Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH2:18][NH2:19])[C:11]=2[CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH2:18][NH:19][S:35]([CH3:34])(=[O:37])=[O:36])[C:11]=2[CH2:20][C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)n1nc(CN)c(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1nc(CNS(C)(=O)=O)c(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution containing 35 mg of 5-(3,5-dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methyl]-1H-pyrazole-3-methylamine in 3 ml of anhydrous dichloromethane at room temperature under nitrogen was treated with 0.024 ml of triethylamine and 0.007 ml of methane sulphonyl chloride. The mixture was stirred at room temperature for 0.5 h. The mixture was partitioned between dichloromethane and saturated sodium hydrogen carbonate then extracted three times. Combined extracts were washed with brine then dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using methanol/dichloromethane (1:19) for the elution to give 21 mg of N-[[5-(3,5-dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methyl]-1H-pyrazol-3-yl]methyl]methanesulfonamide as a brown solid. Mass spectrum (ESI) m/z 465 [M+H]+. 1H NMR (DMSO) 1.30 (d, 6H), 2.90 (s, 3H), 3.92 (s, 2H), 4.20 (d, 2H), 4.73 (m, 1H), 6.89 (s, 2H), 7.11 (d, 2H), 7.38 (s, 1H), 7.56 (t, 1H), 8.30 (d, 2H).
Reaction SMILES: [C:1]1([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:24]([C:26]([CH3:28])=[O:27])=[CH2:25]>CO>[O:27]=[C:26]([CH3:28])[CH2:24][CH2:25][N:16]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:25][CH2:24][C:26](=[O:27])[CH3:28])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CNCCCCCCCNCc2ccccc2)cc1
Reactant: C=CC(C)=O
Solvent: CO
Product: CC(=O)CCN(CCCCCCCN(CCC(C)=O)Cc1ccccc1)Cc1ccccc1

Procedure:
Dissolve N,N'-bis[(phenyl)methyl]-1,7-heptanediamine (9.3 g, 0.03 mol) in methanol (120 ml) and while stirring the mixture introduce methyl vinyl ketone (5.6 ml, 0.066 mol) in a stream of nitrogen gas. Stir the mixture for 18 hours to yield the title compound.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[F:19][C:20]([F:29])([F:28])[CH:21]([CH:23]1[CH2:27][CH2:26][NH:25][CH2:24]1)[OH:22]>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([N:25]3[CH2:26][CH2:27][CH:23]([CH:21]([OH:22])[C:20]([F:28])([F:29])[F:19])[CH2:24]3)=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: OC(C1CCNC1)C(F)(F)F
Agent: Cl
Product: O=C(c1ccc(C2CC2)c(OCC2CC2)n1)N1CCC(C(O)C(F)(F)F)C1
Yield: 48.6 %

Procedure:
In analogy to the procedure described in Example 127 e), 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 3 c, 20 mg, 85.7 μmol) was reacted with 2,2,2-trifluoro-1-(pyrrolidin-3-yl)ethanol hydrochloride (CAN of corresponding free base: 943906-23-8, 21.2 mg, 103 μmol) to obtain the title compound (16 mg, 49%) as colorless liquid, MS (EI): m/e=385.3 [MH+].
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)([CH3:10])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[F:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:43][CH2:44][C:45]1[N:50]([CH2:51][C:52](O)=[O:53])[C:49]2[N:55]=[CH:56][CH:57]=[CH:58][C:48]=2[C:47](=[O:59])[N:46]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:35][C:36]1[C:41]([F:42])=[CH:40][CH:39]=[CH:38][C:37]=1[CH2:43][CH2:44][C:45]1[N:50]([CH2:51][C:52]([N:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH:14]2[CH2:13][CH2:12][N:11]([C:2]([CH3:1])([CH3:10])[C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[CH2:16][CH2:15]2)=[O:53])[C:49]2[N:55]=[CH:56][CH:57]=[CH:58][C:48]=2[C:47](=[O:59])[N:46]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)CC1
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2cccnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3cccnc32)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of 1,1-dimethylethyl 2-methyl-2-[4-({[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]propanoate (Int. B7) (150 mg, 1 equiv), [2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetic acid (Int. D1) (130 mg, 1.2 equiv), DIPEA (0.164 ml, 3 equiv) and DMF (1.0 ml) was stirred at room temperature for 5 min. HATU (180 mg, 1.5 equiv) was added in 1 portion and stirred an additional 5 min. The crude reaction mixture was concentrated, filtered through a plug of silica eluted with acetone and evaporated to obtain crude 1,1-dimethylethyl 2-[4-({[2-[2-(2,3-difluorophenyl)ethyl]-4-oxopyrido[2,3-d]pyrimidin-1(4H)-yl]acetyl}{[4′-(trifluoromethyl)-4-biphenylyl]methyl}amino)-1-piperidinyl]-2-methylpropanoate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=[O:22])[C@:15]([OH:21])([CH3:20])[C:16]([F:19])([F:18])[F:17].N1C=CC=CC=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([S:9]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[N:34][CH:35]=2)(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=[O:22])[C@:15]([OH:21])([CH3:20])[C:16]([F:19])([F:18])[F:17]
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)Cl)c(Cl)c1Cl)C(F)(F)F
Reactant: COc1ccc(N)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2Cl)cn1
Yield: 34.1 %

