Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([N+]([O-])=O)=[CH:4][C:3]=1[C:21]1[O:22][CH2:23][CH2:24][CH2:25][N:26]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([SH:40])=[CH:36][CH:35]=1>CN1CCCC1=O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([S:40][C:37]2[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=2)=[CH:4][C:3]=1[C:21]1[O:22][CH2:23][CH2:24][CH2:25][N:26]=1
Reactant: Nc1c(C2=NCCCO2)cc([N+](=O)[O-])c2c1C(=O)c1ccccc1C2=O
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Nc1c(C2=NCCCO2)cc(Sc2ccc(Cl)cc2)c2c1C(=O)c1ccccc1C2=O
Yield: 51.4 %

Procedure:
14 g of 1-amino-2-(5,6-dihydro-4H-1,3-oxazin-2-yl)-4-nitroanthraquinone, 5.4 g of potassium carbonate, 100 cc of N-methylpyrrolidone and 5.9 g of 4-chlorothiophenol are reacted as in Example 2. The reaction mixture is worked up as described in that example to give 9.2 g of 1-amino-2-(5,6-dihydro-4H-1,3-oxazin-2-yl)-4-(4-chlorophenylmercapto)-anthraquinone, corresponding to a yield of 51% of theory.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:11](=[O:22])[N:10]([NH:23][C:24](=[O:51])[C@@H:25]([C@@H:30]([C:40](=[O:50])[NH:41][O:42]CC2C=CC=CC=2)[CH2:31]/[CH:32]=[CH:33]/[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:26][CH:27]([CH3:29])[CH3:28])[C:9]1=[O:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:15]([N:12]1[C:13](=[O:14])[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:52])[N:10]([NH:23][C:24](=[O:51])[C@@H:25]([C@@H:30]([C:40](=[O:50])[NH:41][OH:42])[CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:26][CH:27]([CH3:29])[CH3:28])[C:11]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)C[C@@H](C(=O)Nn1c(=O)n(Cc2ccccc2)c(=O)n(Cc2ccccc2)c1=O)[C@H](C/C=C/c1ccccc1)C(=O)NOCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@@H](C(=O)Nn1c(=O)n(Cc2ccccc2)c(=O)n(Cc2ccccc2)c1=O)[C@H](CCCc1ccccc1)C(=O)NO
Yield: 4.9 %

