Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]3[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[N:4][CH:3]=1.[CH:18]1([CH2:21][NH2:22])[CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>C(OC(O)C)C>[CH:18]1([CH2:21][NH:22][C:2]2[N:7]=[C:6]([N:8]3[C:12]4[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:11]=4[N:10]=[CH:9]3)[CH:5]=[N:4][CH:3]=2)[CH2:20][CH2:19]1
Reactant: NCC1CC1
Reactant: Nc1ccc2ncn(-c3cncc(Cl)n3)c2c1
Agent: CCOC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc2ncn(-c3cncc(NCC4CC4)n3)c2c1

Procedure:
A solution of 1-(6-chloropyrazin-2-yl)-1H-benzimidazol-6-amine (100 mg, 0.41 mmol) and cyclopropylmethylamine (424 μL, 4.1 mmol) in ethoxyethanol (2 mL) containing DIPEA (140 μL) was heated at reflux overnight under N2. The solution was concentrated under reduced pressure and the residue dissolved in EtOAc (20 mL) and washed successively with H2O (20 mL), 1M HCl (2×20 mL), H2O (20 mL) and brine (20 mL). After drying (Na2SO4) the solvent was removed under reduced pressure and the residue chromatographed eluting with dichloromethane-methanol (9:1-94:6) to separate pure product from the lower fractions (98 mg)
Reaction SMILES: [C:1]([O:18][CH2:19][C@H:20]([CH2:22][O:23][C@H:24]1[O:53][C@H:52]([CH2:54][OH:55])[C@@H:43]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C@H:34]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:25]1[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[OH:21])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(N(CC)CC)C.[Si:63](Cl)([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64].[C:71](Cl)(=[O:87])[CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86]>C(Cl)Cl.O>[C:1]([O:18][CH2:19][C@H:20]([CH2:22][O:23][C@H:24]1[O:53][C@H:52]([CH2:54][O:55][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[C@@H:43]([O:44][CH2:45][C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C@H:34]([O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:25]1[O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[O:21][C:71](=[O:87])[CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH2:84][CH2:85][CH3:86])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCCCCCC(=O)OC[C@@H](O)CO[C@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H](CO[C@H]1O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 86.9 %

Procedure:
To a mixture of 200 mg (0.26 mmol) of 1-O-palmitoyl-3-O-[2,3,4-tri-O-benzyl-α-D-glucopyranosyl]-sn-glycerol, 0.2 ml of triethylamine, 100 mg of N,N-dimethylaminopyridine in 10 ml of methylene chloride is added under stirring 0.5 ml of methylene chloride solution containing 50 mg (0.33 mmol) of tert-butyldimethylsilyl chloride. The mixture is stirred at room temperature for 12 hours, and to the mixture is added 150 mg (0.55 mmol) of palmitoyl chloride. The resulting mixture is stirred for 6 hours, and after addition of 0.2 ml of water, the mixture is further stirred for 30 min. The organic portion is taken out and subjected to the post treatment. Thus treated product is purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=50:1) to give 252 mg of the captioned compound as a syrup. Yield: 86%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][C@H:6]([OH:8])[CH3:7].CCN([CH2:14][CH3:15])CC.[S:16](Cl)([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]>C(Cl)Cl>[OH:8][C@H:6]([CH3:7])[CH2:5][N:4]([S:16]([C:19]1[CH:25]=[CH:24][C:14]([CH3:15])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH2:3][CH2:2][O:1][S:16]([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCN(CC)CC
Reactant: C[C@@H](O)CNCCO
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCN(C[C@@H](C)O)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of (2R)-1-[(2-hydroxyethyl)amino]propan-2-ol (130.0 g, 1.09 mol) in CH2Cl2 (2 L) and Et3N (304 mL, 2.18 mol) was added TsCl (305 g, 1.60 mol) portion-wise at 0° C. The mixture was maintained at room temperature overnight, then washed with water (800 mL) and brine (500 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography, eluting with ethyl acetate/petroleum ether to give the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]3[CH:15]=[CH:14][CH:13]=[CH:12][C:6]3=[CH:7][CH:8]=2)[N:3]=1.[Br:16][Si](C)(C)C.C(#N)CC.[OH-].[Na+]>>[Br:16][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]3[CH:15]=[CH:14][CH:13]=[CH:12][C:6]3=[CH:7][CH:8]=2)[N:3]=1
Reactant: Clc1ccc2ccc3ccccc3c2n1
Reactant: C[Si](C)(C)Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCC#N
Product: Brc1ccc2ccc3ccccc3c2n1
Yield: 96 %

