Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][C:14]=1[NH:15][C:16]([C:18]1[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=1)=[O:17])[NH:11][CH:10]=[CH:9]2)=[O:5])C.[OH-].[Na+]>C1COCC1>[O:28]=[C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=[C:18]1[C:16]([NH:15][C:14]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][C:6]=1[C:4]([OH:5])=[O:3])=[O:17]
Reactant: CCOC(=O)c1cc2cc[nH]c2cc1NC(=O)c1c[nH]c2ccccc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc2cc[nH]c2cc1NC(=O)c1c[nH]c2ccccc2c1=O
Temperature: 85 °C
Yield: 92.6 %

Procedure:
A mixture of 6-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1H-indole-5-carboxylic acid ethyl ester (188) (450 mg, 1.2 mmol) and 1N NaOH solution (5 mL) in THF (10 mL) was heated at 85° C. overnight. The reaction mixture was partitioned between EtOAc and water. The aqueous layer was acidified with 1N HCl solution to pH 5, and the precipitate was filtered, washed with water and air dried to yield 6-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1H-indole-5-carboxylic acid (188-I) (386 mg, 93%). 1H-NMR (400 MHz, DMSO-d6) δ 12.92-12.75 (m, 2H), 11.33 (s, 1H), 8.84 (s, 1H), 8.71 (s, 1H), 8.30 (dd, J=8.1, 0.9 Hz, 1H), 8.22 (s, 1H), 7.80-7.72 (m, 2H), 7.49 (t, J=8.0 Hz, 1H), 7.41 (t, J=2.7 Hz, 1H), 6.51 (m, 1H); HPLC ret. time 2.95 min, 10-99% CH3CN, 5 min run; ESI-MS 376.2 m/z (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)[S:5][CH:6]=1.Cl[C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20][N:21]2[CH2:24][CH3:25])=[CH:16][C:15]=1[F:30]>N1C=CC=CC=1>[CH2:24]([N:21]1[C:22]2[C:17](=[CH:16][C:15]([F:30])=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH:7]([C:4]4[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=4)[CH2:12]3)[CH:23]=2)[C:18](=[O:29])[C:19]([C:26]([OH:28])=[O:27])=[CH:20]1)[CH3:25]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: Cc1csc(C2CNCCN2)c1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cc(C)cs4)C3)cc21
Yield: 24.1 %

Procedure:
A mixture of 10.92 g of 2-(4-methyl-2-thienyl)piperazine and 5.38 g of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid in 30 ml of pyridine was heated at reflux under argon for 18 hours, then allowed to cool and the solvent removed. The residue was triturated with methanol and ether, then filtered and dried, giving 2 g of the desired product, mp 230° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1([F:44])[CH2:31][NH:30][CH2:29][C:28]2([CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)[O:27]1.[CH:45]([C:48]1[S:49][CH:50]=[C:51]([C:53](O)=[O:54])[N:52]=1)([CH3:47])[CH3:46].C(N(CC)CC)C>CN(C=O)C>[F:44][C:26]1([F:25])[CH2:31][N:30]([C:53]([C:51]2[N:52]=[C:48]([CH:45]([CH3:47])[CH3:46])[S:49][CH:50]=2)=[O:54])[CH2:29][C:28]2([CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH2:35][CH2:36]2)[O:27]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(F)(F)O2
Reactant: CC(C)c1nc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1nc(C(=O)N2CC(F)(F)OC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cs1

Procedure:
HATU (1.184 g) was added to a solution of tert-butyl 2,2-difluoro-1-oxa-4,9-diazaspiro[5.5]undecane-9-carboxylate (example 37, step c) (0.7 g) and 2-isopropylthiazole-4-carboxylic acid (0.41 g) and triethylamine (1 mL) in DMF (12 mL) at 20° C. and the resultant mixture stirred for 1 hour. The mixture was partitioned between ethyl acetate and brine, the organic layer was washed twice with brine, dried over sodium sulphate, filtered and the solvent evaporated under reduced pressure. The crude product was purified by flash silica chromatography using 30% ethyl acetate in isohexane as solvent. Pure fractions were evaporated to dryness to afford the subtitled compound. Yield 0.78 g.
Reaction SMILES: C[Si](CC(N)=O)(C)C.[NH2:9][CH:10]1[C:30](=[O:31])[N:12]2[C:13]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[O:18])=[CH:14][CH2:15][S:16][C@H:11]12.[CH:32]([NH:34][C:35]1[S:36][CH:37]=[C:38]([C:40](=[N:44][O:45][CH3:46])[C:41](Cl)=[O:42])[N:39]=1)=[O:33].O>C(Cl)Cl>[CH:32]([NH:34][C:35]1[S:36][CH:37]=[C:38]([C:40](=[N:44][O:45][CH3:46])[C:41]([NH:9][CH:10]2[C:30](=[O:31])[N:12]3[C:13]([C:17]([O:19][CH2:20][C:21]4[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=4)=[O:18])=[CH:14][CH2:15][S:16][C@H:11]23)=[O:42])[N:39]=1)=[O:33]
Reactant: CON=C(C(=O)Cl)c1csc(NC=O)n1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: ClCCl
Solvent: O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(NC=O)n1
Temperature: 40 °C
Yield: 93.9 %

