Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:18][N:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:20](Cl)=[O:21]>>[N+:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:20](=[O:21])[N:19]([CH3:18])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(O)cc2)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-(4-nitro-phenoxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC (71%, white crystals). HPLC-MS m/z=365.0 (M+1), Rt: 4.83 min.
Reaction SMILES: [FH:1].N[C:3]1[C:4]([Cl:10])=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.N([O-])=O.[Na+]>CS(C)=O>[Cl:10][C:4]1[C:3]([F:1])=[CH:8][C:7]([Cl:9])=[CH:6][N:5]=1
Reactant: Nc1cc(Cl)cnc1Cl
Reactant: F
Agent: O=N[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Fc1cc(Cl)cnc1Cl
Reaction time: 4 h
Yield: 88 %

Procedure:
A 500 ml polytetrafluoroethylene reactor equipped with stirrer, thermometer and reflux condenser is charged with 120 g of hydrogen fluoride. A solution of 40.7 g (0.25 mol) of 3-amino-2,5-dichloropyridine in 60 ml of dimethyl sulfoxide is added dropwise at a temperature in the range from 0° C. to +10° C. Then 20.7 g (0.3 mol) of sodium nitrite are introduced into this solution at +40° C. The resultant nitrogen is removed from the reactor through the reflux condenser. Gas evolution ceases after 4 hours at +40° C. 150 ml of methylene chloride are added to the reaction mixture which is then poured into ice water. The two-phase mixture is neutralised with concentrated ammonia solution. The organic phase is separated and the aqueous phase is extracted three times with methylene chloride. The combined organic phases are washed with water, dried over sodium sulfate and filtered through silica gel. The solution is separated by distillation, affording 36.5 g (88% of theory) of 2,5-dichloro-3-fluoropyridine.
Reaction SMILES: [C:1]([C:4]1[C:8]([S:9]([CH3:11])=[O:10])=[C:7]([NH2:12])[N:6]([C:13]2[C:18]([Cl:19])=[CH:17][C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[Cl:24])[N:5]=1)(=[O:3])[CH3:2].[F:25][C:26]([F:30])([F:29])[S:27]Cl>>[C:1]([C:4]1[C:8]([S:9]([CH3:11])=[O:10])=[C:7]([NH:12][S:27][C:26]([F:30])([F:29])[F:25])[N:6]([C:13]2[C:14]([Cl:24])=[CH:15][C:16]([C:20]([F:22])([F:21])[F:23])=[CH:17][C:18]=2[Cl:19])[N:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Reactant: FC(F)(F)SCl
Product: CC(=O)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(NSC(F)(F)F)c1S(C)=O

Procedure:
thiolating 3-acetyl-5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylsulfinylpyrazole with trifluoromethylthio chloride to afford 3-acetyl-1-(2,6dichloro-4-trifluoromethylphenyl)-4-methylsulfinyl-5-trifluoromethylthioaminopyrazole;
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21](O)=[O:22])[NH:3]1.[OH:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([NH2:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][CH:26]=1>>[OH:24][C:25]1[CH:26]=[CH:27][C:28]([CH:31]([NH:38][C:21]([C@H:11]2[CH2:10][CH2:9][C@H:8]3[C@H:7]4[C@H:16]([CH2:15][CH2:14][C@:12]23[CH3:13])[C@:17]2([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]2)=[CH:5][CH2:6]4)=[O:22])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:29][CH:30]=1
Reactant: NC(c1ccccc1)c1ccc(O)cc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Product: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)NC(c1ccccc1)c1ccc(O)cc1
Yield: 77 %

