Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[C:5]([C:7]2[CH:16]=[CH:15][C:14]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[CH:8]=2)[N:6]=1.[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29]1[O:30][C:31]([CH3:46])=[C:32]([CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39]([CH2:42][C:43](O)=[O:44])=[CH:38][CH:37]=2)[N:33]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl>O.CN(C)C=O>[O:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[C:29]1[O:30][C:31]([CH3:46])=[C:32]([CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39]([CH2:42][C:43]([NH:1][C:2]3[S:3][C:4]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[C:5]([C:7]4[CH:16]=[CH:15][C:14]5[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=5[CH:8]=4)[N:6]=3)=[O:44])=[CH:38][CH:37]=2)[N:33]=1
Reactant: CCOC(=O)CCc1sc(N)nc1-c1ccc2c(c1)CCCC2
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(CC(=O)Nc2nc(-c3ccc4c(c3)CCCC4)c(CCC(=O)O)s2)cc1
Reaction time: 72 h
Yield: 56.6 %

Procedure:
A mixture of ethyl 3-[2-amino-4-(5,6,7,8-tetrahydro-2-naphthyl)-5-thiazolyl]propionate (270 mg), [4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]phenyl]acetic acid (250 mg), WSC (170 mg), HOBt (135 mg) and N,N-dimethylformamide (10 ml) was stirred for 3 days. The reaction mixture was poured into water, neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was dissolved in ethanol (9 ml)-tetrahydrofuran (1 ml) and 1N aqueous sodium hydroxide solution (2 ml) was added at 0° C. The mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into water, neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and 3-[2-[[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]phenyl]acetylamino]-4-(5,6,7,8-tetrahydro-2-naphthyl)-5-thiazolyl]propionic acid (270 mg,57%) was obtained as an amorphous oil from a fraction eluted with acetone-hexane (3:2, volume ratio).
Reaction SMILES: [CH3:1][CH:2]([CH:4]([CH2:11][C:12](=[O:21])[CH2:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=1)[CH2:5][C:6]([O:8]CC)=O)[CH3:3].[O-]CC.[Na+]>>[CH3:3][CH:2]([CH:4]1[CH2:5][C:6](=[O:8])[CH:13]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=2)[C:12](=[O:21])[CH2:11]1)[CH3:1]
Reactant: CCOC(=O)CC(CC(=O)Cc1cc(C)ccn1)C(C)C
Agent: CC[O-]
Agent: [Na+]
Product: Cc1ccnc(C2C(=O)CC(C(C)C)CC2=O)c1

