Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C@@H:7]([C:9]([OH:11])=[O:10])[NH2:8])=[CH:4][CH:3]=1.Cl[C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16]>CO>[CH2:18]([O:17][C:15]([NH:8][CH:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=1)[C:9]([OH:11])=[O:10])=[O:16])[CH:19]=[CH2:20]
Reactant: C=CCOC(=O)Cl
Reactant: N[C@@H](Cc1ccc(Cl)cc1)C(=O)O
Solvent: CO
Product: C=CCOC(=O)NC(Cc1ccc(Cl)cc1)C(=O)O

Procedure:
The product is prepared by methods (ET3N, methanol) known from the literature starting from 10 g of 4-chlorophenylalanine and 8 ml of allyl chloroformate. MW=283.71 (calculated monoisotopic); measured value (M+H)+: 284.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.Cl.[C:17]1([S:23]([CH:26]2[CH2:30][CH2:29][NH:28][CH2:27]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:28]1[CH2:29][CH2:30][CH:26]([S:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:25])=[O:24])[CH2:27]1)=[O:15]
Reactant: O=S(=O)(c1ccccc1)C1CCNC1
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Agent: Cl
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCC(S(=O)(=O)c2ccccc2)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-(benzenesulfonyl)pyrrolidine hydrochloride (12.7 mg, 0.051 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (13.5 mg). Calcd for C20H17ClN2O4 S: 416.0598, found 416.0591.
Reaction SMILES: C([NH:18][C@H:19]([C:30]([OH:32])=[O:31])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][CH:22]=1)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.N1CCCCC1>O>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][C@@H:19]([C:30]([OH:32])=[O:31])[NH2:18])=[CH:22][CH:23]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)c1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Solvent: C1CCNCC1
Solvent: O
Product: CC(=O)c1ccc(C[C@H](N)C(=O)O)cc1
Yield: 88 %

Procedure:
Fmoc-p-acetyl-L-phenylalanine was purchased from RSP Amino Acid Analogues, Inc. (Worcester, Mass.). This compound (1.0 g, 2.3 mmol) was stirred with 4 mL of piperidine (20% in dimethyl formamide (DMF)) for 2 hours at room temperature. The solvent was evaporated to obtain white powder. The solid was then resuspended in 10 mL of cold water (0.1% trifluoroacetic acid (TFA)), and the supernatant was collected by filtration. Preparative reverse-phase HPLC (Microsorb C18, Rainin Instrument Co., Inc., Woburn, Mass.) was used to separate the desired product from the reaction mixture (5-30% CH3CN in H2O with 0.1% TFA over 30 min). The eluant (tR=12 min) was lyophilized to obtain a white solid (0.45 g, 88%). 1H NMR (400 MHz D2O): δ 7.85-7.28 (m, 4H), 4.23 (dd, 1H, 5.4 Hz), 3.2 (m, 2H), 2.7 (s, 3H). MS electrospray ionization (ESI): [M+1]+ calcd for C11H13NO3 208.09, found 208.47.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].C[Si]([N:14]=[C:15]=[O:16])(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:15]([NH2:14])=[O:16])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Product: NC(=O)Nc1cc(F)cc(F)c1
Reaction time: 8 h
Yield: 37.6 %

Procedure:
To a stirred solution of 3,5-difluoroaniline (4.0 g, 31 mmol, 1.00 equiv) in CH2Cl2 (50 mL) under argon at room temperature was added dropwise trimethylsilyl isocyanate (3.56 g, 30.90 mmol, 1.00 equiv). The reaction mixture was stirred overnight and quenched by the dropwise addition of CH3OH (50 mL). The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography using CHCl3/CH3OH (10:1 to 7:1) as eluent to yield the title compound (2.0 g, 38%) as a white solid. 1H-NMR (400 MHz, DMSO-d6): δ ppm 8.96 (s, 1H), 7.16-7.10 (m, 2H), 6.72-6.66 (m, 1H), 6.07 (br s, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[C:23]([C:28](O)=[O:29])[CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH3:64][CH:65]1[CH2:70][CH2:69][CH2:68][CH2:67][CH:66]1[NH2:71]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([NH:14][S:15]([C:18]2[C:27]3[C:22](=[C:23]([C:28](=[O:29])[NH:71][CH:66]4[CH2:67][CH2:68][CH2:69][CH2:70][CH:65]4[CH3:64])[CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)(=[O:16])=[O:17])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CCCCC1N
