Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1C=CC([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=2)=CC=1)(=O)CCCCCCCC.[CH2:27]([C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([OH:49])=[O:48])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH2:27]([C:35]1[CH:40]=[CH:39][C:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47]([O:49][C:18]3[CH:19]=[CH:20][C:21]([C:24]([O:26][CH:35]([CH3:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:25])=[CH:22][CH:23]=3)=[O:48])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: CCCCCCCCc1ccc(-c2ccc(C(=O)O)cc2)cc1
Product: CCCCCCCCc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)OC(C)CCCCCC)cc3)cc2)cc1

Procedure:
The titled optically active compound was synthesized in the same manner as in Example 1, except for replacing 4'-nonanoyloxybiphenyl-4-carboxylic acid as used in Example 1-(3) with 4'-octylbiphenyl-4-carboxylic acid.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:5])[CH3:4].Cl[C:7]1[CH:12]=[CH:11][N+:10]([O-:13])=[C:9]([CH3:14])[C:8]=1[CH3:15]>CS(C)=O.O>[CH2:3]([O:5][C:7]1[CH:12]=[CH:11][N+:10]([O-:13])=[C:9]([CH3:14])[C:8]=1[CH3:15])[CH3:4]
Reactant: CCO
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOc1cc[n+]([O-])c(C)c1C
Temperature: 30 °C
Reaction time: 8 h
Yield: 127 %

Procedure:
To a solution prepared by diluting 8.6 g (2.0 eq.) of 60% sodium hydride with 200 mL of dimethylsulfoxide, 9.9 g (2.0 eq.) of anhydrous ethanol was added, and the mixture was allowed to react for one hour at 60° C. The reaction liquid was cooled to 30° C., and then a liquid containing 17.0 g of 4-chlor-2,3-dimethylpyridine-1-oxide dissolved in dimethylsulfoxide (70 mL) was added dropwise. The mixture was allowed to react for 2 hours at 40 to 50° C., and then was left to stand overnight at room temperature. 16 mL of water was added to the reaction liquid, and the mixture was concentrated, to obtain a residue in the form of a black paste. Subsequently, the residue was dissolved in 500 mL of water, and then the aqueous solution was extracted three times with 670 mL of chloroform. The extract was dried over anhydrous magnesium sulfate, and then was concentrated to dryness under reduced pressure. The obtained residue was purified on a silica gel column, to obtain 22.9 g of 4-ethoxy-2,3-dimethylpyridine-1-oxide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:62])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][C:14](=[CH2:16])[CH2:13][CH:12]1[C:17]1[NH:18][C:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:32]4[CH:37]=[CH:36][C:35]([C:38]5[NH:39][C:40]([CH:43]6[CH2:47][CH2:46][CH2:45][N:44]6[C:48](=[O:61])[CH:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]6[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=6)=[N:41][CH:42]=5)=[CH:34][CH:33]=4)[CH:28]=3)[CH:23]=2)=[CH:20][N:21]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:63][O:64]C(NC(C1C=CC=CC=1OC)C(O)=O)=O>>[CH3:1][O:2][C:3](=[O:62])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][C:14](=[CH2:16])[CH2:13][CH:12]1[C:17]1[NH:18][C:19]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:32]4[CH:33]=[CH:34][C:35]([C:38]5[NH:39][C:40]([CH:43]6[CH2:47][CH2:46][CH2:45][N:44]6[C:48](=[O:61])[CH:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]6[CH:51]=[CH:52][CH:53]=[CH:54][C:55]=6[O:64][CH3:63])=[N:41][CH:42]=5)=[CH:36][CH:37]=4)[CH:28]=3)[CH:23]=2)=[CH:20][N:21]=1)=[O:10])[CH:6]([CH3:7])[CH3:8]
Reactant: C=C1CC(c2ncc(-c3ccc4cc(-c5ccc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)c7ccccc7)[nH]6)cc5)ccc4c3)[nH]2)N(C(=O)C(NC(=O)OC)C(C)C)C1
Reactant: COC(=O)NC(C(=O)O)c1ccccc1OC
Product: C=C1CC(c2ncc(-c3ccc4cc(-c5ccc(-c6cnc(C7CCCN7C(=O)C(NC(=O)OC)c7ccccc7OC)[nH]6)cc5)ccc4c3)[nH]2)N(C(=O)C(NC(=O)OC)C(C)C)C1
Yield: 23 %

