Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:9]([CH:18]([NH:22][CH2:23][CH2:24][CH2:25][N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH:19]([CH3:21])[CH3:20])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][C:46]=1[CH3:47])[C:41]([Cl:43])=[O:42].C(N(CC)CC)C>C(Cl)Cl>[F:37][C:38]1[CH:39]=[C:40]([CH:44]=[CH:45][C:46]=1[CH3:47])[C:41]([Cl:43])=[O:42].[CH2:1]([C:8]1[C:9]([CH:18]([N:22]([CH2:23][CH2:24][CH2:25][N:26]2[C:27](=[O:36])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]2=[O:35])[C:41](=[O:42])[C:40]2[CH:44]=[CH:45][C:46]([CH3:47])=[C:38]([F:37])[CH:39]=2)[CH:19]([CH3:20])[CH3:21])=[N:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(NCCCN1C(=O)c2ccccc2C1=O)c1nc2ccccc2cc1Cc1ccccc1
Agent: Cc1ccc(C(=O)Cl)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N(CCCN2C(=O)c3ccccc3C2=O)C(c2nc3ccccc3cc2Cc2ccccc2)C(C)C)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
To a solution of 2-(3-{[1-(3-benzylquinolin-2-yl)-2-methylpropyl]amino}propyl)-1H-isoindole-1,3(2H)-dione 17 (15 mg, 1 eq.) in CH2Cl2 (1 ml), was added 3-fluoro-4-methyl benzoyl chloride 18 (11 mg, 2 eq.). Benzoyl chloride 18 is prepared using conventional means known in the art. Triethylamine (18 μl, 4 eq.) was then added. The reaction mixture was stirred at room temperature overnight. The reaction was quenched by adding water. The organic layer was washed with saturated sodium bicarbonate, saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to yield 19 mg of N-[1-(3-benzylquinolin-2-yl)-2-methylpropyl]-3-fluoro-N-[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)propyl]-4-methylbenzamide 19.
Reaction SMILES: [C:1]1([N:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:8](=[O:29])[O:9][CH2:10][CH2:11][CH:12]2[C:21]3[C:16](=[C:17]([O:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>O1CCOCC1>[C:30]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8](=[O:29])[O:9][CH2:10][CH2:11][CH:12]2[C:21]3[C:16](=[C:17]([O:22][CH2:23][C:24]([OH:26])=[O:25])[CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)COc1cccc2c1CCCC2CCOC(=O)N(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)COc1cccc2c1CCCC2CCOC(=O)N(c1ccccc1)c1ccccc1
Yield: 58.9 %

