Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[N:14]=1)[CH:7]=[C:6]2[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[Br:32][C:33]1[C:41]2[C:36](=[N:37][CH:38]=[N:39][C:40]=2Cl)[NH:35][N:34]=1>>[Br:32][C:33]1[C:41]2[C:36](=[N:37][CH:38]=[N:39][C:40]=2[N:29]2[CH2:28][CH2:27][N:26]([C:6]3[C:5]4[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=4)[CH:9]=[C:8]([C:13]4[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:24])[CH3:25])[N:14]=4)[CH:7]=3)[CH2:31][CH2:30]2)[NH:35][N:34]=1
Reactant: Clc1ncnc2[nH]nc(Br)c12
Reactant: COc1ccc2cc(-c3ccnc(NCCCN(C)C)n3)cc(N3CCNCC3)c2c1
Product: COc1ccc2cc(-c3ccnc(NCCCN(C)C)n3)cc(N3CCN(c4ncnc5[nH]nc(Br)c45)CC3)c2c1

Procedure:
N1-(4-(4-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-6-methoxynaphthalen-2-yl)pyrimidin-2-yl)-N3,N3-dimethylpropane-1,3-diamine was synthesized according to General Procedure E except N′-[4-(6-methoxy-4-piperazin-1-yl-2-naphthyl)pyrimidin-2-yl]-N,N-dimethylpropane-1,3-diamine and 3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine were used. N1-(4-(4-(4-(3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-yl)piperazin-1-yl)-6-methoxynaphthalen-2-yl)pyrimidin-2-yl)-N3,N3-dimethylpropane-1,3-diamine 178 was isolated as a solid. M.p.=152-155° C. LC/MS (m/z/): 618 [M+H].
Reaction SMILES: C(C1C=C(C=CC=1)C#N)(=[O:3])C.BrC1C=NC=C(C(F)(F)C)C=1.[F:23][C:24]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[C:30]#[N:31])([F:26])[CH3:25].CC(C[AlH]CC(C)C)C.Cl>C(Cl)Cl>[F:23][C:24]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[C:30]#[N:31])([F:26])[CH3:25].[F:23][C:24]([C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=[O:3])([F:26])[CH3:25]
Reactant: CC(=O)c1cccc(C#N)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: CC(F)(F)c1cccc(C#N)c1
Agent: CC(F)(F)c1cncc(Br)c1
Solvent: ClCCl
Product: CC(F)(F)c1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-(1,1-difluoroethyl)benzonitrile was synthesized from 3-acetylbenzonitrile following the method described for 3-bromo-5-(1,1-difluoroethyl)pyridine. A solution of 3-(1,1-difluoroethyl)benzonitrile (1.6 g, 9.57 mmol) in CH2Cl2 (25 mL) was cooled to 0° C. and was treated dropwise with a 1 M solution of DIBAL in hexanes (11.5 mL, 11.2 mmol). The mixture was allowed to slowly warm to room temperature. The reaction was monitored by TLC. After 3 h, the reaction mixture was poured into a beaker containing crushed ice and 6 N HCl. The mixture was stirred for about 1 h. The layers were separated and the aqueous phase was extracted with CH2Cl2. The combined organic layer was washed with aqueous NaHCO3 followed by water. The organic layer was dried (Na2SO4), concentrated, and silica chromatographed to afford 3-(1,1-difluoroethyl)benzaldehyde as a light yellow oil, which was used directly for next step without further purification and identification.