Procedure:
A mixture of 2-chlorobenzo[h]quinoline (2.43 g, 11.4 mmol), bromotrimethylsilane (3.00 ml, 22.7 mmol) and propionitrile (12 ml) was heated under reflux for 111 hours. The reaction mixture was then poured into a 10% NaOH solution containing ice. The organic phase was separated and the aqueous phase extracted with Et2O (3×15 ml). The organic phases were combined, dried over anhydrous Na2SO4 and the solvent evaporated under reduced pressure. The residue was purified by chromatography (SiO2, petroleum ether/acetate=9/1) to give 2-bromobenzo[h]quinoline in the form of a yellow solid: 2.82 g (96% yield); melting point: 113-114° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:21]1[S:25][N:24]=[CH:23][N:22]=1)[S:7]([C:10]1[C:19]([F:20])=[CH:18][C:13]2[NH:14][C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].N(/C(OC(C)(C)C)=O)=N\C(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:68][C:69]1[CH:78]=[CH:77][CH:76]=[C:75]2[C:70]=1[CH:71]=[C:72]([NH:79]C(=O)OC(C)(C)C)[N:73]=[CH:74]2>C1COCC1>[NH2:79][C:72]1[N:73]=[CH:74][C:75]2[C:70]([CH:71]=1)=[C:69]([CH2:68][N:14]1[C:13]3[CH:18]=[C:19]([F:20])[C:10]([S:7]([NH:6][C:21]4[S:25][N:24]=[CH:23][N:22]=4)(=[O:9])=[O:8])=[CH:11][C:12]=3[O:16][C:15]1=[O:17])[CH:78]=[CH:77][CH:76]=2
Reactant: CC(C)(C)OC(=O)Nc1cc2c(CO)cccc2cn1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)[nH]c3cc2F)c(OC)c1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1cc2c(Cn3c(=O)oc4cc(S(=O)(=O)Nc5ncns5)c(F)cc43)cccc2cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-(2,4-dimethoxybenzyl)-5-fluoro-2-oxo-N-(1,2,4-thiadiazol-5-yl)-2,3-dihydrobenzo[d]oxazole-6-sulfonamide (50 mg, 0.107 mmol), (E)-di-tert-butyl diazene-1,2-dicarboxylate (49.4 mg, 0.214 mmol) and triphenylphosphine (56.2 mg, 0.214 mmol) were added to a 5 mL RB flask. Then THF was added and r×n mixture was stirred at 0° C. for 10 min before addition of tert-butyl (5-(hydroxymethyl)isoquinolin-3-yl)carbamate (29.4 mg, 0.107 mmol) in THF. After stirring at 0° C. for 2 h, the reaction was filtered and concentrated in vacuo. Residue was dissolved in 1 mL of DCM and treated with 0.25 mL of TFA. After stirring at RT for 30 minutes, the solvent and TFA were removed in vacuo. Purified by reverse phase chromatography (10-95% MeCN in water w/0.1% TFA, C18 column) to yield 26-5. 1H NMR δ (ppm)(CH3 OH-d4): 9.02 (1H, s), 8.38 (1H, s), 7.95 (2H, d, J=8.72 Hz), 7.76 (1H, d, J=5.33 Hz), 7.55 (1H, d, J=7.15 Hz), 7.43 (1H, t, J=7.69 Hz), 7.01 (1H, d, J=9.05 Hz), 5.47 (2H, s). HRMS [M+H]C19H13FN6O4S2 calc'd 473.0496. Found 473.0500.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]([F:26])([F:25])[F:24])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH2:22])=[C:15]3[N:14]=2)[CH:7]=1.C1N=CN([C:32]([N:34]2[CH:38]=N[CH:36]=[CH:35]2)=[O:33])C=1.N1CC[C@H:41]([OH:44])C1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]([F:26])([F:24])[F:25])=[C:6]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH:22][C:32]([N:34]4[CH2:35][CH2:36][C@H:41]([OH:44])[CH2:38]4)=[O:33])=[C:15]3[N:14]=2)[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3C(F)(F)F)nc12
Reactant: O[C@H]1CCNC1
Solvent: ClCCl
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3C(F)(F)F)nc12)N1CC[C@H](O)C1
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a DCM (1 mL) solution of (R)-5-(2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (25 mg, 0.068 mmol) was added CDI (22 mg, 0.14 mmol) at ambient temperature in one portion. After stirring for two hours, (S)-pyrrolidin-3-ol (18 mg, 0.21 mmol) was added in one portion. The reaction was stirred overnight before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 0 to 60% acetonitrile/water to yield the final product as a yellowish solid (28 mg, 86% yield). MS (apci) m/z=479.2 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH:14]=[C:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C>[ClH:36].[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH:14]=[C:15]3[C:16]4[CH:29]=[CH:28][CH:27]=[CH:26][C:17]=4[CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]3=4)[CH2:8][CH2:7]2)=[CH:35][CH:34]=1
Reactant: CCOC(=O)C1(c2ccc(Cl)cc2)CCN(CCC=C2c3ccccc3CCc3ccccc32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cl
Product: O=C(O)C1(c2ccc(Cl)cc2)CCN(CCC=C2c3ccccc3CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 165.4 %

