Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[O:11][C:10]([C:12](O)=[O:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>CN(C=O)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][C:7]2[O:11][C:10]([C:12]([Cl:19])=[O:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(Cc2ccc(F)cc2)o1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Cc2ccc(F)cc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.6 %

Procedure:
To 5-(4-fluorobenzyl)-2-furan carboxylic acid (450 mg, 2 mmol) were added thionylchloride (1 ml, 13.7 mmol) and DMF (0.025 ml). The mixture was stirred for 30 minutes at room temperature. The excess amount of thionylchloride was evaporated. The precipitated residue was washed with n-hexane to give crude 5-(4-fluorobenzyl)-2-furan carboxylic acid chloride (480 mg).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[CH:12]=[C:11]([Cl:23])[C:10]=1[F:24])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:16])[CH:12]=[C:11]([Cl:23])[C:10]=1[F:24]
Reactant: CC(C)(C)OC(=O)NCc1cc(C(=O)N2CCOCC2)cc(Cl)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1cc(C(=O)N2CCOCC2)cc(Cl)c1F

Procedure:
was prepared according to Scheme C3 (step B) from [3-chloro-2-fluoro-5-(morpholine-4-carbonyl)-benzyl]-carbamic acid tert-butyl ester (72 mg, 0.19 mmol) and TFA (1 mL) in CH2Cl2. MS (LC-MS): 273.0 [M]+; tR (HPLC conditions c): 2.64 min.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:21])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[C:13]([Cl:20])[CH:12]=3)[CH:6]=[N:7][CH:8]=1.[C:22](Cl)(=[O:26])[CH2:23][CH2:24][CH3:25].C(N(CC)CC)C>ClCCl>[Cl:20][C:13]1[CH:12]=[C:11]2[C:16]([C:17]([C:18]#[N:19])=[C:9]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH:8]=[N:7][CH:6]=3)[N:10]2[CH3:21])=[CH:15][CH:14]=1
Reactant: Cn1c(-c2cncc(CN)c2)c(C#N)c2ccc(Cl)cc21
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(=O)NCc1cncc(-c2c(C#N)c3ccc(Cl)cc3n2C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(5-aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile (Example 186e, 0.060 g, 0.202 mmol) in dichloromethane (2 mL) is added butyryl chloride (0.024 g, 0.222 mmol) and triethylamine (0.056 mL, 0.405 mmol), and the reaction is stirred at room temperature for 30 min. The reaction mixture is diluted with dichloromethane and washed with water. The organic layer is dried over sodium sulfate and concentrated in vacuo. The residue is purified by silica gel flash chromatography (dichloromethane-methanol, 19:1) to afford N-[5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-butyramide as a white solid. 1H NMR (400 MHz, MeOD) δ ppm 0.98 (t, J=7.5 Hz, 3H), 1.65-1.77 (m, 2H), 2.29 (t, J=7.5 Hz, 2H), 3.82 (s, 3H), 4.57 (s, 2H), 7.38 (dd, J=8.6, 1.8 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.77 (d, J=1.5 Hz, 1H), 8.09 (t, J=2.1 Hz, 1H), 8.73 (d, J=2.0 Hz, 1H), 8.78 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 367.1327 [(M+H)+ Calcd for C20H20N4OCl: 367.1326].
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[S:12][C:11]2[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[NH:7][C:6](=S)[C:5]=2[N:4]=1.FC(F)(F)S(OC)(=O)=O.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH2:37][CH2:38][C@H:39]2[CH2:44][NH:43][CH2:42][CH2:41][NH:40]2)[CH:34]=[CH:35][CH:36]=1>>[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH2:37][CH2:38][C@@H:39]2[NH:40][CH2:41][CH2:42][N:43]([C:6]3[C:5]4[N:4]=[C:3]([C:2]([F:19])([F:18])[F:1])[S:12][C:11]=4[NH:10][C:9]4[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=4[N:7]=3)[CH2:44]2)[CH:34]=[CH:35][CH:36]=1
Reactant: FC(F)(F)c1nc2c(s1)Nc1ccccc1NC2=S
Reactant: COc1cccc(CC[C@H]2CNCCN2)c1
Agent: COS(=O)(=O)C(F)(F)F
Product: COc1cccc(CC[C@H]2CN(C3=Nc4ccccc4Nc4sc(C(F)(F)F)nc43)CCN2)c1
Yield: 67.7 %

