Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:11][C:12](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])(=[O:10])[CH3:9].[H][H]>CO>[C:8]([NH:11][C@@H:12]([C:13]([OH:15])=[O:14])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:10])[CH3:9]
Reactant: [H][H]
Reactant: CC(=O)NC(=Cc1ccccc1)C(=O)O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(=O)N[C@H](Cc1ccccc1)C(=O)O
Temperature: 40 °C
Reaction time: 22 h

Procedure:
The atmosphere in a 25 mL-recovery flask was substituted with nitrogen, and 3 mL of deoxygenized methanol and triethylamine (20.9 μL, 0.15 mmol) were added to the flask as the reaction solvent. α-Acetamidocinnamic acid (0.20 g, 0.98 mmol) and [Rh(CLPL-S)(COD)]BF4 (3.95 mg, 0.0049 mmol) were weighed in a 50 mL-Pyrex (registered trade name) test tube for autoclaving, the tube was put into an autoclave together with a stirrer in the tube, and the atmosphere in the autoclave was substituted with nitrogen. The reaction solvent in a volume of 2 mL was added to the mixture, the atmosphere in the autoclave was sufficiently substituted with hydrogen, and then pressurized with 2 MPa of hydrogen, and the reaction mixture was stirred at 40° C. for 22 hours. After 22 hours, the atmosphere in the autoclave was returned to ordinary pressure, and the reaction mixture was concentrated in an evaporator. The concentrated residue was added with 5 mL of 2 M aqueous sodium hydroxide for dissolution, and the solution was washed with 5 mL of ethyl acetate. The aqueous layer was separated, and added with diluted hydrochloric acid until pH of the aqueous layer became lower than 2, and the produced oil was extracted with 10 mL of ethyl acetate. The organic layer was concentrated in an evaporator to obtain (R)-N-acetylphenylalanine quantitatively.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](=[O:16])[CH2:14][CH3:15])=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[C:9]=2[CH3:27])=[CH:4][CH:3]=1.[C:28]([O-])([O-])=O.[K+].[K+].CI>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](=[O:16])[CH2:14][CH3:15])=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([NH:26][CH3:28])(=[O:24])=[O:25])=[CH:19][CH:18]=3)[C:9]=2[CH3:27])=[CH:4][CH:3]=1
Reactant: CCC(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(N)(=O)=O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CCC(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(=O)(=O)NC)cc1
Reaction time: 0.25 h
Yield: 8.7 %

Procedure:
To a solution of 4-(5-(4-chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide (Compound 1, 0.50 g, 1.19 mmol) in acetonitrile (15 ml) was added K2CO3 (0.25 g, 1.84 mmol) at room temperature and stirred for 15 minutes. To this was added methyl iodide (0.20 g, 0.08 ml, 1.42 mmol). The so obtained mixture was stirred at room temperature for 15 hr. The progress of the reaction was monitored by TLC. The reaction mixture was then concentrated under reduced pressure. The concentrated mass was diluted with water (20 ml). The mixture so obtained was extracted with ethyl acetate (3×30 ml). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to obtain a crude product. The crude product so obtained was purified by column chromatography over silica gel (100-200 mesh) using 40% ethyl acetate in hexanes as an eluent to obtain first title compound (0.05 g, 9.38%) and second title compound (0.045 g, 8.7%).
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:21]([CH3:28])[CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:9]=2[CH:8]=1)=S)[CH2:2][CH3:3].C(O)(=[O:31])C>O.C(OCC)(=O)C>[CH2:1]([NH:4][C:5]([C:7]1[CH:20]=[CH:19][C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:21]([CH3:28])[CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[C:9]=2[CH:8]=1)=[O:31])[CH2:2][CH3:3]
Reactant: CCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Reactant: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Reaction time: 0.5 h

