Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:14][CH2:13][C@H:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([OH:21])[CH2:17][CH2:16]2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[O:29]1C[CH2:32][CH2:31][CH2:30]1.C(Cl)(=O)C=C>O>[C:30]([O:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([C@H:12]2[CH2:11][CH2:10][C@H:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[CH2:14][CH2:13]2)[CH2:16][CH2:17]1)(=[O:29])[CH:31]=[CH2:32]
Reactant: C1CCOC1
Reactant: O[C@H]1CC[C@H]([C@H]2CC[C@H](c3cccc(F)c3F)CC2)CC1
Agent: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: C=CC(=O)O[C@H]1CC[C@H]([C@H]2CC[C@H](c3cccc(F)c3F)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
First, 1.44 g of trans-4-[trans-4-(2,3-difluorophenyl)cyclohexyl]cyclohexanol, 0.61 g of triethylamine, and 20 ml of dry tetrahydrofuran were placed in a 100 ml flask. Then, 0.53 g of acryloyl chloride was added dropwise to the mixture under ice water cooling. The resultant mixture was allowed to warm to room temperature and stirred overnight. Water was added to the reaction mixture, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: benzene/hexane=1/2) and recrystallized from hexane to obtain 0.91 g of trans-4-[trans-4-(2,3-difluorophenyl)cyclohexyl]cyclohexyl acrylate (Y: 53.3%). The compound thus obtained had a purity of 98.8% by GC and 99.4% by HPLC. Furthermore, the phase transition temperature of this compound was as follows.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([O:34][CH2:35][CH2:36][OH:37])[CH2:32][NH2:33])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:33][CH2:32][CH:31]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:26][CH:27]=2)[O:34][CH2:35][CH2:36][OH:37])[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Reactant: NCC(OCCO)c1ccc(OCc2ccccc2)cc1
Product: COC(=O)COc1ccc(CC(C)NCC(OCCO)c2ccc(OCc3ccccc3)cc2)cc1

Procedure:
The title compound was prepared as an oil from 1-(4-carbomethoxymethoxyphenyl)propan-2-one (4.52 g) and 2-(4-benzyloxyphenyl)-2-(2-hydroxyethoxy)ethanamine (5.84 g) as described in Example 1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]=O)=[CH:2]1.C1(P(=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:2]1
Reactant: O=Cc1ccsc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1ccsc1
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of thiophene-3-carbaldehyde (10 g, 89.3 mmol) in THF (500 mL) at 0° C. was added ethyl (triphenylphosphoranylidene)acetate (35 g, 100.5 mmol) in portions. After stirring overnight, the reaction mixture was concentrated and purified by column chromatography to give the title compound (13.6 g, 83%).
Reaction SMILES: C[O:2][C:3](=[O:42])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:39](=[O:41])[CH3:40])[C:10]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[C:28]([OH:35])[C:27]=3[CH2:36][CH2:37][CH3:38])=[CH:11][CH:12]=2)[CH:7]=1.[OH-].[Na+]>CO>[C:39]([C:9]1[C:10]([O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29]([C:32](=[O:34])[CH3:33])=[C:28]([OH:35])[C:27]=2[CH2:36][CH2:37][CH3:38])=[CH:11][CH:12]=[C:13]2[C:8]=1[CH:7]=[C:6]([O:5][CH2:4][C:3]([OH:42])=[O:2])[CH:15]=[CH:14]2)(=[O:41])[CH3:40]
Reactant: CCCc1c(OCCOCCOCCOc2ccc3ccc(OCC(=O)OC)cc3c2C(C)=O)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c(OCCOCCOCCOc2ccc3ccc(OCC(=O)O)cc3c2C(C)=O)ccc(C(C)=O)c1O
Yield: 88.8 %

