Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[CH2:3]([S:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1/[CH:18]=[CH:19]/[C:20]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]([CH3:31])[CH2:23][CH2:22][N:21]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:32]([NH:35][CH2:36][C:37](O)=[O:38])(=[O:34])[CH3:33].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[ClH:1].[ClH:1].[C:32]([NH:35][CH2:36][C:37]([NH:15][C:14]1[CH:16]=[CH:17][C:11]([S:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[C:12](/[CH:18]=[CH:19]/[C:20]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N:24]([CH3:31])[CH2:23][CH2:22][N:21]=2)[CH:13]=1)=[O:38])(=[O:34])[CH3:33]
Reactant: CN1CCN=C(/C=C/c2cc(N)ccc2SCc2ccccc2)c2ccccc21
Reactant: CC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Product: CC(=O)NCC(=O)Nc1ccc(SCc2ccccc2)c(/C=C/C2=NCCN(C)c3ccccc32)c1
Reaction time: 4 h
Yield: 30.7 %

Procedure:
To a mixture of 58 mg (0.114 mmol) of (E)-4-benzylthio-3-[2-(2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-5-yl)vinyl]aniline dihydrochloride (prepared as described in Example 82), 20 mg (0.171 mmol) of N-acetylglycine and 1-hydroxy-7-azabenzotriazole in 5 ml of dimethylformamide was added 44 mg (0.228 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride. The mixture was stirred for 4 hours. The solvent was removed and the residue was purified by column chromatography eluting with 5-20% methanol/dichloromethane and treated with 0.10 ml of 4M hydrogen chloride in dioxan. The solvent was evaporated and the residue was recrystallised from acetone/methanol/diethyl ether to give 10 mg of (E)-2-acetamido-4′-benzylthio-3′-[2-(2,3-dihydro-1-methyl-1H-1,4-benzodiazepin-5-yl)vinyl]acetanilide dihydrochloride as a yellow solid; MS: m/e 499 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]4[NH:27][C:26]5[C:28]([F:33])=[CH:29][C:30]([F:32])=[CH:31][C:25]=5[N:24]=4)=[CH:18][CH:17]=3)[C:9]([C:11]([O:13]CC)=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[OH-].[Na+]>C1COCC1.CO>[NH2:1][C:2]1[C:7]2=[C:8]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]4[NH:27][C:26]5[C:28]([F:33])=[CH:29][C:30]([F:32])=[CH:31][C:25]=5[N:24]=4)=[CH:18][CH:17]=3)[C:9]([C:11]([OH:13])=[O:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cn2ncnc(N)c2c1-c1ccc(Nc2nc3cc(F)cc(F)c3[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ncnn2cc(C(=O)O)c(-c3ccc(Nc4nc5cc(F)cc(F)c5[nH]4)cc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.2 %

