Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2([CH2:26][CH2:27][CH2:28][O:29]CC3C=CC=CC=3)[C:22]3[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=3)[O:16][C:15](=[O:25])[CH2:14]2)[N:10]=[CH:9]1)C1C=CC=CC=1>CO.Cl.[Pd]>[OH:29][CH2:28][CH2:27][CH2:26][C:13]1([C:11]2[N:10]=[CH:9][NH:8][CH:12]=2)[C:22]2[C:17](=[CH:18][C:19]([O:23][CH3:24])=[CH:20][CH:21]=2)[O:16][C:15](=[O:25])[CH2:14]1
Reactant: COc1ccc2c(c1)OC(=O)CC2(CCCOCc1ccccc1)c1cn(Cc2ccccc2)cn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)OC(=O)CC2(CCCO)c1c[nH]cn1

Procedure:
A solution of 1 mmol of 4-(1-benzyl-1H-imidazol-4-yl)-4-(3-benzyloxypropyl)-7-methoxychroman-2-one in 15 ml of methanol and 2 ml of conc HCl is hydrogenated in the presence of 100 mg of 10% Pd/C at 15° C. for 10 hours. The reaction mixture is subjected to clarifying filtration and the filtrate is evaporated. The crude title compound is identified on the basis of the Rf value and reacted further without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:28])[CH2:18][N:19]3[CH:23]=[C:22]([Si](C)(C)C)[N:21]=[N:20]3)[CH2:13][CH2:12]2)[O:8][N:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]=[C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:28])[CH2:18][N:19]3[CH:23]=[CH:22][N:21]=[N:20]3)[CH2:13][CH2:12]2)[O:8][N:7]=1
Reactant: C[Si](C)(C)c1cn(CC(=O)N2CCC(c3nc(-c4cccs4)no3)CC2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(Cn1ccnn1)N1CCC(c2nc(-c3cccs3)no2)CC1
Temperature: 25 °C
Yield: 48 %

Procedure:
38 mg (1 eq.) of the 1-[4-(3-thiophen-2-yl[1,2,4]oxadiazol-5-yl)piperid-1-yl]-2-(4-trimethylsilanyl[1,2,3]triazol-1-yl)ethanone obtained above in the preceding step and 100 μl (1.05 eq.) of tetrabutylammonium fluoride were dissolved in 0.9 ml of THF in a sealed tube, and then refluxed for 1 hour. After cooling to room temperature, the THF was evaporated off and the residue was then purified on silica gel (90/10 CH2Cl2/methanol). 1-[4-(3-Thiophen-2-yl[1,2,4]oxadiazol-5-yl)piperid-1-yl]-2-[1,2,3]triazol-1-ylethanone was obtained in the form of a pale yellow solid, in a yield of 48%.
Reaction SMILES: [CH3:1][Mg+].[Br-].[CH3:4][O:5][C:6]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:7]=1[CH2:8][N:9]1[C:13](=[O:14])[CH2:12][CH:11]([C:15](N(OC)C)=[O:16])[CH2:10]1>C1COCC1.O>[C:15]([CH:11]1[CH2:10][N:9]([CH2:8][C:7]2[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:6]=2[O:5][CH3:4])[C:13](=[O:14])[CH2:12]1)(=[O:16])[CH3:1]
Reactant: COc1ccc(CN2CC(C(=O)N(C)OC)CC2=O)c(OC)c1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2CC(C(C)=O)CC2=O)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
MeMgBr (2.3 mL, 6.8 mmol) was added to a mixture of 1-(2,4-dimethoxybenzyl)-N-methoxy-N-methyl-5-oxopyrrolidine-3-carboxamide (2.0 g, 6.2 mmol) in THF (40 mL) at −10° C. The mixture was stirred at 0° C. for 1 hour then diluted with water and the mixture was extracted with EtOAc. The EtOAc layer was dried over sodium sulfate and concentrated under reduced pressure to afford 4-acetyl-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one. 1H NMR (400 MHz, CDCl3) δ 7.10-7.13 (m, 1H), 6.43-6.45 (m, 2H), 4.41-4.42 (m, 2H), 3.79-3.82 (m, 6H), 3.46-3.20 (m, 3H), 2.61-2.64 (m, 2H), 2.04-2.15 (d, J=7.2 Hz, 3H). MS ESI calc'd. for C15H20NO4 [M+H]+ 278. found 278.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:17])[C@@H:4]([NH:9]C(OC(C)(C)C)=O)[C:5]([CH3:8])([CH3:7])[CH3:6].FC(F)(F)C(O)=O>ClCCl>[CH3:1][NH:2][C:3](=[O:17])[C@@H:4]([NH2:9])[C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CNC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)[C@@H](N)C(C)(C)C
Reaction time: 18 h
Yield: 54.1 %

