Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]1([C:9]([NH2:11])=[O:10])[CH2:8][NH:7][CH2:6]1)[CH3:3].C(N(C(C)C)CC)(C)C.Cl[C:22]1[N:27]2[N:28]=[C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[C:30]([I:31])=[C:26]2[N:25]=[CH:24][CH:23]=1.N1CCC1>CC(C)=O>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:29]1[C:30]([I:31])=[C:26]2[N:25]=[CH:24][CH:23]=[C:22]([N:7]3[CH2:8][C:5]([NH:4][CH2:2][CH3:3])([C:9]([NH2:11])=[O:10])[CH2:6]3)[N:27]2[N:28]=1
Reactant: CCNC1(C(N)=O)CNC1
Reactant: Clc1ccccc1-c1nn2c(Cl)ccnc2c1I
Agent: C1CNC1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC1(C(N)=O)CN(c2ccnc3c(I)c(-c4ccccc4Cl)nn23)C1
Temperature: 50 °C

Procedure:
To a slurry of 3-ethylaminoazetidine-3-carboxylic acid amide, hydrochloride salt (I-1A-3e; 1.13 g, 5.2 mmol) and diisopropylethylamine (3.2 ml, 18 mmol) in acetone (60 ml) was added 7-chloro-2-(2-chlorophenyl)-3-iodopyrazolo[1,5-a]pyrimidine (I-1A-1d; 1.36 g, 3.48 mmol). The mixture was heated to 50° C. overnight. Additional azetidine and diisopropylethylamine were added in portions until the reaction was judged complete by LCMS. A pale yellow precipitate formed and was isolated by vacuum filtration. The filtrate was concentrated to 20 ml and then diluted with diethyl ether to precipitate additional material that was collected by vacuum filtration. The combined solids were triturated from ether to afford product I-2A-1a as a pale yellow solid (1.3 g, 76%): +ESI MS (M+1) 497.0; 1H NMR (400 MHz, DMSO-D6) δ 8.27 (d, J=5.4 Hz, 1H), 7.59 (d, J=7.9 Hz, 1H), 7.52–7.44 (m, 3H), 7.35 (br s, 1H), 7.30 (br s, 1H), 5.98 (d, J=5.0 Hz, 1H), 2.40–2.30 (m, 2H), 0.99 (t, J=7.1 Hz, 3H).
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:12][CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=O)C.C([O-])([O-])=O.[K+].[K+].CC(O)=O>CO>[SH:4][CH2:5][CH:6]([CH2:12][CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)C(CC)CSC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C(CC)CS
Temperature: 0 °C

Procedure:
To a solution of the thioester of Step 1 (5 g, 24.5 mmol) in MeOH (15 mL) at 0° C., under nitrogen, was added K2CO3 (9.67 g, 73.5 mmol). The resulting mixture was stirred at 0° C. for a half hour and then HOAc (8.82 g, 147 mmol) and 25% aq NH4OAc were added. The title thiol was extracted with EtOAc, dried over Na2SO4 and purified by distillation on a Kugelrohr apparatus (200° C./760 mm Hg).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1.[CH3:30][CH:31]([CH3:37])[CH2:32][S:33](Cl)(=[O:35])=[O:34]>>[CH3:30][CH:31]([CH3:37])[CH2:32][S:33]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([NH:12][C:13]2[N:14]=[C:15]3[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]3=[N:17][CH:18]=2)=[O:11])[CH2:4]1)(=[O:35])=[O:34]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(NC(=O)NC3CCCNC3)cnc21
Reactant: CC(C)CS(=O)(=O)Cl
Agent: Cl
Product: CC(C)CS(=O)(=O)N1CCCC(NC(=O)Nc2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
1-[1-(2-M ethyl-propane-1-sulfonyl)-piperidin-3-yl]-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea was prepared in the same manner from 1-piperidin-3-yl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea dihydrochloride and 2-methyl-propane-1-sulfonyl chloride.
Reaction SMILES: [C:1]([C:3]1[S:4][CH:5]=[C:6]([C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:7]=1[NH2:8])#[N:2].[C:18](OC(=O)C)(=[O:20])[CH3:19].C(OCC)(=O)C.C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[C:1]([C:3]1[S:4][CH:5]=[C:6]([C:9]2[C:10]([CH3:17])=[CH:11][C:12]([CH3:16])=[CH:13][C:14]=2[CH3:15])[C:7]=1[NH:8][C:18](=[O:20])[CH3:19])#[N:2]
Reactant: Cc1cc(C)c(-c2csc(C#N)c2N)c(C)c1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1c(-c2c(C)cc(C)cc2C)csc1C#N
Temperature: 110 °C
Reaction time: 1 h