Procedure:
Using a method similar to Example 484, using 2-trifluoromethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione (4.025 g, 13.36 mmol) and methyl trifluoromethanesulfonate (2.27 mL, 20.0 mmol), to form the methylated intermediate. Take 1.38 g of this intermediate (3.0 mmol), combine with (S)2-[2-(3-Methoxy-phenyl)-ethyl]-piperazine (0.65 g, 3.0 mmol), followed by chromatographic purification, eluting with a gradient of a 3.5% solution of 2M ammonia in methanol, in dichloromethane (0–100% in dichloromethane) gives the title compound (0.99 g): mass spectrum (APCI+, m/e): 488 (M+1); 1H NMR (300 MHz, DMSO-d6), δ (ppm): 8.73–8.49 (m, 2H), 7.21–7.15 (m, 1H), 6.99–6.88 (m, 3H), 6.79–6.69 (m, 4H), 4.25–3.98 (br. m, 2H), 3.70 (s, 3H), 3.38–3.17 (m, 3H), 3.14–2.97 (m, 2H), 2.74–2.52 (m, 2H), 1.90–1.80 (m, 2H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:21]=[C:20]4[C:14]([CH2:15][CH2:16][N:17](C(OC(C)(C)C)=O)[CH2:18][CH2:19]4)=[N:13]3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCOCC1.CO>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH:21]=[C:20]4[C:14]([CH2:15][CH2:16][NH:17][CH2:18][CH2:19]4)=[N:13]3)=[CH:8][CH:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ccc(N4CCCC4)cc3)nc2CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: c1cc(-n2cc3c(n2)CCNCC3)ccc1N1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,1-dimethylethyl 2-[4-(1-pyrrolidinyl)phenyl]-4,5,7,8-tetrahydropyrazolo[3,4-d]azepine-6(2H)-carboxylate (may be prepared as described in Description 44) (79 mg, 0.21 mmol) in dioxan (3 ml) was added 4M hydrochloric acid in dioxan (2 ml). The resulting mixture was stirred at room temperature, under argon, overnight. The reaction mixture was diluted with methanol and then purified by SCX, eluting with methanol and then 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo to afford the title compound (D45). MS (ES+) m/e 283 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:7](=[O:8])[O:6][CH2:5][C:4]=1[N:9]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:10]1=[O:26].CI.Cl[CH2:30]CCl>C(Cl)Cl.[Ag]=O>[CH3:30][O:1][CH2:2][C:3]1[C:7](=[O:8])[O:6][CH2:5][C:4]=1[N:9]1[CH2:13][CH2:12][C:11]2([CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:17][CH2:18]2)[C:10]1=[O:26]
Reactant: ClCCCl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(CO)C(=O)OC1)C2=O
Agent: O=[Ag]
Solvent: ClCCl
Solvent: CI
Product: COCC1=C(N2CCC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)COC1=O
Temperature: 25 °C

Procedure:
tert-butyl 2-(4-(hydroxymethyl)-5-oxo-2,5-dihydrofuran-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (0.42 g, 1.15 mmol), silver oxide (0.292 g, 1.26 mmol) and methyl iodide (0.358 mL, 5.73 mmol) were taken up in DCM (5 mL) and stirred over night at room temperature under nitrogen. Additional silver oxide (0.292 g, 1.26 mmol) and methyl iodide (0.358 mL, 5.73 mmol) were added to the mixture with DCE (8 mL) and the resulting mixture was heated at 54° C. overnight. The reaction mixture was filtered through CELITE® to remove silver oxide, concentrated, and purified by silica gel column chromatography (40 g RediSep Gold column) using (20-80) % EtOAc/DCM as mobile phase to afford the title compound.
Reaction SMILES: [Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[C:12]1([C@@H:18](O)[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCl.C(OCC)(=O)C>[Br:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([O:5][C@H:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:19])=[O:4]
Reactant: O=C(O)C(Br)c1ccccc1
Reactant: C[C@H](O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H](OC(=O)C(Br)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.9 %