Procedure:
The title compound was prepared in a yield of 77% in a similar manner to that described in Example 37 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and α-(4-hydroxyphenyl)benzylamine.
Reaction SMILES: [C:1]1(=O)[N:5]([CH2:6]/[CH:7]=C/CBr)[C:4](=O)[C:3]2=[CH:12][CH:13]=CC=[C:2]12.C([NH:19]CC)C.[F-].[K+].[ClH:24]>C(#N)C.C(O)(=O)C>[ClH:24].[ClH:24].[CH2:1]([N:5]([CH2:6][CH3:7])[CH2:4]/[CH:3]=[CH:12]/[CH2:13][NH2:19])[CH3:2]
Reactant: CCNCC
Reactant: O=C1c2ccccc2C(=O)N1C/C=C/CBr
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCN(CC)C/C=C/CN
Yield: 41 %

Procedure:
(E)-1-Phthalimido-4-bromobut-2-ene (4.2 g, 15 mmol), diethylamine (1.1 g, 15 mmol) and KF supported on Celite (7.5 g) were stirred together in acetonitrile (75 ml) at 40° C. for 18 h. The solution was filtered, and the filtrate was concentrated in vacuo to afford an oil, which was dissolved in glacial acetic acid (30 ml) and conc. HCl (30 ml). The mixture was heated at reflux for 30 h. The solution was cooled, filtered and the solvents were removed in vacuo to afford (E)-N,N-diethyl-1,4-diaminobut-2-ene dihydrochloride as an oil (1.32 g, 41%). δH (90 MHz, D2O) 1.19 (6H, m) 3.24 (4H, q), 4.05 (4H, m) and 5.96 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[CH:12][CH:11]=2)O)=[N:4][CH:5]=[CH:6][N:7]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[C:3]([CH:8]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[CH:12][CH:11]=2)[N:24]2[C:20](=[O:30])[C:21]3[C:22](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:23]2=[O:25])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: OC(c1ccc2cccnc2c1)c1nccnc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C(c1ccc2cccnc2c1)c1nccnc1Cl
Temperature: 0 °C
Reaction time: 21.5 h

Procedure:
To a suspension of (3-chloropyrazin-2-yl)-quinolin-7-ylmethanol (600 mg, 2.21 mmol), phthalimide (356 mg, 2.42 mmol), and PS—PPh3 (loading 2.12 mmol/g; 1.56 g, 3.31 mmol) in dry THF (20 mL), cooled by ice/water, was added DIAD (480 μL, 493 mg, 2.44 mmol), then the cooling bath was removed and the flask was vortexed at ambient temperature for 21.5 h. More PS—PPh3 (520 mg, 1.10 mmol) and DIAD (160 μL, 164 mg, 0.81 mmol) were added, and vortexing was continued for 6.5 h. The resin was filtered and washed with THF and CH2Cl2. The crude material was chromatographed on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with hexanes:EtOAc 3:1 (1-14)→2:1 (15-29)→1:1 (30-65)→1:2 (66-80)], yielding the title compound as pale yellow solid; 1H NMR (CDCl3, 400 MHz) δ 7.12 (s, 1H), 7.41 (dd, J=4.4, 8.0 Hz, 1H), 7.54 (dd, J=2.0, 8.4 Hz, 1H), 7.72-7.78 (m, 2H), 7.81-7.89 (m, 3H), 8.01 (d, J=0.8 Hz, 1H), 8.16 (dd, J=0.8, 8.4 Hz, 1H), 8.39 (d, J=2.4 Hz, 1H), 8.50 (d, J=2.4 Hz, 1H), 8.90 (dd, J=1.6, 4.2 Hz, 1H); MS (ES+): m/z 401.0/402.9 (100/38) [MH+].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:11])[C:7]=1[C:8]([NH2:10])=[O:9].Cl[C:13]1[S:14][CH:15]=[CH:16]N=1.N>O>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[C:8](=[O:9])[N:10]1[CH:16]=[CH:15][S:14][C:13]1=[N:11]2
Reactant: Clc1nccs1
Reactant: Cc1cccc(N)c1C(N)=O
Agent: N
Solvent: O
Product: Cc1cccc2nc3sccn3c(=O)c12
Temperature: 140 °C
Yield: 68.8 %

