Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8]O.[NH2:10][C@H:11]([C:17]([OH:19])=[O:18])[CH2:12][CH2:13][C:14]([OH:16])=[O:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCCl>[CH2:7]([CH:13]([C:14]([OH:16])=[O:15])[CH2:12][C@@H:11]([C:17]([OH:19])=[O:18])[NH2:10])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][CH:13]([C:14]([OH:16])=[O:15])[CH2:12][C@@H:11]([C:17]([OH:19])=[O:18])[NH2:10]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: OCC1CC2CCC1C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Solvent: O
Product: N[C@@H](CC(CC1CC2CCC1C2)C(=O)O)C(=O)O
Product: N[C@@H](CC(Cc1ccccc1)C(=O)O)C(=O)O

Procedure:
By a method similar to that of Synthetic Example 4, poly-γ-benzyl-L-glutamic acid was obtained and dissolved in 1,2-dichloroethane. Thereto were added an equivalent amount of norbornane-2-methanol (manufactured by Tokyo Chemical Industry Co., Ltd.) relative to the glutamic acid unit of poly-γ-benzyl-L-glutamic acid and a catalytic amount of p-toluenesulfonic acid monohydrate, and the mixture was stirred at 65° C. for 4 days to give a γ-benzyl-L-glutamic acid/γ-2-norbornylmethyl-L-glutamic acid copolymer. The weight average molecular weight, Mw, of the obtained copolymer was measured by Measurement Method 1 described below. In addition, the composition of the polymer after transesterification reaction was measured by Measurement Method 2 described below.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][NH:7][NH2:8])([O-:3])=[O:2].C([O:15][C:16](=O)[CH:17]=[C:18]([NH2:22])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:22][C:18]1[NH:8][N:7]([CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])[C:16](=[O:15])[CH:17]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1ccccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccccc2[N+](=O)[O-])[nH]1
Reaction time: 8 h

Procedure:
47.8 g of o-nitrobenzylhydrazine were added dropwise, under nitrogen, to a solution of 45.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and a pinch of p-toluenesulphonic acid in 200 ml of ethanol. After standing overnight, the solvent was distilled off in vacuo and the residue was treated with a 2:1 mixture of ether and ethanol. The compound identified above which thereupon precipitated was filtered off and recrystallised from ethanol. Melting point: 190°, 23 g (34%).
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3S[CH:16]=[CH:17][N:18]=3)[S:13][C:6]=12.ClC1C=CN=C2C=C(C3[N:37]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])C=CN=3)SC=12>>[F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:37]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[CH:16]=[CH:17][N:18]=3)[S:13][C:6]=12
Reactant: C[Si](C)(C)CCOCn1ccnc1-c1cc2nccc(Cl)c2s1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(-c4nccs4)sc23)c(F)c1
Product: C[Si](C)(C)CCOCn1ccnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1

Procedure:
Following the procedure described above for the synthesis of compound 11 (example 12, step 3, scheme 2) but substituting compound 10 for compound 109, title compound 110 was obtained as a yellow solid (104 mg, 50% yield). MS (m/z) 487.3 (M+H).
Reaction SMILES: CS([Cl:5])(=O)=O.C(N(CC)CC)C.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:38]=[CH:37][C:22]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:36]=[CH:35][C:32]([CH2:33]O)=[CH:31][CH:30]=2)=[O:24])=[CH:21][CH:20]=1>ClCCl>[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:38]=[CH:37][C:22]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:36]=[CH:35][C:32]([CH2:33][Cl:5])=[CH:31][CH:30]=2)=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(NCCCc1ccc(CO)cc1)c1ccc(-c2ccccn2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCc1ccc(CCl)cc1)c1ccc(-c2ccccn2)cc1
Reaction time: 16 h
Yield: 87.2 %

