Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[CH2:15])[CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][C:5](OC)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:15][C:2](=[CH2:1])[CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][CH2:5][OH:6]
Reactant: C=C(C)C(CC(=O)OC)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)C(CCO)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
The methyl 4-methyl-3-phenyl-4-pentenoate (258.3 g, 1.251 mol) was added, at 0° C. under nitrogen, to lithium aluminum hydride (25 g, 0.625 mol) in dry THF (1 liter), drop-wise. After 30 minutes, the cooling bath was removed and the reaction allowed reaching room temperature. After 24 h, more THF (1 liter) was added and the reaction was cooled to 0° C. and treated successively with water (25 ml), 5% aqueous sodium hydroxide (75 ml) and water (25 ml). The reaction was stirred at room temperature for 30 minutes. Anhydrous solid sodium sulfate was added (100 g) and stirring continued for 5 minutes The solid was filtered off, rinsed with diethyl ether and the filtrate was evaporated under vacuum. The product was purified distillation through a 20-cm Widmer column. 214 g of the desired product were obtained (yield=97%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6](OS(C(F)(F)F)(=O)=O)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.CCOCC.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>[CH2:1]([C:3]1[CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]([C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(OS(=O)(=O)C(F)(F)F)c(C(=O)OC)c1
Reactant: OB(O)c1ccc(F)cc1
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
Solvent: O
Solvent: CCO
Product: CCc1ccc(-c2ccc(F)cc2)c(C(=O)OC)c1
Temperature: 90 °C
Reaction time: 0.08 h

Procedure:
To 1.5 g (4.8 mmol) of product from Step 1 in 12.5 mL of toluene at room temperature was added 0.28 g (0.24 mmol, 0.05 eq.) of Pd(PPh3)4. After stirring for 5 min, 1.1 g (5.7 mmol, 1.2 eq.) of 4-fluorophenylboronic acid in 5.5 mL of EtOH followed by 11.5 mL of 2 M aqueous Na2CO3 were added. After heating at 90° C. for 12 h the reaction was judged complete, cooled and diluted with Et2O (100 mL) and water (50 mL). The resulting layers were separated and the aqueous layer extracted twice with Et2O (100 mL). The combined organic layers are dried over MgSO41 filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to yield the desired methyl 4-ethyl-4′-fluoro-1,1′-biphenyl-2-carboxylate. C16H15O2F+H+ requires 258 found 258.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:15]=[CH:14][C:13]([CH:16]2[CH2:22][C:21](=O)[O:20][C:18](=[O:19])[CH2:17]2)=[CH:12][CH:11]=1.Cl>ClCCl.O1CCOCC1>[ClH:1].[C:10]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:15]=[CH:14][C:13]([CH:16]([CH2:22][C:21]2[NH:9][C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=3[N:8]=2)[CH2:17][C:18]([OH:20])=[O:19])=[CH:12][CH:11]=1
Reactant: Nc1ccc(Cl)cc1N
Reactant: O=C1CC(c2ccc(-c3ccccc3)cc2)CC(=O)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)CC(Cc1nc2ccc(Cl)cc2[nH]1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
Commercial 4-chloro-1,2-phenylenediamine (214 mg) and 3-(biphenyl-4-yl)glutaric anhydride (399 mg) were dissolved in dichloromethane (5 ml) with heating. The dark solution was stirred at rt for 1 h. The precipitate formed was collected by suction filtration, washed with dichloromethane, and dried in vacuo to give a mixture of regioisomeric amides (0.48 g) as light brown solid. This solid was dissolved in 1,4-dioxane (1 ml) with heating. 4M HCl in 1,4-dioxane (3 ml) was added and the solution was heated to reflux for 1.5 h. The precipitate formed is isolated by suction filtration and washed with 1,4-dioxane and diethyl ether. The crude (0.4 g) is crystallised from acetic acid to provide 3-(biphenyl-4-yl)-4-(5-chloro-2-benzimidazolyl)butanoic acid HCl (0.27 g) as light brown crystals.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:23]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:31])[CH2:10][CH2:9]1)C1C=CC=CC=1>C(Cl)Cl.ClC(OC(Cl)C)=O>[NH:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH:23]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:31])[CH2:12][CH2:13]1
Reactant: O=C1Nc2ccccc2C(c2ccc(Cl)cc2)N1C1CCN(Cc2ccccc2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: O=C1Nc2ccccc2C(c2ccc(Cl)cc2)N1C1CCNCC1
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a solution of 1.40 g (3.25 mmol) of 3-(1-benzylpiperidin-4-yl)-4-(4-chlorophenyl)-3,4-dihydro-2(1H)-quinazolinone in methylene chloride, α-chloroethyl chloroformate was added dropwise under ice-cooling and stirred for one hour. After concentration under reduced pressure, the residue was dissolved with 28 ml of methanol and stirred at room temperature for 2 hours and under ice-cooling for one hour. The precipitated crystals were collected to give 1.08 g (3.16 mmol) of the title compound as colorless crystal.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19]([C:21](=[O:29])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:16]=2[N+:30]([O-])=O)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.O.[Cl-].[NH4+]>C(O)C.[Fe]>[C:1]([O:5][C:6](=[O:33])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[C:19]([C:21](=[O:29])[NH:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:18]=[CH:17][C:16]=2[NH2:30])[CH2:11][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cc(C(=O)Nc3ccccc3)ccc2[N+](=O)[O-])CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC1CCN(c2cc(C(=O)Nc3ccccc3)ccc2N)CC1
Temperature: 80 °C
Yield: 98.8 %