Procedure:
A solution of (R)-N-(2,3-Dichloro-4-chlorosulphonylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (Method 1; 0.3 mmol) and pyridine (0.33 mmol) in DCM (5 ml) was added to a solution of 5-amino-2-methoxypyridine (0.3 mmol) in DCM (2 ml). The resultant mixture was stirred at ambient temperature overnight. The DCM was evaporated and resulting mixture was partitioned between EtOAc (5 ml) and 1 M HCl (4 ml), the EtOAc layer was separated and washed with saturated aqueous sodium hydrogen carbonate solution and brine then dried and evaporated to give the title compound as a gum (50 mg). M/z 486.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@@H:22]([O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:21]([CH3:32])[O:20][C@H:12]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:11]1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:51])C=1>C(Cl)Cl>[C:1]([O:9][C@H:10]1[C@@H:22]([O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:21]([CH3:32])[O:20][C@H:12]([S:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:51])[C@H:11]1[O:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CO[C@H]2[C@@H](OC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](C)O[C@@H]2Sc2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(CO[C@H]2[C@@H](OC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H](C)O[C@@H]2S(=O)c2ccccc2)cc1
Temperature: -20 °C

Procedure:
To a solution of phenyl 6-deoxy-3,4-di-O-benzoyl-2-O-(4-methoxybenzyl)-1-thio-β-L-allopyranoside (β-13, prepared above) (400 mg, 0.7 mmol) in 10 mL of CH2Cl2 at -78° C. is added a solution of mCPBA (170 mg, 1.1 mmol) in 2 mL of CH2Cl2. The reaction mixture is allowed to warm to -20° C. and then quenched with TEA (500 μL, 3.59 mmol). The reaction mixture is diluted with 10 mL of CH2Cl2, washed with saturated NaHSO3 (10 mL), saturated NaHCO3 (10 nL), dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography (EtOAc/petroleum ether) to give 1,6-dideoxy-3,4-di-O-benzoyl-2-O-(4-methoxybenzyl)-1-(phenylsulfinyl)-β-L-allopyranose as a mixture of diastereomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[C:19](=[O:30])[C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[C:22](=[O:25])[C:23]=3[CH3:24])[CH:14]=[CH:13][C:12]=2[O:31]C(=O)C)=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10](=[O:35])[C:11]2[CH:16]=[C:15]([CH2:17][C:18]3[C:19](=[O:30])[C:20]([O:28][CH3:29])=[C:21]([O:26][CH3:27])[C:22](=[O:25])[C:23]=3[CH3:24])[CH:14]=[CH:13][C:12]=2[OH:31])=[CH:5][CH:4]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(OC)nc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(OC)nc3)c2)=C(C)C1=O
Yield: 84.4 %

