Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[NH2:13][C:14]1[CH:15]=[C:16]2[C:20]3=[C:21]([CH2:23][O:24][CH2:25][CH2:26][N:19]3[C@H:18]3[CH2:27][CH2:28][N:29](C(OC(C)(C)C)=O)[CH2:30][C@@H:17]23)[CH:22]=1>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH:13][C:14]1[CH:15]=[C:16]2[C:20]3=[C:21]([CH2:23][O:24][CH2:25][CH2:26][N:19]3[C@H:18]3[CH2:27][CH2:28][NH:29][CH2:30][C@@H:17]23)[CH:22]=1
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Product: FC(F)(F)c1ccccc1CNc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCOC2

Procedure:
Using 2-(trifluoromethyl)benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 128. 1H NMR(CDCl3) δ: 7.72-7.60 (m, 2H), 7.52 (t, 1H, J=7.7 Hz), 7.38 (t, 1H, J=7.5 Hz), 6.39 (d, 1H, J=1.8 Hz), 6.21 (d, 1H, J=1.8 Hz), 4.57 (ABq, 2H, JAB=14.3 Hz), 4.50 (s, 2H), 4.20 (app d, 1H, J=12.0 Hz), 3.74 (app t, 1H), 3.36-3.30 (m, 1H), 3.28-3.18 (m, 2H), 3.08 (dd, 1H, J=12.5, 6.2 Hz), 3.00-2.90 (m, 2H), 2.65 (app t, 1H), 2.50 (app t, 1H), 2.02-1.90 (m, 2H). LRMS (ES)+: 404.3 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[N:5][C:4]([N-:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[N:3][CH:2]=1.[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+].Cl>C(O)C>[CH:1]1[CH:2]=[N:3][C:4]([NH:7][S:8]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)(=[O:10])=[O:9])=[N:5][CH:6]=1
Reactant: Nc1ccc(S(=O)(=O)[N-]c2ncccn2)cc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)Nc2ncccn2)cc1

Procedure:
An aqueous solution consisting of 0.5 g sodium sulfadiazine, 0.5 ml ethyl alcohol, 13 ml of 20% sodium sulfate and 20 ml of 5% gelatin (type B: acid processed) was titrated, while under constant agitation with a magnetic stirrer, with 18.4 ml of 0.1N hydrochloric acid solution. This procedure resulted in a white suspension of microencapsulated sulfadiazine particles. The suspension was then stirred for an additional 15 minutes, following which it was poured into 200 ml of cold (5° C.) 7% sodium sulfate solution, and stirred for 30 minutes at ice-bath temperature. This procedure caused gelling of the liquid gelatin shell of the microcapsules. The entire process was monitored by observation of samples in the optical microscope. The microcapsules were of assymetric appearance and of a size less than 10 μm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:19][CH:18]=2)[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16])[CH3:2].[BH4-].[Na+].C(O)(=O)C>C(O)C>[CH2:1]([O:3][C:4](=[O:27])[CH2:5][C:6]1([C:17]2[CH:18]=[CH:19][C:20]([NH:23][C:24](=[O:26])[CH3:25])=[CH:21][CH:22]=2)[CH:14]([OH:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]1[OH:16])[CH3:2]
Reactant: CCOC(=O)CC1(c2ccc(NC(C)=O)cc2)C(=O)c2ccccc2C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CC1(c2ccc(NC(C)=O)cc2)C(O)c2ccccc2C1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 17.3 %

