Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[C:15]([CH:16]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)O)=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2>C(Cl)Cl>[Cl:5][C:6]1[C:15]([CH:16]([Cl:3])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2
Reactant: O=S(Cl)Cl
Reactant: OC(c1cccc(C(F)(F)F)c1)c1ccc2ncccc2c1Cl
Solvent: ClCCl
Product: FC(F)(F)c1cccc(C(Cl)c2ccc3ncccc3c2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Thionyl chloride (8 ml) was added dropwise to a solution of intermediate 5 (8 g) in CH2Cl2 (400 ml) at 0° C. and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was partitioned between CH2Cl2 and water which was alkalized with a saturated K2CO3 solution. The separated organic layer was dried over MgSO4, filtered and the filtrate evaporated, yielding 8.4 g (100%) (±)-5-chloro-6-[chloro[3-(trifluoromethyl) phenyl]methyl]quinoline (intermediate 6).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8](=[O:17])[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH:18]1[C:23]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=2)=[CH:22][CH:21]=[C:20]([N:34]=[C:35]=[O:36])[CH:19]=1>C1(C)C=CC=CC=1>[N:31]([C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:23]2[CH:18]=[CH:19][C:20]([NH:34][C:35]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8](=[O:17])[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:10])=[O:36])=[CH:21][CH:22]=2)=[CH:26][CH:27]=1)=[C:32]=[O:33]
Reactant: O=C=Nc1ccc(Cc2ccc(N=C=O)cc2)cc1
Reactant: O=C(OCCOCCO)C(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(Cc2ccc(NC(=O)OCCOCCOC(=O)C(=O)c3ccccc3)cc2)cc1
Temperature: 110 °C
Reaction time: 19 h

Procedure:
Under argon gas, 2.14 g of the phenylglyoxylic acid (2-hydroxyethoxy)ethyl ester from Example 1 and 2.24 g of 4,4′-diphenylmethane diisocyanate (Desmodur VL, Bayer) in 15 g of toluene are placed as the initial charge in a 50 ml multi-necked flask and refluxed at 110° C. After 19 hours, the solution is cooled and the toluene is concentrated using a rotary evaporator. The residue is dried under a high vacuum for two hours. 4.6 g of a viscous, slightly brownish oil are obtained. The conversion and the composition of the product mixture are verified by 1H-NMR spectrum and IR spectrum (NCO bands).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1.Cl([O-])=[O:22].[Na+].P([O-])(O)(O)=O.[K+]>O1CCOCC1.O>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:22])=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1
Reactant: [O-][Cl+][O-]
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Temperature: 25 °C
Yield: 114 %

Procedure:
In a flask 2-bromo-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (3.11 g, 8.74 mmol) was dissolved in dioxane (120 mL) and H2O (30 mL) and the mixture cooled at 0° C. Sufamic acid (5.09 g, 52.4 mmol) was added, followed by a solution of sodium chlorite (1.28 g, 11.4 mmol) and potassium dihydrogen phosphate (14.3 g, 104.9 mmol) in H2O (75 mL) via an addition funnel over 15 min. The mixture was allowed to warm to room temperature over 2 h. The resulting yellow solid was filtered off, washed with H2O and hexane and dried. The filtrate was then extracted with EtOAc, and the combined organics washed with brine, dried over MgSO4 and concentrated to give additional product. In total 3.71 g of 2-bromo-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid was obtained as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[N:6]=[CH:7]2.C1(C)C=CC=CC=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][N:32]=[C:33]=[O:34]>C1COCC1>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[CH2:31][NH:32][C:33]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]([O:14][CH3:15])=[O:13])[N:6]=[CH:7]2)=[O:34]
Reactant: O=C=NCc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1cc2c(N)cccc2cn1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2c(NC(=O)NCc3ccc(Cl)cc3Cl)cccc2cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72.6 %