Procedure:
To a solution of (2S)-2-tert-butoxycarbonylamino-3,3-dimethylbutanoic acid methylamide (126 g, 519 mmol) in dichloromethane (320 mL) cooled at 0.degree. C. is added trifluoroacetic acid (320 mL). The resulting solution is allowed to warm to 25.degree. C. and is stirred for 18 h. The reaction mixture is concentrated, brought to pH=10 with 2 M sodium hydroxide, and extracted with 4:1 dichloromethane/isopropanol (1000 mL). The organic layer is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide (2S)-2-Amino-3,3-dimethylbutanoic acid methylamide (40.5 g, 79% yield) as a white solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][C:9]([CH2:11][C@@H:12]([C@@H:14]([CH2:16][N:17]=[N+:18]=[N-:19])[OH:15])[OH:13])=[O:10]>N1C=CC=CC=1>[CH3:8][C:9]([CH2:11][C@@H:12]([C@@H:14]([CH2:16][N:17]=[N+:18]=[N-:19])[OH:15])[O:13][C:1](=[O:3])[CH3:2])=[O:10]
Reactant: CC(=O)C[C@H](O)[C@H](O)CN=[N+]=[N-]
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)C[C@H](OC(C)=O)[C@H](O)CN=[N+]=[N-]
Reaction time: 4 h
Yield: 60 %

Procedure:
Acetic anhydride (25 mL) was added to a solution of methyl-5-azido-2.5-dideoxy-D-ribose (6.2 g, 38 mmol) in pyridine (100 mL). After 4 hours at room temperature, the mixture was concentrated in vacuo. The residue (6 g) was purified by flash chromatography eluting with hexanethylacetate (8:2). Evaporation of the eluting solvent gave the product as an oil (4.9 g, 60% yield). NMR
Reaction SMILES: CC1(C)CCN(C2C=CC(SC(F)(F)F)=CC=2)C(=O)N1CC1C2C(=NC=CC=2)NC=1.[CH3:31][C:32]1([CH3:49])[CH2:36][N:35]([C:37]2[CH:42]=[CH:41][C:40]([O:43][C:44]([F:47])([F:46])[F:45])=[CH:39][CH:38]=2)[C:34](=[O:48])[NH:33]1.Cl[CH2:51][C:52]1[CH:53]=[C:54]([C:58]2[S:59][CH:60]=[CH:61][N:62]=2)[CH:55]=[CH:56][CH:57]=1>>[CH3:31][C:32]1([CH3:49])[CH2:36][N:35]([C:37]2[CH:38]=[CH:39][C:40]([O:43][C:44]([F:47])([F:45])[F:46])=[CH:41][CH:42]=2)[C:34](=[O:48])[N:33]1[CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[C:54]([C:58]2[S:59][CH:60]=[CH:61][N:62]=2)[CH:53]=1
Reactant: ClCc1cccc(-c2nccs2)c1
Reactant: CC1(C)CN(c2ccc(OC(F)(F)F)cc2)C(=O)N1
Agent: CC1(C)CCN(c2ccc(SC(F)(F)F)cc2)C(=O)N1Cc1c[nH]c2ncccc12
Product: CC1(C)CN(c2ccc(OC(F)(F)F)cc2)C(=O)N1Cc1cccc(-c2nccs2)c1

