Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[OH-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14].C([O-])([O-])=O.[Na+].[Na+]>O>[CH3:16][O:15][C:13](=[O:14])[O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[CH3:9]
Reactant: Cc1cc(F)ccc1O
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Oc1ccc(F)cc1C
Yield: 81.4 %

Procedure:
4-Fluoro-2-methyl-phenol (25 g, 0.2 mol) was added to a solution of sodium hydroxide (9.7 g, 0.24 mol) in water (160 mL) and the resultant solution was cooled to 0° C. Methyl chloroformate (24.2 g, 0.26 mol) was added dropwise at 0° C. At the completion of the reaction, the pH was adjusted to pH 8 with saturated aqueous Na2CO3 and then the mixture was extracted with ethyl acetate (3×300 mL). The combined organic extracts were washed with water and brine, dried (MgSO4) and concentrated under reduced pressure to provide carbonic acid 4-fluoro-2-methyl-phenyl ester methyl ester (30 g, 82% yield). 1H NMR (300 MHz, DMSO-d6): δ 7.22-7.13 (m, 2H), 7.05 (m, 1H), 3.81 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:7]=[CH:8][N:9]2[CH:13]=[C:12]([C:14]3[C@H:15]([CH3:28])[C@@H:16]4[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[N:17]4[C:18]=3[C:19]([O-:21])=[O:20])[S:11][C:10]=12.[Na+:29].Cl.C(O[C:34](=[NH:36])[CH3:35])C>>[C:34]([NH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:7]=[CH:8][N:9]2[CH:13]=[C:12]([C:14]3[C@H:15]([CH3:28])[C@@H:16]4[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[N:17]4[C:18]=3[C:19]([O-:21])=[O:20])[S:11][C:10]=12)(=[NH:36])[CH3:35].[Na+:29]
Reactant: CCOC(C)=N
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(SCCCN)c4s3)[C@H](C)[C@H]12
Agent: Cl
Agent: [Na+]
Product: CC(=N)NCCCSc1ncn2cc(C3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Yield: 27.7 %

Procedure:
The procedure of Example 12 was repeated, except that 29.1 mg of sodium (1S,5R,6S)-2-[7-(3-aminopropyl)thioimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate and 40 mg of ethylacetimidate hydrochloride were used as the starting compounds. Thus, 8.8 mg of the title compound was prepared.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.[CH2:15]1[O:25][C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16]1.C(=O)(O)[O-].[Na+]>C1COCC1>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:21]1([OH:24])[CH2:22][CH2:23][C:18]2([O:25][CH2:15][CH2:16][O:17]2)[CH2:19][CH2:20]1
Reactant: COc1ccccc1Br
Reactant: O=C1CCC2(CC1)OCCO2
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1C1(O)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-Bromoanisole (1.87 g, 10.0 mmol) in 10 mL THF under Argon was added n-butyllithium (4.0 mL 2.5M in hexane, 10.0 mmol) cooled to -78° C. The solution was stirred 10 min. at -78° C., and a solution of 1,4-Cyclohexanedione mono-ethylene ketal (1.56 g, 10.0 mmol) in 10 mL THF was added slowly. The solution was warmed to r.t. and stirred for 60 min., then poured onto saturated sodium bicarbonate and extracted with ethylacetate. The combined organic layers were washed with saturated sodium chloride, dried with magnesium sulfate, and concentrated in vacuo. The crude solid was crystallized with hexane/diethylether 2:1 to give 8-(2-Methoxy-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[NH2:17].[C:18](OC)(OC)(OC)[CH2:19][CH3:20].Cl.N1C=CC=CC=1>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=[C:18]1[CH2:19][CH3:20]
Reactant: CCC(OC)(OC)OC
Reactant: Nc1cnc2ccccc2c1NCCCCCl
Agent: Cl
Solvent: c1ccncc1
Product: CCc1nc2cnc3ccccc3c2n1CCCCCl
Yield: 72.7 %

Procedure:
