Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[N:12]([CH3:13])[N:11]=[C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[N:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:24][Mg]Br.S(=O)(=O)(O)O.O>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[N:11]=[C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[N:9]=2)([OH:7])[CH3:24])=[CH:22][CH:23]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1C(=O)c1ccc(Cl)cc1
Reactant: C[Mg]Br
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Product: Cn1nc(-c2c(F)cccc2Cl)nc1C(C)(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an atmosphere of nitrogen, to a solution of 1.5 of 5-(4-chlorobenzoyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H 1,2,4-triazole in diethl ether at -70° C. was added dropwise 12 ml of methylmagnesium bromide. After 1 hour, the reaction mixture was warmed to room temperature stirred overnight, Then 36 ml of a 2N aqueous solution of sulfuric acid was added to the solution under iced-cooling, the mixture was poured into iced water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gelchromatography to afford 1.3 g of 5-(4-chloro-α-hydroxy-α-methylbenzyl)-3-(2-chloro-6-fluorophenyl)-1-methyl 1H-1,2,4-triazole. mp.198°-200° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][OH:9])[CH:6]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C.CCOC(C)=O>[Si:19]([O:9][CH2:8][CH2:7][N:5]1[CH:6]=[C:2]([I:1])[CH:3]=[N:4]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: OCCn1cc(I)cn1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCn1cc(I)cn1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 111.4 %

Procedure:
A solution of 2-(4-iodo-1H-pyrazol-1-yl)ethanol (Preparation 57) (1.01 g, 4.24 mmol) in DMF (21 mL) was treated with imidazole (410 mg, 6.03 mmol) followed by tert-butylchlorodiphenylsilane (1.321 mL, 5.09 mmol) and the mixture was stirred to room temperature for 18 hours. The mixture was diluted with EtOAc and quenched with brine. The aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with water and brine, dried and concentrated. The residue was purified by silica gel column chromatography eluting with 0 to 10% EtOAc in cyclohexane to give the title compound (2.25 g, quant).
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[C:13]2[O:12][C:11]([CH:14]([OH:16])[CH3:15])=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[OH:16][CH:14]([C:11]1[O:12][C:13]2[C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:17][N:29]3[CH2:28][CH2:27][N:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[O:19][CH3:18])[CH2:31][CH2:30]3)=[CH:6][CH:7]=[CH:8][C:9]=2[CH:10]=1)[CH3:15]
Reactant: CC(O)c1cc2cccc(OCC3CO3)c2o1
Reactant: COc1ccccc1N1CCNCC1
Product: COc1ccccc1N1CCN(CC(O)COc2cccc3cc(C(C)O)oc23)CC1

Procedure:
The procedures of Example 1 were repeated except that 1.2 g (0.005 mole) of 7-(2,3-epoxypropoxy)-(1-hydroxyethyl)benzofuran and 1.1 g (0.0055 mole) of 1-(2-methoxyphenyl)piperazine were employed. The obtained concentrated residue was crystallized from ether acetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(F)cc1Br
Product: CCOC(=O)COc1ccc(F)cc1Br

Procedure:
The sub-title compound was prepared by the method of Example 2 step a) using 2-bromo-4-fluorophenol and ethyl bromoacetate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:19]C(C)C)=[C:10]([S:15]([O-])(=O)=O)C=CC=2C)=[CH:4][CH:3]=1.[CH2:23]1COCC1>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([CH3:19])[CH2:10][S:15][CH3:23])=[CH:6][N:7]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)[O-])c(CC(C)C)c1-c1ccc(Cl)nc1
Solvent: CCOCC
Product: CSCC(C)Cc1ccc(Cl)nc1
Temperature: 55 °C
Yield: 93 %

