Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:33])([Cl:32])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:31])[C@@H:14]([NH:16][C:17](=[O:30])[C@@H:18]([NH:22]C(OC(C)(C)C)=O)[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6].C[Si](OS(C(F)(F)F)(=O)=O)(C)C>ClCCl>[Cl:32][C:2]([Cl:1])([Cl:33])[CH2:3][O:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13](=[O:31])[C@@H:14]([NH:16][C:17](=[O:30])[C@@H:18]([NH2:22])[CH:19]([CH3:21])[CH3:20])[CH3:15])[NH:8]1)=[O:6]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)OCC(Cl)(Cl)Cl)N1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester (285.0 mg, 0.536 mmol) in dichloromethane (15 mL) at 0° C. was treated with trimethylsilyl-trifluoromethanesulfonate (200 μL, 1.072 mmol). After stirring at 0° C. for 45 min, the reaction was quenched with a saturated solution of sodium bicarbonate. The aqueous layer was extracted with dichloromethane. The combined organics were filtered through a phase separator and the volatiles were removed in vacuo to provide (S)-1-[(S)-2-((S)-2-amino-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid 2,2,2-trichloro-ethyl ester as a white solid. To the white solid was added a solution of (E)-4-[2-((R)-1-acetoxy-ethyl)-quinolin-7-yl]-2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-methyl-but-3-enoic acid (252.7 mg, 0.536 mmol) in anhydrous acetonitrile (10 mL) and the solution was cooled to 0° C. then treated with N,N-diisopropylethylamine (380 μL, 2.144 mmol) and 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate methanaminium (244.6 mg, 0.643 mmol). After stirring at room temperature for 20 h, the reaction was quenched with hydrochloric acid (1 M, 40 mL). The aqueous layer was extracted with ethyl acetate (2×). The organics were combined, washed with a saturated solution of sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 1:4 to provide the title compound (377.2 mg, 80%) as a 1:1 mixture of diastereosiomers and as a white foam. LCMS (m/z) 886.3/884.5 [M+H], Tr=4.14 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[CH:5][C:4]=1[OH:11])#[N:2].[H-].[Na+].Br[C:15]([CH3:19])([CH3:18])[CH:16]=[O:17].O>CN1C(=O)N(C)CCC1>[C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[CH:5][C:4]=1[O:11][C:15]([CH3:19])([CH3:18])[CH:16]=[O:17])#[N:2]
Reactant: CCc1ccc(O)c(C#N)c1
Reactant: CC(C)(Br)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: CCc1ccc(OC(C)(C)C=O)c(C#N)c1
Temperature: 4 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
2-Cyano-4-ethylphenol (1.47 g) was added portionwise to a stirred, ice-cooled suspension of sodium hydride (60% w/w dispersion in mineral oil, 420 mg) in DMPU (10 ml) under argon. Stirring was continued for 1 hour at ambient temperature, the mixture cooled to 4° C. and 2-bromo-2-methylpropanal (2.26 g) in DMPU (2 ml) added. Stirring was continued for 18 hours at ambient temperature. Water (50 ml) was added and the resulting mixture extracted with ether (3×50 ml). The combined extracts were washed with water (2×30 ml) and saturated brine (2×30 ml), then dried (MgSO4). Evaporation of the solvent and purification of the residual oil by flash chromatography, eluting with 20% v/v ethyl acetate in hexane, gave 2-(2-cyano-4-ethylphenoxy)-2-methylpropanal (2.04 g), as a colourless oil; NMR: 1.21 (3H, t, J=7 Hz), 1.51 (6H, s), 2.61 (2 H, q, J=7 Hz), 6.76(1H, d, J=7 Hz), 7.28 (1H, dd, J=7,2 Hz), 7.41 (1H, d, J=2 Hz), 9.85 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:11][CH3:12])=[N:4][C:5]([CH3:10])=[CH:6][C:7]=1[S:8][CH3:9].C(N(CC)CC)C.[Cl:20][CH2:21][C:22](Cl)=[O:23].O>O1CCCC1>[CH3:12][S:11][C:3]1[C:2]([NH:1][C:22](=[O:23])[CH2:21][Cl:20])=[C:7]([S:8][CH3:9])[CH:6]=[C:5]([CH3:10])[N:4]=1
Reactant: CSc1cc(C)nc(SC)c1N
Reactant: O=C(Cl)CCl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSc1cc(C)nc(SC)c1NC(=O)CCl
Reaction time: 10 h
Yield: 75 %