Procedure:
To a mixture of α-bromophenylacetic acid (10.75 g, 0.050 mol), (S)-(−)-1-phenylethanol (7.94 g, 0.065 mol) and DMAP (0.61 g, 5.0 mmol) in dry dichloromethane (100 mL) was added solid EDCI (12.46 g, 0.065 mol) all at once. The resulting solution was stirred at room temperature under Ar for 18 hours and then it was diluted with ethyl acetate, washed (H2O×2, brine), dried (Na2SO4), filtered, and concentrated to give a pale yellow oil. Flash chromatography (SiO2/hexane-ethyl acetate, 4:1) of this oil provided the title compound (11.64 g, 73%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.53-7.17 (m, 10H), 5.95 (q, J=6.6 Hz, 0.5H), 5.94 (q, J=6.6 Hz, 0.5H), 5.41 (s, 0.5H), 5.39 (s, 0.5H), 1.58 (d, J=6.6 Hz, 1.5H), 1.51 (d, J=6.6 Hz, 1.5H).
Reaction SMILES: [CH2:1]([S-:3])[CH3:2].[Na+].[N+]([C:8]1[CH:9]=[CH:10][C:11]([C:14]([O:16]C)=[O:15])=[N:12][CH:13]=1)([O-])=O.C(O)(=O)C>CN(C=O)C>[CH2:1]([S:3][C:8]1[CH:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[N:12][CH:13]=1)[CH3:2]
Reactant: CC[S-]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cn1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCSc1ccc(C(=O)O)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
Sodium ethanethiolate (1.6 g, 17.2 mmol) was added to a solution of methyl 5-nitropicolinate (2.8 g, 16 mmol) in DMF (30 mL), and the resulting mixture was stirred a room temperature. After 3 hours, acetic acid (1 mL) was added, and the mixture was evaporated to dryness. The residue was suspended in methanol (50 mL) and treated with 3N NaOH. The resulting mixture was stirred at room temperature for 16 hours and then evaporated. The residue was dissolved in water (100 mL), washed with ethyl acetate (2×100 mL), and acidified to pH 3-4 (conc. HCl), resulting in precipitation of the product. The precipitate was filtered, rinsed with water (100 mL) and dried under vacuum, providing 2.3 g of 5-(ethylthio)picolinic acid, in 79% yield; 1H NMR (DMSO-d6) δ 1.23 (t, 3H, J=7.3 Hz), 3.14 (q, 2H, J=7.3 Hz), 7.86 (dd, 1H, J=8.4 Hz, J=2.4 Hz), 7.95 (dd, 1H, J=8.4 Hz, J=0.9 Hz), 8.57 (dd, 1H, J=2.4 Hz, J=0.9 Hz), 13.09 (br, 1H).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([NH2:25])[CH:16]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([O-])(O)=O.[Na+].[F:31][C:32]1[C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=[CH:34][N:33]=1.CCOC(C)=O.CCCCCC>C(Cl)Cl>[C:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([NH:25][C:38]([C:37]3[C:32]([F:31])=[N:33][CH:34]=[CH:35][CH:36]=3)=[O:39])[CH:16]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C(Cl)c1cccnc1F
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(N)cc(C(F)(F)F)c2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(NC(=O)c3cccnc3F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
1-Boc-4-(3-amino-5-trifluoromethyl-phenoxy)-piperidine (4.37 g) was dissolved in CH2Cl2 (100 ml) and NaHCO3 (2.4 g, Baker) was added. 2-Fluoropyridine-3-carbonyl chloride (2.12 g) was added an the reaction was stirred at RT for 2.5 h. The reaction was filtered and concentrated in vacuo to yield a yellow foam. (30%) EtOAc/Hexane was added and 1-Boc-4-{3-[(2-fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine precipitated as an off white solid.
Reaction SMILES: O[CH2:2][CH2:3][S:4][CH2:5][CH3:6].NC(N)=[S:9].Cl.[OH-].[K+].Cl.Cl[CH2:16][CH2:17][CH2:18][NH2:19]>O>[NH2:19][CH2:18][CH2:17][CH2:16][S:9][CH2:2][CH2:3][S:4][CH2:5][CH3:6]
Reactant: NC(N)=S
Reactant: NCCCCl
Reactant: CCSCCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCSCCSCCCN

