Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.[CH3:31][N:32]=[C:33]=[O:34]>>[NH2:16][C:15]1[C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8][N:7]([C@@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:33]([NH:32][CH3:31])=[O:34])[CH2:6]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CN=C=O
Reactant: NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Product: CNC(=O)NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1

Procedure:
cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-methyl-urea is prepared as described in Example 26 starting with cis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and methyl isocyanate (ChemService Inc., West Chester, Pa., U.S.A.). Analytical HPLC: tR=6.49 min (Grad 2); ES-MS: m/eo=456.9.
Reaction SMILES: [C:1]([OH:16])(=[O:15])[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(O)(=O)CCCC=CCCCCCCCC>>[C:1]([OH:16])(=[O:15])[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCC=CCCC(=O)O
Agent: CCCCCCCCC=CCCCC(=O)O
Product: CCCCCCCCCCCC=CC(=O)O

Procedure:
4-tetradecenoic acid; 5-tetradecenoic acid;
Reaction SMILES: [CH2:1]([C:6]1[S:10][C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:22])[CH:16]=[C:17]([N+:19]([O-])=O)[CH:18]=2)=[O:13])=[N:8][C:7]=1[C:23]([NH:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:24])[CH2:2][CH:3]([CH3:5])[CH3:4].N#N>CO.[Pd]>[NH2:19][C:17]1[CH:18]=[C:14]([C:12]([NH:11][C:9]2[S:10][C:6]([CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])=[C:7]([C:23]([NH:25][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)=[O:24])[N:8]=2)=[O:13])[N:15]([CH3:22])[CH:16]=1
Reactant: CC(C)CCc1sc(NC(=O)c2cc([N+](=O)[O-])cn2C)nc1C(=O)NCCN1CCOCC1
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: CC(C)CCc1sc(NC(=O)c2cc(N)cn2C)nc1C(=O)NCCN1CCOCC1
Reaction time: 4 h

Procedure:
5-Isopentyl-2-{[(1-methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino}-N-[2-(4-morpholinyl)ethyl]-1,3-thiazole-4-carboxamide (400 mg, 0.836 mmol; see step (i) above) was dissolved in methanol (25 mL) to which was added Pd/C-10% (300 mg) at 0° C. (under N2) with stirring. The reaction mixture was hydrogenated for 4 h at room temperature and atmospheric pressure to give the title compound, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:35]2[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=2)[CH2:38]Cl)[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32]>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH2:38][C:37]2[CH:40]=[CH:41][CH:42]=[C:35]([C:27]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=3)[CH:36]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Product: COc1ccccc1N(Cc1cccc(-c2cc(OC)c(OC)c(OC)c2)c1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
4-(o-Anisidino)-1-(tert-butoxycarbonyl)piperidine (613 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: C(O[C@H](C)[C@H](NC(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)C(O)=O)C1C=CC=CC=1.[C:33]([O:37][C:38]([NH:40][C@H:41]([C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH2:53][O:54][CH:55]2CCCCO2)=[CH:47][CH:46]=1)[C:42]([OH:44])=[O:43])=[O:39])([CH3:36])([CH3:35])[CH3:34].C(OC(N[C@H](C1C=CC(OCC(OC)OCC)=CC=1)C(O)=O)=O)(C)(C)C.C(OC(NC(C1C=CC(OCCOC)=CC=1)C(O)=O)=O)(C)(C)C>>[C:33]([O:37][C:38]([NH:40][C@H:41]([C:45]1[CH:46]=[CH:47][C:48]([O:51][CH2:52][CH2:53][O:54][CH3:55])=[CH:49][CH:50]=1)[C:42]([OH:44])=[O:43])=[O:39])([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OCCOC2CCCCO2)cc1
Agent: CCOC(COc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1)OC
Agent: COCCOc1ccc(C(NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Product: COCCOc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
Prepared by the same method as described in example 3 except that (i) 2-chloro-4-iodo-aniline was used in place of 4-bromo-2-chloro-aniline in step 1, (ii) (S)-2-tert-butoxycarbonylamino-3-phenyl-propionic acid was used in place of (S,S)-2-tert-butoxycarbonylamino-3-phenyl-butyric acid in step 1, and (iii) R)-tert-butoxycarbonylamino-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid was used in place of (R)-tert-butoxycarbonylamino-[4-(2-tert-butoxy-ethoxy)-phenyl]-acetic acid in step 2. (R)-tert-butoxycarbonylamino-[4-(2-methoxy-ethoxy)-phenyl]-acetic acid was prepared as described in example 80.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[F:23])[CH:18]=O>>[F:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[F:23])[CH2:18][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3ccc(F)c(F)c3)CC2)nc[nH]1

