Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[N:22]1([C:28]2[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][CH:29]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[C:34]([C:31]1[CH:30]=[CH:29][C:28]([N:22]2[CH2:23][CH2:24][N:25]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][C:11]=3[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]4=[O:21])[CH2:26][CH2:27]2)=[CH:33][CH:32]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CC(=O)c1ccc(N2CCN(c3cc4c(=O)n(NS(C)(=O)=O)c(=O)[nH]c4cc3[N+](=O)[O-])CC2)cc1
Yield: 44 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (20 mg, 0.0628 mmol) is reacted with 1-(4-piperazin-1-yl-phenyl)-ethanone according to the GPA affording 14 mg (44%) of an orange powder. Rt=3.85 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(CC1CCCC1)c1ccc(N)cc1
Yield: 53.2 %

Procedure:
A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid ethyl ester (7.37 g, 25.3 mmol) in ethyl acetate (316 mL) was treated with 10% palladium on activated carbon (500 g). The reaction mixture was shaken under 60 psi of hydrogen gas at 25° C. for 18 h. The catalyst was then removed by filtration through a pad of celite and washed with ethyl acetate. The filtrate was concentrated in vacuo to give 2-(4-amino-phenyl)-3-cyclopentyl-propionic acid ethyl ester (3.52 g, 53.3%) as a yellow oil: EI-HRMS m/e calcd for C16H23NO2 (M+) 261.1727, found 261.1727.
Reaction SMILES: [Na].[CH2:2]1[CH:4]([C:5]([NH2:7])=[NH:6])[CH2:3]1.Cl.O=[C:10]1[CH2:15][CH2:14][CH2:13][S:12][CH:11]1[C:16](OCC)=[O:17].C(O)(=O)C>CO>[CH:4]1([C:5]2[N:6]=[C:16]([OH:17])[C:11]3[S:12][CH2:13][CH2:14][CH2:15][C:10]=3[N:7]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)C1SCCCC1=O
Reactant: N=C(N)C1CC1
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: CO
Product: Oc1nc(C2CC2)nc2c1SCCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.5 %

Procedure:
Sodium metal (3.94 g, 0.17 g atom) was dissolved in methanol (150 ml) and cyclopropylcarboxamidine hydrochloride (21.0 g, 0.174 mol) was added followed after 1/4 hour stirring by the addition of ethyl 3-oxotetrahydrothiopyran-2-carboxylate (27.2 g, 0.145 mol). The reaction mixture was stirred at 25° C. for 18 hours then treated with ice water (200 ml) and neutralized with acetic acid to give 24.6 g of the title compound which melted at 249°-250° C.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([CH:14]2[CH2:19][CH2:18][CH2:17][CH:16]=[CH:15]2)[CH2:4][CH:3]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>C(O)C.[C].[Pd]>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:4][CH:3]1[NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C1C=CCCC1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
10% palladium carbon (100 mg) was added to a solution of 2-oxo-3-tert-butoxycarbonylamino-5-(2-cyclohexen-1-yl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (500 mg) obtained from Step 1 of Referential Example 10 in ethanol (50 ml), under hydrogen atmosphere the mixture was stirred at room temperature for 3 hours. The reaction mixture was filtrated, the filtrate was concentrated under reduced pressure, to thereby obtain 450 mg of the title compound (Yield: 90%).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:31][O:32][CH2:33][C:34]([OH:36])=[O:35])[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][N+:19]4([CH3:25])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.C(=O)(O)[O-].[Na+].C([O:45][C:46]1[CH:47]=[C:48]([CH:52]=[CH:53][C:54]=1[O:55]C(=O)C)[C:49](Cl)=[O:50])(=O)C>CC(C)=O.O>[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:31][O:32][CH2:33][C:34]([OH:36])=[O:35])[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][N+:19]4([CH3:25])[CH2:20][CH2:21][N:22]([C:49](=[O:50])[C:48]5[CH:52]=[CH:53][C:54]([OH:55])=[C:46]([OH:45])[CH:47]=5)[CH2:23][CH2:24]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: C[N+]1(CC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)C(=NOCC(=O)O)c4nsc(N)n4)[C@H]3SC2)CCNCC1
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[N+]1(CC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)C(=NOCC(=O)O)c4nsc(N)n4)[C@H]3SC2)CCN(C(=O)c2ccc(O)c(O)c2)CC1
Yield: 39.2 %