Procedure:
Methanesulfonyl chloride (294 mg) and triethylamine (0.37 ml) were successively added to a solution of 4-[3-(4-pyridine-2-ylbenzoylamino)propyl]benzylalcohol (0.74 g) in dichloromethane (20 ml). The mixture was allowed to stand at ambient temperature for 16 hours. The reaction mixture was concentrated. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and concentrated to afford crystals. The crystals were washed with a small amount of diisopropyl ether to afford the desired compound (0.68 g).
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:15]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:14][C:13]3[C:21]([CH3:27])=[C:22]([CH3:26])[CH:23]=[C:24]([CH3:25])[C:12]2=3)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C=O.[C:30]([BH3-])#N.[Na+]>C(#N)C>[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:15]3([CH2:16][CH2:17][N:18]([CH3:30])[CH2:19][CH2:20]3)[O:14][C:13]3[C:21]([CH3:27])=[C:22]([CH3:26])[CH:23]=[C:24]([CH3:25])[C:12]2=3)=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: Cc1cc(C)c2c(c1C)OC1(CCNCC1)C2c1ccc(C(C)C)cc1
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(C)c2c(c1C)OC1(CCN(C)CC1)C2c1ccc(C(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.5 %

Procedure:
To a suspension of 3-(4-isopropylphenyl)-4,6,7-trimethylspiro[benzofuran-2(3H),4′-piperidine]hydrochloride (389.6 mg, 1.01 mmol) in acetonitrile (5 ml) was added 37% formalin (2.0 ml) and the mixture was cooled to 0° C. Sodium cyanoborohydride (101.8 mg, 1.62 mmol) was added into this mixture and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and an aqueous saturated solution of sodium hydrogen carbonate was added to the residue. The product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried on magnesium sulfate, filtered, and then concentrated under reduced pressure. The residue was subjected to column chromatography (on Chromatorex NHDM1020 (trade name, manufactured by Fuji Silysia Chemical Ltd.); hexane-ethyl acetate 10:1) to obtain 145.0 mg (40% yield) of the title compound. Melting point: 63-64° C. (Petroleum ether)
Reaction SMILES: [CH:1]1([CH2:7][O:8][N:9]2C(=O)C3=CC=CC=C3[C:10]2=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22](=[O:38])[C:23]1[CH:28]=[CH:27][C:26](C=O)=[CH:25][C:24]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH3:37]>>[CH3:20][O:21][C:22](=[O:38])[C:23]1[CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[CH3:37])[C:25](=[CH:10][NH:9][O:8][CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc(C=O)cc1-c1ccccc1C
Reactant: O=C1c2ccccc2C(=O)N1OCC1CCCCC1
Product: COC(=O)C1=CC=CC(=CNOCC2CCCCC2)C1c1ccccc1C