Procedure:
106 g (1 mole) of 1-hydroxy-3-thiapentane were boiled under reflux for 3 hours with 76 g (1 mole) of thiourea and 110 g (1.1 mole) of 37% hydrochloric acid. A solution of 68 g (1.21 moles) of potassium hydroxide in 100 ml of water was then added dropwise with stirring at 313° to 323° K. After heating for 40 minutes to 363° K., the 3-thiapentane-1-thiol precipitated was separated off in a separation funnel and dissolved under nitrogen at 303° to 313° K. in 400 g of 40% KOH (2.85 moles of KOH) accommodated in a 1000 ml three-necked flask. A solution of 130 g of 3-chloropropylamine hydrochloride (1 mole) in 160 ml of water was then added dropwise with stirring at 343° K. After stirring for another 3 hours at 363° K., the mixture was cooled to 323° K. and separated in a separation funnel. The oil phase was fractionated in vacuo twice.
Reaction SMILES: [C:1]([NH:4][C@:5]1([C:29](=[O:35])[NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17][C:16]([CH3:19])([CH3:18])[C:15]([CH3:21])([CH3:20])[O:14]2)[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6]1)(=[O:3])[CH3:2].[ClH:36].O1CCOCC1>C1COCC1.C(OCC)C>[ClH:36].[C:1]([NH:4][C@:5]1([C:29]([NH:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:35])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17][C:16]([CH3:18])([CH3:19])[C:15]([CH3:20])([CH3:21])[O:14]2)[CH2:8][NH:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CN(C(=O)OC(C)(C)C)C[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reaction time: 2.5 h
Yield: 97 %

Procedure:
While under nitrogen, a stirred solution of tert-butyl (3R,4S)-3-acetamido-3-(tert-butylcarbamoyl)-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidine-1-carboxylate (400 mg, 0.807 mmol) in anhydrous THF (5 mL) was treated with 4 M HCl in 1,4-dioxane (3.03 mL, 12.1 mmol). After 2.5 h, the mixture was diluted with diethyl ether (15 mL) and filtered, washed with additional ether and concentrated to give (3R,4S)-3-acetamido-N-tert-butyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl]pyrrolidine-3-carboxamide hydrochloride (340 mg, 97%) as a white solid. 1H NMR (D2O, 400 MHz) δ 4.11 (d, J=12 Hz, 1 H), 3.58 (dd, J=11.5, 7.7 Hz, 1 H), 3.19 (d, J=12 Hz, 1 H), 3.01 (t, J=11.5, 1 H), 2.42 (m, 1 H), 1.92 (s, 3 H), 1.52 (m, 1 H), 1.30 (m, 2 H), 1.19 (s, 9 H), 1.16 (s, 12 H), 1.08 (m, 1 H), 0.75 (m, 2 H). LC-MS gives ESI+ MS found for C20H38BN3O4 m/z 396.1 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)[CH3:3].Cl[CH2:19][CH:20]([CH3:27])[CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:3][N:2]([CH3:1])[CH2:4][C:5]1([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:19][CH:20]([CH3:27])[CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:13][CH:12]=2)[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: CC(CCl)CN1CCCC1
Reactant: CN(C)CC1(c2ccc(O)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(COc1ccc(C2(CN(C)C)CCOCC2)cc1)CN1CCCC1
Yield: 41.5 %