Procedure:
The solution of 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-(1-methyl-1-piperazinio)methyl-3-cephem-4-carboxylate (syn isomer) (540 mg) in acetone (5 ml) and water (5 ml) was adjusted to pH 7.0 with a saturated aqueous solution of sodium bicarbonate. To the mixture was added 3,4-diacetoxybenzoyl chloride (308 mg) at pH 6.5-7.0. The mixture was stirred for an hour and evaporated in vacuo to remove acetone. The residue was adjusted to pH 8.5 with a saturated aqueous solution of sodium bicarbonate and then stirred for 2 hours at room temperature. The mixture was adjusted to pH 3.5 with 3N hydrochloric acid and then filtered. The filtrate was subjected to column chromatography on Diaion HP-20 using 5% aqueous isopropyl alcohol as an eluent. The eluate was evaporated in vacuo to remove isopropyl alcohol and then lyophilized to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-[1-methyl- 4-(3,4-dihydroxybenzoyl)- 1-piperazinio]methyl-3-cephem-4carboxylate (syn isomer) (265 mg).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9](Cl)=[O:10])=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2].C(NC1C(Cl)=CC(C(O)=O)=C(OC)C=1)(=O)C.[NH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[C:38]2[C:43]=1[CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2.[OH-].[Na+]>ClCCl.C(N(CC)CC)C>[CH3:44][N:41]1[CH2:40][CH2:39][C:38]2[C:43](=[C:34]([NH:33][C:9](=[O:10])[C:8]3[CH:12]=[C:13]([Cl:14])[C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][C:7]=3[O:15][CH3:16])[CH:35]=[CH:36][CH:37]=2)[CH2:42]1
Reactant: CN1CCc2cccc(N)c2C1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)Cl
Agent: COc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)Nc1cccc2c1CN(C)CC2

Procedure:
To a cooled solution of 4-acetylamino-5-chloro-2-methoxybenzoyl chloride, (prepared from 4-acetylamino-5-chloro-2-methoxybenzoic acid, 3.19 g) in dichloromethane was added 8-amino-2-methyl-1,2,3,4-tetrahydroisoquinoline (2.1 g) and triethylamine (4 ml). After stirring at room temperature for 2.5h, the mixture was basified with 10% sodium hydroxide. The organic layer was separated, dried and concentrated in vacuo. The residue was purified by chromatography on alumina eluting with chloroform, and then crystallised from ethyl acethate to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].I[CH3:19].[H-].[Na+]>CN(C)C=O>[CH3:19][O:17][CH2:16][CH:13]1[CH2:12][CH2:11][N:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(N2CCC(CO)CC2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 60 %

Procedure:
To a 0° C. mixture of [1-(4-nitro-phenyl)-piperidin-4-yl]-methanol and iodomethane (0.25 mL, 4.0 mmol) in N,N-dimethylformamide (3 mL) is added sodium hydride (60% dispersion in mineral oil, 80 mg, 2.0 mmol). The cooling bath is removed and the mixture is stirred at room temperature for five hours before it is re-cooled to 0° C. and quenched by the addition of saturated aqueous sodium hydrogen carbonate solution. The precipitated solid is collected by Büchner filtration, washed with water, and dried under house vacuum to give 4-methoxymethyl-1-(4-nitro-phenyl)-piperidine as pale yellow crystals (0.15 g, 60%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:15])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7].[S:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.Cl[C:39]([N:41]=[C:42]=[O:43])=[O:40]>C1(C)C=CC=CC=1>[O:40]=[C:39]1[N:1]([CH2:2][CH2:3][CH2:4][N:5]([CH3:15])[S:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:8])=[O:7])[C:19]2[CH2:18][CH2:17][S:16][CH2:21][C:20]=2[C:42](=[O:43])[NH:41]1
Reactant: CN(CCCN)S(=O)(=O)c1ccccc1
Reactant: O=C1CCSCC1
Reactant: O=C=NC(=O)Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: CN(CCCn1c2c(c(=O)[nH]c1=O)CSCC2)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 42.2 %

