Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([N:14]3[C:19](=[O:20])[C:18]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:17][C:16]4[CH:28]=[CH:29][CH:30]=[N:31][C:15]3=4)[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[CH2:21]([C:18]1[C:19](=[O:20])[N:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:40]([CH3:39])(=[O:42])=[O:41])=[CH:3][CH:4]=3)[CH:9]=2)[C:15]2[N:31]=[CH:30][CH:29]=[CH:28][C:16]=2[N:17]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Nc1ccc(-c2cccc(-n3c(=O)c(Cc4ccccc4)nc4cccnc43)c2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CS(=O)(=O)Nc1ccc(-c2cccc(-n3c(=O)c(Cc4ccccc4)nc4cccnc43)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-[3-(4-aminophenyl)phenyl]-2-benzyl-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (94 mg) and triethylamine (0.04 ml) in dichloromethane (3 ml) was added methanesulfonyl chloride (0.04 ml). The mixture was stirred at room temperature for 30 minutes, then poured into a mixture of ethyl acetate and aqueous sodium bicarbonate. The organic phase was separated, washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel column (35% ethyl acetate in hexane) and crystallized from ethanol to give 2-benzyl-4-[3-(4-methylsulfonylaminophenyl)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (53 mg).
Reaction SMILES: Cl[C:2]1[C:3]2[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][C@@H:13]1[NH:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1.C(OCC)(=O)C>[CH3:12][C@@H:13]1[N:18]([C:2]2[C:3]3[C@H:10]([CH3:11])[CH2:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:14]1
Reactant: C[C@@H]1CCc2ncnc(Cl)c21
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)OC(C)(C)C)C[C@@H]3C)c21
Temperature: 100 °C
Yield: 18.6 %

Procedure:
To a solution of (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.5 g, 3.0 mmol) in NMP (5 mL) were added (S)-tert-butyl 3-methylpiperazine-1-carboxylate (0.59 g, 3 mmol) and diisopropylethylamine (0.52 mL). The mixture was heated to 100° C. for 6 hours. The mixture was cooled and diluted with ethyl acetate (200 mL) and washed with water (6×100 mL). The organic phase was dried and concentrated. The residue was purified by silica gel chromatography, eluting with Hexane/ethyl acetate (1:1) to give (S)-tert-butyl 3-methyl-4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (0.186 g, 19%). 1H NMR (CDCl3, 400 MHz) δ 8.46 (s, 1H), 4.66 (m, 1H), 4.30-3.80 (m, 3H), 3.47 (m, 1H), 3.20 (m, 1H), 3.20-2.80 (m, 4H), 2.22 (m, 1H), 1.70 (m, 1H), 1.49 (s, 9H), 1.29 (m, 3H), 1.17 (m, 3H). MS (APCI+) [M+H]+333.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.C(NC(C)C)(C)C.[F:13][C:14]([F:37])([F:36])[C:15]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH3:26])[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:17]([C:32]([F:35])([F:34])[F:33])[N:16]=1.C(Br)C=C>O1CCCC1>[F:37][C:14]([F:13])([F:36])[C:15]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([CH2:26][CH2:3][CH:2]=[CH2:1])[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:17]([C:32]([F:34])([F:33])[F:35])[N:16]=1
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1C
Reactant: [Li]CCCC
Solvent: C=CCBr
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=CCCc1c(C(=O)OCC)c(C(F)(F)F)nc(C(F)(F)F)c1C(=O)OCC
Temperature: -78 °C

