Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:49])([CH3:48])[C@H:3]([NH:43][C:44](=[O:47])[O:45][CH3:46])[C:4](=[O:42])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10](=[O:41])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([C@@H:30]3[CH2:34][CH2:33][CH2:32][NH:31]3)=[O:29])=[CH:23][CH:22]=2)=[CH:14][CH:13]=1.[C:50]1([C@@H:56]([N:60]2[CH2:64][CH2:63][CH2:62][CH2:61]2)[C:57](O)=[O:58])[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[CH3:46][O:45][C:44]([NH:43][C@H:3]([C:4]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][N:19]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[C@@H:30]3[CH2:34][CH2:33][CH2:32][N:31]3[C:57](=[O:58])[C@@H:56]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:60]3[CH2:61][CH2:62][CH2:63][CH2:64]3)=[CH:23][CH:22]=2)=[CH:16][CH:17]=1)=[O:41])=[O:42])[C:2]([CH3:49])([CH3:48])[CH3:1])=[O:47]
Reactant: O=C(O)[C@@H](c1ccccc1)N1CCCC1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3)cc2)c2ccccc2)cc1)C(C)(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc(CN(Cc2ccc(NC(=O)[C@@H]3CCCN3C(=O)[C@@H](c3ccccc3)N3CCCC3)cc2)c2ccccc2)cc1)C(C)(C)C
Yield: 60.4 %

Procedure:
The product from Example 10A (40 mg, 0.060 mmol) and the product of Example 55A (18.4 mg, 0.090 mmol) were processed using the method described in Example 43 to afford 31 mg (60%) of the title compound. 1H NMR (500 MHz, DMSO-D6) δ ppm 9.94 (bs, 1H), 9.90 (bs, 1H), 7.46 (m, 3H), 7.41 (m, 2H), 7.27 (m, 3H), 7.15 (m, 4H), 7.02 (m, 3H), 6.61 (d, J=8.2 Hz, 2H), 6.52 (t, J=7.3 Hz, 1H), 4.55 (bs, 4H), 4.38 (m, 1H), 4.27 (m, 1H), 4.17 (m, 2H), 3.79 (m, 1H), 3.72 (m, 1H), 3.58 (m, 1H), 3.49 (s, 3H), 3.40 (m, 1H), 2.43 (m, 3H), 2.29 (m, 2H), 2.09 (m, 1H), 1.95 (m, 3H), 1.89 (m, 4H), 1.57 (m, 3H), 0.91 (s, 9H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:15]3[N:16]=[CH:17][NH:18][C:14]=3[CH2:13][CH2:12][NH:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28](O)=[O:29])=[CH:22][CH:21]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][C:28]([N:11]2[CH2:12][CH2:13][C:14]3[NH:18][CH:17]=[N:16][C:15]=3[CH:10]2[C:7]2[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)=[O:29])=[CH:24][CH:25]=1
Reactant: CC(C)c1ccc(C2NCCc3[nH]cnc32)cc1
Reactant: O=C(O)CCc1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)c1ccc(C2c3nc[nH]c3CCN2C(=O)CCc2ccc(F)cc2)cc1
Yield: 33.3 %

Procedure:
A mixture of histamine dihydrochloride (1.85 g, 10.0 mmol), water (10 mL), potassium hydroxide (1.72 g, 30.0 mmol), ethanol (25 mL) and 4-isopropylbenzaldehyde (1.62 g, 10.91 mmol) was heated to reflux for 1.5 h. Ethanol was evaporated and the residue was diluted with water (40 mL). Extraction (5×25 mL DCM), washing of the combined extracts (2×50 mL brine) and drying (MgSO4) yielded 2.29 g (87%) of crude 4-(4-isopropylphenyl)-4,5,6,7-tetrahydro-imidazo[4,5-c]pyridine, which was used for the next synthetic step without further purification. This amine (0.48 g, 1.99 mmol) was dissolved in DCM (5 mL) and added to a 30 min old mixture of 3-(4-fluorophenyl)propionic acid (0.31 g, 1.84 mmol), HOBt (0.27 g, 1.20 mmol) and EDC (0.42 g, 12.19 mmol) in DCM (10 mL). After 18 h the mixture was washed with water (50 mL), dried (MgSO4) and concentrated. The crude product was purified by column chromatography (silica gel, gradient elution with DCM/methanol). 0.24 g (33%) of the title amide was obtained.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH:6]=1)[CH3:3].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=2)=[CH:22][N:21]=1)([O-])=O>N1C=CC=CC=1>[CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]3[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=3)=[CH:22][N:21]=2)[CH:6]=1)[CH3:3]
Reactant: CN(C)Cc1ccnc(CCCCN)c1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Solvent: c1ccncc1
Product: Cc1ccc(Cc2cnc(NCCCCc3cc(CN(C)C)ccn3)[nH]c2=O)cn1
Yield: 43.9 %