Procedure:
A stirred solution of [2-(4-acetylamino-phenyl)-1,3-dioxo-indan-2-yl]-acetic acid ethyl ester (4.0 g, Reference Example 13) in absolute ethanol (250 mL) was treated portionwise with sodium borohydride (1.7 g). After stirring at room temperature for 4 hours the reaction mixture was treated with glacial acetic acid until pH 7 and then evaporated. The residue was treated with water (100 mL) and the mixture was extracted with ethyl acetate (150 mL). The organic extract was dried over magnesium sulfate and then evaporated. The residue was subjected to chromatography on silica eluting with mixtures of dichloromethane and methanol (from 99.5:5 to 96:4, v/v) to give the title compound (0.7 g) as a solid.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26]>CCCCCC>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1O
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: CCCCCC
Product: O=C(Nc1ccccc1O)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and 2-aminophenol (Aldrich) according to the method described in Example 1c. Melting Point: 121-125-165° C. (hexane)
Reaction SMILES: [NH2:1][C@@H:2]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[C:3]([NH:5][C@H:6]([CH2:10][S:11][S:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:7]([OH:9])=[O:8])=[O:4].C(N(C(C)C)C(C)C)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>C(Cl)Cl>[C:36]([NH:1][C@@H:2]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[C:3]([NH:5][C@H:6]([CH2:10][S:11][S:12][C:13]([CH3:14])([CH3:16])[CH3:15])[C:7]([OH:9])=[O:8])=[O:4])(=[O:38])[CH3:37]
Reactant: CC(C)(C)SSC[C@@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@H](CSSC(C)(C)C)C(=O)O
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of (S)-2-((S)-2-amino-3-(1H-indol-3-yl)propanamido)-3-(tert-butyldisulfanyl)propanoic acid (H-Trp-D-Cys(StBu)-OH) (Compound SP643) (870 mg, 2.20 mmol) in methylene chloride (4.4 mL) was mixed with N-ethyldiisopropylamine (DIPEA) (1.15 mL, 6.60 mmol) and acetic anhydride (208 μL, 2.20 mmol) with stirring at room temperature, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (S)-2-((S)-2-acetamido-3-(1H-indol-3-yl)propanamido)-3-(tert-butyldisulfanyl)propanoic acid (Ac-Trp-D-Cys(StBu)-OH) (Compound SP644) (960 mg, 2.20 mmol, 100%).
Reaction SMILES: [CH2:1]=[C:2]1[CH:7]([CH3:8])[C:6](C)([CH3:9])[O:5][C:3]1=[O:4].C=C1C(C)COC1=O>>[CH2:1]=[C:2]1[CH:7]([CH3:8])[CH:6]([CH3:9])[O:5][C:3]1=[O:4]
Reactant: C=C1C(=O)OC(C)(C)C1C
Agent: C=C1C(=O)OCC1C
Product: C=C1C(=O)OC(C)C1C

Procedure:
α-methylene-β-methyl-γ,γ-dimethyl-γ-butyrolactone and, among them, once again, α-methylene-β-methyl-γ-butyrolactone (R1 =R2 =R3 =H, R4 =CH3, R5 =H or R1 =R2 =R3 =H and R4 =H and R5 =CH3).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:29])=[C:4]([CH:26]=[CH:27][CH:28]=1)[C:5]([NH:7][C:8]1[C:13]([Br:14])=[CH:12][C:11]([C:15]([F:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[Br:25])=[O:6].[Cl:30][C:31]1[N:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](Cl)=[O:34]>>[Cl:30][C:31]1[N:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([NH:1][C:2]1[CH:28]=[CH:27][CH:26]=[C:4]([C:5](=[O:6])[NH:7][C:8]2[C:9]([Br:25])=[CH:10][C:11]([C:15]([F:24])([C:16]([F:17])([F:18])[F:19])[C:20]([F:21])([F:22])[F:23])=[CH:12][C:13]=2[Br:14])[C:3]=1[F:29])=[O:34]
Reactant: Nc1cccc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)c1F
Reactant: O=C(Cl)c1cccnc1Cl
Product: O=C(Nc1cccc(C(=O)Nc2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)c1F)c1cccnc1Cl

