Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.Cl.Cl.[NH2:25][CH:26]1[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1>C(Cl)Cl.C1(C)C=CC=CC=1.[OH-].[Na+]>[N:28]12[CH2:33][CH2:32][CH:31]([CH2:30][CH2:29]1)[CH:26]([NH:25][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=1[CH3:1])[CH2:27]2
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: NC1CN2CCC1CC2
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)NC2CN3CCC2CC3)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
2,3-dimethylbenzoic acid (5.0 g; 33.3 mmol), oxalyl chloride (40.0 mmol, 3.5 mL) and dimethylformamide (0.1 mL) were dissolved in methylene chloride (100 mL). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. A solution of the concentrate in toluene (100 mL) was added dropwise to a stirred solution of (RS)-3-amino-1-azabicyclo[2.2.2]octane dihydrochloride (7.0 g; 35 mmol)in toluene (50 mL) and NaOH (2.0N, 50 mL) at 0° C. The reaction mixture was maintained at 0° C. and stirred for 30 minutes. The aqueous layer was extracted with of toluene (2×50 mL) and the combined organic layers dried over magnesium sulfate. Removal of the solvent under reduced pressure gave (RS)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2,3-dimethylbenzamide as a white solid (5.5 g, 25.4 mmol), m.p. 160°-161° C. The hydrochloride salt is prepared from ethanol-hydrogen chloride.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl:9][C:10]1[C:15](I)=[CH:14][N:13]=[CH:12][N:11]=1.[O:17]1[CH2:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH2:19][CH2:18]1>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C(O[Pd]OC(=O)C)(=O)C>[Cl:9][C:10]1[C:15]([C:20]2[CH2:21][CH2:22][O:17][CH2:18][CH:19]=2)=[CH:14][N:13]=[CH:12][N:11]=1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: Clc1ncncc1I
Agent: CC(=O)O[Pd]OC(C)=O
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Clc1ncncc1C1=CCOCC1
Temperature: 80 °C

Procedure:
To a 150 mL sealable flask was added potassium phosphate (4.21 g, 19.83 mmol), dppf (0.264 g, 0.476 mmol), diacetoxypalladium (0.053 g, 0.238 mmol), 4-chloro-5-iodopyrimidine (1.907 g, 7.93 mmol), and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.75 g, 8.33 mmol) as a solution in DME (45.3 mL)/water (7.56 mL). The vessel was sealed and heated to 80° C. for 20 h. The reaction mixture was cooled to room temperature and diluted with water before extracting with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, and concentrated under reduced pressure to a dark brown oil that was used without purification. MS (ESI, pos. ion) m/z: 176.2 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[CH2:22][CH2:21]2)=[O:19])[C:13]([O:15]C)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[OH-].[Na+]>CO>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:36])[CH2:22][CH2:21]2)=[O:19])[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2]
Reactant: CCc1ccc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)OC)cc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1ccc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1CC

Procedure:
The crude product (6 g, 11.84 mmol) described in 7a) was placed in 120 mL MeOH, combined with 40 mL 1M NaOH (40 mmol) and refluxed for 5 h. The reaction mixture was concentrated by evaporation in vacuo, the residue was combined with 150 mL of water and 40 mL 1M HCl, exhaustively extracted with DCM and the combined organic phases were dried over MgSO4. After elimination of the desiccant and solvent the residue was triturated with diisopropylether and suction filtered.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([OH:32])=[O:31].C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:27]4[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=4)[C:30]([OH:32])=[O:31])[CH2:21][CH2:20]3)=[N:15][CH:14]=2)=[O:25])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)nc2)c1
Reactant: O=C(O)c1cccc(Br)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4cccc(C(=O)O)c4)CC3)nc2)c1

