Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19](=[O:29])[N:20]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])=[N:4][N:5]([C:8]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=2[C:10](O)=[O:11])[C:6]=1[CH3:7].[CH2:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][C@@H:32]([CH2:40][OH:41])[NH:31]1.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C>ClCCl>[CH2:25]([N:20]([CH2:21][CH2:22][CH2:23][CH3:24])[C:19]([C:3]1[C:2]([Cl:1])=[C:6]([CH3:7])[N:5]([C:8]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:9]=2[C:10]([N:31]2[C@H:32]([CH2:40][OH:41])[CH2:33][C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30]2)=[O:11])[N:4]=1)=[O:29])[CH2:26][CH2:27][CH3:28]
Reactant: OC[C@@H]1Cc2ccccc2CN1
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(OC)cc2C(=O)O)c(C)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(OC)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 4.5 %

Procedure:
To a stirred solution of 2-(4-chloro-3-dibutylcarbamoyl-5-methyl-pyrazol-1-yl)-5-methoxy-benzoic acid (0.35 g, 0.82 mmol) and (S)-(1,2,3,4-tetrahydroisoquinolin-3-yl)methanol (0.13 g, 0.82 mmol) in dichloromethane (8 mL) under nitrogen atmosphere was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.16 g, 0.82 mmol) and hydroxybenzotriazole (0.13 g, 0.82 mmol). The mixture was stirred at ambient temperature for 5 minutes. Triethylamine (0.34 mL, 2.5 mmol) was added to the mixture. The reaction was stirred for 60 hours at ambient temperature. The mixture was washed with water and purified by eluting through a silica gel column with a 10 to 100% ethyl acetate/heptane gradient to afford the title compound (21 mg, 4.5% yield). MS (ESI) [m/e, (M+H)+]=567.3. 1H NMR (400 MHz, chloroform-d) δ ppm 6.75-7.36 (m, 7H), 4.13-5.41 (m, 4H), 3.80-3.96 (m, 3H), 2.51-3.71 (m, 8H), 2.17-2.32 (m, 3H), 1.48-1.68 (m, 4H), 1.19-1.44 (m, 4H), 0.70-0.97 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5](Br)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].[CH2:14]([NH2:19])[C:15]([CH3:18])([CH3:17])[CH3:16].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([NH:19][CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CC(C)(C)CN
Reactant: CCOC(=O)C(Br)c1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(NCC(C)(C)C)c1cccnc1
Yield: 39.2 %

Procedure:
Bromopyridin-3-yl-acetic acid ethyl ester (2.54 g; 10.2 mmol), prepared in a manner similar to preparation 340, was reacted in refluxing CH2Cl2, overnight with neopentylamine (4.83 mL; 41.0 mmol; 4 equiv) and Et3N (5.8 mL; 41.0 mmol; 4 equiv). The reaction solution was evaporated to dryness, dissolved in CH2Cl2, washed five times with saturated NaHCO3(aq), washed once with saturated NaCl (aq), dried with Na2SO4, filtered, and concentrated in vacuo. The resulting brown oil was purified with silica gel chromatography in a 3×25 cm glass column using a 0.5% methanol/chloroform (v/v) mobile phase. A second column purification with 100% chloroform followed by 1% methanol/chloroform (v/v) produced pure product as a yellow oil (1.0 g; 40% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14])=O.O.[NH2:20][NH2:21].O>C(O)CCC>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[C:5](=[N:20][NH2:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13][CH3:14]
Reactant: NN
Reactant: COc1ccccc1C(=O)c1ccccc1OC
Solvent: CCCCO
Solvent: O
Product: COc1ccccc1C(=NN)c1ccccc1OC
Temperature: 25 °C