Procedure:
To a solution of [1-(2-nitro-5-phenylcarbamoyl-phenyl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl ester (0.13 g, 0.286 mmol) in a mixture of ethanol (8 mL), ethyl acetate (3 mL) and water (3 mL) were added ammonium chloride (0.12 g, 7.6 mmol) and iron powder (0.12 g, 7.5 mmol) and the resulting mixture was heated at 80° C. for 4 hours. The reaction mixture was filtered through a CELITE™ pad, the filter cake was washed with ethyl acetate. The filtrate was washed with and aqueous solution of sodium bicarbonate (5%) and with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to afford 0.12 g (quantitative yield) of [1-(2-amino-5-phenylcarbamoyl-phenyl)-piperidin-4-ylmethyl]-carbamic acid tert-butyl ester as light yellow foam.
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:16]2[C:17]([CH3:25])=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[CH:19]3)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:28](O)(=O)C.C([BH3-])#N.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:1]([N:8]([CH3:28])[C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:16]2[C:17]([CH3:25])=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[CH:19]3)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Cc1c(O[C@@H]2CCC[C@H](NCc3ccccc3)C2)ccc2[nH]ncc12
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1c(O[C@@H]2CCC[C@H](N(C)Cc3ccccc3)C2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 87 %

Procedure:
Under nitrogen, the N-benzyl-N-[cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl]amine (150 mg, 0.447 mmol) obtained in Example 716 and 36%-formaldehyde (56 mg, 0.671 mmol) were suspended in methanol (5 ml), followed by adding thereto acetic acid (0.2 ml), and the resulting mixture was stirred at room temperature for 30 minutes. Then, sodium cyanoborohydride (56 mg, 0.894 mmol) was added thereto and the resulting mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with chloroform and then separated by the addition of a 1N-aqueous sodium hydroxide solution, and the desired compound was further extracted from the aqueous layer with chloroform. The combined chloroform layer was washed with a saturated aqueous sodium chloride solution, dried by the addition of anhydrous magnesium sulfate, and then filtered. The solvent was distilled off under reduced pressure and the resulting concentration residue was purified by a silica gel column chromatography (eluent: acetonitrile/aqueous ammonia=100/0, 100/1) to obtain N-benzyl-N-methyl-N-[cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl]amine (136 mg, yield 87.0%) as a white amorphous substance.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](=[O:20])[C:15]([O:17]CC)=[O:16])[CH:5]=[CH:4][C:3]1=2.C(O)C.[OH-].[Na+]>O>[CH3:1][C:2]1([CH3:21])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14](=[O:20])[C:15]([OH:17])=[O:16])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)C(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C(=O)C(=O)O)ccc21

