Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][N:22]=[C:23]=[O:24].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:21][NH:22][C:23](=[O:24])[O:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][N:9]2[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=1
Reactant: CN=C=O
Reactant: Oc1cccc(C2CCCN2CCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1cccc(C2CCCN2CCc2ccccc2)c1
Reaction time: 4 h
Yield: 84 %

Procedure:
To a solution of 3-[1-(2-phenylethyl)-2-pyrrolidinyl]phenol (0.83 g) in dry tetrahydrofuran (40 ml) was added methyl isocyanate (0.20 ml) followed by milled potassium carbonate (0.51 g)) at ambient temperature, under nitrogen. The reaction mixture was stirred for 4 hrs, filtered through a pad of celite, and the solids were washed with ethyl acetate. The combined filtrates were concentrated, and the residue was purified by flash column chromatography (silica gel 30-75% ether/heptane). The appropriate fractions were collected and concentrated to afford 0.84 g (84%) of product. The analytical sample was prepared by flushing the compound through alumina with ether.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>C(Cl)Cl>[CH2:21]([O:28][C:29]([N:11]1[CH2:12][CH2:13][C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of (3R)-3-(tert-butyloxycarbonylamino)pyrrolidine (10.0 g) and triethylamine (5.43 g) in methylene chloride (100 mL) was added dropwise a solution of benzyloxycarbonyl chloride (7.7 mL) in methylene chloride (20 mL) over a period of 15 minutes under nitrogen gas atmosphere and ice-cooling and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water (70 mL) and the mixture was extracted with chloroform. The extract was washed successively with water (70 mL), 5% citric acid solution (70 mL) and a saturated brine (70 mL) and the organic layer was dried over anhydrous magnesium sulfate. After concentration in vacuo, the resultant product was triturated in diisopropylether to give (3R)-1-benzyloxycarbonyl-3-(tert-butoxycarbonylamino)pyrrolidine (11.8 g, yield: 70%) as crystals.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C@H:19]([NH2:23])[C:20]([OH:22])=O)[CH2:14][CH2:13]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][CH2:33][NH2:34])=[CH:27][CH:26]=1>>[Cl:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([NH:23][C@@H:19]([CH2:18][CH:15]3[CH2:14][CH2:13][CH2:12][CH2:17][CH2:16]3)[C:20]([NH:34][CH2:33][CH2:32][NH:31][C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)=[O:22])[O:3][C:4]=2[CH:10]=1
Reactant: NCCNc1ccc(F)cc1
Reactant: Clc1ccc2nc(Cl)oc2c1
Reactant: N[C@@H](CC1CCCCC1)C(=O)O
Product: O=C(NCCNc1ccc(F)cc1)[C@H](CC1CCCCC1)Nc1nc2ccc(Cl)cc2o1

Procedure:
The title compound was prepared from 2,6-dichlorobenzooxazole, L-cyclohexylalanine and N1-(4-Fluoro-phenyl)-ethane-1,2-diamine.2HCl using the procedure analogous to that described in example 2. 1H NMR (DMSO-d6, 400 MHz) δ 8.30 (d, 1H, J=8.4 Hz), 8.17 (t, 1H, J=5.2 Hz), 7.46 (d, 1H, J=2.0 Hz), 7.13 (d, 1H, J=8.4 Hz), 7.08 (dd, 1H, J=8.4 Hz, J=2.0 Hz), 6.84(m, 2H), 6.51(m, 2H), 4.19(m, 1H), 3.15(m, 2H), 2.98(m, 2H), 1.55(m, 7H), 1.30(m, 1H), 1.05(m, 3H), 0.83(m, 2H). HPLC-MS calcd. for C24H28ClFN4O2(M+H+) 459.19, found 459.4.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10](=[O:12])[CH3:11])[CH2:6][CH2:5]1.[H-].[Na+].Cl[CH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](=[O:25])[N:17]1[C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[N:29][C:30]([Cl:36])=[CH:31][CH:32]=2)[N:27]=1>O1CCCC1>[C:10]([N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][O:1][CH:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[N:17]2[C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[N:29][C:30]([Cl:36])=[CH:31][CH:32]=3)[N:27]=2)[CH2:5][CH2:6]1)(=[O:12])[CH3:11]
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: CC(=O)N1CCN(CCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N1CCN(CCOC2c3ccccc3C(=O)N2c2ccc3ccc(Cl)nc3n2)CC1
Yield: 30.5 %