Procedure:
A three-necked 250 ml flask is heated, desiccated, and purged with argon. Tetrahydrofuran (50 ml) is injected via syringe and the flask is cooled to -78° C. To this is added 8.33 ml (0.0133 mole) of 1.6M n-butyl lithium via syringe followed by 2 ml (0.0133 mole) of diisopropyl amine. To 10 ml of dried tetrahydrofuran, 5 g (0.0133 mole) of the product of Example 2 is added and the solution is injected into the reaction mixture. The mixture is stirred for an hour. Allyl bromide, 2.4 g (0.02 mole) is injected into the flask and the mixture is stirred for 90 minutes at room temperature.
Reaction SMILES: [CH:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl.[NH2:22][OH:23].[OH-:24].[Na+]>C(Cl)Cl.O>[CH:1]([C:4]1[CH:20]=[CH:19][C:7]([C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:22][OH:23])=[O:18])=[CH:12][CH:11]=2)=[O:24])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: NO
Reactant: [OH-]
Reactant: CC(C)c1ccc(COc2ccc(N=C=O)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)c1ccc(C(=O)Oc2ccc(NC(=O)NO)cc2)cc1
Yield: 77.5 %

Procedure:
A solution of 4-(4-isopropylbenzyloxy)phenyl isocyanate (4.5 g) in methylene chloride (50 ml) is added dropwise to a solution of hydroxylamine hydrochloride (5.4 g) and sodium hydroxide (4 g) in water (15 ml) at a temperature below 20° C. The reaction mixture is diluted with water and filtered to give N-[4-(4-isopropylbenzoyloxy)-phenyl]-N'-hydroxyurea (4.1 g).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:11]=[CH:12][C:13]3[C:19](=[O:20])[C:18]([C:21]([O:23]CC)=[O:22])=[CH:17][NH:16][C:14]=3[N:15]=2)[CH2:6][CH2:5]1)(=O)C.Cl>O.C(O)C>[N:7]1([C:10]2[N:11]=[CH:12][C:13]3[C:19](=[O:20])[C:18]([C:21]([OH:23])=[O:22])=[CH:17][NH:16][C:14]=3[N:15]=2)[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]1
Reactant: CCOC(=O)c1c[nH]c2nc(N3CCN(C(C)=O)CC3)ncc2c1=O
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=C(O)c1c[nH]c2nc(N3CCNCC3)ncc2c1=O
Reaction time: 8 h
Yield: 78.4 %

Procedure:
A suspension of ethyl 5,8-dihydro-2-(4-acetyl-1-piperazinyl)-5-oxopyrido[2,3-d]pyrimidine-6-carboxylate (1000 g) and concentrated hydrochloric acid (800 ml) in a mixture of water (1200 ml) and ethanol (1000 ml) was refluxed for 8 hours and allowed to stand overnight. The crystals precipitated were collected, washed with ethanol, and dissolved by heating in an aqueous solution (10 liters) of sodium hydroxide (250 g). The solution was filtered, adjusted to pH 7-8 with acetic acid, and allowed to stand overnight with ice-cooling. The crystalline precipitate was collected, washed with water, and dried at 110° C. to give 5,8-dihydro-2-(1-piperazinyl)-5-oxopyrido [2,3-d]pyrimidine-6-carboxylic acid (625 g). m.p. 299°-305° C. (decomp.).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([O:12]CC=C)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:16])[O:7]2.CCOC(C)=O.CCN([C:28]1[CH:29]=CC=C[CH:33]=1)CC>>[CH3:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]([CH2:29][CH:28]=[CH2:33])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:16])[O:7]2
Reactant: C=CCOc1cc(C)c2ccc(=O)oc2c1
Reactant: CCN(CC)c1ccccc1
Solvent: CCOC(C)=O
Product: C=CCc1c(O)cc(C)c2ccc(=O)oc12