Procedure:
Part A. A solution of 3-amino-2,4-bis(methylthio)-6-methylpyridine (0.38 g,1.88 mmol) and triethylamine (0.30 mL, 2.07 mmol) in tetrahydrofuran (8 mL)was cooled to 0° C., and treated with a solution of chloroacetyl chloride (0.18 mL, 2.26 mmol) in tetrahydrofuran (4 mL). After being stirred for 10 hours, the mixture was poured into water (100 mL), and thiswas extracted with ethyl acetate (2×100 mL). The extracts were combined, dried over anhydrous sodium sulfate, filtered and evaporated. The resulting solid was recrystallized to purity from ether, mp 190°-192° C., to afford N-[2,4-bis(methylthio)-6-methyl-pyridin-3-yl]-2-chloroacetamide (0.39 g, 1.41 mmol, 75%). 1H NMR (CDCl3): δ 7.69 (1H, br s); 6.68 (1H, s); 4.26 (2H, s); 2.53 (3H, s); 2.51 (3H, s); 2.43 (3H, s). Mass spectrum (NH3 -CI/DDIP): m/z 279 (42%); 278 (17%); 277 (100%); 227 (4%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([I:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15].N1C=CN=C1>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]([I:12])[C:9]([O:13][Si:18]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1c(I)cc(Cl)c2cccnc12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1c(I)cc(Cl)c2cccnc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.8 %

Procedure:
A flame-dried, 50-mL, three-necked flask is charged with 5-chloro-8-hydroxy-7-iodoquinoline (2.814 g), which is commercially available, t-butyldimethylchlorosilane (1.76 g), and 10 mL of DMF. Imidazole (1.66 g) is added, and the resulting mixture is stirred at room temperature for 18 h. The reaction mixture is then quenched with 10 mL of saturated aqueous NaHCO3 and extracted with hexane three times. The combined organic layers are dried over MgSO4, filtered and concentrated to give 3.898 g of the title compound as a pale green solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:16]([OH:18])=O)=[N:7][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:9]=1)=[O:4].[C:19](N1C=CN=C1)([N:21]1C=CN=[CH:22]1)=O.CNC>CN(C=O)C>[CH3:19][N:21]([CH3:22])[C:16]([C:6]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:9][N:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:7]=1)=[O:18]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)c1nn(-c2ccccc2)nc1C(=O)O
Agent: CNC
Solvent: CN(C)C=O
Product: COC(=O)c1nn(-c2ccccc2)nc1C(=O)N(C)C
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
A solution of 5-methoxycarbonyl-2-phenyl-2H-1,2,3-triazole-4-carboxylic acid (0.203 g, 0.82 mmol) in dry DMF (3 mL) at 23° C. was treated with carbonyldiimidazole (0.146 g, 0.90 mmol). The resulting mixture was stirred for 1.5 h at 23° C., cooled to 0° C. and treated with dimethylamine (2.0 M, in THF, 2.05 mL, 4.10 mmol). The resulting mixture was allowed to warm to 23° C. over 16 h and concentrated in vacuo. The residue was partitioned between water and EtOAc. The aqueous layer was extracted with an additional portion of EtOAc. The combined organic extracts were washed with HCl (1 M), brine, NaHCO3 (sat. aq. sol.) and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by filtering it through a silica gel plug (EtOAc-hexanes 50:50) to afford 0.201 g (89%) of methyl 5-(N,N-dimethylcarbamoyl)-2-phenyl-2H-1,2,3-triazole-4-carboxylate.
Reaction SMILES: CS[C:3]1[N:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:6]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:5]2[N:4]=1.[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][NH2:25])=[CH:22][CH:21]=1>ClCCl>[C:11]([O:10][C:8]([N:7]1[C@H:6]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:5]2[N:4]=[C:3]1[NH:25][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([F:19])=[CH:21][CH:22]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CSC1=N[C@@H]2CCCC[C@@H]2N1C(=O)OC(C)(C)C
Reactant: NCc1ccc(F)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(NCc2ccc(F)cc2)=N[C@@H]2CCCC[C@@H]21
Temperature: 100 °C
Yield: 98.1 %