Procedure:
A solution of 0.211 g of (E)-N-(3,5-dibenzyl-hexahydro-2,4,6-trioxo-1,3,5-triazin-1-yl)-2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenyl-3-butenyl]-4-methylvaleramide in 10 ml of methanol was hydrogenated in the presence of 0.020 g of 10% palladium-on-carbon for 6 hours. Filtration and evaporation of the filtrate gave a residue which was triturated with diethyl ether to give 0.009 g of N-(3,5-dibenzylhexahydro-2,4,6-trioxo-1,3,5-triazin-1-yl)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenylbutyl]-4-methylvaleramide in the form of a white solid.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]2[CH2:22][O:21]C(C3C=CC=CC=3)[O:19][CH2:18]2)=[CH:12][C:11]=1[O:29][CH:30]([CH3:32])[CH3:31])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CCOC(C)=O>[C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([CH2:18][OH:19])[CH2:22][OH:21])=[CH:12][C:11]=1[O:29][CH:30]([CH3:32])[CH3:31])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Oc1cc(OC2COC(c3ccccc3)OC2)ccc1OC(=O)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(OC(CO)CO)ccc1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A suspension of 10% palladium on carbon (38.9 mg, 0.037 mmol) in a solution of 2-isopropoxy-4-[(2-phenyl-1,3-dioxan-5-yl)oxy]phenyl benzoate (158.7 mg, 0.365 mmol) in EtOAc (3.65 mL) was stirred under H2 (double balloon pressure) at 25° C. for 4 days. The reaction mixture was filtered through a plug of Celite and the filtrate was concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 100% EtOAc over 2394 mL) to afford 4-[2-hydroxy-1-(hydroxymethyl)ethoxy]-2-isopropoxyphenyl benzoate, as a colorless solid. Rf=0.17 (50% EtOAc in hexanes). LCMS calc.=347.15; found=347.06 (M+H)+. 1H NMR (500 MHz, CHCl3): δ 8.18 (d, J=7.8 Hz, 2 H); 7.61 (t, J=7.5 Hz, 1 H); 7.49 (t, J=7.7 Hz, 2 H); 7.03 (d, J=8.7 Hz, 1 H); 6.68 (d, J=2.7 Hz, 1 H); 6.56 (dd, J=8.8, 2.7 Hz, 1 H); 4.45 (p, J=6.1 Hz, 1 H); 4.34 (p, J=4.8 Hz, 1 H); 3.89-3.80 (m, 4 H); 2.88 (s, 2 H); 1.23 (d, J=6.1 Hz, 6 H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]4[CH:18]=[C:19]([C:22]([OH:24])=[O:23])[CH:20]=[CH:21][C:16]=4[N:15]=[C:14]3[C:25](=[O:36])[NH:26][CH:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]3)[CH:8]=2)=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH2:52](O)[CH2:53][OH:54]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:54][CH2:53][CH2:52][O:23][C:22]([C:19]1[CH:20]=[CH:21][C:16]2[N:15]=[C:14]([C:25](=[O:36])[NH:26][CH:27]3[CH2:28][CH2:29][N:30]([CH:33]([CH3:34])[CH3:35])[CH2:31][CH2:32]3)[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[C:17]=2[CH:18]=1)=[O:24]
Reactant: CC(C)N1CCC(NC(=O)c2nc3ccc(C(=O)O)cc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Reactant: OCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCC(NC(=O)c2nc3ccc(C(=O)OCCO)cc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
50 mg (0.08 mmol) 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-benzoimidazole-5-carboxylic acid were dissolved in 10 mL CH2Cl2. Subsequently 3 mg DMAP, 23 mg (0.11 mmol) DCC and 46 μl (0.83 mmol) ethylene glycol were added. The resulting mixture was stirred at room temperature for 16 h and then concentrated under removed pressure. The remaining residue was purified by preparative HPLC (CH3CN/H2O gradient+0.05% formic acid) to give pure 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-3H-benzoimidazole-5-carboxylic acid 2-hydroxy-ethyl ester as a white amorphous solid. The corresponding dihydrochloride was obtained by treatment with a 0.1 M HCl-solution and following lyophilization.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[C:10](OCC)=[O:11])=[N:4][CH:3]=1.CC(C[AlH]CC(C)C)C.[OH-].[Na+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[C:9]([CH2:10][OH:11])[CH:15]=[CH:16][CH:17]=2)=[N:4][CH:3]=1
Reactant: CCOC(=O)c1cccc(-c2ncc(C)s2)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cnc(-c2cccc(CO)c2)s1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A cooled (−78° C.) solution of ethyl 3-(5-methylthiazol-2-yl)benzoate (388 mg; 1.57 mmol) in anh. toluene (4 ml) was treated with a solution of 1 M DIBAH in toluene (4.71 ml; 4.71 mmol), and the resulting mixture was further stirred at −78° C., under nitrogen, for 5 min., and then at 0° C. for 30 min. The obtained mixture was then treated successively with water (35 ml), 1 M aq. NaOH (11 ml), and aq. sat. NaHCO3 (30 ml). The separated aq. layer was further extracted with Et2O (2×100 ml). The mixed organic layers were then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=20/1) afforded (3-(5-methylthiazol-2-yl)phenyl)methanol as a pale yellow oil. LC-MS (conditions A): tR=0.58 min.; [M+H]+: 206.01 g/mol.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3=[N:19][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:21](=[O:22])[C:11]3=[N:10]2)=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[C:21](=[O:22])[C:11]2=[N:10][N:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([C:34]4[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=4)=[CH:3][CH:4]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]2=[N:19]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(Br)nc3)nc-2c1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-c4cnn(C)c4)nc3)nc-2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-[(6-Bromopyridin-3-yl)methyl]-2-(2-methylphenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]cinnolin-3-one [(Example 22) 74 mg, 0.17 mmol] was dissolved in dimethyl sulfoxide (1 mL) and treated with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (59 mg, 0.28 mmol, 1.7 equiv), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-iso-propylbiphenyl (X-PHOS, 36 mg, 0.076 mmol, 0.46 equiv), palladium(II)acetate (8.0 mg, 0.033 mmol, 0.2 equiv), and an aqueous solution (0.2 mL) of potassium carbonate (69 mg, 0.50 mmol, 3.0 equiv). The mixture was placed into an oil bath preheated at 80° C. for 30 minutes, cooled to ambient temperature, poured into water and extracted twice with ethyl acetate. The combined organic extracts were washed once with water and brine, dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 94:6; chloroform:methanol), providing the titled compound: 1H-NMR (400 MHz, CDCl3) δ 8.63 (1H, s), 8.31 (1H, d, J=7.5 Hz), 7.93 (1H, s), 7.91 (1H, s), 7.68-7.53 (4H, m), 7.47-7.41 (2H, m), 7.38-7.31 (3H, m), 5.84 (2H, s), 3.96 (3H, s), 2.38 (3H, s) ppm; high resolution mass spectrometry (ES+) m/z 448.1885 [(M+H)+; calculated for C26H22N7O: 448.1880].
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>[OH-].[Na+].S(=O)(=O)(O)[O-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCCCBr
Reactant: OCCCCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: BrCCCCCOCCCCc1ccccc1