Procedure:
This compound was synthesized using the same method used to synthesize [1-(2-{5-[6-(4-{2-[1-(2-Methoxycarbonylamino-2-phenyl-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-4-methylene-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester using Methoxycarbonylamino-(2-methoxy-phenyl)-acetic acid (0.020 g, 0.082 mmol) giving {1-[2-(5-{6-[4-(2-{1-[2-Methoxycarbonylamino-2-(2-methoxy-phenyl)-acetyl]-pyrrolidin-2-yl}-3H-imidazol-4-yl)-phenyl]-naphthalen-2-yl}-1H-imidazol-2-yl)-4-methylene-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (0.011 g, 23% yield) as a white solid. LCMS-ESI+: calc'd for C49H52N8O7: 864.40 (Me); Found: 865.35 (M+H+).
Reaction SMILES: [N:1]([C:4]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)([CH3:21])[CH2:5][N:6]1[C:14]2[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[C:8]2[CH2:16][N:17]([CH3:20])[CH2:18][CH2:19][C:7]1=2)=[N+]=[N-].[Cl-].[NH4+]>CCO.O.[Zn]>[CH3:20][N:17]1[CH2:18][CH2:19][C:7]2[N:6]([CH2:5][C:4]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)([NH2:1])[CH3:21])[C:14]3[CH:13]=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=3[C:8]=2[CH2:16]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(N=[N+]=[N-])c2cccnc2)CCN(C)C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(C)(N)c2cccnc2)CCN(C)C1
Temperature: 80 °C
Yield: 0.4 %

Procedure:
5-(2-Azido-2-(pyridin-3-yl)propyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (Crude) (500 mg, 1.4 mmol) was dissolved in EtOH (4 mL) and water (1 mL). Ammonium chloride (243 mg, 4.5 mmol) followed by zinc dust (293 mg, 4.5 mmol) were added to the reaction mixture and heated at 80° C. for 1 h. The reaction mixture was concentrated to dryness, basified with aqueous ammonia solution and extracted with EtOAc (150 mL). The organic layer was dried over sodium sulfate, evaporated in vacuo and purified by reverse phase HPLC to afford 2 mg of 1-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)-yl)-2-(pyridin-3-yl)propan-2-amine. 1H NMR (CD3OD, freebase): δ (ppm): 8.39 s (1H), 8.3 d (1H), 7.72 d (1H), 7.32 t (1H), 7.11 (1H), 6.91 d (1H), 6.8 d (1H), 4.18 dd (2H), 3.61 dd (2H), 2.7 m (2H), 2.46 s (3H), 2.35 s (3H), 2.26 m (2H). Chiral HPLC provided enantiomers 149a and 149b.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[CH2:1]([O:8][C@H:9]([C@H:15]([C@H:14]([C@@H:13]([CH2:32][O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[OH:12])[O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:10][OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Temperature: 0 °C
Yield: 90.3 %

Procedure:
2,3,4,6-Tetra-O-benzyl-D-galactopyranose (107 g) was dissolved in ethanol (0.6 L) and, whilst stirring at 0° C., sodium borohydride (31 g) was added. After stirring overnight TLC analysis indicated completion of the reaction. The ethanol solution was partitioned between water (3 L) and ether (1.5 L). The organic phase was dried (Na2SO4), filtered and concentrated. The resulting oil was purified by flash chromatography (gradient elution using 20→50% ethyl acetate/petroleum ether) and then crystallised from a mixture of ethyl acetate/petroleum ether to give 2,3,4,6-tetra-O-benzyl-D-galactitol (97 g, 91%) as a white solid. 1H NMR (CDCl3): δ 2.4 (1H, bs), 3.35 (1H, bs), 3.55 (2H, m), 3.8 (3H, m), 3.9 (2H, m), 4.1 (1H, m), 4.4-4.8 (8H, m, OCH2Ph), 7.2-7.4 (20H, m, ArH). Mass spectrum: m/z 543 (M+H)+ 565 (M+Na)+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[I:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C(Cl)Cl>[I:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:28])=[CH:25][CH:24]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(I)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.1 %

Procedure:
To a stirred solution of 1.8 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 3 ml of triethylamine in 100 ml of methylene chloride at 0° C. is added a solution of 2.8 g of 4-iodobenzoyl chloride in 25 ml of methylene chloride. The reaction mixture is stirred at room temperature for 4 hours and evaporated in vacuo to a residue which is partitioned between water and chloroform. The organic layer is dried over Na2SO4, filtered and evaporated in vacuo to a brown residue which is crystallized from ether-hexane to give 3.0 g of the desired product. Mass spectrum: M+H:323.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[CH3:11][N:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH:14]([CH2:22][NH2:23])[CH2:13]1.C([O-])(O)=O.[Na+]>CCO>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:23][CH2:22][CH:14]2[CH2:13][N:12]([CH3:11])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[O:15]2)[CH:7]=1
Reactant: CN1CC(CN)Oc2ccccc21
Reactant: COc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1nc(Cl)cc(NCC2CN(C)c3ccccc3O2)n1
Yield: 98.8 %