Procedure:
The product of Example 71B (0.156 g, 0.77 mmol) in THF:toluene (10 mL, 1:1) was treated with a solution of 2,4-dichloro-1-(isocyanatomethyl)benzene (0.195 g, 0.97 mmol) in THF (1.0 mL). After stirring for 16 hours at room temperature, the reaction mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether to provide the title compound as a tan solid (0.226 g, 73%). MS (ESI+) m/z 404 (M+H)+; MS (ESI−) m/z 402 (M−H)−; 1H NMR (DMSO-d6, 300 MHz) δ 3.96 (s, 3H), 4.44 (d, J 6.0, 2H), 7.29 (m, 1H), 7.48 (m, 1H), 7.65 (d, J 1.7, 1H), 7.76 (t, J 7.8, 1H), 7.86 (d, J 7.8, 1H), 8.41 (dd, J 1.0, 7.8, 1H), 8.84 (s, 1H), 9.15 (s, 1H), 9.35 (s, 1H); Anal. Calcd for C19H15Cl2N3O3: C, 56.45; H, 3.74; N, 10.39. Found: C, 56.08; H, 3.67; N, 10.03.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH:35]1[CH2:37][CH2:36]1)[CH2:10][O:11][C:12]1[C:30]([F:31])=[CH:29][C:28]([N+:32]([O-])=O)=[CH:27][C:13]=1[CH2:14][N:15](C)[C:16](=O)OCC1C=CC=CC=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>CO.[Pd]>[Si:1]([O:8][C@@H:9]([CH:35]1[CH2:36][CH2:37]1)[CH2:10][O:11][C:12]1[C:13]([CH2:14][NH:15][CH3:16])=[CH:27][C:28]([NH2:32])=[CH:29][C:30]=1[F:31])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc([N+](=O)[O-])cc(F)c1OC[C@@H](O[Si](C)(C)C(C)(C)C)C1CC1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNCc1cc(N)cc(F)c1OC[C@@H](O[Si](C)(C)C(C)(C)C)C1CC1
Reaction time: 5 h
Yield: 97.1 %

Procedure:
To a solution of 21F (92 mg, 0.173 mmol) in MeOH (5 mL) was added 10% Pd—C (50 mg, 0.047 mmol). The mixture was evacuated and flushed with H2 (3×), then was stirred under a balloon of H2 for 5 h. The mixture was filtered and concentrated to give 21G (62 mg, 0.168 mmol, 97% yield). MS (ESI) m/z: 369.4 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH2:12])[CH3:11])=[CH:6][CH:5]=1.C[O:16][C:17](=O)[C:18]1[C:23]([I:24])=[CH:22][C:21]([F:25])=[CH:20][C:19]=1[CH2:26]Br.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[F:25][C:21]1[CH:20]=[C:19]2[C:18](=[C:23]([I:24])[CH:22]=1)[C:17](=[O:16])[N:12]([CH:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=1)[CH3:11])[CH2:26]2
Reactant: CC(N)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1c(I)cc(F)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(c1ccc(OC(F)(F)F)cc1)N1Cc2cc(F)cc(I)c2C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 41.3 %