Procedure:
4-(4-Dimethylaminomethyl-tetrahydro-pyran-4-yl)-phenol (0.91 g, 3.87 mmol), 1-(3-chloro-2-methyl-propyl)-pyrrolidine (500 mg, 3.10 mmol), DMF (5 ml) and K2CO3 (2.14 g, 15.50 mmol) were reacted together according to general procedure B. The organic phase was washed with 2M NaOH (3×20 ml), water (2×20 ml), dried over MgSO4, fitered and concentrated in vacuo at 35° C. The crude material was subjected to chromatography on silica eluting with DCM:MeOH:NH3 (97:2:1) to provide the title compound (464 mg, 42%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ7.20 (d, 2H), 6.88 (d, 2H), 4.00 (dd, 1H), 3.80-3.70 (m, 3H), 3.55 (td, 2H), 2.59-2.43 (m, 5H), 2.40 (s, 2H), 2.33 (dd, 1H), 2.21-2.04 (m, 3H), 1.97 (s, 6H), 1.88 (ddd, 2H), 1.82-1.70 (m, 4H), 1.08 (d, 3H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:9][CH:8]2[N:10]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=3)[CH:5]([CH2:6][CH2:7]2)[CH2:4]1.[Cl:23][CH2:24][CH2:25][C:26](Cl)=[O:27].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:23][CH2:24][CH2:25][C:26]([NH:2][CH:3]1[CH2:4][CH:5]2[N:10]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]([C:21]#[N:22])=[CH:13][CH:12]=3)[CH:8]([CH2:7][CH2:6]2)[CH2:9]1)=[O:27]
Reactant: N#Cc1ccc(N2C3CCC2CC(N)C3)c2ccccc12
Reactant: O=C(Cl)CCCl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2C3CCC2CC(NC(=O)CCCl)C3)c2ccccc12

Procedure:
This compound was synthesized in the same way as 165RL23 using 165RL21 (320 mg, 1.15 mmol), 3-chloropropionyl chloride (120 μL, 1.27 mmol), DIPEA (220 μL, 1.27 mmol) and DMF (10 mL). The crude product was purified by column chromatography using ethyl acetate/MeOH (95:5) to give the title compound (318 mg, 75
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:36](=[O:37])[CH2:35][O:34][CH3:33])[CH2:31][CH2:32]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: Cc1[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc2c1C(=O)NC1CCNCC1
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluorophenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f6) and commercially available methoxyacetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[CH:13]([OH:16])([CH3:15])[CH3:14].[CH2:17]([O:35][CH2:36][CH:37]1[O:39][CH2:38]1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].[ClH:40]>O>[ClH:40].[OH:16][CH:13]([CH2:15][O:35][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:14][N:1]([CH2:38][CH:37]([OH:39])[CH2:36][O:35][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: CC(C)O
Reactant: CCCCCCCCCCCCCCCCCCOCC1CO1
Agent: Cl
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOCC(O)CN(CC(O)COCCCCCCCCCCCCCCCCCC)[C@@H](CCCNC(=N)N)C(=O)O
Yield: 12.3 %

Procedure:
L-arginine (17.4 g, 0.1 mols) was dissolved in 100 ml of water in a three-necked round flask, and 100 ml of i-propanol were added thereto. Then, 65.2 g (0.2 mols) of octadecylglycidyl ether were added dropwise thereto over a period of 30 minutes while being heat-refluxed and stirred. Further, the mixture was stirred under reflux for 3 hours. It was identified through TLC and gas chromatography that octadecylglycidyl ether disappeared. Thereafter, the resulting mixture was neutralized with 10.1 g (0.1 mols) of 36% hydrochloric acid. The reaction solution was concentrated under reduced pressure, and the residue was purified through silica-gel column chromatography (Kieselgel 60, eluent=mixture of chloroform, methanol and acetic acid at a ratio of 3:1:0.5) to give 10.2 g of N,N-bis(2-hydroxy-3-octadecyloxypropyl)-L-arginine hydrochloride (yield 12.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)=[CH:4][C:3]=1[C:22]([NH:24][CH2:25][CH2:26][C:27]12[CH2:36][CH:31]3[CH2:32][CH:33]([CH2:35][CH:29]([CH2:30]3)[CH2:28]1)[CH2:34]2)=[O:23].Cl>CO.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][C:3]=1[C:22]([NH:24][CH2:25][CH2:26][C:27]12[CH2:28][CH:29]3[CH2:30][CH:31]([CH2:32][CH:33]([CH2:35]3)[CH2:34]1)[CH2:36]2)=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Cl)c(C(=O)NCCC34CC5CC(CC(C5)C3)C4)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(NCCC12CC3CC(CC(C3)C1)C2)c1cc(CN2CCNCC2)ccc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4-[[4-chloro-3-[[(2-tricyclo[3.3.1.13,7]dec-1-ylethyl)amino]carbonyl]phenyl]methyl]-1-piperazinecarboxylic acid, 1,1-dimethylethyl ester, (Example 18b, 0.270 g) was dissolved in methanol (3 ml), 4N HCl in dioxane (2 ml) was added and the mixture stirred for 14 h at room temperature. The solvent was removed under vacuum and the resulting solid was triturated with ether to afford the title compound as a white powder (0.207 g).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].C(N(C(C)C)CC)(C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:42]1[CH:61]=[N:60][C:45]2[NH:46][C:47](=[O:59])[N:48]([CH2:50][CH2:51][N:52]3[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]3)[CH2:49][C:44]=2[CH:43]=1>C(#N)CC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:58][N:55]1[CH2:56][CH2:57][N:52]([CH2:51][CH2:50][N:48]2[CH2:49][C:44]3[CH:43]=[C:42](/[CH:3]=[CH:2]/[C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH:61]=[N:60][C:45]=3[NH:46][C:47]2=[O:59])[CH2:53][CH2:54]1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CN1CCN(CCN2Cc3cc(Br)cnc3NC2=O)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CN1CCN(CCN2Cc3cc(/C=C/C(=O)OC(C)(C)C)cnc3NC2=O)CC1