Procedure:
A mixture of 4-(4-dimethylaminomethyl-2-pyridyl)butylamine (1 g) and 2-nitroamino-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone (1.26 g) in pyridine (5 ml) was refluxed for 4.5 hours. The solvent was removed in vacuo, the residue chromatographed and then crystallised from ethanol:ether (1:10) to yield 2-[4(4-dimethylaminomethyl-2-pyridyl)butylamino]-5-(6-methyl-3-pyridylmethyl)-4-pyrimidone (0.86 g) m.p. 135°-137°.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH:6]([O:8][CH3:9])[O:5][CH:4]1[O:10][CH3:11].[CH2:12]([O:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1)=[O:16])[CH3:13]>O1CCCC1>[CH3:11][O:10][CH:4]1[CH:3]([CH2:2][NH:1][C:24]([NH:23][C:20]2[CH:19]=[CH:18][C:17]([C:15]([O:14][CH2:12][CH3:13])=[O:16])=[CH:22][CH:21]=2)=[O:25])[CH2:7][CH:6]([O:8][CH3:9])[O:5]1
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Reactant: COC1CC(CN)C(OC)O1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(NC(=O)NCC2CC(OC)OC2OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.1 %

Procedure:
2.9 g (18 mmol) of 3-aminomethyl-2,5-dimethoxytetrahydrofuran (DE-A 26 45 234) were dissolved in 20 ml of anhydrous tetrahydrofuran. At 0° C., 2.9 g (15 mmol) of 4-ethoxycarbonylphenyl isocyanate dissolved in 10 ml of anhydrous tetrahydrofuran were added dropwise. The mixture was then stirred at room temperature for 1 h and then concentrated under reduced pressure, resulting in 5.5 g of the crude product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]([C:13]1C=CC=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=[C:5]2[OH:23].[Cl:24]C1C=C([Mg]Br)C=CC=1>C1COCC1>[Cl:24][C:2]1[CH:3]=[C:4]([C:5]([C:6]2[CH:7]=[N:8][C:15]([C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)=[O:23])[CH:9]=[CH:10][CH:11]=1
Reactant: Clc1cccc([Mg]Br)c1
Reactant: O=c1[nH]c2ccc(Br)cc2c(O)c1-c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: O=C(c1ccc(C(F)(F)F)nc1)c1cccc(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of N-methoxy-N-methyl-6-(trifluoromethyl)nicotinamide (1.23 g, 5.25 mmol, Intermediate 2: step b) in THF (12 mL) at 4° C. was added 0.5 M (3-chlorophenyl)magnesium bromide in THF (12.7 mL, 6.35 mmol). The mixture was stirred at 4° C. to room temperature overnight, and quenched with NH4Cl (aqueous). The organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic phases were dried (Na2SO4), filtered, concentrated, and purified by flash column chromatography (40 g silica gel column, 0-70% EtOAc in heptanes) to provide the title compound as an oil, which solidified upon standing.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:3]=1[CH2:4][C@@H:5]([NH:23][C:24](=[O:26])[CH3:25])[CH2:6][C:7]1[N:11]2[CH:12]=[CH:13][C:14]3[N:15]([N:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:18]=3)[C:10]2=[N:9][N:8]=1.[H][H]>[Pd].COCCO>[F:1][C:2]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:3]=1[CH2:4][C@@H:5]([NH:23][C:24](=[O:26])[CH3:25])[CH2:6][C:7]1[N:11]2[CH2:12][CH2:13][C:14]3[N:15]([N:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[N:18]=3)[C:10]2=[N:9][N:8]=1
Reactant: [H][H]
Reactant: CC(=O)N[C@H](Cc1cc(F)c(F)cc1F)Cc1nnc2n1ccc1nc(C(F)(F)F)nn12
Agent: [Pd]
Solvent: COCCO
Product: CC(=O)N[C@H](Cc1cc(F)c(F)cc1F)Cc1nnc2n1CCc1nc(C(F)(F)F)nn1-2