Procedure:
4,4-dimethyl-3-[3-(1,3-thiazol-2-yl)benzyl]-1-[4-(trifluoromethoxy)phenyl]imidazolidin-2-one was prepared similar to procedure for compound 5, using the following reagents: 4,4-dimethyl-1-[4-(trifluoromethoxy)phenyl]imidazolidin-2-one and 2-[3-(chloromethyl)phenyl]-1,3-thiazole. 1H NMR (400 MHz, CDCl3): δ 7.94 (s, 1 H); 7.87-7.78 (m, 2 H); 7.58 (d, J=8.6 Hz, 2 H); 7.45 (d, J=7.7 Hz, 1 H); 7.38 (t, J=7.6 Hz, 1H); 7.32 (d, J=3.2 Hz, 1 H); 4.50 (s, 2 H); 3.56 (s, 2 H); 1.28 (s, 6 H). LCMS [M+H]+=448.2.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15](OS(C(F)(F)F)(=O)=O)=[N:16][C:17]([N:19]3[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]3)=[N:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C([O-])([O-])=O.[K+].[K+]>CC(=O)C.C1(C)C=CC=CC=1.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]>[O:25]=[S:22]1(=[O:26])[CH2:21][CH2:20][N:19]([C:17]2[N:16]=[C:15]([C:39]3[CH:40]=[CH:41][C:36]([CH3:35])=[CH:37][CH:38]=3)[C:12]3[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=3[N:18]=2)[CH2:24][CH2:23]1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N3CCS(=O)(=O)CC3)nc(OS(=O)(=O)C(F)(F)F)c2CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: Cc1ccc(-c2nc(N3CCS(=O)(=O)CC3)nc3c2CCNCC3)cc1
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
A mixture of 2-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-4 trifluoromethanesulfonyloxy-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepine-7-carboxylic acid tert-butyl ester (0.0008 mol), (4-methylphenyl)-boronic acid (0.0008 mol), Pd(dppf)Cl2 (0.00008 mol) and K2CO3 (0.0016 mol) in 2-propanone/toluene/water (4:4:1, 8 mL) was stirred in a microwave for 30 min at 130° C. The separated organic layer was filtered over silica gel and the filtrate was concentrated. The residue was purified by FCC (petroleum ether/Et2O). The product fractions were collected and the solvent was evaporated. This residue was dissolved in TFA/DCM/water (5:12:1, 12 mL) and stirred at rt for 90 min. The mixture was concentrated and residue was diluted with 1 M NaOH and extracted with DCM (2×). The combined organic layers were washed with satd. NaCl, dried, and concentrated. The residue was recrystallized from 2-propanol to give 0.190 g (64%) of the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([OH:8])=[O:7])[CH:3]=[N:2]1.[CH3:9][O-].[Na+]>CO.S(=O)(=O)(O)O>[NH:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[CH:3]=[N:2]1
Reactant: O=C(O)c1cn[nH]c1
Reactant: C[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cn[nH]c1