Procedure:
A mixture of the above ester (2.20 g, 0.0044 mol) and 20% sodium hydroxide (2 ml) in ethanol (18 ml) was stirred at room temperature for 24 h and left standing for additional 24 h. Ethanol was evaporated in vacuo and the residue was dissolved in dichloromethane (300 ml). The resulting solution was acidified with acetic acid, washed with water (3×15 ml) and the organic phase was dried (MgSO4). The solvent was evaporated in vacuo, the residue (2.60 g) was dissolved in a mixture of ether and acetone (1:1, 20 ml) and the solution was made acidic with a solution of hydrogen chloride in ether. The solvents were evaporated in vacuo, the amorphous residue was twice dissolved in acetone (20 ml) and re-evaporated in vacuo. The solid was suspended in dry ether (100 ml) and stirred at room temperature for 3 h. The precipitate was filtered off and dried in vacuo, affording 1.85 g (82%) of the title compound.
Reaction SMILES: CO[C:3](=[O:21])[C@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[NH2:5].N[C@H](C(O)=O)CCCCN.[CH3:32][N:33]=[C:34]=[S:35]>C(#N)C>[CH2:14]([O:13][C:11]([NH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:4]1[NH:5][C:34](=[S:35])[N:33]([CH3:32])[C:3]1=[O:21])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN=C=S
Reactant: COC(=O)[C@@H](N)CCCCNC(=O)OCc1ccccc1
Agent: NCCCC[C@H](N)C(=O)O
Solvent: CC#N
Product: CN1C(=O)C(CCCCNC(=O)OCc2ccccc2)NC1=S
Yield: 22.4 %

Procedure:
A solution of Nε-benzyloxycarbonyl-L-lysine methyl ester (4.66 g., 0.016 mol.) (prepared from L-lysine according to the method of Bergmann et al., J. Biol. Chem. 1935, 111, 245) in acetonitrile (20 ml.) was treated with methyl isothiocyanate (1.16 g., 0.016 mol.) and the mixture heated at reflux for 3 hours. The solvent was removed in vacuo and the residual oil triturated with ethanol to give a white solid which recrystallised from ethanol to give the title compound as colourless needles (1.2 g.) m.p. 135°C. (Found: C, 57.3; H, 6.4; N, 12.2; C16H21N3O3S requires: C, 57.3; H, 6.3; N, 12.5%).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][NH:7][C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[OH:16])=[C:4]([F:20])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CC(C)=O>[CH2:32]([O:31][C:29](=[O:30])[CH2:28][O:16][C:10]1[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=1[C:8](=[O:17])[NH:7][CH2:6][C:5]1[CH:18]=[CH:19][C:2]([Br:1])=[CH:3][C:4]=1[F:20])[CH3:33]
Reactant: O=C(NCc1ccc(Br)cc1F)c1ccc(Cl)cc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(Cl)ccc1C(=O)NCc1ccc(Br)cc1F
Temperature: 50 °C
Yield: 93.8 %