Procedure:
A solution of 1.8 g of [[8-acetyl-7-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-naphthalenyl]oxy]acetic acid methyl ester and 31 ml of 1N sodium hydroxide in 60 ml of methanol was stirred at reflux for 1 hour. The methanol was removed in vacuo and the aqueous solution was acidified to pH3. The gummy precipitate was extracted with methylene chloride, washed with water, dried (magnesium sulfate) and concentrated in vacuo to give an oil which was triturated with ether to yield 1.56 g, m.p. 110°-111° C. (89%) of [[8-acetyl-7-[2-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]ethoxy]-2-naphthalenyl]oxy]acetic acid.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]([C:7]1[C:8]([OH:14])=[CH:9][CH:10]=[CH:11][C:12]=1O)=O.C(OC(=O)C)(=O)C.[OH-].[Na+]>C(O)(=O)C>[CH3:4][C:5]1[C:7]2[C:8]([OH:14])=[CH:9][CH:10]=[CH:11][C:12]=2[NH:3][N:2]=1
Reactant: CC(=O)c1c(O)cccc1O
Reactant: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cc1n[nH]c2cccc(O)c12
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
526 mg (10.5 mmol) of hydrazine hydrate and 1 ml of glacial acetic acid are added to 800 mg (5.26 mmol) of 2,6-dihydroxyacetophenone. After 15 minutes of stirring at 110° C., the reaction mixture is cooled to room temperature. After addition of 6 ml of polyphosphoric acid, the mixture is heated at 120° C. for 20 min. After cooling to room temperature, 0.8 g (7.89 mmol) of acetic anhydride is added dropwise. The mixture is once more heated at 120° C. for 20 min. The reaction mixture, cooled to room temperature, is then poured onto ice. The mixture is neutralized using 1N sodium hydroxide solution and extracted three times with ethyl acetate. The combined organic phases are washed twice with water. After drying over sodium sulfate, the solvent is removed under reduced pressure. The product is purified by column chromatography. The mobile phase used is a mixture of cyclohexane and ethyl acetate (1:1).
Reaction SMILES: CCN=C=NCCCN(C)C.C1COCC1.[OH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28].[F:30][C:31]1[C:36](O)=[C:35]([F:38])[C:34]([F:39])=[C:33]([F:40])[C:32]=1[F:41]>O>[OH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([O:24][C:36]2[C:35]([F:38])=[C:34]([F:39])[C:33]([F:40])=[C:32]([F:41])[C:31]=2[F:30])=[O:23])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28]
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc(O)c([N+](=O)[O-])c1
Yield: 56.8 %

Procedure:
WSC (7.9 g) was added to a THF (100 ml) solution of 4-hydroxy-3-nitrobenzoic acid (7.3 g). and pentafluorophenol (7.4 g) at 0° C., and stirred overnight at 25° C. Water (50 ml) was added to the reaction solution, the solvent was evaporated under reduced pressure, and the organic layer was extracted with ethyl acetate. After drying the organic layer over MgSO4, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/4), thereby giving 7.9 g of the desired compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH2:7][NH:8][C:9]1[C:14]([CH2:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:17][CH3:18].C(=O)(O)[O-].[Na+].O1CCOCC1.[Cl:30][CH2:31][C:32](Cl)=[O:33]>CCOCC.O>[Cl:30][CH2:31][C:32]([N:8]([CH2:7][CH:2]1[O:3][CH2:4][CH2:5][CH2:6][O:1]1)[C:9]1[C:14]([CH2:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:17][CH3:18])=[O:33]
Reactant: CCc1cccc(CC)c1NCC1OCCCO1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: CCc1cccc(CC)c1N(CC1OCCCO1)C(=O)CCl
Reaction time: 0.25 h

Procedure:
N-(1,3Dioxan-2-ylmethyl)-2,6-diethylaniline (25 grams), sodium bicarbonate (10 grams), dioxane (30 ml) and water (4 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The mixture is cooled to a temperature of about 0°C and chloroacetyl chloride (15 grams) is added, with stirring, over a period of about 15 minutes. After the addition is completed stirring is continued for a period of about 1 hour. After this time ether (100 ml) is added to the mixture and the resulting solution is washed with water. The washed solution is then dried over anhydrous magnesium sulfate and stripped of solvents leaving a solid residue. The residue is recrystallized to yield the desired product N-α-chloroacetyl-N-(1,3-dioxan- 2-ylmethyl)-2,6-diethylaniline.
Reaction SMILES: C([O:3][C:4]([CH2:6][N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[C:8]1=[O:14])=[O:5])C.[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>CO.O>[CH2:15]([O:13][C:9]1[C:8](=[O:14])[N:7]([CH2:6][C:4]([OH:3])=[O:5])[CH:12]=[CH:11][CH:10]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)Cn1cccc(O)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cn1cccc(OCc2ccccc2)c1=O
Yield: 41 %