Procedure:
A solution of 2-[5-(ethoxycarbonylmethoxy)-1,2,3,4-tetrahydro-1-naphthyl]ethyl N,N-diphenylcarbamate (0.83 g) and 1N sodium hydroxide solution (2.1 ml) in dioxane (5 ml) was stirred at room temperature for 30 minutes and washed with ether. The resulting aqueous layer was acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was powdered from 2-propanol to afford 2-[5-(carboxymethoxy)-1,2,3,4-tetrahydro-1-naphthyl]ethyl N,N-diphenylcarbamate (0.46 g) as a colorless powder. mp: 145° C.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH2:11][CH2:10][C:9]=2[CH:13]=1)([CH3:3])[CH3:2].[N-:14]=[C:15]=[O:16].[Na+]>C(O)(=O)C>[CH:1]([N:4]([C:5]1[CH:6]=[CH:7][C:8]2[O:12][CH2:11][CH2:10][C:9]=2[CH:13]=1)[C:15]([NH2:14])=[O:16])([CH3:3])[CH3:2]
Reactant: [N-]=C=O
Reactant: CC(C)Nc1ccc2c(c1)CCO2
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)N(C(N)=O)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 14.2 g. of N-isopropyl-2,3-dihydro-5-benzofuranamine in 300 ml. of glacial acetic acid, cooled to 15°±5°C. is added 4.9 g. of sodium isocyanate. The mixture is stirred at room temperature for 18 hours and then concentrated in vacuo. The residue is treated with 200 ml. of 2N sodium hydroxide solution and then extracted twice with chloroform. The combined chloroform extracts are dried with anhydrous magnesium fulfate, filtered and concentrated in vacuo to obtain an oil of 1-isopropyl-1-(2,3-dihydro-5-benzofuranyl)urea.
Reaction SMILES: [H-].[CH2:2]([CH:5]1[O:9][C:8](=[O:10])[CH2:7][CH2:6]1)[CH2:3][CH3:4]>C1(C)C=CC=CC=1>[CH2:2]([CH:5]1[O:9][CH:8]([OH:10])[CH2:7][CH2:6]1)[CH2:3][CH3:4]
Reactant: CCCC1CCC(=O)O1
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCC1CCC(O)O1
Temperature: -70 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
A 1.02M solution of diisobutylalminium hydride in toluene (23.4 ml) was added dropwise to a solution of 5-propyldihydrofuran-2-one (1.50 g) in toluene (30 ml) over 50 minutes at −70° C. under nitrogen atmosphere, and the mixture was stirred for 1 hour at −70° C. The reaction solution was quenched with methanol (3.0 ml) at −70° C., and then left to room temperature. After adding a 10% aqueous solution of citric acid, this reaction solution was stirred for 5 minutes. Then this solution was extracted with ethyl acetate, and the organic layer was washed with a brine. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated, and then the residue was purified by silica gel column chromatography (hexane:ethyl acetate=90:10→80:20) to yield 5-propyltetrahydrofuran-2-ol (440 mg) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH3:47])=[C:37]([CH3:48])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:48][C:37]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:19][CH:18]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)[CH:40]=[CH:39][C:38]=1[O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH3:47]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 3-methyl-4-(2-propoxyethoxy)phenyl borate (151 mg) and potassium carbonate (160 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (33 mg), and the mixture was refluxed for 8 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:3) to give crystals, which were recrystallized from ethanol to give colorless crystals of 7-[3-methyl-4-(2-propoxyethoxy)phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 75) (261 mg).
Reaction SMILES: C([O:4][CH2:5][C@@:6]1([CH3:28])[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15](=S)[NH:14][C:12]2=[O:13])[C@H:8]([O:20]C(=O)C)[C@@H:7]1[O:24]C(=O)C)(=O)C.[NH3:29]>>[CH3:28][C@:6]1([CH2:5][OH:4])[O:10][C@@H:9]([N:11]2[CH:19]=[C:17]([CH3:18])[C:15]([NH2:29])=[N:14][C:12]2=[O:13])[C@H:8]([OH:20])[C@@H:7]1[OH:24]
Reactant: CC(=O)OC[C@@]1(C)O[C@@H](n2cc(C)c(=S)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N
Product: Cc1cn([C@@H]2O[C@](C)(CO)[C@@H](O)[C@H]2O)c(=O)nc1N
Temperature: 25 °C
Yield: 57 %

Procedure:
Compound 16 (0.160 g, 0.386 mmol) was treated with methanolic ammonia (previously saturated at −10° C.), (10 mL) at 100° C. in a stainless-steel bomb for 3 hours, then cooled to room temperature. The solvent was evaporated under reduced pressure and the residue was partitioned between methylene chloride (30 mL) and water (30 mL). The aqueous layer was washed with methylene chloride (2×30 mL), concentrated under reduced pressure. The crude material was purified by silica gel column chromatography [eluent: 20% methanol in methylene chloride] to afford 1-(4-C-methyl-β-D-ribofuranosyl)-5-methyl-cytosine (60 mg, 57%). This compound was dissolved in EtOH 100 (1.5 mL), treated with a 2N hydrochloric acid solution (0.3 mL), and the mixture was stirred before being concentrated under reduced pressure. The procedure was repeated twice and 17 was precipitated from absolute ethanol. Mp: 194–200 (dec.); UV (H2O): λmax=275.6 nm (ε=7300), λmin=255 nm (ε=4700); HPLC 100%, 1H-NMR (DMSO-d6): δ 9.34 and 9.10 (2s, 2H, NH2), 8.21 (s, 1H, H-6), 5.80 (d, 1H, H-1′, J1′-2′=6.0 Hz), 5.3–4.3 (m, 3H, OH-2′, OH-3′ and OH-5′), 4.21 (t, 1H, H-2′, J=5.7 Hz), 3.98 (d, 1H, H-3′, J=5.3 Hz), 3.5–3.3 (m, 2H, H-5′ and H-5″), 1.97 (s, 3H, CH3), 1.12 (s, 3H, CH3).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]([CH3:11])[CH2:8][CH2:9]O)=[CH:4][CH:3]=1.O=S(Cl)[Cl:16]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]([CH3:11])[CH2:8][CH2:9][Cl:16])=[CH:4][CH:3]=1
Reactant: CN(CCO)Cc1ccc(Br)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CN(CCCl)Cc1ccc(Br)cc1
Temperature: 60 °C
Yield: 92.8 %