Procedure:
N-(6-Methoxypyridin-3-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.065 g, 0.135 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (1.5 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (ethyl acetate) and then recrystallized from ether to obtain the titled compound (0.050 g, 0.114 mmol, 84%).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.Cl.C(N(CC)CC)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[F:31])[NH2:27].[N:32]1[CH:37]=[CH:36][C:35]([CH2:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42](=O)[NH:41][N:40]=2)=[CH:34][CH:33]=1.[OH-].[Na+]>O.ClCCl>[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[F:31])[NH:27][C:42]1[C:43]2[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:39]([CH2:38][C:35]2[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=2)=[N:40][N:41]=1
Reactant: O=c1[nH]nc(Cc2ccncc2)c2ccccc12
Reactant: Nc1ccc(F)c(Cl)c1
Agent: Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1Cl
Temperature: 200 °C

Procedure:
A mixture of 1.42 g (10 mmol) phosphorus pentoxide, 1.38 g (10 mmol) triethylamine hydrochloride, and 1.46 g (10 mmol) 3-chloro-4-fluoroaniline is heated and stirred in a nitrogen atmosphere at 200° C. until a homogeneous melt has formed. To the melt, 0.593 g (2.5 mmol) 4-(4-pyridylmethyl)-1 (2H)-phthalazinone is added and the reaction mixture stirred for a further 3 h at 200° C. After cooling to RT, the hyalinocrystalline reaction mixture is distributed between 150 ml dichloromethane and a mixture of 10 ml water and 20 ml 2N sodium hydroxide solution with intensive stirring and sonication. The organic phase washed with water and dried over sodium sulfate is concentrated by evaporation and the residue recrystallized from acetate. Title compound is obtained after a second recrystallization from methanol/water and drying under HV (8 h at 10° C.); m.p. 185-187° C.; ESI-MS: (M+H)+=365.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([OH:25])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:27].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[C:17]([O:25][CH3:27])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 4-(N-t-butoxycarbonyl-4-piperidinyloxy)-2-hydroxybenzoate (50 g, 0.14 mol) from Step 4 above and iodomethane (17.4 mL, 0.28 mol) in DMF (300 mL) at 0° C. was added NaH (6.55 g of a 60% suspension in mineral oil, 0.164 mol) in several portions over a period of 2 h. The resulting suspension was warmed to ambient temperature and stirred for 18 h. The mixture was quenched with methanol (5 mL) and concentrated under reduced pressure. The residue was suspended in EtOAc (500 mL) and washed with water (2×250 mL) and brine (250 mL). The EtOAc layer was dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product was purified by pressurized silica gel column chromatography using a gradient elution of 20-40% EtOAc-hexane. Methyl 4-(N-t-butoxycarbonyl-4-piperidinyloxy)-2-methoxybenzoate was obtained as a gum that solidified on standing (TLC: Rf = 0.25 (3:1 hexane:EtOAc); HPLC (method A) retention time= 9.72 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:27](=[O:28])[C:11]2=[CH:12][N:13]([CH2:20][CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1.C(N(CC)CC)C.[CH3:36][N:37]=[C:38]=[O:39]>ClCCl.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:27](=[O:28])[C:11]2=[CH:12][N:13]([CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([C:38]([NH:37][CH3:36])=[O:39])[CH2:25][CH2:26]3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1
Reactant: CN=C=O
Reactant: O=c1c2cn(CC3CCNCC3)c3ccccc3c-2nn1-c1ccccc1F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)N1CCC(Cn2cc3c(=O)n(-c4ccccc4F)nc-3c3ccccc32)CC1
Reaction time: 0.17 h

Procedure:
2-(2-Fluorophenyl)-5-(piperidin-4-ylmethyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (30 mg, 0.080 mmol) was dissolved in dichloromethane (2 ml) and tetrahydrofuran (1 ml), treated with triethylamine (0.011 ml, 0.080 mmol, 1 equiv) and methylimino(oxo)methane (4.55 mg, 0.080 mmol) were added. After 10 minutes, the mixture was concentrated in vacuo and the residue was purified by silica gel gradient chromatography (80:20 to 70:30; dichlormethane:methanol), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 8.85 (1H, s), 8.21 (1H, dd, J=, 7.9, 1.6 Hz), 7.98 (1H, d, J=8.7 Hz), 7.61-7.56 (2H, m), 7.47-7.30 (4H, m), 6.37 (1H, q, J=4.2 Hz), 5.70 (2H, br s), 4.35 (2H, d, J=6.8 Hz), 3.94 (2H, br d, J=13.6 Hz), 2.52 (3H, d, J=4.9 Hz), 2.13-2.02 (1H, m), 1.49 (2H, br d, J=12.3 Hz), 1.25-1.13 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 434.1998 [(M+H)+; calculated for C24H25FN5O2: 434.1987].
Reaction SMILES: N[C@H:2]([C:6]([OH:8])=[O:7])[CH:3](C)C.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][C:16]([OH:18])=O>>[O:18]=[C:16]([CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=1)[CH2:3][CH2:2][C:6]([OH:8])=[O:7]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=C(O)Cc1ccccn1
Product: O=C(O)CCC(=O)Cc1ccccn1

