Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:18][C:19]([C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][NH:27]2)=[CH:23][CH:22]=1)=[O:20])[CH2:9][O:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[CH3:30][C:31]([CH3:33])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:18][C:19]([C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][NH:27]2)=[CH:23][CH:22]=1)=[O:20])[CH2:9][O:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:31]([CH3:33])[CH3:30])[CH2:14][CH2:13]1
Reactant: CC(C)=O
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1Cl)c1ccc2cc[nH]c2c1
Product: CC(C)N1CCC(COCC(NC(=O)c2ccc3cc[nH]c3c2)c2ccccc2Cl)CC1

Procedure:
Using alkylation method A, N-[1-(2-chlorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (195 mg, 0.47 mmol) and acetone (2.0 mL, 27 mmol) afforded, after purification (SiO2: 0 to 2.5% isopropylamine in 1:1 hexane:EtOAc), 120 mg (60%) of the title compound.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OCC)OCC)C(=O)C)=[N-].O>CO>[C:14]([C:13]1[CH:16]=[CH:17][C:10]([S:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)(=[O:9])=[O:8])=[CH:11][CH:12]=1)#[CH:18]
Reactant: O=Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Reactant: O=C([O-])[O-]
Agent: CCOP(=O)(OCC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 41.9 %

Procedure:
To a mixture of 4-(phenylsulfonyl)benzaldehyde (8 g, 32.5 mmol) and potassium carbonate (8.97 g, 65 mmol) in methanol (400 mL) was added diethyl (1-diazo-2-oxopropyl)phosphonate (8.6 g, 39 mmol). The reaction was stirred at room temperature for 3 days then poured into water (600 mL) and extracted with ethyl acetate (×3). The combined organic layers were dried and evaporated. The residue was purified by flash column chromatography on silica, eluting with 5% ethyl acetate/isohexane, to give 1-ethynyl-4-(phenylsulfonyl)benzene (3.3 g, 42%). δH (500 MHz, CDCl3): 7.94-7.88 (4H, m), 7.60-7.50 (5H, m), 3.23 (1H, s).
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([OH:14])=[N:10]2)=[CH:5][CH:4]=1.Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(O)C.CS(C)=O>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH:13]=[N:12][C:11]([O:14][CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:22])=[N:10]2)=[CH:7][CH:8]=1
Reactant: Oc1ncn(-c2ccc(Br)cc2)n1
Reactant: CCOC(=O)C(C)Br
Agent: [Na]
Solvent: CCO
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1ncn(-c2ccc(Br)cc2)n1
Temperature: 0 °C
Yield: 48 %

Procedure:
A 3.9 g portion of sodium was dissolved in 50 ml of ethanol and was added to a solution of 41 g of 1-(4-bromophenyl)-3-hydroxy-1,2,4-1H-triazole in 150 ml of dimethylsulfoxide. The mixture was heated at 60° for 45 minutes, and then 30.9 g of ethyl 2-bromopropionate was added. The mixture was heated for 2 hours more, and was then cooled and poured over ice-water. The solid was collected and dried, and was recrystallized from toluene. The mother liquor was concentrated under vacuum, and the residue was recrystallized from ethanol. That product was combined with the first portion of product and recrystallized from ethanol to obtain 27.9 g of the desired product, m.p. 64°-66°.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[NH:11][NH2:12].N1C=CC=CC=1>C(OCC)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][S:6]([N:11]([NH2:12])[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:8])=[O:7]
Reactant: O=S(=O)(Cl)CCCCCl
Reactant: CC(C)(C)OC(=O)NN
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N(N)S(=O)(=O)CCCCCl
Temperature: 25 °C
Reaction time: 72 h
Yield: 17.1 %