Procedure:
A solution 3-(6-chloropyridin-3-yl)-2-methylpropyl-4-methyl-benzenesulfonate (5.0 g, 14.7 mmol) and sodium methylthiolate (2.10 g, 30 mmol) in THF (50 mL) was stirred overnight at room temperature. The remaining unreacted starting material indicated on TLC was converted into the product completely after the solution was heated at 55° C. for 4 more hours. The mixture was diluted with ether and washed with 2 N NaOH solution (50 mL). The aqueous phase was washed with ether (50 mL). The combined organic phase was washed with brine (50 mL), dried over MgSO4, filtered and concentrated to give 2.94 g of the desired crude sulfide in 93% yield as a yellowish oil: M+=215, 217; δ 2.07 (s, 3H), 0.95 (d, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1>C(OCC)(=O)C.N1C(C)=CC=CC=1C>[N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCC(=O)O1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Product: O=C(O)CCC(=O)Nc1ccc([N+](=O)[O-])cc1

Procedure:
p-Nitroaniline (PNA) (0.1 g, 0.724 mmol) and succinic anhydride (SA) (0.29 g, 2.898 mmol) were dissolved in ethyl acetate (EtOAc) (4 mL). Slight warming was required to dissolve both PNA and SA. The reaction was started by adding 2 drops of 2,6-lutidine. The reaction was held at a temperature of 70° C. overnight (19 hrs). The reaction vessel was placed in the refrigerator and the cold EtOAc was decanted from the solid reaction products. The reaction products were then rinsed with cold EtOAc (1 mL). The crude product, p-nitrosuccinanilic acid, was obtained by removing some reaction co-products using thin layer chromatography (TLC). The solid reaction products were dissolved in N,N-dimethylformamide (DMF) and spotted on Kieselgel 60 F254 HPTLC plates containing a concentration zone (EM Science No. 13728). The plates were developed using solvent system chloroform (CHCl3):EtOAc:methanol (MeOH):formic acid, 86:10:4:1%. The desired product remained at the origin. The origin band was scraped and eluted with DMF. The DMF was removed with a stream of argon gas. The sample was dissolved in 30% MeOH/H2O and made slightly basic using a solution of sodium hydroxide (4 N). The product was collected from HPLC using a 15 cm×4.6 mm, 5 μm, Supelcosil LC-ABZ column with a solvent system of 30% MeOH at a flow rate of 1 mL/min., at 254 nm; sodium p-nitrosuccinanilate (C10H9N2NaO5) in a yield of 59%. Accurate mass measurement was observed by Fast Atom Bombardment on the double sodium ion at 283.0326 (calculated for C10H9N2Na2O5+, 283.03069 (Δ1.91 ppm)).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[N:5]=[N:4][C:3]=1[N:16]1[CH2:21][CH2:20][NH:19][C@H:18]([CH3:22])[CH2:17]1.[CH3:23][O:24][C:25]([C:27]1[CH:32]=[N:31][C:30](Cl)=[CH:29][N:28]=1)=[O:26]>>[CH3:23][O:24][C:25]([C:27]1[N:28]=[CH:29][C:30]([N:19]2[CH2:20][CH2:21][N:16]([C:3]3[N:4]=[N:5][C:6]([CH2:9][C:10]4[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=4)=[C:7]([CH3:8])[C:2]=3[CH3:1])[CH2:17][C@H:18]2[CH3:22])=[N:31][CH:32]=1)=[O:26]
Reactant: Cc1c(Cc2ccncc2)nnc(N2CCN[C@H](C)C2)c1C
Reactant: COC(=O)c1cnc(Cl)cn1
Product: COC(=O)c1cnc(N2CCN(c3nnc(Cc4ccncc4)c(C)c3C)C[C@H]2C)cn1
Yield: 55.6 %

