Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:19](=[O:22])(=[O:21])[NH2:20])[C:10]=1[NH:11][C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6].[OH-].[Li+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[CH2:25]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:19](=[O:21])(=[O:22])[NH2:20])[C:10]=1[NH:11][C:12]1[N:17]=[C:16]([CH3:18])[CH:15]=[CH:14][CH:13]=1)[C:5]([OH:7])=[O:6])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cccc(Nc2c(N)cc(C(=O)O)cc2S(N)(=O)=O)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(Nc2c(NCc3ccccc3)cc(C(=O)O)cc2S(N)(=O)=O)n1

Procedure:
A suspension of 3-amino-4-(2-methyl-6-pyridylamino)-5-sulphamyl-benzoic acid (0.5 g) in water (25 ml) was adjusted to a pH of 8 by addition of 1N lithium hydroxide. To the resulting solution, benzyl bromide (0.2 g) was added while, under stirring, the pH was kept at 8 by automatic titration with 1N lithium hydroxide. After the base consumption had become negligible, the crude 3-benzylamino-4-(2-methyl-6-pyridylamino)-5-sulphamyl-benzoic acid was precipitated from the reaction mixture by adjusting the pH to 5 by means of 1N hydrochloric acid. The compound was collected by suction, recrystallized from aqueous ethanol, and dried. The melting point of the compound was 168°-170° C.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH3:27])=[CH:3]\[C:4]([O:6]CC)=[O:5].[Li+].[OH-].Cl>CO.O>[CH3:1]/[C:2](/[CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:13]\[CH2:14]/[CH:15]=[CH:16]\[CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26][CH3:27])=[CH:3]\[C:4]([OH:6])=[O:5]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC/C(C)=C/C(=O)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC/C(C)=C/C(=O)O
Temperature: 50 °C

Procedure:
Ethyl (2E,7Z,10Z,13Z,16Z,19Z)-3-methyl-docosa-2,7,10,13,16,19-hexaenoate (3) was dissolved in methanol (9 ml) and added LiOH (220 mg, 4.89 mmol) in water (3 ml) and the mixture was heated at 50° C. for 2 hrs. The mixture was cooled, and diluted hydrochloric acid was added to pH 2. Extraction with diethylether, drying (MgSO4) and evaporation of solvents under reduced pressure afforded the acid 4. The acid was purified by flash chromatography on silica gel (8:2 hexane-EtOAc); δH(300 MHz) 0.95 (t, J 7.5, 3H, CH3), 1.55 (m, 2H), 2.0-2.2 (m, 6H), 2.15 (d, J 1.3, 3H, CH3), 2.7-2.9 (m, 8H), 5.2-5.5 (m, 10H), 5.68 (br s, 1H); δc(75 MHz) 14.24, 19.04, 20.53, 25.51, 25.60, 25.62, 25.64, 26.67, 27.28, 40.67, 115.24, 126.99, 127.84, 128.05, 128.11, 128.19, 128.22, 128.53, 128.57, 129.23, 132.00, 163.05, 172.31.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B(O)O)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Cl[C:15]1[C:24]([N:25]([CH:27]([CH3:29])[CH3:28])[CH3:26])=[N:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:30]([O:32][CH3:33])=[O:31])[CH:21]=2)[N:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.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>[CH:27]([N:25]([CH3:26])[C:24]1[C:15]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[N:3]=[CH:4]3)=[N:16][C:17]2[C:22]([N:23]=1)=[CH:21][C:20]([C:30]([O:32][CH3:33])=[O:31])=[CH:19][CH:18]=2)([CH3:29])[CH3:28]
Reactant: Cn1ncc2cc(B(O)O)ccc21
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2nc(-c3ccc4c(cnn4C)c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
To a solution of 1-methyl-1H-indazol-5-ylboronic acid (180 mg, 1.02 mmol) in dioxane (3 mL) was added methyl 2-chloro-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (Scheme I, 109 mg, 0.37 mmol), K3PO4 (175 mg, 0.83 mmol), Pd(PPh3)4 (29 mg, 0.03 mmol) and water (3 drops) with stirring for 1 h at 90° C. in an oil bath with an inert atmosphere of nitrogen. The reaction mixture was concentrated under vacuum and then purified by a silica gel column with 10% ethyl acetate in petroleum ether to afford methyl 3-(isopropyl(methyl)amino)-2-(1-methyl-1H-indazol-5-yl)quinoxaline-6-carboxylate as a light yellow solid (110 mg, 76%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:13][C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: Oc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Oc1ccc(F)cc1

