Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1C=CC=C[C:4]=1B(O)O.C[O:15][C:16](=[O:45])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:34]=3Br)[CH:27]=2)=[CH:21][C:20]=1[CH3:44]>>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:37]=[CH:38][C:33]([O:32][C:28]2[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=2)[O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][C:16]([OH:15])=[O:45])=[C:20]([CH3:44])[CH:21]=2)=[C:34]([C:35]2[CH:19]=[CH:18][CH:17]=[CH:16][C:36]=2[C:39]([F:41])([F:42])[F:40])[CH:4]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: COC(=O)CCc1ccc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2cccc(Oc3ccc(C(F)(F)F)cc3-c3ccccc3C(F)(F)F)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 89 by using 2-trifluoromethylphenyl boronic acid and 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-phenoxy]-2-methyl-phenyl}-propionic acid methyl ester to afford about 108 mg (68%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C30H22O4F6 560, found 561 (M+1,100%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12]([O-:17])(=[S:16])[C:13]([NH2:15])=[O:14].[K+].Cl>O>[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][NH:15][C:13](=[O:14])[C:12]([OH:17])=[S:16]
Reactant: NC(=O)C([O-])=S
Reactant: Cc1[nH]cnc1CSCCN
Agent: Cl
Agent: [K+]
Solvent: O
Product: Cc1[nH]cnc1CSCCNNC(=O)C(O)=S

Procedure:
2-(5-Methyl-4-imidazolylmethylthio)ethylamine is added to a solution of potassium thiooxamate in water. After 2 hours at room temperature the solution is acidified with hydrochloric acid to yield N-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]thiooxamic acid. This is then reacted with 2-(5-methyl-4-imidazolylmethylthio)ethylamine and trilead tetroxide according to the general procedure of Example 2 to yield N,N'-bis-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amidinoformic acid.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CS(C)=O.C([C:13]1[C:22]2[C:17](=[CH:18][C:19]([CH3:23])=[CH:20][CH:21]=2)[C:16](CC)=[C:15]([CH:26]([P:28](=O)([O-:30])[O-:29])[OH:27])[C:14]=1[Br:32])C.[CH2:33](N(CC)CC)[CH3:34]>C(Cl)Cl.O>[Br:32][C:14]1[C:15]([C:26]([P:28](=[O:29])([O:5][CH2:1][CH3:2])[O:30][CH2:33][CH3:34])=[O:27])=[CH:16][C:17]2[C:22]([CH:13]=1)=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCN(CC)CC
Reactant: CCc1c(Br)c(C(O)P(=O)([O-])[O-])c(CC)c2cc(C)ccc12
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: CCOP(=O)(OCC)C(=O)c1cc2cc(C)ccc2cc1Br
Temperature: 25 °C

Procedure:
To a solution of oxalyl chloride (0.15 mL) in 2.5 mL of CH2Cl2 at −78° C. was added DMSO (0.23 mL). The reaction was stirred for 10 minutes after which a solution of diethyl(3-bromo-7-methyl-2-naphthyl)(hydroxy)methylphosphonate (160 mg), in 2.5 mL CH2Cl2 was added dropwise. The reaction was stirred for 1 h at −78° C. after which triethylamine (0.66 mL) was added to the mixture and the temperature was raised to rt. Water (5 mL) was added and the mixture was extracted with CH2Cl2. The organic extracts were combined, dried over Na2SO4 and evaporated to dryness to afford the titled product which was used as such in the next step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15](Br)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[Si:28]([O:35][CH2:36][CH:37]=[O:38])([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1.CCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:37]([OH:38])[CH2:36][O:35][Si:28]([C:31]([CH3:33])([CH3:32])[CH3:34])([CH3:29])[CH3:30])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(C(O)CO[Si](C)(C)C(C)(C)C)nc3N21
Reaction time: 0.5 h
Yield: 46.5 %

