Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:5]([CH2:8][C@@H:9]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:10]([NH:12][C@@H:13]([CH2:32][C:33]1[N:34]=[CH:35][NH:36][CH:37]=1)[C:14]([NH:16][C@@H:17]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C@@H:18]([OH:24])[C@H:19]([CH:21]1[CH2:23][CH2:22]1)[OH:20])=[O:15])=[O:11])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+].[C:69]([O:75][CH2:76]Cl)(=[O:74])[C:70]([CH3:73])([CH3:72])[CH3:71]>C(OCC)(=O)C>[C:69]([O:75][CH2:76][N:36]1[CH:37]=[C:33]([CH2:32][C@H:13]([NH:12][C:10](=[O:11])[C@@H:9]([CH2:8][S:5]([C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:7])=[O:6])[CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:14](=[O:15])[NH:16][C@@H:17]([CH2:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[C@@H:18]([OH:24])[C@H:19]([CH:21]2[CH2:22][CH2:23]2)[OH:20])[N:34]=[CH:35]1)(=[O:74])[C:70]([CH3:73])([CH3:72])[CH3:71]
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: CC(C)(C)C(=O)OCCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)OCn1cnc(C[C@H](NC(=O)[C@H](Cc2ccccc2)CS(=O)(=O)C(C)(C)C)C(=O)N[C@@H](CC2CCCCC2)[C@@H](O)[C@@H](O)C2CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 250 mg (0.4 mmol) of (S)-α-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4-propionamide, 60 mg of 18-crown-6, 250 mg of potassium carbonate and 2 ml of chloromethyl pivalate is stirred at room temperature overnight. Thereafter, the reaction mixture is taken up in ethyl acetate and the ethyl acetate solution is washed with saturated ammonium chloride solution. After drying over sodium sulphate the solution is evaporated under reduced pressure and subsequently, for purification, the crude product obtained (1.3 g) is chromatographed on 120 g of silica gel using a 200:10:1 mixture of methylene chloride, methanol and ammonia as the eluent. There are obtained 145 mg of [4-[(S)-2-[(S)-α-[(tert-butylsulphonyl)methyl]hydrocinnamamido]-2-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]ethyl]imidazol-1-yl]methyl pivalate as a colourless solid; MS: 745 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([CH:7]=[CH:8][C:9]2[N:19]=[C:12]3[C:13]([CH3:18])=[N:14][CH:15]=[C:16]([CH3:17])[N:11]3[N:10]=2)[N:4]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[N:3]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:4]2[C:5]([CH:7]=[CH:8][C:9]3[N:19]=[C:12]4[C:13]([CH3:18])=[N:14][CH:15]=[C:16]([CH3:17])[N:11]4[N:10]=3)=[N:6][C:2]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[N:3]2)=[CH:22][CH:23]=1
Reactant: C1CCNC1
Reactant: COc1ccc(Cn2nc(Br)nc2C=Cc2nc3c(C)ncc(C)n3n2)cc1
Product: COc1ccc(Cn2nc(N3CCCC3)nc2C=Cc2nc3c(C)ncc(C)n3n2)cc1
Yield: 42.7 %

Procedure:
Was prepared in the same manner as described in General Procedure Example 9 using 2-(2-(3-bromo-1-(4-methoxybenzyl)-1H-1,2,4-triazol-5-yl)vinyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (55 mg, 125 μmol, Eq: 1.00) and pyrrolidine (17.8 mg, 20.7 μl, 250 μmol, Eq: 2) as starting materials. Chromatography afforded 2-{2-[2-(4-Methoxy-benzyl)-5-pyrrolidin-1-yl-2H-[1,2,4]triazol-3-yl]-vinyl}-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (23 mg, 42.8%) as a light yellow solid. MS: m/z=431.5 (M+H+)
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[CH:14][C:15]=2[CH3:16])[C:7]([F:20])=[CH:6][C:5]=1[C:21]1[N:25]([CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:24]=[CH:23][C:22]=1[C:32]([O:34]CC)=[O:33]>C(O)C>[F:3][C:4]1[CH:9]=[C:8]([C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[CH:14][C:15]=2[CH3:16])[C:7]([F:20])=[CH:6][C:5]=1[C:21]1[N:25]([CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:24]=[CH:23][C:22]=1[C:32]([OH:34])=[O:33]
Reactant: CCOC(=O)c1cnn(C2CCOCC2)c1-c1cc(F)c(-c2c(C)cc(C)nc2OC)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1nc(C)cc(C)c1-c1cc(F)c(-c2c(C(=O)O)cnn2C2CCOCC2)cc1F
Temperature: 55 °C
Reaction time: 2 h
Yield: 105 %