Procedure:
Mercuric acetate (0.38 g) is added with stirring to a solution of N-propyl-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide neutral fumarate (0.6 g) in acetic acid (10 cc), and stirring is continued for 4 hours 30 minutes at a temperature in the region of 20° C. The black reaction mixture is diluted with distilled water (25 cc) and ethyl acetate (50 cc) and then filtered and alkalinized with stirring with 4N aqueous sodium hydroxide solution to pH 13. After settling has taken place, the organic phase is separated and the aqueous phase is extracted with ethyl acetate (20 cc). The combined organic phases are washed successively with saturated aqueous sodium chloride solution (50 cc). After drying over magnesium sulphate, filtration and concentration to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C., N-propyl-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide (0.43 g) is obtained in the form of a yellow oil.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][C:42](O)=[O:43]>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:42](=[O:43])[CH2:41][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=2)[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Fc1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Reactant: O=C(O)Cc1ccccn1
Agent: Cl
Product: O=C(Cc1ccccn1)N1CC[C@H](OCc2cc(F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (28.8 mg) obtained in Example 26 and 2-pyridineacetic acid hydrochloride (20.8 mg) were reacted and treated in the same manner as in the method described in Example 32 to obtain the title compound.
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[CH:15][C:16]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)=[N:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3]C=1.FC1C=CC2NC=C3C(=O)N(C4C=CC=CN=4)N=C3C=2[N:29]=1>>[N:19]1([C:16]2[CH:15]=[CH:14][C:13]3[NH:12][CH:11]=[C:10]4[C:25](=[O:26])[N:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][N:29]=5)[N:8]=[C:9]4[C:18]=3[N:17]=2)[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]1
Reactant: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccc1
Reactant: O=c1c2c[nH]c3ccc(F)nc3c-2nn1-c1ccccn1
Product: O=c1c2c[nH]c3ccc(N4CCNCC4)nc3c-2nn1-c1ccccn1

Procedure:
The title compound was prepared following the procedure described for 6a using 5b instead of 5a. 1H-NMR (CDCl3) δ (ppm): 2.97 (4H, br), 3.72 (4H, br), 6.82 (1H, d, J=9.34 Hz), 7.42 (4H, m), 7.75 (1H, m), 8.17 (2H, d, J=7.97 Hz), 8.52 (1H, s). m/z 348.4 (MH+).
Reaction SMILES: C(N(CC)CC)C.Cl[Si:9]([CH3:12])([CH3:11])[CH3:10].[CH:13]([O:16][C:17]1[C:18]([OH:27])([CH3:26])[C:19](=[O:25])[C:20]=1[O:21][CH:22]([CH3:24])[CH3:23])([CH3:15])[CH3:14]>C(OCC)C>[CH:13]([O:16][C:17]1[C:18]([O:27][Si:9]([CH3:12])([CH3:11])[CH3:10])([CH3:26])[C:19](=[O:25])[C:20]=1[O:21][CH:22]([CH3:23])[CH3:24])([CH3:15])[CH3:14]
Reactant: CC(C)OC1=C(OC(C)C)C(C)(O)C1=O
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)OC1=C(OC(C)C)C(C)(O[Si](C)(C)C)C1=O
Reaction time: 18 h
Yield: 94.2 %