Procedure:
A solution of N-(4-bromo-2-fluoro-benzyl)-4-chloro-2-hydroxy-benzamide (3.25 g, 9.06 mmol) in acetone (45 mL, 0.2 M) was treated with aq K2CO3 (2 M, 6.8 mL, 14 mmol) and ethyl bromoacetate (1.2 mL, 11 mmol). After being heated to 50° C. for 8 h, the solution was cooled to room temperature and concentrated under reduced pressure until most of the acetone was removed. The solution was acidified to pH 1–2 with 2 N HCl, diluted with ethyl acetate and washed with saturated aq NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. Purification by MPLC (10–60% ethyl acetate in heptane, 23 mL/min, 70 min) gave [2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-chloro-phenoxy]-acetic acid ethyl ester as a white crystalline solid (3.78 g, 94%): mp 126–127° C.; Rf 0.61 (50% ethyl acetate in heptane); 1H NMR (DMSO-d6, 300 MHz) δ 8.90 (t, J=6 Hz, 1 H), 7.82 (d, J=8.4 Hz, 1 H), 7.52–7.47 (m, 1 H), 7.39–7.31 (m, 2 H), 7.28 (d, J=1.8 Hz, 1 H), 7.14 (dd, J1=8.4 Hz, J2=1.8 Hz, 1 H), 5.00, (s, 2 H), 4.49 (d, J=6 Hz, 2 H), 4.16 (q, J=7.2 Hz, 2 H), 1.18 (t, J=6.6 Hz, 3 H). ESI-LC/MS m/z calcd for C18 H11BrClFNO4: 444.7; found 446.0 (M+1)+. Anal. calcd for C16H16BrClFNO4: C, 48.62; H, 3.63; N, 3.15; Cl, 15.95. Found C, 48.57; H, 3.63; N, 3.11; Cl, 16.00.
Reaction SMILES: [C:1](=[N:32]O)([C:8]1[CH:31]=[CH:30][C:11]([C:12](=[N:28]O)[C:13]2[CH:18]=[CH:17][C:16]([C:19](=[N:26]O)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>C(O)C.N.[Ni]>[NH2:26][CH:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]1[CH:15]=[CH:14][C:13]([CH:12]([NH2:28])[C:11]2[CH:30]=[CH:31][C:8]([CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[NH2:32])=[CH:9][CH:10]=2)=[CH:18][CH:17]=1
Reactant: [H][H]
Reactant: ON=C(c1ccccc1)c1ccc(C(=NO)c2ccc(C(=NO)c3ccccc3)cc2)cc1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NC(c1ccccc1)c1ccc(C(N)c2ccc(C(N)c3ccccc3)cc2)cc1

Procedure:
The trioxime from Step 2 (3g) is dissolved in ethyl alcohol (250 ml) saturated with ammonia gas and Raney nickel W-6 (2 g) added. The mixture is subjected to 500 psi hydrogen pressure and heated to 90° for 2 hours. The catalyst is removed by filtration and 220 ml ethyl alcohol by distillation. A pale yellow crystalline material is filtered and dried. Yield 2.5 g (92% of theory) mp 182°-5° .
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1.ClC1N=CN=C2C=1NC=N2.[OH:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH2:30].C(N(CC)CC)C>C(O)CC>[OH:26][C:27]1[CH:34]=[CH:33][CH:32]=[CH:31][C:28]=1[CH2:29][NH:30][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1
Reactant: NCc1ccccc1O
Reactant: Clc1ncnc2c1ncn2C1CCCO1
Agent: Clc1ncnc2nc[nH]c12
Solvent: CCCO
Solvent: CCN(CC)CC
Product: Oc1ccccc1CNc1ncnc2c1ncn2C1CCCO1
Yield: 80 %