Procedure:
A 5 N aqueous sodium hydroxide solution (0.3 mL) was added to a solution of ethyl 5-[2,5-difluoro-4-(2-methoxy-4,6-dimethylpyridin-3-yl)phenyl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxylate (157 mg) in ethanol (3 mL), and the mixture was stirred at 55° C. for two hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was partitioned by adding chloroform, 5 N hydrochloric acid and a saturated aqueous ammonium chloride solution. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to give 5-[2,5-difluoro-4-(2-methoxy-4,6-dimethyl-pyridin-3-yl)phenyl]-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-carboxylic acid (155 mg) as a crude purified product. The carboxylic acid (155 mg) was dissolved in DMF (1 mL) and THF (3 mL). CDI (108 mg) was then added, and the mixture was stirred at room temperature for about 1.5 hours. A 28% aqueous ammonia solution (0.35 mL) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding ethyl acetate and brine. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was solidified by adding n-heptane/MTBE (119) to give the title compound (82 mg). The title compound was used for the next reaction without further purification.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]([CH3:10])[CH2:7][CH:8]=[CH2:9])[CH:2]=[CH2:3].CN1CCOCC1.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH2:1]([N:4]([CH2:5][CH:6]([CH3:10])[CH2:7][CH:8]=[CH2:9])[S:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=1)(=[O:26])=[O:25])[CH:2]=[CH2:3]
Reactant: C=CCNCC(C)CC=C
Reactant: O=S(=O)(Cl)c1ccccn1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C=CCC(C)CN(CC=C)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
Allyl-(2-methyl-pent-4-enyl)-amine (1.0 g, 7.2 mmol) and NMM (1.7 g, 17.2 mmol) were mixed in 30 ml CH2Cl2. 2-pyridinesulphonyl chloride (1.53 g, 8.6 mmol) was added slowly to the solution while it was cooled in an ice-water bath. After addition, the reaction mixture was stirred at RT overnight. The reaction mixture was washed with 10% NaHCO3 and the brine, then was purified by column chromatography to give the title compound as a colorless oil (1.2 g ,60% yield): MS (M+H+) 281.2; 1H-NMR (400 Hz, CDCl3): d=8.70(d, 1H), 8.0–7.75(m, 2H), 7.5 (m, 1H) 5.80–5.60(m, 2H), 5.15–4.92(m, 4H), 4.00–3.90(m, 2H), 3.20–3.06(m, 2H), 2.15(m, 1H), 1.85(m, 2H), 0.89(d, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([OH:19])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[C:22]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([O:19][CH3:22])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc2oc(C(=O)OC(C)(C)C)c(C)c2c1O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(C)ccc2oc(C(=O)OC(C)(C)C)c(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
To 80 mg of 4-hydroxy-3,5-dimethyl-benzofuran-2-carboxylic acid tert-butyl ester was added 1 mL of iodomethane, 80 mg of K2CO3 and 1 mL of DMF. The mixture was stirred at room temperature overnight. The reaction mixture was washed with brine and extracted with ethyl acetate. The combined ethyl acetate solution was washed with brine. Removal of the solvent gave 82 mg of 4-methoxy-3,5-dimethyl-benzofuran-2-carboxylic acid tert-butyl ester as a pale yellow solid.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@@H:14]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C@H:13]([CH3:23])[CH2:12][C@@H:11]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[NH2:30])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br:31][C:32]1[N:37]=[C:36]([C:38](O)=[O:39])[CH:35]=[CH:34][C:33]=1[F:41]>CCOC(C)=O>[Si:1]([O:8][C@H:9]1[C@@H:14]([O:15][Si:16]([C:19]([CH3:21])([CH3:22])[CH3:20])([CH3:18])[CH3:17])[C@H:13]([CH3:23])[CH2:12][C@@H:11]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[NH:30][C:38](=[O:39])[C:36]2[CH:35]=[CH:34][C:33]([F:41])=[C:32]([Br:31])[N:37]=2)[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@@H]1C[C@@H](c2ccncc2N)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C(O)c1ccc(F)c(Br)n1
Solvent: CCOC(C)=O
Product: C[C@@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(Br)n2)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1O[Si](C)(C)C(C)(C)C