Reaction SMILES: C([O:3][C:4](=[O:38])[C@H:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:18][CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.[OH-].[Li+]>C(O)C.O.C(OCC)(=O)C>[C:7]([NH:6][C@H:5]([C:4]([OH:38])=[O:3])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:20][CH:21]=1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCCCCCCCCCCCSCCOc1ccc(C[C@H](NC(=O)c2ccccc2)C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCCCCCCCCSCCOc1ccc(C[C@H](NC(=O)c2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
To a suspension of N-benzoyl-O-dodecanylthioethyl-L-tyrosine ethyl ester (4.2 g, 7.75 mmol) in ethanol (50 ml) was added a solution of lithium hydroxide (0.42 g, 10.08 mmol) in water (5 ml). The solution was stirred at room temperature for 4 hours and then diluted with ethyl acetate and washed with 1N hydrochloric acid and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to give the title material (3.84 g, 96%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:14]([NH:16][C@@H:17]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:18]([OH:47])[CH2:19][C@@H:20]([NH:34][C:35]([C@@H:37]([NH:42][C:43](=[O:46])[O:44][CH3:45])[C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=2)=[O:15])[C:9]1=[O:59])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:60][S:61][CH3:62].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(#N)C.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C@@H:13]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:14]([NH:16][C@@H:17]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:18]([O:47][CH2:60][S:61][CH3:62])[CH2:19][C@@H:20]([NH:34][C:35](=[O:36])[C@H:37]([C:38]([CH3:41])([CH3:40])[CH3:39])[NH:42][C:43]([O:44][CH3:45])=[O:46])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)=[CH:24][CH:23]=2)=[O:15])[C:9]1=[O:59])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSC
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](OCSC)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2ccccc2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
To a solution of the compound of Example 111 (1.4 g, 1.74 mmol) and methyl sulfide (3.2 mL, 43.3 mmol) in acetonitrile (18 mL) at 0° C. was added benzoyl peroxide (1.7 g), and the mixture was warmed to room temperature and stirred for 30 minutes. The reaction was cooled to 0° C. and benzoyl peroxide (1.7 g) was added, and the mixture was warmed to room temperature and stirred for 30 minutes. Water was added and the reaction was diluted with ethyl acetate and washed with 10% Na2CO3 and brine. The organic was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel eluting with a gradient starting with dichloromethane and ending with ethyl acetate to give the title compound (1.24 g, 83% yield).
Reaction SMILES: Cl.[C:2]([C:6]1[NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([C:15]([OH:17])=O)[C:8]=2[N:7]=1)([CH3:5])([CH3:4])[CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][CH:40]([CH2:43][NH2:44])[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].N12CCN(CC1)CC2>CN(C)C=O.O.C(OCC)(=O)C>[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][CH:40]([CH2:43][NH:44][C:15]([C:14]2[C:8]3[N:7]=[C:6]([C:2]([CH3:3])([CH3:4])[CH3:5])[NH:10][C:9]=3[CH:11]=[CH:12][CH:13]=2)=[O:17])[CH2:39][CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)c1nc2c(C(=O)O)cccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: C1CN2CCN1CC2
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)c2cccc3[nH]c(C(C)(C)C)nc23)CC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
To a solution of 2-tert-butyl-1H-benzoimidazole-4-carboxylic acid hydrochloride (1.11 g, 4.37 mmol) in anhydrous N,N-dimethylformamide (5 mL) was added 1,1′-carbonyldiimidazole (0.77 g, 4.75 mmol). The solution was stirred at 50° C. for 2 h, then 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.94 g, 4.39 mmol) was added, followed by 1,4-diazabicyclo[2,2,2]octane (1.46 g, 13 mmol). The solution was stirred at 50° C. for 16 h, allowed to cool and diluted with water (20 mL) and ethyl acetate (60 mL). The aqueous layer was removed, the organic layer washed with water (20 mL), dried over sodium sulfate and concentrated in vacuo to afford the title intermediate (1.32 g, 3.18 mmol, 73%) which was used without further purification. (m/z): [M+H]+ calcd for C23H34N4O3 415.27; found 415.5.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([NH2:16])[N:13]=[C:12]([N:17]3[C@H:22]([CH3:23])[CH2:21][CH2:20][C@H:19]([C:24]([OH:26])=O)[CH2:18]3)[CH:11]=2)=[CH:6][C:5]=1[F:27])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:61]([NH2:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>CN(C=O)C.CCOC(C)=O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([NH2:16])[N:13]=[C:12]([N:17]3[C@H:22]([CH3:23])[CH2:21][CH2:20][C@H:19]([C:24]([NH:68][CH2:61][C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)=[O:26])[CH2:18]3)[CH:11]=2)=[CH:6][C:5]=1[F:27])(=[O:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CC(=O)c1ccc(-c2cc(N3C[C@@H](C(=O)O)CC[C@H]3C)nc(N)n2)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-c2cc(N3C[C@@H](C(=O)NCc4ccccc4)CC[C@H]3C)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.8 %