Procedure:
The desired product was prepared using the method described in Example 1176B starting with the compound from Example 1185A and N-[4-Formyl-2-(2-methylphenyl)benzoic acid methyl ester, prepared using the method of Example 403G and starting with the alcohol prepared in Example 1178C.
Reaction SMILES: [Na].O[C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:38])[CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1.ClCCl.C([OH:44])C>>[CH2:10]([O:9][C:7]([C:6]1[CH:12]=[CH:13][CH:3]=[CH:4][C:5]=1[O:44][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:38])[CH2:26][CH2:27][CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)=[O:8])[CH3:11]
Reactant: O=C(CCCCCCCCCCBr)CCCCOc1ccc(Cl)cc1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCO
Agent: [Na]
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1OCCCCCCCCCCC(=O)CCCCOc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
Sodium (0.69 g; 0.03 M.) was dissolved in absolute ethanol (30 ml.) with protection from atmospheric moisture. Ethyl 4-hydroxybenzoate (4.98 g; 0.03 M.) in absolute ethanol (20 ml.) was added and the mixture was stirred at room temperature for 30 minutes. A solution of 1-bromo-15-(4-chlorophenoxy)-pentadecan-11-one (8.62 g. 0.02 M.) in absolute ethanol (30 ml.) was added and the mixture was boiled under reflux with stirring for 8 hours. After cooling to room temperature dichloromethane (200 ml.) was added, the mixture was extracted with 5% sodium hydroxide solution (2×100 ml.) and water (1×100 ml.). The solution was dried (MgSO4), the solvent evaporated under reduced pressure and the crude product (8.75 g.) was purified by chromatography on silica-gel (300 g.) in dichloromethane to give 1-(ethoxycarbonylphenoxy)-15-(4-chlorophenoxy)-pentadecan-11-one (5.07 g.; 33%), M.P. 95°-96° C.
Reaction SMILES: [CH:1](NC(C)C)([CH3:3])[CH3:2].C([Li])CCC.[CH3:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([S:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])[N:16]=1.BrCC=C>O1CCCC1.CCCCCC>[CH3:22][O:21][C:19]1[CH:20]=[C:15]([O:14][CH3:13])[N:16]=[C:17]([S:23][CH:24]([CH2:3][CH:1]=[CH2:2])[C:25]([O:27][CH3:28])=[O:26])[N:18]=1
Reactant: COC(=O)CSc1nc(OC)cc(OC)n1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: C=CCBr
Solvent: CCCCCC
Product: C=CCC(Sc1nc(OC)cc(OC)n1)C(=O)OC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
1.22 g (12.2 mmol) Diisopropylamine was dissolved in 10 ml tetrahydrofuran under nitrogen and treated with 7.8 ml (12.2 mmol) 1.6M n-butyllithium in hexane at a temperature between -78° and -50° C. The mixture was stirred for 20 minutes and then a solution of 3 g (12.2 mmol) methyl 2-(4,6-dimethoxy-2-pyrimidinylthio)acetate in 30 ml tetrahydrofuran was added to the reaction mixture and the mixture then stirred for 30 minutes. 1.45 g (12.2 mmol) 3-Bromopropene was added, dropwise, to the solution. The reaction mixture was slowly allowed to reach room temperature, with stirring, and then stirred for 20 hours. The mixture was added to 100 ml ice/water and extracted with ethyl acetate. The ethyl acetate phase, after drying over magnesium sulphate, was evaporated and then purified by medium pressure chromatography using hexane/ethyl acetate as eluent.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][O:21][C:20]1=[O:24]>>[N+:1]([C:4]1[N:5]([CH2:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][O:21][C:20]2=[O:24])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: O=C1OCCN1CCCCl
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1OCCN1CCCn1ccnc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
A mixture of 6 g of 2-nitroimidazole (53 mmol) and 7.32 g of K2CO3 was heated at 60° C. for 0.5 hours. Then 8.6 g (53 mmol) of 3-(3-chloropropyl)-2-oxazolidinone (Ann. Pharm. Franc., 13, 565 (1955)) was added and stirring continued for 18 hours at 60° C. The mixture was then cooled and concentrated. The residue was partitioned between CHCl3 and water, the organic layer was dried and concentrated to give 10.4 g of a solid which was recrystallized from ethanol to provide 5.4 g (42%) of the desired product, 3-[3-(2-nitro-1H-imidazol-1-yl)propyl]-2-oxazolidinone; mp 89°-91-° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH3:30])[C:11]3[C:16]4[N:17]=[C:18]([N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[N:19]=[C:20]([O:21][CH2:22][CH3:23])[C:15]=4[S:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[CH2:31]([O:35]C1C=CC(O)=CC=1)[CH2:32][CH2:33][CH3:34].C([O-])([O-])=O.[Cs+].[Cs+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:31]([O:35][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH3:30])[C:11]3[C:16]4[N:17]=[C:18]([N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[N:19]=[C:20]([O:21][CH2:22][CH3:23])[C:15]=4[S:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1)[CH2:32][CH2:33][CH3:34]
Reactant: CCOc1nc(N2CCNCC2)nc2c1sc1nc(-c3ccc(Br)cc3)nc(C)c12
Reactant: CCCCOc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCOc1ccc(-c2nc(C)c3c(n2)sc2c(OCC)nc(N4CCNCC4)nc23)cc1
Temperature: 180 °C