Procedure:
4-Phenylbutanol (5.80 g) was stirred in 1,5-dibromopentane (52 ml) and 5N NaOH solution (50 ml), and tetrabutyl ammonium bisulphate (0.87 g) was added and the reaction mixture was stirred at RT for 72 h. (After 42 h the NaOH layer was replaced by a fresh solution). The two layers were separated and the aqueous phase was extracted with ER (3×50 ml). The combined organic layers were dried (Na2SO+), and evaporated to give a clear liquid. Excess 1,5-dibromopentane was removed by distillation at 60° 1.00 mmHg. The residue was chromatographed on a silica (70-230 mesh, 30 g) column using CX as eluant, with a slowly increasing quantity of ER until the title compound was obtained, which on evaporation gave a colourless oil (3.26 g). T.l.c. (CX-ER (99:1)) Rf 0.15.
Reaction SMILES: [C:1]([C:3]1[CH:27]=[CH:26][C:6]([C:7]([NH:9][C:10](=[O:25])[NH:11][C:12]2[CH:24]=[CH:23][C:15]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CC=CC=1.[SH2:34]>C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10](=[O:25])[NH:11][C:12]2[CH:24]=[CH:23][C:15]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:14][CH:13]=2)=[O:8])=[CH:26][CH:27]=1)(=[S:34])[NH2:2]
Reactant: CCOC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C#N)cc2)cc1
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1ccc(NC(=O)NC(=O)c2ccc(C(N)=S)cc2)cc1

Procedure:
In a similar manner to Example, starting material step 1 (b), the product of step (a) (10.12 g), pyridine (500 ml), triethylamine (80 ml) and H2S gas were reacted to give ethyl 4-[3-(4-thiocarbamoylbenzoyl)ureido]phenoxyacetate (11 g) as a yellow solid: NMR Spectrum (DMSO-d6) 1.21 (3H, t), 4.18 (2H, q), 4.74 (2H, s), 6.93 (2H, d), 7.49 (2H, d), 7.95 (2H, d), 8.03 (2H, d), 9.64 (1H, br s), 10.03 (1H, br s), 10.60 (1H, s), 11.04 (1H, s); Mass Spectrum m/Z 402 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:37]2[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=2)[CH:5]=[C:6]([Cl:36])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][C@@H:12]([CH2:14][O:15]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[O:11][C:10]1=[O:35].C(=O)(O)[O-].[Na+]>ClCCl.CO.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:37]2[CH:38]=[CH:39][C:40]([F:43])=[CH:41][CH:42]=2)[CH:5]=[C:6]([Cl:36])[C:7]=1[CH2:8][C@@H:9]1[CH2:13][C@@H:12]([CH2:14][OH:15])[O:11][C:10]1=[O:35]
Reactant: O=C1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1Cc1c(Cl)cc(-c2ccc(F)cc2)cc1Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C1O[C@H](CO)C[C@H]1Cc1c(Cl)cc(-c2ccc(F)cc2)cc1Cl
Reaction time: 8 h
Yield: 44 %