Procedure:
To a mixture of ethyl 4-amino-5-{4-[(5,7-difluoro-1H-benzimidazol-2-yl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazine-6-carboxylate (5.85 g, 13.0 mmol) in THF (300 mL) and methanol (100 mL) was added 1N aqueous sodium hydroxide solution (130 mL, 130 mmol). The reaction was stirred at rt overnight and then the solution was concentrated under reduced pressure. The residue was diluted in water (500 mL) and then the mixture was adjusted to pH 3 using concentrated hydrochloric acid. The resulting precipitate was collected by filtration and dried to yield the desired product (5.60 g, 100%) containing some trace impurities. 1H-NMR (300 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.17-8.38 (br s, 1H) 8.14 (s, 1H), 7.97 (s, 1 H), 7.77 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.05 (d, J=8.1 Hz, 1H), 6.93 (dd, J=10.2, 10.2 Hz, 1H) 5.22-5.44 (br s, 1H); ES-MS m/z 422.1 (MH)+; HPLC RT (Method B) 2.13 min.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@H:5]([C:13]([O:15]C)=[O:14])[CH2:4][CH2:3]1.[OH-].[Na+]>CO>[O:1]=[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@H:5]([C:13]([OH:15])=[O:14])[CH2:4][CH2:3]1
Reactant: COC(=O)[C@@H]1CCC(=O)N1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@@H]1CCC(=O)N1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
Methyl 5-oxo-1-phenylprolinate (0.054 g, 0.25 mmol) was combined with 2M aqueous sodium hydroxide (0.160 ml, 0.32 mmol) in methanol (1 ml) and stirred overnight at room temperature. The solvent was then evaporated and the residue taken up in ethyl acetate and washed with 2M aqueous hydrogen chloride. The aqueous layer was separated and washed twice more with ethyl acetate and then the combined ethyl acetate layers were dried using a phase separator and evaporated to give 5-oxo-1-phenyl-proline (0.047 g) as a clear oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[C:44]([O:48][C:49]([CH2:51][CH2:52][NH:53][CH2:54][C:55]1[CH:63]=[CH:62][C:58]([C:59]([OH:61])=[O:60])=[CH:57][CH:56]=1)=[O:50])([CH3:47])([CH3:46])[CH3:45]>C(OCC)(=O)C>[C:44]([O:48][C:49]([CH2:51][CH2:52][N:53]([CH2:54][C:55]1[CH:63]=[CH:62][C:58]([C:59]([OH:61])=[O:60])=[CH:57][CH:56]=1)[C:21](=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:24])=[O:50])([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)CCNCc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)O
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCC(=O)N(CCC(=O)OC(C)(C)C)Cc1ccc(C(=O)O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
Hexadecanedioic acid mono-tert-butyl ester (0.3 g, 0.88 mmol) was dissolved in ethyl acetate. N-Ethyl-N-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.167 g, 0.88 mmol) and 1-hydroxy-7-azabenzotriazole (0.119 g, 0.88 mmol) was added and the mixture was stirred at 50° C. for 1 hour. After cooling to room temperature, diisopropylethylamin (0.45 mL, 2.63 mmol) was added followed by 4-[(2-tert-Butoxycarbonylethylamino)methyl]benzoic acid (0.489 g, 1.75 mmol). The mixture was stirred overnight under nitrogen at room temperature. The mixture was separated between ethyl acetate (100 mL) and water (2×50 mL). The organic phase was dried (Na2SO4), solvent removed in vacuo. The crude product was purified by RP-HPLC on C18-column, buffer A: 0.1% TFA, buffer B: MeCN+0.1% TFA; gradient 80-100% B to yield the title compound (145 mg, 27%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.S(Cl)(Cl)=O.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH2:22].C(N(CC)CC)C.Cl>O.C1COCC1>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:21]=1[NH:22][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(OC)c(N)c1
Reactant: COc1ccc(OC)c(C(=O)O)c1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(OC)c(NC(=O)c2cc(OC)ccc2OC)c1
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
A mixture of 2,5-dimethoxybenzoic acid (5.0 g, 27.5 mmol) and thionyl chloride (15 mL) was refluxed for 1 h. The volatiles were removed under vacuum. The residue was dissolved in THF (20 mL) and added into a cold (0° C.) solution of 2,5-dimethoxyaniline (4.6 g, 30.2 mmol), triethylamine (5 mL, 35.9 mmol) and THF (40 mL). The mixture was stirred for 30 min, poured into water, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/EtOAc 2/1) gave a white solid (8.1 g, 93% yield, m.p. 121–123° C.); MS m/e 318 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([OH:18])[CH:12]=[CH:11]2.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.Cl>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([OH:18])[CH:12]=[CH:11]3)=[CH:22][CH:21]=1
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Oc1ccc2cc(-c3ccc(F)cc3)ccc2c1
Temperature: 80 °C
Yield: 73.5 %