Procedure:
100 mg (0.21 mmol) 7-(4-bromophenyl)-4-ethoxy-9-methyl-2-piperazin-1-yl-thieno[2,3-d:4,5-d′]dipyrimidine, 51 mg (0.31 mmol) 4-n-butoxyphenol, 134 mg (0.41 mmol) Cs2CO3, 1 μl (5 mole %) ethyl acetate and 1.5 mg (5 mole %) CuBr were suspended in 5 ml absolute toluene and heated in a microwave oven at 180° C. for 17 h. Thereafter, the solvent was removed and the residue was purified by means of flash chromatography. 4 mg (3%) of the title substance is obtained. ESI-MS [m/z]: 571
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:2]=2[F:1])=[CH:18][CH:17]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Br)cc1)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.9 %

Procedure:
A solution of 2-fluoro-4-(trifluoromethyl)benzoyl chloride (5.05 g, 0.0223 mol) and 4-bromoaniline (3.83 g, 0.0223 mol) in anhydrous dichloromethane (150 mL) was cooled to 0° C. and N,N-diisopropylethylamine (4.26 mL, 0.0245 mol) was added under nitrogen atmosphere dropwise. The resulting mixture was stirred at ambient temperature for 24 hours, concentrated and the residue was partitioned between ethyl acetate (120 mL) and water (100 mL). The organic phase was washed with brine, dried with magnesium sulfate and concentrated. The residue was suspended in cold n-heptane (50 mL) and the precipitate was collected by filtration and dried to yield N1-(4-bromophenyl)-2-fluoro-4-(trifluoromethyl)benzamide (7.1 g, 0.0196 mol) as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 10.74 (s, 1H), 7.90 (m, 2H), 7.74 (d, 1H), 7.68 (d, 2H), 7.56 (d, 2H).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][S@:7]([CH2:9][CH2:10][CH3:11])=[O:8])[CH3:2].[O:12]1[CH2:14][C@@H:13]1[CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>C(O)(C)C>[CH2:1]([N:3]([CH2:4][CH2:5][CH2:6][S@:7]([CH2:9][CH2:10][CH3:11])=[O:8])[CH2:14][C@@H:13]([OH:12])[CH2:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)[CH3:2]
Reactant: N#Cc1ccc(OC[C@H]2CO2)cc1
Reactant: CCC[S@](=O)CCCNCC
Solvent: CC(C)O
Product: CCC[S@](=O)CCCN(CC)C[C@@H](O)COc1ccc(C#N)cc1
Yield: 102.4 %

Procedure:
A mixture of 3 g of ethyl(3-(S*)-propylsulfinyl)propylamine and 3.18 g of (R)-4-(oxiranylmethoxy)-benzonitrile was refluxed for 16 h in 25 ml of isopropyl alcohol. After evaporation of the solvent, the crude product was dissolved in 2M hydrochloric acid, washed with ether, the solution brought to pH 11.5 with 2M sodium hydroxide and extracted with dichloromethane. Evaporation of the organic phase gave 6.11 g of an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([SH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[NH2:9][C:10]1[CH:14]=[CH:13][N:12]([CH3:15])[N:11]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24](I)[CH:25]=2)[N:20]=[CH:19][N:18]=1>>[Cl:1][C:2]1[C:3]([S:8][C:24]2[CH:25]=[C:26]3[C:21](=[CH:22][CH:23]=2)[N:20]=[CH:19][N:18]=[C:17]3[NH:9][C:10]2[CH:14]=[CH:13][N:12]([CH3:15])[N:11]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1ccc(N)n1
Reactant: Sc1ncccc1Cl
Reactant: Clc1ncnc2ccc(I)cc12
Product: Cn1ccc(Nc2ncnc3ccc(Sc4ncccc4Cl)cc23)n1