Procedure:
A mixture of 10 mmol (2240 mg) of 6-chloro-9-(tetrahydrofuran-2-yl)-purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (1478 mg) of 2-hydroxybenzylamine, and 5 ml of triethylamine was refluxed in n-propanol for 3 hours. After removal of the n-propanol by vacuum evaporation, the resulting material was treated with water and extracted into ethyl acetate. The ethyl acetate phase was evaporated and the residuum subsequently washed with 30 ml of petroleum ether. The solid residue was filtered off and the crude product crystallized from methanol. Yield 80%, white solid. TLC (EtOAc:hexane) (1:1) (v:v): single spot; HPLC: purity >98%. 1H NMR (400 MHZ, DMSO): 2.22sep (1H); 2.44m (1H); 3.82q (1H, J=7.3 Hz); 4.15q (1H, J=7.3 Hz); 4.69bs (2H); 6.26m (1H); 6.73t (1H, J=7.5 Hz); 6.82d (1H, J=7.9 Hz); 7.06t (1H, J=7.8 Hz); 7.17d (1H, J=7.3 Hz); 8.05bs (1H); 8.22s (1H); 8.23s (1H); 9.82bs (1H). MS (ES): [M+H]+=312 (100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9]C(=O)C)[CH:5]=[CH:6][C:7]=1[CH3:8].[Cl:13][C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.O>CN(C=O)C>[ClH:13].[CH3:8][C:7]1[C:2]([NH:1][C:14]2[N:19]=[C:18]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:17]=[CH:16][N:15]=2)=[CH:3][C:4]([NH2:9])=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1ccc(C)c(N)c1
Reactant: Clc1ncccn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(N)cc1Nc1nccc(-c2ccccc2)n1
Product: Cl
Temperature: 100 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of N-(3-amino-4-methyl-phenyl) acetamide (5 g, 25 mmol) in DMF (5 mL) was added 2-chloro-pyrimidine (3.8 g, 33 mmol)-and KI (0.5 g), which was stirred at 100° C. overnight, cooled to 10° C. and added to H2O (100 mL). The resulting mixture was extracted with CH2Cl2 (2×100 mL), the combined organic layers dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in conc. HCl (10 mL), stirred at 80° C. for 2 h and concentrated in vacuo to yield 6-methyl-N1-(4-phenylpyrimidin-2-yl)benzene-1,3-diamine hydrochloride (3.75 g, 75%). 1H NMR (CDCl3): 8.36 (dd, J=15.2 & 4.8 Hz, 2H), 7.46 (d, J=2.4 Hz, 1H), 6.97 (d, J=8.0 Hz, 1H), 7.26 (s, 1H), 6.67 (t, J=4.8 Hz, 1H), 6.39 (dd, J=8.0, 2.4, Hz, 1H), 2.20 (s, 3H); MS (ESI) m/e: 201 (M++1).
Reaction SMILES: [NH3:1].Cl[C:3]([CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:4]>C1COCC1>[NH2:1][C:3]([CH2:5][CH2:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:4]
Reactant: COC(=O)CCCC(=O)Cl
Reactant: N
Solvent: C1CCOC1
Product: COC(=O)CCCC(N)=O

Procedure:
6.1 Ammonia is passed into 350 ml of cold THF for 30 minutes. 30 g of methyl 4-chlorocarbonylbutyrate are then added dropwise, with ammonia continuing to be passed in at the same time. The crystals which deposit are separated off, and the residue is boiled a number of times with ethyl acetate. The combined filtrates are distilled off, and the residue is recrystallised from ethyl acetate, giving 23.4 g of methyl 4-aminocarbonylbutyrate (“FA”), m.p. 80°.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10]2)=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:13]1([C:9]2[NH:10][C:11]3[C:7]([CH:8]=2)=[CH:6][CH:5]=[C:4]([NH2:1])[CH:12]=3)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc2cc(-c3ccccc3)[nH]c2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2cc(-c3ccccc3)[nH]c2c1
Temperature: 70 °C
Yield: 35.5 %