Procedure:
While stirring, 22.5 g of 6-methylanthranilamide was added to 18 g of 2-chlorothiazole. The reaction mixture was heated over a 20-minute period to 140° C. and stirred for 4 hours. Water was added to the reaction mixture, and a pH of 10 was set by adding 25% strength ammonia solution. Working up in the conventional manner gave 22.3 g (69%) of compound 3; m.p. 148°-150° C.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[Br:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11](=[O:17])[C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1>C1COCC1>[Br:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([OH:17])([CH:1]([CH3:3])[CH3:2])[C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1
Reactant: O=C1Nc2cc(Br)ccc2C1=O
Reactant: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)C1(O)C(=O)Nc2cc(Br)ccc21

Procedure:
Addition of isopropylmagnesiumchloride to 6-bromoisatin at −78° C. in THF gives after usual workup 6-bromo-3-hydroxy-3-isopropyl-1,3-dihydro-indol-2-one which is reacted with 8-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamine using general procedure 2 to give the title compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18](O)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:46][CH:47]1[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][N:55]([CH3:62])[CH:56]2[CH2:61][CH2:60][O:59][CH2:58][CH2:57]2)[CH2:49][CH2:48]1>C(#N)C.C(N(CC)CC)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([NH:46][CH:47]4[CH2:48][CH2:49][N:50]([CH2:53][CH2:54][N:55]([CH3:62])[CH:56]5[CH2:61][CH2:60][O:59][CH2:58][CH2:57]5)[CH2:51][CH2:52]4)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1
Reactant: CN(CCN1CCC(N)CC1)C1CCOCC1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)NC2CCN(CCN(C)C4CCOCC4)CC2)CCO3)cc1
Reaction time: 1 h
Yield: 36.7 %

Procedure:
Into a solution of 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxylic acid (150 mg) and 1-hydroxybenzotriazole (0.14 g) in acetonitrile (10 ml) was added at room temperature 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g), and the resulting mixture was stirred for one hour. Into the reaction mixture was added a solution of 4-amino-1-[2-[N-methyl-N-(tetrahydropyran-4-yl)amino]ethyl]piperidine dihydrochloride (282 mg), triethylamine (0.15 ml.) and diazabicyclo[5,4,0]-7-undecene (0.37 g) in acetonitrile (15 ml), and the resulting mixture was stirred for 18 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. The resulting organic layer was evaporated to remove the solvent, and then the residue was subjected to purification using column chromatography (triethylamine/ethanol/ethyl acetate 1:10:10) and further to recrystallization (ethyl acetate/hexane) to obtain 7-(4-methylphenyl)-N-[1-[2-[N-methyl-N-(tetrahydropyran-4-yl)amino]ethyl]piperidin-4-yl]-2,3-dihydro-1-benzooxepine-4-carboxamide (compound 62) (99 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:29]=[CH:28][C:7]([CH2:8][C:9]2[N:13]([CH2:14][CH2:15][N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:12]3[CH:21]=[CH:22][C:23]([N+:25]([O-])=O)=[CH:24][C:11]=3[N:10]=2)=[CH:6][CH:5]=1)[CH3:2].Br.C(S[C:39]([C:41]1[O:42][CH:43]=[CH:44][CH:45]=1)=[NH:40])C1C=CC=CC=1>C(OCC)C>[CH2:17]([N:16]([CH2:19][CH3:20])[CH2:15][CH2:14][N:13]1[C:12]2[CH:21]=[CH:22][C:23]([NH:25][C:39]([C:41]3[O:42][CH:43]=[CH:44][CH:45]=3)=[NH:40])=[CH:24][C:11]=2[N:10]=[C:9]1[CH2:8][C:7]1[CH:28]=[CH:29][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=1)[CH3:18]
Reactant: CCOc1ccc(Cc2nc3cc([N+](=O)[O-])ccc3n2CCN(CC)CC)cc1
Reactant: N=C(SCc1ccccc1)c1ccco1
Agent: Br
Solvent: CCOCC
Product: CCOc1ccc(Cc2nc3cc(NC(=N)c4ccco4)ccc3n2CCN(CC)CC)cc1
Temperature: 25 °C
Reaction time: 19.5 h