Procedure:
1-Ethoxycarbonylmethyl-3-hydroxypyrid-2-one (10 g), prepared as described under (B), is dissolved in methanol/water (9:1 v/v) (400 ml). To this solution is added benzyl chloride (3 molar excess) and NaOH until the pH is above 12. The mixture is then refluxed for six hours to give a clear orange solution. The methanol is removed by rotary evaporation and the aqueous solution is extracted with dichloromethane to remove excess benzyl chloride. The aqueous phase is diluted slightly by adding extra water and then acidified to pH 2 using concentrated hydrochloric acid which results in the precipitation of a beige solid. The mixture is cooled and the precipitate filtered off and washed with diethyl ether. The crude product is recrystallised from ethanol to give 3-benzyloxy-1-carboxymethylpyrid-2-one (5.4 g, 41%), m.p. 176°-177° C.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([C:19]([OH:21])=O)[N:15]4[CH3:18])=[C:11]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:10]=3)[C:7]3[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]([OH:41])([CH3:40])[CH3:39])[CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([C:19]([N:32]5[CH2:37][CH2:36][CH:35]([C:38]([OH:41])([CH3:40])[CH3:39])[CH2:34][CH2:33]5)=[O:21])[N:15]4[CH3:18])=[C:11]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:10]=3)[C:7]3[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(O)C1CCNCC1
Reactant: Cn1c(C(=O)O)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(C(=O)N2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Temperature: 25 °C
Reaction time: 19 h
Yield: 52.8 %

Procedure:
A mixture of 2-(2-cyclopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carboxylic acid (200 mg, 0.48 mmol), 2-piperidin-4-ylpropan-2-ol (78 mg, 0.55 mmol), HATU (205 mg, 0.54 mmol) and DIPEA (96 μL, 0.55 mmol) in DCM (5 mL) was allowed to stir at r.t. for 19 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si—PCC, MeOH:DCM, 0-3%) then (Si—PCC, MeOH:EtOAc, 0-5%) affording 798 as a white solid (138 mg, 53%). LCMS (method G): RT 7.50 min, [M+H]+ 545.4. 1H NMR (CDCl3, 400 MHz): δ 7.97-7.96 (1 H, m), 7.68-7.67 (1 H, m), 7.28-7.20 (2 H, s), 4.91-4.82 (1 H, m), 4.68-4.65 (1 H, m), 4.40 (4 H, brd s), 3.97 (3 H, s), 3.86 (4 H, t, J=4.70 Hz), 3.18-3.10 (1 H, m), 2.84-2.83 (2 H, m), 1.94-1.92 (2 H, m), 1.64-1.62 (1 H, m), 1.44-1.43 (2 H, m), 1.35-1.34 (2 H, m), 1.24-1.22 (7 H, m), 1.06-1.05 (2 H, m)
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13]Br.[CH:15]1[C:24]2[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=2[CH:18]=[CH:17][N:16]=1>C(#N)C>[Br-:1].[Br-:1].[CH2:2]([N+:16]1[CH:17]=[CH:18][C:19]2[CH2:20][CH2:21][CH2:22][CH2:23][C:24]=2[CH:15]=1)[CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][N+:16]1[CH:17]=[CH:18][C:19]2[CH2:20][CH2:21][CH2:22][CH2:23][C:24]=2[CH:15]=1
Reactant: BrCCCC/C=C\C=C/CCCCBr
Reactant: c1cc2c(cn1)CCCC2
Solvent: CC#N
Product: C(/C=C\CCCC[n+]1ccc2c(c1)CCCC2)=C/CCCC[n+]1ccc2c(c1)CCCC2
Product: [Br-]