Procedure:
To a solution of 4.00 g (4R,9aR)-6-bromo-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 100 ml toluene was added drop wise at −78° C. 10.86 ml of a 1.5M solution of tert-butyllithium in pentane. The mixture was stirred at this temperature for 30 min. To the resulting solution was added 5.017 g (tert-butyldimethylsilyloxy) acetaldehyde and the mixture was stirred at −78° C. for 30 min. The reaction was quenched by addition of 10% aqueous ammonium chloride. The phases were separated and the organic phase was purified by chromatography on silica gel with heptane:ethyl acetate=4:1 to yield 2.34 g (4R,9aR)-6-[2-(tert-butyl-dimethyl-silanyloxy)-1-hydroxy-ethyl]-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester as slightly yellow oil (MS: 464.4 (M+H+))
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.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.[Cl:65][C:66]1[CH:72]=[CH:71][C:69]([NH2:70])=[CH:68][CH:67]=1>C(Cl)Cl>[Cl:65][C:66]1[CH:72]=[CH:71][C:69]([NH:70][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:29])=[CH:68][CH:67]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: Nc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(Cl)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (200 mg, 0.34 mmol) in methylene chloride (10 mL), HATU (Aldrich, 234 mg, 0.62 mmol) was added followed by the addition of DIPEA (0.30 mL, 1.71 mmol) and 4-chloro-aniline (Aldrich, 88 mg, 0.68 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 5-15% EtOAc/hexanes) to give a white solid. 105 mg.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:10]=[CH:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:4]([CH3:26])[CH:3]=1.[C:27]([Cu])#[N:28].[OH2:30]>CN(C=O)C>[C:27]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:10]=[CH:11][C:12]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:4]([CH3:26])[CH:3]=1)(=[O:30])[NH2:28]
Reactant: N#C[Cu]
Reactant: O
Reactant: CCOC(=O)c1ccn(-c2ccc(OC)cc2)c1-c1ccc(Br)cc1C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccn(-c2ccc(OC)cc2)c1-c1ccc(C(N)=O)cc1C
Temperature: 180 °C
Yield: 66 %

Procedure:
To a mixture of ethyl 2-(4-bromo-2-methylphenyl)-1-(4-methoxyphenyl)-1H-pyrrole-3-carboxylate (1 g, 2.4 mmol) in DMF (50 mL) was added CuCN (0.43 g, 4.8 mmol), and the suspension solution was heated to 180° C. for 12 h. After being cooled down to room temperature, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified on silica gel column chromatography (eluting with 50% ethyl acetate in petroleum ether) to give the title compound (600 mg, 66% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:20][C:19](=[O:21])[N:18]([CH3:22])[C:17]([NH:23]C(=O)OC(C)(C)C)=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:31])[N:11]=[C:10]([F:32])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:33][C:34]1[C:39](B(O)O)=[CH:38][CH:37]=[CH:36][N:35]=1>>[NH2:23][C:17]1[N:18]([CH3:22])[C:19](=[O:21])[CH2:20][C@@:15]2([C:14]3[CH:13]=[C:12]([Cl:31])[N:11]=[C:10]([F:32])[C:9]=3[O:8][C:5]3[C:4]2=[CH:3][C:2]([C:39]2[C:34]([F:33])=[N:35][CH:36]=[CH:37][CH:38]=2)=[CH:7][CH:6]=3)[N:16]=1
Reactant: OB(O)c1cccnc1F
Reactant: CN1C(=O)C[C@@]2(N=C1NC(=O)OC(C)(C)C)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Product: CN1C(=O)C[C@@]2(N=C1N)c1cc(-c3cccnc3F)ccc1Oc1c2cc(Cl)nc1F

Procedure:
The title compound was synthesized by procedures and steps analogous to those described in Example 12 above, but using (R)-tert-butyl 7-bromo-3-chloro-1-fluoro-1′-methyl-6′-oxo-5′,6′-dihydro-1′H-spiro[chromeno[2,3-c]pyridine-5,4′-pyrimidine]-2′-ylcarbamate (Intermediate 1-A) and 2-fluoropyridin-3-ylboronic acid.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C([N:36]2[CH2:40][CH2:39][C:38](F)(F)[CH2:37]2)C2N=NNC=2N=1)(C)(C)C.Br.BrCC1C=CC=CN=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=3)[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Agent: Br
Agent: BrCc1ccccn1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccccn3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(bromomethyl)pyridine hydrobromide and isolated as light-yellow solid (4.2 mg, 27%). MS(m/e): 374.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[O:23])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:32])[CH:3]=1.[CH3:33][N:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40](O)=[O:41])[C:35]1=[O:43].O=C1NC=CN=C1C(OC)=O.IC>>[F:32][C:4]1[CH:3]=[C:2]([NH:1][C:40]([C:36]2[C:35](=[O:43])[N:34]([CH3:33])[CH:39]=[CH:38][N:37]=2)=[O:41])[CH:31]=[CH:30][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[O:23])=[CH:20][CH:21]=3)[S:15][C:8]=12
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCOCC5)cc4)sc23)c(F)c1
Reactant: Cn1ccnc(C(=O)O)c1=O
Agent: COC(=O)c1ncc[nH]c1=O
Solvent: CI
Product: Cn1ccnc(C(=O)Nc2ccc(Oc3ccnc4cc(-c5ccc(C(=O)N6CCOCC6)cc5)sc34)c(F)c2)c1=O
Yield: 25 %