Procedure:
A solution of 5-methyl-7-allyloxycoumarin (IV; 13.8 g) in diethylaniline (60 ml) was refluxed for 5 hours. After cooling, EtOAc (250 ml) was added and the mixture was washed several times with dil. HCl and then with water; the solvent was evaporated from the dried (Na2SO4) organic phase and the residue by crystallization from EtOAc gave 5-methyl-7-hydroxy-8-allylcoumarin (VIII; 4.5 g; m.p. 177° C.). ##STR11##
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@@H:14]3[CH2:17][C@H:16]([OH:18])[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(Cl)Cl>[CH3:36][C:26]1[CH:31]=[CH:30][C:29]([S:32]([O:18][C@H:16]2[CH2:17][C@@H:14]([C:12]([N:8]3[CH2:9][CH2:10][CH2:11][N:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)[CH2:6][CH2:7]3)=[O:13])[CH2:15]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=C([C@H]1C[C@@H](O)C1)N1CCCN(C2CCC2)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@@H](C(=O)N3CCCN(C4CCC4)CC3)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of cis-3-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]cyclobutanol (50 mg, 0.19 mmol) in DCM (2 ml) at RT was added triethylamine (77 mg, 0.7 mmol) and toluene-4-sulfonyl chloride (108 mg, 0.57 mmol). The mixture was stirred at RT for 1 h and then at 35° C. for 2 h. After cooling to RT and dilution with DCM the mixture was washed with 1:1 H2O/saturated NaHCO3. The organic layer was dried (Na2SO4), filtered and concentrated at reduced pressure. Purification by silica FCC (eluting with DCM/MeOH/NH3 90:10:1) provided the title compound as colourless oil (73 mg, 91%).
Reaction SMILES: [CH:1]([O:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:40]=[CH:41][CH:42]=[CH:43][C:44](N2CCSC2)=[O:45])[CH:28]=[C:29]([O:38][CH3:39])[C:30]=1[O:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37]>CN(C)C=O>[CH3:39][O:38][C:29]1[CH:28]=[C:27]([CH:40]=[CH:41][CH:42]=[CH:43][C:44]([N:20]2[CH2:19][CH2:18][N:17]([CH2:16][CH2:15][O:14][CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:22][CH2:21]2)=[O:45])[CH:26]=[C:25]([O:24][CH3:23])[C:30]=1[O:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH3:37]
Reactant: c1ccc(C(OCCN2CCNCC2)c2ccccc2)cc1
Reactant: COCCOCOc1c(OC)cc(C=CC=CC(=O)N2CCSC2)cc1OC
Solvent: CN(C)C=O
Product: COCCOCOc1c(OC)cc(C=CC=CC(=O)N2CCN(CCOC(c3ccccc3)c3ccccc3)CC2)cc1OC
Yield: 25.7 %

Procedure:
To a solution of 794 mg (2.68 mmol) of N-(2-benzhydroxyethyl)piperazine in dry dimethylformamide (4 ml) was added, under argon atmosphere, a solution of 1.15 g (2.61 mmol) of N[5-[3,5-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentadienoyl)thiazolidine in dry dimethylformamide (4 ml), and the mixture was allowed to react at room temperature for 17 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure and the residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (100:1), to give 413 mg (0.670 mmol) of N-[5-[3,5-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentadienoyl]-N'-(2-benzhydroxyethyl)piperazine.
Reaction SMILES: [CH3:1][N:2]([CH:4]=[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][CH:6]1[OH:12])[CH3:3].[Li:13]CCCC>CCCCCC.C1(C)C=CC=CC=1>[CH3:3][N:2]([CH:4]=[C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][CH:6]1[O-:12])[CH3:1].[Li+:13]
Reactant: [Li]CCCC
Reactant: CC1=CC(=CN(C)C)C(O)C=C1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC1=CC(=CN(C)C)C([O-])C=C1
Product: [Li+]