Procedure:
A solution of 40 g of 4-chloro-1-butanesulphonyl chloride in 400 ml of diethyl ether was added dropwise to a solution of 30.4 g of tert-butyl carbazate and 17 ml of pyridine in 400 ml of diethyl ether at room temperature. The mixture was stirred at room temperature for 72 hours and then washed with water. The separated organic phase was dried over anhydrous magnesium sulphate. The oily residue obtained after evaporation of the solvent was purified by flash column chromatography on silica gel using hexane/ethyl acetate (8:2, increasing to 6:4) for the elution. 10.25 g of tert-butyl 2-[(4-chlorobutyl)sulphonyl]carbazate were obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[C:12]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)=[O:13].[C:19](=[O:25])=[N:20]S(Cl)(=O)=O.ClS(NC=O)(=O)=O>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:19]([NH2:20])=[O:25])[C:6](=[O:11])[CH:5]2[C:12]([C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)=[O:13]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: O=C1Nc2ccc(Cl)nc2C1C(=O)c1ccco1
Agent: O=CNS(=O)(=O)Cl
Solvent: CC#N
Product: NC(=O)N1C(=O)C(C(=O)c2ccco2)c2nc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The title compound was prepared from 5-chloro-3-(2-furoyl)-4-azaoxindole (Example 23) according to the procedure of Example 2C, using 5-chloro-3-(2-furoyl)-4-azaoxindole (200 mg, 0.76 mmol), N-chlorosulfonyl isocyanate (0.10 mL, 1.1 mmol) and acetonitrile (8 mL). Hydrolysis of the N-chlorosulfonyl carboxamide was achieved by quenching the above reaction with water and allowing the mixture to stir at room temperature overnight. The product was collected by filtration and recrystallized from DMSO. Yield: 75 mg (32%).
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[OH-].[Na+].Cl.Cl[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]1>C(O)C>[CH3:23][N:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][S:1][C:2]2[NH:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:18][CH2:19]1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CN1CCN(CCCl)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCN(CCSc2nc3ccccc3[nH]2)CC1

Procedure:
Grams 2.2 2-mercapto-1H-benzimidazol and 2.4 g NaOH were dissolved in 40 ml 90% ethyl alcohol, then 3.5 g 1-(2-chloroethyl)-4-methylpiperazine hydrochloride were added thereto. The reaction mixture was refluxed for 2 hours, the solid precipitate removed by filtration, the limpid solution evaporated to dryness and the residue dissolved in chloroform and washed with water. The organic phase was made anhydrous, then evaporated to dryness and the residue chromatographed on a column eluting with chloroform, methyl alcohol, cyclohexane, ammonium hydroxide (68:15:15:0.2). The fractions which contained the product, were collected together and evaporated to dryness and the residue which was triturated with isopropyl ether, gave 0.65 g 2-[2-(4-methylpiperazin-1-yl)ethylthio] benzimidazole melting at 93°-95° C. (with a slight decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([NH:20]C(=O)OC(C)(C)C)[CH2:16][CH2:15]3)[C:6]=2[CH:28]=1.NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][N:7]2[C:6]3[CH:28]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:9][C:8]2=[O:11])[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccc(Cl)cc32)CC1
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: NC1CCN(CCN2C(=O)COc3ccc(Cl)cc32)CC1