Procedure:
A mixture of intermediate 76 (200 mg, 0.0.740 mmol), 4-fluorobenzylamine (0.5 mL, 4.4 mmol) is heated at 100° C. (reaction block) overnight. The reaction mixture is cooled to RT. The reaction mixture is diluted with dichloromethane, washed with 0.1N HCl, and brine. The solvent is evaporated, and the residue triturated with EtOAc, and the insoluble material filtered to give 252 mg of the product 193. 1H NMR (CDCl3) δ 8.55 (s, 1H), 7.55-7.35 (m, 2H), 7.10-7.00 (m, 2H), 5.10-4.90 (m, 2H), 4.30-4.10 (m, 2H), 2.70-2.55 (m, 1H), 2.20-2.05 (m, 1H), 1.80-1.05 (m, 15H); MS: m/z 348 (M++1)
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH3:37])=[C:11]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][C@H:25]5[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]5)[CH:20]=4)[N:15]=[CH:14]3)[CH:12]=2)=[O:6])[CH2:3][CH2:2]1.Cl>O1CCOCC1>[CH:1]1([NH:4][C:5](=[O:6])[C:7]2[CH:8]=[CH:9][C:10]([CH3:37])=[C:11]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][C@H:25]5[CH2:29][CH2:28][NH:27][CH2:26]5)[CH:20]=4)[N:15]=[CH:14]3)[CH:12]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(O[C@H]3CCN(C(=O)OC(C)(C)C)C3)cc2c1=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(O[C@H]3CCNC3)cc2c1=O

Procedure:
Using an analogous procedure to that described paragraph (D) in the portion of Example 18 which is concerned with the preparation of starting materials tert-Butyl (3S)-3-[(3-{5-[(cyclopropylamino)carbonyl]-2-methylphenyl}-4-oxo-3,4-dihydroquinazolin-6-yl)oxy]pyrrolidine-1-carboxylate was reacted with 4N HCl in dioxane. There was thus obtained the title compound; NMR Spectrum: (DMSOd6) 0.54 (m, 2H), 0.68 (m, 2H), 1.80 (m, 1H), 2.04 (m, 1H), 2.11 (s, 3H), 2.84 (m, 4H), 3.08 (m, 2H), 4.98 (m, 1H), 7.48 (m, 3H), 7.71 (d, 1H), 7.81 (s, 1H), 7.89 (d, 1H), 8.16 (s, 1H), 8.42 (d, 1H); Mass Spectrum: M+H+ 405.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=CC(O)=C[CH:5]=1.N[C@H](C(O)=O)CCCCN>>[NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][CH:4]([CH3:9])[CH3:5]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: NCCCC[C@H](N)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
6.44 (6), Tyr; 0.96 (1), Lys; 2.96 (3),
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]1[C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=[N:9]1.[Cl:16][C:17]1[C:18]([NH2:24])=[N:19][C:20]([NH2:23])=[CH:21][N:22]=1>ClCCl.CN(C)C=O>[NH2:24][C:18]1[N:19]=[C:20]([NH:23][C:13]([C:12]2[N:8]([CH3:7])[N:9]=[CH:10][CH:11]=2)=[O:15])[CH:21]=[N:22][C:17]=1[Cl:16]
Reactant: Nc1cnc(Cl)c(N)n1
Reactant: Cn1nccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1nccc1C(=O)Nc1cnc(Cl)c(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 35.7 %

