Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:3][CH2:2]1.[CH3:28][C:29]([CH3:31])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CC(O)=O>[CH:29]([N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:3][CH2:2]1)([CH3:31])[CH3:28]
Reactant: CC(C)=O
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N1CCC(n2c([C@H](C)Nc3ncnc4[nH]cnc34)nc3ccccc32)CC1
Reaction time: 0.08 h
Yield: 24.4 %

Procedure:
To a mixture of (S)—N-(1-(1-(piperidin-4-yl)-1H-benzo[d]imidazol-2-yl)ethyl)-9H-Aurin-6-amine from Example 113 (81 mg, 0.223 mmol) in anhydrous DCM (2 mL) was added acetone (49 μL, 0.67 mmol) followed by AcOH (1 drop). After stirring for 5 min, sodium triacetoxyborohydride (71 mg, 0.335 mmol) was added and stirring was continued for 19 h. The crude reaction mixture was loaded into an Isolute® SCX-2 which was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo and the resulting residue was purified by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 20 min gradient 5-40% 0.1% NH4OH in acetonitrile/water) followed by Isolute® SCX-2 purification. The cartridge was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording 131 as a pale yellow solid (22 mg, 24%). LCMS: RT 1.68 min [M+H]+ 405.1. 1H NMR (DMSO plus TFA, 400 MHz): δ 8.82 (1H, bs), 8.57 (1H, s), 8.22 (1H, d, J=8.16 Hz), 7.77 (1H, d, J=7.78 Hz), 7.64-7.52 (2H, m), 5.97 (1H, bs), 5.49-5.35 (1H, br), 3.79-3.58 (3H, m), 3.43-3.24 (2H, m), 3.00-2.78 (2H, m), 2.68-2.48 (3H, m), 2.38 (1H, bd, J=16.58 Hz), 1.89 (3H, d, J=6.93 Hz), 1.36 (6H, dd, J=6.61, 2.47 Hz)
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[CH:9][CH:8]=1)(=[O:4])=[O:3].[H-].[H-].[H-].[H-].[Li+].[Al+3].CO.C(Cl)(Cl)Cl>C1COCC1>[CH3:1][S:2]([NH:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([CH2:11][OH:12])=[CH:9][CH:8]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1ccc(CNS(C)(=O)=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)NCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a mixture of methyl 4-[(methanesulfonamido)methyl]benzoate (3.6 g, 15 mmol) in THF (150 mL) was added LiAlH4 (1 M in THF, 30 mL, 30 mmol). The reaction mixture was stirred at rt for 1 h and poured into 10% MeOH/CHCl3 containing silica gel. The solids were removed by filtration, washed with 10% MeOH/CHCl3 and the combined washings were evaporated to yield the title compound as a white solid (2.6 g, 80%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=[CH:9][C:2]1=2.[Br:12]Br.O.C(OCC)(=O)C>C(O)(=O)C>[Br:12][C:4]1[C:3]2[CH:6]=[C:7]([CH:10]=[O:11])[CH:8]=[CH:9][C:2]=2[S:1][CH:5]=1
Reactant: BrBr
Reactant: O=Cc1ccc2sccc2c1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ccc2scc(Br)c2c1
Reaction time: 3 h