Procedure:
N,N-Dimethylformamide (3 drops) was added to a suspension of 2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetic acid (syn isomer, 23 g.) in thionyl chloride (230 ml), and stirred at 60° C. for 5 minutes. After concentrating the solution in vacuo, benzene was added to the residue. The presipitates were collected by filtration, washed with benzene (30 ml.) three times and diethyl ether in turn to give 2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetyl chloride (anti isomer, 18 g.). On the other hand, trimethylsilylacetamide (46 g.) was added to a suspension of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (16.8 g.) in methylene chloride (168 ml.), and stirred at 40° C. for an hour. To the suspension was gradually added 2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetyl chloride (anti isomer, 13.6 g.) at -5° to 0° C., and stirred at the same temperature for an hour. Water (150 ml.) was added to the resultant solution and stirred for 15 minutes. The recipitates were collected by filtration, washed with water and dried over phosphorus pentoxide under reduced pressure to give 4-nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (anti isomer, 25.7 g.).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[N:8]=[N:9][C:10]([Cl:13])=[CH:11][CH:12]=1.[CH:14]1(C(O)=O)[CH2:17][CH2:16][CH2:15]1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].N>O.[N+]([O-])([O-])=O.[Ag+]>[Cl:6][C:7]1[N:8]=[N:9][C:10]([Cl:13])=[CH:11][C:12]=1[CH:14]1[CH2:17][CH2:16][CH2:15]1
Reactant: O=C(O)C1CCC1
Reactant: Clc1ccc(Cl)nn1
Agent: [Ag+]
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: Clc1cc(C2CCC2)c(Cl)nn1
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 80.7 %

Procedure:
Concentrated sulphuric acid (53.6 ml, 1.0 mol) was added carefully to a stirred suspension of 3,6-dichloropyridazine (50.0 g, 0.34 mol) in water (1.25 l). This mixture was then heated to 70° C. (internal temperature) before the addition of cyclobutane carboxylic acid (35.3 ml, 0.37 mol). A solution of silver nitrate (11.4 g, 0.07 mol) in water (20 ml) was then added over approximately one minute. This caused the reaction mixture to become milky in appearance. A solution of ammonium persulphate (230 g, 1.0 mol) in water (0.631) was then added over 20-30 minutes. The internal temperature rose to approximately 85° C. During the addition the product formed as a sticky precipitate. Upon complete addition the reaction was stirred for an additional 5 minutes, then allowed to cool to room temperature. The mixture was then poured onto ice and basified with concentrated aqueous ammonia, with the addition of more ice as required to keep the temperature below 10° C. The aqueous was extracted with dichloromethane (×3). The combined extracts were dried (MgSO4), filtered and evaporated to give the title compound (55.7 g, 82%) as an oil. 1H nmr (CDCl3) indicated contamination with approximately 5% of the 4,5-dicyclobutyl compound. However, this material was used without further purification. Data for the title compound: 1H NMR (360 MHz, d6-DMSO) δ1.79-1.90 (1H, m), 2.00-2.09 (1H, m), 2.18-2.30 (2H, m), 2.33-2.40 (2H, m), 3.63-3.72 (1H, m), 7.95 (1H, s); MS (ES+) m/e 203 [MH]+, 205 [MH]+, 207 [MH]30 .
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:12][CH3:13])=[CH:4][C:3]=1F.CC(N(C)C)=[O:17]>O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:12][CH3:13])=[CH:4][C:3]=1[OH:17]
Reactant: COc1nccc2cc(F)c(Cl)cc12
Reactant: CC(=O)N(C)C
Solvent: O
Product: COc1nccc2cc(O)c(Cl)cc12
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A solution of sodium trimethylsilanoate (149.2 mL, 1M in THF) was added to a solution of 7-chloro-6-fluoro-1-methoxyisoquinoline (4, 10 g, 47.2 mmol) in DMA (200 mL) under argon. After stirring at 60° C. for 24 hours, the solution was evaporated under reduced pressure and then freeze dried to give crude product (20.4 g). This was dissolved in water and the pH adjusted to pH=6.5. A light brown precipitate was collected by filtration and purified by reverse phase chromatography (0 to 4 minutes, 15% acetonitrile/water, 4 to 24 minutes 15 to 90% acetonitrile/water and then 100% acetonitrile) to give 7 g of the desired product Rt=2.60 min (Method C). Detected mass: 210.0 (M+H+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].[CH2:28]([NH2:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:28]([NH:35][C:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]2[N:18]=[C:17]([N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=[CH:20]3)[CH:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)=[O:2])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)O)c1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)c1cccc(C(=O)NCc2ccccc2)c1
Temperature: 25 °C