Procedure:
4-Pyrazolecarboxylic acid (514 mg) was dissolved in methanol (10 ml) and sulfuric acid (0.25 ml), and the mixture was stirred at room temperature for 2 hours, followed by refluxing under heating for 4 hours. After cooling, a 28% solution (0.95 ml) of sodium methylate in methanol was added to the reaction mixture for neutralization and the solvent was distilled away. Chloroform was added to the residue, and the residue was washed with water and brine and dried over anhydrous magnesium sulfate. The solvent was distilled away to give 433 mg of the title compound.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([F:16])[CH:8]=1.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[N:26]1[CH2:27][CH2:28][N:29]([C:11]([C:10]2[CH:14]=[CH:15][C:7]([N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:17])=[CH:8][C:9]=2[F:16])=[O:13])[CH2:30][CH2:31]1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1F
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3F)CC2)c(C)c1
Yield: 82.2 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-fluorobenzoic acid (272 mg) described in Preparation Example 23 and 1-(2,4-dimethylphenyl)piperazine (199 mg) and by the reaction and treatment in the same manner as in Example 87, the title compound (371 mg) was obtained.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:27]=[CH:26][C:16]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:15]([S:28][C:29]2[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=2)[CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:27]=[CH:26][C:16]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[C:15]([S:28]([C:29]2[CH:30]=[CH:31][C:32]([S:35]([CH3:38])(=[O:36])=[O:37])=[CH:33][CH:34]=2)=[O:6])[CH:14]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Sc1ccc(S(C)(=O)=O)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1S(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Chloroperoxybenzoic acid (70% purity, 0.2 g) was added to a solution of the product from example 9 step (ii) (0.35 g) in DCM (10 ml) and stirred at 0° C. for 1 h. The mixture was partitioned between DCM/aq. sodium metabisulphite solution, the organics washed with aq. sodium hydrogencarbonate solution, water, dried and evaporated under reduced pressure. Yield 0.34 g
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[C:8]([CH2:12][CH3:13])[C:9]([OH:11])=[O:10])[CH:2]=1.[C:14]1([CH:20]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[CH2:23][CH2:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.C(N=C=NCCCN(C)C)C.ClCCl.[C:53]([OH:60])(=[O:59])/[CH:54]=[CH:55]/[C:56]([OH:58])=[O:57]>C(O)C.C(OCC)C>[C:53]([OH:60])(=[O:59])/[CH:54]=[CH:55]/[C:56]([OH:58])=[O:57].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[C:8]([CH2:12][CH3:13])[C:9]([NH:31][CH2:30][CH2:29][CH2:28][CH2:27][N:24]2[CH2:25][CH2:26][N:21]([CH:20]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:22][CH2:23]2)=[O:11])[CH:2]=1.[C:53]([OH:60])(=[O:59])/[CH:54]=[CH:55]/[C:56]([OH:58])=[O:57].[C:53]([OH:60])(=[O:59])/[CH:54]=[CH:55]/[C:56]([OH:58])=[O:57].[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[C:8]([CH2:12][CH3:13])[C:9]([NH:31][CH2:30][CH2:29][CH2:28][CH2:27][N:24]2[CH2:23][CH2:22][N:21]([CH:20]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:26][CH2:25]2)=[O:10])[CH:2]=1
Reactant: CCC(=Cc1cccnc1)C(=O)O
Reactant: NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCO
Product: CCC(=Cc1cccnc1)C(=O)NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 0.8 g of 3-(3-pyridyl)-2-ethylacrylic acid, 2.2 g of 4-(4-diphenylmethyl-1-piperazinyl)butylamine, 0.87 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and 30 ml of dichloromethane is stirred at room temperature overnight. The reaction mixture is washed with water and dried over magnesium sulfate, and the solvent is distilled off. The residue is chromatographed on silica gel with chloroform-methanol (30:1) to give a brown oil, which is dissolved in 5 ml of ethanol containing 1.0 g of fumaric acid. To the resulting solution is added 15 ml of diethyl ether, and the solid separated is collected to give 1.4 g of the title compound. m.p. 137°-141° C. (recrystallized from ethanol-diethyl ether)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:40])[N:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:27]([CH2:30][CH:31]([OH:33])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[C:41]([NH:51][C@H:52]([C:54](O)=[O:55])[CH3:53])([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:40])[N:26]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:27]([CH2:30][C@H:31]([O:33][C:54](=[O:55])[C@@H:52]([NH:51][C:41]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[O:42])[CH3:53])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(CC(C)O)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)[C@H](C)NC(=O)OCc5ccccc5)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
To a mixture of (R)—N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl-1-(2-hydr-oxypropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (2.0 g, 3.68 mmol), (S)—N-Cbz-alanine (1.647 g, 7.36 mmol, Shanghai Hanhong Chemical CO., LTD.) and DMAP (0.90 g, 7.36 mmol, Aladdin) in CH2Cl2 (30 mL) was added EDC solid (2.116 g, 11.04 mmol, Aladdin) in portions at 0° C. After stirring at 0° C. for 2 hrs, the reaction mixture was warmed up to room temperature and continued to stir at rt for 20 hrs. The mixture was diluted with 180 mL of CH2Cl2. The resulted mixture was washed with 30 mL of 0.1 N HCl, followed by 50 mL of saturated NaHCO3 solution. The aqueous phase was extracted with EtOAc (50 mL×3), and the combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc) to give the desired compound as a pale yellow solid (2.1 g, 73.1%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][NH:14]2)=[C:10]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@H:18]2[CH3:23])[N:9]=1.[Br:24]Br.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[Br:24][C:13]1[NH:14][C:15]2[C:11]([N:12]=1)=[C:10]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][C@H:18]1[CH3:23])[N:9]=[C:8]([N:3]1[CH2:4][CH2:5][O:6][CH2:7][C@H:2]1[CH3:1])[N:16]=2
Reactant: BrBr
Reactant: C[C@@H]1COCCN1c1nc(N2CCOC[C@H]2C)c2nc[nH]c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H]1COCCN1c1nc(N2CCOC[C@H]2C)c2nc(Br)[nH]c2n1
Yield: 53.1 %

