Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC([N:9]2[C@H:12]([CH:13]=[C:14]([CH3:16])[CH3:15])[C@H:11]([O:17][C:18](=[O:20])[CH3:19])[C:10]2=[O:21])=CC=1>C(#N)C.O>[C:18]([O:17][C@H:11]1[C@@H:12]([CH:13]=[C:14]([CH3:16])[CH3:15])[NH:9][C:10]1=[O:21])(=[O:20])[CH3:19]
Reactant: COc1ccc(N2C(=O)[C@@H](OC(C)=O)[C@H]2C=C(C)C)cc1
Solvent: O
Solvent: CC#N
Product: CC(=O)O[C@@H]1C(=O)N[C@@H]1C=C(C)C
Temperature: 2.5 °C
Reaction time: 0.17 h
Yield: 91.3 %

Procedure:
A solution of the (±)-cis-N-(4-methoxyphenyl)-3-acetyloxy-4-isobutenylazetidin-2-one (4.88 g, 16.2 mmol) was dissolved in acetonitrile (50 mL) and cooled to 0-5° C. in an ice bath. To this was added a cold solution of ceric ammonium nitrate (26.6 g, 48.6 mmol, 50 mL) in one portion. The deep red reaction was allowed to stir for 10 min and during that time the color gradually lightened to orange. The cold solution was transferred to a separatory funnel, diluted with water, and extracted with ethyl acetate. The organic fraction was washed with several portions of 10% aqueous sodium sulfite, followed by saturated aqueous sodium bicarbonate. The organic fraction was dried (MgSO4) and concentrated to give the desired product (2.71 g, 91%) as a yellow-orange solid that was used directly in the next step; 1H NMR (300 MHz, CDCl3): δ 6.11 (bs, 1H), 5.73 (dd, 1H, J=2.2, 4.7 Hz), 5.12-5.08 (m, 1H), 4.63 (dd, 1H, 4.7, 9.1 Hz), 2.09 (s, 3H), 1.75 (s, 3H), 1.67 (s, 3H).
Reaction SMILES: Br[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]1Br.S(=O)(=O)(O)[OH:13]>C(#N)C>[O:13]1[C@@H:3]2[CH2:4][C:5]3[C:10]([C@H:2]12)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: O=S(=O)(O)O
Reactant: BrC1Cc2ccccc2C1Br
Solvent: CC#N
Product: c1ccc2c(c1)C[C@H]1O[C@@H]21
Temperature: 40 °C
Reaction time: 5 h
Yield: 25.3 %

Procedure:
Into a 1000 ml four-neck flask, 259.5 g of an acetonitrile solution of 1,2-dibromoindan (corresponding to bromination of 0.559 mol of indene) was introduced. It was then heated to 40° C. To this solution, 86.57 g (0.839 mol) of 97% sulfuric acid was dropwise added at 40°-46° C. in a period of 1.5 hours. The resulting mixture was stirred at the same temperature for 5 hours. According to an HPLC analysis, about 15% of 1,2-dibromoindan was remaining in the mixture. To this mixture, 43.29 g of sulfuric acid was further added. The resulting mixture was stirred at 50°-60° C. for 1.5 hours. According to an HPLC analysis, 1,2-dibromoindan had almost disappeared yielding 11.0% of trans-amide derivative (III: R=CH3) and 25.3% of cis-oxazoline derivative (IV: R=CH3).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C@H:11]([NH:29]S(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:12][NH:13][C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[CH:25]=[N:24][CH:23]=[CH:22]4)[CH:15]=2)=[CH:2]1.N1CCCN2CCCCCC=12.SCCO>CN(C=O)C>[NH2:29][C@@H:11]([CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH2:12][NH:13][C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[N:24][CH:23]=[CH:22]3)[CH:15]=1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)N[C@H](CNc2cc(-c3ccc4cnccc4c3)no2)Cc2c[nH]c3ccccc23)cc1
Agent: OCCS
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: N[C@H](CNc1cc(-c2ccc3cnccc3c2)no1)Cc1c[nH]c2ccccc12
Reaction time: 2 h
Yield: 75.1 %