Procedure:
To a solution of intermediate 3 (6.0 g) in acetic acid (6 ml) was added acetic anhydride (5 g). The reaction mixture was stirred for 1 hour at 110° C. After cooling, the crude mixture was poured into a mixture of ethyl acetate (400 ml), water (600 ml) and saturated NaHCO3 (200 ml). The organic layer was rinsed with water and concentrated. The residue was purified by column chromatography on SiO2 (gradient; hexane:diethyl ether=2:1 to hexane:ethyl acetate=1:1) to give N-[2-cyano-4-(2,4,6-trimethylphenyl)-thiophen-3-yl]-acetamide (intermediate 4).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:13])[C@H:4]([O:6][C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:5].[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[Mg]Br.[Cl-].[NH4+].O>C1COCC1.C(#N)C>[Cl:1][CH2:2][C:3]([C:18]1[CH:17]=[CH:16][C:15]([F:14])=[CH:20][C:19]=1[F:21])([OH:13])[CH:4]([O:6][C:7](=[O:12])[C:8]([CH3:9])([CH3:11])[CH3:10])[CH3:5]
Reactant: Fc1ccc([Mg]Br)c(F)c1
Reactant: C[C@@H](OC(=O)C(C)(C)C)C(=O)CCl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: O
Product: CC(OC(=O)C(C)(C)C)C(O)(CCl)c1ccc(F)cc1F
Reaction time: 0.08 h
Yield: 15 %

Procedure:
A solution of 0.41 g (2.0 mmol) of (R)-1-chloro-3-pivaloyloxybutan-2-one in 5 mL of THF was cooled to 0° C., and 3.2 mL (2.2 mmol) of a 0.69 M solution of 2,4-difluorophenylmagnesium bromide prepared by the same method as that in Example 3 was added dropwise thereto over a period of 5 minutes. After the completion of the dropwise addition, stirring was continued for another 1 hour, and 10 mL of a saturated aqueous solution of ammonium chloride was added to stop the reaction. Furthermore, 10 mL of water was added, and extraction was performed with ethyl acetate (20 mL×2). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a crude product. A quantitative analysis was performed by HPLC. Thereby, the title compound was obtained in a yield of 15% ((2S,3R)/(2R,3R)=92/8) (HPLC, column: YMC-A302 manufactured by YMC Co. Ltd., mobile phase: acetonitrile/20 mM (potassium) phosphate buffer solution (pH=2.5)=6/4, flow rate: 1.0 mL/min, column temperature: 30° C., detector: UV 210 nm, retention time: 10 minutes (2S,3R) and 8 minutes (2R,3R)). 1H-NMR (400 MHz, CDCl3) δ: 1.05 (d, 3H, J=6.3 Hz), 1.25 (s, 9H), 3.86 (d, 1H, J=11.5 Hz), 4.19 (d, 1H, 11.5 Hz), 5.38 (q, 1H, J=6.3 Hz), 6.77-6.80 (m, 1H), 6.91-6.93 (m, 1H), 7.69-7.71 (m, 1H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:28][CH2:29][CH:30]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][C:33]=1[OH:39])[OH:31]>>[OH:39][C:33]1[CH:34]=[C:35]([OH:38])[CH:36]=[CH:37][C:32]=1[CH:30]([OH:31])[CH2:29][NH:28][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:16])=[O:17])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: NCC(O)c1ccc(O)cc1O
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NCC(O)c4ccc(O)cc4O)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and 2-amino-1-(2,4-dihydroxy-phenyl)-ethanol according to the procedure of Example 255 as a pale yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.55-1.75 (m, 2H), 1.95-2.15 (m, 2H), 2.08 (s, 3H), 2.50-3.20 (m, 5H), 3.60-3.70 (m, 2H), 5.04-5.10 (m, 1H), 6.65-6.75 (m, 1H), 6.24 (dd, J=8.1, 2.1 Hz, 1H), 6.32 (d, J=2.1 Hz, 1H), 6.80 (d, J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 7.12 (d, J=8.1 Hz, 1H), 7.59 (d, J=9.0 Hz, 2H), 7.70 (d, J=9.0 Hz, 2H), 9.26 (s, 1H), 9.71 (brs, 1H), 10.44 (s, 1H); MS (ES) m/z: 541.4 (MH+); HRMS Calcd. for C27H33N4O6S(MH+): 541.2121. Found: 541.2084.
Reaction SMILES: C([O:8][CH2:9][C@H:10]([CH:37]([CH3:39])[CH3:38])[CH2:11][C@H:12]1[C@@H:16]([CH2:17][NH:18][C:19](=[O:27])[C:20]([CH3:26])([CH3:25])[CH2:21][CH2:22][CH2:23][CH3:24])[O:15][C:14]([CH3:29])([CH3:28])[N:13]1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[CH3:26][C:20]([CH3:25])([CH2:21][CH2:22][CH2:23][CH3:24])[C:19]([NH:18][CH2:17][C@H:16]1[O:15][C:14]([CH3:28])([CH3:29])[N:13]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[C@H:12]1[CH2:11][C@H:10]([CH2:9][OH:8])[CH:37]([CH3:38])[CH3:39])=[O:27]
Reactant: CCCCC(C)(C)C(=O)NC[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C[C@H](COCc1ccccc1)C(C)C
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCCCC(C)(C)C(=O)NC[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1C[C@H](CO)C(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 0.1 %