Procedure:
2,6-Bis-((R)-3-methyl-morpholin-4-yl)-9H-purine (637 mg, 2 mmol) was dissolved in 50 mL of CH2Cl2 and stirred under argon. Bromine (124 μl, 2.4 mmol) was dissolved in 2 mL of CH2Cl2 and added within 2 minutes. The reaction was stirred for 6 hours at room temperature. 5 mL of aqueous Na2S2O3 were added, the mixture was stirred for 15 minutes, and the organic solvents were separated, washed with brine and aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (40 g SiO2, heptane/EtOAc in a gradient from 2/3 to 4/1) to give a foam (422 mg, 53%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:22])[C@@H:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([F:13])[CH:7]=1.[NH:23]1[CH:27]=[CH:26][CH:25]=[C:24]1[CH:28]=O.C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C(Cl)(Cl)Cl.CO>[F:12][C:10]1[CH:11]=[C:6]([CH:7]=[C:8]([F:13])[CH:9]=1)[CH2:5][C@H:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:18])[CH3:20])[C@H:3]([OH:22])[CH2:2][NH:1][CH2:28][C:24]1[NH:23][CH:27]=[CH:26][CH:25]=1
Reactant: O=Cc1ccc[nH]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CN
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNCc1ccc[nH]1
Reaction time: 8 h
Yield: 62 %

Procedure:
A mixture of tert-butyl (1S,2R)-3-amino-1-(3,5-difluorobenzyl)-2-hydroxypropylcarbamate (170 mg, 0.538 mmol), 1H-pyrrole-2-carbaldehyde (51 mg, 0.538 mmol), and triethylamine (60 mg, 0.592 mmol) was stirred in chloroform (10 mL) containing magnesium sulfate for 4 h. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was dissolved in 2-propanol (10 mL) and sodium borohydride (26 mg, 0.699 mmol) was added. The reaction mixture was stirred overnight and then treated with methanol. The reaction mixture was concentrated under reduced pressure. Purification by flash column chromatography (silica, 9:1 chloroform/methanol) gave tert-butyl (1S,2R)-1-(3,5-difluorobenzyl)-2-hydroxy-3-[(1H-pyrrol-2-ylmethyl)amino]propylcarbamate (132 mg): 1H NMR (300 MHz, CD3OD) δ 6.82 (m, 4H), 6.21 (s, 1H), 6.09 (m, 1H), 4.09 (s, 2H), 3.66 (m, 2H), 3.19 (m, 1H), 3.13 (m, 1H), 3.03 (m, 1H), 2.88 (m, 1H), 1.31 (s, 9H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]([C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[C@H:9]([C:14]([N:16]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:17]1[C:18]([O:20]C(C)(C)C)=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12].C(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[NH:8]([C:29]([O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:30])[C@H:9]([C:14]([N:16]1[CH2:28][CH2:27][CH2:26][CH2:25][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCCC[C@H]1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCCC[C@H]1C(=O)O