Procedure:
Triethylamine (28 mL, 0.20 mol) and chlorotrimethylsilane (13 mL, 0.10 mol) were successively added to a stirred solution of 3,4-diisopropoxy-2-hydroxy-2-methylcyclobut-3-ene-1-one (14.3 g, 0.0667 mol) in diethyl ether (250 mL). The mixture was allowed to stir at ambient temperatures for 18 hrs. The mixture was filtered through SiO2 contained in a sintered glass funnel. The filter cake was washed with additional diethyl ether. The ether was removed to leave 3,4-diisopropoxy-2-trimethylsilyloxy-2-methylcyclobut-3-ene-1-one (18 g, 94% yield) as a clear oil. Trimethylsilyl trifluoromethanesulfonate (150 μL, 0.78 mmol) was added to a stirred solution of the silyl ether (18 g, 0.0628 mol) and 1,2-bis(trimethylsilyloxy)ethane (16.2 mL, 0.066 mmol) in tetrahydrofuran (36 mL). The solution was stirred for 1 hr at 22° C. and additional trimethylsilyl trifluoromethanesulfonate (150 μL) was then added. The solution was stirred for an additional 0.25 hr and was concentrated to dryness. The residue was flash chromatographed on SiO2 (200 g) with diethyl ether-hexanes (1:1) to afford 2,2-ethylenedioxy-3-isopropoxy-4-methylcyclobut-3-ene-1-one (9 g, 73% yield) as a colorless crystalline solid. A solution of n-Bu4N+CN- (140 mg, 0.52 mmol) in tetrahydrofuran (4 mL) was added dropwise to a stirred solution of the ketal (2.0 g, 0.010 mol) and n-Bu3SnSi(CH3)3 (4.03 g, 0.011 mol) in tetrahydrofuran (60 mL) at 22° C. Stirring was continued for 0.66 hr, and the dark solution was concentrated to dryness. The residue was flash chromatographed on SiO2 (80 g) with hexane and then with diethyl ether-hexane (25:75) to afford the title compound as a yellow oil (4.11 g, 95% yield).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2O[C:10](=[O:27])[C:11]3[CH:17]=[CH:16][CH:15]=[C:14]([NH:18][C:19]([C:21]4[CH:26]=[N:25][CH:24]=[CH:23][N:22]=4)=[O:20])[C:12]=3[N:13]=2)=[C:5]([CH3:7])[N:6]=1.[CH3:28][NH2:29]>CO>[CH3:1][C:2]1[S:3][C:4]([C:8]2[N:29]([CH3:28])[C:10](=[O:27])[C:11]3[C:12](=[C:14]([NH:18][C:19]([C:21]4[CH:26]=[N:25][CH:24]=[CH:23][N:22]=4)=[O:20])[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(C)c(-c2nc3c(NC(=O)c4cnccn4)cccc3c(=O)o2)s1
Reactant: CN
Solvent: CO
Product: Cc1nc(C)c(-c2nc3c(NC(=O)c4cnccn4)cccc3c(=O)n2C)s1
Temperature: 80 °C
Yield: 31 %

Procedure:
N-(2-(2,4-dimethylthiazol-5-yl)-4-oxo-4H-benzo[d][1,3]oxazin-8-yl)pyrazine-2-carboxamide 18 (100 mg, 0.26 mmol) was dissolved in 30 wt % solution of CH3NH2 in methanol (10 mL). The reaction mixture was heated at 80° C. for 12 h. The resulting precipitate was collected by filtration and rinsed with DME to give Compound 287 (32 mg, 31% yield). MS (ESI) calc. for C19H16F3N6O2S: 392.11. found: 393 [M+H].
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[CH:22]=[C:21]([CH2:23][CH3:24])[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:17]2[CH:22]=[C:21]([CH2:23][CH3:24])[S:20][C:18]=2[N:19]=1
Reactant: CCc1cc2c(Cl)nc(Cl)nc2s1
Reactant: NCCc1ccc2c(c1)OCO2
Product: CCc1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 2,4-dichloro-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-ethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=[O:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].OS(O)(=O)=O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:10][C:9]([C:7]1[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=1)=[O:11])[CH3:18]
Reactant: CC(=O)c1ccc(C(=O)O)s1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(C(C)=O)s1
Yield: 84 %

