Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH:18]2[C:16]([C:20]3[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=3)([CH2:17]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].[NH:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32].C(N)CN>C1(C)C=CC=CC=1.[Cu]I>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH:18]2[C:16]([C:20]3[CH:25]=[CH:24][C:23]([N:27]4[CH2:31][CH2:30][CH2:29][C:28]4=[O:32])=[CH:22][CH:21]=3)([CH2:17]2)[CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(Br)cc2)C1
Reactant: O=C1CCCN1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: NCCN
Product: CC(C)(C)OC(=O)N1CC2CC2(c2ccc(N3CCCC3=O)cc2)C1
Yield: 51.9 %

Procedure:
To a stifling suspension of potassium carbonate (1.23 g, 8.95 mmol) and CuI (42.5 mg, 0.22 mmol) in anhydrous toluene (10 mL) were added 1-(4-bromo-phenyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (Intermediate I, 1.6 g, 4.5 mmol) dissolved in toluene (10 mL) followed by addition of pyrrolidinone (0.5 mL, 6.2 mmol) and ethylene diamine (0.03 mL, 0.45 mmol). Reaction mixture was refluxed for 16 h. Reaction mixture was then concentrated and the crude product was purified by column chromatography (silica gel, 4:6 EtOAc:Pet. ether) to afford the title compound as white solid (800 mg, 52%).
Reaction SMILES: [C:1]([OH:4])(=O)[CH3:2].C([O-])(=O)C.[K+].ClCC1[C:13]([N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])=[N:14][CH:15]=[C:16]([CH:18]([Cl:20])[Cl:19])[N:17]=1.ClCCl>CS(C)=O.O>[Cl:20][CH:18]([Cl:19])[C:16]1[N:17]=[C:2]([CH2:1][OH:4])[C:13]([N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])=[N:14][CH:15]=1
Reactant: CC(=O)O
Reactant: O=C1c2ccccc2C(=O)N1c1ncc(C(Cl)Cl)nc1CCl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1c1ncc(C(Cl)Cl)nc1CO
Temperature: 25 °C
Reaction time: 72 h
Yield: 47 %

Procedure:
50 ml of glacial acetic acid and 35 g of potassium acetate were added to a solution of 57.7 g (0.16 mole) of 65% strength 3-chloromethyl-5-dichloromethyl-2-phthalimidopyrazine in 1,000 ml of a 95:5 dimethyl sulfoxide/water mixture. The mixture was stirred for three days at room temperature, after which 1,000 ml of dichloromethane and 1,000 ml of ice-water were added, the resulting mixture was mixed thoroughly and phase separation was effected. The aqueous phase was washed once with 500 ml of dichloromethane and once with 250 ml of dichloromethane, and the combined organic phases were washed twice with 1,000 ml of water, dried over sodium sulfate and evaporated down. The resulting black oil was brought to crystallization with 50 ml of methanol, and then recrystallized from 700 ml of methanol. 16.6 g (47%) of 5-dichloromethyl-3-hydroxymethyl-2-phthalimidopyrazine of melting point 191°-192° C. (sublimation with decomposition) were obtained. 1H-NMR (200 MHz, CDCl3): δ3.3 (t, OH), 4.8 (d, 2H), 6.9 (s, 1H), 8.0 (m, 4H), 9.1 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH2:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>C(COC)OC>[NH2:1][C:2]1[N:3]=[C:4]([O:26][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: OCc1ccccc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: N#Cc1c(OCc2ccccc2)nc(N)nc1-c1ccco1
Temperature: 100 °C
Yield: 55.5 %