Procedure:
A mixture of 1-(4-trifluoromethoxy-phenyl)-ethylamine (0.246 mL, 1.2 mmol), 2-bromomethyl-4-fluoro-6-iodo-benzoic acid methyl ester (0.372 g, 1.0 mmol), and K2CO3 (0.276 g, 2 mmol) in toluene (3 mL) was heated with stirring at 100° C. for 2 h. The resulting mixture was filtered and concentrated. Silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-Fluoro-7-iodo-2-[1-(4-trifluoromethoxy-phenyl)-ethyl]-2,3-dihydro-isoindol-1-one (0.192 g, 41%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.68 (d, 3H), 3.88-4.26 (dd, 2H), 5.78 (q, 1H), 7.06 (d, 1H), 7.20 (d, 2H), 7.41 (d, 2H), 7.67 (d, 1H). GC-MS: m/z 465 (M)+, 450 (M−15)+.
Reaction SMILES: Cl.[NH2:2][C:3]1([CH3:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:9][S:10](Cl)(=[O:12])=[O:11]>N1C=CC=CC=1>[CH3:8][C:3]1([NH:2][S:10]([CH3:9])(=[O:12])=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CC1(N)CCCC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC1(NS(C)(=O)=O)CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
To a stirred solution of 1-amino-1-methylcyclopentane hydrochloride (0.165 g, 1.2 mmol) in pyridine (1 mL) was added methanesulfonyl chloride (0.169 mL, 2.2 mmol). The reaction mixture was stirred at room temperature for 16 hrs and then concentrated. The mixture was diluted with ethyl acetate and washed with 1 N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered, and concentrated to afford the product as a brown oil (0.100 g, 46%). 1H NMR (300 MHz, CDCl3) δ 4.27 (br s, 1H), 3.04 (s, 3H), 2.00-1.60 (m, 8H), 1.50 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:33])[CH2:11][N:12]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:15])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:1][O:8][NH:9][C:10](=[O:33])[CH2:11][N:12]([S:22]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)(=[O:24])=[O:23])[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:15]
Reactant: COc1ccc(S(=O)(=O)N(CC(=O)NOCc2ccccc2)CC(=O)N2CCOCC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CONC(=O)CN(CC(=O)N1CCOCC1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
To a solution of N-benzyloxy-[(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino]acetamide (0.33 grams, 0.69 mmol) in methanol (35 mL) was added 5% palladium on activated carbon (85 mg). The mixture was agitated under 2 atmospheres hydrogen in a Parr shaker for 1.5 hours. The catalyst was removed by filtration through nylon (pore size 0.45 μm) and the solvent was evaporated. The residue was chromatographed on silica gel eluting with 5% methanol in methylene chloride to afford N-methoxy-[(4-methoxybenzenesulfonyl)(2-morpholin-4-yl-2-oxoethyl)amino]acetamide as a white solid, 65 mg (24%); 1H NMR (CD3OD): δ 7.82 (d, J=9.0 Hz, 2H), 7.08 (d, J=9.0 Hz, 2H), 4.24 (s, 2H), 3.88 (s, 3H), 3.84 (s, 2H), 3.68-3.64 (m, 4H), 3.581-3.50 (m, 4H); MS (thermospray): m/z 388 (M+1), 387 (M); HRMS calculated for C16H22N3O7S (M+H): 388.1178, Found 338.1180.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.CC1C=CC(S(O[C@H:20]2[CH2:24][CH2:23][O:22][CH2:21]2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C@@H:20]2[CH2:24][CH2:23][O:22][CH2:21]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCOC2)cc1
Reactant: Oc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Brc1ccc(O[C@@H]2CCOC2)cc1
Temperature: 85 °C
Yield: 35.8 %

Procedure:
A mixture of 4-bromophenol (2.1 g, 12.4 mmole), (S)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate (2.5 g, 10.3 mmole) and K2CO3 (4.3 g, 30.9 mmole) in DMF (15 mL) was heated at 85° C. for 15 h. The mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by ISCO (silica gel, elute: 5% ethyl acetate in hexane) to give the title compound (896 mg). MS (ESI) m/z: Found: 244.3 (M++1). Calc. 243.1 (M+).
Reaction SMILES: O[N:2]=[C:3]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH:4]1[CH2:15][C:16]([O:18]CC)=[O:17].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:30](O)=[O:31]>>[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:30]([NH:2][C@H:3]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][C@H:4]1[CH2:15][C:16]([OH:18])=[O:17])=[O:31]
Reactant: CCOC(=O)CC1CN(c2ccccc2)C(=O)C1=NO
Reactant: O=C(O)c1cc2ccccc2[nH]1
Product: O=C(O)C[C@@H]1CN(c2ccccc2)C(=O)[C@@H]1NC(=O)c1cc2ccccc2[nH]1