Procedure:
3-{4-[5-(3-tert-Butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was synthesized from N-(3-tert-butyl-phenyl)-6-piperazin-1-yl-nicotinamide and 3-bromo benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C27H30N4O3 (m/e) 458, obsd 459 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]#[C:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][N:3]=1.[CH:15]1([C:18]2[NH:22][N:21]=[C:20]([NH2:23])[CH:19]=2)[CH2:17][CH2:16]1>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:23][C:20]2[CH:19]=[C:18]([CH:15]3[CH2:17][CH2:16]3)[NH:22][N:21]=2)[C:5]([C:9]#[C:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][N:3]=1
Reactant: C[Si](C)(C)C#Cc1cnc(Cl)nc1Cl
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: CCO
Product: C[Si](C)(C)C#Cc1cnc(Cl)nc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
A mixture of 2,4-dichloro-5-((trimethylsilyl)ethynyl)pyrimidine (1.0 g, 4.1 mmol, 1.0 eq) and 5-cyclopropyl-1H-pyrazol-3-amine (756 mg, 6.2 mmol, 1.5 eq) in EtOH (4 ml) was stirred at room temperature for 2 h. The mixture was purified by silica gel column chromatography (PE/EtOAc=5:1 to 2:1) to afford 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-((trimethylsilyl)ethynyl)pyrimidin-4-amine (900 mg, 66%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:4][CH:3]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:11][C:10]([F:13])([F:12])[CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:17]2[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]2)=[CH:3][CH:4]=1
Reactant: FC(F)(F)COc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(OCC(F)(F)F)cc2)CC1
Temperature: 80 °C
Yield: 158.1 %

Procedure:
1-bromo-4-(2,2,2-trifluoroethoxy)benzene (14.5 g, 57 mmol) was dissolved in toluene (250 ml) under an argon atmosphere. tert-Butyl piperazine-1-carboxylate (12.7 g, 68 mmol), sodium tert-butoxide (7.6 g, 79.5 mmol) rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (200 mg, 0.32 mmol) and tris(dibenzylideneacetone)dipalladium(0) (200 mg, 0.2 mmol) were added and the reaction heated to 80° C. for 4 hours. The mixture was then cooled and filtered through Celite to yield crude tert-butyl 4-[4-(2,2,2-trifluoroethoxy)phenyl]piperazine-1-carboxylate (32.47 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22]([O:24]CC)=[O:23])[N:11]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:10]=1[C:35]([O:37]CC)=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C1COCC1.Cl>C(O)C>[CH2:1]([O:8][C:9]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:12]([C:22]([OH:24])=[O:23])[N:11]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:10]=1[C:35]([OH:37])=[O:36])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(OCc2ccccc2)c(OCc2ccccc2)c(C(=O)OCC)n1-c1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(-n2c(C(=O)O)c(OCc3ccccc3)c(OCc3ccccc3)c2C(=O)O)cc1
Temperature: 25 °C
Yield: 77.5 %

Procedure:
A mixture of diethyl 3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylate (1) (2.8 g, 5.29 mmol), 2M NaOH (aq.) (26.4 mL, 52.9 mmol), in ethanol (12 mL) and THF (20 mL) was stirred at 60° C. for 72 h. After cooling to RT, the mixture was acidified with 6M HCl (aq.) and the resulting precipitate was collected by filtration, washed with water (5 mL), and Et2O (5 mL) to afford 4-bis(benzyloxy)-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylic acid (2) (1.94 g, 67%) as an off-white solid: m/z 474 (M+H)+ (ES+); 472 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ 12.61 (s, 2H), 7.46-7.40 (m, 4H), 7.39-7.29 (m, 6H), 7.16-7.07 (m, 2H), 6.92-6.84 (m, 2H), 5.07 (s, 4H), 3.78 (s, 3H).
Reaction SMILES: [NH2:1][C:2](=[S:26])[C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([F:13])[CH:12]=1)[N:9]=[CH:8][C:7]([C:14]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[O:15])=[C:6]2[OH:25].C1COCC1.C(Cl)Cl.O(C)S(C(F)(F)F)(=O)=O.[N:44]1C=CC=CC=1>>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][NH:16][C:14]([C:7]2[CH:8]=[N:9][C:10]3[C:5]([C:6]=2[OH:25])=[CH:4][C:3]([C:2]([NH:1][NH2:44])=[S:26])=[CH:12][C:11]=3[F:13])=[O:15])=[CH:19][CH:20]=1
Reactant: c1ccncc1
Reactant: NC(=S)c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: COS(=O)(=O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: NNC(=S)c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 0.75 h