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2cccc3c(C(=O)O)cccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCCC1NC(=O)c1cccc2c(S(=O)(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)cccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 125.9 %

Procedure:
4-(5-Carboxy-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester 46 (246 mg, 0.57 mmol) was dissolved in dichloromethane (5 mL). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (323 mg, 0.85 mmol) was added followed by diisopropylethyl amine (214 mg, 0.29 mL, 1.66 mmol) and 2-methyl-cyclohexylamine (71 mg, 0.63 mmol). The reaction was stirred overnight at room temperature. The reaction mixture was charged to a flash column. Elution with 99:1 dichloromethane:methanol afforded 47 (380 mg) as a white foam that was contaminated with tetramethylurea, but suitable for use without further purification. 1H NMR (300 MHz, CDCl3) (1:1 mixture of diastereomers) δ 8.70 (m, 1H), 8.55 (d, 1H), 8.33 (d. 1H), 7.64 (m, 3H), 5.81 (d, 0.5H), 5.55 (d, 0.5H), 4.66 (d, 1H), 3.82 (m, 2H), 3.00 (m, 2H), 2.70 (m, 2H), 1.80 (m, 2H), 1.40 (s, 9H), 1.23 (m, 5H), 1.11 (d, 1.5H), 0.97 (d, 1.5H); LC/MS m/z 530 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]([F:22])=[CH:9][C:10]3[C:15](=[O:16])[N:14]([OH:17])[C:13](=[O:18])[N:12]([CH2:19][CH3:20])[C:11]=3[N:21]=2)[CH2:3]1.F[C:24](F)(F)C([O-])=O>>[CH2:19]([N:12]1[C:11]2[N:21]=[C:7]([N:4]3[CH2:5][CH2:6][N:1]([CH3:24])[CH2:2][CH2:3]3)[C:8]([F:22])=[CH:9][C:10]=2[C:15](=[O:16])[N:14]([OH:17])[C:13]1=[O:18])[CH3:20]
Reactant: O=C([O-])C(F)(F)F
Reactant: CCn1c(=O)n(O)c(=O)c2cc(F)c(N3CCC(N)C3)nc21
Product: CCn1c(=O)n(O)c(=O)c2cc(F)c(N3CCN(C)CC3)nc21

Procedure:
7-(3-Aminopyrrolidin-1-yl)-1-ethyl-6-fluoro-3-hydroxy-1H-pyrido[2,3-d]pyrimidine-2,4-dione, trifluoroacetate;
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:6]=[C:7](Cl)[C:8]2[CH:13]=[CH:12][N:11]([CH3:14])[C:9]=2[N:10]=1)[CH2:2][CH3:3].CCN(C(C)C)C(C)C.Cl.[CH:26]12[NH:33][CH:30]([CH2:31][CH2:32]1)[CH2:29][CH:28]([OH:34])[CH2:27]2.O>C(O)CCC>[CH3:14][N:11]1[C:9]2[N:10]=[C:5]([NH:4][CH2:1][CH2:2][CH3:3])[N:6]=[C:7]([N:33]3[CH:26]4[CH2:32][CH2:31][CH:30]3[CH2:29][CH:28]([OH:34])[CH2:27]4)[C:8]=2[CH:13]=[CH:12]1
Reactant: CCCNc1nc(Cl)c2ccn(C)c2n1
Reactant: OC1CC2CCC(C1)N2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: O
Product: CCCNc1nc(N2C3CCC2CC(O)C3)c2ccn(C)c2n1
Temperature: 125 °C
Reaction time: 16 h
Yield: 56.4 %

Procedure:
To a solution of 2-(n-propyl)amino-4-chloro-7-methyl-pyrrolo[2,3-d]pyrimidine (CXXIV) (1.0 g, 4.5 mmol) in n-butanol (10 mL) were added DIPEA (1.0 g, 7.8 mmol) and 8-aza-bicyclo[3.2.1]octan-3-ol hydrochloride (1.1 g, 6.7 mmol). The mixture was stirred at 125° C. for 16 h. After cooling to room temperature, water (20 mL) was added, and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with water and then with a brine solution, and dried over anhydrous Na2SO4. The solvents were removed in vacuo and the resultant residue was purified by flash column chromatography (pet ether/EtOAc=6/1) to yield 8-(7-methyl-2-(n-propylamino)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-8-azabicyclo[3.2.1]octan-3-ol (CLIV) (800 mg, 57% yield) as a yellow solid. LCMS (ESI) m/z=316 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:21][CH3:22].