Using the general method of Example 1 Part D, N4-(4-chlorobutyl)quinoline-3,4-diamine (30 g, 0.12 mole) was cyclized using trimethyl orthopropionate (23.3 g, 0.13 mol) in the presence of a catalytic amount of pyridine hydrochloride to provide 25.1 g of 1-(4-chlorobutyl)-2-ethyl-1H-imidazo[4,5-c]quinoline as solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2([OH:21])[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:26][CH:25]([NH:27][C:28]([CH2:30][NH:31][C:32](=[O:43])[C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=2)=[O:29])[CH2:24]1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2([OH:21])[CH2:19][CH2:18][CH:17]([N:23]3[CH2:26][CH:25]([NH:27][C:28](=[O:29])[CH2:30][NH:31][C:32](=[O:43])[C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:41])([F:42])[F:40])[CH:34]=4)[CH2:24]3)[CH2:16][CH2:15]2)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cccc(C2(O)CCC(=O)CC2)c1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: CC(C)(C)OC(=O)Nc1cccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
The title compound was prepared as a white solid by reductive amination of [3-(1-hydroxy-4-oxo-cyclohexyl)-phenyl]-carbamic acid tert-butyl ester (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][C@H:10]2[CH2:12][O:11]2)[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[NH:13]1[CH2:15][CH2:14]1>C(Cl)(Cl)Cl>[N:13]1([CH2:12][C@@H:10]([OH:11])[CH2:9][N:5]2[CH:6]=[CH:7][N:8]=[C:4]2[N+:1]([O-:3])=[O:2])[CH2:15][CH2:14]1
Reactant: C1CN1
Reactant: O=[N+]([O-])c1nccn1C[C@H]1CO1
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1nccn1C[C@H](O)CN1CC1

Procedure:
Reaction of (S)-(-)-2-nitro-1-(2-oxiranylmethyl)-1H-imidazole with 1H--aziridine as described in Example 1(e) gives the product, mp 119.5°-121° C. [α]D24 =-28.7° [c1.15, chloroform].
Reaction SMILES: [CH3:1][CH:2]([C:8](=O)[CH3:9])[C:3]([O:5]CC)=O.[C:11]([CH2:13][C:14]([NH2:16])=[O:15])#[N:12].[OH-].[K+].Cl>CO>[OH:15][C:14]1[N:16]=[C:3]([OH:5])[C:2]([CH3:1])=[C:8]([CH3:9])[C:13]=1[C:11]#[N:12]
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: N#CCC(N)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(O)nc(O)c(C#N)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
To a slurry of ethyl 2-methyl-3-oxobutanoate (10 g, 69.4 mmol, 1 equiv) and 2-cyanoacetamide (5.8 g, 69.4 mmol, 1 equiv) was slowly added a solution of KOH (4.9 g, 87 mmol, 1.25 equiv) in MeOH (35 mL). Stir for 1 h during which time solution became homogenous yellow before developing a cream colored precipitate. Heat at reflux for 3 h. Upon cooling to ambient temperature, concentrated HCl (9 mL) was added. The off white solid was filtered and washed with ether to provide the product (10.7 g, 94%) as a cream colored solid. 1H NMR (500 MHz, DMSO-d6) δ 2.22 (s, 3H), 1.90 (s, 3H); LCMS (ESI, M+1): 165.05.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][C:9]2[C:13]([CH3:14])=[N:12][O:11][N:10]=2)[C:6](=[S:15])[NH:5][C:4](=[O:16])[CH:3]=1.[N:17]([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>>[NH2:17][C:3]1[C:4](=[O:16])[NH:5][C:6](=[S:15])[N:7]([CH2:8][C:9]2[C:13]([CH3:14])=[N:12][O:11][N:10]=2)[C:2]=1[NH2:1]
Reactant: O=N[O-]
Reactant: Cc1nonc1Cn1c(N)cc(=O)[nH]c1=S
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: Cc1nonc1Cn1c(N)c(N)c(=O)[nH]c1=S
Yield: 89.6 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 12(c) by using 6-amino-1-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.44 g, 1.8 mmol, obtained from Example 16(b)), sodium nitrite (0.14 g, 2.0 mmol) and sodium dithionite (0.64 g, 3.7 mmol) which gave the title compound (0.41 g, 88% yield).