Procedure:
(4S,5R)-tert-Butyl 4-((S)-2-(benzyloxymethyl)-3-methylbutyl)-5-((2,2-dimethylhexanamido)methyl)-2,2-dimethyloxazolidine-3-carboxylate (3.0 g, 5.5 mol) was dissolved in EtOH (30 mL) and Pd(OH)2/C (300 mg) was added. The reaction mixture was stirred under an atmosphere of hydrogen at rt for about 3-4 h. TLC showed the starting material had been consumed. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give (4S,5R)-tert-butyl 5-((2,2-dimethylhexanamido)methyl)-4-((S)-2-(hydroxymethyl)-3-methylbutyl)-2,2-dimethyloxazolidine-3-carboxylate (2.40 g, 96%) which was used in the next step without purification. 1H NMR (400 MHz, CDCl3): 0.87 (m, 6H), 1.16 (m, 6H), 1.47 (s, 9H), 1.59 (s, 1H), 2.16 (m, 1H), 2.88 (m, 1H), 3.49 (m, 1H), 3.98 (m, 1H); MS: 457 (M++1)
Reaction SMILES: [NH:1]1[C:18](=[O:19])[C@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:9][C:7](=[O:8])[C@@H:2]1[CH2:3][CH:4]([CH3:6])[CH3:5].N[C@H](C(N[C@H](C(O)=O)CC1C=CC=CC=1)=[O:27])CC(C)C>>[NH2:9][C@H:10]([C:18]([NH:1][C@H:2]([C:7]([OH:27])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:19])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)C[C@@H]1NC(=O)[C@H](Cc2ccccc2)NC1=O
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O

Procedure:
As a result, it was confirmed that 6.8 mg/l cyclo(L-Leu-L-Phe), 28.7 mg/l L-Leu-L-Phe and 18.5 mg/l L-Phe-L-Leu were formed. No cyclopeptide or straight-chain peptide was detected in the reaction mixture without ATP incubated in the same manner.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:15][CH:14]=2)=[N:10][CH:11]=1)([O-:5])=[O:4].I[CH3:28]>C1COCC1>[CH3:28][N:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:11][N:10]=2)=[CH:14][CH:15]=1)[C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24]
Reactant: CI
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.8 %