[CH3:23][C:24]1[C:33]2[CH:32]=[N:31][C:30](S(C)=O)=[N:29][C:28]=2[N:27]([C:37]2[CH:38]=[C:39]([NH:43][C:44](=[O:47])[CH:45]=[CH2:46])[CH:40]=[CH:41][CH:42]=2)[C:26](=[O:48])[CH:25]=1.CCN(C(C)C)C(C)C.O1CCOCC1>C(O)(C)(C)C>[CH3:22][O:21][C:3]1[CH:4]=[C:5]([N:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:6]=[CH:7][C:2]=1[NH:1][C:30]1[N:31]=[CH:32][C:33]2[C:24]([CH3:23])=[CH:25][C:26](=[O:48])[N:27]([C:37]3[CH:38]=[C:39]([NH:43][C:44](=[O:47])[CH:45]=[CH2:46])[CH:40]=[CH:41][CH:42]=3)[C:28]=2[N:29]=1
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reactant: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(S(C)=O)nc32)c1
Solvent: C1COCCO1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(N5CCNCC5)cc4OC)nc32)c1
Temperature: 90 °C

Procedure:
To a suspension of tert-butyl 4-(4-amino-3-methoxyphenyl)piperazine-1-carboxylate (18a, 539 mg, 1.753 mmol) and N-(3-(5-methyl-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5b, 432 mg, 1.173 mmol) in tert-butanol (15 mL) at RT was added DIEA (0.61 mL, 3.52 mmol) followed by dioxane (6 mL). The reaction mixture was heated in a heating block at 90° C. for 20 h. LC-MS analysis indicated roughly 13% conversion to the desired product along with unreacted starting materials. The reaction mixture was concentrated on the rotovap and the crude residue was suspended in Et2O and filtered. The greenish brown amorphous solid was washed with Et2O (3×20 mL) and this removed most of the aniline starting material (18a). The crude material contained roughly 19% of the desired product (18b) along with recovered 5b. m/z (ESI, +ve ion) 611.9 (M+H)+. The crude residue was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C([N:8](CC)CC)C.[N:13]1([CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3([CH2:34][NH:35][CH2:36][CH3:37])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[CH:24][CH:23]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1>ClCCl>[NH3:8].[CH2:36]([N:35]([CH2:34][C:28]1([C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][CH2:18][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:27][CH:26]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[S:2]([CH3:1])(=[O:4])=[O:3])[CH3:37]
Reactant: CCNCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCN(CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1)S(C)(=O)=O
Product: N
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
Methanesulfonyl chloride (19 μL, 0.24 mmol) was added dropwise to a solution of triethylamine (31 μL, 0.22 mmol) and N-({4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}methyl)ethanamine (70 mg, 0.20 mmol) in dichloromethane (0.5 mL) at 0° C. then was allowed to warm to ambient temperature and stirred overnight. The reaction was quenched with NaHCO3 (10 mL), extracted using dichloromethane (3×15 mL), dried using Na2SO4 and concentrated in vacuo. The compound was purified by column chromatography on Biotage® silica gel, eluting with dichloromethane:methanol:ammonia, 96.5:3.5:0.35 to 95:5:0.5 to give the title compound as a pale brown oil (60 mg, 71%). 1H NMR (400 MHz, CDCl3) δ 7.24 (d, 2H), 6.90 (d, 2H), 4.02 (t, 2H), 3.84-3.72 (m, 2H), 3.50 (dt, 2H), 3.28 (s, 2H), 2.72-2.60 (m, 7H), 2.58-2.52 (m, 4H), 2.16 (m, 2H), 2.04 (pentet, 2H), 1.96-1.90 (m, 2H), 1.84-1.76 (m, 4H), 0.90 (t, 3H); HRMS (ESI+) 425.2469 (M+H)+.
