Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:36]([O:38][C:39]1[CH:45]=[C:44]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][CH3:54])[CH2:48][CH2:47]2)[CH:43]=[CH:42][C:40]=1[NH2:41])[CH3:37].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:41][C:40]3[CH:42]=[CH:43][C:44]([N:46]4[CH2:51][CH2:50][N:49]([CH2:52][CH2:53][CH3:54])[CH2:48][CH2:47]4)=[CH:45][C:39]=3[O:38][CH2:36][CH3:37])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: CCCN1CCN(c2ccc(N)c(OCC)c2)CC1
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CC(C)O
Product: CCCN1CCN(c2ccc(Nc3nccc(-c4c(-c5ccc(OC)c(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c(OCC)c2)CC1
Temperature: 130 °C
Yield: 40 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 2-(ethyloxy)-4-(4-propyl-1-piperazinyl)aniline (48 mg, 0.18 mmol), and p-toluenesulfonic acid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 130° C. for 48 h. The mixture was transferred to a 50 mL round bottom and neutralized with 3 mL of 0.5 N sodium methoxide 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (52 mg, 0.072 mmol, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.78 (s, 1H), 9.32 (s, 1H), 8.35 (s, 1H), 8.21 (d, J=5.31 Hz, 1H), 8.09 (d, J=2.01 Hz, 1H), 7.76 (dd, J=8.61, 2.01 Hz, 1H), 7.68 (d, J=8.97 Hz, 1H), 7.35-7.45 (m, 3H), 7.26 (d, J=8.79 Hz, 1H), 7.17 (t, J=8.06 Hz, 2H), 6.92 (t, J=6.87 Hz, 1H), 6.64 (d, J=2.20 Hz, 1H), 6.53 (d, J=5.31 Hz, 1H), 6.46 (dd, J=8.79, 2.38 Hz, 1H), 4.04 (q, J=6.96 Hz, 2H), 3.97 (s, 3H), 3.07-3.13 (m, 4H), 2.43-2.51 (m, 4H), 2.26 (t, J=7.23 Hz, 2H), 1.40-1.50 (m, J=7.36, 7.36, 7.36, 7.36, 7.36 Hz, 2H), 1.22 (t, J=6.96 Hz, 3H), 0.85 (t, J=7.42 Hz, 3H). MS (ESI): 719 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[C:7]([C:11]1[C:19]2[O:18][CH2:17][C:16]([CH3:21])([CH3:20])[C:15]=2[CH:14]=[C:13]([NH2:22])[CH:12]=1)([CH3:10])([CH3:9])[CH3:8]>CCOCC>[C:7]([C:11]1[C:19]2[O:18][CH2:17][C:16]([CH3:21])([CH3:20])[C:15]=2[CH:14]=[C:13]([NH:22][C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:6])[CH:12]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1cc(N)cc2c1OCC2(C)C
Reactant: CCCN=C=O
Solvent: CCOCC
Product: CCCNC(=O)Nc1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Reaction time: 0.17 h
Yield: 38.9 %

Procedure:
Propylisocyanate (0.21 mL, 2.28 mmol) is added dropwise to a solution of (7-t-butyl-2,3-dihydro-3,3-dimethyl-5-benzofuranyl)-amine (500 mg, 2.28 mmol) and Et2O (5 mL). A solid forms after 10 min and the reaction is quenched with H2O (10 mL) after 40 min. The reaction is extracted with Et2O (3×10 mL) and the organic layers dried (MgSO4) and evaporated to an off-white solid (650 mg). This solid is recrystallized from EtOAc to give a white solid (270 mg, 39%), mp=193°-194° C.
Reaction SMILES: [Na:1].COC1OCC([CH2:10][O:11][C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)=[O:20])[C:13]=2[CH3:30])CO1.[O:31]1[CH2:36][CH2:35][CH2:34][O:33][CH:32]1CO>>[Na:1].[O:31]1[CH2:36][CH2:35][CH2:34][O:33][CH:32]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH2:18][S:19]([C:21]2[NH:22][C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[N:25]=2)=[O:20])[C:13]=1[CH3:30]
Reactant: COC1OCC(COc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)CO1
Reactant: OCC1OCCCO1
Agent: [Na]
Product: Cc1c(OCC2OCCCO2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 10 %