Procedure:
6-[4-(3,4-Difluoro-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3,4-difluorobenzaldehyde. Mass spectrum (ES) MH+=307.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:20])[C:5]2[CH:6]=[N:7][N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:9]=2[CH:10]=1.CC1(C)C(C)(C)OB([C:29]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:30]=2[CH:31]=[CH:32][NH:33]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH:33]1[C:34]2[C:30](=[C:29]([C:2]3[CH:3]=[C:4]([NH2:20])[C:5]4[CH:6]=[N:7][N:8]([S:11]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)(=[O:13])=[O:12])[C:9]=4[CH:10]=3)[CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:32]1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Reactant: Nc1cc(Br)cc2c1cnn2S(=O)(=O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1cc(-c2cccc3[nH]ccc23)cc2c1cnn2S(=O)(=O)c1ccccc1
Temperature: 100 °C

Procedure:
6-Bromo-1-(phenylsulfonyl)-1H-indazol-4-amine (3 g, 8.52 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (2.278 g, 9.37 mmol), Pd(dppf)Cl2 (0.623 g, 0.852 mmol) and sodium carbonate (2.71 g, 25.6 mmol) were divided between 2× microwave vials and dissolved in 1,4-dioxane (16 mL) and water (16 mL); 8 ml of each solvent in each vial. The vials were heated in the microwave at 100° C. for 10 min. The mixtures were combined and filtered through Celite, washing with EtOAc. The resulting mixture was partitioned between water (100 ml) and EtOAc (100 ml) and the layers separated. The aqueous layer was extracted with further EtOAc (2×50 ml) and the organic extracts were combined, passed through a hydrophobic frit and the solvent removed in vacuo to give a brown solid which was pre-adsorbed onto silica and added to the top of a 100 g silica SPE cartridge. This was eluted with 0-100% EtOAc/cyclohexane over 60 minutes on the FlashMaster II. The product-containing fractions were combined and the solvent was removed in vacuo to afford the title compound as orange crystals which were dried on a high vacuum line for 1 hour.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:26][CH2:27][CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[OH:29]>CO.[Pd]>[OH:29][CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:27][NH:26][CH:22]1[CH2:23][CH2:24][N:19]([C:16]2[CH:17]=[CH:18][C:13]([NH:12][S:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)(=[O:10])=[O:11])=[CH:14][CH:15]=2)[CH2:20][CH2:21]1
Reactant: NCC(O)c1ccccc1
Reactant: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NCC(O)c4ccccc4)CC3)cc2)cc1
Yield: 61.3 %

Procedure:
A mixture of 4-methoxy-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 218) (0.16 g, 0.44 mmol) and 2-amino-1-phenylethanol (0.18 g, 1.3 mmol) in 75 mL of methanol was hydrogenated in the presence of 100 mg of 10% Pd/C under H2 (5˜20 psi) for overnight. The catalyst was then removed by filtering through a short pad of silica gel. The filtrate was concentrated and purified by silica gel chromatography using 5–10% MeOH/CH2Cl2 as eluent to give 0.13 g (61%) of the title compound as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20–1.40 (m, 2 H), 1.78–1.92 (m, 2 H), 2.50–2.80 (m, 5 H), 3.60–3.70 (m, 2 H), 3.79 (s, 3 H), 4.56–4.60 (m, 1 H), 5.26 (brs, 1 H), 6.76 (d, J=9.0 Hz, 2 H), 6.86 (d, J=9.0 Hz, 2 H), 7.04 (d, J=9.0 Hz, 2 H), 7.20–7.25 (m, 1 H), 7.25–7.36 (m, 4 H), 7.58 (d, J=9.0 Hz, 2 H); MS (ES) m/z: 482.4 (MH+); HRMS Calcd. for C26H31N3O4S (M+): 481.2035. Found: 481.2028.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.Cl[CH2:10][CH:11]=O.O>C(O)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[CH:11][N:1]=2)[CH:4]=1
Reactant: O=CCCl
Reactant: Nc1ccc(F)cn1
Solvent: O
Solvent: CCO
Product: Fc1ccc2nccn2c1