Procedure:
Redissolve (3R,5S)-3-(3,5-Dichloro-4′-fluoro-biphenyl-4-ylmethyl)-5-trityloxymethyl-dihydro-furan-2-one in 30 mL of dichloromethane and 50 mL of methanol containing 0.5 mL of concentrate HCl. Stir the mixture overnight and neutralize with aqueous sodium bicarbonate. Most of the methanol and dichloromethane are removed. Extract the product with ethyl acetate. Wash the organic layers with water and then brine. Evaporate the solvent and chromatograph the product on flash silica gel using 5 to 25% acetone in methylene chloride. Evaporate the product containing fractions and recrystallize from ethyl acetate and heptane to afford 2.5 g (44% yield) of (3R,5S)-3-(3,5-dichloro-4′-fluoro-biphenyl-4-ylmethyl)-5-hydroxymethyl-dihydro-furan-2-one.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1.C(OC(C)C)(C)C>O1CCCC1>[CH3:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1])[CH2:10][CH2:9]1
Reactant: CC1CCC(N)CC1
Reactant: C=C1CC(=O)O1
Solvent: C1CCOC1
Solvent: CC(C)OC(C)C
Product: CC(=O)CC(=O)NC1CCC(C)CC1
Temperature: 20 °C
Reaction time: 3 h
Yield: 67.7 %

Procedure:
29 g of diketene were added over 20 minutes to a stirred mixture of 39 g of 4-methylcyclohexylamine in 100 ml of tetrahydrofuran and the mixture was stirred at 20° C. for 3 hours. Isopropyl ether was added thereto and the precipitate formed was recovered by vacuum filtration, was washed and dried to obtain 46 g of N-(4-methylcyclohexyl)-acetylacetamide melting at 111° C. A mixture of 46 g of the latter product, 37 g of methyl orthoformate, 1.5 g of p-toluene sulfonic acid and 100 ml of methanol was stirred for 2 hours at 20° C. and after standing for 16 hours, 3 ml of quinoline were added thereto. The mixture was distilled to dryness under reduced pressure and the residue was added to toluene. The stirred mixture was heated at 145° C. for 3 hours while distilling a toluene-methanol azeotrope and was then cooled and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and elution with an 8-2 methylene chloride-acetone mixture gave 24 g of N-(4'-methylcyclohexyl)-3-methoxy-crotonamide melting at 125° C. The RMN spectra showed the product to be the E isomer.
Reaction SMILES: C([O:8][C:9](=[O:31])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:30])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:23])=[O:22])C1C=CC=CC=1.C(=O)(O)[O-].[Na+].[H][H].Cl>CO.[C].[Pd].O>[C:24]1([S:21]([N:17]2[CH2:18][CH2:19][CH2:20][C@H:16]2[C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]([OH:31])=[O:8])=[O:30])(=[O:23])=[O:22])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: O
Product: O=C(O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1S(=O)(=O)c1ccccc1
Yield: 62.5 %