Procedure:
The procedure of Example 2 was used to prepare the title compound from ethyl 3-(1-methylethyl)-6-(4-methyl-2-pyridinyl)-5-oxohexanoate and sodium ethoxide using a 2 hour reflux period in ethanol. The product was liberated as an oil from the aqueous phase by adjusting the pH to about 5 and recovered by ether extraction. The ether extract was worked up giving a semi-solid which was recrystallized successively from ethyl acetate and isopropyl ether giving the product as a solid, mp 104.5°-106.5° C. The confirmatory elemental analysis is shown in Table II.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:15][CH:14]([NH2:16])[C:13]2[C:8](=[CH:9][C:10]([Cl:18])=[CH:11][C:12]=2[Cl:17])[NH:7]1)=[O:5].C(N(CC)CC)C.[C:26]([O:30][C:31]([NH:33][CH2:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](O)=[O:39])=[O:32])([CH3:29])([CH3:28])[CH3:27].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:2][O:3][C:4]([C@H:6]1[CH2:15][C@H:14]([NH:16][C:38]([C:37]2[CH:41]=[CH:42][CH:43]=[C:35]([CH2:34][NH:33][C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH:36]=2)=[O:39])[C:13]2[C:8](=[CH:9][C:10]([Cl:18])=[CH:11][C:12]=2[Cl:17])[NH:7]1)=[O:5]
Reactant: CC(C)(C)OC(=O)NCc1cccc(C(=O)O)c1
Reactant: COC(=O)C1CC(N)c2c(Cl)cc(Cl)cc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1C[C@H](NC(=O)c2cccc(CNC(=O)OC(C)(C)C)c2)c2c(Cl)cc(Cl)cc2N1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of 2-methoxycarbonyl-5,7-dichloro-4-amino-1,2,3,4-tetrahydroquinoline hydrochloride (Example 9) (300 mg, 0.963 mmol) in anhydrous dichloromethane (15 ml) under an atmosphere of nitrogen was added dry triethylamine (403 μl, 2.89 mol) and the resulting mixture was stirred at room temperature for 5 min. To this was added 3-(tertbutyloxycarbonylamino)methyl benzoic acid (step a) (290 mg, 1.16 mmol), 1-hydroxybenzotriazole (156 mg, 1.16 mol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (222 mg, 1.16 mmol) and stirring was continued for approximately 18 h. The mixture was then concentrated in vacuo and the residue partitioned between ethyl acetate (100 ml) and 0.5M citric acid (150 ml). The organic layer was retained and washed successively with 0.5M citric acid (150 ml), saturated sodium bicarbonate solution (2×150 ml) and brine (100 ml) before drying (Na2SO4). The solvent was removed and the residue was recrystallised from ethyl acetate/hexane to give the title compound as colourless crystals (351 mg), m.p. 222°-223° C. δ (DMSO, 250 MHz) 1.39 (9H, s, C(CH3)3), 1.78 (1H, ddd, J=12.8, 12.6 and 3.9 Hz, CHACHBHCCHD), 2.26 (1H, dm, J=12.8 Hz, CHACHBHCCHD), 3.71 (3H, s, COOCH3), 4.05 (1H, dd, J=13.0 and 3.0 Hz, CHACHBHCCHD), 4.14 (2H, d, J=5.8 Hz, ArCH2NH), 5.26 (1H, m, CHACHBHCCHD), 6.69 (1H, d, J=2.1 Hz, 6-H or 8-H), 6.90 (1H, d, J=2.1 Hz, 6-H or 8-H), 6.93 (1H, s, ArNHCH), 7.37 (3H, m, Ar-H and CH2NHCO), 7.71-7.76 (2H, m, Ar-H), 8.68 (1H, d, J=7.1 Hz); m/e 507 (M+), 198 (100%, M-H, CO2CH2CH3,NHCOC6H4CH2NHCOOC(CH3)3).
Reaction SMILES: N[C:2]1[C:11](N)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C1C2C(OC(=O)C3C=2C2C(C(OC(=O)C=2C=1)=O)=CC=3)=O>CN1C(=O)CCC1>[CH:8]1[C:9]2[C:4](=[CH:3][CH:2]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc2ccccc2cc1N
Agent: O=C1OC(=O)c2ccc3c4c(ccc1c24)C(=O)OC3=O
Solvent: CN1CCCC1=O
Product: c1ccc2ccccc2c1
Temperature: 350 °C