Procedure:
A solution of 5-acetylthiophene-2-carboxylic acid (17.0 g, 100 mmol) in ethanol (500 mL) was treated with a concentrated H2SO4 solution (10 mL) and heated at reflux for 3 days after which time the reaction was evaporated to approximately ¼ volume and partitioned between EtOAc (300 mL) and water (100 mL). The organic portion was then further washed with a saturated aqueous solution of NaHCO3 (2×100 mL) followed by a brine solution (100 mL), then dried over MgSO4, filtered, and evaporated in vacuo to afford product as light brown colored solid (25.0 g, 84%). 1H NMR (CDCl3) 1.39 (t, J=7.0, 3 H), 2.59 (s, 3 H), 4.38 (q, J=7.3, 2 H), 7.64 (d, J=4.0, 1 H), 7.76 (d, J=4.0, 1 H). 13C NMR 14.3, 27.1, 61.9, 131.8, 133.3, 140.3, 148., 161.7, 190.9. LC/MS 5.47 min, [M+1]+ 199.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH:12]=[O:13].P(O)(O)([O-])=[O:15].[Na+].Cl([O-])=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[C:12]([OH:15])=[O:13]
Reactant: O=Cc1ccnc2c(Br)cccc12
Reactant: O=P([O-])(O)O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccnc2c(Br)cccc12
Temperature: 5 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
As shown in step 9-iv of Scheme 9, to a stirred suspension of 8-bromoquinoline-4-carbaldehyde (531.4 g, 2.25 mol) in THF (4.8 L) was added water (4.8 L) and monosodium phosphate (491.1 g, 4.05 mol). The mixture was cooled to 5° C. and, keeping the reaction temperature below 15° C., sodium chlorite (534.4 g, 4.727 mol) was slowly added portionwise as a solid over about 1 hour. After addition was complete the reaction mixture was stirred at 10° C. for 1 hour followed by the portionwise addition of 1N Na2S2O3 (1.18 L) whilst keeping the temperature below 20° C. The reaction mixture was stirred at RT followed by the removal of the THF under reduced pressure. The resulting aqueous solution containing a precipitate was treated with sat'd NaHCO3 (about 1 L) until a pH of 3 to 4 was achieved. This mixture was stirred an additional 15 minutes and the solid was collected by filtration, washed with water (2×1 L), washed with tert butyl methyl ether (2×500 mL), and dried in a convection oven at 60° C. for 48 hours. Additional drying under high vacuum provided 8-bromoquinoline-4-carboxylic acid (compound 2032, 530.7 g, 94% yield from compound 1030) as a yellowish tan solid: LC-MS=252.34 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 14.09 (s, 1H), 9.16 (d, J=4.4 Hz, 1H), 8.71 (dd, J=8.6, 1.2 Hz, 1H), 8.25 (dd, J=7.5, 1.2 Hz, 1H), 8.03 (d, J=4.4 Hz, 1H), 7.64 (dd, J=8.6, 7.5 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15]1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:23](OCC)(OCC)(OCC)[CH2:24][CH3:25]>Cl.N1C=CC=CC=1>[CH2:24]([C:25]1[N:12]([CH2:13][C:14]2([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:17][CH2:16][CH2:15]2)[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:23]
Reactant: CCOC(=O)C1(CNc2c(N)cnc3ccccc23)CCC1
Reactant: CCOC(CC)(OCC)OCC
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1(Cn2c(CC)nc3cnc4ccccc4c32)CCC1
Yield: 91.8 %

Procedure:
The method described in Part E of Example 65 was used to treat ethyl 1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclobutanecarboxylate (6 mmol) with triethyl orthopropionate (1.6 mL, 7.9 mmol) and pyridine hydrochloride (35 mg) and isolate the final product, ethyl 1-[(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanecarboxylate (1.86 g, 5.51 mmol), as a white solid, which was treated with sodium hydroxide (1.8 mL of 6 M) according to the method of Part F of Example 65. The product, 1-[(2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]cyclobutanecarboxylic acid, was isolated as a tan solid (1.49 g) according to the methods of Part F of Example 65.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[CH2:9]1[O:11][C@@H:10]1[CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C@H:10]([OH:11])[CH2:12][OH:13])[N:5]=1)([O-:3])=[O:2]
Reactant: OC[C@@H]1CO1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccn(C[C@H](O)CO)n1
Temperature: 120 °C
Yield: 34.8 %