Procedure:
A mixture of 4,6-dichloro-2-methoxy-pyrimidine (0.27 g, 1.48 mmol), C-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl)-methylamine (0.22 g, 1.23 mmol), and NaHCO3 (0.62 g, 7.4 mmol) in EtOH (7 mL) is heated to reflux for 5 h. The mixture is concentrated in vacuo. The residue is partitioned between EtOAc and water, and extracted with EtOAc. The extracts are dried (Na2SO4), and concentrated to afford (6-chloro-2-methoxy-pyrimidin-4-yl)-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)-amine (0.39 g). LCMS: RT=3.27 minutes; MS: 321 (M+H).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([O:24]C(=O)C2C=CC=CC=2)=[CH:19][C:18]=1[Cl:33])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>CO.O>[C:1]([O:5][N:6]=[C:7]([CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[C:18]([Cl:33])=[CH:19][C:20]([OH:24])=[CH:21][C:22]=1[Cl:23])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(COCCCCCOc1c(Cl)cc(OC(=O)c2ccccc2)cc1Cl)=NOC(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(COCCCCCOc1c(Cl)cc(O)cc1Cl)=NOC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.99 g of 5-(2,6-dichloro-4-(benzoyloxy)phenoxy)-pentyloxyacetone O-tert-butyloxime dissolved in 7.5 ml of methanol is added a solution of 0.15 g of potassium hydroxide dissolved in 1.5 ml of water. After stirring at room temperature for 1 hour, the reaction mixture is acidified by the addition of diluted hydrochloric acid, and concentrated. Water is added to the residue, and the mixture is extracted twice with ethyl acetate. The ethyl acetate layers are combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product is subjected to silica gel chromatography, which affords 5-(2,6-di-chloro-4-hydroxyphenoxy)pentyloxyacetone O-tert-butyloxime.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2([C:23](N)=[O:24])[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1.[OH-:26].[K+].Cl.[OH-].[Na+]>O.C(O)CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2([C:23]([OH:26])=[O:24])[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14][CH2:15]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(NC2(C(N)=O)CCN(Cc3ccccc3)CC2)c1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: COc1cccc(NC2(C(=O)O)CCN(Cc3ccccc3)CC2)c1

Procedure:
A mixture of 100 parts of 4-[N-(3-methoxyphenyl)amino]-1-(phenylmethyl)-4-piperidinecarboxamide, 49.5 parts of potassium hydroxide and 974 parts of 1,2-ethanediol is stirred and refluxed for 24 hours. After cooling, the reaction mixture is poured onto 1500 parts of water and acidified with a concentrated hydrochloric acid solution. The whole is strongly alkalized with a sodium hydroxide solution and the layers are separated. The aqueous phase is concentrated, whereupon the product is separated as an oil. The supernatant aqueous phase is decanted and the residual oil is taken up in a sodium hydroxide solution. The precipitated product is filtered off and dissolved in water. The solution is acidified with acetic acid till pH = 6. The precipitated product is filtered off and warmed in ethanol. It is filtered off again, washed with ethanol and 2,2'-oxybispropane and dissolved in boiling N,N-dimethylformamide. The solution is filtered and the product is allowed to crystallized from the filtrate. It is filtered off, washed successively with N,N-dimethylformamide, water and ethanol, and dried, yielding 4-[N-(3-methoxyphenyl)amino]- 1-(phenylmethyl)-4-piperidinecarboxylic acid; mp. 211.1° C.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=3)[C:10]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:9]=2[CH:8]=1.C[O:38]B(OC)OC.Cl>O1CCCC1>[Br:6][C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([OH:38])=[CH:14][CH:15]=3)[C:10]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:9]=2[CH:8]=1
Reactant: COB(OC)OC
Reactant: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCC1(CCCCCCCC)c2cc(O)ccc2-c2ccc(Br)cc21
Temperature: -70 °C
Reaction time: 1 h
Yield: 44.1 %