Procedure:
N-benzenesulfonyl-L-prolyl-L-proline benzylester (2.17 g, 4.9 mmole) was dissolved in methanol (40 ml), and water (5 ml) solution of sodium bicarbonate (0.42 g, 5 mmole) was added thereto. Hydrogen gas was passed through the solution in the presence of 5% palladium-carbon as a catalyst for 3 hours. The catalyst was removed by filtration, and the solution was concentrated under reduced pressure, and the residue thus obtained was dissolved in water (10 ml). 1N aqueous hydrochloric acid (10 ml) was added to the solution. The white crystals thus obtained were recrystallized from N,N-dimethylformamide, ethyl acetate and petroleum ether to obtain N-benzenesulfonyl-L-prolyl-L-proline (yield 1.08 g, 62.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[CH:6]=[CH:5][CH:4]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][C@H:28]([C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[CH2:27][C@H:26]([N:38]([C:43](=[O:47])[C:44](O)=[O:45])[CH2:39][CH:40]([CH3:42])[CH3:41])[CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>ClCCCl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]=1[NH:9][C:44](=[O:45])[C:43]([N:38]([CH2:39][CH:40]([CH3:41])[CH3:42])[C@H:26]1[CH2:27][C@@H:28]([C:30]([N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)=[O:31])[CH2:29][N:24]([C:22]([O:21][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:23])[CH2:25]1)=[O:47]
Reactant: CC(C)CN(C(=O)C(=O)O)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: COCCCCNc1cccc(OC)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COCCCCNc1cccc(OC)c1NC(=O)C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 53.1 %

Procedure:
6-Methoxy-2-(4-methoxybutylamino)aniline (210 mg), {{(3S,5R)-1-(tert-butoxycarbonyl)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl}(2-methylpropyl)amino}(oxo)acetic acid (308 mg), HOBt (97 mg) and triethylamine (370 μl) were dissolved in 1,2-dichloroethane (15 ml), WSC.HCl (430 mg) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (2:8)-ethyl acetate was concentrated under reduced pressure to give the object product (240 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][CH2:10][CH2:11][N:12]([CH2:13][CH:14]([OH:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1.[Cl:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:28]=1[CH:29]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.C(Cl)Cl>[Cl:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:28]=1[CH2:29][NH:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][CH2:10][CH2:11][N:12]([CH2:13][CH:14]([OH:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:5]2=[N:4][C:3]=1[C:20]1[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=1
Reactant: CC(C)CC(O)CN1CCCn2c1nc(-c1ccncc1)c(N)c2=O
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)CC(O)CN1CCCn2c1nc(-c1ccncc1)c(NCc1c(Cl)cccc1Cl)c2=O
Temperature: 25 °C

Procedure:
To a solution of 3-amino-9-(2-hydroxy-4-methyl-pentyl)-2-pyridin-4-yl-6,7,8,9-tetrahydro-pyrimido[1,2-a]pyrimidin-4-one (100 mg, 0.29 mmol) and 2,6-dichlorobenzaldehyde (130 mg, 0.74 mmol) in 1 mL each of HOAc and CH2Cl2 was added NaBH(OAc)3 (110 mg, 0.52 mmol). The mixture was stirred at 40° C. for 50 min before a second portion of NaBH(OAc)3 (110 mg) was added. After a total of 2 h, the mixture was quenched with NaHCO3 (5 g) in H2O (15 mL) slowly and was allowed to stir over night at room temperature. Partition between CH2Cl2 and H2O followed by extraction with CH2Cl2 afforded the organic residue that was purified on silica (0–5% MeOH in DCM) to yield the desired product as an yellow foam. M+1 503.
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([O:10]C)=O.[NH2:12][C:13](N)=[O:14]>CN(C=O)C>[CH3:7][C:6]1[C:2]2[NH:1][C:13](=[O:14])[NH:12][C:8](=[O:10])[C:3]=2[S:4][CH:5]=1
Reactant: COC(=O)c1scc(C)c1N
Reactant: NC(N)=O
Solvent: CN(C)C=O
Product: Cc1csc2c(=O)[nH]c(=O)[nH]c12
Temperature: 200 °C
Yield: 86.5 %