Procedure:
To 25 mL of round-bottom flask was added N-((S)-3-(1H-indol-3-yl)-1-(3-(isoquinolin-6-yl)isoxazol-5-ylamino)propan-2-yl)-4-nitrobenzenesulfonamide (75 mg, 132 μmol), 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (20 mg, 132 μmol) (commercially available from Aldrich), 2-mercaptoethanol (10 mg, 132 μmol) and 2 mL of DMF. After 2 hours, the reaction mixture was directly purified by preparative LC to give N-((S)-2-amino-3-(1H-indol-3-yl)propyl)-3-(isoquinolin-6-yl)isoxazol-5-amine (38 mg, 75% yield). MS m/z: 384 (M+1); 1H NMR (400 MHz, CD3OD) δ ppm 9.69 (s, 1H), 8.61 (d, J=6.26 Hz, 1H), 8.48 (d, J=8.61 Hz, 1H), 8.37-8.42 (m, 2H), 8.18 (dd, J=8.71, 1.27 Hz, 1H), 7.63 (d, J=7.82 Hz, 1H), 7.46 (d, J=8.22 Hz, 1H), 7.29 (s, 1H), 7.20 (t, J=7.53 Hz, 1H), 7.08 (t, J=7.43 Hz, 1H), 3.81-3.83 (m, 1H), 3.60-3.63 (m, 1H), 3.46-3.54 (m, 1H), 3.20 (d, J=7.24 Hz, 2H),
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]([Cl:13])[C:5]([Cl:12])=[C:6]([C:10]#[N:11])[C:7]=1[C:8]#[N:9].[OH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>C(OCC)(=O)C>[Cl:13][C:4]1[C:5]([Cl:12])=[C:6]([C:10]#[N:11])[C:7]([C:8]#[N:9])=[C:2]([Cl:1])[C:3]=1[O:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:24][CH:25]=1
Reactant: N#Cc1c(Cl)c(Cl)c(Cl)c(Cl)c1C#N
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccc(Oc2c(Cl)c(Cl)c(C#N)c(C#N)c2Cl)cc1

Procedure:
To a 250 mL flask, 4.8 g of tetrachlorophthalonitrile, 3.98 g of methyl 4-hydroxybenzoate, 5 g of potassium carbonate (K2CO3), and 55 mL of acetonitrile are added, followed by heating for 12 hours while refluxing. After completion of the reaction, 30 mL of ethyl acetate is added and filtered to remove the solvent. To the obtained solid, a suitable amount of dichloromethane is added to dissolve the solid, followed by adding hexane for crystallization. The obtained solid is filtered and dried under vacuum to obtain a compound, methyl 4-(2,3,6-trichloro-4,5-dicyano-phenoxy)benzoate. The first step reaction may be represented by Reaction Scheme 1:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1.[CH:17]12[CH2:24][CH2:23][CH:20]([CH:21]=[CH:22]1)[CH:19]1[C:25]([O:27][C:28](=O)[CH:18]21)=[O:26]>O>[C:12]([C:11]1[CH:15]=[CH:16][C:8]([N:7]2[C:25](=[O:26])[CH:19]3[CH:18]([CH:17]4[CH2:24][CH2:23][CH:20]3[CH:21]=[CH:22]4)[C:28]2=[O:27])=[CH:9][CH:10]=1)([OH:14])=[O:13]
Reactant: O=C1OC(=O)C2C3C=CC(CC3)C12
Reactant: Nc1ccc(C(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(N2C(=O)C3C4C=CC(CC4)C3C2=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of K2CO3 (5.88 g, 42.5 mmol) in H2O (100 mL) was added 4-aminobenzoic acid (5.83 g, 42.5 mmol) and bicyclo[2.2.2]oct-5-en-2,3-dicarboxylic anhydride (7.20 g, 40.4 mmol). The reaction mixture was stirred at room temperature for 18 hrs. and then washed with ethylacetate (EtOAc) (75 ml,). The aqueous phase was acidified with conc. HCl until the pH reached 1. The precipitated crystals were filtered and dried: 11.77 g (98%), mp=269° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH2:11]O)[N:10]=[C:4]2[CH:3]=1.S(Cl)([Cl:15])=O.O.C([O-])(O)=O.[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH2:11][Cl:15])[N:10]=[C:4]2[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cn2ccc(Br)cc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: ClCc1cn2ccc(Br)cc2n1
Temperature: 25 °C
Yield: 67.9 %