Procedure:
Prepared from (4-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)phenyl)(morpholino)methanone (prepared as in Example 129, Step A) and 4-methyl-3-oxo-3,4-dihydropyrazine-2-carboxylic acid (prepared from methyl 3-oxo-3,4-dihydropyrazine-2-carboxylate with iodomethane and followed by hydrolysis using the methods described in Example 149, Steps A and B) according to the procedure of Example 89. The crude was purified by silica gel flash column chromatography (5% MeOH in CH2Cl2) to afford 6.6 mg (25%) of the desired product. LRMS (APCI pos) m/e 586.2 (M+1). 1H-NMR (400 MHz, CDCl3/CD3OD) δ 8.47 (d, 1H), 8.07 (dd, 1H), 7.92 (m, 3H), 7.86 (s, 1H), 7.76 (d, 1H), 7.55 (m, 3H), 7.39 (t, 1H), 6.67 (d, 1H), 3.75 (s, 3H), 3.55-3.80 (m, 8H); 19F NMR (376 MHz, CDCl3/CD3OD) δ −128.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].Br[CH2:11][CH2:12][F:13].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:11][CH2:12][F:13]
Reactant: FCCBr
Reactant: Oc1ccc(Cl)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: FCCOc1ccc(Cl)cc1Br
Yield: 88.8 %

Procedure:
A stirred suspension of 2-bromo-4-chlorophenol (2.07 g, 10 mmol), 1-bromo-2-fluoroethane (1.52 g, 12 mmol) and potassium carbonate (1.65 g, 12 mmol) in 2-butanone (10 mL) was heated at reflux temperature for 16 hours. The suspension was allowed to cool and then filtered. The filtrate was concentrated in vacuo and then distilled in vacuo to afford the titled compound as a colorless oil (2.25 g, 89%): bp 80-82° C. @ 0.1 torr
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].[Na+].Cl[C:12]1[N:20]=[CH:19][N:18]=[C:17]2[C:13]=1[NH:14][CH:15]=[N:16]2>O1CCCC1>[CH2:1]([O:8][C:12]1[N:20]=[CH:19][N:18]=[C:17]2[C:13]=1[NH:14][CH:15]=[N:16]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCO
Reactant: Clc1ncnc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCOc1ncnc2nc[nH]c12
Yield: 76.6 %

Procedure:
Heptanol (45.02 g, 0.388 mol) was added to a stirred suspension of a 60% dispersion of sodium hydride in oil (16.62 g, 0.416 mol) in dry tetrahydrofuran (350 ml) under an atmosphere of nitrogen. After gas evolution had ceased (about 1 h), 6-chloropurine (16.04 g, 0.104 mol) was added. The reaction began to foam and more gas was evolved. When gas evolution had ceased (about 0.75 h) the reaction was heated at reflux for 3 h then the solvent was removed in vacuo. The residual oily solid was suspended in water (2l) then concentrated hydrochloric acid (30 ml) was added. The aqueous suspension was neutralised with saturated sodium hydrogen carbonate solution and 60-80 petroleum ether (750 ml) added. The solid was moved from the biphasic mixture by filtration, washed with 60-80 petroleum ether and dried at oil-pump vacuum/40° C. This gave the title compound (1)(18.64 g, 79.7 mmol, 77%) as a white solid.
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]1[C:10](=[O:11])[NH:9][C:7](=[O:8])[C:5]1=[O:6].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[CH3:3][N:4]1[C:5](=[O:6])[C:7](=[O:8])[N:9]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]1=[O:11]
Reactant: CCOC(=O)CBr
Reactant: CN1C(=O)NC(=O)C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CN1C(=O)C(=O)N(C)C1=O

