Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][C:8]1[C:13]([CH3:14])=[C:12]([O:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH:11]=[CH:10][N:9]=1)(=O)C>C(O)C>[OH:6][CH2:7][C:8]1[C:13]([CH3:14])=[C:12]([O:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])[CH:11]=[CH:10][N:9]=1
Reactant: COCCCOc1ccnc(COC(C)=O)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCCOc1ccnc(CO)c1C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
20 ml of acetic anhydride was added to 760 mg (3.6 mmol) of 4-(3-methoxypropoxy)-2,3-dimethyl-pyridine N-oxide to carry out the reaction at 90° C. for one hour. The reaction mixture was distilled to remove the acetic anhydride, followed by the addition of a saturated aqueous solution of sodium hydrogen-carbonate. The obtained mixture was extracted with chloroform. The extract was concentrated to obtain 700 mg of 2-acetoxymethyl-4-(3-methoxypropoxy)-3-methylpyridine as a brown oil. 500 mg of sodium hydroxide and 15 cc of ethanol were added to the 2-acetoxymethyl-4-(3-methoxypropoxy)-3-methylpyridine prepared above. The obtained mixture was stirred at 50° C. for one hour. After the completion of the reaction, the reaction mixture was distilled to remove the ethanol, followed by the addition of water. The obtained mixture was extracted with chloroform. The obtained chloroform layer was concentrated to obtain 450 mg of 2-hydroxymethyl-4-(3-methoxypropoxy)-3-methylpyridine as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:4]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].[Br:17][CH2:18][CH2:19][CH2:20]Br>C(#N)C.O>[Br:17][CH2:18][CH2:19][CH2:20][O:10][C:4]1[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1cccc(C)c1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cccc(C)c1OCCCBr

Procedure:
The mixture of 2.50 g of 2-methoxy-6-methylphenol, 3.75 g of potassium carbonate and 18.3 ml of 1,3-dibromopropane in 50 ml of acetonitrile is stirred at reflux with stirring over 16 hours. The reaction mixture is cooled, diluted with 200 ml of water and extracted with tert-butyl methyl ether (2×200 ml). The organic phases are washed successively with water (200 ml) and brine (200 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.59 (1:1 EtOAc-heptane); Rt=5.10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C:13]([O:15]C)=[O:14])[CH2:7][CH2:6]2.P([O-])([O-])([O-])=O.Cl.CC(=O)OCC(COC(=O)C)OC(=O)C.[OH-].[Na+].C(=O)(O)[O-].[Na+]>C(O)(C)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C@H:8]([C:13]([OH:15])=[O:14])[CH2:7][CH2:6]2
Reactant: COC(=O)C1CCc2cc(OC)ccc2C1
Agent: Cl
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Solvent: CC(=O)OCC(COC(C)=O)OC(C)=O
Solvent: CC(C)(C)O
Product: COc1ccc2c(c1)CC[C@@H](C(=O)O)C2
Reaction time: 5 h
Yield: 38.4 %