Procedure:
The procedure is as in Example 22, but starting with 1-(2-hydroxyethyl)-4-acetylpiperazine (7.75 g) in anhydrous tetrahydrofuran (250 cc), an oily suspension (50% by weight; 2.3 g) of sodium hydride and 3-chloro-2(-7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (10 g). After crystallization successively in 2-propanol and then in ethanol, 3-[2-(4-acetyl-1-piperazinyl)ethoxy]-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (4.3 g), m.p. 172° C., is obtained.
Reaction SMILES: [CH:1]1[CH:6]=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:2]=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1[OH:31])[C:24]([O:26]C)=[O:25].CC(OC(/N=N/C(OC(C)C)=O)=O)C.[OH-].[Na+]>C1COCC1.CO.CC(O)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=1[O:31][CH:1]([CH3:6])[CH3:2])[C:24]([OH:26])=[O:25]
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C(=O)O)cc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 430.8 %

Procedure:
Propan-2-ol (2.45 ml) and PPh3 (1.18 g) were dissolved in THF (30 ml), cooled to 0° C., treated with methyl 3-chloro-4-hydroxybenzoate (6.00 g) followed by the dropwise addition of DIAD (9.44 ml) and stirred at RT overnight. The reaction mixture was then evaporated and purified on silica cartridges (4×100 g), eluting with a 0 to 40% mixture of EtOAc in pentane to give the crude product (7.00 g) as a colourless oil. This was dissolved in MeOH (30 ml) and 2 M aqueous NaOH (30 ml) and stirred at RT for a weekend. The reaction mixture was then evaporated and re-dissolved in H2O. This solution was washed with Et2O, acidified to pH=1 and extracted with Et2O. These latter extracts were dried over MgSO4, filtered and evaporated to give the title compound (4.16 g) as a white solid. δH (MeOD, 400 MHz): 1.37 (6H, d), 4.77 (1H, septet), 7.12 (1H, d), 7.90 (1H, d), 7.98 (1H, s). MS (ES): C10H11ClO3 requires 214; found 215 (MH+).
Reaction SMILES: [CH:1]1([C:5]2[C:13](I)=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:15])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[C:21](=O)([O:24]C)[O:22][CH3:23]>C1COCC1>[CH:1]1([C:5]2[C:13]([C:21]([O:22][CH3:23])=[O:24])=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:15])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)OC
Reactant: Cc1cc(C2CCC2)c(I)cc1C(=O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)O)c(C)cc1C1CCC1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 55.2 %