Procedure:
To a solution of 3 g of benzo[b]thiophene-5-carbaldehyde in 30 ml of acetic acid is dropwise added 1.43 ml of bromine with ice-cooling. The temperature of the reaction mixture is elevated to room temperature, at which temperature the mixture is stirred for three hours. After the reaction, 50 ml of water and 50 ml of ethyl acetate are added to the thus stirred reaction mixture, and the resulting organic layer was separated, washed successively with water, a saturated aqueous sodium hydrogencarbonate solution and a saturated saline solution and then dried over anhydrous magnesium sulfate. Thereafter, the solvent is removed from the thus dried layer by distillation under reduced pressure. The residue obtained is purified by a moderate pressure column chromatography [eluent: hexane:ethyl acetate=20:1], to obtain 4.2 g of 3-bromobenzo[b]thiophene-5-carbaldehyde.
Reaction SMILES: [CH2:1]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:15]=1[OH:25])[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13].[C:26](O)(=[O:29])[CH:27]=[CH2:28].C(N(CC)CC)C.P(Br)(Br)(Br)=O>O.CCCCCCC>[C:26]([O:25][C:15]1[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[CH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[OH:13])(=[O:29])[CH:27]=[CH2:28]
Reactant: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: C=CC(=O)O
Agent: O=P(Br)(Br)Br
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCCCCCC
Product: C=CC(=O)Oc1c(Cc2cc(C)cc(C(C)(C)C)c2O)cc(C)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
To the same flask as used in Example 1 were added 340.51 g (1.0 mole) of 2,2'-methylenebis(6-tert-butyl-4-methylphenol), 72.06 g (1.0 mole) of acrylic acid, 400 g of n-heptane and 212.5 g (2.10 moles) of triethylamine. After replacing the air in the container with nitrogen, 200.7 g (0.70 mole) of phosphorus oxybromide was added dropwise with stirring. After completion of the dropwise addition, the reaction solution was kept at 80° C. for 1 hour. Thereafter, 500 g of water was added, and after cooling to room temperature, the deposited product was filtered off. The product obtained was washed with water until the washing became neutral to obtain 379.6 g of 2,2'-methylenebis(6-tert-butyl-4-methylphenol) monoacrylate as a white crystal. Melting point, 132°-134° C. Yield, 96%.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10](COCC[Si](C)(C)C)[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31]C(C)(C)C)=[O:30])[C:26]([CH2:36][CH2:37][CH2:38][O:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].O.Cl>CCO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]([CH2:36][CH2:37][CH2:38][O:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)ccc1CCCOc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1ccc(CCCOc3ccccc3)c(C(=O)O)n1)CC2
Temperature: 50 °C
Reaction time: 12 h

Procedure:
Compound 121E (55 mg, 0.073 mmol) was dissolved in 1 mL of EtOH. Water (1 mL) was added followed by 1 mL of concentrated HCl. The reaction was stirred at 50° C. for 12 hours. The solids that precipitated were collected by filtration and rinsed with water. The solid was purified by preparative HPLC to give a white solid: 1H NMR (300 MHz, DMSO-d6) δ2.09 (t, 2H), 3.06 (t, 2H), 3.21 (t, 2H), 3.91 (t, 2H), 3.97 (t, 2H), 5.21 (s, 2H), 6.87-6.94 (m, 4H), 7.25-7.42 (m, 5H), 7.46-7.50 (m, 2H), 7.56 (m, 1H), 8.01 (m, 1H); LCMS m/z 565.7 (M+1).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:22]([NH2:24])=S)[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CI>CC(C)=O.O1CCCC1>[CH2:1]([NH:10][C:22]([NH:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([NH:10][C@H:1]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][CH2:2]1)[CH:20]=[CH:19]2)=[NH:24])[C:9]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NC(=S)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CI
Product: N=C(NCc1ccccc1)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 196.3 %

Procedure:
[2-((R)-Indan-1-ylamino)-quinolin-6-yl]-thiourea (600 mg, 1.8 mmol) was dissolved in 20 mL acetone and 10 mL tetrahydrofurane. Methyliodide (306 mg, 2.2 mmol) was added and the reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated and the residue was recrystallized from dichloromethane and diethylether. The title compound (720 mg, 84%) was obtained as a yellow solid; MS: m/e=349.4 (M+H+).
Reaction SMILES: S(O)(O)(=O)=[O:2].[NH2:6][C:7]1[N:15]=[C:14]2[C:10]([NH:11][CH:12]=[N:13]2)=[C:9]([NH2:16])[N:8]=1.NC1N=[C:25]2[C:21](NC=N2)=C(N)N=1.C(O)[C:29](N)([CH2:32][OH:33])[CH2:30][OH:31].Cl>>[CH2:21]1[C@H:25]([N:13]2[C:14]3[N:15]=[C:7]([NH2:6])[N:8]=[C:9]([NH2:16])[C:10]=3[N:11]=[CH:12]2)[O:2][C@H:29]([CH2:30][OH:31])[C@H:32]1[OH:33]
Reactant: NC(CO)(CO)CO
Reactant: Nc1nc(N)c2[nH]cnc2n1
Reactant: O=S(=O)(O)O
Agent: Cl
Product: Nc1nc(N)c2ncn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1