Procedure:
To a stirred suspension of 300 mg (1.14 mmol) 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile in 9 ml dimethoxyethane were added 0.41 ml (4.0 mmol) benzyl alcohol and 0.25 ml (1.7 mmol) DBU and the mixture heated at 100° C. for 1 hour. The reaction mixture was then concentrated in vacuo. Chromatography (ethyl acetate/hexane 2/1) followed by trituration in ether/hexane afforded 185 mg (56%) 2-amino-4-benzyloxy-6-furan-2-yl-pyrimidine-5-carbonitrile as a white crystalline solid. EI-MS m/e (%): 292 (M+, 40), 91 (C7H7+, 100).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[C:7]1[O:11][C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][N:13]=2)=[CH:9][CH:8]=1.[H-].[Na+].Cl.[N:24]1[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][CH:25]=1.O>CN(C=O)C.C(OCC)(=O)C>[O:3]1[CH2:4][CH2:5][CH2:6][O:1][CH:2]1[C:7]1[O:11][C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:30][C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)[N:13]=2)=[CH:9][CH:8]=1
Reactant: c1ccc2c(-c3ccc(C4OCCCO4)o3)n[nH]c2c1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2c(c1)c(-c1ccc(C3OCCCO3)o1)nn2Cc1ccncc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2 g (7.41 mmol) of 3-(5-(1,3-dioxan-2-yl)furan-2-yl)indazole in 10 ml of DMF is added to a suspension of 355 mg of NaH (60 per cent in paraffin) in 10 ml of DMF under argon, and the mixture is stirred at room temperature for 1 hour. 1.46 g of 4-picolyl chloride hydrochloride are then added, followed by 355 mg of NaH (60 percent in paraffin). The mixture is stirred at room temperature for 1 hour and then at 100° C. for 1 hour, introduced into water and extracted with ethyl acetate, the organic phase is dried with sodium sulphate and evaporated in vacuo and the residue is chromatographed over silica gel using toluene/ethyl acetate mixtures as the eluent. 1 g (37% of theory) of an oil is obtained. Rf (SiO2, ethyl acetate): 0.25
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][C:13]([C:15]#[N:16])=[CH:14][C:6]=2[N:5]([C:17]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])[C@H:4]1[CH3:25].[C:26]([N:33]([CH3:39])[C@H:34]([C:36](O)=[O:37])[CH3:35])([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:15]([C:13]1[CH:12]=[CH:11][C:7]2[NH:8][C:9](=[O:10])[C@@H:3]([NH:2][C:36](=[O:37])[C@@H:34]([N:33]([CH3:39])[C:26](=[O:27])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH3:35])[C@H:4]([CH3:25])[N:5]([C:17]([CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[C:6]=2[CH:14]=1)#[N:16]
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Reactant: C[C@H]1[C@H](N)C(=O)Nc2ccc(C#N)cc2N1C(=O)C1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)N[C@@H]1C(=O)Nc2ccc(C#N)cc2N(C(=O)C2CCOCC2)[C@H]1C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
To a 0° C. solution of (3S,4S)-3-amino-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepine-7-carbonitrile hydrochloride (218 mg, 598 μmol) in DMF (1.99 ml) was added Boc-N-methyl-L-alanine (134 mg, 657 μmol), N,N-diisopropylethylamine (414 μl, 2.39 mmol), and HBTU (249 mg, 657 μmol). The reaction was stirred at rt for 30 min, then diluted with EtOAc, washed with H2O, sat. aq. NaHCO3, and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((2S,3S)-8-cyano-2-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (239 mg, 78%) as a white solid. MS m/z 536 (MNa)+.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[N:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(Cl)Cl.[BH3-]C#N.[Na+]>CC(O)=O.CO>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH3:9])[C:4](=[O:10])[C:3]=1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cn1c(=O)[nH]c(N)c(N=Cc2ccccc2)c1=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: Cn1c(=O)[nH]c(N)c(NCc2ccccc2)c1=O
Reaction time: 0.5 h