Procedure:
According to the method of 1-7 of Example 1, a target compound was prepared from 3-amino-N-(2,6-dibromo-4-(perfluoropropan-2-yl)phenyl)-2-fluorobenzamide and 2-chloronicotinic acid chloride.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=O.C(Cl)(Cl)Cl.N=C=N.[CH3:17][O:18][C:19]1[CH:49]=[CH:48][C:22]([C:23]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][C:31]=2[NH:32][C:33](=[O:47])[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=2[O:42][CH2:43][CH2:44][CH2:45][NH2:46])=[O:24])=[CH:21][CH:20]=1>CC=C(C)C>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][C:31]=2[NH:32][C:33](=[O:47])[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=2[O:42][CH2:43][CH2:44][CH2:45][NH:46][C:7]([C:3]2[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=2)=[O:9])=[O:24])=[CH:48][CH:49]=1
Reactant: Cn1cccc1C(=O)O
Reactant: COc1ccc(C(=O)Nc2cnccc2NC(=O)c2ccc(OC)cc2OCCCN)cc1
Agent: CC=C(C)C
Agent: N=C=N
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(=O)Nc2cnccc2NC(=O)c2ccc(OC)cc2OCCCNC(=O)c2cccn2C)cc1
Reaction time: 8 h
Yield: 13.5 %

Procedure:
1-Methyl-2-pyrrolecarboxylic acid (57.6 mg, 460 μmol) was dissolved in amylene stabilized chloroform (8 mL). Resin-supported carbodiimide (1.1 g, 0.85 mm ol/g, 920 μmol) was added. To the resin-acid slurry was added N3-(4-methoxybenzoyl)-N4-[4-methoxy-2-(3-aminopropoxy)benzoyl]-3,4-pyridinediamine (106 mg crude, 230 μmol) in amylene stabilized chloroform (5 mL). The vial was capped and the reaction was agitated overnight on an orbital platform shaker. The slurry was filtered. The filtrate was concentrated and then purified by semipreparative HPLC as described in Example 2-F to provide N3-(4-methoxybenzoyl)-N4-[4-methoxy-2-[3-(1-methylpyrrol-2-ylcarbonyl)aminopropoxy]benzoyl]-3,4-pyridinediamine (17.3 mg, 27%) as ivory needles.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7][CH2:6]2.[H-].[Na+].[F:22][C:23]([F:27])([F:26])[CH2:24]I>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])([CH2:24][C:23]([F:27])([F:26])[F:22])[CH2:7][CH2:6]2
Reactant: FC(F)(F)CI
Reactant: CCOC(=O)CC1CCc2cc(OC)ccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(CC(F)(F)F)CCc2cc(OC)ccc2C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 49.5 %