Procedure:
A solution of 3-nitro-1H-pyrazole (Intermediate 2, 205 mg, 1.81 mmol) in anhydrous N,N-dimethylformamide (3.5 mL) was treated with (R)-glycidol (148 mg, 2.00 mmol) and potassium carbonate (770 mg, 5.58 mmol). The mixture was heated in a sealed vial at 120° C. for 1 h. After this time, the mixture was diluted with water (15 mL) and extracted with ethyl acetate (6×25 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (15 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (Teledyne Isco RediSep Flash Column 40 g, 15-100% ethyl acetate/hexanes) afforded (S)-3-(3-nitro-pyrazol-1-yl)-propane-1,2-diol (118 mg, 34%) as a thick yellow oil. 1H-NMR (400 MHz, CD3OD) δ 3.55 (2H, d, J=5.2 Hz), 4.02-4.05 (1H, m), 4.20 (1H, dd, J=13.6 Hz, 7.6 Hz), 4.39 (1H, dd, J=14.0 Hz, 3.6 Hz), 6.92 (1H, d, J=2.0 Hz), 7.79 (1H, d, J=2.0 Hz).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]([CH2:15]O)=[C:5]2[C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=2)[N:20]=[CH:19][CH:18]=1.ClC1C2C(=CC(Cl)=CC=2)[N:32]=[CH:31]C=1>>[Cl:27][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([C:31]#[N:32])[CH:3]=4)[N:7]([CH2:11][C:12]([OH:14])=[O:13])[C:6]=3[CH3:15])=[CH:18][CH:19]=[N:20]2)=[CH:25][CH:24]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: O=C(O)Cn1c(CO)c(-c2ccnc3cc(Cl)ccc23)c2cc(Cl)ccc21
Product: Cc1c(-c2ccnc3cc(Cl)ccc23)c2cc(C#N)ccc2n1CC(=O)O

Procedure:
The sub-title compound was prepared from the product of example 55, step a) and 4,7-dichloroquinoline by the method of example 55, step b).
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][CH2:13][CH:14]3[CH2:18][O:17]C(C)(C)[O:15]3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)[NH2:25].Cl.[OH-].[Na+]>CO.C(O)(C)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[C:3]3[N:10]([CH2:11][CH2:12][CH2:13][CH:14]([OH:15])[CH2:18][OH:17])[CH:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:39])[F:37])[CH:31]=1
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Reactant: CC1(C)OCC(CCCn2ccc3ncnc(Cl)c32)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CO
Product: OCC(O)CCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 61.1 %

Procedure:
The crude product was obtained by the reaction in the same manner as in Example 201 (iii) using 4-chloro-5-[3-(2,2-dimethyl-1,3-dioxolan-4-yl)propyl]-5H-pyrrolo[3,2-d]pyrimidine (171 mg), 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (195 mg) and isopropyl alcohol (3.5 mL). The crude product was dissolved in methanol (1 mL), 1N hydrochloric acid (0.5 mL) was added, and the mixture was stirred at room temperature for 3.5 hrs. The reaction mixture was treated with 1N aqueous sodium hydroxide solution, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, ethyl acetate:methanol=100:0→95:5) to give the title compound (179 mg) as white crystals.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[C:12]([CH:26]=[O:27])=[C:11]([I:28])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:29]([C:33]1[CH:38]=[CH:37][C:36]([Mg]Br)=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30]>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)[C:12]([CH:26]([C:36]3[CH:37]=[CH:38][C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:34][CH:35]=3)[OH:27])=[C:11]([I:28])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc([Mg]Br)cc1
Reactant: CC1(C)Cc2nc(C3CCCC3)c(C=O)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1
Product: CC1(C)Cc2nc(C3CCCC3)c(C(O)c3ccc(C(C)(C)C)cc3)c(I)c2[C@@H](O[Si](C)(C)C(C)(C)C)C1