Procedure:
To a THF (30 mL) suspension of NaH (60% in oil, 1.22 g) was added tert-butyl {4-[(5-nitropyridin-2-yl)oxy]phenyl}carbamate (7.77 g) at 0° C. After stirring at 0° C. for 10 min, iodomethane (4.33 g) was added and the mixture was stirred at room temperature for 3 hours. The mixture was poured into ice water and extracted with AcOEt. The organic layer was washed with water, saturated aqueous NaCl and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/AcOEt=2/1) to afford the title compound (6.30 g) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH2:15][C:16]([OH:18])=O)=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[C:25]1[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH2:15][C:16]([NH:31][C:28]3[CH:27]=[CH:26][C:25]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][N:19]=4)=[CH:30][N:29]=3)=[O:18])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(-c2cnccn2)cn1
Reactant: O=C(O)Cc1cnc(-c2ccnc(F)c2)c(F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1cnc(-c2ccnc(F)c2)c(F)c1)Nc1ccc(-c2cnccn2)cn1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 2-(2′,3-difluoro-2,4′-bipyridin-5-yl)acetic acid 205-6 (50 mg, 0.2 mmol), 5-(pyrazin-2-yl)pyridin-2-amine 86-3 (34 mg, 0.2 mmol), 1,3-dicyclohexylcarbodiimide (50 mg, 0.24 mmol) and 4-(dimethylamino)pyridine (4 mg, 0.04 mmol) in DMF (0.9 mL) was stirred at room temperature for 10 hours. The crude product was filtered and the filtrate was subjected directly for reverse phase HPLC to give 2-(2′,3-difluoro-2,4′-bipyridin-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide 205 as white solid. MS m/z 405.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 11.16 (s, 1H), 9.31 (d, 1H), 9.12 (d, 1H), 8.72 (dd, 1H), 8.63 (d, 1H), 8.61-8.60 (m, 1H), 8.52 (dd, 1H), 8.41 (d, 1H), 8.21 (d, 1H), 7.94 (dd, 1H), 7.88 (dd, 1H), 7.64 (s, 1H), 4.01 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C1C=CC=CC=1>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:5][CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)(C)C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 88.1 %

Procedure:
Preparation B6, Step 1: To a solution of 4-trifluoromethylaniline (5 g, 0.031 mol) in 50 ml of dry benzene was added triethylamine (6.26 g, 8.63 ml, 0.06 mol) at 0° C. Pivaloyl chloride (4.5 g, 0.04 mol) was added slowly and stirred at RT over night. The RM was quenched with water and extracted with ethyl acetate. The organic layer was washed with water, brine and concentrated. To the solid was triturated with pet-ether and filtered to give N-(4-(trifluoromethyl)phenyl)pivalamide (6.7 g) as white solid.
Reaction SMILES: [S:1]1[C:5]([NH:6][C:7]2[CH:12]=[C:11](Cl)[N:10]=[C:9]([S:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])=[CH:17][CH:16]=3)[N:8]=2)=[N:4][CH:3]=[N:2]1.[NH:31]1[CH2:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>O1CCOCC1>[S:1]1[C:5]([NH:6][C:7]2[CH:12]=[C:11]([N:31]3[CH2:34][CH2:33][CH2:32]3)[N:10]=[C:9]([S:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:30])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])=[CH:17][CH:16]=3)[N:8]=2)=[N:4][CH:3]=[N:2]1
Reactant: O=C(Nc1ccc(Sc2nc(Cl)cc(Nc3ncns3)n2)cc1)c1ccccc1Cl
Reactant: C1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: O=C(Nc1ccc(Sc2nc(Nc3ncns3)cc(N3CCC3)n2)cc1)c1ccccc1Cl
Temperature: 130 °C
Yield: 13 %

Procedure:
In the next step, a mixture of N-(4-(4-(1,2,4-thiadiazol-5-ylamino)-6-chloropyrimidin-2-ylthio)phenyl)-2-chlorobenzamide (188 mg, 0.42 mmol), azetidine (67.5 mg, 1.18 mmol), DiPEA (0.17 mL, 1.0 mmol) in 1,4-dioxane (10 mL) was heated to 130° C. for 20 minutes. The crude product (940 mg) was purified by preparative HPLC to yield 27 mg of N-(4-(4-(1,2,4-Thiadiazol-5-ylamino)-6-(azetidin-1-yl)pyrimidin-2-ylthio)phenyl)-2-chlorobenzamide with 99+% purity (HPLC method B, Rf=7.183 minutes).
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28])=[O:22])([CH3:19])([CH3:18])[CH3:17]>C(N(CC)CC)C>[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([Cl:1])[C:11]=1[N+:12]([O-:14])=[O:13])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Reactant: CC(C)(C)OC(=O)NCCCCN
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12
Reaction time: 1.5 h
Yield: 82.8 %