Procedure:
Add 6-amino-3-methyl-5-(phenylmethyleneamino )pyrimidine-2,4-dione (85 g=0.35 mol) to CH2Cl2 (1.6L) and MeOH (1.6L). Stir the suspension, add HOAc (21.9 ml=0.35 mol), then NaCNBH3 (21.9 g=0.35 mol). Stir 1.5 hr, and add HOAc (2 ml) and NaCNBH3 (2.0 g). After another 30 min, concentrate to ca. 1.6L on a rotovap (35° C. bath). Chill the crystalline mixture, filter, and wash with cold MeOH. Stir the product 15 min in 0.5L boiling MeOH, chill, filter, and dry to obtain the title compound, m.p. 206°-218° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:12](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([O:10][CH3:12])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(Cl)cc(F)c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: COc1c(F)cc(Cl)cc1C=O
Reaction time: 18 h
Yield: 49.5 %

Procedure:
To 5 g (34 mmol) 4-Chloro-2-fluorophenol and 416 mg (3.41 mmol) 4-dimethylaminopyridine in 18 ml THF are added 3.7 ml (37.5 mmol) isopropyl isocyanate and the mixture is heated for 20 hours at 60° C. After cooling down to room temperature 2 M HCl is added and the aqueous phase is extracted with diethyl ether. The combined organic phases are washed with brine, dried over sodium sulfate and evaporated to yield 7.2 g isopropylcarbamic acid 4-chloro-2-fluorophenyl ester as the crude product. To 7.2 g (31 mmol) isopropylcarbamic acid 4-chloro-2-fluorophenyl ester and 5.1 ml tetramethylene diamine in 300 ml diethyl ether are added 5.9 ml (32.5 mmol) (trimethylsilyl)(trifluoromethan)sulfonate at room temperature. After 30 minutes the mixture is cooled to −70° C., 10.2 ml tetramethylene diamine and 27 ml of a 2.5 M n-BuLi solution are added successively. After one hour at −70°24 ml DMF in are added at −70° C. and the mixture is stirred another hour at −70° C. 130 ml ethanol and 36 ml of a 2 M aqueous NaOH are added and the reaction is warmed to ambient temperature over 18 hours. The reaction mixture is set acidic by addition of 100 ml 2 M aqueous HCl and partitioned between diethyl ether and water. The aqueous phase is extracted with diethyl ether, the combined organic phases are washed with brine, dried over sodium sulphate and evaporated. The crude product is purified by chromatography on silica gel to yield 1.1 g 5-chloro-3-fluoro-2-hydroxybenzaldehyde. 1.1 g (6.1 mmol) 5-chloro-3-fluoro-2-hydroxybenzaldehyde and 1.56 g (11.3 mmol) potassium carbonate are stirred vigorously in 11 ml DMF while 0.7 ml methyliodide are added. Stirring is continued for 18 hours and water is added. The aqueous phase is extracted with diethyl ether, the combined organic phases are dried over sodium sulfate and evaporated. The crude product is purified by chromatography on silica gel (ethyl acetate in hexane 0 to 10%) to yield 570 mg 5-chloro-3-fluoro-2-methoxybenzaldehyde. 1H-NMR (CDCl3); δ=4.10 (d, 3H), 7.35 (dd, 1H), 7.59 (m, 1H), 10.35 (s, 1H).
Reaction SMILES: CC(=[O:5])CC.[CH3:6][CH:7]1[CH2:12][CH:11]([O:13][CH2:14][C:15](Cl)=[O:16])[CH:10]([CH:18]([CH3:20])[CH3:19])[CH2:9][CH2:8]1.CO>N1C=CC=CC=1.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.C1COCC1>[CH3:6][CH:7]1[CH2:12][CH:11]([O:13][CH2:14][C:15]([OH:5])=[O:16])[CH:10]([CH:18]([CH3:20])[CH3:19])[CH2:9][CH2:8]1
Reactant: CC1CCC(C(C)C)C(OCC(=O)Cl)C1
Reactant: CCC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Solvent: c1ccncc1
Product: CC1CCC(C(C)C)C(OCC(=O)O)C1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
2-L-menthoxyacetyloxy-2-butene is prepared from 2-butanone, L-menthoxyacetyl chloride, and pyridine catalyst. A 70 mL stainless steel high pressure reactor fitted with a Pyrex glass liner and magnetic stir bar is charged with THF (5 mL), (PPh3)2PdCl2 (0.05 mmol), CH3OH (0.5 mmol), and 2-L-menthoxyacetyloxy-2-butene (0.5 mmol). The reactor is sealed, pressurized to 1000 psig with CO, and stirred for 24 hours at 100° C. The product mixture, isolated after removal of gas from the reactor vessel, contains a diastereomeric mixture of methyl 2-L-menthoxyacetyloxy-L-2-methylbutyrate and methyl 2-L-menthoxyacetyl-D-2-methylbutyrate. The diastereomers are separated by preparative gas chromatography using an SE-30 liquid phase column. Each diastereomer is hydrolyzed separately by treatment with 2N HCl (aq) for 2 hours at 100° C. to give pure L- and D-2-methyl-2-hydroxybutyric acid, methanol, and L-menthoxyacetic acid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=2[F:11])[NH2:7])[CH2:3][CH2:2]1.Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14].N1C=CC=CC=1.O>C(Cl)Cl>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:7][C:13](=[O:14])[O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:8]=[CH:9][C:10]=2[F:11])[CH2:3][CH2:2]1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(F)c(C2CC2)c1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(F)c(C2CC2)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.5 %