Procedure:
The washed cells described above were added to 10 ml of 50 mM Tris-HCl buffer (pH 7.2) containing 100 mM 2′-deoxyribose-1-phosphoric acid and 100 mM 2,6-diaminopurine hemisulfate to a washed cell-concentration of 50 g/ and reacted at 60° C. for 2 hours. The concentration of 2,6-diaminopurine-2′-deoxyriboside produced in the reaction solution was measured by high performance liquid chromatography. The results are shown in Table 1.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:18]=[C:17]([N+]([O-])=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][N:4]=1.[F-:23].[K+]>>[F:23][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([N:2]([CH3:22])[CH3:1])=[N:4][CH:5]=2)[CH:18]=1
Reactant: [F-]
Reactant: CN(C)c1ccc(-c2cc([N+](=O)[O-])c3ccccc3n2)cn1
Agent: [K+]
Product: CN(C)c1ccc(-c2cc(F)c3ccccc3n2)cn1
Yield: 37.4 %

Procedure:
5-(4-Fluoroquinolin-2-yl)-N,N-dimethylpyridin-2-amine T480 was prepared using general procedure M from N,N-dimethyl-5-(4-nitroquinolin-2-yl)pyridin-2-amine (4 mg, 0.014 mmol) and KF (16 mg, 0.28 mmol). The crude product was purified by silica chromatography to afford 5-(4-fluoroquinolin-2-yl)-N,N-dimethylpyridin-2-amine as a light-brown solid (1.4 mg, 37%). 1H NMR (400 MHz, CDCl3): δ 8.89 (d, J=2.8 Hz, 1H), 8.36 (dd, J=11.6 Hz, 1H), 8.09 (m, 1H), 8.04 (m, 1H), 7.73 (m, 1H), 7.51 (m, 1H), 7.47 (d, J=11.6 Hz, 1H), 6.64 (d, J=9.2 Hz, 1H), 3.19 (s, 6H); MS (ESI): 268 (M+H+).
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=1)[C@@H:10]([OH:14])[C:11](O)=[O:12].[H]1[BH2][H][BH2]1.C1COCC1>CO>[Cl:6][C:7]1[CH:8]=[C:9]([C@@H:10]([OH:14])[CH2:11][OH:12])[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)[C@H](O)c1cccc(Cl)c1
Solvent: CO
Solvent: C1CCOC1
Product: OC[C@H](O)c1cccc(Cl)c1
Reaction time: 12 h

Procedure:
Into THF (70 ml) were added (R)-3-chloromandelic acid (10 g) and further, under ice-cooling and dropwise, a 1M-diborane THF solution (81.5 ml) over 2 hours, and then stirring was continued at 25° C. for 12 hours. The reaction mixture was cooled, methanol (20 ml) was added thereto over 30 minutes and then stirring was further continued for 3 hours. The resulting reaction mixture was concentrated and then the residue was recrystallized from diethyl ether to obtain a colorless oily compound mentioned above (7.3 g, 78.9%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:30][CH2:29]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@H:18]([N:31]1[CH:39]([OH:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]1=O)[CH2:17][CH2:16][C@@:15]35[OH:42])C1C=CC=CC=1.[C:43]([CH:47]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:45][CH3:46])=[O:44].C(=O)([O-])O.[Na+].[C:72]1([CH3:78])[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1>>[CH2:78]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH2:27][CH:28]4[CH2:29][CH2:30]4)[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@H:18]([N:31]1[CH:32]([CH2:47][C:43]([O:45][CH3:46])=[O:44])[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:39]1=[O:40])[CH2:17][CH2:16][C@@:15]35[OH:42])[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1
Reactant: O=C1c2ccccc2C(O)N1[C@@H]1CC[C@@]2(O)[C@H]3Cc4ccc(OCc5ccccc5)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)CC1c2ccccc2C(=O)N1[C@@H]1CC[C@@]2(O)[C@H]3Cc4ccc(OCc5ccccc5)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5