Procedure:
5 g of methyl 6-methoxy-1,2,3,4-tetrahydro-2-naphthoate are dissolved in 170 ml of tert-butanol, and 500 ml of phosphate buffer at pH 7 are added to the solution prepared in this way. The pH of the solution, which rises to 7.3-7.5, is lowered to 7.1 by the addition of 1N HCl. 2.5 g of Sigma PPL enzyme (known as porcine pancreatic lipase type II, crude, Sigma L-3126--50 U/mg using triacetin) are added to the mixture. The pH tends to drop as the reaction progresses, but is kept constant by the addition of a 0.25N solution of NaOH, the pH being controlled by an automatic titration apparatus. After 5 hours, sodium bicarbonate is added to the solution until the pH is about 8 in order to stop the reaction by inactivation of the enzyme. Extraction is carried out with ethyl ether and the two phases are separated. The organic phase contains the unreacted ester principally of (S) configuration, which can be recovered. The aqueous phase is acidified with concentrated sulfuric acid and the precipitate formed is filtered off to give 1.8 g of the title acid, which is crystallized from ethyl acetate. ee 93%.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH2:13])[CH:7]=1.C(NC(C)C)(C)C.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:23]=1.Cl>ClCCl>[CH3:2][O:3][C:4](=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][S:28]([C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)(=[O:30])=[O:29])[CH:7]=1
Reactant: COC(=O)Cc1cccc(CN)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: COC(=O)Cc1cccc(CNS(=O)(=O)c2cccnc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (3-aminomethyl-phenyl)-acetic acid methyl ester hydrochloride (0.56 g) and diisopropylamine (2.2 mL) in 10 mL dichloromethane was added pyridine-3-sulfonyl chloride (0.601 g, 2.83 mmol) and the reaction was stirred at room temperature for 16 h. Aqueous 1N HCl was added and the solution was extracted with CH2Cl2. The organic solution was washed with saturated NaHCO3, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound. Purification via flash chromatography on silica gel (2:1 hexanes: EtOAc) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.91 (s, 1H), 8.71 (d, 1H), 8.04 (d, 1H), 7.37 (m, 1H), 7.05-7.24 (m, 4H), 5.87 (bs, 1H), 4.14 (s, 1H), 2H), 3.62 (s, 3H), 3.52 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7](Cl)=[O:8])[CH:3]=1.[CH3:10][NH:11][C@H:12]1[CH2:31][N:16]2[C:17]3[C:22]([C:23]([CH2:24][C:25]([O:27]CCC)=[O:26])=[C:15]2[CH2:14][CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3>>[CH3:10][N:11]([C:7]([C:4]1[CH:3]=[C:2]([CH3:1])[O:6][N:5]=1)=[O:8])[C@H:12]1[CH2:31][N:16]2[C:17]3[C:22]([C:23]([CH2:24][C:25]([OH:27])=[O:26])=[C:15]2[CH2:14][CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: Cc1cc(C(=O)N(C)[C@@H]2CCc3c(CC(=O)O)c4ccccc4n3C2)no1

Procedure:
The title compound was prepared using analogous procedures described in Example 2 (Method B) from 5-methylisoxazole-3-carbonyl chloride and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 368.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[Br:12]N1C(=O)CCC1=O.C(Cl)Cl.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:12][C:5]1[C:6]([C:8]([F:11])([F:9])[F:10])=[N:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1nccc(C(F)(F)F)n1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Nc1ncc(Br)c(C(F)(F)F)n1
Reaction time: 4 h
Yield: 91.7 %

Procedure:
To a solution of 2-amino-4-trifluoromethylpyrimidine (8.0 g, 49.1 mmol) in chloroform (300 mL) was added N-bromosuccinimide (8.9 g, 50 mmol). The solution was stirred in the dark for 16 hours, at which time additional N-bromosuccinimide (4.0 g, 22.5 mmol) was added. After stirring for an additional 4 hours the solution was added to CH2Cl2 (200 mL) and 1N NaOH (200 mL). Upon mixing, the layers were separated and the organic layer was washed with NaCl(sat.) (100 mL), dried over Na2SO4, filtered and concentrated, yielding 10.9 g (82%) of 5-bromo-4-(trifluoromethyl)-2-pyrimidylamine. LCMS (m/z): 242/244 (MH+). 1H NMR (CDCl3): δ 8.52 (s, 1H), 5.38 (bs, 2H).
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:22])=[O:21])=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:35])=[C:4]([O:36][CH3:37])[CH:3]=1.[O:38]1[CH:42]=[CH:41][C:40]([NH2:43])=[N:39]1.C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>CCOC(C)=O>[Br:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([S:20]([NH:43][C:40]4[CH:41]=[CH:42][O:38][N:39]=4)(=[O:21])=[O:22])=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:35])=[C:4]([O:36][CH3:37])[CH:3]=1
Reactant: Nc1ccon1
Reactant: COc1cc(Br)c(C#N)cc1-n1c(=O)ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(Br)c(C#N)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reaction time: 0.25 h
Yield: 67.1 %