Procedure:
To a solution of 72 (2.9 g, 11.9 mmol) in toluene (20 ml) at RT was added SOCl2 (2.83 g, 2 eq, 23.8 mmol) and the mixture was heated to 60° C. for 3 hrs. The solvent was removed and the crude was dissolved in EtOAc then partitioned between water and satd NaHCO3 soln. The organic phase was collected, dried over Na2SO4, filtered and concentrated. The crude was purified by column chromatography (20% EtOAc in hexane) to afford 73 as a brown oil (2.9 g, 93% yield). 1H NMR (DMSO-d6) δ (ppm): 7.45 (m, 2H), 7.21 (m, 2H), 3.57 (t, J=6.85 Hz, 2H), 3.52 (s, 2H), 2.74 (t, J=6.85 Hz, 2H), 2.26 (s, 3H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH3:45])[CH:42]=[CH:43][N:44]=5)=[C:34]([CH3:46])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH3:45])[CH:42]=[CH:43][N:44]=5)=[O:56])=[C:34]([CH3:46])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4C)c(C)c2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4C)c(C)c2)CCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 50.8 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[[(1-methylimidazol-2-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (200 mg) in dichloromethane (10 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (113 mg) in dichloromethane (10 ml) at −78° C. After finishing the dropping, the mixture was stirred for 1 hour at −10° C. to −25° C. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:8), and was recrystallized from hexane-ethyl acetate to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[[(1-methylimidazol-2-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (104 mg) (Compound 356) as yellow crystals, and was recrystallized from hexane-ethyl acetate to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[[(1-methylimidazol-2-yl)methyl]sulfonyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (10 mg) (Compound 357) as yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[CH:22]=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31].C(N(CC)CC)C.[Cl:39][C:40]([Cl:45])([Cl:44])[C:41](Cl)=[O:42].C(OCC)(=O)C>ClCCl.C(Cl)(Cl)Cl>[Cl:39][C:40]([Cl:45])([Cl:44])[C:41]([C:22]1[N:14]2[C:13]([CH2:12][N:11]([C:9]([C:7]3[CH:6]=[CH:5][C:4]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[CH3:31])=[C:3]([O:2][CH3:1])[CH:8]=3)=[O:10])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15]2)=[CH:24][CH:23]=1)=[O:42]
Reactant: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1-c1ccccc1C
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.7 %

Procedure:
A solution of 10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step E (21 mmol) and triethylamine (43 mmol) in anhydrous dichloromethane (45 mL) was cooled in an ice bath. To the stirred solution was added, dropwise, trichloroacetyl chloride (65 mmol). The mixture was allowed to stir at ambient temperature for 72 hours, then was washed with 0.1 N hydrochloric acid and brine, and dried over anhydrous sodium sulfate. Evaporation yielded a foam that solidified by heating with ethyl acetate and chloroform to provide 10.2 g (85%) of the title compound as a white solid, m.p. 221-222° C. MS [(+)ESI, m/z]: 553 [M+H]+
Reaction SMILES: [CH:1]([O:4][C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH2:25][N:26]([CH:28]1[CH2:30][CH2:29]1)[CH3:27])([CH3:3])[CH3:2].O1CCC[CH2:33]1.O.O.[OH-].[Li+]>CO>[CH:1]([O:4][C:5](=[O:31])[C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]([C:21]([OH:23])=[O:22])[CH3:33])=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH2:25][N:26]([CH:28]1[CH2:29][CH2:30]1)[CH3:27])([CH3:2])[CH3:3]
Reactant: C1CCOC1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C(=O)OC(C)C)c(CN(C)C3CC3)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)OC(=O)c1ccc(C#Cc2ccc(C(C)C(=O)O)cc2)cc1CN(C)C1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2-[(cyclopropyl-methyl-amino)-methyl]-4-(4-methoxycarbonylmethyl-phenylethynyl)-benzoic acid isopropyl ester (Intermediate 125, 0.09 g, 0.21 mmol) in a mixture of methanol (2 mL), tetrahydrofuran (2 mL) and water (1 mL) was treated with lithium hydroxide monohydrate (0.042 g, 1 mmol) and the resulting reaction mixture was stirred at ambient temperature for 4 h. The volatiles were evaporated in vacuo, the residue was neutralized with saturated, aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a white solid foam (0.053 g, 61%).
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C@H:3]1[OH:17].C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C1COCC1>[CH3:26][S:27]([O:17][C@H:3]1[C@H:4]([NH:8][C@@H:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])[CH2:5][CH2:6][CH2:7][C:2]1([F:18])[F:1])(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](N[C@H]1CCCC(F)(F)[C@@H]1O)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](N[C@@H]1CCCC(F)(F)[C@H]1OS(C)(=O)=O)c1ccccc1
Temperature: 35 °C
Reaction time: 8 h
Yield: 75.6 %