Procedure:
To a solution of 4-cyclobutyl-5-iodo-2-methylbenzoic acid (compound 230.1, 3.00 g, 9.49 mmol, 1.00 equiv) in THF (40 mL) under nitrogen at −78° C. was added dropwise n-BuLi (9.5 mL, 2.50 equiv, 2.5 M in THF). After 10 minutes, a solution of dimethyl carbonate (2.56 g, 28.4 mmol, 3.00 equiv) in THF (10 mL) was added dropwise at −78° C. The resulting solution was stirred for 1 h at −78° C., then carefully quenched by slow addition of 50 mL of water. The pH was adjusted to ˜4 with hydrogen chloride (aq., 1 M). The resulting mixture was extracted with 2×80 mL of ethyl acetate, the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:10-1:2) as eluent to furnish 1.30 g (55%) of 4-cyclobutyl-5-(methoxycarbonyl)-2-methylbenzoic acid as a white solid.
Reaction SMILES: CC(C)([O-])C.[Na+].Br[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Br.[I:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]#[N:23])=[CH:17][CH:16]=1.Cl>O1CCCC1.C1(C)C=CC=CC=1.CN1CCCC1=O.O1CCCC1.CN1CCCC1=O>[I:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([C:22]#[N:23])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:17][CH:16]=1
Reactant: N#CCc1ccc(I)cc1
Reactant: BrCCCCCBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#CC1(c2ccc(I)cc2)CCCCC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
N-Methylpyrrolidinone (NMP) (197 mL, Sigma-Aldrich) was added to a suspension of sodium tert-butoxide (124.0 g, Alfa-Aesar) in tetrahydrofuran (THF) (197 mL, Univar) under argon. The mixture was cooled to 0° C. and a solution of 1,5-dibromopentane (87.9 mL, Sigma-Aldrich) and 4-iodophenylacetonitrile (78.4 g) in a 50:50 mixture of NMP/THF (173 mL) was added dropwise keeping the internal temperature below 10° C. The mixture was warmed to room temperature and stirred overnight. 2M hydrochloric acid (930 mL) and toluene (930 mL) were added then the aqueous layer was separated and extracted with toluene (2×465 mL). The combined organics were washed with saturated sodium bicarbonate (930 mL), brine (930 mL), 2M sodium thiosulfate (930 mL), dried (magnesium sulphate) and concentrated in vacuo to a yellow/orange solid. Dichloromethane was added and the solid was filtered and washed with dichloromethane to give the product as a white solid. Yield: 22.55 g. 1H NMR (400 MHz, CDCl3): δ 7.70-7.72 (2H, m, ArH), 7.22-7.25 (2H, m, ArH), 2.10-2.13 (2H, m, —CH2—), 1.67-1.89 (7H, m, —CH—), 1.22-1.32 (1H, m, —CH—).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:14])[CH:9]=[C:8]2[C:15]1[N:23]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[CH:16]=1)=[NH:4].[C:34](OC(=O)C)(=O)[CH3:35]>C1(C)C=CC=CC=1>[CH3:14][N:10]1[C:11]2[C:7](=[CH:6][C:5]([C:3]3[N:4]=[C:34]([CH3:35])[O:1][N:2]=3)=[CH:13][CH:12]=2)[C:8]([C:15]2[N:23]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=3)(=[O:26])=[O:25])[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:17]3[CH:16]=2)=[CH:9]1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(C(=N)NO)cc34)cc3cccnc32)cc1
Reactant: CC(=O)OC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2c(-c3cn(C)c4ccc(-c5noc(C)n5)cc34)cc3cccnc32)cc1
Yield: 43.4 %