Procedure:
To a solution of 2-amino-5-fluoropyridine (10 g) in ethanol (200 mL), a solution of chloroacetaldehyde 50% in water (56 mL, 4.0 equiv.) was added. The reaction mixture was heated at reflux 2 Hrs, then was concentrated under reduced pressure to 100 mL. The residue was diluted in AcOEt (100 mL) and washed with a saturated aqueous solution of NaHCO3 (2*150 mL). The combined aqueous were saturated with NaHCO3 and extracted back with AcOEt (2*100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([S:15](Cl)(=[O:17])=[O:16])[CH:6]=1)(=[O:3])[CH3:2].[CH:19]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[CH2:22][NH:21][CH2:20]2>C(Cl)(Cl)Cl.N1C=CC=CC=1>[C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([S:15]([N:21]2[CH2:22][CH:23]3[CH2:26][CH2:27][CH:19]([CH2:25][CH2:24]3)[CH2:20]2)(=[O:17])=[O:16])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(S(=O)(=O)Cl)cc2ccccc12
Reactant: C1CC2CCC1CNC2
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)Oc1cc(S(=O)(=O)N2CC3CCC(CC3)C2)cc2ccccc12
Yield: 63.1 %

Procedure:
4-Acetoxy-2-naphthalenesulfonyl chloride (861 mg, 3.02 mmol) and 3-azabicyclo[3.2.2]nonane (379 mg, 3.02 mmol) were combined in CHCl3 (20 ml) and pyridine (20 ml), and the mixture was stirred at room temperature for 15 hours. At this time, the solvent was evaporated under reduced pressure and the residue was partitioned between EtOAc and 1N aqueous HCl. The EtOAc was then washed with saturated aqueous NaHCO3, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography using 1% acetone in CHCl3 to provide 712 mg of the pure white product as a white foam: 1H NMR (CDCl3) δ 1.52-1.84 (9H, m, 4×CH2), 2.02-2.13 (2.H, br s, 2×CH) 2.46 (3H, s, CH3CO), 3.31 (4H, d, J=4.2 Hz, 2×CH2), 7.56-7.71 (3H, m, ArH), 7.92-8.02 (2H, m ArH).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2([CH2:17][CH2:16][CH2:15][N:14](CC3C=CC=CC=3)[C:13]2=O)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.CO.[C+4].[OH-].[Pd+2].[OH-].[OH-].[OH-].[OH-].[OH-]>[C:1]([O:5][C:6]([N:8]1[C:12]2([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC12CCCN(Cc1ccccc1)C2=O
Agent: [Pd+2]
Agent: [C+4]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC12CCCNC2
Yield: 96.2 %

Procedure:
To a solution of 7-benzyl-6-oxo-1,7-diazaspiro[4.5]decane-1-carboxylic acid tert-butyl ester (76 mg) in tetrahydrofuran/methanol (1 ml/1 ml) was added 20% palladium hydroxide carbon (15 mg), and the mixture was hydrogenated under 4 atmospheres. The mixture was filtered through Celite under nitrogen, and the filtrate was concentrated under reduced pressure to give the titled compound (51 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[CH3:7][C:8]1[CH:22]=[CH:21][C:11]([S:12][C:13]([O:15][CH:16](Cl)[CH:17]([CH3:19])[CH3:18])=[O:14])=[CH:10][CH:9]=1>[Ag-]=O.COC(C)(C)C>[CH3:1][CH:2]([CH3:6])[C:3]([O:5][CH:16]([O:15][C:13]([S:12][C:11]1[CH:21]=[CH:22][C:8]([CH3:7])=[CH:9][CH:10]=1)=[O:14])[CH:17]([CH3:19])[CH3:18])=[O:4]
Reactant: CC(C)C(=O)O
Reactant: Cc1ccc(SC(=O)OC(Cl)C(C)C)cc1
Agent: O=[Ag-]
Solvent: COC(C)(C)C
Product: Cc1ccc(SC(=O)OC(OC(=O)C(C)C)C(C)C)cc1
Temperature: 95 °C