Reaction SMILES: [O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][NH:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]3)[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1.[F:27][C:28]([F:35])([F:34])[C:29](OCC)=[O:30]>CO>[O:1]1[C:10]2[CH:9]=[C:8]([CH2:11][N:12]([CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]3)[C:29](=[O:30])[C:28]([F:35])([F:34])[F:27])[N:7]=[CH:6][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCCC(CNCc2cc3c(cn2)OCCO3)C1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCCC(CN(Cc2cc3c(cn2)OCCO3)C(=O)C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1.3 g of tert-butyl 3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)methyl)piperidine-1-carboxylate in 10 mL of methanol, 0.54 mL of ethyl trifluoroacetate was added, and a mixture was stirred at room temperature for 2 hours, and then stirred at 40 to 45° C. for 3 hours. Thereto was added 0.54 mL of ethyl trifluoroacetate, and the mixture was heated under reflux while stirring for 3 hours. The mixture was cooled to room temperature, and the solvent was then distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography using an eluent of hexane:ethyl acetate=1:1 to obtain 0.47 g of tert-butyl 3-(((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(trifluoroacetyl)amino)-methyl)piperidine-1-carboxylate as a colorless oily substance.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([OH:10])=O.ClCCCl.[F:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:26](=[O:37])[NH:27][C@H:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:29][CH3:30])[C:17]=1[C:18]([OH:20])=O.C(N(CC)CC)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[C:18](=[O:20])[O:37][C:26]([NH:27][C@H:28]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:29][CH3:30])=[C:25]2[C:8](=[O:10])[CH2:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1]
Reactant: O=C(O)CN1CCCC1=O
Reactant: CC[C@H](NC(=O)Cc1cccc(F)c1C(=O)O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC[C@H](Nc1oc(=O)c2c(F)cccc2c1C(=O)CN1CCCC1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a solution of 2-oxo-pyrrolidin-1-yl-acetic acid (1.56 g, 10.9 mmol) in 1,2-dichloroethane (40 ml) oxalyl chloride (0.95 ml, 10.9 mmol) and DMF (1 drop) were added with gas evolution observed. After stirring at r.t. for 1 hour, 2-fluoro-6-[((S)-1-phenyl-propylcarbamoyl)-methyl]-benzoic acid (1.56 g, 4.95 mmol), triethylamine (2.1 ml, 14.9 mmol) and DMAP (85 mg, 0.1 eq.) were added and stirred at r.t. overnight. It was partitioned between mixture of 0.2 M aq. HCl (100 ml)—brine (100 ml) and ethyl acetate (250 ml), washed with water and evaporated to give 1.89 g of crude title compound used in the next step without further purification.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH:5]([N:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([Cl:17])[C:11]=3[C:10]3=[N:18][O:19][C:20]([CH3:21])=[C:9]3[C:8]2=[O:22])[CH:4]=[CH:3]1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH2:31][C:32](O)=[O:33].CCN(CC)CC.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:17][C:12]1[C:11]2[C:10]3[C:9](=[C:20]([CH3:21])[O:19][N:18]=3)[C:8](=[O:22])[N:7]([CH:5]3[CH2:6][CH:2]([NH:1][C:32](=[O:33])[CH2:31][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[O:24][CH3:23])[CH:3]=[CH:4]3)[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: Cc1onc2c1c(=O)n(C1C=CC(N)C1)c1cccc(Cl)c21
Reactant: COc1ccccc1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=O)NC1C=CC(n2c(=O)c3c(C)onc3c3c(Cl)cccc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
To a stirred solution of 5-(4-amino-cyclopent-2-enyl)-9-chloro-3-methyl-5H-isoxazolo[4,3-c]quinolin-4-one (97 mg, 0.31 mmol) in CH2Cl2 (4 mL) was added 2-methoxy phenyl acetic acid (66.3 mg, 0.40 mmol), Et3N (0.11 ml, 0.40 mmol) and EDCI (77 mg, 0.40 mmol) and stirred at r.t. for 18 hours. The mixture was diluted with CH2Cl2, washed (brine), dried (Na2SO4), filtered and concentrated. Column chromatography (silica gel, hexanes/ethyl acetate, gradient) gave the title compound (59 mg, 41%). Mass Spectrum (FIA) (m/z) 464.2 (M+1) Anal. Calc. For C25H22ClN3O4. Theoretical: C, 64.73, H, 4.78, N, 9.06%. Found. C, 64.78, H, 4.91, N, 8.83%.