Procedure:
To a solution of (3S,6R)-1-[6-(4-acetyl-3-fluorophenyl)-2-amino-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (308 mg, 0.827 mmol) and HATU (377 mg, 0.992 mmol) in DMF (3 mL) was added Hunig's base (0.289 ml, 1.654 mmol), and the mixture was stirred at room temperature for 15 minutes. Then benzylamine (0.11 mL, 0.99 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (339 mg) as a yellow solid. LC-MS (ES) m/z=462 [M+H]+.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.C(Cl)(=O)OCC.[C:30]([O:34][C:35](=[O:47])[CH2:36][NH:37][CH:38]1[CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39]1)([CH3:33])([CH3:32])[CH3:31]>O1CCCC1.C(Cl)(Cl)Cl.O>[C:30]([O:34][C:35](=[O:47])[CH2:36][N:37]([C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[CH:38]1[CH2:39][C:40]2[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:46]1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)CNC1Cc2ccccc2C1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Reaction time: 0.25 h
Yield: 86.9 %

Procedure:
N-Carbobenzoxy-L-alanine (21.8 g) and 12.3 ml of triethylamine are dissolved in 200 ml of tetrahydrofuran, and 8.5 g of ethyl chlorocarbonate is added dropwise at -15° C. with stirring. After the dropping, stirring is continued for 15 minutes, and then a solution of 22 g of (indan-2-yl)glycine tert-butyl ester in 100 ml of chloroform is added dropwise at -10° C. or below. After stirring at room temperature for an hour, the reaction mixture is poured into 500 ml of water, and the chloroform layer is separated and the chloroform is distilled off. The residue is dissolved in 300 ml of ethyl acetate, the solution is washed with two 50-ml portions of 1N aqueous sodium hydroxide, one 50-ml portion of water, two 50-ml portions of 20% aqueous phosphoric acid and one 50-ml portion of water, in that order, and then dried over anhydrous magnesium sulfate, and the solvent is distilled off to give 35 g of N-carbobenzoxy-L-alanyl-N-(indan-2 -yl)glycine tert-butyl ester as an oil. This is dissolved in 300 ml of methanol and, after addition of 7 g of oxalic acid and 3.5 g of 10% palladium-carbon (containing 50% water), is subjected to catalytic reduction at ordinary temperature and ordinary pressure. After the reaction, the catalyst is filtered off, the filtrate is distilled off under reduced pressure, and 500 ml of ethanol is added to the residue. On cooling, a precipitate forms, which is collected by filtration and dried to give 21.8 g of L-alanyl-N-(indan-2-yl)glycine tert-butyl ester oxalate melting at 138°-141° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([S:12][C:8]2[C:6]3[N:7]=[C:2]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:3]=[C:4]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:5]=3[N:11]=[CH:10][N:9]=2)=[CH:14][CH:15]=1
Reactant: C1CNCCN1
Reactant: Fc1ccc(Sc2ncnc3c(N4CCOCC4)nc(Cl)nc23)cc1
Product: Fc1ccc(Sc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(4-fluorophenyl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 213°-215° C.) and piperazine.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[C:4]([CH2:13][NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH:3]=1.[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][C@@H:28]([C:31]([OH:33])=O)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].Cl.C(N=C=NCCCN(C)C)C.CC1C=CN=C(N)C=1C>ClCCl.O>[C:19]([O:23][C:24]([N:26]1[CH2:30][CH2:29][C@@H:28]([C:31]([N:14]([CH2:13][C:4]2[CH:3]=[C:2]([Cl:1])[C:7]3[O:8][CH2:9][CH2:10][CH2:11][O:12][C:6]=3[CH:5]=2)[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:33])[CH2:27]1)=[O:25])([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](C(=O)O)C1
Reactant: CC(C)CNCc1cc(Cl)c2c(c1)OCCCO2
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccnc(N)c1C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)CN(Cc1cc(Cl)c2c(c1)OCCCO2)C(=O)[C@@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-(9-chloro-3,4-dihydro-2H-1,5-benzodioxepin-7-ylmethyl)-2-methylpropan-1-amine (1,594 mg), (R)-Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 1,270 mg, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1,480 mg), dimethyl aminopyridine (1,030 mg) in 110 ml dichloromethane was stirred at room temperature overnight. After addition of water (75 mL), the mixture was extracted with ethyl acetate (100 mL 3). The organic layer was washed with saturated sodium bicarbonate, water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The product was purified by column chromatography on silica (33-50% ethyl acetate in hexane) and received as an oil: MS (m+1)=467.3.