Procedure:
The aminopyrrolidinone of Example 63 is coupled with indole-2-carboxylic acid according to the procedure described in Example 4 and the resulting ester is saponified to give the title homologated acid.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:21][C:22]1[N:27]=[CH:26][C:25]([C@H:28]([NH2:30])[CH3:29])=[CH:24][N:23]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:20][C:17]1[CH:18]=[CH:19][C:12]([N:10]2[CH2:9][CH2:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:30][C@@H:28]([C:25]4[CH:24]=[N:23][C:22]([CH3:21])=[N:27][CH:26]=4)[CH3:29])[C:3]=3[CH2:11]2)=[C:13]([CH:16]=1)[C:14]#[N:15]
Reactant: Cc1ncc([C@@H](C)N)cn1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(N[C@H](C)c4cnc(C)nc4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (350 mg, 1.23 mmol) and (R)-1-(2-methylpyrimidin-5-yl)ethanamine (300 mg, 2.19 mmol) in acetonitrile (3 mL) and N,N-diisopropylethylamine (0.86 mL, 4.9 mmol) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by semi-preparative HPLC (100×20.2 mm, C18 column; 30-55% acetonitrile-water [10 mM Et2NH]) to yield an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.CN1CCOCC1>CO>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][S:17]([C:15]2[CH:14]=[CH:13][C:11]3[N:12]=[C:8]([C:3]4[C:4]([CH3:7])=[N:5][NH:6][C:2]=4[NH2:1])[S:9][C:10]=3[CH:16]=2)(=[O:19])=[O:18])=[CH:24][CH:23]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: NCc1ccc(Cl)cc1
Solvent: CO
Solvent: CN1CCOCC1
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCc3ccc(Cl)cc3)cc2s1
Yield: 16.1 %

Procedure:
the title compound (21 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), 4-chlorobenzylamine (74 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 434.4 (Cl35 M+1, 100%), 436.4 (Cl37 M+1, 40%). Yield=16%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1>>[CH3:2][O:3][C:4]([C:6]1([NH:12][C:19]([C:18]2[CH:22]=[CH:23][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[O:20])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1)=[O:5]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)C1(N)CCCCC1
Agent: Cl
Product: COC(=O)C1(NC(=O)c2ccc(OC)cc2)CCCCC1
Yield: 70.8 %

Procedure:
581 mg (3 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride was used instead of 1-aminocyclohexanecarboxylic acid phenylmethyl ester, and 512 mg (3 mmol) of 4-methoxybenzoyl chloride was used instead of phenylacetyl chloride in the process according to Reference Example 1 to obtain 619 mg (71%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[O:14][C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[O:14][C:15]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1O
Reactant: Nc1nc(-c2ccccc2)c(-c2ccccc2)o1
Product: O=C(Nc1nc(-c2ccccc2)c(-c2ccccc2)o1)c1cc(Br)ccc1O

Procedure:
Using 5-bromosalicylic acid and 2-amino-4,5-diphenyloxazole as the raw materials, the same operation as the example 16 gave the title compound. (2-Amino-4,5-diphenyloxazole: refer to Zh. Org. Khim., 1980, 16, 2185.)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]3=[C:15]([O:28][CH3:29])[C:16]([C:18]([NH:20][CH2:21][CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[O:19])=[CH:17][N:13]3[N:12]=[CH:11][N:10]=2)=[C:4]([F:30])[CH:3]=1.[CH3:31]NCCN1CCCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]3=[C:15]([O:28][CH3:29])[C:16]([C:18]([N:20]([CH3:31])[CH2:21][CH2:22][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[O:19])=[CH:17][N:13]3[N:12]=[CH:11][N:10]=2)=[C:4]([F:30])[CH:3]=1
Reactant: CNCCN1CCCC1
Reactant: COc1c(C(=O)NCCN2CCCC2)cn2ncnc(Nc3ccc(Br)cc3F)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1c(C(=O)N(C)CCN2CCCC2)cn2ncnc(Nc3ccc(Br)cc3F)c12
Yield: 86.1 %