Procedure:
To a solution of 110 mg (0.48 mmol) of (7-bromoimidazo[1,2-a]pyrid-2yl)methanol, prepared according to the protocol described in step 8.2, in 8 mL of anhydrous dichloromethane, stirred at room temperature under an inert atmosphere, is added 0.03 mL (0.53 mmol) of thionyl chloride. The reaction mixture is stirred at room temperature for 4 hours, hydrolysed at 0° C. by successive addition of 3 mL of cold water and 5 mL of saturated aqueous NaHCO3 solution and then extracted with three times 10 mL of dichloromethane. The combined organic phases are dried over sodium sulfate and then concentrated under reduced pressure. 80 mg of the expected product are obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].C(N(CC)CC)C.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([O:7][C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)c1ccc[nH]1
Reaction time: 72 h
Yield: 90.9 %

Procedure:
Lit. J. Org. Chem., 44:975 (1979). To a stirred solution of 5.0 g (45.0 mmol) pyrrole-2-carboxylic acid and 31.3 ml (225 mmol) triethylamine in 100 ml DMF was added dropwise 26 ml (225 mmol) benzyl bromide and stirring continued for 72 h at room temperature. The reaction mixture was then concentrated in vacuo and the residue resuspended in dichloromethane and washed twice with saturated sodium bicarbonate solution and twice with water, and the aqueous phases back-extracted with dichloromethane. The combined organic extracts were dried over sodium sulphate and concentrated in vacuo. Flash chromatography (25% EtOAc in hexane) afforded 8.23 g (90%) of the title compound as a yellow oil. MS m/e (%): 201 (M+, 33), 94 ([M−OBn]+, 22), 91 (Bn+, 100).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:10]=1[C:11]([O:13][CH3:14])=[O:12].[Cl:20][C:21]1[CH:22]=[C:23]([CH2:27][C:28](Cl)=[O:29])[CH:24]=[CH:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Br:19][C:16]1[CH:17]=[CH:18][C:9]([NH:8][C:28](=[O:29])[CH2:27][C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([Cl:20])[CH:22]=2)=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C(Cl)Cc1cccc(Cl)c1
Reactant: COC(=O)c1cc(Br)ccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Br)ccc1NC(=O)Cc1cccc(Cl)c1
Temperature: 0 °C