Procedure:
2-Methylpropanoic acid (5 mL) and silver (I) oxide (2.3 g) were charged to a vessel at room temperature. 1-Chloro-2-methylpropyl (4-methylthiophenoxy)formate (2.46 g) D4 was added to the reaction vessel. The reaction was heated to 95° C. and the mixture was maintained at approximately 90° C. for 1 hour. The reaction was then cooled to room temperature and tert-butyl methyl ether (20 mL) was added. The solid was filtered and the filter was washed with tert-butyl methyl ether (2×15 mL). The organic phase was washed with water (4×25 mL), bicarbonate (2×25 mL), and dried over sodium sulfate. The organic volatiles were removed under vacuum to provide 3.2 g of the title compound D5 as a pale-yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH:12]=[C:13]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)=[N:6][CH:7]=1.[CH:29](I)([CH3:31])[CH3:30].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH:29]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]([CH:26]=[CH:27][CH:28]=2)[CH:12]=[C:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:15][CH2:14]2)=[N:6][CH:7]=1)([CH3:31])[CH3:30]
Reactant: CC(C)I
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(O)cn3)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1ccc(Oc2cccc(C=C3CCN(C(=O)OC(C)(C)C)CC3)c2)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
To a stirred solution of tert-butyl 4-(3-(5-hydroxypyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.6 g, 1.56 mmol) in acetone (5 mL) cooled to 0° C. was added isopropyliodide (0.33 g, 1.96 mmol) and K2CO3 (0.43 g, 3.12 mmol). The reaction mixture was stirred at 80° C. overnight. The reaction mixture was evaporated to dryness and water (10 mL) was added and the mixture was extracted with ethyl acetate three times. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (1:19 acetone:hexane) to give the title compound (0.5 g, 75%). 1H NMR (500 MHz, CDCl3): δ 7.86 (d, J=3.3 Hz, 1H), 7.28 (m, 2H), 6.96 (d, J=7.5 Hz, 1H), 6.91 (m, 2H), 6.84 (d, J=8.5 Hz, 1H), 6.32 (s, 1H), 4.45 (m, 1H), 3.49 (m, 2H), 3.38 (m, 2H), 2.45 (m, 2H), 2.31 (m, 2H), 1.47 (s, 9H), 1.33 (d, J=6 Hz, 6H); m/z (425.2, M+ H+).
Reaction SMILES: Br[CH2:2][C:3]1[S:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)[N:4]=1.[F:19][C:20]1[C:28]([OH:29])=[CH:27][CH:26]=[C:25]([F:30])[C:21]=1[C:22]([NH2:24])=[O:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:19][C:20]1[C:28]([O:29][CH2:2][C:3]2[S:7][N:6]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=3)[N:4]=2)=[CH:27][CH:26]=[C:25]([F:30])[C:21]=1[C:22]([NH2:24])=[O:23]
Reactant: FC(F)(F)Oc1ccc(-c2nsc(CBr)n2)cc1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(F)ccc(OCc2nc(-c3ccc(OC(F)(F)F)cc3)ns2)c1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 9.4 %