Procedure:
To 25.0 g (146 mmol) of methyl 3-amino-4-methylthiophene-2-carboxylate was added 43.5 g (730 mmol) of urea, and the resulting mixture was heated at 200° C. for 1.5 hours. The mixture was allowed to resume room temperature, and DMF (400 ml) was added thereto, followed by heating under reflux for one hour. After completion of the reaction, ice water was added to the reaction mixture, and crystals thus precipitated were filtered to give 23.0 g (yield: 93.7%) of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].[H-].[Na+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C)C=O>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][O:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH2:6][C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)[CH3:22]
Reactant: Oc1ccccc1Cc1ncc[nH]1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1Cc1ncc[nH]1

Procedure:
Treatment of 2-(1-imidazolylmethyl)phenol with sodium hydride in dry N,N-dimethylformamide followed by ethyl bromoacetate as described in Example 11B gave 2-(1-imidazolylmethyl)phenoxyacetic acid ethyl ester as an oil which was used without further characterisation.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.O[C:14]1[CH:15]=C2C(=C[CH:23]=1)NC(=O)CC2>>[CH2:15]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2)[CH:14]=[CH2:23]
Reactant: O=C1CCc2cc(O)ccc2N1
Reactant: O=c1ccc2cc(O)ccc2[nH]1
Product: C=CCOc1ccc2[nH]c(=O)ccc2c1

Procedure:
In this process, a starting material, i.e., a known compound 6-hydroxy-1H-quinoline-2-one or 6-hydroxy-3,4-dihydro-(1H)-quinoline-2-one of the formula (IV), and a halogenated acetylene derivative are subjected to dehydrohalogenation according to a conventional method to give a 6-(2-propenyloxy) quinoline-2-one derivative of the formula (V), and the resulting compound (V) is subjected to cyclization reaction according to a conventional method to give a compound of the formula (VII). (Steps A, B)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([C:11](=[CH2:15])[C:12]([OH:14])=[O:13])[CH2:6][CH2:5]2.[C:16]([OH:19])(=[S:18])[CH3:17]>C(Cl)(Cl)Cl>[C:16]([S:18][CH2:15][CH:11]([CH:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1)[C:12]([OH:14])=[O:13])(=[O:19])[CH3:17]
Reactant: CC(O)=S
Reactant: C=C(C(=O)O)C1CCc2cc(Br)ccc21
Solvent: ClC(Cl)Cl
Product: CC(=O)SCC(C(=O)O)C1CCc2cc(Br)ccc21

Procedure:
The ethylene compound obtained in Step E (48.83 mmol) is dissolved in 100 ml of CHCl3 and thioacetic acid (170.89 mmol, 3.5 eq.) is added. The mixture is stirred at reflux for 16 hours. The solvent and excess thioacetic acid are removed by evaporation under reduced pressure to yield the title compound in the form of four stereoisomers that can be separated into two enantiomer pairs:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[C:5]2Cl.[O:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1.CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[C:5]2[NH:22][CH:19]1[CH2:20][CH2:21][O:16][CH2:17][CH2:18]1
Reactant: NC1CCOCC1
Reactant: NC(=O)c1cnc2ccc(Br)cc2c1Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: NC(=O)c1cnc2ccc(Br)cc2c1NC1CCOCC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
A mixture of 6-bromo-4-chloroquinoline-3-carboxamide (50 g, 175.4 mmol), tetrahydro-2H-pyran-4-amine (26.2 g, 193 mmol) and DIPEA (56.13 mL, 438.5 mmol) in DMA (500 mL) was stirred at 90° C. overnight. The mixture was allowed to cool and poured into water (1500 mL). The precipitate was filtered, washed with water (2×200 mL) and dried under reduced pressure to afford the desired material (57.3 g, 93%) as a white solid. NMR Spectrum: 1H NMR (400 MHz, DMSO-d6) δ 2.88-1.92 (2H, m), 2.59-2.78 (2H, m), 3.50-3.62 (3H, m), 3.96-4.08 (2H, m), 4.92-4.98 (1H, m), 7.80 (1H, m), 7.99 (1H, dd), 8.46 (1H, d), 8.74 (1H, s).