Procedure:
Triethylamine (18 mL, 130 mmol) was added to methyl 2-amino-5-bromobenzoate (25 g, 110 mmol) in DCM (150 mL). The mixture was cooled to 0° C. and 2-(3-chlorophenyl)acetyl chloride (24.3 g, 130 mmol) in DCM (100 mL) was added. The mixture was allowed to warm to room temperature overnight with stirring. Aqueous K2CO3 (10 wt. %) was added and the mixture was extracted with DCM. The organic phase was dried (MgSO4), filtered, and concentrated to yield the title compound.
Reaction SMILES: [C:1]1([PH:7](=[S:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([N:17]([CH2:22][CH3:23])[C:18](=[O:21])[CH2:19]Cl)[CH3:16].[OH-].[K+].O>C(Cl)Cl>[CH2:15]([N:17]([CH2:22][CH3:23])[C:18]([CH2:19][P:7](=[S:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:21])[CH3:16]
Reactant: S=[PH](c1ccccc1)c1ccccc1
Reactant: CCN(CC)C(=O)CCl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCN(CC)C(=O)CP(=S)(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
A stirred mixture of diphenylphosphine sulfide (4.365 g, 0.02 mol) and N,N-diethylchloroacetamide (4.189 g, 0.028 mol) in methylene chloride (80 ml) was cooled to 8–10° C. in an ice-water bath. Small pieces of solid potassium hydroxide (3.927 g, 0.07 mol) were added while stirring under nitrogen atmosphere. After 30 minutes, water (25 ml) was added and the organic layer was separated, washed with more water (25 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure using a rotary evaporator and the oily residue was crystallized from ethyl acetate-hexane mixture to give 3.5 g (53%) of large cubes. mp: 108–110° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=1)(=O)[CH3:2].[CH3:16][N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[NH:26][NH2:27]>CO.C(O)(=O)C>[CH3:16][N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[NH:26][N:27]=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=1)[CH3:2]
Reactant: CC(=O)c1cccc(-c2ccccc2)n1
Reactant: Cn1c(NN)nc2ccccc21
Solvent: CC(=O)O
Solvent: CO
Product: CC(=NNc1nc2ccccc2n1C)c1cccc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 2-acetyl-6-phenylpyridine (0.50 g, 2.53 mmol) and 1-methyl-2-hydrazinobenzimidazole (0.41 g, 2.53 mmol) in 10 ml of methanol is stirred at room temperature for 12 hours after the addition of 6 drops of glacial acetic acid. The reaction is monitored by means of thin layer chromatography (Polygram Sil G/UV254 prefabricated foils; eluting agent: CH2Cl2:MeOH (12:1)). Subsequently, the reaction mixture is diluted with distilled water until a precipitate forms and stored for 24 hours in a refrigerator at approximately 5° C. The precipitate is filtered, washed several times with water, and dried. The product is recrystallized from a mixture of methanol and water. Yield: 0.51 g (59% of theory).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:4][C@H:3]1[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:21][NH:22][O:23][CH3:24]>ClCCl>[CH3:24][O:23][N:22]([CH3:21])[C:5]([C@@H:3]1[CH2:4][C@H:2]1[CH3:1])=[O:7]
Reactant: C[C@@H]1C[C@H]1C(=O)O
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)[C@@H]1C[C@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1R,2R)-2-methylcyclopropanecarboxylic acid (44 g, 0.44 mol) in dichloromethane (600 mL) was added 1,1′-carbonyldiimidazole (79 g, 0.45 mol) portion-wise at 20° C. The reaction was stirred at 25° C. for 2 hours. N,O-Dimethylhydroxylamine hydrochloride (52 g, 0.53 mol) was added portion-wise and stirring was continued at 25° C. for 16 hours. The reaction mixture was washed with water (100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (Gradient: 2% to 20% ethyl acetate in petroleum ether) provided the product as a colorless oil. Yield: 52 g, 363 mmol, 82%. 1H NMR (400 MHz, CDCl3) δ 3.74 (s, 3H), 3.19 (s, 3H), 1.80-1.86 (m, 1H), 1.30-1.38 (m, 1H), 1.17 (dt, J=8.5, 4.3 Hz, 1H), 1.12 (d, J=6 Hz, 3H), 0.64 (ddd, J=8.2, 6.1, 3.8 Hz, 1H).
Reaction SMILES: [CH3:1][CH2:2][C:3]([C:6]([O:8][C@@H:9]1[C@@H:14]2[C@@H:15]([CH2:20][CH2:21][C@@H:22](O)[CH2:23][C@@H:24]([OH:29])[CH2:25][C:26]([O-:28])=[O:27])[C@@H:16]([CH3:19])[CH:17]=[CH:18][C:13]2=[CH:12][C@H:11]([CH3:31])[CH2:10]1)=O)([CH3:5])[CH3:4].[NH4+].S([O-])(O)(=O)=O.[K+].[OH2:39]>C(#N)C>[CH3:1][CH2:2][C:3]([C:6]([O:8][C@@H:9]1[C@@H:14]2[C@@H:15]([CH2:20][CH2:21][C@H:22]3[O:28][C:26](=[O:27])[CH2:25][C@H:24]([OH:29])[CH2:23]3)[C@@H:16]([CH3:19])[CH:17]=[CH:18][C:13]2=[CH:12][C@H:11]([CH3:31])[CH2:10]1)=[O:39])([CH3:4])[CH3:5]
Reactant: CCC(C)(C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)[O-])[C@H]21
Reactant: O
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [NH4+]
Solvent: CC#N
Product: CCC(C)(C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Temperature: 42.5 °C
Reaction time: 3.5 h