Procedure:
To a solution of 5-bromomethyl-3-(4-trifluoromethoxyphenyl)-[1,2,4]thiadiazole (0.11 g, 0.32 mmol) in DMF (5 ml) was added 2,6-difluoro-3-hydroxybenzamide (0.056 g, 0.32 mmol) and potassium carbonate (0.16 g, 1.13 mmol). The reaction mixture was stirred at 25° C. for 12 h under nitrogen atmosphere. After the completion of the reaction (TLC monitoring), the reaction mixture was evaporated to dryness under vacuum, added 30 ml water and extracted with ethyl acetate (3×20 ml). The combined organic layer was dried over Na2SO4, filtered and concentrated under vacuum. The crude residue was purified over silica gel (100-200 M, 50% EtOAc-Hexane) to get the desired product (0.013 g, 9%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]Br>[OH-].[Na+]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[O:9][CH2:12][CH2:11][Br:10]
Reactant: BrCCBr
Reactant: Oc1cc(Br)ccc1Br
Agent: [Na+]
Agent: [OH-]
Product: BrCCOc1cc(Br)ccc1Br
Temperature: 80 °C
Reaction time: 40 h
Yield: 51.4 %

Procedure:
A mixture of 2,5-dibromophenol (134) (1.26 g, 5 mmol) and 1,2-dibromoethane (135) (431 μl, 5 mmol) in 5 ml 1N NaOH was stirred at 80° C. for 40 h. After cooling down, the reaction mixture was extracted with diethyl ether. Org. phase was washed with 1 N NaOH and brine subsequently. Org. phase was dried over sodium sulfate concentrated to give 922 mg (yield 51%, purity ca 90%) 1,4-dibromo-2-(2-bromoethoxy)benzene (136) as orange-red oil which was used directly for further reaction without purification.
Reaction SMILES: C([O:8][N:9]([C:16](=[O:54])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([O:46]CC1C=CC=CC=1)[C:25](=[O:45])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:33]([O:37]CC1C=CC=CC=1)[C:34](=[O:36])[CH3:35])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])C1C=CC=CC=1.[ClH:55]>CO.[Pd]>[ClH:55].[OH:8][N:9]([C:16](=[O:54])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([OH:46])[C:25](=[O:45])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][N:33]([OH:37])[C:34](=[O:36])[CH3:35])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]
Reactant: CC(=O)N(CCCCCCCC(=O)N(CCCCCCCC(=O)N(CCCCC#N)OCc1ccccc1)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(=O)N(O)CCCCCCCC(=O)N(O)CCCCCCCC(=O)N(O)CCCCCN

Procedure:
Compound [VII] (1.20 g, 1.62 mmol) was hydrogenated in CH3OH and 0.1N HCl with 10% Pd-C by the procedure used for [A]. Purification by Sephadex LH-20 column chromatography with 15% EtOH/toluene as the eluant produced 0.386 g (47%) of [A] as a colorless solid: NMR (CO3OD) δ 1.17-1.87 (m, 26H), 2.07 (s, 3H), 2.30-2.55 (m, 4H), 2.90 (t, 2H, J=6), 3.43-3.70 (m, 6H). Anal. (C23H47ClN4O6) C, H, N.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([NH2:27])[CH2:5][NH:6][C:7]([N:9]1[CH2:26][CH2:25][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:11][CH2:10]1)=[O:8].[C:29]([N:32]1[C@@H:36]([C:37](O)=[O:38])[CH2:35][S:34][CH2:33]1)(=[O:31])[CH3:30].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3](=[O:28])[CH:4]([NH:27][C:37]([C@H:36]1[CH2:35][S:34][CH2:33][N:32]1[C:29](=[O:31])[CH3:30])=[O:38])[CH2:5][NH:6][C:7]([N:9]1[CH2:10][CH2:11][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:25][CH2:26]1)=[O:8]
Reactant: CC(=O)N1CSC[C@@H]1C(=O)O
Reactant: COC(=O)C(N)CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1)NC(=O)[C@H]1CSCN1C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
To a solution of 331 mg (0.85 mmol) of 2-amino-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester in 8.5 ml of dichloromethane, 149 mg (0.85 mmol) of (S)-3-acetylthiazolidin-4-carboxylic acid, 376 mg (0.85 mmol) of BOP reagent and 0.16 ml (0.95 mmol) of N,N-diisopropylethylamine were added, and the resulting mixture was stirred overnight at room temperature. To the reaction mixture, 10 ml of semi-saturated saline was added, and the resulting mixture was extracted with ethyl acetate. Organic phases were combined, washed with 0.5M hydrochloric acid, with saturated aqueous sodium hydrogen carbonate solution and with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=100:1-10:1) to obtain 305 mg of 2-(((S)-3-acetylthiazolidin-4-carbonyl)amino)-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester (yield: 65%).
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].[C:12]([CH2:15][C:16](=O)[CH3:17])(=O)[CH3:13]>C(O)C>[CH3:13][C:12]1[CH:15]=[C:16]([CH3:17])[N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[N:2]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CC(=O)CC(C)=O
Solvent: CCO
Product: Cc1cc(C)n(-c2ccc(C(=O)O)cc2)n1
Yield: 0.1 %