Procedure:
Oxalyl chloride (0.288 ml, 3.32 mmol) was added to a suspension of 1-methyl-1H-pyrazole-5-carboxylic acid (0.279 g, 2.21 mmol) in dichloromethane (5 ml) followed by 1 drop of dimethylformamide. The mixture was stirred at room temperature for 4 hours before concentrating in vacuo and azeotroping with dichloromethane. The residue was taken up in pyridine (1 ml) and added to a solution of 3-chloro-pyrazine-2,6-diamine (Preparation 1) (0.16 g, 1.11 mmol) and the mixture heated at 60° C. for 3 hours before cooling to room temperature and concentrating in vacuo. The residue was purified by silica gel column chromatography, eluting with ethylacetate:heptane 1:1, to afford the product as a pale solid (100 mg).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:10][O:11][CH2:12][CH2:13][O:14][C:15](Cl)=[O:16].O>[OH-].[Na+]>[CH3:10][O:11][CH2:12][CH2:13][O:14][C:15]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:16]
Reactant: CC(C)C[C@H](N)C(=O)O
Reactant: COCCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCOC(=O)N[C@@H](CC(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.5 %

Procedure:
L-Leucine (25 g, 0.19 mol) was dissolved in a 2M aqueous sodium hydroxide solution (0.12 L), to which chloroformic acid 2-methoxyethyl ester (30 g, 0.22 mol) and a 1M aqueous sodium hydroxide solution were simultaneously and slowly added under ice-cold conditions. This solution was stirred at room temperature for 18 hours, followed by dilution with water (600 mL) and washing with diethyl ether (2×200 mL). The aqueous layer was cooled in an ice bath, and the pH was adjusted to 3 with 6M hydrochloric acid. This solution was extracted with ethyl acetate (5×150 mL). The organic layer was dehydrated with anhydrous magnesium sulfate and concentrated in vacuo to yield N-((2-methoxyethoxy)carbonyl)-L-leucine (41 g, 92%) as a colorless oil.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(O)=O.[Br:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>O1CCCC1>[Br:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][CH:5]=[O:7]
Reactant: Nc1ccccc1Br
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Solvent: C1CCOC1
Product: O=CNc1ccccc1Br
Temperature: 25 °C
Yield: 83.8 %

Procedure:
To acetic anhydride (74.2 g, 727 mmol) was added formic acid (32.9 mL, 872 mmol) under a nitrogen atmosphere while stirring at room temperature, followed by stirring at 70° C. for 3 hours. The reaction mixture was allowed to cool down to room temperature, and tetrahydrofuran (50 mL) was added. To the solution was added a solution of 2-bromoaniline (50.0 g, 291 mmol) in tetrahydrofuran (50 mL) at room temperature, followed by stirring at the same temperature for 1 hour, and concentration was carried out. To the resultant crude crystals was added ethanol (200 mL), followed by heating and stirring at 60° C. After the crystals dissolved, the mixture was allowed to cool down to room temperature, then water (400 mL) was added, followed by stirring for 3 hours. The precipitated crystals were collected by filtration to give 48.8 g of the title compound as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[C:54]([NH:57][C:58]1[S:59][CH:60]=[C:61]([C:63]2[CH:68]=[CH:67][C:66]([S:69](Cl)(=[O:71])=[O:70])=[CH:65][CH:64]=2)[N:62]=1)(=[O:56])[CH3:55]>>[CH3:1][O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([CH:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][N:24]1[S:69]([C:66]1[CH:67]=[CH:68][C:63]([C:61]2[N:62]=[C:58]([NH:57][C:54](=[O:56])[CH3:55])[S:59][CH:60]=2)=[CH:64][CH:65]=1)(=[O:71])=[O:70])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Reactant: CC(=O)Nc1nc(-c2ccc(S(=O)(=O)Cl)cc2)cs1
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1S(=O)(=O)c1ccc(-c2csc(NC(C)=O)n2)cc1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3