Procedure:
tert-Butyl {1-[2-(6-chloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 57) (640 mg, 1.56 mmol) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was used without further purification for the next step (quantitative yield).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=1)[NH:6][C:7]2=[O:12].[C:26]([N:30]=[C:31]=[O:32])([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[C:26]([NH:30][C:31]([N:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:16]2[CH:15]=[CH:14][C:13]([C:5]3[NH:6][C:7](=[O:12])[C:8]4[C:3]([CH:4]=3)=[C:2]([CH3:1])[CH:11]=[CH:10][CH:9]=4)=[CH:18][CH:17]=2)[CH2:21][CH2:22]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: Cc1cccc2c(=O)[nH]c(-c3ccc(CN4CCNCC4)cc3)cc12
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Product: Cc1cccc2c(=O)[nH]c(-c3ccc(CN4CCN(C(=O)NC(C)(C)C)CC4)cc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
To a stirred solution of 5-methyl-3-(4-piperazin-1-ylmethyl-phenyl)-2H-isoquinolin-1-one (40 mg, 0.12 mmol) in CH2Cl2 (0.5 mL) was added tert-butyl isocyanate (0.014 mL, 0.12 mmol) and the reaction mixture stirred at RT for 1 h after which time the solvent was removed in vacuo and the crude residue purified by reverse phase preparative HPLC-MS to afford 4-[4-(5-methyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzyl]-piperazine-1-carboxylic acid tert-butylamide as a white solid (28 mg, 54%).
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]([NH2:11])[CH2:4]2.[I:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21](O)=[O:22])=[CH:15][CH:14]=1>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]([NH:11][C:21](=[O:22])/[CH:20]=[CH:19]/[C:16]1[CH:17]=[CH:18][C:13]([I:12])=[CH:14][CH:15]=1)[CH2:4]2
Reactant: O=C(O)/C=C/c1ccc(I)cc1
Reactant: NC1CN2CCC1CC2
Agent: Cl
Product: O=C(/C=C/c1ccc(I)cc1)NC1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from racemic 1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(4-iodophenyl)propenoic acid; MS (ES+) 357 (MH+).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[N:12][CH:13]=2)=[O:7])[CH2:2]1.CCN(C(C)C)C(C)C.[C:30](Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[CH3:32][C:31]([CH3:34])([CH3:33])[C:30]([N:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[CH:13]=[N:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[N:10][CH:9]=2)=[O:7])[CH2:2]1)=[O:35]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C(NC1CNC1)c1cnc(-c2cccc(F)c2)nc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)N1CC(NC(=O)c2cnc(-c3cccc(F)c3)nc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
To a solution of N-azetidin-3-yl-2-(3-fluorophenyl)pyrimidine-5-carboxamide (50 mg, 0.16 mmol) in DMF (1.0 mL) was added DIPEA (0.06 mL, 0.32 mmol) and pivaloyl chloride (30 mg, 0.24 mmol). The mixtures were stirred at room temperature overnight. The mixture was partitioned between ethyl acetate and brine. The organic layer was dried (MgSO4), filtered and concentrated to give a solid, which was purified by chromatography (silica, 80% EtOAc/Hex) to give the product, N-[1-(2,2-dimethylpropanoyl)azetidin-3-yl]-2-(3-fluorophenyl)pyrimidine-5-carboxamide (50 mg, 86%). HRMS (M+H)=357.1727 expected, observed=357.1799.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[C:19]([O:20][CH3:21])=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([F:22])[CH:13]=1.[H-].[Na+].Br[CH2:26][CH3:27].O>CN(C)C(=O)C>[CH2:26]([N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[C:19]([O:20][CH3:21])=[CH:18][C:15]([CH:16]=[O:17])=[C:14]([F:22])[CH:13]=1)[CH3:27]
Reactant: COc1cc(C=O)c(F)cc1OCc1nc2ccccc2[nH]1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCn1c(COc2cc(F)c(C=O)cc2OC)nc2ccccc21
Yield: 89 %

Procedure:
To a solution of 4-(1H-benzoimidazol-2-ylmethoxy)-2-fluoro-5-methoxy-benzaldehyde (215, 4.0 g, 13 mmol) in N,N-dimethylacetamide (80 mL) was added sodium hydride (60% dispersion in mineral oil, 0.65 g, 16 mmol) portion wise. After the addition was complete, the reaction was stirred for 30 minutes after which bromoethane (1.2 mL, 16 mmol) was added and then allowed to stir for several hours. The reaction mixture was then poured into water (1 L) with stirring and the precipitated solid was filtered, washed with water and dried to give the desired compound (216, 3.8 g, 87% yield).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([O:8][C:9]([C:11]1[C:12]2[N:13]=[CH:14][CH:15]=[N:16][C:17]=2[C:18]([C:21]2[C:26]([F:27])=[C:25]([O:28][CH3:29])[CH:24]=[C:23]([O:30][CH3:31])[C:22]=2F)=[CH:19][CH:20]=1)=[O:10])[CH3:7]>CC#N>[CH2:6]([O:8][C:9]([C:11]1[C:12]2[N:13]=[CH:14][CH:15]=[N:16][C:17]=2[C:18]([C:21]2[C:26]([F:27])=[C:25]([O:28][CH3:29])[CH:24]=[C:23]([O:30][CH3:31])[C:22]=2[Cl:4])=[CH:19][CH:20]=1)=[O:10])[CH3:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Solvent: CC#N
Product: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Yield: 82.7 %