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-2-cyclopentyl-4-iodo-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 4-tert.-butylphenylmagnesium bromide. The product is obtained as a diastereomic mixture, which is used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]3[CH:19]=[C:18]([Sn](CCCC)(CCCC)CCCC)[N:17]=[CH:16]3)[N:9]=2)=[CH:4][C:3]=1[CH3:33].[CH3:34][C:35]([NH:38][S:39]([C:42]1[S:46][C:45](Br)=[CH:44][CH:43]=1)(=[O:41])=[O:40])([CH3:37])[CH3:36].CCCCCCC>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:35]([NH:38][S:39]([C:42]1[S:46][C:45]([C:18]2[N:17]=[CH:16][N:15]([C:10]3[N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:33])[CH:4]=4)[CH:13]=[C:12]([CH3:14])[N:11]=3)[CH:19]=2)=[CH:44][CH:43]=1)(=[O:40])=[O:41])([CH3:37])([CH3:34])[CH3:36]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(C)cc(-c3ccc(Cl)c(C)c3)n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: Cc1cc(-c2ccc(Cl)c(C)c2)nc(-n2cnc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.4 %

Procedure:
A stirred mixture of 4-(4-chloro-3-methyl-phenyl)-6-methyl-2-(4-tributylstannanyl-imidazol-1-yl)-pyrimidine (Example G.8) (0.59 g, 1.03 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.34 g, 1.13 mmol), tetrakis(triphenylphosphine)palladium (0.071 g, 0.062 mmol) in toluene (8 ml) was heated under reflux conditions for 15 h, heptane (10 ml) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and dried to yield 5-{1-[4-(4-chloro-3-methyl-phenyl)-6-methyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.54 g) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=2)[CH2:11][N:12]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=1.[NH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[OH:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][NH:27][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=3)[CH2:11][N:12]([CH2:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=2)=[CH:31][CH:32]=1
Reactant: NCCc1ccc(O)cc1
Reactant: CS(=O)(=O)N(Cc1cccnc1)Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CS(=O)(=O)N(Cc1cccnc1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 13 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 490. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.5 (d, 2H) 8.4 (s, 1H) 8.3 (d, 1H) 7.9 (m, 4H) 7.4 (d, 2H) 7.3 (m, 1H) 7.1 (d, 2H) 6.9 (d, 1H) 6.7 (d, 1H) 5.6 (m, 1H) 4.4 (d, 4H) 3.7 (m, 2H) 2.9 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([CH2:33][O:34]CC[Si](C)(C)C)[C:9](=[O:32])[C@:10]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C@H:13]([CH2:23][C:24]([OH:26])=[O:25])[C:12](=[O:27])[N:11]3[CH2:28][CH:29]3[CH2:31][CH2:30]3)[C:5]2=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([CH2:33][OH:34])[C:9](=[O:32])[C@:10]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C@H:13]([CH2:23][C:24]([OH:26])=[O:25])[C:12](=[O:27])[N:11]3[CH2:28][CH:29]3[CH2:30][CH2:31]3)[C:5]2=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@@]2(c3ccc(Cl)cc31)[C@@H](c1cccc(Cl)c1)C[C@H](CC(=O)O)C(=O)N2CC1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C[C@H]1C[C@H](c2cccc(Cl)c2)[C@]2(C(=O)N(CO)c3cc(Cl)ccc32)N(CC2CC2)C1=O
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of (rac) 2-((2′S,3′R,S′R)-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)-2,6′-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)spiro[indoline-3,2′-piperidine]-5′-yl)acetic acid (Example 62, Step K) (47 mg, 0.078 mmol) in DCM (0.8 mL) at room temperature was added 0.2 mL TFA. The reaction mixture was stirred at room temperature for 19 h before concentrating under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 50 to 100% EtOAc in hexanes) to give the title compound.