Procedure:
For example: Acryloyl chloride and 4-fluorophenol react in dichloromethane in the presence of triethylamine to give 4-fluorophenyl acrylate 10 (R=4-fluorophenyl). Compound 10 is then added to a solution of 9 in ethanol and diethylamine to give 11 (R=4-fluorophenyl) after usual workup.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24]([OH:26])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)[NH:36][CH2:37][CH2:38][C@H:39]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:40][OH:41])C1C=CC=CC=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:24]([NH:36][CH2:37][CH2:38][C@H:39]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:40][OH:41])=[O:26])[CH2:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CCNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCC[C@@H](CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under argon, 0.082 g (0.22 mmol) of N2-[(benzyloxy)carbonyl]-N5-(tert-butoxycarbonyl)-L-ornithine and 0.059 g (0.29 mmol) of benzyl{(3S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxybutyl}carbamate (Example 237A) are dissolved in 6 ml of dimethylformamide. Then, at 0° C. (ice bath), 0.056 g (0.29 mmol) of EDC and 0.009 g (0.067 mmol) of HOBt are added. The mixture is slowly warmed to RT and stirred at RT for 12 h. The solution is concentrated in vacuo and the residue is taken up with ethyl acetate. The organic phase is washed successively with saturated sodium bicarbonate and sodium chloride solutions, dried over magnesium sulfate and evaporated in vacuo. The remaining solid is dried to constant weight under high vacuum.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19](F)=[C:20]([F:25])[CH:21]=2)[NH:16][C:15]1=[O:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:20]([F:25])[CH:21]=2)[NH:16][C:15]1=[O:27])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: O=c1[nH]c2cc(F)c(F)cc2c(=O)n1OCc1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=c1[nH]c2cc(N3CCCC3)c(F)cc2c(=O)n1OCc1ccccc1
Yield: 86.6 %

Procedure:
Pyrrolidine (0.065 mL, 0.8 mmol) was added to a solution of 3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example B, 0.2 g, 0.65 mmol) and triethylamine (0.18 mL, 1.2 mmol) in 30 mL of acetonitrile. The solution was warmed to reflux for 18 hours, cooled, and filtered to give 0.2 g of the title compound as a solid, mp>250° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:13]([N:1]([C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:4][C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:2]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1ccccc1N
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccccc1N(Cc1ccccc1)Cc1ccccc1

Procedure:
Reaction of ethyl 2-aminobenzoate with two molar equivalents of benzyl Chloride in acetone in the presence of potassium carbonate affords ethyl 2-(N,N-dibenzylamino)-benzoate which, on saponification in aqueous ethanolic potassium hydroxide and isolation of the product from a neutral medium, affords 2-(N,N-dibenzylamino)benzoic acid.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:16][CH3:17])=[C:12]([CH:15]=2)[CH:13]=O)=[CH:4][CH:3]=1.[C:18]([O:22][C:23](=[O:33])[N:24]([CH:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1)[CH3:25])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23](=[O:33])[N:24]([CH:26]1[CH2:27][CH2:28][CH:29]([NH:32][CH2:13][C:12]2[CH:15]=[C:8]([C:5]3[CH:6]=[N:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:9]=[CH:10][C:11]=2[O:16][CH3:17])[CH2:30][CH2:31]1)[CH3:25])([CH3:21])([CH3:19])[CH3:20]
Reactant: COc1ccc(-c2ccc(F)nc2)cc1C=O
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(N)CC1
Product: COc1ccc(-c2ccc(F)nc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Following the synthetic protocol described in Method C′; {4-[5-(6-Fluoro-pyridin-3-yl)-2-methoxy-benzylamino]-cyclohexyl}-methyl-carbamic acid tert-butyl ester is prepared starting from 5-(6-Fluoro-pyridin-3-yl)-2-methoxy-benzaldehyde and (4-Amino-cyclohexyl)-methyl-carbamic acid tert-butyl ester. The desired product is isolated in 84%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.[CH2:16]([O:18][CH:19]([O:27][CH2:28][CH3:29])[CH2:20][N:21]1[CH:25]=[C:24](I)[N:23]=[CH:22]1)[CH3:17].CC(OC)(C)C>C1COCC1.[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:24]3[N:23]=[CH:22][N:21]([CH2:20][CH:19]([O:27][CH2:28][CH3:29])[O:18][CH2:16][CH3:17])[CH:25]=3)[S:10][C:3]=12
Reactant: CCOC(Cn1cnc(I)c1)OCC
Reactant: Clc1ccnc2ccsc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCOC(Cn1cnc(-c2cc3nccc(Cl)c3s2)c1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.4 %

