[O:16])=[O:15])([C:33]([OH:35])=[O:34])[CH2:22][CH2:21]1)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COC(=O)C1(S(=O)(=O)c2ccc(Oc3ccccc3)cc2)CCN(C(=O)OCc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(OCc1ccccc1)N1CCC(C(=O)O)(S(=O)(=O)c2ccc(Oc3ccccc3)cc2)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1-((Benzyloxy)carbonyl)-4-((4-phenoxyphenyl)sulfonyl)piperidine-4-carboxylic acid was synthesized as shown in FIG. 11. A 250 ml RBF was charged with the 1.75 g of 1-benzyl 4-methyl 4-((4-phenoxyphenyl)sulfonyl)piperidine-1,4-dicarboxylate (3.39 mmole), 0.57 g (10.16 mmole) potassium hydroxide in 30 ml ethanol/7.5 ml water. The reaction mixture was stirred at 50° C. with LCMS monitoring. LCMS analysis indicated ˜80% conversion after 1 hr and approximately 90% conversion after 2 hr with a trace of impurities appearing. The solution was concentrated to ¼ volume and partitioned between EA and 10% aq. Citric acid. The organics were washed with brine, dried, and concentrated in vacuo. The product was vacuum dried overnight to yield 1.6 g (95% yield) white solid that was used in Step 3.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C@@H:7]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8](OCC)=[O:9])=[O:5].C1COCC1.[H-].[Na+]>O>[CH2:13]([C@H:7]1[C:8](=[O:9])[NH:1][C:2]2[N:23]=[CH:22][CH:21]=[CH:20][C:3]=2[C:4](=[O:5])[NH:6]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1cccnc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1N[C@@H](Cc2ccccc2)C(=O)Nc2ncccc21
Reaction time: 8 h

Procedure:
(S)-Ethyl 2-(2-aminonicotinamido)-3-phenylpropanoate (5.7 g, 18.1 mmol) was dissolved into THF (125 mL) under argon. Sodium hydride (1.07 g, 60% dispersion in oil, 26.8 mmol) was added and the reaction was stirred overnight. Water (5 mL) was carefully added and the resulting white precipitate was collected. The precipitate was dissolved into ethyl acetate (200 mL), washed with water (50 mL) and brine (50 mL), dried over MgSO4 and concentrated to a yellow solid (2.1 g, 44%): ESI MS m/z 268 [C15H13N3O2+H]+.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39][C:40]([OH:42])=O)=[CH:33][CH:32]=2)=[C:28]([CH:43]([CH3:45])[CH3:44])[NH:27][N:26]=1)(=O)C.Cl.[NH2:47][CH2:48][C:49]([NH2:51])=[O:50].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[C:49]([CH2:48][NH:47][C:40]([CH2:39]/[CH:38]=[CH:37]/[C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:43]([CH3:44])[CH3:45])=[CH:32][CH:33]=1)=[O:42])(=[O:50])[NH2:51]
Reactant: NCC(N)=O
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CC(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(/C=C/CC(=O)NCC(N)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.7 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-({4-[(1E)-3-carboxyprop-1-enyl]phenyl}methyl)-5-isopropyl-1H-pyrazole (0.34 g) in N,N-dimethylformamide (1 mL) were added glycinamide hydrochloride (0.12 g), 1-hydroxybenzotriazole (0.09 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.15 g) and triethylamine (0.27 g), and the mixture was stirred at room temperature overnight. The insoluble material was removed by filtration. To the filtrate was added 5 mol/L aqueous sodium hydroxide solution (0.5 mL), and the mixture was stirred at room temperature for 1 hour. The insoluble material was removed by filtration, and the filtrate was purified by preparative reverse phase column chromatography (Shiseido CAPCELL PAK UG120 ODS, 5 μm, 120 Å, 20×50 mm, flow rate 30 mL/minute linear gradient, water/acetonitrile=90/10-10/90) to give 4-({4-[(1E)-3-(carbamoylmethylcarbamoyl)prop-1-enyl]phenyl}methyl)-3-(β-D-glucopyranosyloxy)-5-isopropyl-1H-pyrazole (0.03 g). This material was dissolved in methanol (1 mL). To the solution was added 10% palladium-carbon powder (0.01 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the solvent of the filtrate was removed under reduced pressure to give the title compound (0.02 g).
Reaction SMILES: [O:1]=[C:2]1[N:7]2[N:8]=[CH:9][C:10]3[CH:14]=[CH:13][S:12][C:11]=3[C:6]2=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=[C:3]1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:25]([BH3-])#N.[Na+]>C(O)=O.O1CCCC1>[CH3:25][N:8]1[CH2:9][C:10]2[CH:14]=[CH:13][S:12][C:11]=2[C:6]2=[C:5]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=[C:3]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:2](=[O:1])[N:7]12
Reactant: [BH3-]C#N
Reactant: COC(=O)c1cc(-c2ccccc2)c(=O)n2ncc3ccsc3c12
Agent: [Na+]
Solvent: O=CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CN2C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.34 g of methyl 7-oxo-8-phenyl-7H-pyrido[1,2-b]thieno[2,3-d]pyridazine-10-carboxylate in 10 ml of formic acid are treated dropwise under argon at 25°-30° with 0.31 g of sodium cyanoborohydride in 2 ml of tetrahydrofuran. The mixture is left to stir at room temperature for 24 hours. The solution is poured into 50 ml of ice-water. The yellowish crystals are removed by filtration and washed with water. After drying in vacuo, recrystallization is carried out from ethyl acetate. There is obtained methyl 4,5-dihydro-5-methyl-7-oxo-8-phenyl-7H-pyrido[1,2-b]thieno[2,3-d]-pyridazine-10-carboxylate of m.p. 180°-181°.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][C:9]([CH3:15])([CH3:14])[CH2:10][NH:11]2)=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][C:9]([CH3:15])([CH3:14])[CH2:10][NH:11]2)=[CH:6][CH:5]=1
Reactant: CC1(C)CNc2cc([N+](=O)[O-])ccc2C1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CNc2cc(N)ccc2C1
Yield: 91 %