Procedure:
2-[(S)-1-(3-carboxyphenyl)ethylamino]-4-[benzimidazol-1-yl]pyrimidine (22.6 mg) and benzylamine (7.5 μL) were mixed in CH2Cl2 under nitrogen. Triethylamine (26 μL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (approx. 18 mg) and 4-dimethylaminopyridine (approx. 1 mg) were added and the mixture stirred at room temperature. After approximately 1.5 h another portion of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.5 mg) was added. One hour later the mixture was eluted directly on silica gel (95:5 CH2Cl2:MeOH) to yield 17.8 mg of the title compound. 1H NMR (500 MHz, CDCl3, partial): δ 8.46 (br s, 1H); 8.38 (d, J=5.2 Hz, 1H); 7.94 (s, 1H); 7.81 (d, J=7.7 Hz); 7.67 (m, 1H); 7.59 (d, J=7.8 Hz, 1H); 7.44 (t, J=7.7 Hz, 1H); 6.78 (d, J=5.5 Hz, 1H); 6.44 (s, 1H); 5.77 (br s, 1H); 5.24 (br s, 1H); 4.65 (m, 2H); 1.65 (d, J=6.8 Hz, 3H). Mass Spectrum (ESI): m/e 449.2 (M+1).
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:15][NH:16]3)=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>C1COCC1.O>[C:37]([N:16]1[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH2:7][C:4]3[CH:3]=[CH:2][C:1]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:6][CH:5]=3)[CH:18]=2)[CH2:13][CH:14]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:15]1)(=[O:39])[CH3:38]
Reactant: CN(C)CCC1CNc2cc(OCc3ccc(-c4ccccc4)cc3)ccc2C1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1CC(CCN(C)C)Cc2ccc(OCc3ccc(-c4ccccc4)cc3)cc21
Reaction time: 1 h

Procedure:
To a solution of 7-(4-biphenylyl)methoxy-3-[2(N,N-dimethylamino)ethyl]-1,2,3,4-tetrahydroquinoline (250 mg) in THF (17 ml) was added triethylamine (0.33 ml) followed by addition of acetyl chloride (0.09 ml) at 0° C. After stirring in an ice bath for one hr, the reaction mixture was further stirred at room temperature for one hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by alumina column chromatography (eluent:ethyl acetate:hexane=1:20 to 1:6) and the resulting precipitated crystals were washed with diisopropyl ether to obtain the titled compound (210 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19](Cl)[N:18]=[C:17]([O:22][CH3:23])[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[NH2:33][CH2:34][CH2:35][OH:36]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([NH:33][CH2:34][CH2:35][OH:36])[N:18]=[C:17]([O:22][CH3:23])[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCO
Reactant: COc1nc(Cl)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(NCCO)nc(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 50 °C
Yield: 90.5 %