Procedure:
{2-[2-(4-Ethoxy-benzyl)-5-nitro-benzoimidazol-1-yl]-ethyl}-diethyl-amine 7a (108 mg, 0.272 mmol) was reduced to the amine 8a as outlined above and the resulting ethanolic solution charged to a small, argon purged flask fitted with a magnetic stirbar. Furan-2-carboximidothioic acid benzyl ester hydrobromide 9c (168 mg, 0.564 mmol) is added to the flask and the reaction was stirred under Ar at ambient temperature for 19.5 hours. The solution was diluted with diethyl ether (100 mL) and cooled in and ice bath resulting in the formation of a off-white precipitate that was collected on a sintered glass funnel and washed with ether. The hygroscopic solid was solubilized on the funnel in methanol and the solvent collected and evaporated to yield crude solid. The solid was partitioned between H2O and ethyl acetate and 1M sodium hydroxide solution added to adjust pH to 11. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with brine (twice), dried over magnesium sulphate, filtered and concentrated to afford crude. The product was purified using silica gel column chromatography eluting with 5% 2M NH3 in methanol/95% dichloromethane to afford an off white solid 13 N-(1-(2-(diethylamino)ethyl)-2-(4-ethoxybenzyl)-1H-benzo[d]imidazol-5-yl)-furan-2-carboximidamide. Yield: 125 mg (100%) 1H NMR (DMSO) δ: 0.83 (t, 6H, J=7.1), 1.27 (t, 3H, J=6.9), 2.39-2.50 (2×m, 6H), 3.97 (q, 2H, J=6.9), 4.09 (t, 2H, J=6.8), 4.21 (s, 2H), 6.10 (br s, 2H), 6.58-6.63 (m, 1H), 6.72 (d, 1H, J=7.9), 6.86 (d, 2H, J=8.5), 6.99 (br s, 1H), 7.10 (d, 1H, J=3.1), 7.17 (d, 2H, J=8.6), 7.34 (d, 1H, J=8.6), 7.78 (s, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]1[N:19]=[C:18](Cl)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.[NH:21]([CH2:25][CH2:26][OH:27])[CH2:22][CH2:23][OH:24]>CN(C)C=O>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]1[N:19]=[C:18]([O:24][CH2:23][CH2:22][NH:21][CH2:25][CH2:26][OH:27])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: OCCNCCO
Reactant: Cn1c([N+](=O)[O-])cnc1-c1nc(Cl)c2ccccc2n1
Solvent: CN(C)C=O
Product: Cn1c([N+](=O)[O-])cnc1-c1nc(OCCNCCO)c2ccccc2n1
Temperature: 100 °C