Procedure:
The same procedure as in the steps (6b) to (6f) of Example 6 was repeated using 1,3-dioxan-2-ylmethanol obtained in the step (32b) to obtain the title compound (148 mg, total yield:10%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[Br:12]Br.[OH-].[Na+]>C(O)(=O)C.CCOCC>[NH2:1][C:2]1[C:7]([Br:12])=[CH:6][C:5]([C:8]([F:9])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(F)(F)F)cn1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: Nc1ncc(C(F)(F)F)cc1Br
Reaction time: 1 h

Procedure:
To a solution of 2-amino-5-trifluoromethylpyridine (9 g) in acetic acid (75 mL) at r.t. was added bromine (5.8 mL) slowly. After 1 h, the acid was neutralized by the careful addition of sodium hydroxide (10N) at 0° C. The resulting orange precipitate was dissolved in ether and washed successively with saturated potassium carbonate, saturated Na2SO3 and brine, dried and concentrated. The residual solid was stirred vigorously in hexane for 1 h to provide, after filtration, the title compound as a white solid (10.2 g).
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([NH:12][C:13]([N:15]1[C:19]([CH3:20])=[CH:18][C:17]([O:21][C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:33])=[N:16]1)=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C(O)(=O)C>[CH2:6]([NH:12][C:13]([N:15]1[C:19]([CH3:20])=[C:18]([Cl:4])[C:17]([O:21][C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:30])[F:31])=[CH:24][C:23]=2[Cl:33])=[N:16]1)=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCNC(=O)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCCCCCNC(=O)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c(Cl)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
Sulfuryl chloride (0.16 g, 1.2 mmol) was added to a solution of N-hexyl-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.44 g, 1.0 mmol) in acetic acid (5 ml), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant. The solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane 1/10), to give a white solid of N-hexyl-4-chloro-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.40 g, yield: 84.8%). mp: 86-88° C.; 1H-NMR (CDCl3, TMS, ppm): δ 0.88 (t, J=6.8 Hz, 3H), 1.26 (m, 6H), 1.40-1.60 (m, 2H), 2.62 (s, 3H), 3.15-3.35 (m, 2H), 6.50-6.70 (m, 1H), 7.67 (s, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([NH2:10])(=[O:9])=[O:8])[CH:2]=1.[H-].[Na+].[C:13](=O)([O:39]C1C=CC=CC=1)[O:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]3[CH:28]=[C:29]([Cl:36])[C:30]([C:32]([F:35])([F:34])[F:33])=[CH:31][C:26]=3[N:25]=[C:24]2[CH2:37][CH3:38])=[CH:19][CH:18]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:36][C:29]1[C:30]([C:32]([F:34])([F:33])[F:35])=[CH:31][C:26]2[N:25]=[C:24]([CH2:37][CH3:38])[N:23]([C:20]3[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][O:14][C:13](=[O:39])[NH:10][S:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)(=[O:9])=[O:8])=[CH:22][CH:21]=3)[C:27]=2[CH:28]=1
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)NS(=O)(=O)c2cccnc2)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 18.9 %