Procedure:
To a stirred solution of 4-(4-chloro-6-methoxy-[1,3,5]triazin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.03 g, 3.0 mmol, 1.0 equiv) in acetonitrile (45 mL) was added N-ethyl diisopropylamine (1.56 mL, 1.18 g, 9.0 mmol, 3.0 equiv) at rt, followed by 2-amino-ethanol (0.36 mL, 0.37 g, 6.0 mmol, 2.0 equiv). The reaction mixture was heated to 50° C. for 3.5 h, then poured into crashed ice and extracted twice with ethyl acetate. The combined organic layers were washed with brine and water, then dried over MgSO4, filtered and concentrated by evaporation under reduced pressure. The crude product was purified by column chromatography on silica eluting with a gradient of dichloromethane/methanol to give 1.00 g (90%) of the title compound as colorless foam. MS (ISP): 369.1 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:26]=[CH:25][C:7]([C:8]([C:10]2[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:12][NH:13][C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:9])=[C:6]([N+:27]([O-])=O)[CH:5]=1>O.Cl.C([O-])(=O)C.[Ni+2].C([O-])(=O)C>[Cl:3][C:4]1[CH:26]=[CH:25][C:7]([C:8]([C:10]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:13][NH:12][C:11]=2[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:9])=[C:6]([NH2:27])[CH:5]=1
Reactant: CCOC(=O)c1n[nH]c(C(=O)OCC)c1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Ni+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Product: CCOC(=O)c1n[nH]c(C(=O)OCC)c1C(=O)c1ccc(Cl)cc1N
Temperature: 8 °C
Reaction time: 6 h
Yield: 96.5 %

Procedure:
Alternatively, the title compound can be prepared as follows: A mixture of nickel acetate (444 g, 1.78 moles) and water (6.6 L) was cooled to 8° C. with stirring under nitrogen: then a solution of sodium borohydride (271 g, 7.16 moles) in water (3.55 L) was added dropwise over 1.5 hours maintaining the reaction temperature between 8° C. and 12° C. The reaction mixture was then stirred for 1.5 hours at 8-12° C. The reaction mixture was filtered through a coarse scintered glass filter funnel, keeping, the black filter cake wet (Caution: this black powder may be pyrophoric if allowed to dry). The filter cake was washed first with water (6×2 L), then with ethanol (2×2 L) and finally with methanol (1 L). The methanol wet filter cake (Ni2B, pyrophoric) was transferred to a 22 L flask with methanol (8 L). A solution of diethyl 4-(4-chloro-2-nitrobenzoyl)-1H-pyrazole-3,5-dicarboxylate (111.0 g, 0.28 mole) in hydrochloric acid (2.52 L) was added. The reaction mixture was heated to 64° C. and was kept at 64° C. for 6 hours; then was allowed to cool to room temperature and was filtered through CELITE™. The CELITE™ layer was washed with methanol (2×2 L). The filtrate and wash liquors were combined and the methanol was distilled off under water aspirator vacuum. Water (1 L) was added to the reaction and the mixture was filtered. The filter cake was washed with water (2×500 mL) and dried under vacuum at 40° C. to give the title compound as a yellowish solid (98.81 g, 96%).
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH:7]([O:9][CH2:10][CH3:11])=[CH2:8].CCOCC>ClCCl>[C:1]([O:6][CH2:8][CH2:7][O:9][CH2:10][CH3:11])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: C=COCC
Solvent: ClCCl
Solvent: CCOCC
Product: C=C(C)C(=O)OCCOCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
To a solution of 20 g methacrylic acid in 50 ml dichloromethane was added 19 g ethyl vinyl ether in 30 ml dichloromethane. The mixture was stirred overnight at room temperature and poured into ether and washed with a saturated aqueous solution of sodium bicarbonate until the solution ceased effervescing. The organic layer was dried with MgO/MgSO4 and concentrated in vacuo. The residue was distilled at 25° C./0.1 torr to give 7.1 g (19% yield) of ethoxyethyl methacrylate. A mixture of 7.0 g ethoxyethyl methacrylate and 0.076 g AIBN in 7 ml MEK was heated to 60° C. for 24 hr and 7 ml MEK was added. This solution (solution E) was used for further evaluation.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:18][Si:19]([CH3:46])([CH3:45])[CH2:20][CH2:21][O:22][CH2:23][N:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH2:29][NH:30][CH2:31][C:32]1[N:33]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:34]=[CH:35][N:36]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.CN(C)C1C=CN=CC=1.O>[CH3:18][Si:19]([CH3:46])([CH3:45])[CH2:20][CH2:21][O:22][CH2:23][N:24]1[CH:28]=[CH:27][N:26]=[C:25]1[CH2:29][N:30]([CH2:31][C:32]1[N:33]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:34]=[CH:35][N:36]=1)[C:15](=[O:17])[CH2:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1
Reactant: C[Si](C)(C)CCOCn1ccnc1CNCc1nccn1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)N(Cc2nccn2COCC[Si](C)(C)C)Cc2nccn2COCC[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15.9 %