Procedure:
To a suspension of N-hydroxy-1-methyl-3-[1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1H-indole-5carboxamidine [0.7 g, Reference Example 26] in toluene (30 mL) at ambient temperature under nitrogen was added acetic anhydride (0.467 g). The reaction mixture was heated at reflux for 4.5 hours then filtered. The filtrate was evaporated to give the title compound (0.32 g) as a dark red oil which was used immediately without further purification.
Reaction SMILES: [NH3:1].[C:2]1([S:8]([C:11]2[C:12]([S:29][CH3:30])=[N:13][N:14]3[C:19](Cl)=[CH:18][C:17]([CH2:21][N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.CN(C=O)C>[C:2]1([S:8]([C:11]2[C:12]([S:29][CH3:30])=[N:13][N:14]3[C:19]([NH2:1])=[CH:18][C:17]([CH2:21][N:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CSc1nn2c(Cl)cc(CN3CCN(C)CC3)nc2c1S(=O)(=O)c1ccccc1
Solvent: CO
Solvent: CN(C)C=O
Product: CSc1nn2c(N)cc(CN3CCN(C)CC3)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
10 ml of a 50% solution of NH3 in MeOH were added to a solution of 0.8 g (1.77 mmol) of 3-benzenesulphonyl-7-chloro-5-(4-methyl-piperazin-1-ylmethyl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 20 ml of DMF and stirred at RT for 4 hrs. The reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH/NH40H 90:10:1) yielded 0.59 g (77%) of 3-benzenesulphonyl-5-(4-methyl-piperazin-1-ylmethyl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p. 203-205°.
Reaction SMILES: [C:1]1(=[O:30])[N:5]([CH2:6][CH2:7][C:8]2[C:9](=[O:24])[NH:10][C:11](=[O:23])[N:12]([C@@H:14]3[O:22][CH2:21][C@@H:19]([OH:20])[C@@H:17]([OH:18])[C@H:15]3[OH:16])[CH:13]=2)[C:4](=[O:25])[C:3]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:2]12.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Cl-].[NH4+]>N1C=CC=CC=1.ClCCl>[C:31]([O:16][C@@H:15]1[C@H:17]([OH:18])[C@H:19]([OH:20])[CH2:21][O:22][C@H:14]1[N:12]1[CH:13]=[C:8]([CH2:7][CH2:6][N:5]2[C:4](=[O:25])[C:3]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:2]3[C:1]2=[O:30])[C:9](=[O:24])[NH:10][C:11]1=[O:23])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1cn([C@@H]2OC[C@@H](O)[C@@H](O)[C@H]2O)c(=O)[nH]c1=O
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(O[C@@H]1[C@H](O)[C@H](O)CO[C@H]1n1cc(CCN2C(=O)c3ccccc3C2=O)c(=O)[nH]c1=O)c1ccccc1
Temperature: -70 °C
Reaction time: 0.58 h
Yield: 60597.3 %

Procedure:
10.6 g (0.025 mmol) of 5-(2-phtalimidoethyl)-1-(β-D-ribopyranosyl)uracil were dissolved in 20 ml of pyridine in a heated and argon-flushed 1 l four-necked flask and mixed with 200 ml of dichloromethane. The mixture was cooled to −70° C., 3.82 ml (0.033 mmol) of benzoyl chloride in 5 ml of pyridine and 20 ml of dichloromethane were slowly added dropwise with cooling and the mixture was stirred at −70° C. for 35 min. The reaction mixture was poured onto 600 ml of cooled ammonium chloride solution and the aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water, dried and concentrated to dryness in vacuo. Chromatography on silica gel (ethyl acetate/heptane 1:1) yielded 7.9 g (60%) of 1-(2′-O-benzoyl-β-D-ribopyranosyl)-5-(2-phtalimidoethyl)uracil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][S:15][C:16]2[N:17]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[C:18]([C:21]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([O:31][CH3:32])[CH:25]=3)([CH3:23])[CH3:22])=[CH:19][N:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]([C:18]2[N:17]([C:33]3[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=3)[C:16]([S:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[N:20][CH:19]=2)([CH3:23])[CH3:22])=[CH:25][C:26]=1[O:31][CH3:32]
Reactant: COc1cc(C(C)(C)c2cnc(SCC3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccc(F)cc2)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(C)(C)c2cnc(SCC3CCNCC3)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
To a 0° C. solution of tert-butyl-4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)piperidine-1-carboxylate (0.755 g, 1.31 mmol) in DCM (4 mL) was added TFA (1 mL). After stirring at room temperature 2 h, when the reaction was determined to be complete by LCMS, the reaction was concentrated in vacuo. The residue was diluted with DCM, washed with satd NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo to afford 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)piperidine (0.491 g) as a white solid. MS (ES): 474 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:5]2[N:6]([N:27]=[N:28][N:29]=2)[C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.[H][H]>[Pt].C(O)C>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][NH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]3[N:27]=[N:28][N:29]=[C:5]3[C:4]=2[NH2:1])[CH:22]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1c(NCCOCCCc2cccnc2)c2ccccc2n2nnnc12
Agent: [Pt]
Solvent: CCO
Product: Nc1c(NCCOCCCc2cccnc2)c2ccccc2n2nnnc12
Yield: 97.2 %