Procedure:
2.5M n-butyllithium in hexanes (20.0 cm3, 0.05 mol) was added dropwise to a solution of 2,7-dibromo-9,9-dioctylfluorene (20.0 g, 0.0364 mol) and tetrahydrofuran (300 cm3) maintaining a temperature of −70° C. After stirring for 1 h, trimethylborate (9.45 g, 0.09 mol) was added dropwise. After allowing the solution to reach RT, 20% hydrochloric acid (100 cm3) was added and the solution stirred for a further 1.5 h. The product was extracted into diethyl ether (2×100 cm3) and the combined extracts washed with water (2×100 cm3), dried (MgSO4) and concentrated to a pale yellow oil. Diethyl ether (200 cm3) and hydrogen peroxide (30%, 100 cm3) were added and the solution heated under gentle reflux for 2.5 h with vigorous stirring. The ether layer was separated off and the aqueous layer extracted into diethyl ether (3×50 cm3). The combined organic layers were washed with saturated sodium metabisulphite solution (2×100 cm3), dried (MgSO4), filtered and evaporated down under slightly reduced pressure to a pale yellow oil, which was purified by column chromatography [silica gel, dichloromethane:hexane:ethanol 50:50:1] and recrystallisation from hexane to yield a white crystalline solid (yield 7.80 g, 45%), GC: 99%, mpt 110° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:22]([O:29][C:30](=[O:38])[CH2:31][C@@H:32]([NH2:37])[CH2:33][N:34]([CH3:36])[CH3:35])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([O:29][C:30](=[O:38])[CH2:31][C@@H:32]([NH:37][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:33][N:34]([CH3:35])[CH3:36])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)CCCCCCCCCCc1ccccc1
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCCCCc1ccccc1

Procedure:
The title compound, m/e=391.5 ([M+H]+), was produced in analogy with intermediate 1, steps 3 and 4. Thus, commercially available 11-phenylundecanoic acid was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-4-dimethylamino-3-(11-phenyl-undecanoylamino)-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[CH2:18][CH3:19])[C:5]1=[O:23])(=O)C.[CH3:24][N:25]([CH3:40])[CH2:26][CH2:27][N:28]([S:36]([CH3:39])(=[O:38])=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1>>[CH3:24][N:25]([CH3:40])[CH2:26][CH2:27][N:28]([C:29]1[CH:30]=[CH:31][C:32]([NH:35]/[C:17](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[CH2:18][CH3:19])=[CH:33][CH:34]=1)[S:36]([CH3:39])(=[O:38])=[O:37]
Reactant: CN(C)CCN(c1ccc(N)cc1)S(C)(=O)=O
Reactant: CCOC(CC)=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21
Product: CC/C(Nc1ccc(N(CCN(C)C)S(C)(=O)=O)cc1)=C1/C(=O)Nc2cc(OC)c(OC)cc21

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone and N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenediamine
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]3=[CH:11][NH:12][C:13](=[O:17])[C:14]([C:15]#[N:16])=[C:8]3[NH:7][C:6]=2[CH:18]=1.C(OO)(=[O:21])C>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10](=[O:21])[C:9]3=[CH:11][NH:12][C:13](=[O:17])[C:14]([C:15]#[N:16])=[C:8]3[NH:7][C:6]=2[CH:18]=1
Reactant: N#Cc1c2c(c[nH]c1=O)Sc1ccc(Cl)cc1N2
Reactant: CC(=O)OO
Solvent: CC(=O)O
Product: N#Cc1c2c(c[nH]c1=O)S(=O)c1ccc(Cl)cc1N2
Temperature: 25 °C
Reaction time: 27 h

Procedure:
A mixture of 1 part of 7-chloro-2,3-dihydro-3-oxo-5H-pyrido[3,4-b][1,4]benzothiazine-4-carbonitrile, 14 parts of ethaneperoxoic acid, and 58 parts of acetic acid is stirred at room temperature for 27 hours, whereupon insoluble solids are filtered out, dried in air, and recrystallized from aqueous N,N-dimethylformamide to give 7-chloro-2,3-dihydro-3-oxo-5H-pyrido[3,4-b][1,4]benzothiazine-4-carbonitrile 10-oxide as a colorless solid melting above 300°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[S:10][N:9]=1.[ClH:26].C(OCC)(=O)C>CO>[ClH:26].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([N:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)[S:10][N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(-c3ccccc3F)ns2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Fc1ccccc1-c1nsc(N2CCNCC2)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.5 %

Procedure:
A mixture of tert-butyl 4-[3-(2-fluorophenyl)-1,2,4-thiadiazol-5-yl]piperazine-1-carboxylate (5.70 g, 15.6 mmol), 4 N hydrogen chloride/ethyl acetate (200 ml) and methanol (100 ml) was stirred at room temperature for 12 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of methanol and ether to give 4.31 g (86.5%) of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8](=[O:27])[NH:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH2:28](O)[CH3:29].CN1CCCN(C)C1=O.ICC>C(=O)([O-])[O-].[Ag+2]>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([O:27][CH2:28][CH3:29])=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CCO
Reactant: O=c1[nH]c(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(Cl)nccn12
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CN1CCCN(C)C1=O
Solvent: CCI
Product: CCOc1nc(-c2ccc3ccc(-c4ccccc4)nc3c2)c2c(Cl)nccn12
Temperature: 40 °C