Reaction SMILES: O.Cl.[Cl:3][C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][C:7]([N+:13]([O-])=O)=[CH:6][N:5]=1>C(O)C.[Fe]>[NH2:10][C:9]1[C:4]([Cl:3])=[N:5][CH:6]=[C:7]([NH2:13])[CH:8]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1cnc(Cl)c(N)c1
Temperature: 80 °C
Reaction time: 0.03 h
Yield: 51 %

Procedure:
The mixture of 2.19 g of iron powder, 5 ml of water, and 10 ml of ethanol was stirred at 80° C. for 2 minutes. After incremental addition of 1 ml concentrated hydrochloric acid, the mixture was stirred at the same temperature until the solution became neutral. To the reaction solution was incrementally added suspension of 1 g 2-chloro-3,5-dinitropyridine in 5 ml ethanol, and the mixture was stirred at 80° C. for 40 minutes. The reaction solution was allowed to cool, and the iron was removed by filtration with celite, and the solvent of the filtrate was distilled off. Ethanol was added to the residue to disperse the solid content, and the solid content was collected by filtration to obtain 360 mg of the title compound.
Reaction SMILES: [CH3:1][N+:2]([CH2:5][CH:6]([OH:11])[CH2:7][C:8]([OH:10])=[O:9])([CH3:4])[CH3:3].[Cl-].[OH-].[Na+]>C(O)C>[OH:11][CH:6]([CH2:7][C:8](=[O:9])[O-:10])[CH2:5][N+:2]([CH3:4])([CH3:1])[CH3:3]
Reactant: C[N+](C)(C)CC(O)CC(=O)O
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[N+](C)(C)CC(O)CC(=O)[O-]

Procedure:
A solution of DL-carnitine hydrochloride (1.0 g, 5.05 mmol) and sodium hydroxide (0.303 g, 7.58 mmol) in ethanol (15 ml) was stirred at room temperature for 2 h. The formed white precipitate (NaCl) was removed by filtration, and the solvent was evaporated under reduced pressure to give a white solid, carnitine inner salt. A suspension of the carnitine inner salt and 1-iodooctadecane (2.31 g, 6.06 mmol) in DMF-dioxane (3:5, 40 ml) was heated with an oil-bath at 120° C. under Ar2 for 4 h. The solvent was removed by rotavapor and vacuum, and the residue was chromatographied with silica gel column using CH3OH—CH3Cl as eluant to give 2.22 g (81%) of stearyl carnitine ester as a white solid: 1H NMR (CDCl3) δ 4.79 (m, 1 H), 4.43 (d, J=5.3, 1H), 4.09 (t, J=6.9, 2H), 4.03 (d, J=13.0, 1H), 3.67 (dd, J=10.3, 13.3, 1H), 3.51 (s, 9H), 2.79 (dd, J=5.7, 17.0, 1H), 2.66 (dd, J=7.0, 17.1, 1H), 1.80-1.60 (m, 4H), 1.26 (broad s, 28H), 0.88 (t, J=6.6, 3H).