Procedure:
Sulfuryl chloride (0.35 mL, 4.33 mmol, 1.1 equiv) in CH3CN (10 mL) was added dropwise to a cold (−30° C.) solution of 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 143.1) (1.4 g, 3.93 mmol) in CH3CN (40 mL). The reaction mixture was quenched by addition of a saturated solution of NaHCO3, allowed to warm to it and concentrated. The residue was diluted in EtOAc and a saturated solution of NaHCO3. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (Hex/EtOAc, 3:2) to provide 1.27 g of the title compound as a white solid. Title compound: ESI-MS: 391.1 [M+H]+; tR=4.71 min (System 1); TLC: Rf=0.12 (Hex/EtOAc, 3:2).
Reaction SMILES: [Li]C(C)(C)C.[CH3:6][C:7]([Si:10]([CH3:20])([CH3:19])[O:11][CH2:12][CH2:13][C:14]1[O:15][CH:16]=[CH:17][CH:18]=1)([CH3:9])[CH3:8].[CH2:21]1[O:23][CH2:22]1.[NH4+].[Cl-]>C1COCC1>[CH3:9][C:7]([Si:10]([CH3:19])([CH3:20])[O:11][CH2:12][CH2:13][C:14]1[O:15][C:16]([CH2:21][CH2:22][OH:23])=[CH:17][CH:18]=1)([CH3:6])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OCCc1ccco1
Reactant: C1CO1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(CCO)o1
Temperature: 0 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
t-BuLi (1.2 M in pentane, 10 mL, 16.99 mmol) was added to a stirred solution of 255B (3.49 g, 15.44 mmol) in 13 mL of THF at −78° C. dropwise. The mixture was stirred for an additional 4 h at 0° C. Ethylene oxide (1.05 mL) was added at −78° C. to the reaction solution. The mixture was warmed to rt and stirred overnight. Aqueous sat. NH4Cl was added and most of the THF was removed under reduced pressure. The mixture was extracted with ether (3×) and the combined organic layers were washed with water (1×) and brine (1×) and dried over Na2SO4. Purification by flash chromatography on silica gel eluting with 5% EtOAc/95% CH2Cl2 gave 2.8 g (10.4 mmol, 67%) of compound 255C as a yellow oil.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11](=[O:37])([S:13][CH2:14][CH2:15][C@H:16]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[O:18])[CH3:12]>C(Cl)Cl>[C:11](=[O:37])([S:13][CH2:14][CH2:15][C@H:16]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C:17](=[O:18])[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[O:25])[CH3:12]
Reactant: CC(=O)SCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCCCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(=O)SCC[C@H](NC(=O)OCc1ccccc1)C(=O)NCCCCC=O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 67 %