Procedure:
A RBF was charged with perfluorophenyl 1-(4-bromo-5-cyano-2-methoxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (330.64 mg, 0.550 mmol), isoxazol-3-amine (46.7 μl, 0.632 mmol) and THF (3666 μl) to give a clear solution. The flask was cooled in an ice-water bath for 10 min, then lithium bis(trimethylsilyl)amide (1M in THF) (1155 μl, 1.155 mmol) was added dropwise. After 15 min, the mixture was diluted with EtOAc and washed with 1N aq. HCl. The aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography (45-g Redi-Sep column, 25-g silica gel loading column, 0-5% MeOH/DCM) to give 1-(4-bromo-5-cyano-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (185 mg, 0.369 mmol, 67.1% yield) as a light-yellow solid. 1 H NMR (400 MHz, DMSO-d6) □=11.67 (br. s., 1 H), 8.73 (d, J=1.8 Hz, 1 H), 8.38 (d, J=2.2 Hz, 1 H), 8.27-8.21 (m, 1 H), 8.12-8.06 (m, 1 H), 7.90-7.78 (m, 2 H), 6.90 (d, J=9.0 Hz, 1 H), 6.85-6.76 (m, 1 H), 6.45 (d, J=1.8 Hz, 1 H), 3.81 (s, 3 H). m/z/(ESI) 501.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]([F:21])([F:20])[F:19])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH2:14])=[CH:8][CH:7]=1.[CH3:22][O:23][C:24]1[N:29]=[CH:28][C:27]([CH2:30][C:31]2[C:32](=[O:39])[N:33]=[C:34](SC)[NH:35][CH:36]=2)=[CH:26][N:25]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[C:18]([F:19])([F:20])[F:21])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C:34]2[NH:35][CH:36]=[C:31]([CH2:30][C:27]3[CH:26]=[N:25][C:24]([O:23][CH3:22])=[N:29][CH:28]=3)[C:32](=[O:39])[N:33]=2)=[CH:8][CH:7]=1
Reactant: NCCc1ccc(Oc2ccc(C(F)(F)F)c(Cl)c2)cc1
Reactant: COc1ncc(Cc2c[nH]c(SC)nc2=O)cn1
Solvent: CCO
Product: COc1ncc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(C(F)(F)F)c(Cl)c4)cc3)nc2=O)cn1
Temperature: 125 °C
Reaction time: 50 h
Yield: 20.2 %

Procedure:
2-[4-(3-chloro-4-trifluoromethyl-phenoxy)-phenyl]-ethylamine (0.317 mmol, 1 eq) and 5-(2-methoxy-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (0.322 mmol, 0.95 eq) were dissolved in dry ethanol (300 μL) and stirred at 125° C. for 50 hours. Solvent was evaporated and crude product was purified on Biotage SP1 Snap Si 25; 25 ml/min in the gradient of MeOH in DCM: 0-10% in 25CV. The appropriate fractions were combined and evaporated in vacuo to give the required product 2-{2-[4-(3-chloro-4-trifluoromethyl-phenoxy)-phenyl]ethylamino}-5-(2-methoxy-pyrimidin-5-ylmethyl)-1H-pyrimidin-4-one (0.064 mmol, yield: 20%, UPLC-MS/UV: [M+H]+=517.97; rt: 11.53 mins; purity: 90%). 1H NMR (300 MHz; CDCl3) δ/ppm 2.92 (t, J=7.76, 2H), 3.51 (s, 2H), 3.59-3.70 (m, 2H), 3.94 (s, 3H), 5.33 (br.s., 1H), 6.86 (dd, J=9.07, J=2.01, 1H), 6.96-7.03 (m, 2H), 7.23-7.31 (m, 3H), 7.58 (d, J=8.82, 1H), 7.67 (s, 1H), 8.39 (s, 2H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]([O:14][CH3:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:17][N:18]1[CH:22]([CH2:23][CH2:24]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:21][N:20]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[C:19]1=[O:47].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([O:14][CH3:15])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:24][CH2:23][CH:22]2[CH2:21][N:20]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:39][CH:38]=3)[C:19](=[O:47])[N:18]2[CH3:17])=[CH:11][CH:12]=1)[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1)OC
Temperature: 55 °C
Yield: 65.5 %