Procedure:
Dioxane (100 mL) and 2M sodium carbonate solution (15 mL) were added to a mixture of 6-bromo-2-naphthol (2.3 g, 10 mmol), 4-fluorobenzeneboronic acid (2.2 g, 15 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.6 g). The reaction was heated to 80° C. under nitrogen for 5 hours. The cooled reaction mixture was poured into dilute hydrochloric acid (200 mL) and extracted with ethyl acetate (x3). The combined organic layers were washed with water (x2) and brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 10-20% ethyl acetate/isohexane, to give 6-(4-fluorophenyl)-2-naphthol as a white solid (1.75 g, 74%). 1H NMR (500 MHz, CDCl3) δ 7.91 (1H, s), 7.80 (1H, d, J=8.8 Hz), 7.75 (1H, d, J=8.5 Hz), 7.65-7.63 (3H, m), 7.18-7.12 (4H, m), 4.97 (1H, s).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13](=O)[N:14]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][F:36])=[CH:26][CH:25]=2)=[CH:18][CH:17]=1)C)(C)(C)C>ClCCl>[F:36][CH2:35][CH2:34][O:33][CH2:32][CH2:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH:23]=[CH:22][C:19]2[CH:20]=[CH:21][C:16]([NH:14][CH3:13])=[CH:17][CH:18]=2)=[CH:25][CH:26]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C=Cc2ccc(OCCOCCF)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNc1ccc(C=Cc2ccc(OCCOCCF)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
Trifluoroacetic acid (0.5 ml) was added slowly to a solution of compound 11a (7.0 mg, 0.017 mmol) in dichloromethane (1 ml). The mixture was then stirred at room temperature for 1 hour. After standard workup with dichloromethane, the residue was purified by silica gel preparative TLC (1.0% methanol in dichloromethane) to afford 12a (3 mg, 56%): 1H NMR δ 7.37 (m, 4H), 6.90 (m, 4H), 6.65 (d, 2H, J=8.4 Hz), 4.60 (d, t, 2H, J1=46 Hz, J2=4.0 Hz), 4.17 (t, 2H), 3.90 (t, 3H), 3.76 (t, 1H), 2.88 (s, 3H). Anal. (C19H22FNO2)C. H. N.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Cl:7].[CH3:8][S:9]([OH:11])=[O:10].CCO.O>CO.C(Cl)Cl>[Cl:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:9]([CH3:8])(=[O:11])=[O:10]
Reactant: CS(=O)O
Reactant: ClCCCCCBr
Solvent: CO
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)CCCCCCl
Yield: 53.6 %

Procedure:
The reaction was conducted following the procedure for Example 171: step a, using 1-bromo-5-chloro-pentane (0.400 g, 2.150 mmol), methane sulfinic acid, (1.090 g, 10.75 mmol), EtOH [3 mL], H2O, [3 mL]. Chromatography of the residue (0%–25% MeOH/DCM) yielded the title compound (0.213 g 53%). 1H-NMR (CDCl3): δ 3.55 (t, 2H, J=6.3 Hz), 3.03 (t, 2H, J=8.0 Hz), 2.91 (s, 3H), 1.85 (m, 4H), 1.63 (m, 2H)
Reaction SMILES: [C:1]1([C:7]2[C:15]3[CH2:14][CH2:13][NH:12][CH2:11][C:10]=3[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.O>[Cl:16][C:17]1[C:25]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([N:12]1[CH2:13][CH2:14][C:15]2[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:8][NH:9][C:10]=2[CH2:11]1)=[O:20]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Reactant: c1ccc(-c2n[nH]c3c2CCNC3)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(-c3ccccc3)n[nH]c2C1
Reaction time: 8 h