Procedure:
To a suspension of the title compound of Example 52 (0.60 g) in 20 mL 1:1 THF:CH2Cl2 at room temperature is added methyl triflate (0.2 mL). The reaction is stirred for 45 minutes after which time everything goes into solution. Pyridine (0.38 mL) is added and then H2S is bubbled in for 1 hour. Nitrogen is then purged through the reaction for 30 minutes. Hydrazine monohydrate (0.28 mL) is added dropwise to the reaction mixture. The reaction is stirred for 1 hour after which time the solution turned from an orange to a pale yellow color and a precipitate is observed. The solid in the reaction is filtered and dried to give the desired product (0.26 g).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:15]=[CH:14][C:13]3[N:12]=[C:11]([CH3:16])[NH:10][C:9](=[O:17])[C:8]=3[C:7]=2[CH:18]=1.[CH3:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)=[O:21].C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:20]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH2:2][C:3]2[CH:4]=[CH:5][C:6]3[CH:15]=[CH:14][C:13]4[N:12]=[C:11]([CH3:16])[NH:10][C:9](=[O:17])[C:8]=4[C:7]=3[CH:18]=2)=[CH:24][CH:23]=1)(=[O:21])[CH3:19]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: Cc1nc2ccc3ccc(CBr)cc3c2c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(NCc2ccc3ccc4nc(C)[nH]c(=O)c4c3c2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
9-Bromomethyl-3-methyl benzo[f]quinazolin-1(2H)-one (1 g, 3.3 mmole) and 4-aminoacetophenone (0.89 g, 6.6 mmole) (Aldrich) were dissolved in dimethylformamide (15 ml). The solution was stirred under nitrogen at 100° C. for 30 min. Sodium bicarbonate (0.55 g, 6.6 mmole) was added and stirring was continued for a further 30 min. Dimethylformamide was removed in vacuo, the residue triturated with water and the solid collected by filtration. The dried solid was subjected to chromatography on silica (methanol/methylene chloride (1:19)). Fractions containing product were concentrated until solid began to precipitate. The solution was chilled at 5° C. for 12 hours, then the solid filtered off and dried under high vacuum to yield the title compound (0.48 g, 41%). Mp>235° C. 1H NMR (DMSO-d6, 300 MHz) δ: 2.37 (s, 3H, CH3); 2.43 (s, 3H, CH3); 4.59 (d, J=6 Hz, 2H, CH2); 6.65 (d, J=9 Hz, 2H, Ar); 7.37 (t, J=6 Hz, 1H, ArNH); 7.59 (d, J=9 Hz, 1H, Ar); 7.61 (dd, J=8, 2 Hz, 1H, Ar); 7.69 (d, J=9 Hz, 2H, Ar); 8.00 (d, J=8 Hz, 1H, Ar); 8.21 (d, J=9 Hz, 1H, Ar); 9.85 (s, 1H, Ar); 12.52 (s, 1H, NH). Anal Calculated for C22H19N3O2.1/2 H2O: C,72.11; H,5.50; N,11.47. Found: C,72.26; H,5.46; N,11.35.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:15])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.[Cl:16][S:17](O)(=[O:19])=[O:18].C(Cl)(=O)C(Cl)=O.CN(C)C=O>ClCCl>[CH3:1][O:2][C:3]1[C:4]([S:17]([Cl:16])(=[O:19])=[O:18])=[CH:5][C:6]2[CH2:7][CH2:8][C:9](=[O:15])[C:10]([CH3:13])([CH3:14])[C:11]=2[CH:12]=1
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc2c(cc1S(=O)(=O)Cl)CCC(=O)C2(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the dichloromethane (2 ml) solution of 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 200 mg, 0.980 mmol), chlorosulfonic acid (110 μl, 1.70 eq.) was added and the mixture was stirred at room temperature for 2 hr. To the reaction solution, oxalyl chloride (297 μl, 3.0 eq.) and N,N-dimethyl formamide (45 μl, 0.6 eq.) were added in three divided portions, and the mixture was stirred at room temperature for 30 min. The reaction solution was concentrated under reduced pressure to obtain the title compound (295 mg). Since the title compound is unstable, its structure was identified in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]23[O:15][C@@:12]([CH2:16][OH:17])([CH2:13][O:14]2)[C@@H:11]([OH:18])[C@H:10]([OH:19])[C@H:9]3[OH:20])=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=1.[C:31](Cl)(=[O:33])[CH3:32].CO>N1C(C)=CC(C)=CC=1C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]23[O:15][C@@:12]([CH2:16][O:17][C:31](=[O:33])[CH3:32])([CH2:13][O:14]2)[C@@H:11]([OH:18])[C@H:10]([OH:19])[C@H:9]3[OH:20])=[CH:4][C:3]=1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH3:30])=[CH:26][CH:27]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Reactant: CC(=O)Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](COC(C)=O)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a vigorously stirred solution of (1S,2S,3S,4R,5S)-5-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-1-hydroxymethyl-6,8-dioxa-bicyclo[3.2.1]octane-2,3,4-triol (1A, 0.481 g, 1.1 mmol) in collidine (2.5 mL) cooled to −35 degrees Celsius was added drop-wise over 10 minutes acetyl chloride (0.149 mL, 2.1 mmol). After 1 hour, methanol (0.5 mL) was added and the reaction mixture was allowed to warm to room temperature. The crude mixture was concentrated under reduced pressure and codistilled three times with toluene. The crude material was purified by flash chromatography over silica gel using the biotage automated chromatography unit (50 g silica gel column) and eluting with a gradient of 0 to 15% methanol in dichloromethane. 456 mg (87% yield) of product obtained as a white solid.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH2:13][NH:12][CH2:11][CH2:10]3)[CH2:5][C@H:4]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[O:3]1.C(N(CC)CC)C.[CH2:33]([O:40][CH2:41][C:42](Cl)=[O:43])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[CH2:13][N:12]([C:42](=[O:43])[CH2:41][O:40][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:11][CH2:10]3)[CH2:5][C@H:4]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:24])[CH3:23])[O:3]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc3c(c2)CCNC3)C(=O)O1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H]1CN(c2ccc3c(c2)CCN(C(=O)COCc2ccccc2)C3)C(=O)O1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
A solution of 1,1-dimethylethyl [[(5S)-2-oxo-3-[1,2,3,4-tetrahydro-6-isoquinolinyl]-5-oxazolidinyl]methyl]carbamate (Example 6, Step 2, 347 mg, 0.999 mmol) and triethylamine (0.21 mL, 1.50 mmol) in dry CH2Cl2 at 0° C. under N2 is treated with benzyloxyacetyl chloride (0.19 mL, 1.20 mmol), and the resulting mixture is stirred at 0° C. for 1 hr and then allowed to warm to ambient temperature. The reaction mixture is then diluted with CH2Cl2 (20 mL), washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue is chromatographed on a Flash 40S silica gel (40 g, 32-63 μm) cartridge, eluting with a gradient of MeOH/CH2Cl2 (1/99-2/98), and those fractions with an Rf=0.72 by TLC (MeOH/CHCl3, 10/90) are pooled and concentrated to give 425 mg (86%) of the title compound as an amorphous, glassy solid. MS (ESI+) for C27H33N3O6 m/z 496 (M+H)+.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[O:10][CH:9]([CH3:14])[CH2:8]2)(=[NH:4])[NH2:3].C([C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)O[CH:22]([CH3:27])[CH2:21]2)(O)=O.C[O-].[Na+]>CO>[CH3:14][CH:9]1[CH2:8][C:7]2[C:11](=[CH:12][CH:13]=[C:5]([C:2]3[N:3]=[CH:13][C:5]([C:26]4[CH:18]=[CH:19][C:20]([CH2:21][CH2:22][CH2:27][CH2:9][CH2:8][CH2:7][CH2:11][CH3:12])=[CH:24][CH:25]=4)=[CH:2][N:4]=3)[CH:6]=2)[O:10]1
Reactant: CC1Cc2cc(C(=N)N)ccc2O1
Reactant: CC1Cc2cc(C(=O)O)ccc2O1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCc1ccc(-c2cnc(-c3ccc4c(c3)CC(C)O4)nc2)cc1
Yield: 58.4 %