Reaction SMILES: CS[S:3][CH3:4].N(OC(C)(C)C)=O.N[C:13]1[C:17]([Cl:18])=[C:16]([C:19]2[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:29])([F:28])[F:27])=[CH:21][C:20]=2[Cl:30])[N:15]([CH3:31])[N:14]=1.O>C(Cl)Cl>[Cl:18][C:17]1[C:13]([S:3][CH3:4])=[N:14][N:15]([CH3:31])[C:16]=1[C:19]1[C:24]([Cl:25])=[CH:23][C:22]([C:26]([F:28])([F:27])[F:29])=[CH:21][C:20]=1[Cl:30]
Reactant: CSSC
Reactant: Cn1nc(N)c(Cl)c1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: CC(C)(C)ON=O
Solvent: ClCCl
Solvent: O
Product: CSc1nn(C)c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Dimethyl disulfide (0.14 ml) and 0.2 ml of tert-butyl nitrite were added dropwise to a solution of 0.2 g of 3-amino-4-chloro-5-(2,6-dichloro-4-trifluoromethylphenyl)-1-methylpyrazole (18) in 5 ml of dry methylene chloride with ice cooling. The mixture was stirred at 0° C. for 30 minutes and thereafter poured into water, followed by extraction with chloroform. The organic layer was washed with brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by column chromatography on silica gel, giving 0.2 g of the desired compound in the form of a light brown oil (quantitative yield).
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][C@@H:6]([CH2:27][O:28]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][NH:2][C:3]([O:5][C@@H:6]([CH2:27][OH:28])[CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:4]
Reactant: CCCCCCCCCCCCCCCCCCOC[C@H](COC(c1ccccc1)(c1ccccc1)c1ccccc1)OC(=O)NC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOC[C@H](CO)OC(=O)NC

Procedure:
A solution of 0.57 g of (R)-2-O-(methyl-carbamoyl)-1-O-octadecyl-3-O-tritylglycerine in 15 ml of dichloromethane is treated with 0.5 ml of trifluoroacetic acid. The solution is washed with water and with sodium bicarbonate, dried and evaporated. The residue is recrystallized from dichloromethane-n-hexane. There is obtained (S)-2-O-(methylcarbamoyl)-1-O-octadecylglycerine of melting point 68°-69° C.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH2:7]([CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C@H:24]3[CH2:29][CH2:28][C@H:27]([CH:30]=O)[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)[CH2:8][CH3:9]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:7]([CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:29][CH2:28][CH:27]([CH:30]=[CH2:1])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)[CH2:8][CH3:9]
Reactant: CC(C)(C)[O-]
Reactant: CCCC1CCC(CCc2ccc([C@H]3CC[C@H](C=O)CC3)cc2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC1CCC(c2ccc(CCC3CCC(CCC)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
THF solution (5 ml) including methyltriphenylphosphonium bromide (0.25 g, 0.7 mmol) was slowly added by potassium tert-butoxide (0.07 g, 0.7 mmol) for 3 minutes and then stirred for 1 hour at a room temperature. The resulting solution was added slowly dropwise by THF solution (2 ml) of trans-4-{4-[2-(4-propylcyclohexyl)ethyl]phenyl}cyclohexane-carbaldehyde (0.2 g, 0.58 mmol) and stirred for 24 hours with maintaining the same temperature. After the reaction termination, white precipitate was removed by filtration. The filtered solution was extracted by ether (10 ml×3 times) and the organic layer was collected and washed by distilled water (10 ml×2 times) and salt water (10 ml×2 times). The residue was purified by column chromatography (petroleum ether) to obtain a final product of 1-[2-(4-propylcyclohexyl)ethyl]-4-(4-vinylcyclohexyl)benzene (0.12 g, 65%).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][C:4]([NH2:6])=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:11]>C1COCC1>[NH2:6][C:4](=[S:11])[CH2:3][CH2:2][C:1]([O:8][CH3:9])=[O:7]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)CCC(N)=O
Solvent: C1CCOC1
Product: COC(=O)CCC(N)=S
Temperature: 25 °C
Reaction time: 6 h
Yield: 57.2 %

Procedure:
A solution of methyl succinamate (2.5 g, 0.019 mol) in THF (60 mL) was cooled to 0° C. and P2S5 (4.2 g, 0.019 mol) was added. The reaction mixture was warmed to room temperature and stirred for 6 h. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 35-40% EtOAc in petroleum ether) to afford methyl 4-amino-4-thioxobutanoate (1.6 g, yield 57%). 1H NMR (300 MHz, CDCl3) δ 7.49 (br s, 2H), 3.72 (s, 3H), 2.95-2.86 (m, 4H). MS (ESI) m/z: Calculated for C5H9NO2S: 147.04. found: 248.2 (M+H)+.