Procedure:
A stirred suspension of 2,2′-dimethoxybenzophenone (20.72 g, 0.0855 mol) and 20 mL (0.412 mol) of hydrazine monohydrate in 25 mL of 1-butanol was heated to reflux overnight. After cooling to room temperature the two phase reaction mixture was poured into water and cooled to induce crystallization. The white precipitate was filtered, washed with water and petroleum ether and dried in vacuo to yield 2,2′-dimethoxybenzophenone hydrazone (1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:20][OH:21])[C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=[O:14])=[CH:9][CH:8]=1.CN(C)C=O>[O-]CC.[Na+].C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:20][O:21][CH2:19][CH2:7][CH2:8][CH3:9])[C:7]1[CH:19]=[CH:18][C:10]([O:11][C:12]([CH3:17])([CH3:16])[C:13]([O:15][CH2:6][CH2:2][CH2:3][CH3:4])=[O:14])=[CH:9][CH:8]=1
Reactant: CC(C)(Oc1ccc(C(=NO)c2cccs2)cc1)C(=O)O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCCON=C(c1ccc(OC(C)(C)C(=O)OCCCC)cc1)c1cccs1
Reaction time: 3 h

Procedure:
2-[4-(2-Thienyl-hydroxyiminomethyl)-phenoxy]-2-methyl propionic acid (6.7 g) is dissolved in a sodium ethoxide solution in ethanol (100 ml; prepared from 1.3 g sodium), and the solution is then refluxed for 1 hour, after which dimethylformamide (75 ml) is added thereto and the ethanol is evaporated off. Butyl bromide (9 g) is added to the solution at 80° C. and the mixture is stirred for 3 hours, after which the solvent is evaporated under reduced pressure. Water and chloroform are then added to the resulting material. After stirring the mixture, the chloroform phase is decanted off and is then washed with an aqueous alkaline solution. After drying, the solvent is evaporated off and the desired ester is isolated as an oil consisting of an admixture of equivalent amounts of both stereoisomers Z/E. nd22 =1.545.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:15])[O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.N1C=CC=CC=1.[S:22](Cl)(Cl)=[O:23].[CH3:26][NH:27][S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29]>O1CCCC1>[C:31]1([S:28]([N:27]([CH3:26])[S:22]([N:2]([CH3:1])[C:3](=[O:15])[O:4][C:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][CH:6]=2)=[O:23])(=[O:30])=[O:29])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CNS(=O)(=O)c1ccccc1
Reactant: CNC(=O)Oc1cccc2ccccc12
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CN(C(=O)Oc1cccc2ccccc12)S(=O)N(C)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-naphthyl methylcarbamate (4.0 g, 0.02 mol) in 20 ml dry tetrahydrofuran was added pyridine (2.0 g, 0.025 mol) followed by thionyl chloride (2.5 g, 0.021 mol). The mixture was stirred at room temperature for 4 hours. Pyridine (2 g, 0.025 mol) was added and followed by 3.5 g (0.02 mol) N-methylbenzenesulfonamide and the mixture was stirred at room temperature overnight.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1C=CC=CC=1>[CH:7](=[N:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: CN(C)CCN
Solvent: c1ccccc1
Product: CN(C)CCN=Cc1ccccc1

Procedure:
A solution of 88.0 g of N,N-dimethylethylenediamine in 150 ml. of benzene is treated with a solution of 106 g of freshly distilled benzaldehyde in 150 ml. of benzene. This mixture is stirred and refluxed for 2 hours while collecting 22 ml. of an aqueous layer in a Dean-Stark tube. The solvent is then distilled and the residue fractionated to give 156 g of distillate, boiling point 98°-100° C. at 4 mm. of Hg.
Reaction SMILES: [Cl-].[Li+].[OH-:3].[K+].[Cl:5][C:6]1[C:13]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:12]([O:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9].C(Br)(Br)Br.[O:32]1[CH2:37]COCC1>O>[Cl:5][C:6]1[C:13]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:12]([O:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27])[CH:11]=[CH:10][C:7]=1[CH:8]([OH:9])[C:37]([OH:32])=[O:3]
Reactant: COCCOCOc1ccc(C=O)c(Cl)c1OCOCCOC
Reactant: C1COCCO1
Reactant: [OH-]
Agent: [Cl-]
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: BrC(Br)Br
Product: COCCOCOc1ccc(C(O)C(=O)O)c(Cl)c1OCOCCOC
Temperature: 0 °C
Reaction time: 24 h