Procedure:
According to the protocol described below for example 46, 4,5-dimethyl-3-((R)-3-methylpiperazin-1-yl)-6-pyridin-4-ylmethyl-pyridazine (155 mg, 0.51 mmol) and 5-chloro-pyrazine-2-carboxylic acid methyl ester (99 mg, 0.56 mmol) afforded the title compound as an orange oil (123 mg, 56%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][NH:25][C:26](=[O:43])[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:33]=[C:28]([CH2:27][C:26]([NH:25][CH3:24])=[O:43])[CH:29]=[N:30][CH:31]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CNC(=O)Cc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Product: CNC(=O)Cc1cncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)c1

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and N-methyl-2-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-acetamide (Stage 228.1.1) to give the title compound as an off-white foam. (HPLC: tR 1.97 min (Method A); M+H=442 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.55-8.53 (m, 1H), 8.45-8.43 (m, 1H), 8.16-8.12 (m, 2H), 8.07-8.01 (m, 1H), 7.95-7.90 (m, 1H), 7.77-7.74 (m, 1H), 7.59-7.57 (m, 1H), 3.92 (s, 3H), 3.58 (s, 3H), 3.51 (s, 2H), 2.60 (d, 3H), 1.95 (s, 3H))
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.Cl[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].N1C(C)=CC(C)=CC=1C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20])[CH2:6][CH2:5]2
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: Clc1ccc2c(c1)CCN2
Solvent: CN(C)C=O
Solvent: Cc1cc(C)nc(C)c1
Product: O=[N+]([O-])c1cc(Cl)ccc1N1CCc2cc(Cl)ccc21
Temperature: 25 °C
Yield: 40 %

Procedure:
A stirred solution of 123 g (0.80 mole) of 5-chloroindoline, 134 g (0.70 mole) of 1,4-dichloronitrobenzene and 97 9 (0.80 mole) of collidine in 1000 ml of dimethylformamide was heated under nitrogen at 150° C. for 48 hours. The mixture was ten cooled, filtered from some insolubles, and the solvent was removed in vacuo with warming. The residue was partitioned between 1000 ml of dichloromethane and 500 ml of water. The water layer was removed and the organic phase was washed twice with 2N-hydrochloric acid, once with 2N-sodium hydroxide, once more with water, dried over Na2SO4 and concentrated to an oil weighing 230 g. This was dissolved in 170 ml of methanol and stirred at room temperature and then at 0° C. The resultant crystals were collected, washed well with cold methanol, and dried. This afforded 86.5 g (40% yield) of product, m.p. 130°-133° C. 4 g of 5-chloro-1-(4-chloro-2-nitrophenyl)indoline were recrystallized from methanol in 85% yield (overall yield: 34%); m.p. 133°-135° C.
Reaction SMILES: [CH2:1]([N:8]([C:15]1[CH:16]=[C:17]([C:33]2[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][CH:34]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1)[C:9](=[O:14])[C:10]([O:12]C)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+].Cl>O1CCCC1>[CH2:1]([N:8]([C:15]1[CH:16]=[C:17]([C:33]2[CH:34]=[CH:35][C:36]([O:39][C:40]([F:41])([F:42])[F:43])=[CH:37][CH:38]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1)[C:9](=[O:14])[C:10]([OH:12])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)N(Cc1ccccc1)c1cc(-c2ccc(OC(F)(F)F)cc2)ccc1OCc1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(COc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2N(Cc2ccccc2)C(=O)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
A mixture of methyl N-benzyl-N-{4-[4-(tert-butyl)benzyloxy]-4′-(trifluoromethoxy)biphenyl-3-yl}oxamate (115 mg, 0.194 mmol), methanol (11.0 ml), 2N aqueous sodium hydroxide (0.2 ml) and tetrahydrofuran (11.0 ml) was stirred at room temperature for 1 hour. The reaction mixture was adjusted to pH 5-6 by addition of 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (ethyl acetate methanol=4:1) to give the title compound (75 mg, 67%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][CH2:6][OH:7].[S:10](Cl)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].O>N1C=CC=CC=1>[CH3:17][C:16]1[CH:18]=[CH:19][C:13]([S:10]([O:7][CH2:6][CH2:5][O:4][CH2:3][C:2]([F:9])([F:8])[F:1])(=[O:12])=[O:11])=[CH:14][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCC(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(2,2,2-trifluoroethoxy)ethanol (intermediate BR) (12.7 g) was dissolved in anhydrous pyridine, then TsCl (1.3 eq) was added, and the mixture was stirred at room temperature for 16 h, after which TLC showed the reaction was complete. Then the mixture was poured into water, extracted with EA, washed with water and brine, and dried with anhydrous Na2SO4. The solvent was removed and the residue purified by column chromatography to obtain intermediate BS (0.3 g).
Reaction SMILES: [Na].[Cl-].[NH2:3][C:4]([NH2:6])=[NH2+:5].[F:7][C:8]([F:30])([F:29])[C:9]1[CH:17]=[C:16]2[C:12]([C:13](=[O:28])[N:14]([CH2:24][CH:25]([CH3:27])[CH3:26])[CH:15]2[CH2:18][C:19](OCC)=[O:20])=[CH:11][CH:10]=1>C(O)C.C(OCC)C>[CH2:24]([N:14]1[C:13](=[O:28])[C:12]2[C:16](=[CH:17][C:9]([C:8]([F:7])([F:29])[F:30])=[CH:10][CH:11]=2)[CH:15]1[CH2:18][C:19]([NH:5][C:4]([NH2:6])=[NH:3])=[O:20])[CH:25]([CH3:27])[CH3:26]
Reactant: NC(N)=[NH2+]
Reactant: CCOC(=O)CC1c2cc(C(F)(F)F)ccc2C(=O)N1CC(C)C
Agent: [Cl-]
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CC(C)CN1C(=O)c2ccc(C(F)(F)F)cc2C1CC(=O)NC(=N)N
Temperature: 20 °C
Reaction time: 16 h
Yield: 7.6 %