Procedure:
Trifluoroacetic acid (3 mL) was added to a solution of CBZ-L-Leu-L-Pip-OtBu (0.57 g, 1.3 mmol) in CH2Cl2 (6 mL) at 23° C. The reaction mixture was stirred at 23° C. for 1.5 h after which CCl4 (6 mL) was added. The volatiles were then removed under reduced pressure to afford crude CBZ-L-Leu-L-Pip as a colorless oil. The crude acid thus obtained was immediately utilized in the following coupling procedure.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]([CH3:14])[N:11]([C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:10]([CH3:21])[CH2:9]1)=O)(C)(C)C.[ClH:22]>C(O)C>[ClH:22].[CH3:21][CH:10]1[CH2:9][NH:8][CH2:13][CH:12]([CH3:14])[N:11]1[C:15]1[N:16]=[CH:17][CH:18]=[CH:19][N:20]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CC(C)N1c1ncccn1
Agent: Cl
Solvent: CCO
Product: CC1CNCC(C)N1c1ncccn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3,5-Dimethyl-4-pyrimidin-2-ylpiperazine-1-carboxylic acid tert-butyl ester (294 mg) was dissolved in ethanol (2 ml), 4N hydrochloric acid (ethyl acetate solution, 2 ml) was added and the mixture was stirred at room temperature for 4 hr. The solvent was evaporated, and ethyl acetate (3 ml) was added to the obtained residue. The solid insoluble in ethyl acetate was collected by filtration and dried to give the title compound (281 mg).
Reaction SMILES: [Cl-].[Na+].[CH3:3][NH:4][C:5](=[N:8][N+:9]([O-:11])=[O:10])OC.[OH-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH2:22])=[CH:17][N:16]=1.Cl>O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:5]([NH:4][CH3:3])=[N:8][N+:9]([O-:11])=[O:10])=[CH:17][N:16]=1
Reactant: CNC(=N[N+](=O)[O-])OC
Reactant: NCc1ccc(Cl)nc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CNC(=N[N+](=O)[O-])NCc1ccc(Cl)nc1
Yield: 88.9 %

Procedure:
1.3 g of sodium chloride and 4.65 g of water were mixed, and the resulting mixture was cooled to −10 degree centigrade. N,O-dimethyl-N′-nitroisourea (4.5 g, 0.03 mole) was introduced into the above solution, and 0.58 g (4.64 mmole) of 32% NaOH was further added to the suspension and stirred. Thereafter, [(2-chloro-5-pyridyl)methyl]amine (4.93 g, 0.03 mole) was introduced dropwise to the suspension. Sodium chloride was dissolved in water with 78% of the saturated solubility at a water temperature of −10 degree centigrade. The solution was stirred at −10 degree centigrade for 4 hours and then heated to 20 degree centigrade, and further stirred for 6 hours. Then, 35% hydrochloric acid (0.7 g, 6.71 mmole) was added to the suspension so that the pH became not more than 4. The resulting solution was extracted with ethyl acetate and concentrated under a reduced pressure, and then recrystallized. Thus, 6.5 g of a 1-[(2-chloro-5-pyridyl)methyl]-3-methyl-2-nitroguanidine was obtained. The isolated yield at this time was 81%.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]([NH:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]3)=[N:11]2)=[CH:6][CH:5]=1.[CH:26]1([CH2:32][C:33](Cl)=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(OC(C)=O)(C)C.[Cl-].[Na+].O>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]([N:19]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:33](=[O:34])[CH2:32][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: Clc1ccc(-n2nc3ccccc3c2NC2CCCCC2)cc1
Reactant: O=C(Cl)CC1CCCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)C
Solvent: O
Product: O=C(CC1CCCCC1)N(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 6.5 %

Procedure:
To an ice cold suspension of NaH (13 mg, 340 μmol) in DMF (5 ml) under an argon atmosphere was added a solution of [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-amine (100 mg, 310 μmol; example 11.1) in DMF (1 ml) within 10 min. The suspension was stirred for 1 h at 0° C. A solution of cyclohexyl-acetyl chloride (50 μl, 340 μmol; [23860-35-7]) in DMF (1 ml) was added within 5 min. The reaction mixture was stirred for 14 h at ambient temperature, poured onto ice water/brine 1/1 and extracted two times with iPrOAc. The combined extracts were washed with ice water/brine 1/1 and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, iPrOAc/heptane) to give the title compound (8 mg, 20 μmol; 6%) as yellow oil. MS: m/e=450.0 [M+H+].