Procedure:
Following Method 9, 4-((1R,3R,4S,5R)-3,4-bis(tert-butyldimethylsilyloxy)-5-methylcyclohexyl)pyridin-3-amine and 6-bromo-5-fluoropicolinic acid were coupled and following addition of EtOAc and washing with H2O, NaCl(sat.) and drying over MgSO4, N-(4-((1R,3R,4S,5R)-3,4-bis(tert-butyldimethylsilyloxy)-5-methylcyclohexyl)pyridin-3-yl)-6-bromo-5-fluoropicolinamide was obtained. LCMS (m/z): 652.5, 652.4 (MH+); LC Rt=5.82 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]([O:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:10][CH:9]=2)[O:5][C:4](=[O:21])[C:3]=1[S:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[Na+]>O1CCCC1>[OH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:19][CH:20]=2)[O:5][C:4](=[O:21])[C:3]=1[S:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)COc1ccc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(-c2cc(O)c(SCCc3ccccc3)c(=O)o2)cc1
Reaction time: 5 h

Procedure:
To a tetrahydrofuran (10 ml) solution of 4-[4-hydroxy-2-oxo-3-[(2-phenylethyl)thio]-2H-pyran-6-yl]phenoxyacetic acid, ethyl ester (0.939 mmol) was added 1N sodium hydroxide (2.34 mmol). The reaction was stirred for 5 hrs, and then quenched by addition of water (10 ml) followed by acidification with conc. hydrochloric acid to pH 2. The aqueous layer was then extracted with 2× with ethyl acetate (100 ml). The combined organic extracts were then washed with saturated sodium chloride and dried over anhydrous magnesium sulfate. After evaporation of the solvents in vacuo, the crude product was purified by column chromatography (silica gel-230 to 400 mesh) using 94/5/1 methylene chloride/methanol/acetic acid as the eluent. m.p. 182-183° C.; 1H NMR (400 MHz, DMSO-d6) δ2.76 (t, 2 H), 2.97 (t, 2 H), 4.78 (s, 2 H), 6.67 (s, 1 H), 7.06 (d, 2 H), 7.21 (m, 5 H), 7.75 (d, 2 H).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[N:9]=[N:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.[C:12](=S)=[S:13].Cl>CO>[CH3:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:12]([SH:13])=[N:11][N:10]=2)[N:9]=1
Reactant: S=C=S
Reactant: Cc1ccc(NN)nn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc2nnc(S)n2n1
Yield: 85 %

