Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([F:11])[CH:4]=1.[P:12]([O:19]CC)([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15]>>[CH2:14]([O:13][P:12]([CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([F:11])[CH:4]=1)(=[O:19])[O:16][CH2:17][CH3:18])[CH3:15]
Reactant: CCOP(OCC)OCC
Reactant: N#Cc1ccc(CBr)cc1F
Product: CCOP(=O)(Cc1ccc(C#N)c(F)c1)OCC
Temperature: 150 °C
Reaction time: 4 h

Procedure:
2.2 g 4-Bromomethyl-2-fluoro-benzonitrile were dissolved in 2.0 ml triethyl phosphite and stirred at 150° C. for four hours. Then the triethyl phosphite was removed in vacuo to obtain 2.5 g (4-Cyano-3-fluoro-benzyl)-phosphonic acid diethyl ester as an oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][C:11]=2[N+:19]([O-])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16](=[O:18])[CH3:17])=[CH:12][C:11]=2[NH2:19])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(C2CCN(C(C)=O)CC2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(=O)c1ccc(C2CCN(C(C)=O)CC2)c(N)c1

Procedure:
A solution of 23 g of crude N-acetyl-4-(2-nitro-4-acetylphenyl)-piperidine in 250 ml of ethanol is hydrogenated with 4.5 g of palladium (5%) on barium carbonate (decomposed) until 3 equivalents of hydrogen have been absorbed. The catalyst is then filtered off, and the filtrate is concentrated in vacuo to dryness. The crude N-acetyl-4-(2-amino-4-acetyl-phenyl)-piperidine thus obtained is purified by way of the hydrochloride, m.p. 220°-222° (from ethanol).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14](OCC)=[O:15])[CH:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+].O>C(O)C>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[C:11]([CH2:14][OH:15])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCc1cc(-c2ccc(C(F)(F)F)cc2)on1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Ethyl 5-[4-(trifluoromethyl)phenyl]isoxazole-3-carboxylate (130 mg) was dissolved in ethanol (10 ml), cooled to 0° C., and sodium borohydride (26 mg) was added in portions to the stirred solution. The mixture was stirred at room temperature for 4 hours, then excess water added. Solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography, eluting with 5% methanol/ethyl acetate, to provide {5-[4-(trifluoromethyl)phenyl]isoxazol-3-yl}methan-1-ol, a compound of formula (24).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]3[NH:13][CH:14]=[CH:15][C:10]3=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](O)(=[O:18])C.C1N2CN3CN(C2)CN1C3.C(=O)([O-])O.[Na+]>O>[C:1]1([C:7]2[N:12]=[C:11]3[NH:13][CH:14]=[C:15]([CH:16]=[O:18])[C:10]3=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ccc3cc[nH]c3n2)cc1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=Cc1c[nH]c2nc(-c3ccccc3)ccc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 11 %

Procedure:
6-Phenyl-1H-pyrrolo[2,3-b]pyridine (0.10 g, 0.52 mmol) was successively added with acetic acid (0.2 mL), water (0.4 mL), and hexamethylenetetramine (0.11 g, 0.77 mmol), and then the mixture was stirred overnight at 120° C. in a sealed tube. The reaction mixture was cooled to room temperature, and then added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (99:1→99:5)) to obtain a solid containing the objective substance. The solid was washed with a mixed solvent of chloroform and methanol to obtain 6-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.013 g, 11%).
Reaction SMILES: F[C:2]1[C:7](F)=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].N1CCC(CNC(=O)OC(C)(C)C)CC1.C(N(CC)C(C)C)(C)C>CCO.CCOC(C)=O>[N+:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1cccc(F)c1F
Agent: CC(C)(C)OC(=O)NCC1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1