Procedure:
Simvastatin ammonium salt (25 g) was taken in acetonitrile (100 ml) under nitrogen atmosphere. To the reaction mixture, potassium hydrogen sulfate (18.7 g) taken in water (50 ml) was added. The reaction mixture was stirred for 3-4 hours at 40-45° C. Water (250 ml) was added to the reaction mixture under stirring. The resulting lactonized product obtained was filtered and washed with water, dried under vacuum to yield crude simvastatin. The crude simvastatin was recrystallized from methanol and water to obtain pure simvastatin.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:30])[C:3]([NH:5][C@@H:6]([CH:27]([CH3:29])[CH3:28])[C:7]([N:9]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:12]2[CH2:11][C@H:10]1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])=[O:8])=[O:4].[O:31]1CC(O)O[CH2:33][CH:32]1O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:21]1([NH:20][C:18]([C@H:10]2[N:9]([C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:33][CH2:32][OH:31])[CH3:30])[CH:27]([CH3:29])[CH3:28])[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[CH2:11]2)=[O:19])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: OC1COC(O)CO1
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)[C@H](NC(=O)[C@H](C)NCCO)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 146.2 %

Procedure:
In a 50 mL round-bottomed flask, (S)-1-((S)-2-((S)-2-aminopropanamido)-3-methylbutanoyl)-N-phenyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carb ox amide (55 mg, 134 μmol, Eq: 1.00) was combined with MeOH (3 mL) to give a colorless solution. 1,4-Dioxane-2,5-diol (8.87 mg, 73.9 μmol, Eq: 0.55) was added followed by acetic acid (8 μL, 134 μmol, Eq: 1.00) and sodium cyanoborohydride (13 mg, 210 μmol, Eq: 1.5). The reaction was stirred at rt for 4 h and then quenched by dropwise addition of 1 M aqueous HCl. The reaction mixture was basified with 0.1 M aqueous NaOH, extracted with EtOAc, washed with brine, dried over Na2SO4 and concentrated in vacuo to give (S)-1-{(S)-2-[(S)-2-(2-Hydroxy-ethylamino)-propionylamino]-3-methyl-butyryl}-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid phenylamide as a white solid (49 mg), m/z=454.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]1[NH:25][C:26]([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[O:27])=O)C1C=CC=CC=1.[H][H]>[Pd].C(O)(C)C>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@H:13]1[NH:25][C:26]([O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])=[O:27]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](NC(=O)OCC[Si](C)(C)C)C1
Agent: [Pd]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](NC(=O)OCC[Si](C)(C)C)C1
Yield: 61.8 %