Procedure:
N,N-Dimethyl-2-aminomethylene-4-methylpheno1 (11.5 g, 57.8 mmol as 97.3% pure), was added slowly to n-BuLi (44 ml of a 1.6M solution in hexane, 70.25 mmol) in toluene (30 ml). A very exothermic reaction occurred and the mixture was cooled whilst addition was taking place. A clear straw coloured solution resulted, which was continually stirred until the temperature dropped to ambient. Solvent was next removed until a white precipitate formed. From which recrystallisation from hexane by refrigeration (12 h) caused large pyramidal crystals to form.
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].[CH3:5][C:6]([CH3:10])([OH:9])[C:7]#[N:8].N1C=CC=CC=1.C(=O)=O.CC(O)C>CCOCC>[Cl:3][C:1]([O:9][C:6]([C:7]#[N:8])([CH3:10])[CH3:5])=[O:2]
Reactant: O=C(Cl)Cl
Reactant: CC(C)(O)C#N
Agent: O=C=O
Solvent: CC(C)O
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C#N)OC(=O)Cl
Reaction time: 2 h
Yield: 83.4 %

Procedure:
Into a one liter round bottom flask equipped with a phosgene inlet tube, a dry ice cooled condenser, a Teflon blade stirrer and a dropping funnel were added 200 milliliters (ml) of anhydrous ether. The flask was cooled in a dry ice/2-propanol bath and 100 ml of liquid phosgene (1.5 moles) were introduced. A mixture of acetone cyanohydrin (85 grams, 1 mole) and pyridine (80 ml, 1 mole) in 400 ml of anhydrous ether was added dropwise to the pool of phosgene, through the dropping funnel. When the addition was completed, the dry ice/2-propanol bath was replaced by an ice bath and stirring was continued for two hours. The reaction mixture was then stirred at room temperature for an additional two hours. Nitrogen was introduced into the reactor through the reactor inlet tube to remove the excess phosgene. The phosgene containing nitrogen gas stream removed from the reactor was forwarded to a packed column into the top of which was sprayed a solution of 15 weight percent sodium hydroxide and 0.8 weight percent pyridine. After degassing, the reaction mixture was filtered and dried over anhydrous magnesium sulfate. The ether solvent was evaporated and 123 grams (72% yield) of 1-cyano-1-methylethyl chloroformate as a light yellow liquid was obtained. Identification of the product as 1-cyano-1-methylethylchloroformate was confirmed by infrared and nuclear magnetic resonance (NMR) spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)C(O)=C[CH:4]=1.[C:14]([O:17][C:18](=[O:20])[CH3:19])(=O)[CH3:15]>>[C:18]([O:17][C:14]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[CH:4][CH:15]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(O)c2ccccc12
Product: COc1ccc(OC(C)=O)c2ccccc12

Procedure:
1.75 g. (10 mMole) 4-Methoxy-1-naphthol is boiled under reflux for 2.5 hours in 18 ml. acetic anhydride. Thereafter, the solution is evaporated in a vacuum and the oily residue purified by column chromatography (silica gel; toluene/ethyl acetate 40:1 v/v). After evaporation of the appropriate fractions, the crude product is recrystallised from petroleum ether (b.p. 90°-110° C.). Yield 1.27 g. (58% of theory) of colourless crystals; m.p. 51°-53° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][C:11]([OH:13])=[O:12].[C:14](Cl)(=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.[Sn](Cl)(Cl)(Cl)Cl.[CH2:30](Cl)Cl>>[CH3:30][O:12][C:11](=[O:13])[CH2:10][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]=1[C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: O=C(O)Cc1cc2ccccc2o1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: ClCCl
Agent: Cl[Sn](Cl)(Cl)Cl
Product: COC(=O)Cc1oc2ccccc2c1C(=O)c1ccc(OC)cc1
Temperature: 2.5 °C