Procedure:
Add 3-cyclopropyl-4-fluoro-aniline (600 mg, 3.97 mmol), phenyl chloroformate (620 mg, 3.97 mmol) and pyridine (314 mg, 3.97 mmol) in DCM (30 mL), stir at room temperature (25° C.) for 4 hrs. After the reaction is complete, add water (15 mL), extract with EtOAc (15 mL×2), combine the organic layers, wash with 1M HCl solution (15 mL) and brine (15 mL) sequentially, dry over anhydrous Na2SO4. Concentrate under reduced pressure to give a crude product (350 mg) which is used directly without further purification.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[O:13]=[C:14]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]1[CH2:31][C:32]([OH:34])=O.[S:35]1[CH:39]=[CH:38][N:37]=[C:36]1[CH2:40][NH2:41]>ClCCl>[O:13]=[C:14]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:17][CH2:16][N:15]1[CH2:31][C:32]([NH:41][CH2:40][C:36]1[S:35][CH:39]=[CH:38][N:37]=1)=[O:34]
Reactant: NCc1nccs1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)NCc1nccs1
Reaction time: 8 h

Procedure:
N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.050 g, 0.169 mmol) and thiazol-2-ylmethanamine (0.021 g, 0.186 mmol) were combined and stirred together in dichloromethane (0.5 mL) at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.69 (d, J=3.3 Hz, 1H), 7.19-7.38 (m, 11H), 6.77 (t, J=5.8 Hz, 1H), 4.67 (d, J=5.8 Hz, 2H), 4.09 (s, 2H), 3.53 (t, J=6.5 Hz, 2H), 2.84 (t, J=6.5 Hz, 2H); MS (ESI+) m/z 392 (M+H)+.
Reaction SMILES: [C:1]([N:6]([CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][CH2:8][CH2:9][CH2:10]CC(O)=O)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH:28]([NH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([O:49]CC)=[O:48])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[OH-].[K+].[CH2:54]([OH:56])[CH3:55]>>[C:1]([N:6]([CH:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:55][C:54]([N:41]([CH:28]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48])=[O:56])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CCO
Reactant: CC(C)C(=O)N(CCCCCC(=O)O)C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CCCCCNC(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Product: CC(C)C(=O)N(CCCCCC(=O)N(CCCCCC(=O)O)C(c1ccccc1)c1ccccc1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-isobutyryl-6-benzhydrylaminocaproic acid and ethyl 6-benzhydrylaminocaproate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-isobutyryl-6-benzhydrylaminohexanoyl]-6-benzhydrylaminocaproic acid.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][N:16]([CH2:27][CH:28]=O)[C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:30][O:31][CH2:32][CH2:33][NH:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH3:56].C(O)(=O)C>C1COCC1.C(OCC)(=O)C>[CH3:30][O:31][CH2:32][CH2:33][N:34]([CH2:28][CH2:27][N:16]([CH3:15])[C:17](=[O:26])[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][O:49][CH2:50][CH2:51][O:52][CH2:53][CH2:54][O:55][CH3:56]
Reactant: CN(CC=O)C(=O)OCc1ccccc1
Reactant: COCCNCCOCCOCCOCCOCCOCCOCCOC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCCOCCOCCOCCOCCOCCOCCN(CCOC)CCN(C)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 54.6 %

