Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:12][OH:13])[CH:7]=[C:8]([CH2:10][OH:11])[CH:9]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH2:12][OH:13])[CH:7]=[C:8]([CH2:10][OH:11])[CH:9]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(CO)cc(CO)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cc(CO)cc(CO)c1
Reaction time: 5 h

Procedure:
To a solution of 5-Nitro-m-xylene-α,α′-diol (890 mg, 5.4 mmol) in methanol (50 mL) was added Pd/C (10%, 287 mg). A hydrogen atmosphere was introduced and the mixture was hydrogenated under pressure (H2, 5˜8 psi) for 5 hours at room temperature. The solution was filtered through celite and the filtrate was evaporated by rotary evaporation in vacuo to give 5-amino-m-xylene-α,α′-diol, which was then dissolved in THF (10 mL)/DMF (15 ml). 4-methyldithio-4,4-dimethyl butanoic acid (1.05 g, 5.4 mmol) dissolved in THF (5 ml) was added at room temperature followed by the addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.1 g, 10.8 mmol) and 4-dimethylamino pyridine (66 mg, 0.54 mmol). The obtained mixture was stirred at room temperature overnight then quenched with 10% ammonium chloride, extracted with ethylacetate, washed and dried. It was filtered and the solvents were removed by rotary evaporation in vacuo. The residue was purified by flash chromatography (CH2Cl2/MeOH, 15:1, 10:1, 7:1) to furnish 5-(N-4-methyldithio-4,4-dimethylbutanoyl)-amino-1,3-bis-(hydroxymethyl)-benzene as a white solid (729 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13](=[O:16])[CH2:14]Cl)[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1>>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13]([CH2:14][N:27]2[CH2:26][CH2:25][N:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([Cl:17])[CH:19]=3)[CH2:29][CH2:28]2)=[O:16])[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1cc(NC(=O)CCl)c(OC)nc1C
Reactant: Clc1cccc(N2CCNCC2)c1
Product: CCc1cc(NC(=O)CN2CCN(c3cccc(Cl)c3)CC2)c(OC)nc1C
Yield: 68 %

Procedure:
N-(5-ethyl-2-methoxy-6-methylpyridine -3-yl)chloroacetamide and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 69 to obtain the titled compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12].[CH:17](O[Na])=[O:18]>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:17]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])=[O:18]
Reactant: CON(C)C(=O)c1n[nH]c2ccc(I)cc12
Reactant: O=CO[Na]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1n[nH]c2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 15.6 %

Procedure:
A mixture of 5-iodo-N-methoxy-N-methyl-1H-indazole-3-carboxamide (5 g, 15.1 mmol), HCOONa (1.85 g, 30.2 mmol), and PdCl2(PPh3)2 (320 mg, 0.453 mmol) in DMF (20 mL) was put under vacuum, and charged with CO. This process was repeated three times, and the mixture was kept at 110° C. for 6 hr. After cooling to rt, the reaction mixture was diluted with brine and extracted with EtOAc. The organic phases were combined, washed with brine, dried, and concentrated. The crude product was purified by column chromatography to afford 5-formyl-N-methoxy-N-methyl-1H-indazole-3-carboxamide (550 mg, 15.6%) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9].[CH2:21]([C:28]1[C:33]([I:34])=[CH:32][CH:31]=[C:30]([N:35]2[CH2:39][C@H:38]([O:40][CH3:41])[C@@H:37]([OH:42])[CH2:36]2)[N:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:21]([C:28]1[C:33]([I:34])=[CH:32][CH:31]=[C:30]([N:35]2[CH2:39][C@H:38]([O:40][CH3:41])[C@@H:37]([O:42][S:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=3)(=[O:18])=[O:19])[CH2:36]2)[N:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@@H]1O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@@H]1OS(=O)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100.6 %