Procedure:
To a stirred solution of 7-chlorothieno[3,2-b]pyridine (9.26 g, 54.6 mmol) in THF (88 mL) at −15° C. was added n-BuLi (21.84 mL, 54.6 mmol). After 30 min, a solution of ZnCl2 0.5M in THF (109 mL, 54.6 mmol) was added at −15° C. and the reaction mixture was warmed to RT over 45 min. A solution of palladium tetrakistriphenylphosphine (0.841 g, 0.73 mmol) and iodide 260 (11.29 g, 36.4 mmol) in THF (33 mL) was added and the mixture was heated to reflux for 3 h then concentrated. The residue was diluted with water and ammonium hydroxide and extracted with DCM. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 80 g cartridge; AcOEt/Hex:0/100 to 100/0 over 20 CV) to produce a material that upon trituration with. MTBE afforded the title compound 261 (1.2 g, 3.41 mmol, 9% yield) as light-brown solid. MS (m/z): 437.45 (M+H).
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1.C[O:18][C:19]([NH:21][NH2:22])=[S:20]>C1(C)C=CC=CC=1>[C:13]([NH:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[CH:4][CH:3]2[CH2:2][S:20][C:19](=[O:18])[NH:21][NH:22]2)=[CH:7][CH:8]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1ccc(C=CC(=O)CCl)cc1
Reactant: COC(=S)NN
Solvent: Cc1ccccc1
Product: CC(=O)Nc1ccc(C=CC2CSC(=O)NN2)cc1

Procedure:
A mixture containing 4.0 g of 1-chloro-4-(4-acetamidophenyl)-2-oxo-3-butene (J. Org. Chem., 28, 2446, 1963) and 2.3 g of hydrazinecarbothioic acid O-methylester in 150 ml of toluene was refluxed for 3 h. The crystals were filtered and washed with toluene. Yield 3.0 g (65%), mp. 235°-240° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([O:17]C2C=CC([N+]([O-])=O)=CC=2)=O)=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:28]1[CH2:35][CH2:34][CH2:33][C@H:29]1[C:30]([OH:32])=[O:31].C(N1CCOCC1)C>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH2:13][CH2:14][C:15]([N:28]2[CH2:35][CH2:34][CH2:33][C@H:29]2[C:30]([OH:32])=[O:31])=[O:17])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: COC1=C(OC)C(=O)C(CCC(=O)Oc2ccc([N+](=O)[O-])cc2)=C(C)C1=O
Agent: CCN1CCOCC1
Solvent: CN(C)C=O
Product: COC1=C(OC)C(=O)C(CCC(=O)N2CCC[C@H]2C(=O)O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 46.1 %

Procedure:
To a solution of p-nitrophenyl 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)propionate (187 mg, 0.5 mmol) and L-proline (57 mg, 0.5 mmol) in N,N-dimethylformamide (5 ml) was added N-ethylmorpholine (128 μl, 1.0 mmol). The mixture was stirred at room temperature for 2 days. Thereafter, the reaction mixture was further treated in the same manner as Example 1 to give 3-(2,3-dimethoxy-5-methyl-1,4-benzoquinon-6-yl)propionyl-L-proline (81 mg), melting at 131° C.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[H-].[Na+].C[O:12][C:13](=[O:27])[C@@H:14]1[CH2:18][C@@H:17]([OH:19])[CH2:16][N:15]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[Br:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>C1COCC1.O>[C:20]([N:15]1[CH2:16][C@H:17]([O:19][CH2:33][C:32]2[CH:35]=[CH:36][C:29]([Br:28])=[CH:30][CH:31]=2)[CH2:18][C@H:14]1[C:13]([OH:12])=[O:27])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: BrCc1ccc(Br)cc1
Agent: O=C(O)[C@@H]1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccc(Br)cc2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 30.6 %