Procedure:
To a solution of KOH (11.3 g, 0.202 mol) in methanol (100 mL) was added (6-methyl-pyridazin-3-yl)-hydrazine (25 g, 0.202 mol) at room temperature. The reaction mixture was placed in an ice-water bath and carbon disulfide (98 mL, 1.61 mol) was slowly added. The resultant yellow solution was heated to reflux overnight before removal of solvent. The yellow residue was acidified with 2 N aqueous HCl to pH˜4, filtered, and washed with water. Upon drying 33 g of 6-methyl-[1,2,4]triazolo[4,3-b]pyridazine-3-thiol was obtained as a yellow powder (85% yield): 1H NMR (DMSO-d6): δ 2.5 (s, 3H), 7.28 (d, 1H), 8.05 (d, 1H), 14.66 (br s, 1H); MS (m/z) 167 [M+H+]+.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:11]([CH2:29][CH:30]2OCCO2)[C:12]2[C:17]([C:18]=1[CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[CH:16][CH:15]=[C:14]([C:25]([O:27][CH3:28])=[O:26])[CH:13]=2.[OH-].[Na+].CO.[BH3-]C#N.[Na+]>C1COCC1.C(O)(=O)C>[CH:19]1([C:18]2[C:17]3[CH:16]=[CH:15][C:14]([C:25]([O:27][CH3:28])=[O:26])=[CH:13][C:12]=3[N:11]3[CH2:29][CH2:30][NH:2][CH2:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[C:10]=23)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CN)n(CC3OCCO3)c2c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNCc1ccccc1-3
Temperature: 25 °C
Yield: 46 %

Procedure:
3M aqueous HCl (16 eq) was added to a solution of methyl 2-[2-(aminomethyl)phenyl]-3-cyclohexyl-1-(1,3-dioxolan-2-ylmethyl)-1H-indole-6-carboxylate in THF (0.03 M). The reaction was heated with stirring at reflux for 24 h, before being allowed to cool to RT, basified with aqueous NaOH (2N) and extracted into EtOAc (3 times). The combined organics were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the crude intermediate as a yellow oil. This oil was taken up immediately in MeOH (0.1 M, 1 eq) and the solution acidified to pH 4 with glacial acetic acid. After stirring for 20 min, NaCNBH3 (1.3 eq) was added and the reaction stirred for a further 1 h. The reaction was quenched by addition of sat. aq. NaHCO3 and extracted into EtOAc (×3). The combined organic extracts were washed with brine before being dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash column chromatography (2.5% MeOH/0.5% Et3N/CH2Cl2) gave the title compound as a pale yellow solid (46%); MS (ES+) m/z 389 (M+H)+
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:36][CH2:37][CH2:38][CH:39]([CH3:59])[CH:40]([C:52]1[CH:57]=[CH:56][C:55]([F:58])=[CH:54][CH:53]=1)[C:41]([NH:43][NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[O:42])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.[Cl-].[NH4+]>C1COCC1>[F:58][C:55]1[CH:54]=[CH:53][C:52]([CH:40]([CH:39]([CH3:59])[CH2:38][CH2:37][OH:36])[C:41]([NH:43][NH:44][C:45]([O:47][C:48]([CH3:49])([CH3:51])[CH3:50])=[O:46])=[O:42])=[CH:57][CH:56]=1
Reactant: CC(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(C(=O)NNC(=O)OC(C)(C)C)c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(CCO)C(C(=O)NNC(=O)OC(C)(C)C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
TBAF (2.7 mL; 1 M solution in THF) was added to a solution of tert-butyl N′-[5-(tert-butyldiphenylsilanyloxy)-2-(4-fluorophenyl)-3-methylpentanoyl]hydrazinecarboxylate (1.04 g) in THF (20 mL). The reaction solution was stirred at room temperature for 1 hours. Then, ethyl acetate and a saturated ammonium chloride solution were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 525 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][NH:5][CH2:4][C@@H:3]1[CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:19][O:20][C:21]1[CH:30]=[C:29]2[C:24]([CH:25]=[CH:26][C:27](=[O:34])[N:28]2[CH2:31][CH:32]=O)=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CO>[OH:1][C@@H:2]1[CH2:6][N:5]([CH2:32][CH2:31][N:28]2[C:29]3[C:24](=[CH:23][CH:22]=[C:21]([O:20][CH3:19])[CH:30]=3)[CH:25]=[CH:26][C:27]2=[O:34])[CH2:4][C@@H:3]1[CH2:7][NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(NC[C@H]1CNC[C@H]1O)OCc1ccccc1
Reactant: COc1ccc2ccc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2ccc(=O)n(CCN3C[C@H](CNC(=O)OCc4ccccc4)[C@H](O)C3)c2c1
Reaction time: 1 h