Procedure:
To a solution of 15.82 g (100 mmol) of 2,3-diamino naphthalene in 100 mL of NMP was added 3.4 g (50 mmol) of 1,4,5,8-naphthalenetetracarboxylic dianhydride (NDA), and the formulation was mixed on a roller mill for 16 hours to form the 2:1 amic adduct. Ten grams of this solution was added to 75 g of a 16% solution of polyamic ethyl ester (PAETE). The NMP solution was spin coated on a quartz substrate to a thickness of 2 μm and heated at 350° C. for 20 min. The resulting film exhibited absorbance of 0.68 at 405 nm and 0.35 at 436 nm; thermogravimetric analysis (TGA) indicated a weight loss of 0.18% when heated from 350° to 450° over a period of 100 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:14]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][N:12]([C:20](Cl)=[O:21])[CH:11]3[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[F:30])[C:5]2=[CH:4][CH:3]=1.CC1(C)[O:37][C@@H:36]([CH2:38][CH2:39][NH2:40])[CH2:35][O:34]1.C(N(CC)CC)C.Cl>O1CCCC1>[OH:37][C@H:36]([CH2:35][OH:34])[CH2:38][CH2:39][NH:40][C:20]([N:12]1[CH2:13][CH:14]([CH2:15][C:16]([CH3:18])([CH3:17])[CH3:19])[C:10]2([C:5]3[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:9]2=[O:31])[CH:11]1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[F:30])=[O:21]
Reactant: CC(C)(C)CC1CN(C(=O)Cl)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CC1(C)OC[C@H](CCN)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1CN(C(=O)NCC[C@H](O)CO)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
To a solution of rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carbonyl chloride (0.14 g, 0.28 mmol) in tetrahydrofuran (5 mL) was added 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine prepared in Example 7 (49 mg, 0.34 mmol) and triethylamine (0.078 mL, 0.56 mmol). The reaction mixture was stirred at room temperature for 1 h. An aqueous HCl solution (1 N, 2 mL) was added. The reaction mixture was stirred at room temperature for 0.5 h. The solvents were removed and the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3 solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichlormethane and hexanes to give rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (Yield 75 mg, 50%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:9][NH:8][N:7]=1)=[O:5])[CH3:2].[H-].[Na+].[CH:20]([N:23]([CH2:27]C)[CH:24](C)C)(C)[CH3:21].ClCCN(C)C.Cl>CN(C=O)C.[I-].[K+].O>[CH2:1]([O:3][C:4]([CH:6]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)=[CH:9][NH:8][N:7]1[CH2:21][CH2:20][N:23]([CH3:27])[CH3:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]cc1-c1ccc(F)cc1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)CCCl
Agent: Cl
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1C(c2ccc(F)cc2)=CNN1CCN(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.3 %

Procedure:
4-(4-Fluoro-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (2.4 g, 10 mmol) was added to an ice-cooled slurry of sodium hydride (0.82 g, 60% dispersion in mineral oil, 20 mmol) in DMF (20 ml), under argon. N,N-diisopropylethylamine (1.8 ml, 10 mmol) was added followed by 2-chloro-ethyl dimethylamine.HCl (1.48 g, 10 mmol) and potassium iodide (5 mg). The reaction mixture was stirred at room temperature for 16 h then at 80° C. for 48 h. 2N HCl and water were added and the product extracted with ethyl acetate (3×). The combined organics were washed with brine, dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel, 3-10% methanol-dichloromethane) afforded 2-(2-dimethylamino-ethyl)-4-(4-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid ethyl ester (900 mg) and the title compound (630 mg).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:37])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19]([N:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][C@@H:24]3[CH3:36])=[N:18][N:17]=[CH:16]4)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Cl>CO>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:37])=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[C:19]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][C@@H:24]3[CH3:36])=[N:18][N:17]=[CH:16]4)[CH:12]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)nncc2c1
Agent: Cl
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCNC[C@@H]3C)nncc2c1
Reaction time: 1 h

Procedure:
(3S)-Tert-butyl 4-(6-(5-(cyclopropylcarbamoyl)-2-methylphenyl)phthalazin-1-yl)-3-methylpiperazine-1-carboxylate (0.2, 0.4 mmol) (Method A) was dissolved in 10 mL MeOH and treated with a 4M solution of HCl (1 mL, 4 mmol) at RT and stirred for 1 h. The mixture was concentrated in vacuo, diluted with 100 mL dichloromethane, washed with sat. NaHCO3, dried over anhydrous Na2SO4 and concentrated in vacuo. The mixture was purified by silica gel chromatography, eluting with 2 M ammonia MeOH/dichloromethane to give the title compound. Found MS (ES+): 402(M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([O:15][C:16](=[O:41])[C:17]([CH2:39][CH3:40])([CH2:37][CH3:38])[CH2:18][C:19]1[S:20][C:21]([C:24]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33](=[NH:35])[NH2:34])=[CH:29][C:28]=2[F:36])=[O:25])=[CH:22][CH:23]=1)C1C=CC=CC=1>CC(O)C.O.[OH-].[Pd+2].[OH-]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:33]([C:30]1[CH:31]=[CH:32][C:27]([O:26][C:24]([C:21]2[S:20][C:19]([CH2:18][C:17]([CH2:39][CH3:40])([CH2:37][CH3:38])[C:16]([OH:41])=[O:15])=[CH:23][CH:22]=2)=[O:25])=[C:28]([F:36])[CH:29]=1)(=[NH:34])[NH2:35]
Reactant: CCC(CC)(Cc1ccc(C(=O)Oc2ccc(C(=N)N)cc2F)s1)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC(C)O
Product: CCC(CC)(Cc1ccc(C(=O)Oc2ccc(C(=N)N)cc2F)s1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.8 %