Procedure:
A solution of 7-nitro-1,2,3,4-tetrahydro-3,3-dimethylquinoline (39 mg, 0.187 mmol) in ethyl acetate (2 mL) was hydrogenated under an atmosphere of hydrogen with 10% Pd/C (4 mg) at rt for 2 h. Filtration over Celite™ afforded 30 mg (91%) of 7-amino-1,2,3,4-tetrahydro-3,3-dimethylquinoline (structure 72A of Scheme LII, where R1-2 =R5 =H, R3-4 =methyl) that was used without further purification in the next step. Compound 437 was prepared by General Method 13 (EXAMPLE 147) from 7-amino-1,2,3,4-tetrahydro-3,3-dimethylquinoline (30 mg, 0.17 mmol), ZnCl2 (34 mg, 025 mmol) and ethyl 4,4,4,-trifluoroacetoacetate (25 mL, 0.17 mol) to afford 13 mg (26%) of Compound 437 as a yellow solid. Data for Compound 437: 1H NMR (400 MHz, DMSO-d6) 11.71 (bs, 1 H), 7.11 (s, 1 H), 7.01 (s, 1 H), 6.40 (s, 1 H), 6.37 (s, 1 H), 2.89 (s, 2 H), 2.51 (s, 2 H), 0.93 (s, 6 H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH2:20][CH:21]([CH3:23])[CH3:22])=[C:5]([C:16]([O:18][CH3:19])=[O:17])[C:6]([CH:13]([F:15])[F:14])=[N:7][C:8]=1[C:9]([F:12])([F:11])[F:10].[C:24]([C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:29]=[CH:30][C:31]([S:34][CH2:2][C:3]2[C:4]([CH2:20][CH:21]([CH3:23])[CH3:22])=[C:5]([C:16]([O:18][CH3:19])=[O:17])[C:6]([CH:13]([F:15])[F:14])=[N:7][C:8]=2[C:9]([F:12])([F:11])[F:10])=[CH:32][CH:33]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(CCl)c1CC(C)C
Reactant: CC(C)(C)c1ccc(S)cc1
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(CSc2ccc(C(C)(C)C)cc2)c1CC(C)C