Procedure:
A solution of 0.98 g (4.3 mmol) of N-(3-aminopropyl)-N-methylphenylsulphonamide [preparation according to P. Daetwyler et al., Helv. Chim. Acta, 61, 2646 (1978)], 0.55 g (4.73 mmol) of tetrahydrothiopyran-4-one and a catalytic amount of camphorsulphonic acid in 50 ml of toluene is heated at reflux for 3 hours using a Dean-Stark separator. After cooling to room temperature, the Dean-Stark separator is removed, 0.54 g (5.16 mmol) of chlorocarbonyl isocyanate are added and the mixture is refluxed for another hour. The solvent is removed using a rotary evaporator and the resulting residue is purified by preparative HPLC (RP-C18, acetonitrile/water gradient). This gives 717 mg (42% yield) of an amorphous solid.
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.[N+:9]([C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[CH:19]([CH3:21])[CH3:20])[NH2:15])([O-:11])=[O:10].CO[C:24](=[O:36])[C:25]([CH3:35])([NH:27][CH2:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=1)[CH3:26]>ClCCCl.C1COCC1>[CH3:35][C:25]1([CH3:26])[N:27]([CH2:28][C:29]2[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=2)[C:2](=[O:1])[N:15]([C:14]2[CH:16]=[CH:17][C:18]([CH:19]([CH3:21])[CH3:20])=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=2)[C:24]1=[O:36]
Reactant: COC(=O)C(C)(C)NCc1ccncc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)c1ccc(N)cc1[N+](=O)[O-]
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(C)c1ccc(N2C(=O)N(Cc3ccncc3)C(C)(C)C2=O)cc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
6.04 g (30 mmol) diphosgene in 50 ml 1,2-dichlorethane were treated at −20° C. with a solution of 2 g (11.1 mmol) 3-nitro-4-isopropyl-aniline in 20 ml 1,2-dichlorethane. The mixture was allowed to come to room temperature and then was heated to 50° C. for 5 h. After standing over night, the solvent was evaporated and the residual oil was taken up in 40 ml THF. 3.93 g (18.7 mmol) 2-methyl-2-[(pyridin-4-ylmethyl)-amino]-propionic acid methyl ester in 30 ml THF were added and the mixture was refluxed for 6 h. The solvent was evaporated and the residue taken up in ethylacetate and washed with water. THe organic phase was dried, the solvent evaporated and the residue was purified by preparative HPLC. (C18 reversed phase column, elution with a water (0.1% trifluoracetic acid)/acetonitrile gradient) Yield: 2.7 g.
Reaction SMILES: [Mg].C(O[Ge:5]([O:12][CH2:13][CH3:14])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])C.Br[C:16]1[C:17]2[C:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=3[CH:29]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2>C1COCC1>[CH2:13]([O:12][Ge:5]([O:6][CH2:7][CH3:8])([O:9][CH2:10][CH3:11])[C:16]1[C:17]2[C:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=3[CH:29]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:14]
Reactant: Brc1cc2ccccc2c2ccccc12
Reactant: CCO[Ge](OCC)(OCC)OCC
Agent: [Mg]
Solvent: C1CCOC1
Product: CCO[Ge](OCC)(OCC)c1cc2ccccc2c2ccccc12