Procedure:
cis-cis-1,12-Dibromo-dodeca-5,7-diene was added to a solution of 5,6,7,8-tetrahydro-isoquinoline (3 mmol) in acetonitrile and the solution refluxed for 24 hours. The acetonitrile was removed in vacuum and the resulting residue was partitioned between ether and water. The aqueous layer was washed extensively with ether until no isoquinoline left in the aqueous layer. The resulting aqueous solution of the product was lyophilized to yield the pure product. (75%). 1HNMR (300 MHz, D2O, ppm), 8.30 (s, 2H), 8.19 (d, J=6.6, 2H), 7.50 (d, J=6.3, 2H), 6.09-6.16 (m, 2H), 5.28-5.36 (m, 2H), 4.27 (t, J=7.2, 4H), 2.29-2.82 (br, 4H), 2.67-2.74 (br, 4H), 2.02 (q, J=7.2, 4H), 1.81 (p, J=7.2, 4H), 1.62-1.69 (m, 8H), 1.22 (p, J=7.2, 4H). CNMR158.82, 143.10, 139.60, 138.96, 132.28, 127.92, 124.09, 60.82, 49.13, 30.07, 29.35, 26.32, 26.20, 25.43, 21.01.
Reaction SMILES: C([CH:9]([O:16][C:17]([NH:19][CH2:20][C:21]1([CH2:27][C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)C1C=CC=CC=1.[CH:31]1[CH:36]=[C:35](Cl)[CH:34]=[C:33]([C:38]([O:40]O)=[O:39])[CH:32]=1.C([O-])(O)=O.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:38]([O:40][CH:9]([O:16][C:17]([NH:19][CH2:20][C:21]1([CH2:27][C:28]([OH:30])=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)(=[O:39])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:31][CH:32]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(O)CC1(CNC(=O)OC(C(=O)c2ccccc2)c2ccccc2)CCCCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)CC1(CNC(=O)OC(OC(=O)c2ccccc2)c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of 1-{[(α-benzoylbenzyloxy)carbonyl]aminomethyl}-1-cyclohexane acetic acid (61) (1.89 g, 4.6 mmol) in 40 mL of CH2Cl2 was added 77% mCPBA (2.07 g, 9.2 mmol) and NaHCO3 (0.78 g, 9.2 mmol), respectively, at room temperature and the resulting mixture was stirred at room temperature overnight. The reaction mixture was acidified with 10% citric acid and extracted with CH2Cl2. The organic extract was washed with brine and dried over Na2SO4. After removing the solvent under reduced pressure, the residue was purified by reverse phase preparative HPLC (acetonitrile-water, 0.1% formic acid) to afford 960 mg (49%) of the title compound (59). 1H NMR (CDCl3, 400 MHz): δ 1.58–1.35 (m, 10H), 2.34 (s, 2H), 3.26 (dd, J=6.8, 0.8 Hz, 2H), 5.38 (t, J=6.8 Hz, 1H), 7.46–7.26 (m, 5H), 7.63–7.55 (m, 3H), 7.89 (s, 1H), 8.08 (dd, J=8.8, 1.2 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:5][CH:4]([CH:6]([NH:20][C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[C:26]([F:31])[CH:25]=3)[C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13]C(C)(C)C)=[O:12])=[CH:9][CH:8]=2)[CH2:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:32])[CH2:3][CH:4]([CH:6]([NH:20][C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][CH:27]=[C:26]([F:31])[CH:25]=3)[C:7]2[CH:19]=[CH:18][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:5]1
Reactant: CC1(C)CC(C(Nc2cnc3cc(F)ccc3c2)c2ccc(C(=O)OC(C)(C)C)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CC(C(Nc2cnc3cc(F)ccc3c2)c2ccc(C(=O)O)cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 103.8 %