Procedure:
A solution of 1C (25 g, 95 mmol) in DMF (40 mL) was added over a period of 30 min to an ice cold solution of NaH (9.53 g, 238 mmol) in DMF (20 mL), and the mixture was stirred for 10 min. Trifluoroethyl iodide (50 g, 238 mmol) was then added, and the mixture was stirred for 3 h at room temperature. The reaction mixture was then brought to 0° C., excess NaH was quenched with ice water, and the aqueous layer with extracted with ethyl acetate (2×200 mL). The combined organic layers were dried over sodium sulfate and filtered, and the filtrate was concentrated under vacuum to give the title compound (16.2 g, 42%) as a solid. 1H NMR (300 MHz, CDCl3): δ 8.02 (d, J=9.3 Hz, 1H), 6.85 (dd, J1=2.7 Hz, J2=9.0 Hz, 1H), 6.68 (d, J=2.7 Hz, 1H), 4.1 (q, J=6.9 Hz, 2H), 3.86 (s, 3H), 3.05-2.9 (m, 4H), 2.6-2.4 (m, 4H), 1.23 (t, J=6.9 Hz, 3H). ESI-MS m/z: 345 (M+H)+.
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3][CH2:2]1.[CH:12]1([CH:15]=O)[CH2:14][CH2:13]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClC(Cl)C>[CH:12]1([CH2:15][N:3]2[CH2:4][CH2:5][C:6]3([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]3)[CH2:1][CH2:2]2)[CH2:14][CH2:13]1
Reactant: C1CCC2(CC1)CCNCC2
Reactant: O=CC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: C1CCC2(CC1)CCN(CC1CC1)CC2
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of 3-azaspiro[5,5]undecane (0.34 g, 2.2 mmol), cyclopropanecarbaldehyde (0.14 g, 2 mmol) and NaBH(OAc)3 (0.64 g, 3 mmol) in dichloroethane (10 mL) were added AcOH (0.12 mL, 2 mmol), the resulting suspension was stirred overnight, quenched with NaHCO3 and extracted with CH2Cl2 twice, the combined organic layer was washed with brine, and dried with MgSO4. The solution was filtered, concentrated in vacuo and purified by flash chromatography. The compound was converted to the hydrochloride by passing HCl gas into the ether solution of 3-(cyclopropylmethyl)-3-azoniaspiro[5,5]undecane at 0° C., followed by decanting the ether supernatant, the final white solid (0.39 g, 80% yield) was dried in vacuo. 1H NMR (360 MHz, CDCl3) δ 2.45 (t, J=5.66 Hz, 4H), 2.23 (d, J=6.51 Hz 2H), 1.49 (t, J=5.66 Hz, 4H), 1.48-1.40 (m, 6H), 1.38-1.30 (m, 4H), 0.92-0.82 (m, 1H), 0.52-0.47 (m, 2H), 0.11-0.17 (m, 2H); 13C NMR (90 MHz, CDCl3) δ 64.55, 49.67, 36.47, 35.46, 31.00, 27.12, 21.73, 8.74, 4.19; ESI-MS: Calculated for C14H25N (M+H)+ 208.4, Found: 208.4.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH:5]=[CH:6][CH:7]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[S:24][C:25]([CH3:28])=[CH:26][CH:27]=2)[O:21][CH:22]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[O:1][CH2:17][C:18]2[N:19]=[C:20]([C:23]3[S:24][C:25]([CH3:28])=[CH:26][CH:27]=3)[O:21][CH:22]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Cc1ccc(-c2nc(CCl)co2)s1
Reactant: Oc1cccc(CCCn2ccnc2)c1
Product: Cc1ccc(-c2nc(COc3cccc(CCCn4ccnc4)c3)co2)s1
Yield: 71 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(3-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(5-methyl-2-thienyl)oxazole to give 4-[3-[3-(1-imidazolyl)propyl]phenoxymethyl]-2-(5-methyl-2-thienyl)oxazole. The yield was 71%. Oily substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:11][C@H:10]([OH:12])[CH2:9]2)=[CH:4][CH:3]=1.[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][NH:20]2)=[CH:16][C:15]=1B1OCC(C)(C)CO1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C(OCC)(=O)C.O>[Cl:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][NH:20]2)=[CH:16][C:15]=1[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:11][C@H:10]([OH:12])[CH2:9]2)=[CH:4][CH:3]=1
Reactant: O[C@H]1C[C@H](c2ccc(Br)cc2)C1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc([C@H]4C[C@H](O)C4)cc3)cc12
Temperature: 110 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
To a solution of trans-3-(4-bromophenyl)cyclobutanol (200 mg, 0.88 mmol) in toluene/ethanol (4 mL, v/v=1/1) was added methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (296 mg, 0.968 mmol), potassium carbonate (360 mg, 2.64 mmol), water (1 mL) and Pd(dppf)C12 (46 mg, 0.06 mmol) under nitrogen. The mixture was stirred at 110° C. for 2 hours. The mixture was diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by silica gel combiflash to give the title compound (190 mg, 61%) as a light yellow solid. 1H NMR (500 MHz, CD3OD) δ 8.02 (s, 1 H), 8.01 (s, 1 H), 7.60 (s, 1 H), 7.40-7.35 (m, 4 H), 4.52 (m, 1 H), 3.88 (s, 3 H), 3.66 (m, 1 H), 2.57-2.44 (m, 4 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:21]([N:23]2[CH2:28][CH2:27][C:26]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:29]([NH2:31])=[O:30])[CH2:25][CH2:24]2)=[O:22])[S:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:45][CH2:46][CH2:47][OH:48]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:21]([N:23]2[CH2:24][CH2:25][C:26]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)([C:29]([NH2:31])=[O:30])[CH2:27][CH2:28]2)=[O:22])[S:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:45][CH2:46][CH2:47][OH:48])=[CH:18][CH:19]=1
Reactant: NC(=O)C1(c2ccccc2)CCN(C(=O)c2cc(-c3ccc(Cl)cc3Cl)c(-c3ccc(O)cc3)s2)CC1
Reactant: OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)C1(c2ccccc2)CCN(C(=O)c2cc(-c3ccc(Cl)cc3Cl)c(-c3ccc(OCCCO)cc3)s2)CC1
Temperature: 110 °C
Yield: 54.3 %