Reaction SMILES: I(O)(=O)(=O)=[O:2].[C:6]([O:10][C:11]([N:13]1[C@@H:17]([CH2:18][OH:19])[CH2:16][C@@H:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:14]1=[O:28])=[O:12])([CH3:9])([CH3:8])[CH3:7]>C(#N)C.[O-2].[O-2].[O-2].[Cr+6]>[C:6]([O:10][C:11]([N:13]1[C:14](=[O:28])[C@H:15]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:16][C@@H:17]1[C:18]([OH:2])=[O:19])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: COc1ccc([C@@H]2C[C@H](CO)N(C(=O)OC(C)(C)C)C2=O)cc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC#N
Product: COc1ccc([C@@H]2C[C@H](C(=O)O)N(C(=O)OC(C)(C)C)C2=O)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A stock solution containing 12.0 grams of periodic acid and chromium trioxide (24 mg) in wet acetonitrile (0.75 volume % water) was prepared. A portion of this solution (9.6 mL) was added to a solution of (3S, 5R)-5-hydroxymethyl-3-(4-methoxyphenyl)-2-oxopyrrolidine-1-carboxylic acid tert-butyl ester (510 mg, 1.58 mmol) in wet acetonitrile (0.75 volume % water) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours and then quenched by addition of a solution of dibasic sodium phosphate (1.2 grams) in water (20 mL). The mixture was extracted with ethyl acetate and the organic extract was washed with aqueous sodium bisulfite solution and brine. After drying over magnesium sulfate, the solvent was evaporated to provide the title compound as a white solid, 518 mg (98%).
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=4)[CH2:16][N:15]([CH2:28][CH2:29][OH:30])[C:14]3=[O:31])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl.O>[CH3:34][S:35]([O:30][CH2:29][CH2:28][N:15]1[CH2:16][CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:33][CH:32]=3)=[CH:12][CH:11]=2)[C:14]1=[O:31])(=[O:37])=[O:36]
Reactant: O=C1N(CCO)CC(c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)OCCN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a solution of 3-(4-(4-chlorophenoxy)phenyl)-1-(2-hydroxyethyl)-4-(3-(trifluoromethyl)phenyl)imidazolidin-2-one (340 mg, 0.713 mmol) in DCM (3.5 mL) at 0° C. are added MsCl (111 μL, 1.43 mmol) and TEA (199 μL, 1.43 mmol). The reaction mixture is stirred at room temperature overnight before removal of the solvent. The residue is taken in H2O (40 mL) and extracted with EtOAc (3×20 mL). The combined organic layer is washed with brine, dried over MgSO4, concentrated, and purified by silica gel chromatography (20˜70% EtOAc/hexanes) to provide the title compound (337 mg, 85% yield) as a colorless oil-like product; HPLC-MS calculated for C25H22ClF3N2O5S (M+H+) 555.1, found 555.1.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[C:13](Cl)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[OH-].[Na+].S(=O)(=O)(O)O>O.CC(C)=O>[C:13]([NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCCCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Temperature: 20 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
To 35.0 g of L-arginine were added 118.7 g of acetone and 200 g of water. Thereto were concurrently added dropwise 36.5 g of lauroyl chloride (“lauroyl chloride” manufactured by Nippon Oil and Fats Co., Ltd.) and 45 ml of 8N NaOH aqueous solution over a period of 2 hours with the pH being maintained at 11.5 to 12.0 and the reaction temperature being maintained at 15 to 25° C. After 2 hours of aging, the reaction mixture was adjusted to pH 5.0 with 6N sulfuric acid with cooling and then poured into about 300 ml of ice-water to precipitate crude crystals of mono-Nα-lauroyl-L-arginine, which were collected by filtration and then dried (yield 55 g). The crude crystals were washed by stirring in 300 ml of petroleum benzine and then filtered, and the crystals were dried under reduced pressure to obtain 51 g of mono-Nα-lauroyl-L-arginine (yield 85%).