Procedure:
(S)-3-(4′-Cyano-biphenyl-4-yl)-2-({(S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-propionic acid methyl ester was treated with 4-(2-acetylamino-thiazol-4-yl)-benzenesulfonyl chloride according to General Procedure E to give (S)-2-({(S)-7-[4-(2-acetylamino-thiazol-4-yl)-benzenesulfonyl]-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[CH:9][N:8]([CH2:11][C:12]2[O:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=2)[N:7]=1)([O-:5])=[O:4].[CH3:19][Mg]Br>C1COCC1.[NH4+].[Cl-]>[N+:3]([C:6]1[CH:10]=[CH:9][N:8]([CH2:11][C:12]2[O:16][C:15]([CH:17]([OH:18])[CH3:19])=[CH:14][CH:13]=2)[N:7]=1)([O-:5])=[O:4].[N+:3]([C:6]1[CH:10]=[CH:9][N:8]([CH2:11][C:12]2[O:16][C:15]([CH:17]=[O:18])=[CH:14][CH:13]=2)[N:7]=1)([O-:5])=[O:4]
Reactant: C[Mg]Br
Agent: N#N
Agent: O=Cc1ccc(Cn2ccc([N+](=O)[O-])n2)o1
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(O)c1ccc(Cn2ccc([N+](=O)[O-])n2)o1
Temperature: -78 °C
Reaction time: 4 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(3-nitro-pyrazol-1-ylmethyl)-furan-2-carbaldehyde (10.50 g, 47.47 mmol) in THF (479.2 mL) was treated at −78° C. with methylmagnesium bromide (47.47 mL of a 1M solution in THF, 47.47 mmol). The reaction mixture was stirred at −78° C. for 4 h. It was then poured in sat. aq. NH4Cl (450 mL). The aq. phase was extracted with EA (2×500 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound as a mixture with 5-(3-nitro-pyrazol-1-ylmethyl)-furan-2-carbaldehyde. TLC: rf (50:50 hept-EA)=0.24. LC-MS-conditions 02: tR=0.78 min. 1H NMR (400 MHz, CDCl3) characteristic signals 81.53 (d, J=6.5 Hz, 3H), 2.15-2.24 (m, 1H), 4.81-4.91 (m, 1H), 5.35 (s, 2H), 6.24 (d, J=3.0 Hz, 1H), 6.43 (d, J=3.3 Hz, 1H), 6.89 (d, J=2.3 Hz, 1H), 7.49 (d, J=2.5 Hz, 1H).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19](Br)=[CH:20][CH:21]=2)[CH:16]=[C:15]1[C:24]([OH:26])=[O:25])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1B(O)O>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)=[CH:20][CH:21]=2)[CH:16]=[C:15]1[C:24]([OH:26])=[O:25])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2cc(Br)ccc2n1C(c1ccccc1)c1ccccc1
Reactant: OB(O)c1cccs1
Product: O=C(O)c1cc2cc(-c3cccs3)ccc2n1C(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in Example 109 except that 1-benzhydryl-5-bromo-1H-indole-2-carboxylic acid and 2-thiopheneboronic acid were used.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12.[CH3:12][O:13][CH2:14][CH2:15][NH2:16]>>[CH3:12][O:13][CH2:14][CH2:15][NH:16][N:11]1[C:3]2[C:4](=[N:5][C:6]([CH3:8])=[CH:7][CH:2]=2)[CH:9]=[N:10]1
Reactant: Cc1cc(Cl)c2[nH]ncc2n1
Reactant: COCCN
Product: COCCNn1ncc2nc(C)ccc21