Procedure:
In 10 mL of toluene, 200 mg (0.35 mmol) of 2-(3-benzyloxy-17-cyclopropylmethyl-4,5α-epoxy-14-hydroxy-morphinan-6β-yl)-3-hydroxy-2,3-dihydro-isoindol-1-one obtained in Example 26-1 was dissolved, and 147 mg (0.43 mmol) of (carbomethoxymethylene)triphenylphosphorane was added thereto, followed by heating the mixture to reflux for 15 hours. Thereafter, aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the resulting mixture was extracted with chloroform. Organic layers were combined, washed with saturated saline, dried over anhydrous magnesium sulfate and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography to obtain the captioned compound as 33 mg of low polarity component and 38 mg of high polarity component (yields: 15% and 17%, respectively).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([O:10][CH3:11])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].B(O)(O)[C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:27])=[O:26])=[CH:21][CH:20]=1.[CH2:30](O)[CH3:31]>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>[CH2:30]([O:27][C:25](=[O:26])[C:22]1[CH:23]=[CH:24][C:19]([C:2]2[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([C:8]#[N:9])[N:7]=2)=[CH:20][CH:21]=1)[CH3:31]
Reactant: CCO
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: COc1ccc(Br)nc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccc(OC)c(C#N)n2)cc1
Temperature: 80 °C

Procedure:
A solution of 6-bromo-3-methoxy-pyridine-2-carbonitrile from Example 13c in toluene is treated with 2 M Na2CO3 (aqueous), 4-carboxylphenylboronic acid (1 equiv.), ethanol and catalytic (Ph3P)4Pd) and is heated at 80° C. for 18 h. The reaction mixture is evaporated and the residue is dissolved in ethanol with 4 N HCl in dioxane and heated at reflux for 18 h. The reaction mixture is evaporated, the residue taken into ethyl acetate, washed with 5% Na2CO3 (aqueous), dried over MgSO4 and evaporated to give 4-(6-cyano-5-methoxy-pyridin-2-yl)-benzoic acid ethyl ester.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([NH:10][CH2:11][C:12]([NH:14][C@H:15]([C:23]([NH:25][C:26]1[CH:35]=[C:34]2[C:29]([C:30]([CH3:37])=[CH:31][C:32](=[O:36])[O:33]2)=[CH:28][CH:27]=1)=[O:24])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:22])[NH2:21])=[O:13])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[OH:6].C(N(CC)CC)C.[C:45](OC1C=CC([N+]([O-])=O)=CC=1)(=[O:47])[CH3:46].CCOCC>CN(C=O)C>[C:45]([NH:1][C@H:2]([C:8]([NH:10][CH2:11][C:12]([NH:14][C@H:15]([C:23]([NH:25][C:26]1[CH:35]=[C:34]2[C:29]([C:30]([CH3:37])=[CH:31][C:32](=[O:36])[O:33]2)=[CH:28][CH:27]=1)=[O:24])[CH2:16][CH2:17][CH2:18][NH:19][C:20](=[NH:21])[NH2:22])=[O:13])=[O:9])[CH2:3][CH2:4][C:5](=[O:6])[OH:7])(=[O:47])[CH3:46]
Reactant: CC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCCNC(=N)N)NC(=O)CNC(=O)[C@@H](N)CCC(=O)O)ccc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)N[C@@H](CCC(=O)O)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)Nc1ccc2c(C)cc(=O)oc2c1
Yield: 91.6 %