Procedure:
3-[5-(4-Amidino-2-fluorophenoxycarbonyl)thiophen-2-yl]-2,2-diethylpropanoic acid benzyl ester trifluoroacetic acid salt (4.3 g, 7.21 mmol) was dissolved in 2-propanol (160 mL) and water (40 mL), palladium hydroxide (0.9 g) was added, and the mixture was stirred at room temperature overnight under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Water and acetonitrile was added to the residue, the mixture was lyophilized to give the title compound (3.61 g, 7.12 mmol, 99%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH3:16])=[C:11]([CH2:13][CH2:14]Cl)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:18][C:19]1[CH:33]=[CH:32][C:22]2[C:23]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:24][O:25][C:21]=2[CH:20]=1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH3:16])=[C:11]([CH2:13][CH2:14][N:29]3[CH2:28][CH2:27][CH:26]([C:23]4[C:22]5[CH:32]=[CH:33][C:19]([F:18])=[CH:20][C:21]=5[O:25][N:24]=4)[CH2:31][CH2:30]3)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(sc(CCCl)c2C)C1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Product: CC(=O)N1CCc2c(sc(CCN3CCC(c4noc5cc(F)ccc45)CC3)c2C)C1

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.0 g of 6-acetyl-2-(2-chloroethyl)-4,5,6,7-tetrahydro-3-methylthieno[2,3-c]pyridine and 1.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 6-acetyl-2-(2-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-3-methylthieno[2,3-c]pyridine as an oil.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[C:20]([OH:23])[CH:21]=[CH:22][C:13]2=3)=[O:11])[CH:6]=[CH:7][CH:8]=1.[Cl:26][C:27]1[CH:32]=[C:31](Cl)[N:30]=[CH:29][N:28]=1>CC(C)=O.O.[OH-].[Na+].CCOC(C)=O>[F:25][C:2]([F:24])([F:1])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[C:20]([O:23][C:31]4[CH:32]=[C:27]([Cl:26])[N:28]=[CH:29][N:30]=4)[CH:21]=[CH:22][C:13]2=3)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)N1CCCCc2cc(O)ccc21
Reactant: Clc1cc(Cl)ncn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(C(F)(F)F)c1)N1CCCCc2cc(Oc3cc(Cl)ncn3)ccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 1.00 g (2.85 mMol) of 7-hydroxy-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide (Step 6.2) and 447 mg (3.0 mMol) 4,6-dichloro-pyrimidine in 8 ml acetone, 5 ml H2O and 3 ml NaOH 1 M is stirred at rt for 5 h. The reaction mixture is diluted with water and EtOAc, the aqueous phase separated off and extracted twice with EtOAc. The organic layers are washed with water and brine, dried (Na2SO4) and concentrated. Chromatography (Combi Flash; hexane/EtOAc 19:1→7:3→1:4) gives the title compound: m.p.: 120° C.; MS: [M+1]+=463/465; Anal.: C,H,N,F,Cl.
Reaction SMILES: [Cl-].[NH2:2][C:3]([NH2:5])=[NH2+:4].CC(C)([O-])C.[K+].[CH2:12]([NH:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH:25]=[C:26]([CH3:32])[C:27](OCC)=[O:28])=[O:18])[CH:13]([CH3:15])[CH3:14]>CN(C)C=O>[CH2:12]([N:16]1[C:17](=[O:18])[C:19]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:25]1[CH:26]([CH3:32])[C:27]([NH:4][C:3]([NH2:5])=[NH:2])=[O:28])[CH:13]([CH3:15])[CH3:14]
Reactant: CCOC(=O)C(C)=Cc1ccccc1C(=O)NCC(C)C
Reactant: NC(N)=[NH2+]
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CN1C(=O)c2ccccc2C1C(C)C(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 73.1 %