Procedure:
tert-Butyl acrylate (830 μL, 5.64 mmol), diisopropylethylamine (500 □L, 2.82 mmol) and P(o-tolyl)3 (86 mg, 0.28 mmol) were successively added to a suspension of 6-bromo-3-(2-(4-methylpiperazin-1-yl)ethyl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(1H)-one (500 mg, 1.41 mmol) in propionitrile (6 mL) and dimethylformamide (2 mL). The resulting mixture was purged with argon prior to the addition of palladium acetate (32 mg, 0.14 mmol). The mixture was then purged a second time with argon and refluxed overnight. The reaction mixture was filtered on Celite® and washed with ethyl acetate (100 mL) and dichloromethane (100 mL). The filtrate was concentrated to dryness and the residue was solubilized in dichloromethane (100 mL). The resulting solution was washed with a saturated solution of sodium chloride (3×100 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel using dichloromethane/methanol/ammoniac (1:0:0.1 to 98:2:0.1) as eluent. The title product was obtained as a brown solid (83 mg, 15%).
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2([C:34](=[O:42])[NH:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:16][CH2:15][N:14]([C:17](=[O:33])[CH:18]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[OH-].[Na+]>C1COCC1.CO>[C:29]([O:28][C:26]([NH:25][C@@H:18]([CH2:19][C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)[C:17]([N:14]1[CH2:15][CH2:16][C:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:43])=[O:2])=[CH:9][CH:8]=2)([C:34](=[O:42])[NH:35][CH:36]2[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]2)[CH2:12][CH2:13]1)=[O:33])=[O:27])([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)c1ccc(CC2(C(=O)NC3CCCCC3)CCN(C(=O)C(Cc3cccs3)NC(=O)OC(C)(C)C)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccs1)C(=O)N1CCC(Cc2ccc(C(=O)O)cc2)(C(=O)NC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[1-(2-tert-butoxycarbonylamino-3-thiophen-2-yl-propionyl)-4-cyclohexylcarbamoyl-piperidin-4-ylmethyl]-benzoic acid methyl ester (4.46 mmol; 2.73 g) in THF (30 mL) and methanol (10 mL) was added a 1M solution of sodium hydroxide (6.69 mmol; 6.69 mL) and the resulting mixture was stirred overnight at room temperature. The resulting mixture was then evaporated and water (20 mL) was added. A 1N hydrochloric acid solution (10 mL) was added dropwise. A precipitate formed that was separated via filtration to yield 4-[1-(2-(S)-tert-butoxycarbonylamino-3-thiophen-2-yl-propionyl)-4-cyclohexylcarbamoyl-piperidin-4-ylmethyl]-benzoic acid after drying. MS (ESI) m/z 598.23 [M+H]+.