Procedure:
0.40 g (1.88 mM) of 5-amidino-2-methylcoumaran hydrochloride (M5) as an intermediate product prepared in Example 1, 0.79 g (1.90 mM) of 3-dimethylamino-2-(4-octylphenyl)-N,N-dimethylpropene-(2)-ammonium perchlorate 0.41 g (7.59 mM) of sodium methylate and 15 ml of methanol were placed in a 50 ml-round bottomed flask and refluxed for 5 hours and 10 minutes under stirring. After the reaction, the reaction mixture was cooled on an ice-common salt bath to precipitate a crystal. The crystal was recovered by filtration, followed by washing with water. The resultant crystal was dissolved in toluene and dried with mirabilite. After distilling-off of the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluent:toluene/ethyl acetate=100/1) and recrystallized from a mixture solvent of toluene and methanol to obtain 0.44 of 2 (-2methylcoumaran-5-yl)-5-(4-octylphenyl)pyrimidine (Ex. Comp. No. I-235) (Yield: 58.4%). The product showed the following phase transition temperatures (°C.). ##STR92##
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:8][CH:7]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[C:36]([NH2:41])[CH:35]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].Cl.CN(C)CCCN=C=NCC.C(Cl)Cl>CN(C)C1C=CN=CC=1.CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[F:20])[O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14]([NH:41][C:36]2[CH:35]=[C:34]([CH:31]3[CH2:30][CH2:29][N:28]([C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:33][CH2:32]3)[CH:39]=[CH:38][C:37]=2[F:40])=[O:16])=[CH:10][CH:11]=1
Reactant: O=C(O)CCc1ccc(Oc2ccc(F)c(F)c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)c(N)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(F)c(NC(=O)CCc3ccc(Oc4ccc(F)c(F)c4)cc3)c2)CC1
Reaction time: 12 h
Yield: 25.1 %