Procedure:
Reaction of methyl 5-chloromethyl-2-(difluoromethyl)-4-(2-methylpropyl)-6-(trifluoromethyl)-3-pyridinecarboxylate (example 3 of U.S. Pat. No. 5,169,432) with 4-t-butylbenzenethiol according to the procedure of example 29 of U.S. Pat. No. 5,169,432 yielded the product as an oil.
Reaction SMILES: [N+:1]([O-])(O)=O.[Cl:5][C:6]1[C:11]2[CH2:12][C:13]([CH3:16])([CH3:15])[O:14][C:10]=2[C:9]([C:17]([OH:19])=[O:18])=[CH:8][CH:7]=1>S(=O)(=O)(O)O>[NH2:1][C:7]1[CH:8]=[C:9]([C:17]([OH:19])=[O:18])[C:10]2[O:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]=2[C:6]=1[Cl:5]
Reactant: O=[N+]([O-])O
Reactant: CC1(C)Cc2c(Cl)ccc(C(=O)O)c2O1
Agent: O=S(=O)(O)O
Product: CC1(C)Cc2c(Cl)c(N)cc(C(=O)O)c2O1
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 40 ml of nitric acid and 40 ml of sulfuric acid cooled to 5° C. by means of an external ice bath were added 10 g of 4-chloro-2,2-dimethyl-2,3-dihydro-7-benzofurancarboxylic acid over a period of 28 minutes. After stirring at 5° C. for 10 minutes, the mixture was added to ice with stirring. The resulting solid was collected by filtration and washed with water. After air drying, the residue was crystallized twice from ethyl acetate/hexane to provide 3.5 g of the desired subtitle intermediate, m.p. 260°-262° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[C:15]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:13])[F:14])[CH:11]=2)[CH2:7][C:8]1=[O:12])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: O=C1Cc2ccc(C(F)(F)F)cc2N1
Product: CC(=O)N1C(=O)Cc2ccc(C(F)(F)F)cc21

Procedure:
Prepared from 6-trifluoromethyl-2-indolinone and acetic anhydride
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7](O)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[N:12]([O-])=[O:13].N([O-])=[O:16].[Na+].N([O-])=O.[K+]>>[N:12]([CH2:2][C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[OH:16])=[O:3])=[O:13]
Reactant: O=N[O-]
Reactant: CC(=O)Nc1cccc(O)c1
Agent: [K+]
Agent: [Na+]
Product: O=NCC(=O)Nc1ccccc1O

Procedure:
According to this scheme 1a, the compounds of formula (Ia) are prepared by reaction of an appropriate 3-acetamidophenol compound (1) with a nitrite (2), such as a sodium nitrite (X═Na), a potassium nitrite (X═K), etc., at a temperature of −3° C. The nitroso acetamidophenol (3) thus obtained is subsequently reacted with 1,3-dihydroxynaphthalene (4) in a solvent such as butanol, by heating to a temperature of approximately 70° C., then adding concentrated sulfuric acid and continuing the heating to 90° C., and then cooling, so as to form the appropriate 9-acetamido-benzo[a]phenoxazin-5-one. The latter compound is subsequently hydrolyzed by heating with moderately concentrated sulfuric acid so as to give the 9-amino-benzo[a]phenoxazin-5-one (5). The last step is equivalent to that of scheme 1.
Reaction SMILES: [I:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[N:4]([CH3:18])[C:3]=1[C:19]([OH:21])=O.Cl.Cl.[NH:24]1[CH2:29][CH2:28][CH:27]([N:30]2[CH2:34][CH2:33][CH2:32][C@@H:31]2[CH2:35][OH:36])[CH2:26][CH2:25]1>>[OH:36][CH2:35][C@H:31]1[CH2:32][CH2:33][CH2:34][N:30]1[CH:27]1[CH2:28][CH2:29][N:24]([C:19]([C:3]2[N:4]([CH3:18])[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:15])([F:17])[F:16])[CH:8]=3)=[N:6][C:2]=2[I:1])=[O:21])[CH2:25][CH2:26]1
Reactant: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(I)c1C(=O)O
Reactant: OC[C@H]1CCCN1C1CCNCC1
Agent: Cl
Product: Cn1c(-c2cccc(OC(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCC[C@@H]2CO)CC1