Procedure:
A mixture of 52.1 mg (0.114 mmol) of N-{(1R)-1-(2,4,5-trifluorobenzyl)-2-[8-(trifluoromethyl)bis[1,2,4]triazolo[1,5-c:4′,3′-a]pyrimidin-3-yl]ethyl}acetamide, 52 mg of 10% palladium on carbon, and 5 mL of 2-methoxyethanol was shaken with hydrogen (52 psi) for 26 h. The catalyst was removed by filtration through Celite, and the filtrate was concentrated to dryness. The residue was purified by preparative thin-layer chromatography on silica gel (three successive developments in 92.5:7.5 dichloromethane:methanol) to provide the title compound. LC-MS 460 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:15]=[N:14][C:5]2[N:6]=[CH:7][C:8](=[O:13])[N:9]([CH2:10][CH:11]=C)[C:4]=2[CH:3]=1.I([O-])(=O)(=O)=[O:17].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[CH:15]=[N:14][C:5]2[N:6]=[CH:7][C:8](=[O:13])[N:9]([CH2:10][CH:11]=[O:17])[C:4]=2[CH:3]=1
Reactant: C=CCn1c(=O)cnc2ncc(F)cc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=CCn1c(=O)cnc2ncc(F)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-Fluoro-1-(2-propen-1-yl)pyrido[2,3-b]pyrazin-2(1H)-one (163 mg, 0.795 mmol) was dissolved in 1,4-dioxane (5 ml) and water (5 ml). Sodium periodate (426 mg, 1.99 mmol) was added, followed by osmium tetroxide (0.17 ml of 4% aqueous solution). The mixture stirred at rt for 2 h, and then treated with water (20 ml) and extracted with 20% MeOH/DCM (3×100 ml). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and evaporated to give (7-fluoro-2-oxopyrido[2,3-b]pyrazin-1(2H)-yl)acetaldehyde (existing mostly as the methyl hemiacetal) as an impure brown oil (193 mg, 117%).
Reaction SMILES: C([N:9]1[C:13]2=[N:14][C:15]([Br:18])=[CH:16][CH:17]=[C:12]2[CH:11]=[CH:10]1)(=O)C1C=CC=CC=1.[OH-].[Na+]>CO>[Br:18][C:15]1[N:14]=[C:13]2[NH:9][CH:10]=[CH:11][C:12]2=[CH:17][CH:16]=1
Reactant: O=C(c1ccccc1)n1ccc2ccc(Br)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Brc1ccc2cc[nH]c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A solution of 1-benzoyl-6-bromo-1H-pyrrolo[2,3-b]pyridine (0.046 g, 0.15 mmol) in methanol (5.0 mL) was added with 5 N aqueous sodium hydroxide (1.0 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, the residue was extracted with diethyl ether, and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 6-bromo-1H-pyrrolo[2,3-b]pyridine (0.028 g, 95%).
Reaction SMILES: N1CCCCC1.[C:7]([C:9]1[C:10](=[O:49])[NH:11][C:12](=[O:48])[N:13]([CH:47]=1)[C@@H:14]1[O:45][C@H:17]([CH2:18][O:19][C:20](=[O:44])[C@H:21]([C@H:40]([CH2:42][CH3:43])[CH3:41])[NH:22]C(OCC2C3CC4C(=CC=CC=4)C=3C=CC=2)=O)[C@@H:16]([F:46])[CH2:15]1)#[CH:8]>CN(C)C=O>[C:7]([C:9]1[C:10](=[O:49])[NH:11][C:12](=[O:48])[N:13]([CH:47]=1)[C@@H:14]1[O:45][C@H:17]([CH2:18][O:19][C:20](=[O:44])[C@H:21]([C@H:40]([CH2:42][CH3:43])[CH3:41])[NH2:22])[C@@H:16]([F:46])[CH2:15]1)#[CH:8]
Reactant: C#Cc1cn([C@H]2C[C@H](F)[C@@H](COC(=O)[C@@H](NC(=O)OCc3cccc4c3Cc3ccccc3-4)[C@@H](C)CC)O2)c(=O)[nH]c1=O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: C#Cc1cn([C@H]2C[C@H](F)[C@@H](COC(=O)[C@@H](N)[C@@H](C)CC)O2)c(=O)[nH]c1=O