Procedure:
Sodium triacetoxyborohydride (2.21 g, 10.4 mmol) was added portionwise at room temperature to benzyl methyl(2-oxoethyl)carbamate (1.66 g, 8.03 mmol), N-(2-methoxyethyl)-2,5,8,11,14,17,20-heptaoxadocosan-22-amine 135c.2 (3.19 g, 8.03 mmol), and acetic acid (0.92 mL, 16.1 mmol) in THF (50 mL). The mixture was stirred for 2 hours, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried (Mg2SO4) and evaporated. The residue was purified by PTLC (10% methanol/20% ethyl acetate/dichloromethane) to give product as an oil (2.58 g, 55%); MS for C29H52N2O10 m/z 589 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[N:9]/[S:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[C:4]([F:16])[CH:3]=1.[CH3:17][Mg]Cl>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:9][S:10]([C:12]([CH3:13])([CH3:15])[CH3:14])=[O:11])[CH3:17])=[C:4]([F:16])[CH:3]=1
Reactant: C[Mg]Cl
Reactant: CC(C)(C)S(=O)/N=C/c1ccc(Br)cc1F
Solvent: ClCCl
Product: C[C@@H](NS(=O)C(C)(C)C)c1ccc(Br)cc1F

Procedure:
To a solution of N-[(1E)-(4-bromo-2-fluorophenyl)methylidene]-2-methylpropane-2-sulfinamide (32.65 g, 0.1066 mol) in 550 mL CH2Cl2 at −48° C. was added methylmagnesium chloride (3.0 M solution is ether, 53.31 mL, 0.1599 mol) dropwise. The reaction was quenched with aqueous ammonium chloride and the aqueous layer was extracted with methylene chloride. The combined organics were dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was subjected to column chromatography on silica gel eluted with 10-50% ethyl acetate in hexanes to afford N-[(1R)-1-(4-bromo-2-fluorophenyl)ethyl]-2-methylpropane-2-sulfinamide as a white solid that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 324.14 for M+H+ (81Br).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:15]O)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:36]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH2:15][Br:36])[CH:3]=1
Reactant: OCc1cc(Br)cc(-c2ccc(F)cc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(-c2cc(Br)cc(CBr)c2)cc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(5-Bromo-4′-fluorobiphenyl-3-yl)methanol (0.42 g, 1.5 mmol) and triphenylphosphine (0.78 g, 2.98 mmol) were combined in tetrahydrofuran (8 mL) and cooled to 0° C. N-Bromosuccinimide (0.59 g, 3.1 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with ethyl acetate, washed with concentrated sodium bicarbonate (2×), then brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (5% ethyl acetate/hexanes) gave 0.4 g (78%) as a white powder. 1H-NMR (CDCl3, 500 MHz) 7.60 (m, 1H), 7.50-7.54 (m, 3H), 7.47 (m, 1H), 7.12-7.15 (m, 2H), 4.47 (s, 2H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][NH:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(N(CC)CC)C>ClCCCl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12]1[C:20]2[C:19]3[CH2:21][N:22]([C:25](=[O:27])[CH3:26])[CH2:23][CH2:24][C:18]=3[NH:17][C:16]=2[N:15]=[CH:14][CH:13]=1
Reactant: c1ccc2cc(Nc3ccnc4[nH]c5c(c34)CNCC5)ccc2c1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(=O)N1CCc2[nH]c3nccc(Nc4ccc5ccccc5c4)c3c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.9 %