Procedure:
To a stirred solution of 3-pyridinesulfonamide (Rafik, Karaman; et al., J. Am. Chem. Soc., 1992, 114, 4889, 120 mg, 0.76 mmol) in DMF (3 mL) was added NaH (60% oil dispersion, 27 mg, 0.68 mmol) at room temperature. After 10 min., phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1, 313 mg, 0.64 mmol) was added, and the mixture was stirred for 9 h at 80° C. The mixture was diluted with ethyl acetate (50 mL), and washed with water and brine. The organic layer was dried (Na2SO4) and concentrated. Purification by TLC developing with dichloromethane/methanol (6:1) and TLC developing with dichloromethane/methanol (10:1) gave 67 mg (19%) of the title compound as colorless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[NH:11][CH2:10][CH2:9][CH2:8][N:7]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[C:6]=2[N:22]=1.[O:23]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][NH:31][C:32]([C:34]2[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=2)=[O:33])[CH2:25][CH2:24]1>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:7]1[CH2:8][CH2:9][CH2:10][NH:11][C:5]2[N:4]=[CH:3][C:2]([C:38]3[CH:39]=[C:34]([CH:35]=[CH:36][CH:37]=3)[C:32]([NH:31][CH2:30][CH2:29][N:26]3[CH2:25][CH2:24][O:23][CH2:28][CH2:27]3)=[O:33])=[N:22][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCCNc3ncc(Br)nc32)c1Cl
Reactant: O=C(NCCN1CCOCC1)c1cccc(B(O)O)c1
Product: O=C(NCCN1CCOCC1)c1cccc(-c2cnc3c(n2)N(Cc2c(F)ccc(F)c2Cl)CCCN3)c1

Procedure:
The entitled compound can be prepared from 2-Bromo-9-(2-chloro-3,6-difluorobenzyl)-6,7,8,9-tetrahydro-5H-pyrazino[2,3-b][1,4]diazepine and 3-(2-morpholinoethylcarbamoyl)phenyl boronic acid as described in example 1 or 30.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:22][C@@H:21]([CH3:23])[N:11]2[C:12]3[CH:13]=[C:14]([CH3:20])[C:15](Br)=[CH:16][C:17]=3[CH:18]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:22][C@@H:21]([CH3:23])[N:11]2[C:12]3[CH:13]=[C:14]([CH3:20])[CH:15]=[CH:16][C:17]=3[CH:18]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2c(cc1Br)cc1n2[C@H](C)CN(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2cc3n(c2c1)[C@H](C)CN(C(=O)OC(C)(C)C)C3
Reaction time: 6 h
Yield: 49 %

Procedure:
To a solution of 1.52 g (R)-8-bromo-4,7-dimethyl-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester in 15 ml, ethanol was added 0.15 g 10% palladium on charcoal and the mixture was stirred under a hydrogen atmosphere for 6 h. A further 0.15 g 10% palladium on charcoal was added and the mixture was stirred a further 6 h under a hydrogen atmosphere. Again 0.15 g 10% palladium on charcoal was added and the mixture was stirred a further 6 h under a hydrogen atmosphere. The catalyst was removed by filtration over dicalite and the filtrate was evaporated. The residue was purified by chromatography on silica gel with 4:1 hexane:ethyl acetate to yield 0.59 g of the title compound as a white foam. MS: (M+H)=301.3.
Reaction SMILES: [NH2:1][CH:2]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:3]([NH:7][CH:8]([C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11])[CH3:9])[C:4]([OH:6])=[O:5].[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:24]([NH:1][CH:2]([CH2:20][CH:21]([CH3:23])[CH3:22])[CH:3]([NH:7][CH:8]([C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:11])[CH3:9])[C:4]([OH:6])=[O:5])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)CC(N)C(NC(C)C(=O)N1CCC[C@H]1C(=O)O)C(=O)O
Product: CC(C)CC(NC(=O)c1ccccc1)C(NC(C)C(=O)N1CCC[C@H]1C(=O)O)C(=O)O

Procedure:
A solution of N-(2-amino-1-carboxy-4-methylpentyl)-D,L-alanyl-L-proline (prepared as described in Example 78) in aqueous alkali is treated with benzoyl chloride to yield N-(2-benzamido-1-carboxy-4-methylpentyl)-D,L-alanyl-L-proline. The mass spectrum of disilylated material had peaks at 562 (M+ -15), 460,389 (base peak), 364,242 and 174 m/e.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:20]([O:21][CH3:22])=[CH:19][C:6]2[S:7][C:8]([C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[O:12])=[C:9]([CH3:10])[C:5]=2[CH:4]=1.[Br:23]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:10][C:9]1[C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:20]([O:21][CH3:22])=[CH:19][C:6]=2[S:7][C:8]=1[C:11]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2sc(C(=O)N3CCOCC3)c(C)c2cc1OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc2sc(C(=O)N3CCOCC3)c(CBr)c2cc1OC