Procedure:
A mixture of cis-tert-butyl 4-(benzyloxycarbonylamino)-3-((2-(trimethylsilyl)ethoxy)carbonylamino)piperidine-1-carboxylate (1.8 g, 3.6 mmol) and 10% palladium on carbon (180 mg) in isopropanol (60 mL) was stirred under 1 atm hydrogen atmosphere (hydrogen balloon) at room temperature for 3 hours. After that, the mixture was filtered through a pad of celite. The filtrate was concentrated and purified by silica gel column chromatography (methanol/dichloromethane=1/30 to 1/10) to afford the title compound (800 mg, 61%) as a yellow oil. MS (ES+) C16H33N3O4Si requires: 359, found: 360 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([S:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)(=[O:23])=[O:22])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:14]=2[N:13](COC)[C:12]([C:18]([NH2:20])=[O:19])=[CH:11]3)[CH2:3][CH2:2]1.O.O.C(O)(=O)C(O)=O.CO>O>[CH:1]1([CH2:4][N:5]([S:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)(=[O:22])=[O:23])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:14]=2[NH:13][C:12]([C:18]([NH2:20])=[O:19])=[CH:11]3)[CH2:3][CH2:2]1
Reactant: COCn1c(C(N)=O)cc2cccc(N(CC3CC3)S(=O)(=O)c3cccs3)c21
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CO
Product: NC(=O)c1cc2cccc(N(CC3CC3)S(=O)(=O)c3cccs3)c2[nH]1
Temperature: 70 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
A mixture of 7-[(cyclopropylmethyl)(2-thienylsulfonyl)amino]-1-(methoxymethyl)-1H-indole-2-carboxamide (390 mg), oxalic acid dihydrate (351 mg), methanol (15 mL) and water (15 mL) was stirred at 70° C. for 1 hr, and further at 90° C. for 14 hr. The reaction mixture was allowed to cool to room temperature. The resulting crystals were collected by filtration, washed successively with water, a diethyl ether-hexane mixture and hexane, and dried to give the title compound (286 mg, yield 81%) as crystals. melting point 229-231° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:35])[O:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1>N1C=CC=CC=1>[C:24](=[O:35])([O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:14])[NH:12][N:13]=2)[CH2:4][CH2:3]1)[O:25][C:26]1[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=c1ccc(N2CCC(O)CC2)n[nH]1
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCN(c2ccc(=O)[nH]n2)CC1
Temperature: 30 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
To a solution of 6-(4-hydroxypiperidin-1-yl)pyridazin-3(2H)-one (3.9 g, 20 mmol) in pyridine (10 mL) was added DIPEA (3.87 g, 30.0 mmol) and 4-nitrophenyl carbonochloridate (6.03 g, 30 mmol) and the resulting mixture was stirred at 30° C. for 2 h. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (DCM to DCM/MeOH=20/1) to afford the title compound (3.3 g, 46%) as a white solid. [LCMS: Rt=1.47 min, m/z 361.1 (M+H)]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[N:28]2[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]2)[CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([CH:31]4[CH2:30][CH2:29][N:28]([C:26]5[CH:25]=[CH:24][CH:23]=[C:22]6[C:27]=5[N:18]=[CH:19][CH:20]=[CH:21]6)[CH2:33][CH2:32]4)[CH2:14][CH2:13]3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: Clc1cc(N2CCNCC2)c2ncccc2c1
Reactant: O=C1CCN(c2cccc3cccnc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Clc1cc(N2CCN(C3CCN(c4cccc5cccnc45)CC3)CC2)c2ncccc2c1

Procedure:
Using the synthetic methods described in previous examples, 6-chloro-8-(piperazin-1-yl)quinoline (Example O, step 2, above) and 1-quinolin-8-yl-piperidin-4-one (Example A, Step 5, above) were reacted with sodium triacetoxyborohydride to give the desired product as a white solid; MP. 209-211° C.; MS (ES) m/z (relative intensity) 459 (M+H)+ (100).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[S:9]1[C:13]([C:14]2[N:22]3[C:17]([CH2:18][CH2:19][CH2:20][CH2:21]3)=[C:16]([C:23]([NH2:25])=[O:24])[CH:15]=2)=[CH:12][N:11]=[CH:10]1>C(#N)C.C(OCC)C>[Cl:1][C:15]1[C:16]([C:23]([NH2:25])=[O:24])=[C:17]2[N:22]([C:14]=1[C:13]1[S:9][CH:10]=[N:11][CH:12]=1)[CH2:21][CH2:20][CH2:19][CH2:18]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: NC(=O)c1cc(-c2cncs2)n2c1CCCC2
Solvent: CC#N
Solvent: CCOCC
Product: NC(=O)c1c(Cl)c(-c2cncs2)n2c1CCCC2
Temperature: 20 °C
Reaction time: 2 h

Procedure:
N-Chlorosuccinimide is added in 0.05 g portions to a solution of 0.1 g of 3-(5-thiazolyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide in 10 cm3 of acetonitrile at 65° C. After 2 hours a precipitate is seen to form. The mixture is allowed to cool to approximately 20° C., the solid is filtered off and washed with two times 0.5 cm3 of acetonitrile. The operation was repeated another two times on 0.1 g of 3-(4-thiazolyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide. The solids obtained in the three tests were combined and chromatographed on a column of 1.8 cm diameter containing 40 g of silica (0.063-0.220). Elution is carried out with a 95/5 mixture of dichloromethane and methanol, 2-cm3 fractions being collected. The homogeneous fractions are combined and concentrated at reduced pressure (2.7 kPa) at a temperature close to 40° C., to give a white solid which is taken up in ethyl ether and then filtered off and dried in air. 0.12 g of 2-chloro-3-(5-thiazolyl)-5,6,7,8-tetrahydroindolizine-1-carboxamide are thus obtained in the form of a white solid which melts at 227° C.