Procedure:
A 3-neck 500 mL flask was filled with magnesium turnings (8 g), THF (100 g) and tetraethoxygermane (35 g), and heated to reflux. 9-Bromophenanthrene (30 g) was added to the flask in small portions. Grignard started after a few minutes and kept refluxing by its own heat for ten minutes. The reaction was allowed to cool for 1 hour, after which magnesium salts were precipitated with heptanes (300 mL). The solution was filtered, followed by evaporation of volatiles by rotary evaporator. The material was distilled three times at <1 mbar, giving colorless 9-(triethoxygermyl)phenanthrene (bp. 170 . . . 190° C., 21 g, 46.7% overall yield based on 2-bromophenanthrene, purity 99.5% by GC/MS).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[C:5]1([CH3:11])[CH:10]=[CH:9][CH:8]=CC=1.CCOCC.C1(N)CCCC1>C(O)(=O)C>[CH:8]1([NH:1][C:2](=[O:3])[NH2:4])[CH2:9][CH2:10][CH2:5][CH2:11]1
Reactant: NC(N)=O
Reactant: Cc1ccccc1
Agent: NC1CCCC1
Solvent: CCOCC
Solvent: CC(=O)O
Product: NC(=O)NC1CCCC1

Procedure:
A mixture of 10.3 g of N-[4-(β-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl]-urea (m.p. 171° - 173°C), 300 ml of toluene, 30 ml of glycolmonomethyl ether, 1.65 g of glacial acetic acid and 2.4 g of cyclopentyl-amine was refluxed for 5 hours. Subsequently, the mixture was concentrated in vacuo and the residue was treated with alcohol. N-[4-(β-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl] -N'-cyclopentyl-urea obtained as a raw product was separated by suction-filtration and recrystallized from methanol. Melting point 184° - 185°C.
Reaction SMILES: [B-]C#N.[Na+].[CH3:5][C:6]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=2)[CH2:9][NH:8][CH2:7]1.C(O)(=O)C.[CH:24]1([CH:30]=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>CO>[CH:24]1([CH2:30][N:8]2[CH2:7][C:6]([CH3:19])([CH3:5])[C:15]3[C:10](=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=3)[CH2:9]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=CC1CCCCC1
Reactant: CC1(C)CNCc2cc([N+](=O)[O-])ccc21
Agent: O=C([O-])O
Agent: [B-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1(C)CN(CC2CCCCC2)Cc2cc([N+](=O)[O-])ccc21
Temperature: 35 °C
Reaction time: 16 h

Procedure:
Sodium cyanotrihydroborate (0.600 g, 9.55 mmol) was added to a solution of 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (0.600 g, 2.91 mmol), acetic acid (0.210 mL, 3.66 mmol) and cyclohexanecarbaldehyde (0.4 g, 3.57 mmol) in methanol (40 mL). The reaction mixture was stirred at 35° C. for 16 hours. The reaction was neutralized with saturated sodium bicarbonate solution, and the mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified with silica gel column chromatography (3% ethyl acetate/petroleum ether) to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1([C:11]([OH:13])=[O:12])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[OH:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]([OH:20])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:44][C:45]1[CH:46]=[C:47]([CH2:51][CH2:52]O)[CH:48]=[CH:49][CH:50]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:44][C:45]1[CH:46]=[C:47]([CH2:51][CH2:52][O:14][C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:18]([NH:1][C:2]2([C:11]([OH:13])=[O:12])[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:10]2)=[O:20])[CH:48]=[CH:49][CH:50]=1
Reactant: Cc1ccc(C(=O)O)cc1O
Reactant: OCCc1cccc(Cl)c1
Reactant: NC1(C(=O)O)Cc2ccccc2C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1OCCc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
The synthesis was carried out on 0.15 g of PL Wang resin (1.7 mmol/g). The attachment of 2-amino-indane-2-carboxylic acid and the acylation with 3-hydroxy-4-methylbenzoic acid were performed as in described in example 173. After the acylation step, the resin was washed with THF and a solution of triphenylphosphine (10 equivalents) and 2-(3-chlorophenyl)-ethanol (10 equivalents) in THF was added to the resin. The slurry was cooled to 0° C., DIAD (10 equivalents) was added to the cooled mixture, and the reaction mixture was shaken overnight at room temperature. The resin was washed with DCM. The compound was cleaved, isolated and purified as in described in example 173. Yield: 2.3 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C@H:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.CS[C:18]1[NH:24][C:22](=[O:23])[CH:21]=[CH:20][N:19]=1>N1C=CC=CC=1>[O:23]=[C:22]1[CH:21]=[CH:20][NH:19][C:18]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[C@H:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=3)=[CH:4][CH:3]=2)=[N:24]1
Reactant: CSc1nccc(=O)[nH]1
Reactant: C[C@@H]1CC(=O)NN=C1c1ccc(N)cc1
Solvent: c1ccncc1
Product: C[C@@H]1CC(=O)NN=C1c1ccc(Nc2nc(=O)cc[nH]2)cc1