Procedure:
2.42 g of lithium chloride and 7.02 g of potassium hydroxide were dissolved in 30 ml of water at 0° C. and a solution of 10 g of 2-chloro-3,4-bis-[(2-methoxy-ethoxy)-methoxy]benzaldehyde (synthesized in Preparation 1), 2.8 ml of bromoform and 38 ml of dioxane were added to this mixture. The mixture was stirred for 24 hours at 0° C. and then another 2.8 ml of bromoform were added. The mixture stood for 16 hours and after dilution with 100 ml of water, the solution was washed with ether, decanted, cooled to 0° C. and acidified until the pH was 2.5-3. Extraction was carried out with ether and the organic phase was washed with water and dried. The solvent was driven off to collect 11.4 g of the desired product in the form of an oil with a Rf=0.1 [eluant: methylene chloride-methanol-acetic acid (89-10-1)].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[CH2:32](O)[CH3:33].[C:35]([O-:38])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[C:26]([C:33]4[CH:32]=[CH:11][C:10]([CH:35]=[O:38])=[CH:9][CH:14]=4)[CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCO
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(Br)c3)oc2C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4ccc(C=O)cc4)c3)oc2C)cc1
Temperature: 25 °C

Procedure:
A solution of 2-(4-{2-[2-(3-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (0.907 mmol) (see Ex. 3, part F) and 1-(4-formylphenyl)boronic acid (0.998 mmol) in toluene:ethanol (18.2 mL of a 1:1 solution) was treated with Na2CO3 (aq) (0.906 mL of a 2M solution). A nitrogen atmosphere was applied, Pd(PPh3)4 (0.045 mmol) was added, and the orange mixture was heated at reflux for 2 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate (20 mL) and H2O (30 mL). The layers were separated, and the aqueous phase was back-extracted with ethyl acetate (2×10 mL). Combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (20 g SiO2, 3:7 ethyl acetate:hexanes). Rf=0.24 in 1:4 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ10.03 (s, 1H), 9.21 (s, 1H), 9.02-8.94 (m, 3H), 8.81-8.78 (m, 2H), 8.46-8.41 (m, 1H), 8.36-8.30 (m, 1H), 6.79-6.71 (m, 4H), 4.23-4.16 (m, 4H), 2.94 (t, 2H), 2.37 (s, 3H), 1.26 (s, 6H), 1.24 (t, 3H); MS (EI) 514.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:18])[C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1.Cl.[OH-].[Na+]>CC(C)=O>[C:2]1([NH:1][C:8](=[O:18])[C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:14])=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1)c1ccc(C(=O)Nc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 84.2 %