Reaction SMILES: CCCCCC.C([Li])CCC.[F:12][C:13]1[CH:21]=[CH:20][C:16]2[S:17][CH:18]=[CH:19][C:15]=2[CH:14]=1.[Br:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]([CH:33]=[O:34])[CH:24]=1.[Cl-].[NH4+]>C1COCC1>[Br:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]([CH:33]([C:18]2[S:17][C:16]3[CH:20]=[CH:21][C:13]([F:12])=[CH:14][C:15]=3[CH:19]=2)[OH:34])[CH:24]=1
Reactant: O=Cc1cc(Br)c2ccccc2c1
Reactant: Fc1ccc2sccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OC(c1cc(Br)c2ccccc2c1)c1cc2cc(F)ccc2s1
Reaction time: 0.17 h
Yield: 68.9 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.6 M, 1.68 ml, 2.68 mmol) was added dropwise to a solution of 5-fluorobenzo[b]thiophene (410 mg, 2.68 mmol) in THF (10 ml) and the reaction solution was stirred at the same temperature for 10 minutes. To this solution, a solution of 4-bromonaphthalene-2-carbaldehyde (600 mg, 2.55 mmol) in THF (5 ml) was added dropwise at −78° C. The obtained mixture was stirred at the same temperature for two hours, and then a saturated ammonium chloride aqueous solution was added and the mixture was extracted with ether. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:10)] to obtain the title compound (680 mg, 69%).
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:22][CH2:23][C:24](Cl)=[O:25]>ClCCl>[Cl:22][CH2:23][C:24]([NH:12][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)=[O:25]
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 4-phenoxyaniline (1.85 g, 10 mmoles) and triethylamine (2.07 ml, 15 mmoles) in 25 ml dry dichloromethane, is added stepwise a solution of chloroacetyl chloride (1.18 g, 10.5 mmoles) in 10 ml dry dichloromethane. The resulting reaction mixture is stirred for 1 hour at room temperature. Afterwards said reaction mixture is washed with 2×30 ml HCl (2 N) 1×30 ml water, dried with sodium sulfate and the solvent evaporated. 2.48 g. (Yield 95%) of 2-chloro-N-(4-phenoxyphenyl)acetamide were obtained.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:9]\[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.[CH2:35]([N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:36]#[CH:37].C(NC(C)C)(C)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:24][C:14]1[CH:13]=[C:12]([O:11][CH2:10]/[CH:9]=[C:8](\[C:5]2[CH:4]=[CH:3][C:2]([C:37]#[C:36][CH2:35][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:7][CH:6]=2)/[C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=2)[CH:23]=[CH:22][C:15]=1[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: C#CCN1CCOCC1
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of the above ester (13.9 g, 23.9 mmol), N-propargylmorpholine (5.98 g, 47.7 mmol) and N,N-diisopropylamine (11.35 g, 112 mmol) in tetrahydrofuran (250 mL) was cooled down and degassed; bis(triphenylphosphine)palladium(II) dichloride (0.84 g, 1.19 mmol) and copper(I) iodide (0.365 g, 1.9 mmol) were added. The reaction mixture was stirred at ambient temperature for 18 h. The mixture was evaporated in vacuo and the residue was purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate/methanol 64:32:4) yielding the title compound as a white crystals.
Reaction SMILES: [O:1]=O.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH2:9][C:8]=2[CH:27]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].C1(C)C=CC=CC=1>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[C:11]([OH:1])([C:15]([O:17][CH3:18])=[O:16])[CH:10]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[CH2:9][C:8]=2[CH:27]=1
Reactant: O=O
Reactant: COC(=O)C1C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C1(O)C(=O)Nc2ccc(Cl)cc2CC1c1ccc(OC)cc1
Reaction time: 1 h

Procedure:
Oxygen was bubbled through a solution of 7-chloro-1,3,4,5-tetrahydro-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one (7.0 g, 19.46 mmole) in 100 ml of dry tetrahydrofuran at 0° C. while a 0.67M solution of potassium hexamethyldisilazide in toluene (87.64 ml, 58.76 mmole) was added dropwise over 15 minutes. The reaction was continued for 1 hour with the continued bubbling of oxygen at 0° C. The reaction was quenched with 75 ml of a 5% solution of potassium bisulfate, followed by the addition of solid sodium sulfite and 10 ml of methanol. The reaction was stirred for 30 minutes and extracted twice with ethyl acetate. The combined organic layers were washed with 1N hydrochloric acid, saturated sodium bicarbonate, and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was recrystallized from isopropyl alcohol to yield 4.5 g of the title compound.