Procedure:
To a solution of 2,3-difluoronitrobenzene (5.0 g, 31 mmol) in EtOH (25 mL) were added tert-butyl piperidin-4-ylmethylcarbamate (8.1 g, 38 mmol), and N,N-diisopropylethylamine (6.6 mL, 38 mmol). The reaction was irradiated to 110° C. for 20 min by microwave. The crude reaction mixture was diluted with EtOAc, washed with 1 N HCl and brine, dried over MgSO4 and concentrated to yield nitrobenzene Int-2a (11.2 g, 99%) as yellow crystals. The crude product was used without further purification.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([NH:51][C:32]([N:12]2[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=[C:11]2[C:8]2[CH:9]=[N:10][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:6][C:7]=2[O:35][CH2:36][CH3:37])=[O:33])[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
In a manner analogous to the method described in example 3, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was reacted with 4-amino-piperidine-1-carboxylic acid tert-butyl ester (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C39H50Cl2N5O4 [(M+H)+] 722.3235, observed 722.3235.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:21]1([C@@H:27]2[CH2:29][C@H:28]2[N:30]=[C:31]=[O:32])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH:20][C:31]([NH:30][CH:28]3[CH2:29][CH:27]3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:32])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Reactant: O=C=N[C@@H]1C[C@H]1c1ccccc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)NC1CC1c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.2 %

Procedure:
To 4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl amine (165 mg, 0.61 mmol, 1 equiv.) dissolved in 2.5 mL anhydrous THF was added, via syringe, trans-2-phenyl-cyclopropyl-isocyanate (90 uL, 0.60 mmol, 1 equiv.). The mixture was left stirring at room temperature for 18 h under inert atmosphere, then the solvent was removed in vacuo. The product was purified by column chromatography on SiO2, using 2-4% MeOH in EtOAc as eluent. A taupe foam was isolated, which recrystallized from hot acetonitrile to afford the title compound as a white solid (60 mg), mp 156-157° C.
Reaction SMILES: [CH:1]1([CH:4]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[C:5]2[C:13]3[C:8](=[C:9]([CH2:14][S:15][CH3:16])[CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[CH2:3][CH2:2]1.ClC1C=CC(C(C2CC2)C2C3C(=C(CS(C)=[O:44])C=CC=3)NC=2)=CC=1>>[CH:1]1([CH:4]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[C:5]2[C:13]3[C:8](=[C:9]([CH2:14][S:15]([CH3:16])=[O:44])[CH:10]=[CH:11][CH:12]=3)[NH:7][CH:6]=2)[CH2:2][CH2:3]1
Reactant: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Reactant: CSCc1cccc2c(C(c3ccc(F)cc3F)C3CC3)c[nH]c12
Product: CS(=O)Cc1cccc2c(C(c3ccc(F)cc3F)C3CC3)c[nH]c12

Procedure:
The title compound was prepared starting from 50 mg (0.15 mmol) of the compound from Example 228 in analogy to the synthesis of the compound from Example 235. 43 mg (82% of theory) of the target compound were obtained as mixture of diastereomers.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:19]([NH:21][N:22]1[C:27](=[O:28])[NH:26][C:25](=[O:29])[NH:24][C:23]1=[O:30])=[O:20])[CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C.[Pt](=O)=O>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C@@H:18]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:19]([NH:21][N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[NH:24][C:23]2=[O:30])=[O:20])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC(C)C[C@@H](C(=O)Nn1c(=O)[nH]c(=O)[nH]c1=O)[C@H](CCCc1ccccc1)C(=O)OC(C)(C)C
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(C)C[C@@H](C(=O)Nn1c(=O)[nH]c(=O)[nH]c1=O)[C@H](CCCC1CCCCC1)C(=O)OC(C)(C)C
Yield: 25.5 %

Procedure:
A solution of 0.500 g of 2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenylbutyl]-4-methyl-N-(2,4,6-trioxo-1,3,5-triazin-1-yl)valeramide (prepared as described in Example 44, part (i)) in 7 ml of glacial acetic acid was hydrogenated in the presence of 0.05 g of platinum (IV) oxide for 1.5 hours. Filtration and evaporation gave a residue which was purified by flash column chromatography on silica gel using ethyl acetate/hexane (1:1) as the eluant to give 0.129 g of 2(R)-[4-cyclohexyl-1(S)-(tert-butoxycarbonyl)butyl]-N-(2,4,6-trioxo-1,3,5-triazin-1-yl)-4-methylvaleramide in the form of a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=[C:11]2[C:10]([Br:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH2:1]([N:8]1[C:12]2=[N:13][C:14]([NH:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:15][CH:16]=[C:11]2[C:10]([Br:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ncc2c(Br)nn(Cc3ccccc3)c2n1
Reactant: NCCN1CCOCC1
Product: Brc1nn(Cc2ccccc2)c2nc(NCCN3CCOCC3)ncc12