Procedure:
7-(L-glutamylglycyl-L-arginyl)amino-4-methyl-coumarin (100 mg, 0.18 mM) was dissolved in DMF (2 ml), and triethylamine (0.03 ml) was added thereto with stirring and cooling. This mixture was adjusted to pH about 7, and then p-nitrophenyl acetate (36.1 mg, 0.23 mM) was added thereto. This mixture was stirred for 2 days at room temperature. Excess ether was added to the mixture and the produced precipitate was separated by filtration and dried. This product was dissolved in 80% methyl alcohol (2 ml) and ethyl acetate (30 ml) was added thereto for re-precipitation to give 7-(Nα -acetyl-L-glutamylglycyl-L-arginyl)amino-4-methylcoumarin [VI] (99 mg, yield: 84.9%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].[N+:19]([C:22]1[CH:23]=[C:24]([CH:34]=[CH:35][CH:36]=1)[C:25](OC1C=CC=CC=1)=[O:26])([O-:21])=[O:20].Cl>CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]([C:25](=[O:26])[C:24]2[CH:34]=[CH:35][CH:36]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=2)[C:4]2[C:9]([C:10]=1[CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=C(Oc1ccccc1)c1cccc([N+](=O)[O-])c1
Reactant: Cc1[nH]c2ccccc2c1CCCC(=O)O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1c(CCCC(=O)O)c2ccccc2n1C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 20 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
A solution of 4-(2-methylindol-3-yl)butyric acid (600 mg) in N,N-dimethylformamide (10 ml) was added to a suspension of sodium hydride (60% dispersion in mineral oil, 243 mg) in N,N-dimethylformamide (5 ml) at 20° C. and the mixture was stirred at 20° C. for 1 hour. A solution of phenyl 3-nitrobenzoate (671 mg) in tetrahydrofuran (10 ml) was added to the mixture at -35° C. and the resulting mixture was stirred at the same temperature for 2 hours. The mixture was poured into a mixture of ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, and dried over magnesium sulfate. After evaporation of solvent, the residue was chromatographed on a silica gel (25 g) column with a mixture of hexane and ethyl acetate (10:1 to 1:1) to give 4-[2-methyl-1-(3-nitrobenzoyl)indol-3-yl]butyric acid (749 mg) as yellow crystals.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:10]=3[NH:9][C:8]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:19][CH:20]1[O:25][CH2:24][CH2:23][N:22]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:21]1>>[ClH:16].[CH2:26]([N:22]1[CH2:23][CH2:24][O:25][CH:20]([CH2:19][N:9]2[C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8]2=[O:17])[CH2:21]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2n1-c1ccccc1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Product: Cl
Product: O=c1n(CC2CN(Cc3ccccc3)CCO2)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
The condensation of 0.1 mol of 1-phenyl-6-chloro-2,3-dihydro-benzimidazol-2-one and 0.1 mol of 2-chloromethyl-4-benzyl-morpholine is carried out in accordance with the procedure of Example 1. By washing the product with hot acetone, 28 g of 4-benzyl-2-(1-phenyl-6-chloro-2,3-dihydrobenzimidazol-2-on-3-yl-methyl)-morpholine hydrochloride are obtained, m.p. 185° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:8]([Cl:13])=[N:9][CH:10]=[CH:11][CH:12]=1.ClC1C([Li])=CC=CN=1.[CH:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1>CCCCCC.CCOCC.O>[Cl:13][C:8]1[C:7]([CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=2)[OH:31])=[CH:12][CH:11]=[CH:10][N:9]=1
Reactant: Clc1ncccc1Br
Reactant: COc1cccc(C=O)c1
Agent: [Li]CCCC
Agent: [Li]c1cccnc1Cl
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: COc1cccc(C(O)c2cccnc2Cl)c1
Reaction time: 1 h
Yield: 59.8 %