Procedure:
A suspension of 4 g of 2-(1-methyl-5-nitro-2-imidazolyl)-4-chloroquinazolin and 1.6 g of diethanolamine in 25 ml of dimethyl formamide is heated at 100° C for 11/2 hours. After cooling, the resulting crystals are filtered off, washed with tetrahydrofuran and water, and dried to obtain the heading compound, m.p. 236°-239° C.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[C:8]=2[N:9]=1)[CH3:2].[H-].[Na+].I[CH3:31].O>CN(C)C=O>[CH2:1]([S:3][C:4]1[N:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[CH:13]=[CH:12][N:11]([CH3:31])[C:10](=[O:14])[C:8]=2[N:9]=1)[CH3:2]
Reactant: CCSc1nc2c(=O)[nH]ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1nc2c(=O)n(C)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 2-(ethylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]-3,7-dihydropyrido[3,4-d]pyrimidine-4,8-dione (40 mg) in N,N-dimethylformamide (5 ml) was added sodium hydride (60% in oil, 193 mg) at room temperature, and the mixture was stirred for 10 min. To the reaction mixture was added iodomethane (0.009 ml), and the mixture was stirred at room temperature for 3 hr. To the reaction mixture was added water, and the precipitate was collected by filtration. The obtained solid was suspended in toluene, and the suspension was concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of hexane/ethyl acetate/methanol to give the title compound (33 mg).
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[Br:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([Br:40])[CH:39]=1)[C:34](O)=[O:35]>>[Br:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([Br:40])[CH:39]=1)[C:34]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:29])[CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)=[O:18])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:35]
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Agent: Cl
Product: CN(C(=O)c1cc(Br)cc(Br)c1)[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 3,5-dibromobenzoic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(3,5-dibromobenzoyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 626 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1.[Li].CON(C)[C:25]([C:27]1[S:28][C:29]([Cl:32])=[CH:30][CH:31]=1)=[O:26].[Cl-].[NH4+]>C1COCC1>[Cl:20][C:16]1[CH:15]=[C:14]([C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:25]([C:27]4[S:28][C:29]([Cl:32])=[CH:30][CH:31]=4)=[O:26])[CH:3]=3)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CON(C)C(=O)c1ccc(Cl)s1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(Br)ccc2n1
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccc(Cl)s3)ccc2n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46.2 %

Procedure:
To a solution of 6-bromo-4-(3-chloro-phenyl)-2-methoxy-quinoline (500 mg, 1.43 mmol) in THF (2 ml) was added n-buthyl lithium (2.5 M in hexane, 0.63 ml, 1.58 mmol) dropwise at −78° C. under an atmosphere of dry N2. After stirring at −78° C. for 30 minutes, a solution of 5-chloro-thiophene-2-carboxylic acid methoxy-methyl-amide (440 mg, 2.15 mmol) in THF (1 ml) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 15 hours. To the mixture was added a saturated aqueous solution of ammonium chloride at 0° C. THF was removed from the resulting heterogeneous solution. The aqueous mixture was extracted with chloroform (CHCl3). The organic layer was washed with brine, dried over MgSO4 and concentrated under vacuum to yield the crude product. It was chromatographed on silica gel with MeOH—CHCl3—NH4OH (2:98:0.2 to 5:95:0.5) as eluents to afford the title compound of example 40A (273.5 mg, 46% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH:5]=[C:6]([C:16](OCC)=[O:17])[C:7]([CH3:15])=[N:8]2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH:5]=[C:6]([CH:16]=[O:17])[C:7]([CH3:15])=[N:8]2
Reactant: CCOC(=O)c1cc2c(OC)ccc(OC)c2nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(OC)c2nc(C)c(C=O)cc12
Temperature: 50 °C
Reaction time: 16 h
Yield: 3 %

Procedure:
A solution of ethyl 5,8-dimethoxy-2-methylquinoline-3-carboxylate (4.0 g, 0.0145 mol) in tetrahydrofuran is added to a slurry of lithium aluminum hydride (0.72 g, 0.019 mol) in ether. The reaction is stirred for 16 hours at 50° C. After cooling, the reaction is quenched by the sequential addition of water and 15% aqueous sodium hydroxide. Additional ether and anhydrous magnesium sulfate are added and the reaction mixture is filtered. The product is purified by chromatography using silica gel and ethyl acetate in hexanes as eluant. The resulting alcohol (1.50 g) is dissolved in methylene chloride and added to a slurry of pyridinium chlorochromate in methylene chloride. The resulting solution is stirred for 3 hours at room temperature. Diatomaceous earth is added, the reaction mixture is diluted with ether and filtered. The filtrate is concentrated in vacuo and the product purified by chromatography using silica gel and ethyl acetate in hexanes as eluant to yield the title compound (0.10 g, 5%) as a yellow solid, identified by IR and NMR spectral analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:16]2=[N:17][CH:18]=[C:19]([CH2:21][NH:22][C:23](=O)[N:24]([CH3:26])[CH3:25])[N:20]=[C:15]2[CH:14]=1.O=P(Cl)(Cl)Cl>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:36])[CH3:34])[C:16]2[N:17]=[CH:18][C:19]3[N:20]([C:23]([N:24]([CH3:26])[CH3:25])=[N:22][CH:21]=3)[C:15]=2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3nc(CNC(=O)N(C)C)cnc3n1COCC[Si](C)(C)C)cn2C
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc2c(c1)c(-c1cc3c(ncc4cnc(N(C)C)n43)n1COCC[Si](C)(C)C)cn2C
Temperature: 85 °C
Yield: 427.6 %