Procedure:
The compound of formula (P5), wherein R′ is 4-Bromo and the bonds linking the benzyloxy and methyl ester groups (depicted in P5 as wavy bonds) define the trans, L-proline configuration (2S,4R) was prepared as follows. To a suspension of sodium hydride (60% in oil) (0.12 g) (1.5 eq.) in 5 mL of dry THF was added trans-N-Boc-4-hydroxy-L-proline methyl ester (0.5 g) in 5 mL of dry THF. The reaction mixture was stirred for 45 minutes and a solution of 4-bromobenzyl bromide (0.75 g) (1.5 eq.) in 5 mL of dry THF was added. The reaction mixture was refluxed for 3 hours. After cooling to RT, the reaction mixture was diluted with water and extracted with EtOAc. The aqueous layer was acidified and extracted with DCM. The combined organic extracts were washed with water, dried over MgSO4, and evaporated under reduced pressure to afford trans-N-Boc-4-(4-bromo-benzyloxy)-L-proline (0.25 g). NMR (CDCl3, 200 MHz): 7.47 (2H, d), 7.2 (2H, d), 4.50-4.30 (3H, m), 4.25-4.1 (1H, m), 3.75 (3H, s), 3.8-3.5 (2H, m), 2.5-2.3 (1H, m), 2.15-1.95 (1H, m), 1.5-1.35 (9H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)([C:8]#[N:9])[CH2:4][CH2:3]1.[CH2:24](O)[CH2:25][OH:26].CC1C=CC(S(O)(=O)=O)=CC=1.CC1C=CC=CC=1>O>[C:18]1([CH2:17][O:16][C:13]2[CH:14]=[CH:15][C:10]([C:5]3([C:8]#[N:9])[CH2:6][CH2:7][C:2]4([O:26][CH2:25][CH2:24][O:1]4)[CH2:3][CH2:4]3)=[CH:11][CH:12]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCCO
Reactant: N#CC1(c2ccc(OCc3ccccc3)cc2)CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC1(c2ccc(OCc3ccccc3)cc2)CCC2(CC1)OCCO2
Yield: 47 %

Procedure:
A mixture of 65 parts of 4-oxo-1-[4-(phenylmethoxy)phenyl]-1-cyclohexanecarbonitrile, 15.7 parts of 1,2-ethanediol, 0.2 parts of 4-methylbenzenesulfonic acid and 360 parts of methylbenzene is stirred and refluxed overnight with water-separator. The reaction mixture is cooled, washed successively with water, with a sodium hydroxide solution 5% and again with water, dried, filtered and evaporated. The residue is crystallized from 2-propanol, yielding 33.5 parts (47%) of 8-[4-(phenylmethoxy)phenyl]-1,4-dioxaspiro[4,5]decane-8-carbonitrile.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:4]([CH3:31])=[C:5]([C:26]([CH3:30])=[CH:27][C:28]=1[CH3:29])[CH2:6][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:32]([O:34][C:35](=[O:46])[CH:36]=[C:37]([CH3:45])[CH:38]=[CH:39][CH:40]=[C:41]([CH:43]=O)[CH3:42])[CH3:33]>>[CH2:32]([O:34][C:35](=[O:46])[CH:36]=[C:37]([CH3:45])[CH:38]=[CH:39][CH:40]=[C:41]([CH3:43])[CH:42]=[CH:6][C:5]1[C:26]([CH3:30])=[CH:27][C:28]([CH3:29])=[C:3]([Cl:2])[C:4]=1[CH3:31])[CH3:33]
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Reactant: Cc1cc(C)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(C)c1Cl
Agent: [Cl-]
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(C)cc(C)c(Cl)c1C

Procedure:
3-chloro-2,4,6-trimethyl-benzyl-triphenyl-phosphonium chloride is condensed with 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester to produce 9-(3-chloro-2,4,6-trimethyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester, m.p.: 84°-85° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)[CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:3])=[O:2].O.NN>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:16][NH2:17])[CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
The obtained 2-[(3-nitro-4-phenylphenyl)methyl]-2,3-dihydro-1H-isoindole-1,3-dione was dissolved in ethanol (30 mL), an aqueous solution of hydrazine monohydrate (2 mL) was added thereto, and the mixture was stirred at 70° C. for 1 hour. The reaction solution was filtered, to the filtrate was added 0.6 M hydrochloric acid and ethyl acetate, and the mixture was stirred vigorously. The aqueous layer was separated and, after being neutralized with a 5M aqueous solution of sodium hydroxide, extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (3-nitro-4-phenylphenyl)methanamine as a crude material (305.5 mg)
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.O[C@@H:14]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:16]([C:26]([O:28][CH3:29])=[O:27])[CH2:15]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:3]([O:12][C@H:14]2[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C@H:16]([C:26]([O:28][CH3:29])=[O:27])[CH2:15]2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Oc1nc2ccccc2nc1Cl
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H](Oc2nc3ccccc3nc2Cl)CN1C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
A solution of 3-chloroquinoxalin-2-ol (1.44 g, 7.97 mmol) and 1-tert-butyl 2-methyl (2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxylate (2.05 g, 8.37 mmol) in THF (190 ml) was cooled to 0° C., then treated with PPh3 (2.51 g, 9.57 mmol). DIAD (1.86 ml, 9.57 mmol) was added dropwise, and the mixture was stirred at 20° C. for 1 h. After evaporation of the volatiles, the residue was purified on silica gel (gradient elution, 0-70% EtOAc/petroleum ether) to afford the title compound (2.5 g, 77%). LCMS (ES+) m/z 408 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:17]([CH2:18][CH3:19])[S:16][C:15](=[O:20])[NH:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10]C.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28]O[CH2:26][CH2:25]1>>[N:24]1([CH2:29][CH2:28][N:14]2[N:13]=[C:12]([C:5]3[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:17]([CH2:18][CH3:19])[S:16][C:15]2=[O:20])[CH2:25][CH2:26][CH2:22][CH2:23]1
Reactant: CCOc1ccc(C2=NNC(=O)SC2CC)cc1OC
Reactant: ClCCN1CCOCC1
Product: CCC1SC(=O)N(CCN2CCCC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
of 5-(3-methoxy-4-ethoxyphenyl)-6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one with 1-chloro-2-morpholinoethane:
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)=[O:12])=[CH:8][CH:9]=2)[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:3]1.[OH-].[Na+].Cl>CO.O1CCCC1>[CH3:1][C:2]1([CH3:30])[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[O:12])=[CH:8][CH:9]=2)[C:4]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:3]1
Reactant: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)C(c2ccccc2)=CC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)C=C(c2ccccc2)c2cc(C(=O)Nc3ccc(C(=O)O)cc3)ccc21
Yield: 94.5 %