Procedure:
Phenylmethyl {[(3R,4S)-4-hydroxy-3-pyrrolidinyl]methyl}carbamate (840 mg, 3.35 mmol) and [7-(methyloxy)-2-oxo-1(2H)-quinolinyl]acetaldehyde (663 mg, 3.05 mmol) were combined in anhydrous DCM (10 ml) and anhydrous MeOH (2 ml) with a spatula of solid sodium carbonate. The reaction mixture was stirred under nitrogen for 1 h then sodium triacetoxyborohydride (2.03 g, 9.12 mmol) was added and stirred overnight. The reaction mixture was concentrated and the title compound was obtained as a pale yellow oil (1 g, 71%) after column chromatography (90:10:1: DCM:MeOH:NH4OH).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][S:5][CH2:6][CH2:7][NH2:8].[N+](N[C:13]1[NH:18][C:17](=[O:19])[C:16]([CH2:20][C:21]2[CH:22]=[N:23][C:24](C)=[CH:25][CH:26]=2)=[CH:15][N:14]=1)([O-])=O>C(O)C>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][C:16]2[C:17](=[O:19])[NH:18][C:13]([NH:1][CH2:2][CH2:3][S:4][S:5][CH2:6][CH2:7][NH:8][C:13]3[NH:18][C:17](=[O:19])[C:16]([CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[CH:15][N:14]=3)=[N:14][CH:15]=2)[CH:22]=1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: NCCSSCCN
Solvent: CCO
Product: O=c1[nH]c(NCCSSCCNc2ncc(Cc3cccnc3)c(=O)[nH]2)ncc1Cc1cccnc1

Procedure:
Cystamine is reacted with 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone by heating in ethanol to give 2-[5-(3-pyridylmethyl)-4-oxo-2-pyrimidylamino]ethyl disulphide which is reduced with dithiothreitol to give 2-(2-mercaptoethylamino)-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone which is reacted with 5-dimethylaminomethyl-2-furylmethanol in cold aqueous hydrochloric acid to give 2-[2-(5-dimethylaminomethyl-2-furylmethylthio)ethylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone.
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[C:25]([O:29][C:30]([NH:32][C@H:33]([C:44](O)=[O:45])[C@@H:34]([CH3:43])[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([S:15]([N:5]([C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:44]([C@@H:33]([NH:32][C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:31])[C@H:34]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:43])=[O:45])[CH2:1][CH:2]([CH3:3])[CH3:4])(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)OCc2ccccc2)C(=O)O)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine (100 mg, 0.29 mmol, example 1, step E) as described in general procedure Bc using commercially available Nα-tert-butoxycarbonyl-O-benzyl-L-threonine (93 mg, 0.3 mmol). The final product was triturated with ether to yield 195 mg (98%) of the desired material.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:24][O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH2:28].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C.CN(C)C=O>[CH3:24][O:25][C:26](=[O:33])[C@H:27]([CH2:29][CH:30]([CH3:32])[CH3:31])[NH:28][C:20](=[O:22])[C@@H:12]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 6.65 g. of Nα -benzyloxycarbonyl-D-phenylalanine (0.022 mol) and 4.38 g. (0.022 mol) of L-leucine methyl ester hydrochloride in 60 ml. of spectrograde dimethylformamide is chilled in ice and treated with 3.0 ml. of triethylamine (2.24 g.). 1-Hydroxybenztriazole, 3.3 g., and dicyclohexylcarbodiimide, 5 g., are added and the reaction stirred to room temperature overnight and for 24 hours at room temperature. The mixture is filtered and the solvent evaporated under reduced pressure. The residue is dissolved in 200 ml. of ethyl acetate and washed with 0.1N hydrochloric acid, saturated salt solution, 5% sodium bicarbonate solution, saturated salt solution and water. The ethyl acetate solution is dried over magnesium sulfate, filtered and evaporated to a crystalline residue. The product is recrystallized twice from ethyl acetate and petroleum ether; 7.3 g.; m.p. 125°-126° C.; [α]D23 -20.3° (c 1.02, methanol).
Reaction SMILES: [C:1]([NH:18][C@H:19]([C:23](O)=[O:24])[CH2:20][CH2:21][CH3:22])([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].S(Cl)(Cl)=O>CO.C(OC(=O)C)C>[CH:7]1[C:6]2[CH:5]([CH2:4][O:3][C:1]([NH:18][C@H:19]([CH:23]=[O:24])[CH2:20][CH2:21][CH3:22])=[O:2])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC[C@@H](C=O)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 109.1 %