Procedure:
N-[2-(2-Isobutyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl)-acetyl]-guanidine is prepared as described in Example 9, starting with 10 cm3 of absolute ethanol, 0.13 g of sodium, 0.52 g of guanidinium chloride and 1.25 g of ethyl (6-trifluoromethyl-2-isobutyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetate in 10 cm3 of absolute ethanol. The reaction mixture is stirred at a temperature in the region of 20° C. for 16 hours and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is then taken up in a mixture of 5 cm3 of water and 15 cm3 of diethyl ether and then concentrated to dryness again under the same conditions. The residue is taken up in 100 cm3 of ethyl acetate and the organic phase is washed with twice 50 cm3 of aqueous 1N sodium hydroxide solution and then with 30 cm3 of aqueous 4N hydrochloric acid solution. The acidic aqueous phase is treated with aqueous 30% sodium hydroxide solution to pH 14, and then extracted with 3 times 50 cm3 of ethyl acetate. The organic extracts are combined and washed with saturated sodium chloride solution, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The white solid thus obtained is taken up in 20 cm3 of diethyl ether-and stirred at a temperature in the region of 20° C., and then filtered. The solid is dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 0.099 g of N-[2-(2-Isobutyl-3-oxo-6-trifluoromethyl-2,3-dihydro-1H-isoindol-1-yl)-acetyl]-guanidine is thus obtained in the form of a pale yellow solid melting at 154° C. Mass spectrum: EI: m/e 356 (M+), m/e 269, m/e 200, m/e 86 (base peak).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].[OH-].[Na+].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O1CCOCC1>[C:13]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4])([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: CC(C)(C)[C@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 23 °C
Reaction time: 8 h
Yield: 200.1 %