Procedure:
To a solution of Compound A of Example 98 (20 mg, 0.052 mmol) in DMF (1 mL) was added 1-(2-methylaminoethyl)-pyrrolidine (10 mg, 0.078 mmol) and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (25 mg, 0.056 mmol). After 1 hr at 25° C. the mixture was purified directly by preparative HPLC, the product was collected, converted to its HCl salt and lyophilized to provide 22 mg (80%) of the title compound. MS: [M+H]+=491,493 (1:1);1H NMR (CD3OD): δ 8.27 (s, 1H), 7.83 (s, 1H), 7.73 (d, J=7.9 Hz, 1H), 7.65–7.55 (m, 2H), 4.09 (s, 3H), 3.99–3.96 (m, 4H), 3.85 (br s, 2H), 3.58–3.51 (m, 2H), 3.29–3.15 (m, 5H), 2.19–2.07 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[N:10]([CH2:18][CH2:19][CH3:20])[C:9]=1[CH3:21].[CH2:22]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:30])[C:26]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:18][CH2:19][CH3:20])[C:9]([CH3:21])=[C:8]2[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])([CH3:28])[CH3:27])[CH3:23]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCn1c(C)c(-c2ccccc2Cl)c2cc(O)ccc21
Product: CCCn1c(C)c(-c2ccccc2Cl)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
Following a procedure analogous to that of Example 10, the above compound was prepared from 3-(2-chloro-phenyl)-2-methyl-1-propyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([O:9][CH2:10][C:11](O)=[O:12])[C:3]=1[Cl:14].[NH3:15]>>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([O:9][CH2:10][C:11]([NH2:15])=[O:12])[C:3]=1[Cl:14]
Reactant: N
Reactant: Nc1c(Cl)cnc(OCC(=O)O)c1Cl
Product: NC(=O)COc1ncc(Cl)c(N)c1Cl
Temperature: 70 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
To a 75 milliliter stainless steel bomb is added 15 grams (0.06 mole) of 4-amino-3,5-dichloro-2-(pyridyloxy)acetic acid:ethyl ester, prepared as in Example I. The bomb was cooled to about minus 70° C. in a dry ice bath and thereafter 7 grams (0.04 mole) of ammonia was distilled into the bomb. The bomb was sealed and allowed to stand at room temperature for 48 hours. The bomb was opened and the unreacted ammonia allowed to escape. The solid residue which remained was removed from the bomb and recrystallized from 250 milliliters of ethanol. The 4-amino-3,5-dichloro-2-(pyridyloxy)acetamide product was dried azeotropically with benzene and was recovered in a yield of 72 percent of theoretical and melted at 192°-193° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH:10]1[CH2:16][CH:15]2[N:17]([CH3:18])[CH:12]([CH2:13][CH2:14]2)[CH2:11]1)=O.O.[NH2:20][NH2:21]>C(O)C>[NH:20]1[C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]([CH:10]2[CH2:16][CH:15]3[N:17]([CH3:18])[CH:12]([CH2:13][CH2:14]3)[CH2:11]2)=[N:21]1
Reactant: NN
Reactant: CN1C2CCC1CC(C(=O)c1ccccc1F)C2
Solvent: O
Solvent: CCO
Product: CN1C2CCC1CC(c1n[nH]c3ccccc13)C2
Temperature: 25 °C