Procedure:
Prepared as described above in Example 8 starting from 1-benzyl-3-bromo-6-methanesulfonyl-1H-pyrazolo[3,4-d]pyrimidine and N-aminoethylmorpholine to give the title compound (1-benzyl-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-(2-morpholin-4-yl-ethyl)-amine; LC/MS (m/e)=419.2 (MH+), Rt=1.47 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl[C:50](Cl)([O:52]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.CCCCCC>[N:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11]([CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C@@H:17]([NH:26][C:27](=[O:40])[CH2:28][C:29]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])([CH3:31])[CH3:30])[C:16]2=[O:41])=[CH:12][CH:13]=1)=[C:50]=[O:52]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3N)cc2)C1=O)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3N=C=O)cc2)C1=O)NC(=O)OC(C)(C)C
Yield: 78.9 %

Procedure:
A solution of 2.0 g (3.6 mmol) of N-[1-[[(2'-amino)[1,1'-biphenyl]-4-yl]methyl]-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepin-3(R)-yl]-3-t-butoxycarbonylamino-3-methylbutanamide (Example 2, Step B) and 2.0 mL of triethylamine (14 mmol) in 40 mL of methylene chloride under a nitrogen atmosphere was cooled to -10° C. and treated with 2.12 g (7.15 mmol) of triphosgene in one portion. An exotherm occurred. The reaction was stirred at room temperature for 1.5 hours when no starting amine was detected by thin layer chromatography on silica (hexanethyl acetate (1:1)). The reaction mixture was diluted with 40 mL of hexane and filtered. The filtrate was passed over 150 g of silica gel and eluted with hexane/ethyl acetate (1:1) to give 1.65 g (2.84 mmol, 79%) of the product. 1H NMR (400 MHz, CDCl3): δ 1.34 (s, 6H), 1.39 (s, 9H), 1.84 ((m, 1H), 2.40 (m, 1H), 2.49 (dd, 1H), 2.52 (m, 1H), 4.51 (m, 1H), 4.88 (d, 1H), 5.25 (d, 1H), 5.34 (br s, 1H), 6.71 (d, 1H), 7.20 (m, 12H).
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.Cl[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[CH:19]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:14][N:15]=2)=[O:9])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: N#CSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: ClCCN1CCOCC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: O=C(Nc1ncc(SCCN2CCOCC2)s1)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and N-(2-chloroethyl)-morpholine
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:15][CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]2)=[CH:3][C:4]=1[C:11]([F:14])([F:13])[F:12])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Temperature: 100 °C
Yield: 86 %

Procedure:
To a solution of 4-fluoro-1-nitro-2-(trifluoromethyl)benzene (5 g, 24 mmol) in DMSO (50 ml) was added tert-butyl 4-aminopiperidine-1-carboxylate (4.78 g, 23.9 mmol, 1 eq.) and potassium carbonate (9.9 g, 72 mmol, 3 eq.). The resulting mixture was stirred with heating overnight at 100° C. (oil bath) and then diluted with water (300 ml). The solids were collected by filtration to afford tert-butyl 4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]piperidine-1-carboxylate as a yellow powder (8 g, 86%); (ES, m/z): [M+H]+ 390.0; 1H NMR (300 MHz, DMSO-d6): δ 8.06 (d, J=9.3 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.08 (d, J=2.1 Hz, 1H), 6.89 (dd, J=2.4, 9.3 Hz, 1H), 3.87 (d, J=13.5 Hz, 2H), 3.68 (m, 1H), 2.95 (m, 2H), 2.54 (s, 0.6H), 1.89 (m, 2H), 1.39 (s, 9H), 1.28 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(N(CC)C(C)C)(C)C.[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl>C1COCC1>[Cl:1][CH2:2][C:3]1[N:4]([CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: ClCc1nc2ccccc2[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c(CCl)nc2ccccc21
Reaction time: 72 h
Yield: 67.7 %