Procedure:
N-[2-(2-Isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionyl]guanidine is prepared as described in Example 30, starting with 3.73 g (39.0 mmol) of guanidinium chloride in 20 cm3 of dimethylformamide and 3.94 g (35.1 mmol) of potassium tert-butoxide. The mixture is stirred for 45 minutes at a temperature in the region of 20° C., followed by dropwise addition of a solution of 1.13 g (3.90 mmol) of ethyl 3-(2-isobutylcarbamoylphenyl)-2-methylacrylate in 15 cm3 of dimethylformamide, and the mixture is stirred for 3 hours at a temperature in the region of 20° C. After leaving the solution to stand overnight, the solvent is removed and the residue is dissolved in aqueous 2N hydrochloric acid solution. After extracting once with dichloromethane, the organic phase is concentrated and the residue is then taken up in 2N hydrochloric acid solution, filtered and then freeze dried. 862 mg of N-[2-(2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionyl]guanidine are thus obtained in the form of a mixture of the diastereomers. The pH of the aqueous phase is adjusted to a value of 12 with potassium hydroxide and the precipitate thus obtained is filtered off*. The solid thus obtained is taken up in aqueous 2N hydrochloric acid solution and, after filtration and a freeze drying procedure, about 255 mg of one of the two diastereomers produced (diastereomer A) are obtained in the form of the hydrochloride enriched in a ratio of 9:1 (MS(ES): M+H, 303.1). *The first filtrate obtained is subjected to double extraction with dichloromethane. The combined organic extracts are dried over sodium sulfate and then concentrated. The residue is taken up in aqueous 2N hydrochloric acid solution, filtered and then freeze dried; 78 mg of the second diastereomer (diastereomer B) are thus isolated in the form of the hydrochloride enriched in a ratio of greater than 10:1 (MS (ES): M+H, 303.1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C:9](=[O:14])[CH2:8][C:7]=2[CH:15]=1)#[N:2].CC(C)([O-])C.[K+].CN(C)C=O.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)(=O)C>[C:27]1([NH:33][C:34]([C:8]2[C:7]3[CH:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[O:11][C:10]([CH3:13])([CH3:12])[C:9]=2[OH:14])=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC1(C)Oc2ccc(C#N)cc2CC1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc(C#N)cc2C(C(=O)Nc2ccccc2)=C1O
Temperature: 0 °C
Yield: 21.4 %

Procedure:
To a mixture of 0.5 g of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-3-one, 0.39 g of potassium t-butoxide, and 5 ml of dried N,N-dimethylformamide was added dropwise a mixture of 0.42 g of phenyl isocyanate and 1.5 ml of dried N,N-dimethylformamide while stirring under cooling with ice. After stirring for 4 hours under ice-cooling, ice-water was added thereto, and the mixture was made acidic with acetic acid and extracted with diethyl ether. The ether layer was washed with water and dried over sodium sulfate. Diethyl ether was removed by distillation, and the residue was purified by silica gel column chromatography (developing solution: CH2Cl2) to obtain 0.17 g of N-phenyl-6-cyano-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-carboxamide represented by formula shown below.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][N:9]=[C:10]=[O:11])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCOCC1.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>[C:1]([O:6][CH2:7][CH2:8][NH:9][C:10]([O:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCN=C=O
Reactant: OCc1ccccc1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1COCCO1
Product: C=C(C)C(=O)OCCNC(=O)OCc1ccccc1
Yield: 80.6 %