Procedure:
According to the method of W. Steglich and P. Gruber (Angew. Chem., 1971, 83, 727-728), 4-oxo-5-(pyridin-2-yl)pentanoic acid is synthesized from valine and 2-(pyridin-2-yl)-acetic acid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:17]=[C:11]2[C:12](=[O:16])[NH:13][CH2:14][CH2:15][N:10]2[N:9]=1)=[O:7])[CH3:4].Br[CH2:19][CH:20]1[CH2:22][CH2:21]1>CN(C=O)C.O>[CH2:3]([O:5][C:6]([C:8]1[CH:17]=[C:11]2[C:12](=[O:16])[N:13]([CH2:19][CH:20]3[CH2:22][CH2:21]3)[CH2:14][CH2:15][N:10]2[N:9]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cc2n(n1)CCNC2=O
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2n(n1)CCN(CC1CC1)C2=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.3 %

Procedure:
A 60% dispersion of sodium hydride in mineral oils (0.11 g, 2.74 mmol) was added to a stirred solution of 4,5,6,7-tetrahydro-4-oxo-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (0.48 g, 2.28 mmol) in DMF (11.4 mL) at 0° C. The mixture was stirred at room temperature for 15 minutes and then bromomethylcyclopropane (0.26 mL, 2.74 mmol) was added. The mixture was stirred at room temperature for 16 hours, diluted with water and extracted with AcOEt. The organic layer was separated, washed with brine, dried (NaSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 40/60). The desired fractions were collected and the solvents evaporated in vacuo to yield 5-cyclopropylmethyl-4-oxo-4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester (0.32 g, 54% yield) as a white solid.
Reaction SMILES: [C:1]([C:4]1(C)[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=O)N.[OH-].[K+].Br[N:21]1C(C)(C)C(=O)N(Br)C1=O.S([O-])([O-])=O.[Na+].[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C.O.C(OCC)(=O)C>[NH2:21][C:4]1([CH3:1])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC(C)(C(N)=O)CC1
Agent: O=P([O-])([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 171.3 %

Procedure:
To a suspension of tert-butyl 4-carbamoyl-4-methylpiperidine-1-carboxylate (2.52 g, 10.4 mmol) in acetonitrile (7.6 mL) and water (23.4 mL) was added KOH (2.63 g, 46.8 mmol) at 0° C. Then 1,3-dibromo-5,5-dimethylhydantoin (1.64 g, 5.72 mmol) was added in one portion at 0° C. and after stirring at 0° C. for 30 minutes the solution was allowed to warm up to room temperature and stirred for 1 hour. Sodium sulfite (131 mg, 1.04 mmol) was added and the mixture was stirred for 15 minutes at room temperature, then ethyl acetate was added and the reaction was cooled to 10° C. K3PO4 (2.34 g, 11.0 mmol) was added and the mixture was warmed up to room temperature and extracted with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to give the title compound (2.1 g, 94%) as a colourless oil. MS ISP (m/e): 215.3 [(M+H)+].
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:9]=3[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>>[CH3:18][O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([C:11]1[S:10][C:9]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:8]=2[C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:23]
Reactant: COc1ccc2c(-c3ccccc3)csc2c1
Reactant: COc1ccccc1C(=O)Cl
Product: COc1ccc2c(-c3ccccc3)c(C(=O)c3ccccc3OC)sc2c1
Yield: 97 %