Procedure:
To a solution of L-tert-leucine (5.12 g, 39 mmol, 1 equiv) in 1,4-dioxane (80 mL) and 1M NaOH (39 mL, 39 mmol, 1.0 equiv) at 0° C. was added benzyl chloroformate (6.24 mL, 43.68 mmol, 1.12 equiv). The reaction mixture was stirred at 23° C. overnight, then concentrated, poured into 1M HCl (80 mL), and extracted with CH2Cl2 (2×100 mL). The organic layers were dried over Na2SO4 and concentrated to give crude CBZ-L-tert-leucine (20.7 g) as a clear oil: IR (cm-1) 3336, 1715, 1521, 1232; 1H NMR (CDCl3) δ 1.02 (s, 9H), 4.21 (d, 1H, J=9.9), 5.11 (s, 2H), 5.35 (d, 1H, J=9.0), 7.34-7.37 (m, 5H).
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[O:8][CH:7]=[N:6][C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CN(C)C=O.S(Cl)([Cl:22])=O>C(Cl)(Cl)Cl>[Cl:22][CH2:2][CH2:3][C:4]1[O:8][CH:7]=[N:6][C:5]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCCc1ocnc1-c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: ClCCc1ocnc1-c1ccccc1

Procedure:
5-(2-Hydroxyethyl)-4-phenyloxazole (10.0 g) was dissolved in chloroform (100 ml) and N,N-dimethylformamide (4.4 ml) was added. Under ice-cooling and stirring, 12.6 ml of thionyl chloride was added dropwise and the mixture was refluxed for an hour. The solvent was distilled off, followed by addition of saturated aqueous sodium hydrogen carbonate and extraction with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off to give an oil (11.0 g) of 5-(2-chloroethyl)-4-phenyloxazole. This product was dissolved in methyl ethyl ketone (150 ml), followed by addition of sodium iodide (13.0 g). The mixture was refluxed under stirring for 24 hours. The resulting precipitate was filtered off and the filtrate was concentrated, followed by addition of water and extraction with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off to give an oil of 5-(2-iodoethyl)-4-phenyloxazole, yield 14.4 g (83.2%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].O(CC)[C:14]([S-])=[S:15].[K+].C(O)C>O>[SH:15][C:14]1[O:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1cc(C(F)(F)F)ccc1O
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: FC(F)(F)c1ccc2oc(S)nc2c1
Yield: 31.9 %

Procedure:
A mixture of 2-amino-4-trifluoromethylphenol (8.85 g, 0.05 mole), potassium ethyl xanthate (8.8 g, 0.055 mole) and ethanol was heated under gentle reflux for a period of 24 hours. After cooling, the mixture was filtered and the filtrate was distilled under reduced pressure to remove the solvent and to give an orange solid. The solid was dissolved in water, the aqueous solution extracted with ethyl acetate and the organic phase evaporated to give a red wolid. The solid was triturated with boiling petroleum ether (bp 100°-120° C.) and the insoluble material collected by filtration to give the title compound (3.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=O)[CH2:8][CH2:7]2>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([N+:13]([O-:15])=[O:14])[CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7]2
Reactant: O=C1CCc2cc([N+](=O)[O-])cc(F)c2N1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(F)c2c(c1)CCCN2
Temperature: 0 °C