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.[CH2:16]([O:18][C:19](=[O:27])[CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH3:17].[Cl:28][C:29]1[N:34]=[C:33]([Cl:35])[C:32]([CH2:36]I)=[CH:31][N:30]=1>O1CCCC1.C(OCC)(=O)C>[CH2:16]([O:18][C:19](=[O:27])[CH:20]([C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:36][C:32]1[C:33]([Cl:35])=[N:34][C:29]([Cl:28])=[N:30][CH:31]=1)[CH3:17]
Reactant: Clc1ncc(CI)c(Cl)n1
Reactant: CCOC(=O)Cc1cccnc1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1cnc(Cl)nc1Cl)c1cccnc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of N-isopropylcyclohexylamine (1.44 g, 10.0 mmol) (Aldrich) in dry tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M in hexanes, 4.0 mL, 10.0 mmol) (Aldrich) at −78° C. under argon. After 10 minutes, a solution of 2-pyridin-3-yl-acetic acid ethyl ester (1.65 g, 10.0 mmol) (Acros) in tetrahydrofuran (5 mL) was added by injection via a syringe and the reaction mixture was stirred at −78° C. for another 10 minutes. To the reaction mixture was added a solution of 2,4-dichloro-5-iodomethyl-pyrimidine (1.45 g, 5.0 mmol) (from Example 1c supra) in tetrahydrofuran (5 mL) at −78° C. and the reaction mixture was stirred at the same temperature for 2 hours then slowly allowed to warm up to −20° C. and stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (100 mL), water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to give 3-(2,4-dichloro-pyrimidin-5-yl)-2-pyridin-3-yl-propionic acid ethyl ester as a brown oil. (Yield 1.10 g, 68.0%).
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)=[O:27])[CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(O)C.Cl>O.O1CCCC1>[C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]4[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:34][CH:35]=4)=[O:27])[CH:21]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCc1cn(Cc2cccc(C(=O)NCc3ccc(C(F)(F)F)cc3)c2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: O=C(O)CCc1cn(Cc2cccc(C(=O)NCc3ccc(C(F)(F)F)cc3)c2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
A mixture of ethyl 3-[3-phenyl-1-[3-(4-trifluoromethylbenzylaminocarbonyl)benzyl]-1H-pyrazol-4-yl]propionate (870 mg), 1 N aqueous sodium hydroxide solution (2 ml), ethanol (6 ml), and tetrahydrofuran (4 ml) was stirred at room temperature for one hour. The reaction mixture was poured into water, then 1 N hydrochloric acid (2 ml) was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The obtained crystals were collected by filtration, and 3-[3-phenyl-1-[3-(4-trifluoromethylbenzylaminocarbonyl)benzyl]-1H-pyrazol-4-yl]propionic acid (730 mg, yield: 89%) was obtained. This was recrystallized from acetone-isopropyl ether. Melting point: 165–166° C.
Reaction SMILES: [NH:1]([C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])[NH2:2].O.C(=O)([O-])O.[Na+].[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25]>O1CCCC1.C(OCC)(=O)C>[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([NH:2][NH:1][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])=[O:25]
Reactant: NNC(=O)OCc1ccccc1
Reactant: O=C(Cl)c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NNC(=O)c1ccco1)OCc1ccccc1
Reaction time: 1 h
Yield: 88.4 %

Procedure:
Benzyl hydrazinecarboxylate (1.66 g, 10.0 mmol) was dissolved in tetrahydrofuran (20 mL) and water (20 mL) and added sodium hydrogen carbonate (1.68 g) thereto. Under ice cooling, furan-2-carbonyl chloride (1.30 g, 10 mmol) was gradually added, followed by stirring for 1 hour. After completion of the reaction, to the reaction solution was added 300 ml of ethyl acetate, followed by washing with saturated ammonium chloride solution and saturated brine. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and 5 ml of ethyl acetate was dissolved in the resulting residue, followed by gradually adding hexane (100 ml) to afford 2.30 g of the title compound as a solid (yield 88.4%).