Procedure:
To a stirred solution of 2-chloromethylbenzimidazole (1.89 g, 11.4 mmol) in dry THF (57 mL) was added N,N-diisopropylethylamine (3.00 mL, 17.2 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (1.90 mL, 10.8 mmol) both via syringe under nitrogen at room temperature. The mixture was stirred for 3 days at which time the solvent was removed in vacuo. The residue was taken up in CH2Cl2 (100 mL) and washed with water (100 mL) and brine (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product as a yellow oil. Purification by flash chromatography (silica gel, 100:2:1 CH2Cl2-methanol-ammonium hydroxide) provided 2.17 g (65%) of the title compound as a yellow oil, which solidified on standing. 1H NMR (CDCl3) δ−0.06 (s, 9H), 0.92 (t, 2H, J=7.5 Hz), 3.57 (t, 2H, J=7.5 Hz), 4.91 (s, 2H), 5.65 (s, 2H), 7.31–7.36 (m, 2H), 7.50 (d, 1H, J=7.5 Hz), 7.78 (d, 1H, J=7.5 Hz).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]1[N:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:14]=1[C:15]([O:17]C)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCOCC1.O>[CH2:1]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]1[N:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:14]=1[C:15]([OH:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(Cl)cnc1N1CCCC1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(Cl)cnc1N1CCCC1Cc1ccccc1
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 97.8 %

Procedure:
To methyl 2-(2-benzylpyrrolidin-1-yl)-5-chloronicotinate (D74) (75 mg, 0.226 mmol) in a mixture 1,4-dioxane/water (3 ml/1 ml), lithium hydroxide monohydrate (14.3 mg, 0.34 mmol) was added and the resulting mixture was stirred at 150° C. under microwave irradiation for 10 min (2 cycles of 5 min each). Solvents were evaporated in vacuo. The obtained residue was diluted with water/1M HCl (5 ml/15 ml) and extracted with ethyl acetate (3×30 ml). Collected fractions after solvent evaporation afforded the title compound (D100) (70 mg).
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:71][O:72][C:73](=[O:85])[CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH3:84])[CH2:16][S:17][CH2:18][C@H:19]([NH:53]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:20](=[O:52])[NH:21][CH2:22][CH2:23][CH2:24]OCCCCOCCCNC(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH:86]1CCC[CH2:88][CH2:87]1>C(#N)C>[C:73]([O:72][CH2:71][C@@H:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:16][S:17][CH2:18][C@H:19]([NH2:53])[C:20]([NH:21][CH2:22][CH2:23][CH2:24][CH2:88][CH2:87][NH2:86])=[O:52])(=[O:85])[CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH3:84]
Reactant: C1CCNCC1
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCCOCCCCOCCCNC(=O)OCC1c2ccccc2-c2ccccc21)OC(=O)CCCCCCCCCCC
Solvent: CC#N
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCCCCN)OC(=O)CCCCCCCCCCC
Reaction time: 0.5 h

Procedure:
A solution of (19R, 23R)-19-(((9H-fluoren-9-yl)methoxy)carbonylamino)-1-(9H-fluoren-9-yl)-3,18-dioxo-2,8,13-trioxa-21-thia-4,17-diazatetracosane-23,24-diyl didodecanoate in acetonitrile (0.1M) was stirred at room temperature. Piperidine (final conc. 20%) was then added and the reaction stirred for 30 minutes. After concentration, the product was purified by mass triggered HPLC using a 50-100% MeCN in H2O (0.1% TFA) gradient to give (R)-3-((R)-2-amino-3-(5-aminopentylamino)-3-oxopropylthio)propane-1,2-diyl didodecanoate). 1H NMR (DMSO d-6): δ 8.49 (t, 1H), 5.12 (m, 1H), 4.26-4.32 (dd, 1H), 4.08-4.12 (m, 1H), 3.85 (t, 1H), 3.32-3.41 (m, 7H), 3.20 (m, 2H), 3.11 (m, 1H), 2.91 (dd, 1H), 2.82 (m, 4H), 2.73 (m, 1H), 2.52 (m, 2H), 2.29-2.34 (q, 4H), 1.71-1.79 (m, 2H), 1.62-1.68 (m, 2H), 1.49-1.52 (m, 8H), 1.21-1.34 (m, 32H), 1.18-1.21 (t, 2H), 0.88 (t, 6H). LRMS [M+H]=747.1.
Reaction SMILES: ClCC(O)CSSCC(O)CCl.[OH-].[Na+].NC(N)=S.C(OC(=O)C)(=O)C.O1CC1C[CH:29]1[S:42][CH:30]1[CH2:31][S:32][S:33][CH2:34][CH:35]1[S:41][CH:36]1CC1OC1>C1(C)C=CC=CC=1.CO>[S:41]1[CH2:36][CH:35]1[CH2:34][S:33][S:32][CH2:31][CH:30]1[S:42][CH2:29]1
Reactant: C1OC1CC1SC1CSSCC1SC1CC1CO1
Agent: NC(N)=S
Agent: OC(CCl)CSSCC(O)CCl
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: C(SSCC1CS1)C1CS1
Temperature: 36 °C
Reaction time: 0.5 h