Procedure:
In analogy to the procedure described for example 2, 5-iodo-3-methyl-2-(3-trifluoromethoxy-phenyl)-3H-imidazole-4-carboxylic acid (example 19) and ((R)-1-piperidin-4-yl-pyrrolidin-2-yl)-methanol di-hydrochloride (intermediate 2) gave the title compound as light red amorphous solid. MS: 579.3 (MH+).
Reaction SMILES: [CH:1]([C:3]1[C:11]([Cl:12])=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[Cl:13])=[O:2].S(Cl)([Cl:16])=O.CN(C)C=O>C1(C)C=CC=CC=1>[CH:1]([C:3]1[C:11]([Cl:12])=[CH:10][C:6]([C:7]([Cl:16])=[O:8])=[CH:5][C:4]=1[Cl:13])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=Cc1c(Cl)cc(C(=O)O)cc1Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=Cc1c(Cl)cc(C(=O)Cl)cc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 115.8 %

Procedure:
A mixture of 4-formyl-3,5-dichlorobenzoic acid (15.0 g, 0.06 moles), thionyl chloride (12.1 g, 0.107 moles), and dimethylformamide (5 ml) in toluene (100 ml) was slowly warmed to 70° C. and stirred at that temperature for 2 hours. The toluene was eliminated in the rotavap to yield 16.5 g of 4-formyl-3,5-dichlorobenzoyl chloride used in the next step as such.
Reaction SMILES: [NH2:1][C:2](=[O:25])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH:9]=[CH:8][C:7]=1[NH:17]C(=O)OC(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:17][C:7]1[CH:8]=[CH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[C:2]([NH2:1])=[O:25]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)C(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)C(=O)Nc1cc(-c2cccs2)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
To a solution of tert-butyl (2-(2-amino-2-oxoacetamido)-4-(thiophen-2-yl)phenyl)carbamate (0.1 g, 0.28 mmol) in DCM (3 mL) was added TFA (1 mL, 13 mmol) at 0° C. The reaction was warmed to room temperature and stirred for 2 h. The reaction was then concentrated under reduced pressure. The residue was basified with a saturated aqueous solution of Na2CO3. The obtained solid was filtered, washed with water and ether then dried to afford N1-(2-amino-5-(thiophen-2-yl)phenyl)oxalamide (40 mg, 55% yield). ESI+ MS: m/z 262 ([M+H]+), 1H NMR (500 MHz, d6-DMSO): δ 9.89 (s, 1H), 8.24 (s, 1H), 7.94 (s, 1H), 7.59 (d, J=2.0 Hz, 1H), 7.6 (d, J=5 Hz, 1H), 7.29-7.26 (m, 1H), 7.23 (d, J=4.0 Hz, 1H), 7.05 (t, J=4.0 Hz, 1H), 6.80 (d, J=9.0 Hz, 1H), 5.16 (s, 2H).
Reaction SMILES: O=S(Cl)[Cl:3].O[CH2:6][C:7]1[CH:21]=[CH:20][C:10]2[O:11][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:9]=2[CH:8]=1.C(C1C=CC2OC(C3C=CC=CC=3)OC=2C=1)(OC)=O>>[Cl:3][CH2:6][C:7]1[CH:21]=[CH:20][C:10]2[O:11][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:13][C:9]=2[CH:8]=1
Reactant: OCc1ccc2c(c1)OC(c1ccccc1)O2
Reactant: O=S(Cl)Cl
Agent: COC(=O)c1ccc2c(c1)OC(c1ccccc1)O2
Product: ClCc1ccc2c(c1)OC(c1ccccc1)O2

Procedure:
The starting compound, 5-chloromethyl-2-phenyl benzo [d]-1,3-dioxole (nD25 = 1.597) was prepared by chlorination, with SOCl2, of 5-hydroxymethyl-2-phenyl benzo [d]-1,3-dioxole melting (K) at 75° C, itself prepared by reduction, with Li Al H4, of 5-carbomethoxy-2-phenyl benzo [d]-1,3-dioxole, B.P./0.05 mm = 155° to 157° C, nD25 = 1.583.