Procedure:
To a solution of oxalyl chloride (2 M solution in DCM, 0.093 mL, 1.1 mmol) in DCM (1.5 mL) cooled to −78° C. was added DMSO (0.150 mL, 2.12 mmol) dropwise followed by a solution of (S)—S-3-(benzyloxycarbonylamino)-4-(5-hydroxypentylamino)-4-oxobutyl ethanethioate (300 mg, 0.757 mmol) in DCM (3 mL). After the addition, the resulting solution was stirred at −78° C. for 45 min. Then, TEA (0.464 mL, 3.33 mmol) was added. The mixture was stirred at −30° C. to −35° C. for 1 hr. The reaction was quenched with addition of EtOAc and 5% of aqueous KHSO4. The separated organic layer was washed with 5% aqueous KHSO4, water, saturated aqueous NaHCO3, saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The residue was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-100% EtOAc/Hex to give (S)—S-3-(benzyloxycarbonylamino)-4-oxo-4-(5-oxopentylamino)butyl ethanethioate (200 mg, 0.507 mmol, 67.0% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 9.76 (s, 1H), 7.45-7.28 (m, 5H), 6.42 (s, 1H), 5.53 (d, J=6.6 Hz, 1H), 5.12 (s, 2H), 4.13 (d, J=6.7 Hz, 1H), 3.28 (dd, J=12.9, 6.4 Hz, 2H), 2.97 (dd, J=14.2, 7.1 Hz, 1H), 2.91-2.76 (m, 1H), 2.48 (dd, J=10.0, 3.8 Hz, 2H), 2.34 (s, 3H), 2.12 (td, J=14.0, 6.3 Hz, 1H), 1.91 (dt, J=14.3, 7.3 Hz, 1H), 1.74-1.47 (m, 4H).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[C:13]1([CH2:19][O:20][C:21]([NH:23][C:24]2([C:30]([OH:32])=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ON1C2C=CC=CC=2N=N1.[NH2:43][C@H:44]([CH2:48][OH:49])[CH:45]([CH3:47])[CH3:46]>C(Cl)Cl>[C:13]1([CH2:19][O:20][C:21]([NH:23][C:24]2([C:30]([NH:43][C@H:44]([CH2:48][OH:49])[CH:45]([CH3:47])[CH3:46])=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)=[O:22])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(NC1(C(=O)O)CCCCC1)OCc1ccccc1
Reactant: CC(C)[C@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)[C@@H](CO)NC(=O)C1(NC(=O)OCc2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
After 422 mg (2.2 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 555 mg (2 mmol) of 1-[[(phenylmethoxy)carbonyl]amino]cyclohexanecarboxylic acid, 322 mg (2.1 mmol) of 1-hydroxybenzotriazole and 206 mg (2 mmol) of L-valinol in 20 ml of methylene chloride under ice-cooling, the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution, and then saturated brine. The organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 662 mg (91%) of the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19](C3ON=CC=3)=[CH:18][CH:17]=2)[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=1.[N:30]1(C2C=C(C=CC=2)N)[CH:34]=[N:33][N:32]=[N:31]1>>[N:30]1([C:20]2[CH:21]=[C:16]([NH:15][C:13]3[C:12]([C:27]([NH2:29])=[O:28])=[CH:11][N:10]=[C:9]([NH:8][C@@H:3]4[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]4[NH2:1])[N:14]=3)[CH:17]=[CH:18][CH:19]=2)[CH:34]=[N:33][N:32]=[N:31]1
Reactant: Nc1cccc(-n2cnnn2)c1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(-c2ccno2)cc1
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(-n2cnnn2)c1

Procedure:
This compound was synthesised using the synthetic scheme described for the synthesis of compound 122, and using 3-(1H-tetrazol-1-yl)aniline in step 1. MS: 395.5 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.Cl[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])[CH2:30][CH2:29]1>C(#N)C.O>[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH:19]1[CH2:24][CH2:23][N:22]([CH2:26][CH2:27][N:28]2[CH2:29][CH2:30][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[O:40][CH3:41])[CH2:32][CH2:33]2)[CH2:21][CH2:20]1
Reactant: COc1ccccc1N1CCN(CCCl)CC1
Reactant: Fc1ccc2[nH]cc(C3CCNCC3)c2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCN2CCC(c3c[nH]c4ccc(F)cc34)CC2)CC1
Yield: 82.7 %