Procedure:
(5,6-Dimethoxy-3-methylbenzo[b]thiophen-2-yl)morpholin-4-yl-methanone (2.0 g) from Example 20, N-bromosuccinimide (1.18 g) and 2,2′-azobis(2-methylpropionitrile) (40 mg) in carbon tetrachloride (6 ml) was refluxed under argon for 4 hours. The mixture was cooled and filtered and the filtrate evaporated to dryness. The product was a mixture of (4-bromo-5,6-dimethoxy-3-methyl-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone and (3-bromomethyl-5,6-dimethoxy-benzo[b]thiophen-2-yl)-morpholin-4-yl-methanone. The compounds were separated by flash chromatography using ethyl acetate/heptane (1:4) as an eluent.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[O:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[C:9](S(C(F)(F)F)(=O)=O)=[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:7]=1.[Cl:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[O:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([C:38]2[CH:37]=[CH:36][CH:35]=[C:34]([Cl:33])[CH:39]=2)=[C:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:7]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COc1nc(Oc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1S(=O)(=O)C(F)(F)F
Product: COc1nc(Oc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1cccc(Cl)c1

Procedure:
This derivative was prepared by the method described in Example 132 using 2-(3,4-difluorophenoxy)-4-methoxy-5-trifluoromethansulfonyl-6-[2,4-dichlorophenyl]pyrimidine (27 mg, 0.05 mmol) as described in Reference Example 17 and 3-chlorobenzeneboronic acid (Lancaster, 16 mg, 0.1 mmol). HPLC Rt=4.82 min. 1H-NMR 500 MHz (CDCl3): 3.88 (s, 3H), 6.45 (d, J=8 Hz, 1H), 6.51 (s, 1H), 6.67 (d, J=8 Hz, 1H), 6.71 (s, 1H), 6.95 (m, 1H), 7.05 (t, J=9 Hz, 1H), 7.8 (m, 2H), (7.39 s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[NH2:16].[C:17]1(B(O)O)[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1>>[C:17]1([C:2]2[CH:7]=[C:6]([CH2:8][CH2:9][N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH:5]=[CH:4][C:3]=2[NH2:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: Nc1ccc(CCN2CCOCC2)cc1Br
Reactant: OB(O)C1=CCCCC1
Product: Nc1ccc(CCN2CCOCC2)cc1C1=CCCCC1