Procedure:
4-Nitro-N-[2-(3-pyridin-3-ylpropoxy)ethyl]tetrazolo[1,5-a]quinolin-5-amine (34.3 g, 87.2 mmol) was added to a 3 liter stainless steel pressure flask containing ethanol (1.25 L, absolute). Platinum on carbon (3.00 g, 5% w/w) was added and the flask was placed on a Parr hydrogenation apparatus. The reaction was shaken under 45 psi (3.15 Kg/cm2) of hydrogen for 24 hours. The catalyst was removed by filtration through Celite™ and the Celite pad was washed with several portions of ethanol. The filtrate was concentrated in vacuo to provide 30.8 g of N5-[2-(3-pyridin-3-ylpropoxy)ethyl]tetrazolo[1,5-a]quinoline-4,5-diamine as an orange/red oil. MS (CI) m/e 364 (MH+), 336.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([Cl:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1>C(Cl)Cl>[ClH:37].[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][S:34]([C:31]3[CH:32]=[CH:33][C:28]([CH3:27])=[CH:29][CH:30]=3)(=[O:36])=[O:35])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2ccc(N)c3ccccc23)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2ccc(N3CCN(C(C)C)CC3)c3ccccc23)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(4-isopropyl-1-piperazinyl)-1-naphthylamine (0.209 g, 0.776 mmol) (prepared according to Methods A and B) and pyridine (438 μL, 5.43 mmol) in CH2Cl2 (3.0 mL) was added 4-methylbenzenesulfonyl chloride (0.163 g, 0.850 mmol) in CH2Cl2 (1.0 mL). The solution was stirred at room temperature for 16 hours and the solid was collected by filtration as the HCl-salt to yield 0.236 g (66%); 1H NMR (DMSO-d6) δ 10.65 (br s, 1H), 9.95 (br s, 1H), 8.10–8.05 (m, 1H), 8.02–7.94 (m, 1H), 7.56–7.49 (m, 2H), 7.48–7.37 (m, 2H), 7.28–7.22 (m, 2H), 7.02–6.94 (m, 2H), 3.53–3.40 (m, 3H), 3.37–3.15 (m, 8H), 2.28 (s, 3H), 1.32–1.28 (m, 6H); MS (posES-FIA) m/z=423.1972 (M+H)(calc 423.1980).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([OH:11])[CH2:8][C@H:7]1[C:12](=[O:17])[NH:13][CH2:14][C:15]#[N:16])=[O:5])[CH3:2].[S:18]([O-])(=[O:21])(=[O:20])[CH3:19]>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([O:11][S:18]([CH3:19])(=[O:21])=[O:20])[CH2:8][C@H:7]1[C:12](=[O:17])[NH:13][CH2:14][C:15]#[N:16])=[O:5])[CH3:2]
Reactant: CS(=O)(=O)[O-]
Reactant: CCOC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)NCC#N
Product: CCOC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)C[C@H]1C(=O)NCC#N

Procedure:
(1R,2R,4S)-2-(Cyanomethyl-carbamoyl)-4-hydroxy-cyclopentanecarboxylic acid ethyl ester (second fraction from step 2) was converted to the corresponding mesylate according to the procedure from example 1, step 4 to give (1R,2R,4S)-2-(cyanomethyl-carbamoyl)-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester as a colorless solid. MS: 319.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2](C)([O-:4])[CH3:3].[K+].C1OCCOCCOCCOCCOCCOC1.[CH3:25][C:26]1[C:30]2[C:31](=[O:37])[NH:32][CH2:33]CC(=O)[C:29]=2[NH:28][CH:27]=1.CI>C1COCC1.CN(C=O)C>[CH3:29][N:28]1[C:3]2[C:2](=[O:4])[CH2:1][CH2:33][NH:32][C:31](=[O:37])[C:30]=2[C:26]([CH3:25])=[CH:27]1
Reactant: Cc1c[nH]c2c1C(=O)NCCC2=O
Reactant: CC(C)(C)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cn(C)c2c1C(=O)NCCC2=O
Temperature: 25 °C