Procedure:
To a stirred solution of 8-fluoro-6-nitro-3,4-dihydroquinolin-2(1H)-one (950 mg, 4.52 mmol) in tetrahydrofuran (5 ml) was added borane-tetrahydrofuran complex (45.2 ml, 45.2 mmol) as a solution in THF. The reaction mixture was then heated to reflux temperature overnight. The reaction mixture was then cooled to 0° C. and quenched with methanol. The quenched mixture was then concentrated in vacuo, redissolved in methanol and reconcentrated, then refluxed in methanol for 2 h. The mixture was then concentrated onto silica gel, and chromatographed using 0-20% ethyl acetate in hexanes. 1H NMR (DMSO-d6) δ 7.77-7.71 (m, 1H), 7.73 (m, 1H), 7.31 (brs, 1H), 3.35-3.28 (m, 2H), 2.77 (t, J=6.2 Hz, 2H), 1.85-1.77 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:17](=[O:24])[C:18]3[C:23]([C:15]=2[C:14]2[C:9](=[CH:10][C:11]([OH:25])=[CH:12][CH:13]=2)[N:8]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:3].[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].O>ClCCl.CN(C)C1C=CN=CC=1>[CH3:3][N:2]([CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:17](=[O:24])[C:18]3[C:23]([C:15]=2[C:14]2[C:9](=[CH:10][C:11]([O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:12][CH:13]=2)[N:8]=1)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:1]
Reactant: CN(C)CCNc1nc2cc(O)ccc2c2c1C(=O)c1ccccc1-2
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CN(C)CCNc1nc2cc(OC(=O)C(C)(C)C)ccc2c2c1C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
To a solution of 6-(((dimethylamino)ethyl)amino)-3-hydroxy-7H-indeno[2,1-c]quinoline-7-on obtained in example 3 (100 mg, 0.3 mmol) in dichloromethane (10 ml) was added 4-dimethylaminopyridine (100 mg, 0.8 mmol) and pivaloyl chloride (37 μl, 0.3 mmol), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water to wash the organic layer, which was dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (eluent; chloroform:ethanol=10:1(v/v)) and crystallized from hexane to give 105 mg (yield: 80.0%) of title compound. The physicochemical properties thereof are shown in table 1.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:8](O)[CH2:9][OH:10].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:2]([CH:1]1[O:10][CH2:9][CH2:8][O:7]1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCO
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCCCCC1OCCO1
Temperature: 25 °C

Procedure:
30 g (0.29 mole) of hexanol, 31 g (0.5 mol) of ethylene glycol, 100 mg of p-toluenesulfonic acid (p-Ts) in 100 ml of benzene are placed in 250 ml round-bottomed flask equipped with a Dean-Stark trap, a condenser and a mechanical stirrer. The mixture is heated to reflux until no more water has separated from the benzene phase. The mixture is then cooled to room temperature, washed with 100 ml of 5% sodium bicarbonate, 100 ml of saturated NaCl solution, and finally water. The solution is dried over sodium sulfate. After removing the solvent, the oil is fractionated. A yield of 19.6 g of colorless oil (46%) is obtaind nD20 =1.4554.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][C@@H:6]([C:29]1[CH:37]=[CH:36][C:32]2[CH2:33][CH2:34][O:35][C:31]=2[CH:30]=1)[NH:7][C:8](=[O:28])[CH2:9][N:10]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[CH2:23][CH2:22][CH2:21][NH:20][C:19]=3[N:18]=2)[C:11]1=[O:27])C.[Li+].[OH-]>CCO.O>[O:35]1[C:31]2[CH:30]=[C:29]([C@@H:6]([NH:7][C:8](=[O:28])[CH2:9][N:10]3[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][C:17]4[CH:26]=[CH:25][C:24]5[CH2:23][CH2:22][CH2:21][NH:20][C:19]=5[N:18]=4)[C:11]3=[O:27])[CH2:5][C:4]([OH:38])=[O:3])[CH:37]=[CH:36][C:32]=2[CH2:33][CH2:34]1
Reactant: CCOC(=O)C[C@H](NC(=O)CN1CC[C@H](CCc2ccc3c(n2)NCCC3)C1=O)c1ccc2c(c1)OCC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C[C@H](NC(=O)CN1CC[C@H](CCc2ccc3c(n2)NCCC3)C1=O)c1ccc2c(c1)OCC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of the ester 15-7 (0.038 g, 0.073 mmol) in EtOH/H2O (4.5 mL/0.5 mL) was treated with LiOH (0.009 g, 0.365 mmol) and the homogeneous solution stirred at room temperature for 4 h. The solution was concentrated to a solid residue which was dissolved in H2O and purified by preparative HPLC (gradient conditions: 95:05 to 50:50 H2O/MeCN with 0.1% TFA) to give the acid 15-8 as a white solid (as the bis-trifluoroacetate salt).