Reaction SMILES: [C:1]1([P:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([NH:17][CH2:18][CH3:19])[CH3:16]>C1(C)C=CC=CC=1>[P:7]([N:17]([CH2:18][CH3:19])[CH2:15][CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CCNCC
Solvent: Cc1ccccc1
Product: CCN(CC)P(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diphenylchlorophosphine (2.0 mL, 2.38 g, 10.79 mmol) was added to a stirred solution of diethylamine (2.5 mL, 1.82 g, 24.9 mmol) in toluene (20 mL). The resulting white slurry was stirred overnight at ambient temperature and filtered. The filtered solid was washed with toluene (2×10 mL). The combined filtrate was reduced in volume by distillation in vacuum to approximately 20 mL and transferred to a graduated Schlenk tube equipped with a Yong valve. The volume of the solution was adjusted to 31.0 mL by addition of toluene to give 0.348 M solution of Ph2PNEt2. 31P{1H} NMR (toluene, 25° C.), δ: 51.0 (s).
Reaction SMILES: CN1CCOCC1.O.[NH2:9][C@H:10]([C:15]([NH:17][C@@H:18]([C:20]([NH2:22])=[O:21])[CH3:19])=[O:16])[CH2:11][C:12](=[O:14])[OH:13].Cl.O1CCOCC1.ClC1C=C(Cl)C(Cl)=CC=1[O:39][C:40](=O)[C@H:41]([CH2:50][CH2:51][S:52][CH3:53])[NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44]>CN(C)C=O>[C:46]([O:45][C:43]([NH:42][C@H:41]([C:40]([NH:9][C@H:10]([C:15]([NH:17][C@@H:18]([C:20]([NH2:22])=[O:21])[CH3:19])=[O:16])[CH2:11][C:12](=[O:13])[OH:14])=[O:39])[CH2:50][CH2:51][S:52][CH3:53])=[O:44])([CH3:49])([CH3:48])[CH3:47]
Reactant: C[C@@H](NC(=O)[C@@H](N)CC(=O)O)C(N)=O
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)Oc1cc(Cl)c(Cl)cc1Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C)C(N)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
14.5 Parts of N-methylmorpholine is added to a stirred solution of 14.33 parts of L-aspartyl-D-alanine amide monohydrate in 189 parts of dimethylformamide and 12.6 parts by volume of a 5.60 N HCl/dioxane solution. Then, 33.2 parts of N-t-butoxycarbonyl-L-methionine 2,4,5-trichlorophenyl ester is added and the resulting mixture stirred for about 18 hours at room temperature. The solvent is removed in vacuo and the resultant syrupy oil dissolved in ethyl acetate. To this solution is added 0.82 parts of N,N-diethylaminoethylamine and the resulting mixture is stirred for about 35 minutes. The mixture is then washed twice with 5% potassium hydrogen sulfate solution, dried over anhydrous sodium sulfate, and stripped under reduced pressure to a gummy residue. The gum is triturated with ethyl ether, to yield crystals which are filtered and dried to afford N-t-butoxycarbonyl-L-methionyl-L-aspartyl-D-alanine amide. This product melts at about 107-110° C., and is represented by the following formula.
Reaction SMILES: I[C:2]1[C:7]2[N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)CCO>O.C(COC)OC.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>[NH2:21][C:22]1[CH:27]=[C:26]([C:2]2[C:7]3[N:8]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:9]=[N:10][C:6]=3[CH:5]=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: FC(F)(F)c1cc(I)c2c(c1)ncn2-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: OCCCO
Product: Nc1cccc(-c2cc(C(F)(F)F)cc3ncn(-c4ccccc4)c23)c1

Procedure:
A mixture of 7-iodo-1-phenyl-5-trifluoromethylbenzimidazole (3.2 g, 8.2 mmol), 3-aminophenyl boronic acid (1.68 g, 12.3 mmol), sodium carbonate (5.68 g, 41 mmol), 1,3-propanediol (2.94 ml, 41 mmol) and bis(triphenylphosphin)palladium dichloride (200 mg, 0.28 mmol) in a mixture of water (13 ml) and dimethoxyethane (26 ml) was stirred at reflux overnight The cooled reaction mixture was partitioned between ethyl acetate and water, and the organic extract was purified by column chromatography on silica gel eluting with a mixture of dichloromethane and methanol (99:1, v/v). The product was isolated by removal of solvent from appropriate eluate fractions followed by crystallisation of the residue from 2-propanol (50 ml). Yield: 2.7 g (93%), m/z, 354.1 (M+H)+.