Procedure:
To a suspension of potassium t-butoxide (1.62 g, 14.4 mmole) and 18-crown-6 (317 mg, 1.2 mmole) in THF (20 ml), a suspension of 3-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepine-4,8-dione (2.12 g, 12 mmole) in THF (20 ml) and a solution of methyl iodide (2.55 g, 18 mmole) in THF (5 ml) were successively added dropwise, and the reaction mixture was stirred at room temperature. Twenty-four hours later, a solution of-potassium t-butoxide (0.81 g, 7.2 mmole) and methyl iodide (1.28 g, 9.0 mmole) in DMF (5 ml) was added, and 24 hours later, a solution of potassium t-butoxide (0.81 g, 7.2 mmole) and methyl iodide (1.28 g, 9 mmole) in DMF (5 ml) was added further. The reaction mixture was then stirred at room temperature for 3 hours.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[Cl:16])=[O:5])#[N:2].[I:17][C:18]1[CH:19]=[C:20]([NH2:29])[CH:21]=[CH:22][C:23]=1[O:24][CH2:25][CH2:26][O:27][CH3:28].[CH2:30](OC(OCC)OCC)C>C(O)(C)C>[C:1]([C:3](=[CH:30][NH:29][C:20]1[CH:21]=[CH:22][C:23]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[C:18]([I:17])[CH:19]=1)[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[Cl:16])=[O:5])#[N:2]
Reactant: CCOC(OCC)OCC
Reactant: COc1cc(NC(=O)CC#N)c(Cl)cc1Cl
Reactant: COCCOc1ccc(N)cc1I
Solvent: CC(C)O
Product: COCCOc1ccc(NC=C(C#N)C(=O)Nc2cc(OC)c(Cl)cc2Cl)cc1I
Temperature: 25 °C
Yield: 78.9 %

Procedure:
A suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide (3.2 g, 12.4 mmol) and [3-iodo-4-(2-methoxyethoxy)phenyl]amine (4.0 g, 13.7 mmol) in 350 mL of iso-propanol was heated to reflux and triethylorthoformate (5.6 mL, 33.7 mmol) was added dropwise. The reaction mixture was heated at reflux for 3 hours. Additional triethylorthoformate (2.0 mL, 12.0 mmol) was added dropwise and the reaction mixture was heated at reflux overnight. The mixture was allowed to cool to room temperature and the solid was collected by filtration, washed with iso-propanol, diethyl ether, and ethyl acetate and then dried in vacuo to give 5.5 g of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-{[3-iodo-4-(2-methoxyethoxy)phenyl]amino}acrylamide as a yellow solid, mp 209-210° C.; MS (ES) 560.0, 562.1 (M−H)−
Reaction SMILES: Br[CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:25][C@H:26]1[CH2:32][CH2:31][C@H:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:29][N:28]([CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:27]1=[O:47].[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C.CN(C)C=O>[C:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][CH:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH:2]([NH:25][C@H:26]2[CH2:32][CH2:31][C@H:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:29][N:28]([CH2:39][C:40]([O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:41])[C:27]2=[O:47])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:13][CH2:14]1)=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)CN1C[C@@H](c2ccccc2)CC[C@H](N)C1=O
Reactant: CCOC(=O)C(Br)CCCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(CCCCC1CCN(C(=O)OC(C)(C)C)CC1)N[C@H]1CC[C@H](c2ccccc2)CN(CC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1.08 g of ethyl 2-bromo-6-(1-t-butoxycarbonyl4-piperidyl)hexanoate, 0.85 g of t-butyl rel-α-[3(S)amino-2-oxo-6(R)-phenylperhydroazepin-1-yl]acetate, 0.4 g of sodium iodide and 1.4 g of sodium carbonate were added to 15 ml of dimethylformamide, and the mixture was stirred at room temperature for 3 days. Ethyl acetate and water were then added to the reaction mixture, and, after stirring, the ethyl acetate layer was separated, washed with an aquous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was then removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using a 2:1 by volume mixture of cyclohexane and ethyl acetate as the eluent.