Procedure:
A solution of 4-hydrazino-benzoic acid (0.60 g, 3.95 mmol) and acetyl acetone (0.405 ml, 3.95 mmol) in ethanol (20 ml) refluxed for 1 hour. Ethanol was removed in vacuum and the remaining solid was triturated with water and collected by filtration to produce 285 (0.71 mg, 83% yield). [M−1]− 215.1.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[C:12][Si](C)(C)C)=[CH:8][CH:9]=2)[N:4]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[N:18]=2)[N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:11]([C:7]1[CH:6]=[C:5]2[C:10]([C:2]([CH3:1])=[N:3][N:4]2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[N:18]=2)=[CH:9][CH:8]=1)#[CH:12]
Reactant: Cc1nn(-c2ccnc(N)n2)c2cc(C#C[Si](C)(C)C)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc2c(C)nn(-c3ccnc(N)n3)c2c1
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
To a solution of 4-{3-methyl-6-[2-(trimethylsilyl)ethynyl]indazol-1-yl}pyrimidin-2-amine (600 mg, 1.87 mmol) in THF (15 ml) was added TBAF (2.24 mL of a 1M solution in THF, 2.24 mmol) and the reaction mixture was allowed to stand for 0.5 hr. The reaction mixture was concentrated in vacuo, DCM (5 ml) was added and the concentration repeated (×2). The crude product was purified by flash chromatography (Biotage, 3-10% methanol in DCM) to give the title intermediate as a yellow solid (300 mg): 1H NMR (500 MHz, DMSO) delta 2.58 (3H, s), 4.37 (1H, s), 7.14-6.86 (3H, m), 7.40 (1H, dd, J=8.2, 1.1 Hz), 7.85 (1H, d, J=8.2 Hz), 8.26 (1H, d, J=5.5 Hz), 8.98 (1H, s); LC-MS: m/z=+250.35 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[S:5][CH:6]=1.[H-].[Na+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Br)=[CH:18][CH:17]=1>CN(C)C=O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:9]2[CH2:10][CH2:11][N:7]([C:4]3[S:5][CH:6]=[C:2]([CH3:1])[N:3]=3)[C:8]2=[O:12])=[CH:18][CH:17]=1
Reactant: Cc1csc(N2CCNC2=O)n1
Reactant: BrCCCCCCOc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1csc(N2CCN(CCCCCCOc3ccc(Br)cc3)C2=O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 1-(4-methyl-1,3-thiazol-2-yl)-2-imidazolidinone (0.11 g, 0.61 mmol) dissolved in 10 mL of dimethylformamide at 0° C. was added NaH (60% dispersion in mineral oil, 36.6 mg, 0.92 mmol). The mixture was stirred at room temperature for 30 minutes and then cooled in ice bath. 1-Bromo-4-[(6-bromohexyl)oxy] benzene (0.21 g, 0.61 mmol) was added, and the mixture was stirred at room temperature for additional 4 hours. The reaction was quenched with methanol, and the solvents were removed under reduced pressure. A saturated aqueous NH4Cl solution and dichloromethane were successively added to the residue. The dichloromethane layer was separated and dried over MgSO4, filtered, evaporated, and purified by column chromatography (ethyl acetate:MeOH=10:1) to give the product (i.e., Compound 10) as a yellow viscous oil (0.19 g, 74%).