Procedure:
A mixture of 3-(4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester 0.027 g, 0.120 mmol), toluene-4-sulfonic acid 2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethyl ester (0.061 g, 0.133 mmol) and Cs2CO3 (0.059 g, 0.181 mmol) in DMF (4 mL) was heated to 55° C. under N2 for 16 h. The reaction was cooled and quenched with 1 N HCl (10 mL) and worked up extractively with Et2O and water. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 4:1 then 3:1 hexanes:acetone to afford 0.040 g (64%) 2-methoxy-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester. 1H NMR. MS (ES+) Calc'd for C26H32N2O5F3 (M+1) 509. Found m/z 509 (100%).
Reaction SMILES: Cl[Sn]Cl.[NH2:4][C:5]1[C:10]([N+:11]([O-])=O)=[C:9]([CH3:14])[C:8]([Br:15])=[C:7]([CH3:16])[N:6]=1.[OH-].[Na+]>Cl>[Br:15][C:8]1[C:9]([CH3:14])=[C:10]([NH2:11])[C:5]([NH2:4])=[N:6][C:7]=1[CH3:16]
Reactant: Cc1nc(N)c([N+](=O)[O-])c(C)c1Br
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: Cc1nc(N)c(N)c(C)c1Br
Temperature: 80 °C

Procedure:
A solution of 4.1 g (21.6 mmol) of SnCl2 in 20 ml of concentrated HCl is cooled in an ice bath. 1.32 g (5.4 mmol) of product obtained in Stage B are added gradually. The mixture is heated at 80° C. for 30 minutes. It is allowed to cool and then poured onto crushed ice. The resulting mixture is basified by addition of sodium hydroxide. The precipitate formed is filtered off, washed with water and then dried. 1.06 g of white powder are thus collected. The product is recrystallized from toluene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:14]([OH:16])=O)[CH2:13][CH2:12][CH2:11][CH2:10]1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=2[CH3:33])[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:14]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][C:32]=3[CH3:33])[CH2:23][CH2:22]2)=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Reactant: O=C(O)C1(c2ccc(F)cc2Cl)CCCC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C2(c3ccc(F)cc3Cl)CCCC2)CC1