Procedure:
Pulverized potassium carbonate (0.35 g, 2.5 mmole) and potassium iodide (0.44 g, 2.5 mmole) was added to a mixture of 4-(5-fluoro-1H-indol-3-yl)piperidine (0.5 g, 2.3 mmole) and 1-(2-chloroethyl)-4-(2-methoxyphenyl)piperazine (0.58 g, 2.3 mmole) in 20 ml of acetonitrile. The resulting mixture was heated to reflux under nitrogen for 3 hours. After cooling, it was diluted with water (150 ml) and the product extracted into ethyl acetate (50 ml). The organic layer was washed with water (50 ml), brine (50 ml), and after drying over sodium sulfate, filtration and concentration in vacuo afforded the required product as a white solid (0.83 g, 83 %). Treatment with an excess of 1M etheral hydrochloric acid gave the acid addition salt, which was recrystallized from methanol.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH:17]([CH:18]=[CH:19][CH:20]([OH:27])[CH:21]([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:16][CH2:15][C:10]21OCC[O:11]2>Cl>[OH:27][CH:20]([CH:21]([CH3:26])[CH2:22][CH2:23][CH2:24][CH3:25])[CH:19]=[CH:18][CH:17]1[CH2:16][CH2:15][C:10](=[O:11])[CH:9]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1]
Reactant: CCCCC(C)C(O)C=CC1CCC2(OCCO2)C1CCCCCCCO
Agent: Cl
Product: CCCCC(C)C(O)C=CC1CCC(=O)C1CCCCCCCO
Temperature: 60 °C
Reaction time: 2 h
Yield: 33.9 %

Procedure:
A mixture of crude 6-(7-hydroxyheptyl)-7-(3-hydroxy-4-methyloct-1-enyl)-1,4-dioxaspiro[4,4]nonane (0.5 g.) and hydrochloric acid (50 ml; 2N) was stirred at 60° C. for 2 hours, cooled to ambient temperature and then extracted with diethyl ether. The ether extract was washed with water and dried over magnesium sulphate. Removal of the solvent under reduced pressure gave a crude product (0.4 g.) which was purified by preparative thin layer chromatography on silica gel, using a mixture of diethyl ether, ethyl acetate and hexane (2:1:1 v/v) as eluant, to give 7-[2-(3-hydroxy-4-methyloct-1-enyl)-5-oxocyclopentyl]heptanol (0.15 g.), νmax 3400 cm-1, 1725 cm-1, 970 cm-1 ; Elemental analysis: Found C, 74.8; H, 11.7%; C21H38O3 requires C, 74.5; H, 11.53%; N.M.R. (approximately 10% solution in deuterochloroform): multiplets at 5.7-5.5 δ, 3.98 δ and 1.05-0.7 δ, triplet at 3.6 δ (J = 6 cycles/sec.), based singlet at 2.05 δ.
Reaction SMILES: F[B-](F)(F)F.[N:6]1(OC(N(C)C)=[N+](C)C)[C:10]2C=CC=C[C:9]=2N=N1.[OH:23][C:24]([CH3:57])([CH3:56])[CH2:25][C@@:26]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:31][C:30](=[O:32])[N:29]([C@H:33]([C:35]2[CH:40]=[CH:39][C:38]([C:41]3[CH:42]=[CH:43][C:44]([C:47]([OH:49])=O)=[N:45][CH:46]=3)=[CH:37][CH:36]=2)[CH3:34])[CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.C(N)C>CN(C)C=O>[CH2:10]([NH:6][C:47]([C:44]1[CH:43]=[CH:42][C:41]([C:38]2[CH:37]=[CH:36][C:35]([C@@H:33]([N:29]3[CH2:28][CH2:27][C@:26]([CH2:25][C:24]([OH:23])([CH3:56])[CH3:57])([C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=4)[O:31][C:30]3=[O:32])[CH3:34])=[CH:40][CH:39]=2)=[CH:46][N:45]=1)=[O:49])[CH3:9]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: C[C@@H](c1ccc(-c2ccc(C(=O)O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: CCN
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (75 mg) was added to a solution of 5-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]ethyl}-phenyl)-pyridine-2-carboxylic acid (0.10 g) and diisopropylethylamine (50 μL) in dimethylformamide (1 mL) at room temperature. The resulting solution was stirred for 25 min, before ethylamine (70% in water, 50 μL) was added. The solution was stirred at room temperature overnight and then concentrated under reduced pressure. The crude product was purified by HPLC on reversed phase (MeCN/H2O) to afford the title compound as a foam-like solid. Yield: 25 mg (24% of theory). Mass spectrum (ESI+): m/z=502 [M+H]+