Procedure:
The compound of Example 74 was manufactured by the same method as in Example 1, by a similar method thereto or by a combination of such a method with a conventional method using 3-chloro-2-mercapto-pyridine, 3-amino-1-methylpyrazole and 4-chloro-6-iodoquinazoline.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].CC([O-])(C)C.[Na+].[CH3:16][O:17][C:18]([C:20]1[S:32][C:23]2[C:24]3[CH:25]=[CH:26][C:27]([Cl:31])=[CH:28][C:29]=3[S:30][C:22]=2[C:21]=1[OH:33])=[O:19].O>CN(C=O)C>[CH3:16][O:17][C:18]([C:20]1[S:32][C:23]2[C:24]3[CH:25]=[CH:26][C:27]([Cl:31])=[CH:28][C:29]=3[S:30][C:22]=2[C:21]=1[O:33][CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])=[O:19]
Reactant: COC(=O)c1sc2c(sc3cc(Cl)ccc32)c1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1sc2c(sc3cc(Cl)ccc32)c1OCC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 67.8 %

Procedure:
tert-Butyl bromoacetate (0.10 ml, 0.65 mmol, 1.3 equiv) was added to a mixture of NaOt-Bu (60 mg, 1.2 equiv) and 6-chloro-1-hydroxy-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester (150 mg, 0.5 mmol) in DMF (6 ml) and stirred at 60° C. for 2.5 hr then at RT for 3 days. Water was added and the mixture was extracted with EtOAc. After removal of solvent, purification by column chromatography gave 140 mg (68%) of 1-tert-butoxycarbonylmethoxy-6-chloro-3,8-dithia-cyclopenta[a]indene-2-carboxylic acid methyl ester as orange solids.
Reaction SMILES: [C:1]([C:8]1[CH:23]=[CH:22][C:11]([C:12]([NH:14][CH:15]([C:19](=[NH:21])[NH2:20])[C:16]([OH:18])=O)=[O:13])=[CH:10][CH:9]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N:24]1([CH2:30][C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[C:1]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:14][CH:15]([C:19](=[NH:21])[NH2:20])[C:16]([N:27]2[CH2:26][CH2:25][N:24]([CH2:30][C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])[CH2:29][CH2:28]2)=[O:18])=[O:13])=[CH:22][CH:23]=1)([O:3][C:4]([CH3:7])([CH3:5])[CH3:6])=[O:2]
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)NC(C(=N)N)C(=O)O)cc1
Reactant: O=C(CN1CCNCC1)OCc1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(C(=O)NC(C(=N)N)C(=O)N2CCN(CC(=O)OCc3ccccc3)CC2)cc1

Procedure:
4-(4-Amidinobenzamidoacetyl)piperazin-1-ylacetic acid, FAB 348, is obtained analogously from 4-(4-BOC-amidinobenzamidoacetyl)piperazin-1-ylacetic acid (FAB 448; obtainable by condensing 4-BOC-amidinobenzamidoacetic acid with benzyl piperazin-1-ylacetate to give benzyl 4-(4-BOC-amidinobenzamidoacetyl)piperazin-1-ylacetate and hydrogenolyzing the benzyl ester group).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH2:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+]>C1(C)C=CC=CC=1.O>[CH2:10]([O:17][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCc1ccccc1
Reactant: N#Cc1ccc(Cl)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(OCc2ccccc2)nc1
Temperature: 70 °C
Reaction time: 7 h
Yield: 40.3 %