Procedure:
16 g (55.6 mmol) of ethyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylglyoxylate and 50 ml of ethyl alcohol were introduced into a round-bottomed flask. A solution of 2.5 g (58.5 mmol) of sodium hydroxide in 50 ml of water was added and the mixture was heated at reflux for one hour. The reaction medium was evaporated to dryness, taken up in water and ethyl ether, the aqueous phase decanted off, acidified to pH 1 with concentrated hydrochloric acid, extracted with ethyl ether, the organic phase decanted off, dried over magnesium sulfate and evaporated. 14 g (97%) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylglyoxylic acid were recovered in the form of a colorless oil.
Reaction SMILES: [CH3:1][S:2][CH:3]1[NH:6][C:5](=[O:7])[CH2:4]1.[H-].[Na+].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH3:1][S:2][CH:3]1[N:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5](=[O:7])[CH2:4]1
Reactant: CSC1CC(=O)N1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSC1CC(=O)N1Cc1ccccc1
Yield: 55.4 %

Procedure:
A solution of 4-methylthioazetidin-2-one (1.0 g, 8.53 mmol) in dry THF (10 ml) was added dropwise to a suspension of NaH (0.35 g, 8.63 mmol) in dry THF (5 ml) at -20° C. under an inert atmosphere. Benzyl bromide (1.46 g, 8.53 mmol) in dry THF (10 ml) was added dropwise over 15 minutes at -55° C. The resultant mixture was stirred for 2 hours at room temperature, poured onto ice/water (50 g) and filtered, washed with brine and water, dried (MgSO4), and evaporated under reduced pressure to a yellow oil (1.62 g). This was purified by flash chromatography on silica gel eluted with petroleum ether/ethyl acetate to give a yellow solid (0.98 g, 55%), m.p. 26-28° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](I)[C:7]([CH:11]([F:13])[F:12])=[CH:6][C:5]=1[NH2:14].[CH3:16][N:17]1[C:21]([Sn](CCCC)(CCCC)CCCC)=[CH:20][CH:19]=[N:18]1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:21]2[N:17]([CH3:16])[N:18]=[CH:19][CH:20]=2)[C:7]([CH:11]([F:13])[F:12])=[CH:6][C:5]=1[NH2:14]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C
Reactant: COC(=O)c1cc(I)c(C(F)F)cc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)c(C(F)F)cc1N
Temperature: 90 °C
Reaction time: 18 h
Yield: 31.1 %

Procedure:
To a solution of 2-amino-4-difluoromethyl-5-iodo-benzoic acid methyl ester (750 mg, 2.29 mmol) in dioxane (30 mL) were added 1-methyl-5-tributylstannanyl-1H-pyrazole (1.28 g, 1.5 equiv) and Pd(PPh3)2Cl2 (246 mg, 0.15 equiv) and the resulting mixture was stirred at 90° C. for 18 h. The solvent was removed in vacuo to afford a dark oil. The crude product was purified by flash chromatography (silica gel, EtOAc/hexanes (0:100 to 50:50)) to provide the title compound as a yellow oil (200 mg, 31%). ES-MS: m/z 282.3 [M+H]+, rt 4.97 min.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[O:28])=[CH:25][C:24]=1[O:39][CH3:40].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:16]1([CH2:15][N:7]2[CH2:8][CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:38]=[CH:37][C:26]([C:27]([NH:29][CH:30]5[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]5)=[O:28])=[CH:25][C:24]=4[O:39][CH3:40])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC1CN(CC2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(CC1CCCC1)CC(C)C(=O)N2C
Yield: 56 %

Procedure:
A solution of 0.050 g (0.00016 mole) of (rac)-2-chloro-9-cyclopentylmethyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-55), 0.050 g (0.00016 mole) of 4-amino-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide, 0.047 g (0.00016 mole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 180 degrees for 2 hours in a microwave reactor. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phases were extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with dichloromethane-methanol (100:0-75:25) to give 0.048 g of (rac)-4-(9-cyclopentylmethyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diaze-pin-2-ylamino)-3-methoxy-N-(1-methyl-piperidin-4-yl)-benzamide (I-55) as white powder. HRMS (ES+) m/z Calcd for C29H41N7O3+H [(M+H)+]: 536.3344. Found: 536.3344.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1>O>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]4)[CH2:2][CH2:3]2)=[CH:32][CH:31]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCc2cc(N3CCN(Cc4ccc(Cl)cc4)CC3)ccc2N1
Reaction time: 4 h
Yield: 32.5 %