Procedure:
7-Chloro-5-methyl-1H-pyrazolo[4,3-b]pyridine (D4) (1 g, 0.06 mole) was heated at reflux under nitrogen in methoxyethylamine for 1 week. Volatile material was removed under vacuum and the residue treated with water (15 ml) and a little methanol. A small amount of insoluble material was filtered off and the filtrate reevaporated to dryness. Chromatography on basic alumina eluting with ethyl acetate with methanol added to a maximum of 15% gave white gum. This was further purified by passing through Dowex 50W column, previously treated with dilute HCl, eluting initially with methanol, then water and finally 5% 0.880 ammonia in water. The fractions containing UV active material were freeze dried giving the title compound as a white solid (0.38 g,31%) m.p. 167°-170° (Found: C, 57.18; H, 6.84; N, 27.06 C10H14N4O.O.2H2O requires C,57.23; H, 6.90; N, 26.70%), δ(DMSOd-6) 2.4 (3H,s), 3.2-3.7 (4H,m), 6.25 (1H,s), 6.35 (1H,br.s), 7.9 (1H,s).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([CH:20]=[O:21])C>>[C:1]([O:21][CH:20]=[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=2)[NH:12][C:11]1=[O:16])([CH3:7])([CH3:6])[CH3:2]
Reactant: CN(C)C=O
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Product: CC(C)(C)OC=C1C(=O)Nc2ccc(-c3ccccc3)cc21
Yield: 10 %

Procedure:
A solution of 0.62 g (3.0 mmol) of 5-phenyl-1,3-dihydro-indol-2-one (Hewawasam and Meanwell, Tetrahedron Letters 1994, 35, 7303-6) in 10 mL of DMF was treated with 0.90 g (4.5 mmol) of DMF di-tert-butyl acetal for 2 h at rt. DMF was removed under high vaccum, and the residue was subjected to chromatography on silica gel, eluting with hexane:EtOAc (1:1), to yield 0.09 g (10%) of 3-tert-butoxymethylene-5-phenyl-1,3-dihydro-indol-2-one: 1H NMR (DMSO-d6): δ 1.46 (s, 9H), 6.85 (d, J=8.0 Hz, 1H), 7.27 (t, J=7.3 Hz, 1H), 7.34-7.39 (m, 1H), 7.41 (d, J 7.5 Hz, 2H), 7.53 (d, J=7.5 Hz, 2H), 7.72 (s, 1H), 7.83 (s, 1H), 10.28 (s, 1H); APCI+MS m/z 316 (M+23)+. Further elution with EtOAc:MeOH (98:2) gave 0.11 g (14%) of 3-dimethylaminomethylene-5-phenyl-1,3-dihydro-indol-2-one.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:10]2=[O:38])[O:5][N:4]=1)[CH3:2].[ClH:39].C(OCC)C>C(Cl)Cl.O1CCOCC1>[ClH:39].[CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]2=[O:38])[O:5][N:4]=1)[CH3:2]
Reactant: CCc1cc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)on1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCc1cc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)on1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of tert-butyl 4-{1-[(3-ethylisoxazol-5-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (820 mg; compound B3) in DCM (20 ml) is added a solution of hydrogen chloride in 1,4-dioxane (3 ml, 4.0 M). The reaction mixture is stirred for 1 d at RT. Diethyl ether is added and the resulting precipitate is filtered off, washed with diethyl ether and dried in vacuo to afford the title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]([NH:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[CH:20]2)=[O:15].C([Sn](CCCC)(CCCC)[C:31]1[S:32][CH:33]=[CH:34][N:35]=1)CCC>>[NH:22]1[C:23]2[C:19](=[CH:18][C:17]([NH:16][C:14](=[O:15])/[CH:13]=[CH:12]/[C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=3[C:31]3[S:32][CH:33]=[CH:34][N:35]=3)=[CH:25][CH:24]=2)[CH:20]=[CH:21]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: O=C(/C=C/c1ccc(C(F)(F)F)cc1Br)Nc1ccc2[nH]ccc2c1
Product: O=C(/C=C/c1ccc(C(F)(F)F)cc1-c1nccs1)Nc1ccc2[nH]ccc2c1

Procedure:
Analogous to the procedure used to prepare Example 100, (2E)-3-[2-bromo-4-(trifluoromethyl)phenyl]-N-indol-5-ylprop-2-enamide, Example 97, (100 mg, 0.24 mmol) and 2-tributylstannylthiazole (155 mg, 0.42 mmol, Frontier Scientific) provided, after purification by silica gel chromatography (gradient: 0-35%EtOAc in hexane), the title product as an orange solid. MP 203-204° C. MS (ESI, pos. ion) m/z: 414 (M+1).