Procedure:
To the BFAA methyl ester from Step 1 (assumed 1× mole fraction) was added p-anisoyl chloride (approximately 1.08 parts by weight; 1.1× mole fraction), followed by methylene chloride (approximately 3.11 parts by weight). The mixture was stirred and cooled to about 0-5° C. Tin(IV) chloride (approximately 1.46 parts by weight) was added while controlling the batch temperature below about 10° C. The reaction was stirred at about 0-10° C. for about 3 hours then was warmed and stirred at about 20-25° C. for several hours. Methylene chloride was added and the reaction was cooled and quenched with 4% aqueous hydrochloric acid while controlling the temperature to below about 10° C. The organic layer was separated and washed with water. The organic layer was concentrated under vacuum and dried by distillation of more methylene chloride. The resulting product was dissolved in methylene chloride and transferred to a clean vessel.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14]([C:15]([OH:17])=O)[CH2:13][C:10]2([CH2:12][CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:44][CH2:45][C:46]([C:48]1[CH:53]=[CH:52][C:51]([Br:54])=[CH:50][CH:49]=1)=[O:47].CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH:14]([C:15](=[O:17])[NH:44][CH2:45][C:46]([C:48]2[CH:53]=[CH:52][C:51]([Br:54])=[CH:50][CH:49]=2)=[O:47])[CH2:13][C:10]2([CH2:11][CH2:12]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC2(CC2)CC1C(=O)O
Reactant: NCC(=O)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2(CC2)CC1C(=O)NCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.9 %

Procedure:
5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-tert-butyl ester (350 mg, 1.45 mmol) was mixed with HATU (551 mg, 1.45 mmol) in DMF (5 mL) and the mixture was stirred at room temperature for 30 minutes. 2-Amino-1-(4-bromo-phenyl)-ethanone bis HCl salt (416 mg, 1.45 mmol) in 2 mL DMF was added, followed by DIEA (3.5 eq., 0.88 mL) dropwise at 0° C. The reaction was stirred at 0° C. for 40 minutes. The reaction mixture was diluted in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 6-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-5-aza-spiro[2.4]heptane-5-carboxylic acid tert-butyl ester (424 mg, 67%). LCMS-ESI−: calc'd for C20H25BrN2O4: 437.33. Found: 460.1 (M+Na+).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].C([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)#N.O>C1(C)C(C)=CC=CC=1>[N:21]1[CH:22]=[CH:23][C:18]([C:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[OH:8])=[CH:19][CH:20]=1
Reactant: N#Cc1ccncc1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1C
Product: OC(c1ccccc1)(c1ccccc1)c1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
Benzophenone (54.6 grams, 0.3 mole) was charged into a 1 liter roundbottom three neck flask equipped with a mechanical stirrer, reflux condenser and dropping funnel. Xylene (300 ml) and sodium metal (16.6 grams, 0.72 mole) cut into small pieces were then added. The flask was heated slowly and refluxed under an inert atmosphere (nitrogen) with mechanical stirring for 30 minutes. 4-cyanopyridine (38.2 grams, 0.37 mole) dissolved in xylene (200 ml) was then added over a period of 1 hour, whereafter the mixture was refluxed for an additional three hours. The reaction mixture was then cooled to room temperature and water (300 ml) was carefully added. The solid was then filtered and washed with water and acetone to give 4-pyridyl diphenyl carbinol (73.1 grams, 93% yield)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([OH:18])[CH:11]=1.[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CN(C)C=O.O>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH:11]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1O
Reactant: CCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCOc1cc(C(=O)Nc2c(Cl)cncc2Cl)ccc1OC
Temperature: 25 °C