Procedure:
1229.34 g (4.89 mol) of bis(3-chloro-2-hydroxypropyl)disulfide, 1300 g of toluene, and 800 g of methanol were put into a 10-liter reactor. The reaction temperature was adjusted to 30° C. with stirring. When the reaction temperature reached 25° C., NaOH (50% aq., 783.08 g, 9.78 mol) was added dropwise within 1 h. The reaction was carried out while maintaining a temperature of 35-37° C. After standing at 37° C. for about 30 min, 2000 g of toluene was added to the reaction mixture, followed by stirring for about 10 min. The resulting mixture was left standing for layer separation. The upper organic layer was washed twice with water, and then the water was removed as much as possible. To the organic layer was added 400 g of methanol. After stirring, thiourea (1117.65 g, 14.30 mol) and acetic anhydride (70 g) were added at a temperature of 8° C. The reaction was continued at 18° C. for 18 h. The reaction was stopped when almost all the starting materials disappeared, which was confirmed by HPLC, and the content of 2,3-epoxypropyl(2,3-epithiopropyl)disulfide reached 10%, which was confirmed by GC analysis. After completion of the reaction, stirring was stopped for layer separation. The obtained organic layer was washed three times with water and the organic solvent was removed, affording bis(2,3-epithiopropyl)disulfide (BEPDS). The product had a refractive index (nD, 20° C.) of 1.631.
Reaction SMILES: [O:1]=[C:2]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27]CC2C=CC=CC=2)[CH:22]=1)[CH:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])[CH2:7][CH2:6]1)[CH3:4].[ClH:35].[H][H]>CO.[C].[Pd]>[ClH:35].[OH:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=1)[CH:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12]2=[O:20])[CH2:7][CH2:6]1)[CH3:4]
Reactant: CC(C(=O)c1cccc(OCc2ccccc2)c1)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C(O)c1cccc(O)c1)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reaction time: 24 h
Yield: 88.6 %

Procedure:
0.7 g of 1-[3-oxo-3-(3-benzyloxyphenyl)-2-propyl]-4-(2-keto-1-benzimidazolinyl)-piperidine is dissolved in 50 ml of methanol, and 1 ml of methanol solution containing 0.1 g of hydrogen chloride is added thereto. Further, 0.2 g of palladium-carbon is added to the solution, and the mixture is shaked in an autoclave at room temperature with a hydrogen pressure of 10 atmospheric pressures to reduce the compound. After 24 hours, the reaction solution is subjected to filtration, and the mother liquor is concentrated under reduced pressure. Ethyl acetate is added to the residue, and filtered. The mixture is dried to obtain 0.55 g of 1-[3-hydroxy-(3-hydroxyphenyl)-2-propyl]-4-(2-keto-1-benzimidazolinyl)piperidine hydrochloride as powder.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:13][CH3:14]>[Pd]>[NH2:10][C:8]1[CH:7]=[CH:6][C:5]([O:13][CH3:14])=[C:4]([CH:9]=1)[C:3]([NH:2][OH:1])=[O:15]
Reactant: COc1ccc([N+](=O)[O-])cc1C(=O)NO
Agent: [Pd]
Product: COc1ccc(N)cc1C(=O)NO
Reaction time: 1.5 h
Yield: 61.7 %

Procedure:
N-Hydroxy-2-methoxy-5-nitrobenzamide (approx. 47.39 mmol) was taken up in IMS (500 ml) and 10% Pd on C (50% wet) (1 g) was added. The mixture was hydrogenated at 50 psi for 1.5 hr, then filtered through celite, and the celite washed with 2M NaOH (200 ml). The MeOH was removed in vacuo and the resulting aqueous residue washed with MTBE (100 ml). The pH of the aqueous was lowered to 7 by the careful addition of concentrated HCl, and the resulting precipitated solid collected by filtration, washed with H2O, then MTBE and dried under high vacuum overnight to give 5.33 g of the title compound (62%) as a light brown solid.