Procedure:
N,N'-diphenylterephthalamide (Structure I) is synthesized from aniline and terephthaloyl chloride using acetone as a reaction media and an aqueous solution of NAOH to neutralize the HCl generated. Terephthaloyl chloride (87.2 grams, 0.43 moles) is first added to a stirred, 2-liter reaction flask containing one liter of acetone. After the terephthaloyl chloride has dissolved, aniline (80.0 grams, 0.86 moles) is added dropwise using an addition funnel over a 30 minute period. During the course of this addition, a white precipitate is formed. A 200 ml aqueous solution of NaOH (34.3 grams, 0.86 moles) is then added, also using an addition funnel, over a 30 minute period. The reaction temperature during both the aniline and NAOH addition is maintained below 35° C. by blowing air onto the outside of the reaction flask. After the NAOH addition, the reaction mixture is stirred for three hours and then vacuum filtered (filtrate pH=7). The filter cake obtained is washed with 400 ml of acetone and then added to one liter of deionized water, stirred for 15 minutes and filtered. This filter cake is washed with 500 ml of acetone and then dried in a 105° C. vacuum oven to a constant weight. This final product (114.4 grams, yield=84.2%) exhibited a sharp melting endotherm by differential scanning calorimetry (DSC) at 346° C. Also Fourier transform infrared (FTIR) analysis showed the following absorbances which are indicative of the structure for the final product: 3329 cm-1 (N-H stretch), 1528 cm-1 (Amide II band) and 1650 cm--1 (Amide I band). ##STR9##
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH:10]2[CH2:15][N:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][CH2:12][N:11]2[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:6][CH:5]=1)([O-])=O.CO.[Sn].[OH-].[Na+]>O.C(OCC)(=O)C>[C:16]1([N:14]2[CH2:13][CH2:12][N:11]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:10]([CH2:9][O:8][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[CH:30][CH:29]=3)[CH2:15]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(OCC2CN(c3ccccc3)CCN2Cc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Agent: [Sn]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(OCC2CN(c3ccccc3)CCN2Cc2ccccc2)cc1

Procedure:
Dissolve 2-[(4-nitrophenoxy)methyl]-4-phenyl-1-(phenylmethyl)piperazine (7.15 g, 17.7 mmol) in a 1/1 mixture of methanol and ethyl acetate (350 mL) and add tin II chloride dihydrate (20.0 g, 88.6 mmol). Stir the mixture and heat the reaction to reflux. Monitor the progress of the reaction by thin-layer chromatography and add more tin II chloride dihydrate as needed. Upon completion of the reaction, pour reaction mixture into water (200 mL) and add 4N sodium hydroxide to pH=12. Extract with a solution of ethyl acetate/methanol (2/1) (2×200 mL). Wash the combined extracts with water (200 mL) and remove the solvent in vacuo. Flash chromatograph the residue on flash silica gel (250 g) with an ethyl acetate/hexanes [gradient (1/1-1/0)] to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][P:9]([CH2:19][NH:20][S:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)(=[O:23])=[O:22])(=[O:18])[O:10]C2C=CC=C(Cl)C=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].O>O1CCOCC1>[NH4+:20].[Cl:1][C:2]1[CH:3]=[C:4]([O:8][P:9]([CH2:19][NH:20][S:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)(=[O:23])=[O:22])(=[O:10])[O-:18])[CH:5]=[CH:6][CH:7]=1
Reactant: O=P(CNS(=O)(=O)c1cccs1)(Oc1cccc(Cl)c1)Oc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=P([O-])(CNS(=O)(=O)c1cccs1)Oc1cccc(Cl)c1
Product: [NH4+]
Reaction time: 3 h
Yield: 80.9 %

Procedure:
To a solution of diester (viii) (86 mg, 0.18 mmol) in dioxane (1.5 mL) was added 1 N sodium hydroxide solution (720 μL, 0.72 mmol) and water (4 mL). After 3 h, the solution was neutralized and concentrated. the residue was purified by flash chromatography (elution with chloroform:methanol:concentrated ammonium hydroxide; 8.2:2:0.25) to afford the title compound (28 mg, 40%) as a colorless solid: 1H NMR (400 MHz, D2O) δH 7.84 (d, J=5 Hz, 1H, Ar—H), 7.71 (d, J=3.5 Hz, Ar—H), 7.30 (t, J=8 Hz, 1H, Ar—H), 7.15-7.21 (m, 3H, Ar—H), 7.01-7.03 (m, 1H, Ar—H), 3.23 (d, J=14 Hz, 2H, NCH2P); 31P NMR: (164 MHz, D2O), δP 14.5.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.C(N(CC)CC)C.[NH:27]1[CH2:32][CH2:31][CH2:30][CH:29]([C:33]([OH:35])=[O:34])[CH2:28]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:4]1[N:3]=[C:2]([N:27]2[CH2:32][CH2:31][CH2:30][CH:29]([C:33]([OH:35])=[O:34])[CH2:28]2)[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: O=C(O)C1CCCNC1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCCC(C(=O)O)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 2 h