Procedure:
Methyl 4-[(1,1-dimethyl-3-phenyl-1H-indene-5-carbonyl)amino]benzoate (359 mg, 0.90 mmol) was stirred with 4.5 mL of 2N NaOH in 5 mL of methanol and 5 mL of tetrahydrofuran for 10 hours. The solution was acidified with 1N HCl and concentrated under reduced pressure. After addition of 15 mL of water, the mixture was extracted with ethyl acetate (15 mL×3). The combined extracts were washed with water (10 mL), dried over magnesium sulfate, and evaporated. The residue was triturated in etherhexane to give 326 mg (94% yield) of the title compound as solids; 1H-NMR (DMSO-d6) δ1.39 (s, 6H), 6.68 (s, 1H), 7.39-7.53 (m, 3H), 7.64-7.68 (m, 3H), 7.85-7.97 (m, 6H), 10.54 (s, 1H), 12.75 (bs, 1H); MS m/e 384 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([N:17]2C(=O)C3C(=CC=CC=3)[C:18]2=[O:27])[C:13](=[O:28])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.[C:31]1([C:37]2[N:42]=[CH:41][C:40](C(Cl)=O)=[CH:39][N:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CO.CCOC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([NH:17][C:18]([C:40]2[CH:41]=[N:42][C:37]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[N:38][CH:39]=2)=[O:27])[C:13](=[O:28])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cnc(-c2ccccc2)nc1
Reactant: O=C(OCc1ccccc1)N1CCN(N2C(=O)c3ccccc3C2=O)C(=O)C1
Agent: NN
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(NN1CCN(C(=O)OCc2ccccc2)CC1=O)c1cnc(-c2ccccc2)nc1
Yield: 183.8 %

Procedure:
A solution of 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-oxo-piperazine-1-carboxylic acid benzyl ester (53 mg, 0.14 mmol) in MeOH (10 mL) is treated with anhydrous hydrazine (0.3 mL, 9.56 mmol). The reaction mixture is stirred at reflux under N2 for 3.5 h. The reaction mixture is concentrated. The residue is dissolved in a mixture of DMF (2 mL) and DCM (2 mL), and treated with 2-phenyl-pyrimidine-5-carbonyl chloride (32 mg, 0.15 mmol). The mixture is stirred under N2 for 16 h, and then diluted with EtOAc (35 mL). The mixture is washed successively with saturated aqueous KHCO3, (15 mL), water (2×15 mL), and saturated aqueous NaCl (15 mL), dried (MgSO4), filtered, and concentrated in vacuo. The residue is purified by flash silica gel chromatography (80:20 to 0:100 heptane:EtOAc gradient elution) to afford 3-oxo-4-[(2-phenyl-pyrimidine-5-carbonyl)-amino]-piperazine-1-carboxylic acid benzyl ester as an oil (111 mg, 18%). MS: 432 (M+H); 1H NMR (300 MHz, CDCl3) δ 9.70-10.10 (br, 1H), 9.06 (s, 2H), 8.46 (dd, J=7.8, 1.7 Hz, 2H), 7.44-7.60 (m, 3H), 7.25-7.40 (m, 5H), 5.18 (s, 2H), 4.36 (s, 2H), 3.93 (t, J=5.1 Hz, 2H), 3.69-3.81 (br s, 2H). IC50=103.5 nM.