Procedure:
77.5 g of methacryloyloxyethyl isocyanate (Karenzu MOI, available from Showa Denko K.K.) and 60 g of benzyl alcohol were dissolved in 260 g of dioxane. To the solution were then added 5 drops of di-n-butyltin dilaurate. The reaction mixture was then allowed to undergo reaction at a temperature of 65° C. for 3 hours. The dioxane and excess benzyl alcohol were then distilled off under reduced pressure. The residue was poured into water, extracted with ethyl acetate, and then dried. The solvent was then distilled off to obtain 106 g of benzyloxycarbonylaminoethyl methacrylate in the form of colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]3[CH:14]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[NH:16][C:12]=3[CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[H-].[Na+].Br[CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=1>CN(C=O)C.O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][CH2:25][CH2:24][N:16]2[C:12]3[CH:11]=[CH:10][N:9]=[C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=4)[C:13]=3[CH:14]=[C:15]2[C:17]([O:19][CH3:20])=[O:18])=[CH:28][CH:29]=1
Reactant: Clc1ccc(OCCBr)cc1
Reactant: COC(=O)c1cc2c(-c3ccnc(F)c3)nccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(-c3ccnc(F)c3)nccc2n1CCOc1ccc(Cl)cc1
Temperature: 60 °C
Yield: 81.8 %

Procedure:
To a solution of methyl 4-(2-fluoropyridin-4-yl)-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (67 mg, 0.247 mmole) in DMF (1.2 mL) was added NaH (60% dispersion in mineral oil, 13 mg, 0.325 mmole) at RT. After gas evolution had ceased 1-(2-bromoethoxy)-4-chlorobenzene (76 mg, 0.321 mmole) was added and the mixture was heated to 60° C. After 3 hr the mixture was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were washed with H2O and brine, dried (MgSO4), filtered, and concentrated. Flash column chromatography (Biotage-SNAP-10 g SiO2, 35% EtOAc/hexanes) gave the title compound (86 mg, 82%) as a white foam. 1H NMR (400 MHz, CDCl3): δ 8.58 (d, J=5.9 Hz, 1 H); 8.39 (d, J=5.2 Hz, 1 H); 7.79 (d, J=5.4 Hz, 1 H); 7.60-7.51 (m, 3 H); 7.18-7.15 (m, 2 H); 6.72-6.67 (m, 2 H); 5.02-4.96 (m, 2 H); 4.39-4.33 (m, 2 H); 3.97 (s, 3 H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[N:8]1[CH2:13][CH2:12][C:11]([C:25]#[CH:26])([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[N+:22]([O-:24])=[O:23])[CH2:10][CH2:9]1.[C:27]1([O:33][C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl.CCOCC>[O:33]([C:34]([N:8]1[CH2:13][CH2:12][C:11]([C:25]#[CH:26])([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[N+:22]([O-:24])=[O:23])[CH2:10][CH2:9]1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C#CC1(Oc2ccc(F)cc2[N+](=O)[O-])CCN(C)CC1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: ClCCl
Product: C#CC1(Oc2ccc(F)cc2[N+](=O)[O-])CCN(C(=O)Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.1 %

Procedure:
To a stirred suspension of 5.01 g of potassium carbonate, 50 ml of dichloromethane (dried over anhydrous magnesium sulfate) and 10.1 g of 1-N-methyl-4-ethynyl-4-(4-fluoro-2-nitrophenoxy)piperidine was added dropwise a solution of 5.66 g of phenylchloroformate in 50 ml of dichloromethane (dried over anhydrous magnesium sulfate). The mixture was stirred 12 hr at ambient temperature and 6 hr at reflux under nitrogen. The suspension was poured into ice, extracted with dichloromethane, washed with 15% sodium hydroxide solution, 1N hydrochloric acid and saturated sodium chloride solution. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered and the solvent evaporated to provide an oil. The oil was dissolved in ether, washed with water, 1N hydrochloric acid and saturated sodium chloride solution. The solution was dried over anhydrous sodium sulfate, filtered and the solvent evaporated to provide an oil. The oil was dried overnight at room temperature (1 mm) during which time it crystallized to provide 10.3 g (73.8%) of product. Recrystallization from cyclohexane/ethyl acetate provided the analytical sample, mp 82°-83°.