Procedure:
1 g of the compound obtained in stage 4B), 0.376 g of potassium carbonate and 0.223 g of 3-chloropropan-1-ol are added to 6 ml of DMF. The reaction medium is heated at 110° C. for 3 hours. The reaction medium is subsequently poured onto distilled water and the compound obtained is extracted with ethyl acetate. The organic phase is dried and evaporated. After purifying by chromatography on silica (eluent: CH2Cl2-MeOH (gradient from 0% to 4%)), 0.6 g of the expected compound is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20](B4OC(C)(C)C(C)(C)O4)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:33]1[CH:42]=[CH:41][C:36]([C:37]([NH:39][CH3:40])=[O:38])=[CH:35][N:34]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]2[CH2:18][C:17]3[CH:19]=[C:20]([C:33]4[CH:42]=[CH:41][C:36]([C:37](=[O:38])[NH:39][CH3:40])=[CH:35][N:34]=4)[CH:21]=[CH:22][C:16]=3[O:15]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3O2)CC1
Reactant: CNC(=O)c1ccc(Br)nc1
Product: CNC(=O)c1ccc(-c2ccc3c(c2)CC(C2CCN(C(=O)OC(C)(C)C)CC2)O3)nc1

Procedure:
The title compound is prepared from 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid tert-butyl ester and 6-bromo-N-methylnicotinamide following a procedure analogous to that described in Example 1. LC (method 10): tR=1.69 min; Mass spectrum (ESI+): m/z=438 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[C:15]2[C:23]([NH:25][CH3:26])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CNC(C1N(C)C2C(C=1)=CC=CC=2)=O>>[CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([CH2:13][N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[C:15]2[CH2:23][NH:25][CH3:26])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)c1cc2ccccc2n1Cc1ccc(OCc2ccccc2)cc1
Agent: CNC(=O)c1cc2ccccc2n1C
Product: CNCc1cc2ccccc2n1Cc1ccc(OCc2ccccc2)cc1
Yield: 63.1 %

Procedure:
According to the procedure of Preparation 1(b), except substituting 1-(4-benzyloxybenzyl)-N-methylindole-2-carboxamide (44.4 g, 120.1 mmole) for the N,1-dimethylindole-2-carboxamide, the title compound (27.0 g, 63%) was prepared as a white solid: MS (ES) m/e 358 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[NH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH:30]([CH2:33][NH2:34])[CH2:29][CH2:28]1>O1CCOCC1>[NH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][CH:30]([CH2:33][NH:34][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[N:6]3[C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH2:29][CH2:28]1
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Reactant: NCC1CCC(CN)CC1
Solvent: C1COCCO1
Product: NCC1CCC(CNc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 80 °C
Yield: 75.2 %