Procedure:
2.7 g of potassium hydroxide was dissolved in 150 ml of ethanol. 5.1 g of 1-methylparabanic acid and 10 ml of ethyl bromoacetate were added thereto and the solution was heated under reflux for 6 hours. After cooling, the insoluble substance was filtered off and ethanol was distilled away. The residue was dissolved in ethyl acetate, washed with 5% sodium carbonate and brine, dried over anhydrous sodium sulfate, and passes through silica gel column. Ethyl acetate was distilled away and the residue was recrystallized from hexane to give 3.1 g of ethyl 1-methyl-2,4,5-trioxoimidazolidine-3-acetate (Compound 1).
Reaction SMILES: C([O:3][C:4](=[O:16])[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][O:7]1)C>C1COCC1.CO.[OH-].[Na+]>[CH:6]1([CH2:5][C:4]([OH:16])=[O:3])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][O:7]1
Reactant: CCOC(=O)CC1OCCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC1OCCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (±)-isochroman-1-yl-acetic acid ethyl ester (1.90 g, 8.63 mmol, 1 eq.) in THF (40 mL) and MeOH (10 mL), 1M aq. NaOH soln. (17.3 mL, 17.3 mmol, 2 eq.) was added. The pale yellow solution was stirred at r.t. for 2 hours, then the organic solvents were removed in vacuo. The aq. layer was washed with AcOEt (1×10 mL). The aq. layer was acidified with 1N aq. HCl (pH=1). The resulting emulsion was extracted with DCM (3×25 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo to give the title compound as a colorless oil that solidifies upon standing. The product was used without further purification.
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][N:23]([C:46](=[O:52])[CH2:47][CH2:48][N:49]([CH3:51])[CH3:50])[CH2:24][CH2:25][O:26][C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Br:53][CH2:54][CH2:55][OH:56]>C(#N)C>[Br-:53].[C:1]([O:20][CH2:21][CH2:22][N:23]([CH2:24][CH2:25][O:26][C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:46](=[O:52])[CH2:47][CH2:48][N+:49]([CH2:54][CH2:55][OH:56])([CH3:51])[CH3:50])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CCN(C)C
Reactant: OCCBr
Solvent: CC#N
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CC[N+](C)(C)CCO
Product: [Br-]
Temperature: 80 °C
Reaction time: 8 h

Procedure:
In a sealed system, (((Z)-((3-(dimethylamino)propanoyl)azanediyl)bis(ethane-2,1-diyl) dioleate (588 mg, 0.802 mmol) was dissolved in ACN (10 mL) and 2-bromoethanol (200 uL) was added. The reaction vessel was flushed with inert gas and then sealed. Reaction was heated to 80° C. and stirred overnight, then cooled and concentrated in vacuo. Purification by silica gel chromatography with a DCM/MeOH gradient yielded 3-(bis(2-(oleoyloxy)ethyl)amino)-N-(2-hydroxyethyl)-N,N-dimethyl-3-oxopropan-1-aminium bromide (160 mg). QTOF MS ESI+: m/z 764.3 (M+H).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[CH2:6][N:7]([CH2:11][C:12]1[CH:13]=[C:14]2[C:29]([CH3:30])=[N:28][N:27]([CH3:31])[C:15]2=[N:16][C:17]=1[N:18]([CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:19][CH3:20])[C:8]([NH2:10])=[O:9]>C(O)(C)(C)C>[F:40][C:2]([F:39])([F:1])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:37])([F:38])[F:36])[CH:34]=1)[CH2:6][N:7]([CH2:11][C:12]1[CH:13]=[C:14]2[C:29]([CH3:30])=[N:28][N:27]([CH3:31])[C:15]2=[N:16][C:17]=1[N:18]([CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:19][CH3:20])[C:8]1[O:9][CH:34]=[C:3]([C:2]([F:40])([F:39])[F:1])[N:10]=1
Reactant: CCN(CC1CCCC1)c1nc2c(cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(N)=O)c(C)nn2C
Solvent: CC(C)(C)O
Product: CCN(CC1CCCC1)c1nc2c(cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nc(C(F)(F)F)co1)c(C)nn2C
Temperature: 25 °C
Yield: 20 %