Procedure:
Naphthalen-2-yl-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (79 mg, 0.25 mmol), acetic anhydride (25 μL, 0.25 mmol), and triethylamine (104 μL, 0.75 mmol) were dissolved in 1,2-dichloroethane (2 mL), and stirred for 30 min at room temperature. The reaction was quenched with H2O, and the resulting material was filtered through an Extrelut column. The column was washed with EtOAc, and the filtrate was concentrated. The crude material was purified via Biotage eluting with a gradient of 0 to 10% MeOH in DCM. Lyophilization of the purified product provided 60 (24 mg, 26% yield) as a tan powder. LC-MS (M+H=357, obsd.=357).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH2:47]([O:49][C:50](=[O:68])[CH2:51][CH2:52][C:53]1[O:54][C:55]2[CH:67]=[CH:66][CH:65]=[CH:64][C:56]=2[C:57]=1[CH2:58][CH:59]1[CH2:63][CH2:62][CH2:61][NH:60]1)[CH3:48]>CN1C(=O)CCC1.C(OCC)C>[CH2:47]([O:49][C:50](=[O:68])[CH2:51][CH2:52][C:53]1[O:54][C:55]2[CH:67]=[CH:66][CH:65]=[CH:64][C:56]=2[C:57]=1[CH2:58][CH:59]1[CH2:63][CH2:62][CH2:61][N:60]1[C:13](=[O:15])[CH:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH:10]([CH3:11])[CH3:12])[CH3:48]
Reactant: CCOC(=O)CCc1oc2ccccc2c1CC1CCCN1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCOCC
Solvent: CN1CCOCC1
Product: CCOC(=O)CCc1oc2ccccc2c1CC1CCCN1C(=O)C(NC(=O)OC(C)(C)C)C(C)C
Reaction time: 0.17 h
Yield: 96.8 %

Procedure:
A solution containing Boc-L-valine (352 mg, 1.6 mmol) in NMP (3 mL) was treated with HATU (543 mg, 1.4 mmol) followed by NMM (0.2 mL, 1.8 mmol) at ambient temperature. After 10 min, amine 48 (0.4 g, 1.3 mmol) in NMP (5 mL) was added in a dropwise fashion. After 16 h, the reaction mixture was diluted with diethyl ether and washed successively with NaHCO3, 1 M HCl, water, and brine. The organic extract was dried over anhydrous Na2SO4, filtered and concentrated to afford 630 mg (96%) of 49 which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ7.82-7.79 (m, 1H), 7.38-7.35 (m, 1H), 7.28-7.21 (m, 2H), 5.37 (d, J=9.3 Hz, 1H), 4.50-4.44 (m, 1H), 4.31 (dd, J=6.0, 9.0 Hz, 1H), 4.14 (q, J=6.9 Hz, 2H), 3.72-3.60 (m, 3H), 3.38 (t, J=7.2 Hz, 1H), 3.29 (dd, J=3.0, 13.5 Hz, 1H), 3.12 (app t, J=7.5 Hz, 2H), 2.80-2.74 (m, 4H), 2.46-2.35 (m, 2H), 2.11-1.92 (m, 2H), 1.81-1.73 (m, 1H), 1.69-1.65 (m, 1H), 1.44 (s, 9H), 1.25 (t, J=6.0 Hz, 3H), 1.03 (d, J=6.3 Hz, 3H), 0.96 (d, J=6.6 Hz, 3H) ppm. Mass spectrum: m/z 501 [M+H]+; and, 523 [M+Na]+.