Procedure:
A mixture of (2-fluorophenyl) (8-methyl-8-azabicyclo-[3.2.1]octan-3-yl) methanone (24.6 g), hydrazine hydrate (14.4 ml), and ethanol (250 ml) was heated to reflux for four hours. The reaction was cooled to room temperature and concentrated to an oil. This residue was dissolved in dimethylformamide (DMF) (250 ml). Potassium carbonate (28 g) was added to the mixture which was subsequently heated at reflux for 2 days. The reaction mixture was cooled and filtered and the DMF was removed in vacuo. residue was dissolved in ethanol and 5.2 g of 3-(1H-indazol-3-yl)-8-methyl-8-azabicyclo[3.2.1]octane precipitated from solution, as a powder, m.p. 191°-192° C.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:29]=1[CH:30]=O.[OH-].[Na+]>CO>[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:29]=1[CH:30]=[CH:2][C:1]([C:4]1[CH:26]=[CH:25][C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(=O)C=Cc2c(Cl)cccc2Cl)cc1
Reaction time: 72 h
Yield: 85 %

Procedure:
To a stirred solution at room temperature of III (150 mg, 0.42 mmol), 2,6-dichlorobenzaldehyde (148 mg, 0.85 mmol) or aldehyde (1.5–2.0 equiv.) in MeOH (10 ml) was added a solution of NaOH (1.7 ml, 1N in H2O). A pale yellow precipitate appeared. After 3 days, the reaction mixture was filtered off, rinsed with H2O. The solid residue was then dissolved in AcOEt, dried over anhydrous MgSO4, filtered and concentrated. The crude residue was finally purified by flash chromatography on silica gel (AcOEt/hexane:20/80→40/60) to afford the title compound IVc (185 mg, 0.36 mmol, 85% yield) as a pale yellow foam. 1H NMR (300 MHz, CDCl3) δ(ppm): 9.48 (bs, 1H), 8.11 (s, 4H), 7.96 (d, J=17.1 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.68 (d, J=16.3 Hz, 1H), 7.42 (d, J=7.9 Hz, 2H), 7.35–7.15 (m, 4H), 6.68 (s, 1H), 1.54 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[F:11])#[N:2].[CH3:12][Mg+].[Br-]>C1COCC1.CCOCC>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]([OH:8])[CH3:12])=[CH:5][C:4]=1[F:11])#[N:2]
Reactant: C[Mg+]
Reactant: N#Cc1ccc(C=O)cc1F
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1ccc(C#N)c(F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 4-cyano-3-fluorobenzaldehyde, as described above in Step B, (250 mg, 1.68 mmol) in THF, under argon, at −78° C. was added MeMgBr dropwise (0.59 mL of a 3.0 M solution in Et2O, 1.77 mmol). The reaction mixture was stirred at −78° C. for 1 hour, then quenched with saturated aqueous NH4Cl, allowed to warm to ambient temperature, and extracted with CH2Cl2 (2×40 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with a gradient of hexane—20% to 40% EtOAc, to yield the titled product as a white solid.
Reaction SMILES: [Cl-].[CH2:2]([O:4][C:5]([C:7]1[N:8]=[C:9]([CH:12]2[CH2:17][CH2:16][NH2+:15][CH2:14][CH2:13]2)[S:10][CH:11]=1)=[O:6])[CH3:3].[CH3:18][C:19]1[N:23]([CH2:24][C:25](O)=[O:26])[N:22]=[C:21]([C:28]([F:31])([F:30])[F:29])[CH:20]=1>>[CH3:18][C:19]1[N:23]([CH2:24][C:25]([N:15]2[CH2:16][CH2:17][CH:12]([C:9]3[S:10][CH:11]=[C:7]([C:5]([O:4][CH2:2][CH3:3])=[O:6])[N:8]=3)[CH2:13][CH2:14]2)=[O:26])[N:22]=[C:21]([C:28]([F:30])([F:29])[F:31])[CH:20]=1
Reactant: CCOC(=O)c1csc(C2CC[NH2+]CC2)n1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Agent: [Cl-]
Product: CCOC(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1

Procedure:
4-[4-(Ethoxycarbonyl)-1,3-thiazol-2-yl]piperidinium chloride (VI-1, 4.65 g) is reacted analogously to Example IV-1 with [5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetic acid (3.50 g). This gives, after chromatographic purification, ethyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (5.00 g, 69%).