Procedure:
A 80 mL sealed tube is charged with 8-chloro-1-(2-phenyl-quinolin-7-yl)-2H-imidazo[1,5-a]pyrazin-3-one (50.00 mg, 0.1341 mmol), silver carbonate (74 mg, 0.27 mmol), anhydrous ethanol (2.00 mL, 0.034 mol), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.002 mL, 0.01 mmol), and iodoethane (0.012 mL, 0.15 mmol). The reaction was sealed under an atmosphere of nitrogen and heated at 40° C. for 24 hours. The reaction was cooled and filtered. Water and EtOAc were added and the organic layer was isolated, dried over sodium sulfate, filtered and concentrated in vacuo to yield a yellow gum. The crude product was purified via silica gel column chromatography, (Jones, 5 gram column eluting with 50% EtOAc: Hex) to yield the title compound as a yellow gum; MS (ES+): m/z 401.03 (100) [MH+], 402.98 (30) [MH+++]; HPLC: tR=4.13 min (OpenLynx, polar—5 min); 1HNMR (400 MHz, CHLOROFORM-d) δ ppm 1.41-1.72 (m, 3H), 4.55-4.86 (m, 2H), 7.18 (d, J=4.80 Hz, 1H), 7.38-7.65 (m, 4H), 7.75-8.00 (m, 3H), 8.09-8.33 (m, 3H), 8.52 (br. s., 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:36][C@H:37]([C:45]([OH:47])=[O:46])[CH2:38][CH2:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C(O)(=O)C>[C:45]([OH:47])(=[O:46])[CH3:37].[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[OH:16])[C@H:9]2[C:24]2[CH:49]=[CH:48][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:36][C@H:37]([C:45]([OH:47])=[O:46])[CH2:38][CH2:39][CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1
Reactant: CN(C)CCCC[C@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)CCCC[C@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Yield: 150.6 %

Procedure:
N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-N6,N6-dimethyl-L-lysine (0.05 g, 0.007 mmole) was dissolved in methanol (1.5 mL). NaBH4 (0.0065 g, 0.0172 mmole) was added and after about 15 min the reaction was complete according to LC-MS. A few drops of acetic acid were added. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on a Kromasil C8-column using 33.5% MeCN in 0.1M ammonium acetate buffer as eluent. After freeze-drying, 0.004 g (73%) of the desired product as the acetate-salt was obtained.
Reaction SMILES: [I:1][C:2]1[CH:42]=[CH:41][C:5]([CH2:6][NH:7][C:8](=[O:40])[C@@H:9]([NH:16][C:17](=[O:39])[C@@H:18]([NH:25][C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([S:35](=[O:38])(=[O:37])[NH2:36])=[CH:31][CH:30]=2)=[S:27])[CH2:19][CH2:20][C:21]([O:23]C)=[O:22])[CH2:10][CH2:11][C:12]([O:14]C)=[O:13])=[CH:4][CH:3]=1.[OH-].[Li+]>CO.O>[C:12]([CH2:11][CH2:10][C@H:9]([NH:16][C:17](=[O:39])[C@@H:18]([NH:25][C:26]([NH:28][C:29]1[CH:30]=[CH:31][C:32]([S:35](=[O:37])(=[O:38])[NH2:36])=[CH:33][CH:34]=1)=[S:27])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:8]([NH:7][CH2:6][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:42][CH:41]=1)=[O:40])([OH:14])=[O:13]
Reactant: COC(=O)CC[C@H](NC(=O)[C@H](CCC(=O)OC)NC(=S)Nc1ccc(S(N)(=O)=O)cc1)C(=O)NCc1ccc(I)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: NS(=O)(=O)c1ccc(NC(=S)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)NCc2ccc(I)cc2)cc1
Yield: 25.9 %

Procedure:
A solution of (S)-methyl 5-(4-iodobenzylamino)-4-((S)-5-methoxy-5-oxo-2-(3-(4-sulfamoylphenyl)thioureido)pentanamido)-5-oxopentanoate (0.200 g, 0.27 mmol) and lithium hydroxide (48 mg) in methanol (3.0 mL) and water (1.0 mL) was stirred at room temperature for overnight. The reaction mixture was purified by HPLC to give the title product (49.4 mg) as a yellow solid. MS (ESI), 728 (M+Na)+.