Procedure:
This compound is prepared by Suzuki coupling of 2-bromo-4-(2-morpholin-4-yl-ethyl)-phenylamine (as prepared in the previous step) and 1-cyclohexen-1-yl-boronic acid according to the procedure in Example 1, step (e). Mass spectrum (ESI, m/z): Calcd. for C18H26N2O, 287.2 (M+H). found 287.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][OH:10].[H-].[Na+].Br[C:14]1[C:15]([NH2:21])=[N:16][CH:17]=[C:18]([Br:20])[N:19]=1>O1CCCC1>[Br:20][C:18]1[N:19]=[C:14]([O:10][CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[C:15]([NH2:21])=[N:16][CH:17]=1
Reactant: OCc1c(Cl)cccc1Cl
Reactant: Nc1ncc(Br)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1ncc(Br)nc1OCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To an ice cooled solution of (2,6-dichloro-phenyl)-methanol (5 g, 28.2 mmol) in anhydrous tetrahydrofuran (200 mL) was added sodium hydride (1.13 g, 28.2 mmol, 60% disp.) slowly under nitrogen atmosphere. After stirring for 30 minutes, 3,5-dibromo-pyrazin-2-ylamine (7.08 g, 28.2 mmol) in anhydrous tetrahydrofuran (50 mL) was added via an addition funnel. Once the addition was complete the ice bath was removed and the reaction was refluxed under nitrogen and monitored by reversed phase HPLC. After 18 hr HPLC showed that the majority of the starting 3,5-dibromo-pyrazin-2-ylamine had been consumed and the reaction was allowed to cool to room temperature. The reaction mixture was concentrated in vacuum until 50 mL remained. The mixture was diluted with ethyl acetate (200 mL) and extracted with 50% brine (2×200 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuum. The crude product was purified using a silica gel column eluting with 1:1 ethyl acetate/dichloromethane to yield 5-bromo-3-(2,6-dichloro-benzyloxy)-pyrazin-2-ylamine as a white solid (8.17 g, 83% yield).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]1[C:9]1[CH:10]=[C:11](C2OC=CC=2)[C:12]([O:30][CH3:31])=[C:13]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:20][CH2:21]3)=[CH:17][CH:16]=2)[CH:14]=1.[O:37]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38]1>>[O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]1[C:9]1[CH:10]=[C:11]([C:39]2[CH:40]=[CH:41][O:37][CH:38]=2)[C:12]([O:30][CH3:31])=[C:13]([C:15]2[CH:23]=[C:22]3[C:18]([C:19]([CH2:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:20][CH2:21]3)=[CH:17][CH:16]=2)[CH:14]=1
Reactant: COc1c(-c2ccc3c(c2)CC=C3CNS(C)(=O)=O)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccco1
Reactant: OB(O)c1ccoc1
Product: COc1c(-c2ccoc2)cc(-n2ccc(=O)[nH]c2=O)cc1-c1ccc2c(c1)CC=C2CNS(C)(=O)=O
Yield: 45 %

Procedure:
The product from Example 63, Part A (25.9 mg, 0.050 mmol) was reacted with furan-3-yl boronic acid (7.2 mg, 0.064 mmol) as described in Example 63, Part B to give the title compound as an off-white solid (10.6 mg, 45%). 1H NMR (300 MHz, DMSO-d6) δ 11.46 (s, 1H) 7.84 (d, J=8.09 Hz, 1H) 7.80 (t, J=1.84 Hz, 1H) 7.68-7.75 (m, 2H) 7.54-7.64 (m, 2H) 7.50 (t, J=6.07 Hz, 1H) 7.35 (d, J=2.57 Hz, 1H) 7.08 (d, J=1.47 Hz, 1H) 6.57 (s, 1H) 5.68 (d, J=8.09 Hz, 1H) 3.47 (s, 2H) 3.30 (s, 3H) 2.96 (s, 3H).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([OH:15])=[O:14])[CH:8]=1)[CH2:4][OH:5].[C:16]([N:20]=[C:21]=[S:22])([CH3:19])([CH3:18])[CH3:17]>C(O)C.C(N(CC)CC)C>[C:16]([NH:20][C:21]([NH:2][C@H:3]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([OH:15])=[O:14])[CH:8]=1)[CH2:4][OH:5])=[S:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)N=C=S
Reactant: N[C@@H](CO)Cc1cccc(C(=O)O)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)NC(=S)N[C@@H](CO)Cc1cccc(C(=O)O)c1
Temperature: 60 °C

Procedure:
The process is performed as in Example 2, starting with 1.82 g of (2R)-2-amino-3-(3-carboxyphenyl)-1-propanol hydrochloride in 20 cm3 of ethanol, 4.2 cm3 of triethylamine and 1.7 cm3 of tert-butyl isothiocyanate. After heating for 21 hours at a temperature in the region of 60° C. and an identical work-up, 2.31 g of N-(tert-butyl)-N′-[(1R)-2-hydroxy-1-(3-carboxybenzyl)ethyl]thiourea are obtained in the form of a light brown foam. (Rf=0.33 in a 12/6/1 by volume mixture of chloroform/methanol/aqueous ammonia, on a Merck 60F254R silica plate).
Reaction SMILES: CCC([N:5]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:14][CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=O.C(N1CCCCC1=[O:40])CC1C=CC=CC=1.NC1C=CC=CC=1>>[NH:5]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14](=[O:40])[CH2:13]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C1CCCCN1CCc1ccccc1
Reactant: CCC(=O)N(c1ccccc1)C1CCN(CCc2ccccc2)CC1
Solvent: Nc1ccccc1
Product: O=C1CC(Nc2ccccc2)CCN1CCc1ccccc1
Yield: 50 %