Procedure:
3-Phenyl-6-methoxybenzo[b]thiophene and 2-methoxybenzoyl chloride were converted to the title compound by the procedure of Example 1 in 97% yield, after crystallization from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=O)[CH2:13][N:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=[S:42])[CH2:13][N:14]=1
Reactant: O=C1CN=C(c2ccccc2Cl)c2cc(CCc3ccc(-c4ccccc4)cc3)sc2N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=C1CN=C(c2ccccc2Cl)c2cc(CCc3ccc(-c4ccccc4)cc3)sc2N1
Yield: 131.5 %

Procedure:
A suspension of 7.2 g of 5-(2-chlorophenyl)-7-[2-(4-phenylphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one, melting at 187°-189° C. and 3.9 g of Lawesson reagent in 100 ml of toluene is stirred at 58°-60° C. for an hour. The resultant solution is concentrated under reduced pressure, and the residue is subjected to chromatography on silica gel and then eluted with chloroform-methanol (100:1 to 100:2). The objective fraction is concentrated under reduced pressure to give 6 g of 5-(2-chlorophenyl)-7-[2-(4-phenylphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione, melting at 190°-191° C. with decomposition.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccccc2)c1
Yield: 72.5 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and benzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (264 mg, yield: 72.5%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:17][O:16][C:15](=[O:18])[C@H:14]([CH2:19]C(O)=O)[C@@H:13]([O:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[C@H:12]([CH3:29])[O:11][C:10]1=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.SC1C=CC=C[N+]=1[O-].C(N(CC)CC)C.C(I)(I)[I:62]>C1COCC1.[Al].[Hg].O>[C:24]([O:23][C@@H:13]1[C@@H:14]([CH2:19][I:62])[C:15](=[O:18])[O:16][CH2:17][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10](=[O:30])[O:11][C@H:12]1[CH3:29])(=[O:28])[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CC(=O)O
Reactant: IC(I)I
Agent: CC(C)COC(=O)Cl
Agent: [Al]
Agent: [Hg]
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)C(=O)O[C@H]1[C@H](C)OC(=O)[C@@H](NC(=O)OC(C)(C)C)COC(=O)[C@@H]1CI
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
To a solution of 2-((3S,7R,8R,9S)-3-(tert-butoxycarbonylamino)-8-(isobutyryloxy)-9-methyl-2,6-dioxo-1,5-dioxonan-7-yl)acetic acid (9.90 g, 23 mmol) in THF (100 mL) was added N-methylmorpholine (2.5 mL, 23 mmol) followed by isobutylchloroformate (3.0 mL, 23 mmol) at 0° C. After stirring for 10 min, a solution of 2-mercaptopyridine N-oxide (3.5 g, 27.5 mmol) and triethylamine (TEA; 3.8 mL, 27.5 mmol) in THF (50 mL) was added slowly and the reaction stirred at 0° C. for 1.5 h in the dark (wrapped flask in aluminum foil). The precipitated N-methylmorpholine-HCl salt was removed by vacuum filtration and the filtrate was removed in vacuo at ambient temperature (about 22° C.). The oily residue was dissolved in CH2Cl2 (250 mL) and treated with Iodoform (11.8 g, 30 mmol). The solution was transferred to a UV reactor and irradiated with a 450 W mercury lamp with water cooling. After 1 h, the orange solution was removed from the reactor, adsorbed to Celite® and partially purified via flash chromatography (SiO2, 20% EtOAc/DCM). Additional flash chormatography (SiO2, 10% EtOAc/DCM) followed by recrystallization from EtOAc/hexanes afforded the title compound (5.99 g, 51%) as an off-white solid: mp 168-171° C.; IR (neat) 3386, 2977, 1771, 1760, 1742, 1689, 1510 cm−1; 1H NMR (400 MHz, CDCl3) δ 5.36 (s, 1H), 5.21 (m, 1H), 5.00 (t, J=9.7 Hz, 1H), 4.86 (m, 2H), 3.68 (brs, 1H), 3.31 (dd, J=11.5, 9.3 Hz, 1H), 3.02 (m, 2H), 2.63 (m, 1H), 1.45 (s, 9H), 1.27 (d, J=6.3 Hz, 3H), 1.22 (d, J=7.0 Hz, 6H); ESIMS m/z 536.3 ([M+Na]+).