Reaction SMILES: C(OC1C(OC)=CC=C(I)C=1O)C1C=CC=CC=1.C(N1C=C(C#C)C=N1)C1C=CC=CC=1.COC1C=C(I)C=C(OC)C=1OC.[CH2:46]([N:53]1[CH:57]=[C:56]([C:58]2[O:59][C:60]3[C:80]([O:81]CC4C=CC=CC=4)=[C:79]([O:89][CH3:90])[CH:78]=[CH:77][C:61]=3[C:62]=2[C:63]([C:65]2[CH:70]=[C:69]([O:71][CH3:72])[C:68]([O:73][CH3:74])=[C:67]([O:75][CH3:76])[CH:66]=2)=[O:64])[CH:55]=[N:54]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CCCCCC.C(OCC)(=O)C>[CH2:46]([N:53]1[CH:57]=[C:56]([C:58]2[O:59][C:60]3[C:80]([OH:81])=[C:79]([O:89][CH3:90])[CH:78]=[CH:77][C:61]=3[C:62]=2[C:63]([C:65]2[CH:66]=[C:67]([O:75][CH3:76])[C:68]([O:73][CH3:74])=[C:69]([O:71][CH3:72])[CH:70]=2)=[O:64])[CH:55]=[N:54]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: COc1cc(C(=O)c2c(-c3cnn(Cc4ccccc4)c3)oc3c(OCc4ccccc4)c(OC)ccc23)cc(OC)c1OC
Agent: C#Cc1cnn(Cc2ccccc2)c1
Agent: COc1cc(I)cc(OC)c1OC
Agent: COc1ccc(I)c(O)c1OCc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)c2c(-c3cnn(Cc4ccccc4)c3)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Reaction time: 8 h

Procedure:
Application of the general procedure to 2-benzyloxy-6-iodo-3-methoxy-phenol, 1-benzyl-4-ethynyl-1H-pyrazole and 3,4,5-trimethoxy-iodo-benzene (NB—the initial coupling proceeded slowly and was continued overnight) and silica-gel flash chromatography (eluent=40% ethyl acetate in hexane) gave a mixture of the title compound, [2-(1-benzyl-1H-pyrazol-4-yl)-7-benzyloxy-6-methoxy-benzofuran-3-yl]-(3,4,5-trimethoxyphenyl)-methanone and the corresponding non-carbonyl inserted derivative. This mixture was again subjected to silica-gel flash chromatography (sequential elution—2% diethyl ether in DCM, 10%). Concentration of the first eluted fractions afforded a mixture of the 7-benzyloxy derivative and the non-carbonyl inserted material and was used in subsequent chemistry. The later fractions gave the title compound (2% yield) as a pale yellow solid. An analytical sample was obtained by recrystallisation from DCM and hexane. 1H-NMR (CDCl3) δ 8.08 (s, 1H), 8.03 (s, 1H), 7.36-7.27 (m, 3H), 7.22-7.19 (m, 2H), 7.10 (s, 2H), 6.80 (d, J=8.6 Hz, 1H), 6.74 (d, J=8.6 Hz, 1H), 5.28 (s, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 3.74 (s, 6H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][CH2:6][C:7]1[C:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1.C(N(CC)CC)C>C1COCC1>[C:1]([NH:5][CH2:6][C:7]1[C:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: NCc1ncccc1CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCc1ncccc1CCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Add dropwise with stirring a solution of 1.24 gm acetyl chloride in 10 ml THF to a cooled solution of 3.2 gm of 2-aminomethyl-3-(2-phenylethyl)pyridine and 2.3 ml triethylamine in 100 ml THF. Warm the reaction mixture to room temperature and then stir for an additional 0.5 hour. Filter off the triethylamine hydrochloride and evaporate the filtrate under reduced pressure. Chromatograph on silica gel using 40% THF in chloroform to obtain 2-acetamidomethyl-3-(2-phenylethyl)pyridine.