Procedure:
A flask was charged with 3-((6-(5-methoxy-1-methyl-1H-indol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl)methyl)-1,1-dimethylurea (0.114 g, 0.224 mmol, Preparation #X.1) and DCE (5 mL). A solution of POCl3 (0.063 mL, 0.672 mmol) in DCE (2 mL) was added and mixture was heated to about 85° C. for about 3 h. The mixture was concentrated under reduced pressure and then diluted with EtOAc (15 mL) and washed with saturated aqueous NaCl (10 mL). The organic layer was dried with anhydrous MgSO4, filtered and concentrated in vacuo. The material was purified using silica gel chromatography with an elution gradient of 0 to 100% EtOAc/heptane to give 7-(5-methoxy-1-methyl-1H-indol-3-yl)-N,N-dimethyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-amine (0.47 g, 43%): LC/MS (Table 2, Method b) Rt=3.14 min; MS m/z: 491 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([C:23]4[C:24](=[O:30])[NH:25][CH:26]=[CH:27][C:28]=4Cl)[NH:20]3)=[C:16]([CH3:31])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[NH2:40][CH2:41][C@H:42]([C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[CH:45]=1)[OH:43]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([C:23]4[C:24](=[O:30])[NH:25][CH:26]=[CH:27][C:28]=4[NH:40][CH2:41][C@H:42]([C:44]4[CH:49]=[CH:48][CH:47]=[C:46]([Cl:50])[CH:45]=4)[OH:43])[NH:20]3)=[C:16]([CH3:31])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: NC[C@@H](O)c1cccc(Cl)c1
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(-c3c(Cl)cc[nH]c3=O)nc12
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(-c3c(NC[C@@H](O)c4cccc(Cl)c4)cc[nH]c3=O)nc12
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[8-(4-chloro-2-oxo-1,2-dihydro-pyridin-3-yl)-6-methyl-9H-purin-2-yl]-piperazine-1-carboxylic acid t-butyl ester (200 mg, 0.448 mmol) in acetonitrile (10 mL) was added triethylamine (125 μl, 0.896 mmol) and (S)-2-amino-1-(3-chlorophenyl)-ethanol hydrochloride (99 mg, 0.493 mmol). The reaction mixture was stirred at 80° C. for 18 hours in a sealed tube and concentrated. The residue was dissolved in CH2Cl2 (50 mL) washed with H2O (2×30 mL), dried over MgSO4 and concentrated. The crude material was purified by crystallization in hot MeOH (35 mL) to give the title compound as a beige solid. (0.197 g, 76%). HPLC 98%; LCMS (+ESI, M+H+) m/z 581; IR (KBr, cm−1) 3419, 3271, 2975, 1696, 1496, 1232; 1H NMR (400 MHz, DMSO+D2O) δ 10.79 (br s, 1H), 7.59–7.32 (m, 5H), 6.22 (d, J=7.6 Hz, 1H), 5.00 (br t, 1H), 3.73 (br s, 4H, 3.60 (m, 1H), 3.44 (br s, 4H), 2.58 (s, 3H); HRMS calcd for C28H33ClN8O4: 581.2391; found 581.2389.