Procedure:
6-Nitro-2-phenyl-1H-indole (175 mg, 0.73 mmol), ammonium chloride (80 mg, 1.47 mmol) and iron powder (205 mg, 3.68 mmol) were suspended in ethanol/water (4 mL/2 mL) and heated at 70° C. for 2 h. After cooling, the solution was filtrated through a pad of Celite®, which was washed with ethanol. The organic layer was evaporated into vacuo to obtain a solid, which was purified by column chromatography eluting using a gradient (ethyl acetate/hexanes 10:90 v/v to ethyl acetate/hexanes 50:50 v/v) to afford 54 mg (35%) of the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([NH2:12])=[S:11])=[CH:5][CH:4]=1)#[N:2].Cl[CH2:14][C:15]([CH2:17]Cl)=O.[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])=[CH:30][CH:29]=2)[C:23]([C:40]#[N:41])=[C:22]([SH:42])[N:21]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:19][C:20]1[C:25]([C:26]#[N:27])=[C:24]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])=[CH:32][CH:33]=2)[C:23]([C:40]#[N:41])=[C:22]([S:42][CH2:17][C:15]2[N:12]=[C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[S:11][CH:14]=2)[N:21]=1
Reactant: N#Cc1ccc(NC(N)=S)cc1
Reactant: CN(C)CCOc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Reactant: O=C(CCl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(-c2c(C#N)c(N)nc(SCc3csc(Nc4ccc(C#N)cc4)n3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 26.6 mg (0.15 mmol) of N-(4-cyanophenyl)thiourea and 19 mg (0.15 mmol) of 1,3-dichloroacetone in 0.4 ml of DMF is stirred at +80° C. for 3 h. After cooling to RT, a solution of 50.9 mg (0.15 mmol) of the compound from Example 34A in 0.2 ml of DMF and 50 mg (0.6 mmol) of sodium bicarbonate are added. The mixture is then stirred at RT for 12 h. The reaction mixture is filtered and purified directly by preparative HPLC (column: Macherey Nagel VP50/21 Nucleosil 100-5 C18 Nautilus, 5 μm, 21 mm×50 mm; wavelength: 220 nm; flow rate: 25 ml/min; mobile phase A=water+0.1% formic acid, mobile phase B=acetonitrile; gradient: 0 min 10% B→2 min 10% B→6 min 90% B→7 min 90% B→7.1 min 10% B→8 min 10% B). The product-containing fractions are combined and concentrated using a rotary evaporator.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@@H:10]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@H:11]([OH:26])[CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[C:19]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[C:42]([Cl:44])[CH:43]=1)[C:38](O)=[O:39].O.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[C:42]([Cl:44])[CH:43]=1)[C:38]([NH:1][C@H:2]([C:7]([NH:9][C@@H:10]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C@H:11]([OH:26])[CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[C:19]([NH:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:39]
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCC[C@H]1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NC(=O)[C@@H]1CCCC[C@H]1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.9 %

Procedure:
A mixture of 60 mg (0.13 mol) of 2(S)-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1(R)-cyclohexanecarboxamide, 25 mg (0.13 mmol) of 3,5-dichlorobenzoic acid, 18 mg (0.13 mmol) of hydroxybenzotriazole hydrate and 27 mg (0.13 mmol) of dicyclohexylcarbodiimide in 2 ml of dimethylformamide was stirred at room temperature under nitrogen for 20 hours. The mixture was then filtered and the solid was washed with dichloromethane. The combined filtrate and washings were evaporated to dryness and the residue was partitioned between 50 ml of ethyl acetate and 10 ml of saturated aqueous sodium hydrogen carbonate solution. The separated organic phase was dried over anhydrous magnesium sulphate and evaporated. The residue was chromatographed on silica gel using 5% methanol in dichloromethane for the elution. The product was purified further by recrystallization from a mixture of 2 ml of dichloromethane and 10 ml of n-hexane to give 37 mg of 2(S)-[3(S)-[[N-(3,5-dichlorobenzoyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1(R)-cyclohexanecarboxamide as a white solid of melting point 220°-226° C.