Procedure:
A stirred solution of N-(3,5-dichloropyrid-4-yl)-3-hydroxy-4-methoxybenzamide (2.0 g; that is prepared as described in Reference Example 12) in dimethylformamide (20 mL) at room temperature under nitrogen is treated portionwise with a suspension of sodium hydride (60% dispersion in oil; 0.26 g), and then it is stirred for a further hour at room temperature. It is then treated dropwise with 1-bromononane (1.2 mL) and stirred at 60° C. for 5 hours. The solution is then cooled to room temperature, diluted with water (60 mL), and extracted with ethyl acetate (2×100 mL). The combined organic extracts are dried over magnesium sulfate and evaporated, to give a white solid, which is subjected to flash chromatography on silica gel, eluting with t-butyl methyl ether, to give N-(3,5-dichloropyrid-4-yl)-3-nonyloxy-4-methoxybenzamide (0.56 g), m.p. 151-153° C. [Elemental analysis: C,60.3; H,6.45; N,6.3%; calculated: C,60.1; H,6.4; N,6.4%].
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CN(C=O)C.[NH2:14][C:15]1[N:20]=[C:19]([NH:21][C@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:18]=[CH:17][C:16]=1[C:36]([NH:38][C:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:41])[CH3:40])=[O:37].O>C(OCC)(=O)C>[NH2:14][C:15]1[N:20]=[C:19]([NH:21][C@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:18]([Cl:1])=[CH:17][C:16]=1[C:36]([NH:38][C:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:40])[CH3:41])=[O:37]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1Nc1ccc(C(=O)NC(C)(C)c2ccccc2)c(N)n1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1Nc1nc(N)c(C(=O)NC(C)(C)c2ccccc2)cc1Cl
Reaction time: 1 h
Yield: 78.2 %

Procedure:
N-chlorosuccinimide (17 mg) was added to a DMF (5 ml) solution containing tert-butyl cis-2-(6-amino-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate (60 mg) at 0° C., followed by stirring for 1 hour. Water and ethyl acetate were added to the reaction mixture. The organic layer was collected, washed with saturated saline, and dried over anhydrous sodium sulfate, and then the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (silica gel: silica gel 60 (spherical shape) (Kanto Chemical Co., Inc.); hexane:ethyl acetate=3:1), and a white solid of tert-butyl cis-2-(6-amino-3-chloro-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate (50 mg) was thus obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9](=[O:11])[CH3:10])[CH:4]=1.[C:12](OCC)(=[O:18])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[CH2:16]([O:15][C:13](=[O:14])[C:12](=[O:18])[CH2:10][C:9]([C:5]1[CH:4]=[C:3]([S:2][CH3:1])[CH:8]=[CH:7][N:6]=1)=[O:11])[CH3:17]
Reactant: CSc1ccnc(C(C)=O)c1
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)CC(=O)c1cc(SC)ccn1
Yield: 58 %

Procedure:
The general procedure of Referential Example 17 was repeated through use of 1-(4-methylthio-2-pyridyl)ethanone (1.76 g) and diethyl oxalate (2.86 mL), to thereby give the title compound as a solid (1.64 g, 58%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][CH:16]1[C:21](=[O:22])[N:20]2[CH:23]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[C:24](=[O:30])[N:25]([CH:27]([CH3:29])[CH3:28])[CH2:26][CH:19]2[N:18]([S:39]([C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:43]=2[Cl:49])(=[O:41])=[O:40])[CH2:17]1>CC(O)=O.CC#N.CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:15][CH:16]2[C:21](=[O:22])[N:20]3[CH:23]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[C:24](=[O:30])[N:25]([CH:27]([CH3:28])[CH3:29])[CH2:26][CH:19]3[N:18]([S:39]([C:42]3[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:43]=3[Cl:49])(=[O:41])=[O:40])[CH2:17]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Solvent: CC#N
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1CC2N(C(=O)C(NC3CCN(Cc4ccccc4)CC3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 121.2 %

Procedure:
115 mg (0.61 mmol) of 1-benzyl-4-piperidone and then 130 mg (4.1 mmol/g) of (polystyrylmethyl)trimethylammonium cyanoborohydride were added to a solution of 100 mg (0.18 mmol) of 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione in 1.2 ml of 5% HOAc/CH3CN and 3 drops of MeOH. The reaction mixture was shaken at room temperature for 18 hours, filtered and concentrated. 160 mg of beige oil were obtained. The crude product was isolated by flash chromatography in a column packed with 4 g of silica gel (elution with 5% MeOH/EtOAc). Concentration of the appropriate fractions resulted in 110 mg (85%) of the above compound in the form of a clear oil. LC/MS (expected, monoisotopic MW=731.19; measured value (M+H)=732.20)