Procedure:
To a stirred solution of 1-(3,5-bis-trifluoromethyl-benzyl)-1-[6-(cyclopentylmethyl-ethyl-amino)-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-ylmethyl]-urea (0.250 g, 0.430 mmol) in tert-butanol (10 mL) was added 1,1,1-trifluoromethyl acetyl bromide (0.20 g, 0.480 mmol). This mixture was refluxed for 3 h and then cooled to RT. After concentration in vacuo, water (10 mL) was added to the residue, and the product was extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate and concentrated under vacuum to afford the crude residue, which was purified by column chromatography over 100-200 mesh silica gel using 5% ethyl acetate and petroleum ether, to yield the title compound as a white solid (yield: 20%).
Reaction SMILES: Cl.C(OC([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2([C:19]([O:21]C(C)(C)C)=[O:20])[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)=O)(C)(C)C>O1CCOCC1>[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([C:19]([OH:21])=[O:20])[CH2:18][CH2:17]2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc(C2(C(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.0 M HCl in dioxane was added to tert-butyl 1-{4-[(tert-butoxycarbonyl)amino]phenyl}cyclopropanecarboxylate (160 mg, 0.00048 mol). After stirring at rt for 2 h, the volatiles were removed in-vacuo and the resulting residue was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:40])[C:5]([CH3:39])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:35]C(=O)C)=[C:17]([CH:34]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([S:27]([C:30]([F:33])([F:32])[F:31])(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:40])[C:5]([CH3:39])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:35])=[C:17]([CH:34]=2)[C:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([S:27]([C:30]([F:31])([F:32])[F:33])(=[O:28])=[O:29])=[CH:25][CH:26]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(S(=O)(=O)C(F)(F)F)cc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(S(=O)(=O)C(F)(F)F)cc3)c2)=C(C)C1=O
Yield: 37.8 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-(trifluoromethylsulfonyl)aniline (0.060 g, 0.103 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (2 ml), the solution was stirred at room temperature for 2 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.021 g, 0.0389 mmol, 38%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH4-].[Na+]>CN(C=O)C.C(O)C.O>[CH2:13]([N:10]1[CH2:11][CH:12]=[C:7]([CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH2:8][CH2:9]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1csc(Cc2ccncc2)c1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: C1=C(Cc2cccs2)CCN(Cc2ccccc2)C1
Temperature: 100 °C
Reaction time: 3 h
Yield: 106.3 %

Procedure:
To a stirred solution of 4-(thiophen-2-ylmethyl)pyridine (H) (3.1 g, 11.52 mmol) in DMF (10 mL) was added benzyl bromide (2.16 g, 12.67 mmol) at 20-35° C. and the reaction mixture was allowed to stir at 100° C. for 3 h. Then the reaction mixture was cooled to 20-35° C., diluted with ethanol (30 mL) and NaBH4 (0.65 g, 17.28 mmol) was added slowly portionwise at 0° C. and then heated at 70-80° C. for 2 h. The reaction mixture was rotary evaporated, resultant residue was diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was rotary evaporated under vacuum to get residue which was purified by column chromatography using a mixture of 20% ethyl acetate/hexane as an eluent to get the desired compound as a light brown oily liquid (3.3 g, 67%); 1H NMR (400 MHz, DMSO-d6) δ 7.33-7.28 (m, 5H), 7.28-7.22 (m, 1H), 6.94 (dd, J=3.4, 5.4 Hz, 1H), 6.84-6.82 (m, 1H), 5.46 (s, 1H), 3.51 (s, 2H), 3.46 (s, 2H), 2.87 (s, 2H), 2.46 (t, J=5.9 Hz, 2H), 1.98 (s, 2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:49])[CH:7]([NH:31][C:32](=[O:48])[CH:33]([NH:38][C:39]([N:41]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)=[O:40])[CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23]C(OC(C)(C)C)=O)[CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:49])[CH:7]([NH:31][C:32](=[O:48])[CH:33]([NH:38][C:39]([N:41]1[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]1)=[O:40])[CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(OCc2cccc(NC(=O)OC(C)(C)C)c2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(OCc2cccc(N)c2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The product from Example 28 was dissolved in CH2Cl2 and treated with trifluoroacetic acid. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and purified to give the title compound.