Procedure:
To a solution of Intermediate 58 (433 mg, 1.38 mmol) in DCM (5 mL) was added 2-chloro-3-(trifluoromethyl)benzoic acid (310.3 mg, 1.38 mmol), triethylamine (1.15 mL, 8.29 mmol) and BOP (611.03 mg, 1.38 mmol). The solution was allowed to stir overnight. Following dilution with water, the mixture was extracted with DCM three times. The combined organic layers were dried over Na2SO4 and conc. The resulting residue was purified by basic HPLC (0-99% acetonitrile). (356 mg, 56%). MS (ESI): mass calcd. for C20H15ClF3N3O, 405.81. m/z found, 406.2 [M+H]+. 1H NMR (CDCl3): 7.76 (ddd, J=12.1, 7.8, 1.4 Hz, 1H), 7.56-7.33 (m, 7H), 5.17-4.97 (m, 1H), 4.52-4.33 (m, 1H), 4.28 (dt, J=12.9, 5.4 Hz, 1H), 3.99-3.83 (m, 1H), 3.54-3.41 (m, 1H), 2.97 (t, J=5.8 Hz, 1H), 2.79-2.68 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH2:10]Br)=[O:4].CO.[NH3:14]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[CH2:10][NH2:14])=[O:4]
Reactant: N
Reactant: COC(=O)c1sccc1CBr
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1sccc1CN
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
3-Bromomethyl-thiophene-2-carboxylic acid methyl ester (1.297 g, 5.54 mmol) is dissolved in DMF (30 mL) and MeOH/NH3 is added (30 mL). The reaction mixture is stirred at room temperature for 1 hour, and concentrated in vacuo. Purification of the residue by silica gel column chromatography eluting with 95:5 and 93:7 DCM:MeOH affords the title compound (0.82 g, 86%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][S:13]([CH2:16][CH2:17][C:18]([NH:21]C(=O)OCC1C=CC=CC=1)([CH3:20])[CH3:19])(=[O:15])=[O:14])(=[O:3])[CH3:2]>CO.[Pd]>[C:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][S:13]([CH2:16][CH2:17][C:18]([NH2:21])([CH3:20])[CH3:19])(=[O:14])=[O:15])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCOCCOCCS(=O)(=O)CCC(C)(C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(=O)OCCOCCOCCS(=O)(=O)CCC(C)(C)N
Reaction time: 1.5 h

Procedure:
To a solution of benzyl 4-(2-(2-(2-acetoxyethoxy)ethoxy)ethylsulfonyl)-2-methylbutan-2-ylcarbamate (440.2 mg, 0.959 mmol) in methanol (5 ml) was added Pd on carbon (10%, 83 mg). The suspension was put under a N2 atmosphere and H2 (1.3 atm) introduced. The suspension was stirred for 1.5 hours, filtered (0.45 um, PTFE), and concentrated in vacuo. The residue was used without any further purification. LRMS (ESI/APCI) m/z 326 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][CH:9]=[C:8]([CH2:11][O:12][C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[C:16]([C:22]([OH:24])=O)[NH:17]4)[C:7]=2[CH:25]=1.Cl.Cl.Cl.[N:29]1([CH2:36][CH2:37][N:38]2[CH2:43][CH2:42][CH:41]([NH2:44])[CH2:40][CH2:39]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>>[N:29]1([CH2:36][CH2:37][N:38]2[CH2:39][CH2:40][CH:41]([NH:44][C:22]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[C:13]([O:12][CH2:11][C:8]3[C:7]5[CH:25]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[O:10][CH:9]=3)[CH:21]=[CH:20][CH:19]=4)=[O:24])[CH2:42][CH2:43]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: COc1ccc2occ(COc3cccc4[nH]c(C(=O)O)cc34)c2c1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Agent: Cl
Product: COc1ccc2occ(COc3cccc4[nH]c(C(=O)NC5CCN(CCN6CCCCCC6)CC5)cc34)c2c1

Procedure:
This compound is synthesized from 4-(5-methoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (121) (preparation see below) and amine 5 analogously to the method described in example 1.
Reaction SMILES: [F:1][C:2]1[CH:26]=[C:25]([O:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)[C:8]([OH:10])=O)=[O:5].[NH2:34][CH2:35][CH2:36][OH:37]>>[F:1][C:2]1[CH:26]=[C:25]([O:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][CH:7]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]([F:21])([F:20])[F:22])=[CH:16][CH:17]=1)[C:8]([NH:34][CH2:35][CH2:36][OH:37])=[O:10])=[O:5]
Reactant: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O)c1ccc(OCCC(F)(F)F)cc1F
Reactant: NCCO
Product: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)NCCO)c1ccc(OCCC(F)(F)F)cc1F