Procedure:
To a vial containing tert-butyl 4-((3,3-dimethylcyclobutyl)(7-fluoroquinolin-3-ylamino)methyl)benzoate (12.0 mg, 0.0280 mmol) was added methylene chloride (0.140 mL) and trifluoroacetic acid (0.140 mL, 0.0280 mmol). The reaction was stirred at room temperature for 1.5 h. The mixture was concentrated and azeotrophed with toluene to provide crude 4-((3,3-dimethylcyclobutyl)(7-fluoroquinolin-3-ylamino)methyl)benzoic acid (11 mg, 99% yield) as an oil. (M+1): 379.2.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8](=O)[CH3:9])[CH2:3][CH2:2]1.[Na].[C:12](OCC)(=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl.[NH2:23][NH2:24]>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:24][N:23]=2)[CH2:3][CH2:2]1
Reactant: NN
Reactant: CC(=O)CN1CCOCC1
Reactant: CCOC(=O)C(=O)OCC
Agent: Cl
Agent: [Na]
Product: CCOC(=O)c1cc(CN2CCOCC2)n[nH]1
Yield: 18 %

Procedure:
The title compound was prepared from 1-morpholinopropan-2-one (4.192 g, 29.3 mmol), Sodium (0.43 g, 29.3 mmol), diethyl oxalate (4.28 g, 29.3 mmol) and hydrazine hydrochloride (2 g, 29.3 mmol) using the method of Example 225(a). Yield 18%. 1H NMR (400 MHz; CDCl3): δ 1.39 (t, 3H), 2.48 (m, 4H), 3.60 (d, 2H), 3.71 (m, 4H), 4.38 (q, 2H), 6.74 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1.C(N(CC)CC)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl.[O:45]1[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][NH2:53])[CH2:47][CH2:46]1>C(Cl)(Cl)Cl.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:34]([NH:53][CH2:52][CH2:51][N:48]2[CH2:49][CH2:50][O:45][CH2:46][CH2:47]2)=[O:36])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c([N+](=O)[O-])c3)c2cc1OC
Reactant: NCCN1CCOCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NCCN4CCOCC4)c([N+](=O)[O-])c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.6 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2-nitroaniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (131 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, 2-morpholino-1-ethanamine (57 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (30 mg, yield 21%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:10]1([C:30]([O:32]CC)=[O:31])[NH:15][C:14](=[O:16])[CH:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[N:12]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11]1=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.C(OCC)(=O)C>C(O)C.O>[CH2:3]([C:10]1([C:30]([OH:32])=[O:31])[NH:15][C:14](=[O:16])[CH:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[N:12]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11]1=[O:29])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1(Cc2ccccc2)NC(=O)C(CC(C)C)N(OCc2ccccc2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)CC1C(=O)NC(Cc2ccccc2)(C(=O)O)C(=O)N1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
5.3 ml of 1N sodium hydroxide was added to 25 ml of a suspension of 2.32 g of (3RS,6SR)-3-benzyl-1-benzyloxy-3-ethoxycarbonyl-6-isobutylpiperazine-2,5-dione in ethanol. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was adjusted to pH 3 with 1N hydrochloric acid. Thereto were added 80 ml of ethyl acetate and 80 ml of water to conduct distribution. The organic layer was dried with anhydrous magnesium sulfate and then subjected to vacuum distillation to remove the solvent at room temperature to obtain 2.17 g of (3RS,6SR)-3-benzyl-1-benzyloxy-3-carboxy-6-isobutylpiperazine-2,5-dione as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[S:17][C:16]([S:18]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)(=[O:20])=[O:19])=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[S:17][C:16]([S:18]([N:21]3[CH:25]=[CH:24][CH:23]=[CH:22]3)(=[O:19])=[O:20])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Product: COc1ccc(-c2ccc(S(=O)(=O)n3cccc3)s2)cc1