Procedure:
To a solution of (23) (1.02 g, 4.01 mmol) in THF (20 mL) was added triethyl amine (0.56 mL, 4.01 mmol), followed by methanesulfonyl chloride (0.34 mL, 4.41 mmol). The reaction was allowed to stir at 35° C. overnight. After cooling to room temperature, the reaction mixture was filtered and then concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel, 20-60% ethyl acetate in hexanes) to yield (1S,6R)-2,2-difluoro-6-{[(1R)-1-phenylethyl]amino}cyclohexyl methanesulfonate (1.01 g, 3.03 mmol, 76% yield). In a microwave vial, the sulfonate intermediate (1.02 g, 3.07 mmol) was dissolved in THF (15.4 mL) and triethylamine (0.58 mL, 4.15 mmol). The vial was sealed and was heated to 100° C. and was stirred overnight. After cooling to room temperature, the reaction mixture was concentrated under pressure. The resultant residue was directly purified by column chromatography (silica gel, 0-70% ether in hexanes, linear gradient) to yield aziridine 73.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([S:7]([C:10]2([CH2:15][NH2:16])[CH2:14][CH2:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N:18]([C:21]1[C:26]([CH:27]([CH3:29])[CH3:28])=[CH:25][CH:24]=[CH:23][C:22]=1[CH:30]([CH3:32])[CH3:31])=[C:19]=[O:20]>>[CH:30]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([CH:27]([CH3:28])[CH3:29])[C:21]=1[NH:18][C:19]([NH:16][CH2:15][C:10]1([S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:17])=[CH:6][CH:5]=2)(=[O:9])=[O:8])[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:20])([CH3:31])[CH3:32]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: Cc1ccc(S(=O)(=O)C2(CN)CCCC2)cc1
Product: Cc1ccc(S(=O)(=O)C2(CNC(=O)Nc3c(C(C)C)cccc3C(C)C)CCCC2)cc1
Yield: 75.6 %

Procedure:
Similarly to Example 1(c), by reaction of 200 mg (0.8 mmol) of C-[1-(toluene-4-sulfonyl)-cyclopentyl]-methylamine with 177 mg (0.87 mmol) of 2-isocyanato-1,3-diisopropyl-benzene. 276 mg of 1-(2,6-diisopropyl-phenyl)-3-[1-(toluene-4-sulfonyl)cyclopentylmethyl]-urea is obtained in the form of an off-white powder. (Yield=77%).
Reaction SMILES: [NH2:1][C:2]1([CH2:6][C:7]([O:9]CC)=O)[CH2:5][O:4][CH2:3]1.[CH3:12][NH:13][CH3:14].O>C1(C)C=CC=CC=1>[NH2:1][C:2]1([CH2:6][C:7]([N:13]([CH3:14])[CH3:12])=[O:9])[CH2:5][O:4][CH2:3]1
Reactant: CCOC(=O)CC1(N)COC1
Reactant: CNC
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)CC1(N)COC1
Temperature: 25 °C
Reaction time: 168 h
Yield: 87 %

Procedure:
In a microwave tube was added ethyl 2-(3-aminooxetan-3-yl)acetate (CAN 1207175-54-9, 470 mg, 2.95 mmol). Toluene (7.0 ml) and 40%-dimethylamine solution in water (8.9 g, 10.0 ml, 79.0 mmol) were added. The tube was sealed and the reaction mixture was stirred vigorously at room temperature for 7 days. The reaction mixture was concentrated in vacuo and azeotroped several times with 30 mL toluene. The crude solid was dried under high vacuum at 40° C. for 3 hours to yield the title compound (405 mg, 87%). MS (ESI, m/z): 159.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])/[C:4](/[C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N:21]2[C:25]([CH3:26])=[N:24][N:23]=[N:22]2)[CH:12]=1)=[CH:5]/[CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[C:13]([N:21]2[C:25]([CH3:26])=[N:24][N:23]=[N:22]2)[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)/C(=C/C1CCCC1)c1ccc(S(C)(=O)=O)c(-n2nnnc2C)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(-n2nnnc2C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 102.9 %