Procedure:
A reaction similar to that described in Example 32 (32c) was conducted using 2-{[2-fluoro-4-(3,3,3-trifluoropropoxy)benzoyl]amino}-3-[4-(trifluoromethoxy)phenyl]propanoic acid (145 mg) prepared in Example 84 (84b) and 2-aminoethanol (22 μL) to give 128 mg of the title compound (white powder).
Reaction SMILES: [Li+].[OH-].[NH2:3][C:4]1[N:5]=[C:6]([CH3:29])[C:7]2[CH:13]=[C:12]([C:14]([O:16]CCCC)=[O:15])[C:11](=[O:21])[N:10]([C@H:22]3[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]3)[C:8]=2[N:9]=1.Cl>C1COCC1.CO.[Cl-].[Na+].O.O.CCO.C(Cl)Cl>[NH2:3][C:4]1[N:5]=[C:6]([CH3:29])[C:7]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[C:11](=[O:21])[N:10]([C@H:22]3[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]3)[C:8]=2[N:9]=1
Reactant: CCCCOC(=O)c1cc2c(C)nc(N)nc2n([C@H]2CC[C@H](O)CC2)c1=O
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: Cc1nc(N)nc2c1cc(C(=O)O)c(=O)n2[C@H]1CC[C@H](O)CC1
Reaction time: 2.5 h

Procedure:
A 1M solution of LiOH in H2O (0.81 mL, 0.81 mmol) was added to a suspension of butyl 2-amino-8-(trans-4-hydroxycyclohexyl)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylate (0.25 g, 0.68 mmol) in THF (7 mL) and MeOH (2 mL). After 2.5 h, DCM, EtOH, water, brine, celite and 0.7 mL of 1 M HCl were added. The mixture was filtered. The organic layer was seperated and concentrated by rotary evaporation to affored 0.25 g of 2-amino-8-(trans-4-hydroxycyclohexyl)-4-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylic acid.
Reaction SMILES: OCCCNC(=O)C(C(CO)(C)C)O.[Cl-].[Cl:16][CH:17]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:18][CH2:19][N+:20]([CH2:23][CH:24]([OH:26])[CH3:25])([CH3:22])[CH3:21].[OH-].[Na+]>O>[Cl-:16].[O:26]1[CH2:25][CH:24]1[CH2:23][N+:20]([CH2:19][CH2:18][CH2:17][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])([CH3:22])[CH3:21]
Reactant: CCCCCCCCCCCCCCCC(Cl)CC[N+](C)(C)CC(C)O
Agent: CC(C)(CO)C(O)C(=O)NCCCO
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCCCCCCC[N+](C)(C)CC1CO1