Procedure:
To a mixture of 1.0 g of 6-(1-piperazinyl)-3,4-dihydrocarbostyril, 1.11 g of potassium carbonate and 20 ml of DMF was added 780 mg of 4-chlorobenzyl chloride and the mixture was stirred at 70°-80° C. for 4 hours. The reaction mixture was poured into a large amount of water and extracted with chloroform. Chloroform was distilled off and the residue was purified through silica gel column chromatography. Recrystallization from chloroform-methanol gave 500 mg of 6-[4-(4-chlorobenzyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 190°-191.5° C., colorless needles.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16](=[O:17])[C:15]3([CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[N:14]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:13]2)=[CH:8][CH:7]=1)(=[O:4])=[O:3].Cl>O1CCOCC1>[O:17]=[C:16]1[C:15]2([CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:14]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:13][N:12]1[C:9]1[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(c1ccc(NS(C)(=O)=O)cc1)CN2c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1ccc(N2CN(c3ccccc3)C3(CCNCC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To tert-butyl 3-(4-(methylsulfonamido)phenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.91 g, 1.82 mmol) was added 4M solution of HCl in dioxane (10 mL). After stirring at room temperature for 18 hours, the reaction mixture was concentrated in vacuo to obtain N-(4-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)phenyl)methanesulfonamide as a hydrochloride salt (0.7 g).
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([CH3:14])=[CH:11][CH:12]=2)[N:7]([CH:15]([CH3:17])[CH3:16])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Br-:18].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[Br:18][C:11]1[CH:12]=[C:13]2[C:8]([N:7]([CH:15]([CH3:17])[CH3:16])[CH2:6][CH2:5][N:4]2[CH:1]([CH3:3])[CH3:2])=[CH:9][C:10]=1[CH3:14]
Reactant: Cc1ccc2c(c1)N(C(C)C)CCN2C(C)C
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: Cc1cc2c(cc1Br)N(C(C)C)CCN2C(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.5 %

Procedure:
A mixture of 1,4-diisopropyl-6-methyl-1,2,3,4-tetrahydroquinoxaline (516 mg, 2.22 mmol) and tetrabutylammonium tribromide (1.18 g, 2.45 mmol) in anhydrous dichloromethane (20 mL) was stirred at room temperature for 4 hours. The solution was washed successively with a saturated aqueous solution of NaHCO3 (150 mL), water (150 mL), a saturated aqueous solution of NaCl (150 mL), dried over MgSO4 and filtered. Removal of the solvent under reduced pressure gave a solid which was purified by column chromatography, using a Biotage 40S cartridge, eluting with 5% ethyl acetate/95% hexane, to give 7-bromo-1,4-diisopropyl-6-methyl-1,2,3,4-tetrahydroquinoxaline as a white solid (480 mg, 70%).
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7]1)(=O)=O.[NH:23]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24]1.C(N(CC)CC)C>C(#N)C>[C:11]1([CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:9][CH:6]([N:23]3[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24]3)[CH2:7]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: OC1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: OC1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)C1
Yield: 92.6 %