Procedure:
Example 135 was prepared from 1-(2-chloro-4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-amino propyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.56 (dd, 1H, J=8.7, 6.3 Hz), 7.32 (s, 1H), 7.22–7.15 (m, 2H), 7.06 (dd, 1H, J=8.7, 3.0 Hz), 7.05–6.95 (m, 2H), 5.90–5.84 (m, 1H), 3.21 (q, 2H, J=5.7 Hz), 2.87–2.80 (m, 2H), 2.59–2.49 (m, 1H), 2.44 (septet, 1H, J=6.5 Hz), 2.41–2.40 (m, 2H), 2.26 (t, 2H, J=5.7 Hz), 2.19 (s, 3H), 2.04–1.96 (m, 2H), 1.93–1.85 (m, 2H), 1.82–1.71 (m, 3H), 1.64–1.48 (m, 7H), 1.17 (d, 6H, J=6.5 Hz); ESMS m/e: 542.2 (M+H)+.
Reaction SMILES: CS[C:3]([N:14]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[N:15]1)=[N:4][S:5]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)(=[O:7])=[O:6].[CH3:32][NH2:33]>CO>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:16]2[CH:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][N:14]([C:3]([NH:33][CH3:32])=[N:4][S:5]([N:8]3[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]3)(=[O:7])=[O:6])[N:15]=2)=[CH:26][CH:27]=1
Reactant: CSC(=NS(=O)(=O)N1CCCCC1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Reactant: CN
Solvent: CO
Product: CNC(=NS(=O)(=O)N1CCCCC1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1
Temperature: 50 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
To a cooled mixture (<0° C.) of 3-(4-chlorophenyl)-N-((piperidin-1-yl)sulfonyl)-4-phenyl-4,5-dihydro-1H-pyrazole-1-carboximidothioic acid methyl ester (10.0 gram, 21 mmol) in methanol (75 mL) is added cold methylamine (15 mL). The resulting mixture is allowed to attain room temperature and stirred for 3 hours at 50° C. After cooling to room temperature the mixture is concentrated in vacuo, dissolved in dichloromethane, washed twice with water, dried over Na2SO4, filtered and concentrated in vacuo. Subsequent flash chromatography (EtOAc/MeOH/NH4OH (25% aq.)=95/5/0.5 (v/v)), followed by recrystallisation from diisopropyl ether gives 3-(4-chlorophenyl)-N-methyl-4-phenyl-N′-((piperidin-1-yl)sulfonyl)-4,5-dihydro-1H-pyrazole-1-carboxamidine (7.87 gram, 81% yield) as a white solid. MP: 175-177° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH3:22])[C:15]([CH3:24])([CH3:23])[CH2:14]2)[N:5]=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[N:33]([O:38][CH3:39])[C:32]([CH3:41])([CH3:40])[CH2:31]2)[N:3]=1.[NH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O-:50])=[O:49].[Na+]>>[CH3:39][O:38][N:33]1[C:34]([CH3:37])([CH3:36])[CH2:35][CH:30]([CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:4]2[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]3[CH2:14][C:15]([CH3:23])([CH3:24])[N:16]([O:21][CH3:22])[C:17]([CH3:20])([CH3:19])[CH2:18]3)[N:7]=[C:2]([NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([OH:50])=[O:49])[N:3]=2)[CH2:31][C:32]1([CH3:40])[CH3:41]
Reactant: NCCCCCC(=O)[O-]
Reactant: CON1C(C)(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C
Agent: [Na+]
Product: CON1C(C)(C)CC(CCCCNc2nc(NCCCCCC(=O)O)nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared from 2-chloro-4,6-bis[N-(1-methoxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine and sodium 6-aminohexanoate according to the procedure of Example 15.
Reaction SMILES: [CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C1(N=C=NC2CCCCC2)CCCCC1.[F:39][C:40]([F:44])([F:43])[CH2:41]O.CCOC(C)=O>C(Cl)Cl>[CH2:1]([O:15][C:16]1[O:20][C:19]([C:21]([O:23][CH2:41][C:40]([F:44])([F:43])[F:39])=[O:22])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: OCC(F)(F)F
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCC(F)(F)F)o1
Yield: 69.5 %