Procedure:
In a two liter reaction flask, fitted with a stirrer, thermometer, reflux condenser, heating mantle and a feed funnel, 205 grams of deionized water was charged. 205 grams (1 mole) of d,l- panthenol was charged into the water and stirred until dissolved. In a separate stirred one liter vessel, 852 grams (1 mole) of 50% aqueous QUAB 426 (3-Chloro-2-hydroxypropyl stearyl dimethylammonium chloride) was reacted with approximately 80 grams (1 mole) of 50% aqueous sodium hydroxide solution, to form a solution of QUAB 393 (2,3-Epoxypropyl stearyl dimethyl ammonium chloride), to a pH of ~ 9.5. The batch was heated to 50°-60° C., and the QUAB 393 solution was added to the panthenol solution through the feed funnel. The pH of the reaction mixture was checked, and adjusted to ~ 9.5 with a small additional amount of 50% sodium hydroxide solution, as required. The batch was then agitated at 50°-60° C. for a four hour period to assure complete reaction. The pH of the batch was then adjusted to 6.5-8.0 with a small amount of lactic acid. The resultant product was a clear yellow solution, containing approximately 50% solids, of which approximately 43% was stearyl dimethyl quaternized panthenol. An in vitro efficacy test of this material versus a 50% panthenol solution was tested for uptake on human hair swatches and showed an approximate 27% greater uptake than the unquaternized panthenol. Adjusting the results for concentration of active material, the stearyl dimethyl quaternized panthenol showed an approximate 31% greater uptake than the unquaternized panthenol.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[C:8]([CH3:25])[C:9]([CH2:21][N:22]([CH3:24])[CH3:23])=[C:10]([CH3:20])[C:11]=2[NH:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:6][CH2:5]1)(=O)C.[OH-].[Na+]>CO.O>[CH3:23][N:22]([CH2:21][C:9]1[C:8]([CH3:25])=[C:7]2[C:12](=[C:11]([NH:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[C:10]=1[CH3:20])[NH:4][CH2:5][CH2:6]2)[CH3:24]
Reactant: CC(=O)N1CCc2c(C)c(CN(C)C)c(C)c(NC(=O)C(C)(C)C)c21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(CN(C)C)c(C)c(NC(=O)C(C)(C)C)c2c1CCN2
Temperature: 60 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
N-(1-Acetyl-5-dimethylaminomethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide (1.0 g) was dissolved in MeOH (10 ml) and a solution of NaOH (580 mg) in water (3 ml) was added, which was followed by stirring at 60° C. for 2 hr. MeOH was evaporated under reduced pressure and CHCl3 (100 ml) was added. The mixture was washed with saturated brine and dried over anhydrous sodium sulfate. CHCl3 was evaporated under reduced pressure to give 700 mg of N-(5-dimethylaminomethyl-4,6-dimethylindolin-7-yl)-2,2-dimethylpropanamide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.[OH-].[Na+].[CH3:15]I>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.O>[CH3:15][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc2ccc(C)nc12
Reaction time: 8 h

Procedure:
A mixture of 8-hydroxyquinaldine (5.0 g) and tetrabutyl ammonium iodide (1.1 g) in tetrahydrofuran (9 ml) was treated at room temperature with sodium hydroxide (4.5 g) in water (45 ml). Methyl iodide (3.7 ml) was added and the reaction stirred overnight. The THF was removed in vacuo and the remaining solution partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous layer was re-extracted with ethyl acetate and the organic extracts combined. The organic layer was washed with saturated aqueous sodium hydrogen carbonate (100 ml) and saturated aqueous sodium chloride (100 ml). The organic layer was dried over magnesium sulphate, filtered and the filtrate evaporated in vacuo to yield the desired product as an off-white solid (5.85 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C(Cl)Cl.C(O)(=O)C.CO>[F:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:26])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[O:6])=[CH:20][CH:19]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCC(C(=O)c2cccc(NC(=O)Nc3ccc(F)cc3)c2)CC1
Yield: 67 %

Procedure:
4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 4-fluorophenyl isocyanate (39 μL, 0.344 mmol) in methylene chloride (2 mL) were mixed for 72 h at ambient temperature. The solution was diluted with 10% acetic acid in methanol and poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed extensively with methanol to remove impurities, then treated with a 2M ammonia in methanol to elute the product from the column. The solvent was evaporated and the residue was stirred with 5N sodium hydroxide solution (1 mL). The solvent was removed under vacuum and the residue was purified by silica gel chromatography (methylene chloride:methanol:ammonium hydroxide, 97.5:2.5:0.25 then 95:5:0.5). The solvent was evaporated to give 27.4 mg (67%) of the title compound.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6]Br.[O:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15]CC)=O.[Cl-].[NH4+]>O1CCCC1>[O:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1([OH:15])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: BrCCCCBr
Reactant: CCOC(=O)C1CCCO1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OC1(C2CCCO2)CCCC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
A flask was charged with 13.6 g of magnesium and 300 ml of tetrahydrofuran, to which 60.3 g of 1,4-dibromobutane was added dropwise at 50° C. After the completion of dropwise addition, the solution was stirred at 60° C. for one hour. To the solution below 40° C., 31.0 g of ethyl tetrahydrofurancarboxylate was added dropwise. The solution was stirred at room temperature for one hour, after which an aqueous solution of ammonium chloride was added for hydrolysis. Ordinary post-treatment yielded 30.2 g of 1-(2-tetrahydrofuranyl)cyclopentanol.