Procedure:
A 20% solution of piperidine in dry dimethylformamide (5 ml) was added to 2',3'-dideoxy-5-ethynyl-5'-O-(N-fluorenylmethoxycarbonyl-L-isoleucinyl)-3'-fluorouridine (0.57 g, 0.96 mmol) and after 4 minutes at room temperature, the solvents were evaporated rapidly under high vacuum with minimal heating. Trituration of the residue with several portions of ether afforded a crop of the title compound containing ~5% of N,N'-dicyclohexylurea.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH2:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([CH2:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: CCc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-ethylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f50) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: N[C:2]1[C:10](Cl)=[CH:9][C:5]([C:6](O)=[O:7])=[C:4](OC)[CH:3]=1.C1N=C[N:16](C(N2C=NC=C2)=O)C=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:6]([NH2:16])(=[O:7])[C:5]1[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-amino-5-chloro-2-methoxybenzoic acid in freshly distilled DMF is added CDI (1 equivalent). After 1 hour at room temperature a solution of amine 35 (1 equivalent) in DMF is added. The reaction mixture is stirred at room temperature for 16 hours and concentrated in vacuo to give a residue which is treated with 15% potassium carbonate and extracted with chloroform (3X). The combined organic extracts are washed successively with water and brine and then dried over sodium sulfate. Concentration gives a solid which is purified on silica gel eluting with 7/93 MeOH(NH3)/chloroform to give the title compound 36 as a colorless solid.
Reaction SMILES: O=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=2[NH:3]1.P(Cl)(Cl)([Cl:17])=O>O>[Cl:17][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2[nH]c(=O)[nH]c2c1
Solvent: O
Product: COC(=O)c1ccc2nc(Cl)[nH]c2c1

Procedure:
Methyl 2-oxo-2,3-dihydro-1H-benzimidazole-6-carboxylate (43 g, 0.22 mol) was charged into Phosphorus oxychloride (286 ml). Dry hydrogen chloride was bubbled through the boiling reaction mass for 12 hours. After cooling reaction mass was poured in mixture of ice and water (2 kg). Precipitate was filtered out. Filtrate was diluted with water (1.25 l) and ammonia solution (˜800 ml). After that pH was adjusted to 5.6 with use of ammonia solution. Precipitate was filtered and rinsed with water. Yield 39.5 g (84%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=CN=1.[CH2:8]([O:10][C:11](=[O:14])[CH2:12]Br)C.C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[CH3:8][O:10][C:11](=[O:14])[CH2:12][C@@H:2]1[CH2:7][CH2:6][CH2:5][O:1]1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C[C@@H]1CCCO1
Temperature: 25 °C

Procedure:
A mixture of crude hydroxy-pyridine 22b (30.0 g, 0.151 mol), bromo-acetic acid ethyl ester (16.9 ml, 0.151 mol) and K2CO3 (41.7 g, 0.301 mol) in acetone (1000 mL) is heated to reflux for 5 h. The mixture is cooled to RT, poured into water (800 mL) and extracted with EtOAc (500 mL×2). The combined organic layers are washed with brine, dried (Na2SO4). The solvent is evaporated and the residue is purified by column to afford ester 22c.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[N-:11]=[N+:12]=[N-:13].[Na+].[Al+3].[Cl-].[Cl-].[Cl-]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:10])[NH:13][N:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C=Nc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]nnn1-c1ccc(Br)cc1

Procedure:
To a solution of 1-bromo-4-isocyanatobenzene (5.0 g, 25 mmol) and sodium azide (5.0 g, 77 mmol) in THF (30 mL) was added a solution of AlCl3 (4.0 g, 30 mmol) in THF (18 mL) dropwise. The reaction mixture was heated to reflux overnight. The organic solvent was removed under reduced pressure, then water (50 mL) was added. The solids formed were collected by filtration to obtain compound 53a as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C7H5BrN4O: 241.0 (M+H). Found 241.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[N:15](=[C:17]([C:27](=O)[CH3:28])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19])[OH:16]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:27]([CH3:28])[C:17](=[N:15][OH:16])[C:18]([NH:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:19]
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CC(=O)C(=NO)C(=O)Nc1ccccc1
Product: CC(=NNc1c(Cl)cc(C(F)(F)F)cc1Cl)C(=NO)C(=O)Nc1ccccc1