Procedure:
Under an argon atmosphere at room temperature, [1-(tert-butoxycarbonyl)-4-piperidinyl]acetic acid (500 mg) and the compound 2 (899 mg) were dissolved in anhydrous dimethyl formamide (12 mL), and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (590 mg), 1-hydroxybenztriazole (417 mg) and 4-dimethylaminopyridine (377 mg) were added, followed by stirring at room temperature for 16 hours. After the addition of city water and stirring, the obtained solution was extracted three times with ethyl acetate. The organic layer was collected and then washed with saturated brine. After drying over anhydrous sodium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography to obtain the title compound (216 mg) having the following physical properties.
Reaction SMILES: Cl.[CH3:2][C:3]1[O:4][C:5]2[C:14]3[CH:13]([CH2:15][CH2:16][NH2:17])[CH2:12][CH2:11][C:10]=3[CH:9]=[CH:8][C:6]=2[N:7]=1.C(N(CC)CC)C.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>O1CCCC1>[CH2:25]([NH:27][C:28]([NH:17][CH2:16][CH2:15][CH:13]1[C:14]2[C:5]3[O:4][C:3]([CH3:2])=[N:7][C:6]=3[CH:8]=[CH:9][C:10]=2[CH2:11][CH2:12]1)=[O:29])[CH3:26]
Reactant: CCN=C=O
Reactant: Cc1nc2ccc3c(c2o1)C(CCN)CC3
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)NCCC1CCc2ccc3nc(C)oc3c21
Reaction time: 0.25 h
Yield: 11.4 %

Procedure:
2-(2-Methyl-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl)ethanamine hydrochloride (156 mg, 0.617 mmol) and triethylamine (86.1 μL, 0.617 mmol) were dissolved in tetrahydrofuran (6.2 mL), ethyl isocyanate (58.6 μL, 0.741 mmol) was added under ice-cooling, and the mixture was stirred for 15 min. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (20.2 mg, yield 11%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[O:22]=[C:23]1[C:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][N:24]1[CH2:40][C:41](O)=[O:42].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]2[CH2:10][CH2:11][N:12]([C:41](=[O:42])[CH2:40][N:24]3[CH2:25][CH2:26][C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:23]3=[O:22])[CH2:13][CH2:14]2)=[CH:16][CH:17]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(bis(4-fluorophenyl)methyl)piperazine (0.29 g, 1.00 mmol) in dichloromethane (20 mL) under nitrogen was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.30 g, 1.00 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (0.61 mg, 0.005 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated, and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:1) gave the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.42-7.47 (m, 4H), 7.21-7.33 (m, 10H), 7.11-7.17 (m, 4H), 4.41 (s, 1H), 4.14-4.15 (br s, 2H), 3.37-3.47 (m, 4H), 3.35 (t, J=6.6 Hz, 2H), 2.71 (t, J=6.5 Hz, 2H), 2.21-2.26 (m, 4H); MS (DCI+) m/z 566 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:5]Cl.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][C:24]([O:26]C)=[O:25])[CH:19]=[CH:20][C:21]=1[OH:22]>CO.O>[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][C:24]([OH:26])=[O:25])[CH:19]=[CH:20][C:21]=1[O:22][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH:12]([CH3:13])[CH3:14])=[C:2]([Cl:1])[CH:3]=1
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Reactant: CC(C)COc1ccc(CCl)cc1Cl
Solvent: O
Solvent: CO
Product: CC(C)COc1ccc(COc2ccc(CC(=O)O)cc2Cl)cc1Cl

Procedure:
The procedure of Example (1) (e) was repeated wherein 3-chloro-4-isobutyoxybenzyl chloride was reacted with methyl 3-chloro-4-hydroxyphenylacetate to yield 3-chloro-4-(3'-chloro-4'-isobutoxybenzyloxy) phenylacetic acid (52.4yield), m.p. 127.5°-129° C. (methanol-water).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:35]=1[NH2:41]>>[CH3:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:35]=1[NH:41][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:27]3[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:26]=3[O:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc12
Reactant: Cc1ccc(C)c(N)c1
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC4(CC3)COc3c(F)cccc34)cnc12
Yield: 60.7 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(7-fluoro-2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.145 g, 0.318 mmol) obtained in Example 145, step 2 and 2,5-dimethylphenylamine (0.046 mL, 0.372 mmol), the title compound (0.105 g, 61%) was obtained.