Procedure:
To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.449 mg, 1.66 mmol) in CH2Cl2 was added 5 equivalents of triethylamine followed by the addition of piperidine-3-carboxylic acid as a TFA salt. The reaction was stirred for 2 hours and quenched with water. The layers were separated, and the organic extracts were dried over MgSO4, filtered, and concentrated to give 1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidine-3-carboxylic acid which was used without further purification. LC/MS: m/z 364.3 (M+H)+ at 2.22 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([CH:3]=[CH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)(Cl)Cl>[CH2:1]([CH:3]=[CH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]2[O:20][CH:8]2[CH:7]=1)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC=CCc1ccccc1
Solvent: ClC(Cl)Cl
Product: CCC=CCC1=CC2OC2C=C1
Reaction time: 96 h
Yield: 42.7 %

Procedure:
3.8 g of p-ethylallylbenzene was added to 5.9 g of m-chloroperbenzoic acid dissolved in 70 ml of chloroform and the mixture was allowed to stand at about 5° C for 4 days. The resulting mixture was washed with sodium hydroxide solution, Mohr's salt solution, then water and dried over anhydrous sodium sulfate. The solvent was evaporated and the concentration was distilled under reduced pressure to obtain 1.8 g (yield 43%) of p-ethylallylbenzene oxide having a boiling point of 144° to 143° C/38 mmHg as oily substance.
Reaction SMILES: CS(Cl)(=O)=O.C([CH:8]1[C:12](O)([C:13]([OH:15])=[O:14])[C:11]2[C:17](=[O:22])[CH2:18][CH:19]([CH3:21])[CH2:20][C:10]=2[O:9]1)C.[CH2:23](N(CC)CC)[CH3:24].[OH-].[Na+]>ClCCl>[O:22]=[C:17]1[C:11]2[C:12]([C:13]([O:15][CH2:23][CH3:24])=[O:14])=[CH:8][O:9][C:10]=2[CH2:20][CH:19]([CH3:21])[CH2:18]1
Reactant: CCN(CC)CC
Reactant: CCC1OC2=C(C(=O)CC(C)C2)C1(O)C(=O)O
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOC(=O)c1coc2c1C(=O)CC(C)C2
Reaction time: 2 h
Yield: 99.8 %

Procedure:
A solution of methanesulfonyl chloride (6.1 mL, 78.5 mmol) in dichloromethane (50 mL) was added to a stirring solution of ethyl 3-hydroxy 4-oxo-6-methyl-2,3,4,5,6,7-hexahydrobenzofuran-3-carboxylic acid (18.48 g, 76 mmol) and triethylamine (21.4 mL, 154 mmol) in dichloromethane (150 mL) at 0° C. The mixture was allowed to reach ambient temperature, stirred for 2 hours, then poured into aqueous 1N sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give ethyl 4-oxo-6-methyl-4,5,6,7-tetrahydrobenzofuran-3-carboxylate (16.86 g).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([OH:17])[CH:11]=[CH:10]2>O.C(O)(=O)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([N:1]=[O:3])=[C:12]([OH:17])[CH:11]=[CH:10]2
Reactant: O=N[O-]
Reactant: COc1ccc2cc(O)ccc2c1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(N=O)c(O)ccc2c1