Procedure:
2,6-Dichloro-4-trifluoromethylphenylhydrazine was reacted with 2,3-dioxobutyranilide 2-oxime, in a similar manner to above to give 2,3-dioxobutyranilide 3-(2,6-dichloro-4-trifluoromethylphenylhydrazone) 2-oxime, m.p. 185°-186°. This was then treated with acetic anhydride in acetic acid to give 2,3-dioxobutyranilide 2-acetyloxime 3-(2,6-dichloro-4-trifluoromethylphenylhydrazone). This was cyclised with caesium carbonate to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-5-methyl-2H-1,2,3-triazole-4-carboxanilide, m.p. 185°-186°.
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[C:4]([CH2:18][CH3:19])([CH3:17])[O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:18]([C:4]1([CH3:17])[C:3](=[O:20])[C:2]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([CH3:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[O:5]1)[CH3:19]
Reactant: CCC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(Br)C1=O
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2ccccc2)C1=O
Yield: 30.2 %

Procedure:
To a stirred solution of 4-bromo-2-ethyl-2-methy-5-{4-(methysulfonyl)-phenyl}-3(2H)-furanone (200 mg) in 15 ml of toluene, were added 40 mg of tetrakis(triphenylphosphine)palladium(0), 5 ml of 2 M aqueous sodium carbonate solution, and 100 mg of benzeneboronic acid. The reaction solution was stirred at reflux for 12 hours. Then the reaction solvent was evaporated under reduced pressure. The resulting residue was extracted with water and dichloromethane (30 ml×3). The organic layer was concentrated in vacuo. The resulting crude product mixture was purified by column chromatography (hexane/ethylacetate=2:1) to give 60 mg of 2-ethyl-2-methyl-5-{4-(methylsulfonyl)phenyl}-4-phenyl-3(2H)-furanone as a solid. mp: 115-117° C. NMR: δ0.96 (t, J=7.5 Hz, 3H), 1.55 (s, 3H), 1.97 (q, J=7.5 Hz, 2H), 3.07 (s, 3H), 7.37 (m, 5H), 7.85 (d, J=8.7 Hz, 2H), 7.93 (d, J=8.7 Hz, 2H). IR (cm−1): 2928, 1697, 1620, 1403, 1318, 1149, 959, 769, 552.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:29])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH3:28])([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)[CH:9]=[CH:8]2)(=[O:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:4][C:5]1[C:6]([CH3:29])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[CH:23][CH:24]=1)([CH3:28])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)C=CC(C)(COc1ccc([N+](=O)[O-])cc1)O2
Agent: [Pd]
Solvent: CO
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc(N)cc1)O2

Procedure:
Following the procedure described in Preparation 58, 100 mg of 6-acetoxy-2,5,7,8-tetramethyl-2-(4-nitrophenoxymethyl)-2H-chromene (prepared as described in Preparation 49) were dissolved in 2 ml of methanol and, in the presence of 20 mg of 10% w/w palladium-on-carbon, the compound was reduced under 1 atmosphere (about 1 bar) pressure of hydrogen, to give the title compound melting at 138°-140° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:31])[CH2:3][CH:4]([C:17]1[CH:30]=[CH:29][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[CH:19][CH:18]=1)[NH:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2C.Br[C:33]1C=NC2C(C=1)=CC(C)=CC=2>>[CH3:31][CH:2]([CH3:1])[CH2:3][CH:4]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[CH:29][CH:30]=1)[NH:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([CH3:33])=[CH:11][CH:10]=2
Reactant: Cc1cccc2cc(NC(CC(C)C)c3ccc(C(=O)NCCC(=O)O)cc3)cnc12
Reactant: Cc1ccc2ncc(Br)cc2c1
Product: Cc1ccc2ncc(NC(CC(C)C)c3ccc(C(=O)NCCC(=O)O)cc3)cc2c1