Procedure:
0.72 g (2.97 mmol) of 2,4-Dichloro-3-nitroquinoline and 0.56 g (2.97 mmol) of N-(tert-butoxycarbonyl)-1,4-diaminobutane were heated in 12 ml of triethylamine at 70° C. and stirred for 1.5 hours. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in methylene chloride, washed with water, and dried (MgSO4). The solvent was distilled off under reduced pressure. The residue was triturated with n-hexane-diethyl ether (1:1 (v/v)) and collected by filtration to obtain 0.97 g (2.46 mmol) of 4-[4-(tert-butoxycarbonylamino)butylamino]-2-chloro-3-nitroquinoline shown below as yellow powder (mp: 125-126.5° C.). ##STR41## Its spectroscopic data are as follows: IR (KBr) cm-1 : 3340, 3280, 1680, 1540, 1520. 1H-NMR (CDCl3) δ (ppm) :1.46 (9H, s), 1.63 (2H, m), 1.78 (2H, m), 3.19 (2H, q, J=6.4 Hz), 3.47 (2H, q, J=61 Hz), 4.68 (1H, br), 6.41 (1H, b r), 7.52 (1H, t, J=7.7 Hz), 7.74 (1H, t, J=7.8 Hz), 7.91 (1H, d, J=8.4 Hz), 8.11 (1H, d, J=8.4 Hz).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:35])[C:6]1[CH:11]=[C:10]([S:12](=[O:33])(=[O:32])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:7]=1[CH3:34]>CO>[CH3:34][C:7]1[CH:8]=[CH:9][C:10]([S:12](=[O:33])(=[O:32])[NH:13][C:14]2[CH:15]=[CH:16][C:17]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:18][CH:19]=2)=[CH:11][C:6]=1[C:5]([OH:35])=[O:4]
Reactant: COC(=O)c1cc(S(=O)(=O)Nc2ccc(SCc3ccc(C(F)(F)F)cc3)cc2)ccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)Nc2ccc(SCc3ccc(C(F)(F)F)cc3)cc2)cc1C(=O)O
Temperature: 25 °C
Yield: 93.4 %

Procedure:
A solution of 1.0N aqueous sodium hydroxide (9.1 ml, 9.16 mmol) was added to a solution of 2-methyl-5-[4-(4-trifluoromethyl-benzylsulfanyl)-phenylsulfamoyl]-benzoic acid methyl ester (1.13 g, 2.29 mmol) in 100 ml methanol and the resulting solution was heated at reflux overnight under nitrogen. The reaction solution was then cooled to room temperature and concentrated under reduced pressure. The residue was stirred in 1.0N aqueous hydrochloric acid solution (25 ml) and filtered to yield the title compound as a white solid (1.03 g, 94% yield). MS: 480.2 (M−1); 1H NMR (400 MHz, CD3OD): δ2.49 (s, 3H), 4.04 (s, 2H), 6.96 (d, 2H), 7.1 (d, 2H), 7.29 (m, 2H), 7.33 (d, 1H), 7.47 (m, 3H), 7.94 (b, 1H).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([Cl:17])=[N:9][N:8]=1>O1CCCC1>[Cl:17][C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([CH2:6][O:4][CH2:1][C:2]#[CH:3])=[N:8][N:9]=1
Reactant: C#CCO
Reactant: Clc1nnc(CBr)c2ccccc12
Solvent: C1CCOC1
Product: C#CCOCc1nnc(Cl)c2ccccc12
Reaction time: 3 h
Yield: 23.1 %

Procedure:
A solution of propargyl alcohol (46 mg, 0.81 mmol) and KN(TMS)2 (1.63 mL, 0.81 mmol) in tetrahydrofuran (1.5 mL) is stirred under argon for 30 min before 1-bromomethyl-4-chlorophthalazine (2) (140 mg, 0.54 mmol) is added. The mixture is stirred for 3 h, quenched with 2 N HCl (5 mL) and H2O (15 mL), and extracted with ethyl acetate (80 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the residue is purified on silica gel (20% to 25% ethyl acetate/hexane) to give 29 mg (23%) of 3 as a colorless solid, mp 131-132° C. IR 3079, 1406, 1325 cm−1; 1H NMR (CDCl3) δ 2.60 (t, J=2.4 Hz, 1H, CH≡CCH2O), 5.17 (s, 2H, CH2), 5.36 (d, J=2.4 Hz, CH≡CCH2O), 7.90-8.02 (m, 2H, 6,7-PhthH), 8.21 (m, 1H, 5-PhthH), 8.36 ppm (m, 1H, 8-PhthH).
Reaction SMILES: CCN(C(C)C)C(C)C.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.Br[CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(#N)C>[C:23]1([CH:17]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: C1CCNCC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(c1ccccc1)N1CCCCC1