Procedure:
A stirred mixture of (R)-6-(4-aminophenyl)-5-methyl-4,5-dihydro-3(2H)-pyridazinone and 2-methylthiouracil in dry pyridine are heated together to afford the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][PH:10](=[O:12])[OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13]O>>[C:1]1([CH2:7][CH2:8][CH2:9][PH:10](=[O:11])[O:12][CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CO
Reactant: O=[PH](O)CCCc1ccccc1
Product: CO[PH](=O)CCCc1ccccc1

Procedure:
Prepared in a similar manner as Reference Example 24 from 3-phenylpropylphosphinic acid and methanol to give a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[NH:11][C:12](=[O:19])[C:13]3[C:18]([C:9]=2[C:8]2[CH:7]=[C:6]([Cl:20])[CH:5]=[CH:4][C:3]1=2)=[CH:17][CH:16]=[CH:15][CH:14]=3.[H-].[Na+].[CH2:23]([O:25][CH2:26][CH2:27]Br)[CH3:24]>>[CH3:24][CH2:23][O:25][CH2:26][CH2:27][O:19][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]2[C:8]3[CH:7]=[C:6]([Cl:20])[CH:5]=[CH:4][C:3]=3[N:2]([CH3:1])[C:10]=2[N:11]=1
Reactant: Cn1c2ccc(Cl)cc2c2c3ccccc3c(=O)[nH]c21
Reactant: CCOCCBr
Agent: [H-]
Agent: [Na+]
Product: CCOCCOc1nc2c(c3ccccc13)c1cc(Cl)ccc1n2C