Procedure:
To a solution of 6-chloro-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purine (78 mg, 0.21 mmol, 1 eq.) in 2 mL of dioxane was added [4-(aminomethyl)cyclohexyl]methanamine (89 mg, 0.62 mmol, 2 eq.). The reaction was heated to 80° C. for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% CMA 80/ethyl acetate to yield 76 mg (76%) of N-{[4-(aminomethyl)cyclohexyl]methyl}-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-amine which was carried forward. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.85-1.13 (m, 2 H) 1.40-1.72 (m, 8 H) 1.74-2.01 (m, 2 H) 2.85-3.15 (m, 2H) 3.48-3.75 (m, 2H) 4.25-4.74 (m, 2 H) 5.98 (br. s., 1 H) 7.05-7.59 (m, 8 H) 8.44 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:28]1([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=2)[CH2:30][CH2:29]1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:31]([CH:28]2[CH2:30][CH2:29]2)[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=2)=[O:26])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: Cc1cccc(CNC2CC2)c1
Product: Cc1cccc(CN(C(=O)CN(c2cccc(N(C)C)c2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)C2CC2)c1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with cyclopropyl-(3-methyl-benzyl)-amine
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[OH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+]>C(O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:14][CH2:15][CH:10]([OH:9])[CH2:11][CH2:12]2)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: OC1CCN(c2ccc(Br)cn2)CC1
Temperature: 110 °C
Yield: 493.5 %

Procedure:
A mixture of 2,5-dibromopyridine (100 mg, 0.42 mmol), 4-hydroxypiperidine (49 mg, 0.46 mmol) and K2CO3 (64 mg, 0.46 mmol) in ethanol (4 mL) was heated to 110° C. for 52 h. The crude reaction mixture was concentrated under reduced pressure to dryness and the residue was treated with water. Crude product was collected by vacuum filtration and purified by flash chromatography using EtOAc/hexanes (1:4 to 2:3) to give the title compound as a white solid (533 mg, 41%). 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=2.2 Hz, 1H), 7.53 (dd, J=9.0, 2.3 Hz, 1H), 6.59 (d, J=9.0 Hz, 1H), 4.04-3.94 (m, 3H), 3.18 (t, J=11 Hz, 2H), 2.00-1.95 (m, 2H), 1.63-1.54 (m, 2H); MS ESI 256.9 [M+H]+, calcd for [C10H13BrN2O+H]+ 257.02.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[CH2:24]([C:26]([C:49]1[CH:54]=[CH:53][C:52]([B:55]2[O:59][C:58]([CH3:61])([CH3:60])[C:57]([CH3:63])([CH3:62])[O:56]2)=[C:51]([CH3:64])[CH:50]=1)([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]2([O:43][Si](C)(C)C)[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[C:31]([CH3:48])[CH:30]=1)[CH2:27][CH3:28])[CH3:25]>>[CH2:24]([C:26]([C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]2([OH:43])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[C:31]([CH3:48])[CH:30]=1)([C:49]1[CH:54]=[CH:53][C:52]([B:55]2[O:59][C:58]([CH3:60])([CH3:61])[C:57]([CH3:62])([CH3:63])[O:56]2)=[C:51]([CH3:64])[CH:50]=1)[CH2:27][CH3:28])[CH3:25]
Reactant: CCC(CC)(c1ccc(CCC2(O[Si](C)(C)C)CCCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(CCC2(O)CCCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reaction time: 3 h
Yield: 76.2 %

Procedure:
A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.95 mL, 0.95 mmol) was added to 2-[4-(1-ethyl-1-{3-methyl-4-[2-(1-trimethylsilanyloxy-cyclohexyl)-ethyl]-phenyl}-propyl)-2-methyl-phenyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Example 37-(1); 0.23 g, 0.39 mmol), and the mixture was stirred for three hours. The reaction mixture was purified by silica gel chromatography (14% ethyl acetate/hexane) to give the title compound (0.15 g, 76%).