Procedure:
To a chilled solution of Fmoc-norvaline (25 g, 73.75 mmol) in anhydrous methanol (469 mL) was added thionyl chloride (53.76 mL, 0.74 mol) over one hour. Thin layer chromatography in ethylacetate taken an hour later confirmed the completion of the reaction (Rf=0.85). The reaction mixture was concentrated and the remaining residue was picked-up in ethylacetate. The organic layer was washed with three 200 ml portions of saturated sodium bicarbonate followed by brine. The organic layer was dried and concentrated to afford the title product as a white solid (26.03 g) in quantitative yield. NMR δ ppm (CD3OD): 7.7 (m, 2H), 7.6 (m, 2H), 7.4 (m, 2H), 7.3 (m, 2H), 4.3 (m, 2H), 4.1 (m, 2H), 3.7 (s, 3H), 1.7 (m, 1H), 1.6 (m,1H), 1.4 (m, 2H), 0.95 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([C:11]1[N:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=1)C(OCC)=O)[CH3:2].[Cl-].[Na+].CS(C)=O>O>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:11]1[N:12]=[N:13][C:14]([Cl:17])=[CH:15][CH:16]=1)[CH3:2]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(Cl)nn1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1ccc(Cl)nn1
Temperature: 150 °C
Reaction time: 4.5 h

Procedure:
A mixture of 2-(6-chloro-pyridazin-3-yl)-malonic acid diethyl ester (from step 1, ca. 65%, 19.0 g), sodium chloride (11.8 g), water (1.3 mL), and dimethyl sulfoxide (80 mL) was stirred at 150° C. for 4.5 h. More sodium chloride (5.0 g) and water (0.6 mL) were then added and stirring was continued at 160° C. for another 2 h. After cooling to room temperature, water was added and the resulting mixture was extracted with tert-butyl methyl ether. The combined extracts were washed with water and brine and dried (MgSO4). The solvent was evaporated to give the crude title compound that was submitted to the next reaction step without further purification. Yield: 9.0 g (64% of theory); LC (method 1): tR=1.18 min.
Reaction SMILES: [CH:1]1([N:7]([CH3:11])[CH2:8][CH2:9]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:14])=O>C(OCC)C>[CH:1]1([N:7]([CH2:8][CH2:9][Cl:14])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(CCO)C1CCCCC1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: CN(CCCl)C1CCCCC1
Temperature: 70 °C

Procedure:
N-Cyclohexyl-N-methyl-2-aminoethanol (25 g) is added dropwise to thionyl chloride (120 cc) and then the mixture is heated for 24 hours at 70° C. After the excess thionyl chloride has been distilled off, the orange oil obtained is stirred into ethyl ether (200 cc) to give a white solid, which is separated off by filtrattion and then washed with ether. 2-(N-Cyclohexyl-N-methyl-amino)-1-chloroethane (30 g) is obtained in the form of a white solid melting at 154° C.