Procedure:
Prepared analogous to 3-{4-[3-Methyl-1-(8-methyl-quinolin-3-ylamino)-butyl]-benzoylamino}-propionic acid, Example 25, using 3-bromo-6-methylquinoline. m/z (M+1)=420.2.
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:17][CH2:16][CH2:15][C:14]3[CH:18]=[CH:19][C:20]([C:22](=[O:31])[CH2:23][CH2:24][CH:25]4[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)=[CH:21][C:13]=3[CH2:12]2)=[CH:6][CH:5]=1.[Cl:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]Br>>[ClH:32].[ClH:1].[Cl:32][C:33]1[CH:34]=[C:35]([CH2:36][N:28]2[CH2:27][CH2:26][CH:25]([CH2:24][CH2:23][C:22]([C:20]3[CH:19]=[CH:18][C:14]4[CH2:15][CH2:16][CH2:17][N:11]([CH2:10][C:7]5[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=5)[CH2:12][C:13]=4[CH:21]=3)=[O:31])[CH2:30][CH2:29]2)[CH:38]=[CH:39][CH:40]=1
Reactant: Clc1cccc(CBr)c1
Reactant: O=C(CCC1CCNCC1)c1ccc2c(c1)CN(Cc1ccc(F)cc1)CCC2
Agent: Cl
Product: O=C(CCC1CCN(Cc2cccc(Cl)c2)CC1)c1ccc2c(c1)CN(Cc1ccc(F)cc1)CCC2

Procedure:
Using 1-[2-[(4-fluorophenyl)methyl]-2,3,4,5-tetrahydro-1H-2-benzazepin-8-yl]-3-(4-piperidinyl)-1-propanone(free base) obtained in Example 211, and 3-chlorobenzyl bromide, the procedure of Example 51-3 was otherewise repeated to provide the title compound as colorless amorphous powders.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH:9]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])(=[O:13])=[O:12])[CH2:8][N:7]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:25]=1)=[O:5])C.[OH-].[Li+]>>[CH3:33][S:30]([C:26]1[CH:25]=[C:24]([N:7]2[CH2:8][CH:9]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:20]([F:22])([F:23])[F:21])(=[O:12])=[O:13])[CH2:10][CH:6]2[C:4]([OH:5])=[O:3])[CH:29]=[CH:28][CH:27]=1)(=[O:31])=[O:32]
Reactant: CCOC(=O)C1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cccc(S(C)(=O)=O)c1
Agent: [Li+]
Agent: [OH-]
Product: CS(=O)(=O)c1cccc(N2CC(S(=O)(=O)c3ccccc3C(F)(F)F)CC2C(=O)O)c1

Procedure:
In analogy to the procedure described in example 253e, 1-(3-methanesulfonyl-phenyl)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid ethyl ester was saponified in the presence of lithium hydroxide to give the title compound as white solid which was used in the next step without further purification. MS (ESI): m/z=476.1 [M−H]−.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:32])[C:12]2[O:18][C:17]3[C:19]([Cl:28])=[CH:20][C:21]([NH:23][C:24](=[O:27])[CH2:25]Cl)=[CH:22][C:16]=3[CH2:15][S:14](=[O:30])(=[O:29])[C:13]=2[CH:31]=1)=[O:8]>CN(C=O)C>[CH3:5][O:6][C:7]([C:9]1[CH:10]=[C:11]([CH3:32])[C:12]2[O:18][C:17]3[C:19]([Cl:28])=[CH:20][C:21]([NH:23][C:24](=[O:27])[CH2:25][NH:4][CH:1]4[CH2:3][CH2:2]4)=[CH:22][C:16]=3[CH2:15][S:14](=[O:30])(=[O:29])[C:13]=2[CH:31]=1)=[O:8]
Reactant: NC1CC1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CCl)cc(Cl)c1O2
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NC(=O)CNC3CC3)cc(Cl)c1O2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Cyclopropyl amine (0.285 ml, 4.067 mmol) was added to a solution of Example 133 (0.6 g, 1.35 mmol) in DMF (15 mL) and the reaction mixture was stirred at 80° C. for 2 h. It was concentrated, treated with water and the solid that precipitated was filtered, washed with water and purified using flash chromatography (silica gel, 2% methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.58 g (92%); 1H NMR (CDCl3): δ 0.6 (s, 4H, 2CH2), 2.4 (m, 1H, CH), 2.67 (s, 3H, CH3), 3.6 (s, 2H, CH2), 3.9 (s, 3H, OCH3), 4.7 (s, 2H, CH2), 7.6 (s, 1H, Ar), 7.65 (s, 1H, Ar), 8.1 (s, 1H, Ar), 8.45 (s, 1H, Ar), 9.35 (bs, 1H, NH); MS: m/e (ES+) 465 (M+1).