Procedure:
A 25-mL RB-flask was charged with 3-[4-(3,4-difluorophenoxy)phenyl]propanoic acid (180 mg, 0.650 mmol), tert-butyl-4-(3-amino-4-fluorophenyl)-1-piperidine carboxylate (180 mg, 0.610 mmol), 1-[3-(Dimethylamino) propyl]-3-ethylcarbodimide hydrochloride (1.22 mmol, 190 mg), 4-dimethylaminopyridine (20 mg) in DMF:DCM (0.4:4.0 mL) at room temperature. The reaction mixture was stirred for 12 h and water (10.0 mL) was added to the reaction mixture. The organic layer was separated and the aqueous layer was extracted with CHCl3 (3×10 mL) The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by chromatography (silica gel, hexanes:EtOAc 6:1) to afford tert-butyl 4-[3-({3-[4-(3,4-difluorophenoxy)phenyl]propanoyl}amino)-4-fluorophenyl]-1-piperidinecarboxylate (85.0 mg, 25.0%): 1H NMR (400 MHz, CDCl3) δ 8.32-8.15 (m, 1H), 7.47-6.45 (m, 10H), 4.41-4.07 (br, 2H), 3.17-2.96 (m, 2H), 2.90-2.67 (m, 4H), 2.67-2.56 (m, 1H), 1.91-1.69 (m, 2H), 1.68-1.48 (m, 2H), 1.47 (s, 9H); ESMS m/e 553.3 (M−H+).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][C:17]3[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:24])=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:25](O)=[O:26])#[N:2].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[CH2:52]([NH2:56])[CH:53]([CH3:55])[CH3:54].C(N(C(C)C)CC)(C)C>CN(C)C=O.ClCCl>[CH2:52]([NH:56][C:25]([C:7]1[N:6]([CH2:5][CH2:4][CH2:3][C:1]#[N:2])[C:14]2[C:9]([CH:8]=1)=[CH:10][C:11]([O:15][CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])=[CH:12][CH:13]=2)=[O:26])[CH:53]([CH3:55])[CH3:54]
Reactant: CC(C)CN
Reactant: N#CCCCn1c(C(=O)O)cc2cc(OCc3c(Cl)cccc3Cl)ccc21
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CNC(=O)c1cc2cc(OCc3c(Cl)cccc3Cl)ccc2n1CCCC#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.3 %

Procedure:
1-(3-Cyanopropyl)-5-(2,6-dichlorobenzyloxy)-1H-indole-2-carboxylic acid (0.10 g, 0.25 mmol), from Example 2(a), was dissolved in dimethylformamide (15 mL). PyBroP (bromo-tris-pyrrolidino-phosphonium hexafluorophosphate) (0.13 g, 0.27 mmol) was added followed by isobutylamine (0.054 g, 0.74 mmol), diisopropylethylamine (0.13 g, 0.99 mmol), and a catalytic amount of N,N-dimethylaminopyridine. The reaction mixture was stirred for 18 h under argon at ambient temperature. The solution was diluted with dichloromethane and washed with water (3X) and brine. The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification by flash chromatography (silica gel, 30% ethyl acetate/hexanes) yielded a white solid (0.076 g, 67%). MS(ES) m/e 458.2 [M +H]+.