Procedure:
A solution of nickel (II) chloride hexahydrate (12.2 mg, 0.05 mmol) and (E)-3-cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]-acrylic acid methyl ester (100 mg, 0.26 mmol) in methanol (5 mL) was cooled to 0° C. and then treated with sodium borohydride (29 mg, 0.77 mmol). After the addition, the black reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 15 h. The reaction mixture was concentrated in vacuo, and the residue was diluted with a 3N aqueous hydrochloric acid solution (10 mL) and ethyl acetate (25 mL). The two layers were separated. The organic layer was washed with a saturated aqueous sodium chloride solution (1×25 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford racemic 3-cyclopentyl-2-[4-methanesulfonyl-3-(5-methyl-tetrazol-1-yl)-phenyl]-propionic acid methyl ester (105 mg, 99%) as a viscous oil: EI-HRMS m/e calcd for C18H24N4O4S (M+) 392.1518, found 392.1526.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20][C:19]([NH:21][C:22](=[O:24])[CH3:23])=[N:18][C:17]=2[CH3:25])=[CH:12][CH:11]=1>CS(C)=O.O>[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[S:20][C:19]([NH:21][C:22](=[O:24])[CH3:23])=[N:18][C:17]=2[CH3:25])=[CH:14][C:15]=1[Br:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(N)cc2)s1
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)Nc1nc(C)c(-c2ccc(N)c(Br)c2)s1

Procedure:
NBS (2.52 g, 14.7 mmol) is added to a stirred solution of N-[5-(4-amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 1a) (3.5 g, 14.7 mmol) in dry dimethylsulphoxide (50 ml) at 10° C. After 10 minutes the solution is diluted with water (200 ml) and the resulting precipitate is removed by filtration. Crystallisation from ethyl acetate—methanol affords the title compound. MH+ (TOF, MS ES+): 325.9, 328.9
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]([NH:9][C:10]([C:12]1[S:13][C:14]([CH3:17])=[CH:15][CH:16]=1)=[O:11])[C:6](=O)[CH3:7].C(OC(=O)C)(=O)C.OS(O)(=O)=O>O>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[N:9]=[C:10]([C:12]2[S:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[O:11][C:6]=1[CH3:7]
Reactant: COC(=O)CC(NC(=O)c1ccc(C)s1)C(C)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: COC(=O)Cc1nc(-c2ccc(C)s2)oc1C
Temperature: 90 °C
Yield: 30.4 %

Procedure:
In a 100 mL flask, 3-[(5-methyl-thiophene-2-carbonyl)-amino]-4-oxo-pentanoic acid methyl ester (12 g, 45 mmol), and acetic anhydride (30 mL) were combined. Following addition of concentrated H2SO4 (1 mL), the solution was heated to 90° C. for 30 min and then cooled to ambient temperature. The reaction was slowly diluted with DI water (30 mL, potential exotherm). The reaction mixture was partitioned between CH2Cl2 and water. The organic phase was washed with DI water and brine (150 mL), and then dried over MgSO4 and concentrated to obtain a brown oil. The residue was purified by column chromatography (700 mL SiO2, 30% EtOAc/hexanes) to provide the desired product (3.44 g) as a pale yellow oil. Rf=0.39 (50% EtOAc/hexanes); 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=3.6 Hz, 1H), 6.73 (dd, J=3.6, 0.8 Hz, 1H), 3.71 (s, 3H), 3.55 (s, 2H), 2.51 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: N1CCOCC1.[C:7]([OH:11])(=[O:10])[CH:8]=O.[CH3:12][CH2:13][CH2:14][CH2:15][CH:16]=[O:17].Cl>CCCCCCC>[OH:17][CH:16]1[O:11][C:7](=[O:10])[CH:8]=[C:15]1[CH2:14][CH2:13][CH3:12]
Reactant: CCCCC=O
Reactant: O=CC(=O)O
Agent: Cl
Solvent: C1COCCN1
Solvent: CCCCCCC
Product: CCCC1=CC(=O)OC1O
Temperature: 0 °C

Procedure:
Heptane (394 mL) and morpholine (127.5 mL) are introduced in a reactor while stirring. The mixture is cooled to 0° C. and glyoxylic acid (195 g, 150 mL, 50 wt % in water) is added. The mixture is heated to 20° C. during 1 hour and then n-valeraldehyde (148.8 mL) is added. The reaction mixture is heated at 45° C. during 20 hours. After cooling down to 20° C., a 37% aqueous solution of hydrochloric acid (196.9 mL) is slowly added to the mixture, which is then stirred during 2 hours.