Procedure:
To a stirred solution of 6-chloronicotinonitrile (1 g, 7.2 mmol) and benzyl alcohol (780 mg, 7.2 mmol) in toluene (15 mL) was added KOH (729 mg, 12.99 mmol) and 18 crown ether (2.86 g, 10.8 mmol). The resulting mixture was stirred at 70° C. for 7 hrs. The mixture was diluted with cold water and the product was extracted with EtOAc. The organic layer was washed with saturated brine solution and dried over Na2SO4. The organic layer was then concentrated under reduced pressure. The obtained residue was purified by column chromatography (using neutral alumina and 5% MeOH: CHCl3 as eluent) to afford 610 mg (40.1% yield) of 6-benzyloxy-nicotinonitrile. LCMS Purity: 77.69%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=2)[C:18](O)=[O:19])(=[O:14])=[O:13])=[CH:7][CH:6]=1)=[O:4].C(Cl)(=O)C(Cl)=O.[NH2:30][C:31]1[S:32][C:33]2[CH2:60][CH2:59][CH2:58][CH2:57][C:34]=2[C:35]=1[C:36]([NH:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][C:47]2[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][CH:48]=2)=[CH:41][CH:40]=1)=[O:37]>CN(C=O)C.ClCCl.N1C=CC=CC=1>[CH3:54][O:53][C:51]([C:50]1[CH:49]=[CH:48][C:47]([CH2:46][CH2:45][C:42]2[CH:41]=[CH:40][C:39]([NH:38][C:36]([C:35]3[C:34]4[CH2:57][CH2:58][CH2:59][CH2:60][C:33]=4[S:32][C:31]=3[NH:30][C:18]([C:17]3[CH:16]=[C:15]([S:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=4)(=[O:14])=[O:13])[CH:23]=[CH:22][CH:21]=3)=[O:19])=[O:37])=[CH:44][CH:43]=2)=[CH:56][CH:55]=1)=[O:52]
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(N)sc4c3CCCC4)cc2)cc1
Reactant: COC(=O)c1ccc(NS(=O)(=O)c2cccc(C(=O)O)c2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(S(=O)(=O)Nc5ccc(C(=O)OC)cc5)c4)sc4c3CCCC4)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.3 %

Procedure:
A mixture of 347 mg of 3-{[4-(methoxycarbonyl)phenyl]sulfamoyl}benzoic acid, 0.090 mL of oxalyl chloride, 3.0 mL of dichloromethane, and one drop of DMF was stirred at room temperature for 2 hours, and then the reaction mixture was concentrated under reduced pressure. A mixture of the obtained crude product and 3.0 mL of dichloromethane was added to a mixture of 0.071 mL of pyridine, 300 mg of methyl 4-[2-(4-{[(2-amino-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate, and 2.5 mL of dichloromethane, followed by stirring at room temperature overnight. The reaction mixture was purified by silica gel column chromatography (hexane-chloroform) to obtain 505 mg of methyl 4-({[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)phenyl]sulfonyl}amino)benzoate as a yellow foamed solid. ESI+: 752
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:25](Cl)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C.ClCCl>CO>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([OH:24])[CH2:22][O:23][C:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCC(O)COCCCCCCCCCCCCC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: OC(COCCCCCCCCCCCCC1CCCCC1)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 129.6 %

Procedure:
A mixture of 23.5 g (68.6 mmole) of 1-(12-cyclohexyldodecyloxy)-2,3-propanediol, 28.7 g (103 mmole) of trityl chloride, 13.7 g (137 mmole) of triethylamine and 200 ml of dichloromethane was stirred at room temperature for 2 days. To the reaction mixture was added 10 ml of methanol and the resulting mixture was further stirred for 3 hours. The mixture was washed with water and dried (MgSO4) and the solvent was distilled off to give 52 g (quantitative) of crude 1-(12-cyclohexyldodecyloxy)-3-trityloxy-2-propanol. In 100 ml of tetrahydrofuran (THF) was dissolved 17 g (23 mmole) of this product, and 1.84 g (46 mmole) of 60% sodium hydride was added thereto. The mixture was stirred at room temperature for 1 hour and 4 ml of methyl iodide was added to the mixture. The reaction mixture was stirred at room temperature overnight and then 5 ml of methanol was added thereto. The solvent was distilled off under reduced pressure, and the residue was dissolved in 200 ml of hexane and washed with water and 1N hydrochloric acid, in order. After hexane was distilled off, 30 ml of 1N hydrochloric acid and 60 ml of dioxane were added to the residue, and the mixture was stirred at 80° C. for 10 hours. The mixture was neutralized with sodium bicarbonate and then 60 ml of ethyl acetate was added to the mixture. The resulting mixture was washed with water and dried (MgSO4), and the solvent was distilled off. The residue was subjected to column chromatography on silica gel (200 g) and eluted with dichloromethane-ethyl acetate (5:1) to give 6.6 g (yield: 81%) of the above-mentioned compound as colorless solid.