Procedure:
A solution of sodium nitrite (3.19 g) in water (23.6 ml) is slowly added to a stirring solution of 6-methoxy-2-naphthol [8.0 g, prepared as described in Organic Synthesis 49, 90 (1969)] in acetic acid (46 ml) and water (4.6 ml) at 0° C. The resulting slurry is allowed to stand at room temperature for several hours and diluted with water. The solid is collected, washed, dried and crystallized from methanol to give 6-methoxy-1nitroso-2-naphthol, mp 147°-148° C.
Reaction SMILES: C(OC([N:8]1[CH2:15][CH:14]2[N:16](C(OC(C)(C)C)=O)[CH:10]([CH2:11][C:12]([C:39]3[O:43][N:42]=[C:41]([CH2:44][CH2:45][CH2:46][O:47][C:48]4[C:53]([F:54])=[CH:52][CH:51]=[C:50]([Cl:55])[C:49]=4[F:56])[CH:40]=3)=[C:13]2[C:24](=[O:38])[N:25]([CH:35]2[CH2:37][CH2:36]2)[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[CH2:9]1)=O)(C)(C)C.ClC(Cl)(Cl)C(NC(=O)[O-])(C)C>C1COCC1.CC(O)=O.[Zn]>[CH:35]1([N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[Cl:34])[C:24]([C:13]2[CH:14]3[NH:16][CH:10]([CH2:11][C:12]=2[C:39]2[O:43][N:42]=[C:41]([CH2:44][CH2:45][CH2:46][O:47][C:48]4[C:53]([F:54])=[CH:52][CH:51]=[C:50]([Cl:55])[C:49]=4[F:56])[CH:40]=2)[CH2:9][NH:8][CH2:15]3)=[O:38])[CH2:37][CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3cc(CCCOc4c(F)ccc(Cl)c4F)no3)=C(C(=O)N(Cc3cccc(Cl)c3Cl)C3CC3)C(C1)N2C(=O)OC(C)(C)C
Agent: CC(C)(NC(=O)[O-])C(Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(C1=C(c2cc(CCCOc3c(F)ccc(Cl)c3F)no2)CC2CNCC1N2)N(Cc1cccc(Cl)c1Cl)C1CC1

Procedure:
This compound is prepared from compound F9, according to the above-described procedure B. After cleaving the Boc-group the trichloro-tert-butylcarbamate was cleaved using Zn-powder in THF/AcOH 3:1. LC-MS: tR=0.90 min; ES+: 637.24.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.Cl[C:10](=[O:15])[C:11]([O:13][CH3:14])=[O:12]>>[CH3:14][O:13][C:11](=[O:12])[C:10]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1)=[O:15]
Reactant: Cc1ccc(N)nc1
Reactant: COC(=O)C(=O)Cl
Product: COC(=O)C(=O)Nc1ccc(C)cn1

Procedure:
The method described in Referential Example 242 was performed by use of 2-amino-5-methylpyridine and methyl chlorooxoacetate, whereby the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][N:21]=1.CN1CCCC1=O.Cl>C(O)C.C(OCC)(=O)C.[OH-].[Na+]>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:3]2[CH:4]=[C:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:6]=[CH:7][C:2]=2[CH3:1])=[N:21][CH:22]=1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)cc1Oc1ccc([N+](=O)[O-])cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc(NC(=O)OCc2ccccc2)cc1Oc1ccc(N)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 166.3 %

Procedure:
To a solution of benzyl {4-methyl-3-[(5-nitropyridin-2-yl)oxy]phenyl}carbamate (36.9 g, 97.4 mmol) in ethanol (200 mL)/1-methylpyrrolidin-2-one (50 mL) were added 1N hydrochloric acid (50 mL) and reduced iron (27.2 g, 487 mmol), and the mixture was stirred at 100° C. for 3 hr. The reaction mixture was diluted with ethyl acetate (200 mL), and 2N aqueous sodium hydroxide solution (50 mL) was added. The insoluble material was filtered off through a celite pad, and the insoluble material was washed with ethyl acetate (1 L). Benzyl {4-methyl-3-[(5-nitropyridin-2-yl)oxy]phenyl}carbamate (38.3 g, 101 mmol) was treated in the same manner as above. The obtained filtrates were combined, washed with saturated brine (3×200 mL), and purified by silica gel (ethyl acetate). The obtained solution was concentrated under reduced pressure, and the crystals precipitated during concentration were collected by filtration to give the title compound (56.6 g, 82%) as a pale-orange solid.