Procedure:
1-(Diphenylmethyl)azetidin-3-yl methanesulfonate (see J. Org. Chem.; 56; 1991; 6729; 310 mg, 0.98 mmol) was dissolved in acetonitrile (3.5 mL). Pyrrolidin-3-ol (104 mg, 1.2 mmol) and triethylamine (124 mg, 1.2 mmol) were added and the mixture was subjected to microwave single node heating for 10 minutes. The solvent was removed by evaporation and the residue was dissolved in ethyl acetate. The solution was washed with water, dried over MgSO4 and then the solvent was evaporated. There was obtained 280 mg (93%) of 1-[1-(diphenylmethyl)azetidin-3-yl]pyrrolidin-3-ol as an oil. 1H NMR (300 MHz, CDCl3): 1.6-1.8 (m, 1H), 2.1-2.3 (m, 2H), 2.4-2.6 (m, 2H), 2.6-2.8 (m, 1H), 2.9-3.0 (m, 2H), 3.1-3.2 (m, 1H), 3.3-3.4 (m, 2H), 4.3 (m, 1H), 4.4 (s, 1H), 7.1-7.5 (m, 10H); LCMS: m/z 309 (M+1)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28](O)=[O:29])=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[NH2:32][CH2:33][C@H:34]([OH:37])[CH2:35][OH:36].CCN=C=NCCCN(C)C.Cl.Cl>ClCCl.CN(C)C1C=CN=CC=1>[OH:37][C@H:34]([CH2:35][OH:36])[CH2:33][NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:29]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: NC[C@H](O)CO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NC[C@H](O)CO)[nH]2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.3 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (338 mg, 0.759 mmol) synthesized in Example (18a) was dissolved in dichloromethane (10 mL), and (S)-(−)-3-amino-1,2-propanediol (105 mg, 1.15 mmol), WSCI•HCl (220 mg, 1.15 mmol) and 4-dimethylaminopyridine (185 mg, 1.51 mmol) were added, followed by stirring at room temperature for 3 days under nitrogen atmosphere. 1N hydrochloric acid (10 mL) was added, and the solution was separated with dichloromethane (15 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=70%-100%) to afford the desired product (265 mg, yield 68%) as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:15]=[N:14][C:13]2[C:12]3=[N:16][N:17]=[CH:18][N:11]3[C:10](=[O:19])[NH:9][C:8]1=2.C(=O)([O-])[O-].[K+].[K+].[CH2:26](I)[CH:27]([CH3:29])[CH3:28]>CN(C=O)C.O>[CH2:26]([N:9]1[C:8]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH:15]=[N:14][C:13]=2[C:12]2=[N:16][N:17]=[CH:18][N:11]2[C:10]1=[O:19])[CH:27]([CH3:29])[CH3:28]
Reactant: CC(C)CI
Reactant: O=c1[nH]c2c(ncn2C2CCCCO2)c2nncn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cn1c(=O)n2cnnc2c2ncn(C3CCCCO3)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-(tetrahydro-2H-pyran-2-yl)-6,7-dihydro-5H-[1,2,4]triazolo[3,4-i]purin-5-one (2.08 g, 4.0 mmol) in DMF (20 ml), was added potassium carbonate (1.10 g, 8.0 mmol) and isobutyl iodide (1.47 g, 8.0 mmol). The mixture was stirred at room temperature overnight. The reaction was diluted with water and extracted with EtOAc three times. The combined organic layers was dried with sodium sulfate, filtered, and concentrated in vacuo to give the product. LCMS calculated for C15H21N6O2(M+H): 317.2; found: 317.1.
Reaction SMILES: [CH3:1][C:2](=[CH2:22])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1)=[O:4].S(Cl)(Cl)=O.O[C:28]1[CH:37]=[C:36]2[C:31]([CH:32]=[CH:33][C:34](=[O:38])[O:35]2)=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C=O)C.C1COCC1>[CH3:22][C:2](=[CH2:1])[C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([O:19][C:28]2[CH:29]=[CH:30][C:31]3[CH:32]=[CH:33][C:34](=[O:38])[O:35][C:36]=3[CH:37]=2)=[O:18])=[CH:20][CH:21]=1)=[O:4]
Reactant: C=C(C)C(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Reactant: O=c1ccc2ccc(O)cc2o1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: C=C(C)C(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc3ccc(=O)oc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
8.5 g (0.028 mol) of 4-[6-(2-methyl-acryloyloxy)-hexyloxy]-benzoic acid were treated with 10 ml of thionyl chloride and 3 drops of DMF and boiled under reflux for 4 hours. The excess thionyl chloride was removed completely, firstly in a water-jet vacuum and subsequently in a high vacuum. The acid chloride remaining was taken up in 20 ml of THF and slowly added dropwise at 0° C. to a suspension of 4.09 g (0.025 mol) of 7-hydroxy-coumarin and 4.25 ml of triethylamine in 30 ml of THF. The batch was stirred at room temperature overnight, filtered and the filtrate was evaporated to dryness. The residue was purified by column chromatography and subsequently by recrystallization from ethanol. 6.71 g of 2-oxo-2H-1-benzopyran-7-yl 4-[6-(2-methyl-acryloyloxy)-hexyloxy]-benzoate were isolated as a white powder; m.p. 98-104.5° C.