Procedure:
5-β-Ethoxyethyloxy-7-methyl-10-chloro-7H-indolo(2,3-c)isoquinoline (melting point 93.5°-95.5° C.) is prepared from 7-methyl-10-chloro-7H-indolo(2,3-c)isoquinolin-5(6H)-one, sodium hydride and β-ethoxyethyl bromide by the method described in Example 8.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([NH:12][C:13]2[CH:14]=[C:15]([C:20]3[N:24]=[C:23]([CH2:25][CH:26]4[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]4)[O:22][N:21]=3)[CH:16]=[CH:17][C:18]=2[CH3:19])=[O:11])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12>C(O)(C(F)(F)F)=O>[NH:28]1[CH2:29][CH:26]([CH2:25][C:23]2[O:22][N:21]=[C:20]([C:15]3[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([NH:12][C:10]([C:3]4[N:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]5=[N:1][CH:2]=4)=[O:11])[CH:14]=3)[N:24]=2)[CH2:27]1
Reactant: Cc1ccc(-c2noc(CC3CN(C(=O)OC(C)(C)C)C3)n2)cc1NC(=O)c1cnc2ccccn12
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-c2noc(CC3CNC3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-((3-(3-(Imidazo[1,2-a]pyridine-3-carboxamido)-4-methylphenyl)-1,2,4-oxadiazol-5-yl)methyl)azetidine-1-carboxylate (54) (29.3 mg, 0.06 mmol) was dissolved in TFA (0.5 mL) and stirred at room temperature for 10 minutes. Then TFA was removed under vacuum to yield crude N-(5-(5-(azetidin-3-ylmethyl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (55) which was used without further purification. MS m/z 389.2 (M+1)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH3:8])=[CH:3][CH:2]=1.O.NN>CO>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:9])[CH3:8])=[CH:3][CH:2]=1
Reactant: CC(c1ccncc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: CC(N)c1ccncc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-[1-(Pyridin-4-yl)ethyl]isoindoline-1,3-dione (283 mg, 1.12 mmol) in methanol (3 mL) was mixed with hydrazine monohydrate (272 μL, 5.61 mmol) and stirred at room temperature for 16 hours. After completion of the reaction, the solid was filtered off with chloroform, and the filtrate was evaporated under reduced pressure repeatedly to give the desired product.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:19]=[CH:18][C:7]2[C:8]([C:11]3[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=3)=[N:9][O:10][C:6]=2[CH:5]=1.CC1C=CC(S(O[CH2:31][C@H:32]2[O:34][CH2:33]2)(=O)=O)=CC=1>CN(C)C=O>[F:3][C:4]1[CH:19]=[CH:18][C:7]2[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:31][C@@H:32]4[CH2:33][O:34]4)[CH:12]=3)=[N:9][O:10][C:6]=2[CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: Oc1cccc(-c2noc3cc(F)ccc23)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc2c(-c3cccc(OC[C@@H]4CO4)c3)noc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a cold (0° C.) solution of sodium hydride (1.83 g, 45.79 mmol) in dimethylformamide (120 mL) and under a nitrogen atmosphere, add a solution of 3-(6-fluoro-benzo[d]isoxazol-3-yl)-phenol (10 g, 43.63 mmol) in dimethylformamide (50 mL) and stir for 1 hour. Add, dropwise, (2S)-(+)-glycidyl tosylate (10.47 g, 45.87 mmol) dissolved in dimethylformamide (40 mL), over a period of time of 0.5 hours. Let reaction mixture warm to room temperature and stir for 2 days. Quench with water, concentrate and add ethyl acetate/water. Wash with water, saturated sodium chloride and dry (MgSO4) to give the crude compound. Purify by column (silica) chromatography eluting with a graded solvent mixtures of toluene to 1% ether in toluene to give the title compound as a white solid (10.07 g, 81% Yield). NMR and microanalysis (C, H, N) are consistent with the final, desired compound. Chiral HPLC, 18.14 minutes [Chiralcel OD (250×4.6 mm), 98:2 heptane/ethanol @ 0.8 mL/min, UV @ 285 nm, 18.14] shows the title compound as 88.3% e.e. mp=83-84° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1([CH2:21][CH3:22])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8](=O)[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19].Cl.[NH2:25][OH:26].N1C=CC=CC=1>O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1([CH2:21][CH3:22])[C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8](=[N:25][OH:26])[CH2:7][O:6]1)=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:18][CH3:19]
Reactant: NO
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CCc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3=NO

Procedure:
The ester of Example 4, Step B (0.5 g, 1.6 mmol), hydroxylamine hydrochloride (0.17 g, 2.4 mmol), and 25 ml pyridine were refluxed for 3.5 h. The reaction mixture was poured into water, extracted with CHCl3. The organic phase was then washed with 1.0N HCl, water, dilute NaHCO3, water, and brine, dried (MgSO4) and evaporated to yield a crude solid which was purified by filtration through a pad of silica gel and celite. The product, 0.33 g was isolated as a solid, m. p. 188°-190° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:31])([F:30])[F:29])[O:13][N:12]=[C:11]([C:14]3[C:22]4[N:18]([CH:19]=[CH:20][CH:21]=4)[C:17]([C:23]([O:25]CC)=[O:24])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].[ClH:34]>O.CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:28]([F:30])([F:31])[F:29])[O:13][N:12]=[C:11]([C:14]3[C:22]4[N:18]([CH:19]=[CH:20][CH:21]=4)[C:17]([C:23]([OH:25])=[O:24])=[CH:16][CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[C:7]=1[Cl:34]
Reactant: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2cccn12
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)c2cccn12
Yield: 65 %

Procedure:
A solution of ethyl 8-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-5-carboxylate (130 mg, 0.26 mmol) and NaOH (52 mg, 1.29 mmol) in H2O-MeOH (1:1, 20 mL) was stirred at rt for 3 h. The mixture was acidified with 2 N HCl and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC to give 8-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-5-carboxylic acid (80 mg; yield 65%) as a yellow solid. MS: m/z=477.0 (M+1, ESI+).