Procedure:
71.5 ml of a 2.1N solution of n-butyllithium in hexane are added to 19.2 g 3-bromo-2-chloropyridine (obtained according to J. D. Cook et. al. J. Chem. Soc., Section C, 1969 1973-8) in 300 ml anhydrous ether at -60° C. and under a static nitrogen atmosphere. To this freshly prepared solution of 2-chloro-3-pyridyllithium, a solution of m-anisaldehyde (13.6 g) in 100 ml anhydrous ether is added dropwise. The reaction mixture is stirred for 1 hr. at -60° C. and then is added to ice:water. The organic phase is separated and the aqueous phase is extracted with ether. The combined organic solutions are washed with water, dried (MgSO4) and solvent evaporated. The crude oil is chromatographed over SiO2 and eluted with chloroform, obtaining 14.9 g of title product as an oil which spontaneously crystallises. Recrystallisation from methanol: water affords pure product, m.p. 114°-5° C.; Cl 14.65 (14.20).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].Br[CH2:14][CH:15]([O:18][CH3:19])[O:16][CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]([O:10][CH2:14][CH:15]([O:18][CH3:19])[O:16][CH3:17])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: COc1cc(Br)cc(C=O)c1O
Reactant: COC(CBr)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(Br)cc(C=O)c1OCC(OC)OC

Procedure:
A heterogeneous solution of 31 g (0.134 mol) of 5-bromo-2-hydroxy-3-methoxybenzaldehyde, 28 g (0.166 mol) of 2-bromo-1,1-dimethoxyethane and 49 g (0.150 mol) of caesium carbonate in 150 ml of dimethylformamide is heated at 160° C. for 3 hours. After returning to room temperature, the mixture is filtered. The filtrate is then evaporated under reduced pressure. The solid so obtained is taken up in 250 ml of dichloromethane and filtered again. The homogeneous solution is then washed twice with 200 ml of 0.1N hydrochloric acid each time and subsequently with 200 ml of a saturated sodium chloride solution. The organic phase is then dried over sodium sulphate and subsequently evaporated under reduced pressure, yielding the expected product.
Reaction SMILES: [H-].[Na+].C1(C)C=CC(S([CH:12]([N+:14]#[C-])C)(=O)=O)=CC=1.[C:17](#[N:24])[CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH3:23].CS(C)=O.[CH2:29](OCC)[CH3:30]>O>[CH2:20]([C:19]1[C:18]([C:12]#[N:14])=[CH:17][NH:24][C:29]=1[CH3:30])[CH2:21][CH2:22][CH3:23]
Reactant: CCOCC
Reactant: CCCCC=CC#N
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1c(C#N)c[nH]c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (60%, 0.096 g) in diethyl ether (3 mL) were added a solution of 1-(toluene-4-sulfonyl)ethylisocyanide (0.42 g) and 2-heptenenitrile (0.22 g) in a mixed solvent of diethyl ether (3 mL) and dimethylsulfoxide (3 mL) at room temperature, and this mixture was stirred at room temperature for 1 hour. To this reaction mixture was added water (15 mL). This mixture was extracted with ethyl acetate, and this organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane) to give the title compound (0.19 g).
Reaction SMILES: ClC(Cl)(Cl)C[CH:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:14]([OH:17])(=[O:16])[CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:14]([OH:17])(=[O:16])[CH:15]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)O
Reactant: ClC(CC(Cl)(Cl)Cl)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=C(O)C=Cc1ccccc1
Yield: 79.6 %

Procedure:
A mixture of 129 g of 1,1,1,3-tetrachloro-3-phenylpropane, 74 g of glacial acetic acid, and 31 g of monohydrate of p-toluenesulphonic acid is heated while stirring to the boiling point 115° to 120° C. for 13 h with gradual addition of 18 g of water. The precipitated crystals are filtered off, washed with water, to give 59 g of cinnamic acid. Then, the filtrate, is condensed, crystals are filtered off and washed with water to give another 11 g of cinnamic acid with the total yield of 94.5% (melting point 131° to 133° C., min. 98% purity).