Procedure:
DIPEA (0.86 ml, 4.94 mmol) and piperidine (0.49 ml, 4.94 mmol) were sequentially added to a solution of ethyl 2-bromo-2-phenylacetate (0.72 ml, 4.11 mmol) in acetonitrile (13 ml). The pale yellow solution was stirred at room temperature monitoring by TLC (petroleum ether/EtOAc=9/1). After 1.5 hours complete conversion into the desired product was detected. Solvent was evaporated and the residue (pale yellow solid) was triturated with Et20 (30 ml). The solid was filtered off and the ethereal solution was evaporated to dryness. The residue was purified by flash chromatography (petroleum ether/EtOAc=95/5) to collect ethyl 2-phenyl-2-(piperidin-1-yl)acetate (990 mg, 97% yield) as a colorless oil.
Reaction SMILES: [CH3:1][NH:2][CH:3]([C:6]([CH3:19])([OH:18])[CH2:7][CH2:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:4][OH:5].N1C=CC=CC=1.Cl.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1.O>ClC(Cl)C>[CH3:1][N:2]([CH:3]([C:6]([OH:18])([CH3:19])[CH2:7][CH2:8][CH2:9][CH:10]([CH3:17])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:4][OH:5])[C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1
Reactant: CNC(CO)C(C)(O)CCCC(C)CCCC(C)C
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)CCCC(C)CCCC(C)(O)C(CO)N(C)C(=O)c1cccnc1
Temperature: -30 °C
Reaction time: 3 h
Yield: 86.7 %

Procedure:
In 100 ml of dichloroethane were dissolved 10 g of 2-(methylamino)-3,7,11-trimethyl-1,3-dodecanediol and 8.7 g of pyridine and the solution was cooled to -30° C. To this solution was added 7.2 g of nicotinoyl chloride hydrochloride gradually and the mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction mixture was poured into water and extracted with dichloroethane. The organic layer was washed with aqueous sodium hydrogen carbonate and after drying over anhydrous magnesium sulfate, the solvent was distilled off. Finally, the residue was subjected to silica gel column chromatography (elution with ethanol) to give 12.0 g of N-methyl-N-(1,3-dihydroxy-3,7,11-trimethyldodecan-2-yl)nicotinamide [Compound (66)]. Yield 93%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]([F:29])([F:28])[F:27])=[N:4][N:5]([CH2:8][C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([OH:23])[C:20]([Cl:24])=[CH:19][C:18]=3[Cl:25])[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7].I[CH:31]([CH3:33])[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[C:3]([C:26]([F:29])([F:28])[F:27])=[N:4][N:5]([CH2:8][C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[C:21]([O:23][CH:31]([CH3:33])[CH3:32])[C:20]([Cl:24])=[CH:19][C:18]=3[Cl:25])[CH2:13][CH2:12]2)=[O:10])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)C1CCN(c2cc(O)c(Cl)cc2Cl)CC1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)C1CCN(c2cc(OC(C)C)c(Cl)cc2Cl)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-1-(1-(2,4-dichloro-5-hydroxyphenyl)piperidin-4-yl)ethanone (30 mg, 0.064 mmol) in anhydrous acetonitrile (1.5 mL) was treated with 2-iodopropane (0.019 mL, 0.191 mmol) and cesium carbonate (41.5 mg, 0.127 mmol) and the mixture stirred at 50° C. for 1 h. After this time, the mixture was concentrated on a rotary evaporator and the resultant residue was partitioned between water and EtOAc. The EtOAc phase was washed with brine, dried (MgSO4) and concentrated to give 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)-1-(1-(2,4-dichloro-5-isopropoxyphenyl)piperidin-4-yl)ethanone. LC-MS: 512.20, [M+H]; tR=2.30 min (method a).