Procedure:
To a stirred, room temperature suspension of 5-(tetradecyloxy)furan-2-carboxylic acid (1.3 g, 4.0 mmol) in CH2Cl2 (40 mL) was added N,N′-dicyclohexylcarbodiimide (0.990 g, 4.8 mmol), N,N-dimethylaminopyridine (0.488 g, 4.0 mmol) and 2,2,2-trifluoroethanol (0.875 mL, 12.0 mmol). The flask was capped and stirring was continued for 16 hrs at which time TLC (10% EtOAc in Hexanes Rf=0.05 (SM) and 0.25 (Prod)) indicated complete consumption of the starting material. The resulting suspension was diluted with CH2Cl2 (40 mL), filtered and concentrated. This crude material was purified by flash chromatography eluting with 5-20% EtOAc in Hexanes. The resulting solid was further purified by recrystallization in 30 mL of hot 2-propanol with the addition of a minimum amount of water to yield 1.13 g (70%) of the title compound as white needles. MS (m/z, ES−): 406.0 (M−1, 100%); EA found for C23H36F3NO2: C, 62.20; H, 8.18; calcd: C, 62.05; H, 8.18; 1H NMR (400 MHz, DMSO-d6) δ: 7.4 (d, 1H), 5.7 (d, 1H), 4.9 (q, 2H), 4.2 (t, 2H), 1.50-1.57 (m, 2H), 1.10-1.20 (m, 22H), 0.85 (t, 3H).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH2:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=[N+:2]=[N-:3].[CH3:16][C@H:17]1[C:25]2[C:24]([C:26]3[S:30][C:29]([C:31](O)=[O:32])=[CH:28][CH:27]=3)=[N:23][CH:22]=[N:21][C:20]=2[CH2:19][CH2:18]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[N:1]([CH2:4][C@@H:5]([NH:15][C:31]([C:29]1[S:30][C:26]([C:24]2[C:25]3[C@H:17]([CH3:16])[CH2:18][CH2:19][C:20]=3[N:21]=[CH:22][N:23]=2)=[CH:27][CH:28]=1)=[O:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC[C@@H](N)Cc1ccc(Cl)cc1Cl
Reactant: C[C@@H]1CCc2ncnc(-c3ccc(C(=O)O)s3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CCc2ncnc(-c3ccc(C(=O)N[C@H](CN=[N+]=[N-])Cc4ccc(Cl)cc4Cl)s3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
(S)-1-Azido-3-(2,4-dichlorophenyl)propan-2-amine (33 mg, 0.134 mmol) was added to a solution of (R)-5-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxylic acid (35 mg, 0.134 mmol) in DCM (0.7 mL). HBTU (56 mg, 0.148 mmol) was added, followed by DIPEA (0.23 mL, 1.34 mmol). The reaction mixture was stirred at room temperature for 1 hour. LC-MS of the reaction mixture showed no more starting material. The solvent was removed, and the resulting residue was purified on silica gel (0%-50% EtOAc/hexanes) gradient elution to yield N-((S)-1-azido-3-(2,4-dichlorophenyl)propan-2-yl)-5-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamide as an oil (59 mg, 90%). m/z 486 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=3)[C:12]([C:22]([F:25])([F:24])[F:23])=[CH:11][N:10]=2)[C:5]([CH3:26])=[CH:4][C:3]=1[CH:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1.[BH4-].[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=3)[C:12]([C:22]([F:24])([F:25])[F:23])=[CH:11][N:10]=2)[C:5]([CH3:26])=[CH:4][C:3]=1[C@H:27]1[CH2:28][CH2:29][C@H:30]([OH:33])[CH2:31][CH2:32]1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCC(=O)CC4)cc3C)ncc2C(F)(F)F)n[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Nc2nc(Nc3cc(C)c([C@H]4CC[C@H](O)CC4)cc3C)ncc2C(F)(F)F)n[nH]1

Procedure:
To a solution of 4-(2,5-dimethyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanone (100 mg, 0.22 mmol) in MeOH (15 mL) was added NaBH4 (33.2 mg, 0.87 mmol). The reaction was stirred 30 for min., concentrated and purified by silica chromatography (MeOH/DCM: 8:92) to afford trans-4-(2,5-dimethyl-4-(4-(5-methyl-1H-pyrazol-3-ylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)phenyl)cyclohexanol; Rf: 0.35 (silica; MeOH/DCM 8:92); ESMS m/z 461.2 (M+H+).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:12]3([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[N:11]([C:25]3[CH:30]=[CH:29][C:28]([I:31])=[CH:27][CH:26]=3)[C:10](=[O:32])[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCOCC1.[ClH:39].C(Cl)[Cl:41]>CO>[ClH:41].[ClH:39].[CH:1]1([NH:7][C:8]2[C:12]3([CH2:13][CH2:14][NH:15][CH2:16][CH2:17]3)[N:11]([C:25]3[CH:26]=[CH:27][C:28]([I:31])=[CH:29][CH:30]=3)[C:10](=[O:32])[N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(NC1CCCCC1)=NC(=O)N2c1ccc(I)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C1N=C(NC2CCCCC2)C2(CCNCC2)N1c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of tert-butyl 4-(cyclohexylamino)-1-(4-iodophenyl)-2-oxo-1,3,8-triazaspiro[4.5]dec-3-ene-8-carboxylate (10.9 g, 19.7 mmol) in 4N HCl dioxane (99 mL, 395 mmol) was added small amounts of DCM and MeOH to obtain a solution. After stirring at rt for 1 h, the reaction mixture was concentrated in vacuo, the residue was triturated with diethyl ether and the product was isolated as a white solid by filtration. LRMS (M+1)=453. LC analysis and 1H NMR indicate the presence of an unknown (20%), the titled compound was used as is in subsequent steps, allowing for purification at a later stage.