Procedure:
N-[5-(4-methoxyphenyl)thiophene-2-sulfonyl]pyrrole was prepared, in the same manner as described in Example 32C, from 4-methoxyphenylboronic acid and N-(5-bromothiophene-2-sulfonyl)pyrrole. Recrystallization using hexane/ethyl acetate gave a solid in quantitative yield.
Reaction SMILES: CS[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:6]=2[N:7]=1.[NH2:15][C:16]1[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[CH:18]C=1O.Cl.[C:27](OCC)(=O)[CH3:28]>>[N+:12]([C:9]1[CH:10]=[CH:11][C:5]2[O:4][C:3]([N:22]3[CH:20]4[CH2:21][CH2:16][N:15]([CH2:18][CH2:19]4)[CH2:28][CH2:27]3)=[N:7][C:6]=2[CH:8]=1)([O-:14])=[O:13]
Reactant: CSc1nc2cc([N+](=O)[O-])ccc2o1
Reactant: Nc1cc([N+](=O)[O-])ccc1O
Reactant: CCOC(C)=O
Agent: Cl
Product: O=[N+]([O-])c1ccc2oc(N3CCN4CCC3CC4)nc2c1
Yield: 36 %

Procedure:
The title compound was prepared from 2-methylsulfanyl-5-nitro-benzooxazole (prepared from 2-amino-4-nitrophenol by the methods described in Example 5 and Example 7) by the procedure described in Example 9 in 36% yield: 1H NMR (CDCl3, 400 MHz) δ 7.84 (d, 1H, J=2.1 Hz), 7.97 (dd, 1H, J=8.7, 2.1 Hz), 7.28 (d, 1H, J=8.7 Hz), 4.56-4.55 (m, 1H), 3 97 (t, 2H, J=5.8 Hz), 3.23-3.16 (m, 4H), 3.08-3.01 (m, 2H), 2.23-2.15 (m, 2H), 1.94-1.85 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 163.1, 152.8, 145.2, 144.3, 117.2, 111.7, 108.5, 56.4, 50.5, 45.9, 43.8, 26.3; MS (Cl) m/z 289.2 (M+1); HPLC retention time=3.11 min. The hydrochloride salt was prepared by diluting in ethyl acetate and adding a 2.5 N HCl solution in ethyl acetate: mp=240.2° C.
Reaction SMILES: [ClH:1].N([O-])=O.[Na+].[C:6]([O:10][CH2:11][CH3:12])(=[O:9])[CH:7]=[CH2:8].N[C:14]1[CH:45]=[CH:44][C:17]([O:18][CH2:19][C:20]2([CH3:43])[CH2:29][C:28](=[O:30])[C:27]3[C:22](=[C:23]([CH3:42])[C:24]([CH3:41])=[C:25]([O:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:26]=3[CH3:31])[O:21]2)=[CH:16][CH:15]=1>O.CC(C)=O>[C:37]([O:36][C:34]([CH2:33][O:32][C:25]1[C:26]([CH3:31])=[C:27]2[C:22](=[C:23]([CH3:42])[C:24]=1[CH3:41])[O:21][C:20]([CH2:19][O:18][C:17]1[CH:16]=[CH:15][C:14]([CH2:8][CH:7]([Cl:1])[C:6]([O:10][CH2:11][CH3:12])=[O:9])=[CH:45][CH:44]=1)([CH3:43])[CH2:29][C:28]2=[O:30])=[O:35])([CH3:38])([CH3:39])[CH3:40]
Reactant: C=CC(=O)OCC
Reactant: Cc1c(C)c2c(c(C)c1OCC(=O)OC(C)(C)C)C(=O)CC(C)(COc1ccc(N)cc1)O2
Reactant: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CC(=O)c3c(C)c(OCC(=O)OC(C)(C)C)c(C)c(C)c3O2)cc1
Reaction time: 0.5 h

Procedure:
16 ml of concentrated hydrochloric acid, 7 ml of an aqueous solution containing 3.1 g of sodium nitrite and 37 ml of ethyl acrylate were added, in that order, at 5°-10° C. to a mixture of 16 g of 2-(4-aminophenoxymethyl)-6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethylchroman-4-one (prepared as described in Preparation 62) and 160 ml of acetone. Then 0.5 g of cuprous oxide was added gradually at an internal temperature of 40°-43° C. After about 30 minutes, the evolution of nitrogen had ceased. The reaction mixture was then poured into water and extracted with benzene. This extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled from the extract under reduced pressure, and the residue was purified by silica gel column chromatography eluted with a 9:1 by volume mixture of cyclohexane and ethyl acetate, to give the title compound.