Procedure:
Fentanyl was first synthesized in 1960 by Paul Janssen founder of Janssen Pharmaceutica involving reacting N-phenethylpiperidone with aniline to produce 4-anilino-N-phenethylpiperidone with yield of about 50-80% using sodium borohydride at room temperature followed by reacting with propionyl chloride in presence of pyridine wherein the reaction is exothermic and thus requires stringent process conditions. The fentanyl thus obtained with a yield over 90% is further purified by crystallization.
Reaction SMILES: C([O:4][C:5]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=1)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CC(C)=O>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][O:9][C:8]1[C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:6][C:5]([OH:4])=[CH:17][C:16]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:15]
Reactant: CCOC(=O)COc1c(-c2ccccc2)cc(OC(C)=O)cc1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CC(C)=O
Product: CCOC(=O)COc1c(-c2ccccc2)cc(O)cc1-c1ccccc1
Temperature: 100 °C
Yield: 55.9 %

Procedure:
Ethyl 4-acetoxy-2,6-diphenylphenoxyacetate (7.2 g, 18.5 mmol) was dissolved in wet toluene (400 ml) and a catalyst (25 g SiO2 treated with a solution of 2 g 4-toluenesulfonic acid in 10 ml acetone and evaporated in vacuo) was added. The mixture was stirred and heated at 100° C. for 6 h, cooled and filtered through a column of silica gel (50 g). Elution with benzene afforded 3.6 g (56%) of (2,6-diphenyl-4-hydroxy-phenoxy)-acetic acid ethyl ester as white crystals, which were recrystallized from benzene/petroleum ether. M.p. 91–93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[OH:22].C(N(CC)CC)C.Cl[CH:31]([C:36]([CH3:38])=[O:37])[C:32]([O:34][CH3:35])=[O:33].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[O:22][CH:31]([C:36](=[O:37])[CH3:38])[C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
10.0 g of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol was dissolved in 30 ml of N,N-dimethylformamide, to this was added 5.0 ml of triethylamine, then 5.0 g of methyl 2-chloroacetoacetate was added to the resulted mixture at room temperature with stirring. Then, stirring was continued for 10 minutes at room temperature and for 1 hour at 60° C. 2.0 ml of triethylamine and 2.0 g of methyl 2-chloroacetoacetate were added to this solution, then, the mixture was further stirred for 1 hour at 60° C. The reaction solution was stirred overnight at room temperature, then, the reaction solution was poured into ice water and dilute hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 7.86 g methyl 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-3-oxobutyrate.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[CH:14][C:15]([CH3:20])([CH3:19])[O:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>C(O)C.[Pd]>[CH3:19][C:15]1([CH3:20])[CH2:14][CH:13]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:28])[F:30])[CH:22]=2)[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][CH:11]=2)[O:16]1
Reactant: CC1(C)C=C(c2cccc(C(F)(F)F)c2)c2ccc(OCc3ccccc3)cc2O1
Agent: [Pd]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(O)cc2O1
Reaction time: 18 h
Yield: 98 %

Procedure:
7-Benzyloxy-2,2-dimethyl-4-(3-trifluoromethylphenyl)-2H-chromene (10.0 g) was dissolved in ethanol (100 ml) and 10% Pd/C (1 g) added. This was hydrogenated at 60° and 5 atmospheres pressure for 18 hours. Filtration through kiesleguhr and evaporation of the solvent under reduced pressure gave an oil which solidified on addition of carbon tetrachloride. Recrystallisation from carbon tetrachloride gave the title compound (7.7 g), m.p. 63°-68° C., (analysing as compound plus 1 mole of carbon tetrachloride).