Procedure:
300 mg of 4-dimethylaminopyridine, 10 ml of triethylamine and 9.7 g of 3-nitrobenzenesulfonyl chloride were added to a solution of 10.0 g of 2-benzyl-3-iodo-6-[(3S,4S)-3-hydroxy-4-methoxypyrrolidine-1-yl]pyridine obtained in the same manner as in Example 10-c in 150 ml of ethyl acetate, followed by stirring at room temperature for 3 days. The reaction solution was first filtered through 50 g of silica gel, and washed with ethyl acetate. Further, the filtrate was filtered through 50 g of NH-silica gel and washed with ethyl acetate. The filtrate was concentrated, to give 14.6 g of the target compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([CH3:35])=[CH:29][C:30]([CH3:34])=[N:31]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:34][C:30]1[CH:29]=[C:28]([CH3:35])[C:27]2[C:32](=[CH:33][C:24]([O:23][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:25][CH:26]=2)[N:31]=1
Reactant: Cc1cc(C)c2ccc(O)cc2n1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4c(C)cc(C)nc4c3)ncnc2cc1OCCCN1CCCC1
Temperature: 90 °C
Yield: 35.2 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (100 mg, 0.31 mmol), (prepared as described for the starting material in Example 9), and 7-hydroxy-2,4-dimethylquinoline (64 mg, 0.36 mmol), (Chem. Berichte, 1903, 36, 4016), in DMF (3 ml) containing potassium carbonate (86 mg, 0.62 mmol) was heated at 90° C. for 3 hours. After cooling, the mixture was poured onto a column of silica and eluted with 2.5M ammonia in methanol/methylene chloride (5/95) to give 4-(2,4-dimethylquinolin-7-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (50 mg, 35%).
Reaction SMILES: [NH2:1][C@@:2]([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=2)=[N:9][N:10]=1)([CH3:5])[CH2:3][OH:4].C([O:32][P:33](Cl)([O:35]CC)=[O:34])C.C(N(CC)CC)C.Br[Si](C)(C)C>C(Cl)Cl>[P:33]([OH:35])([OH:34])([O:4][CH2:3][C@:2]([NH2:1])([C:6]1[S:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[C:13]([C:26]([F:28])([F:27])[F:29])[CH:12]=2)=[N:9][N:10]=1)[CH3:5])=[O:32]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCCCCCCCOc1ccc(-c2nnc([C@@](C)(N)CO)s2)cc1C(F)(F)F
Agent: C[Si](C)(C)Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCOc1ccc(-c2nnc([C@@](C)(N)COP(=O)(O)O)s2)cc1C(F)(F)F
Reaction time: 36 h
Yield: 5.7 %

Procedure:
Crude product from E3 (30 mg, 0.069 mmol) was added to diethylchlorophosphate (100 μL, 0.69 mmol) and triethylamine (194 μL, 1.39 mmol,) in DCM and stirred for approx 36 hrs. The reaction mixture was then condensed and treated with bromotrimethylsilan (0.3 mL) in DCM (5 mL) to provide the title compound (˜2 mg). MS (ESI): 511.98 (MH+),
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31](C3CC(=O)N(O)C3=O)=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.O>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([NH:1][CH:2]([C:7]3[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=3)[CH2:3][C:4]([OH:6])=[O:5])=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)C1CC(=O)N(O)C1=O
Reactant: NC(CC(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CC(NC(=O)OCC1c2ccccc2-c2ccccc21)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.6 %

Procedure:
A cold (0°) solution of 3-amino-3-(4-nitrophenyl)propanoic acid (3.2 g, 15 mmol) in 10% aqueous sodium carbonate (60 ml) and 1,4-dioxan (30 ml) was treated portion-wise with 9-fluorenylmethoxycarbonyl-N-hydroxysuccinimide (5.6 g, 17 mmol) in 1,4-dioxan (15 ml) and the mixture stirred at room temperature for 12 h. The mixture was poured into water (300 ml) and the aqueous phase washed 3 times with ether. The aqueous layer was then acidified with solid citric acid and extracted into ether. The combined organic layers were dried (MgSO4) and evaporated to a yellow oil then triturated from hexane and EtOAc to afford the title compound as a yellow solid (2.83 g); m/z (ES+, 70V) 432 (MH+).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH:24]([O:27][C:28]1[C:29]([O:43][CH3:44])=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)([CH3:26])[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][C:29]([O:43][CH3:44])=[C:28]([O:27][CH:24]([CH3:25])[CH3:26])[CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1OC(C)C
Product: COc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2C)c(=O)n4C)cc1OC(C)C

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-isopropoxy-2-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 93.1.1) to give the title compound as a white solid. (HPLC: tR 2.73 min (Method A); M+H=459 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.96 (s, 1H), 8.11-8.07 (m, 2H), 7.97-7.93 (m, 1H), 7.92-7.90 (m, 1H), 7.53-7.51 (m, 1H), 7.23-7.21 (m, 1H), 4.70 (hp, 2H), 3.89 (s, 3H), 3.89 (s, 3H), 3.58 (s, 3H), 1.98 (s, 3H), 1.36-1.30 (m, 6H))
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[N+:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)([O-:12])=[O:11].Cl.C1COCC1>O>[Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH:9][C:17](=[O:18])[C:16]2[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(NNc1ccc(Cl)nn1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (6-chloropyridazin-3-yl)hydrazine, 4-nitrobenzoic acid, WSCD hydrochloride and THF was stirred at room temperature for 2 hours. The reaction solution was combined with water, and the precipitate was collected by filtration, washed with water and diethyl ether to obtain N′-(6-chloropyridazin-3-yl)-4-nitrobenzohydrazide. To this, acetic acid was added, and the mixture was stirred at 110° C. for 2 hours, the reaction solution was concentrated under reduced pressure, and the resultant crude crystal was washed with ethanol to obtain 6-chloro-3-(4-nitrophenyl)-1,2,4-triazolo[4,3-b]pyridazine. Dat (F:276).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[Cl:26])=[C:16]([C:27]([O:29]CC)=O)[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[Cl:26])=[C:16]([C:27]([N:42]3[CH2:43][CH2:44][CH:39]([C:36]4[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=4)[CH2:40][CH2:41]3)=[O:29])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1cccc(Cl)c1Cl
Product: CC(C)(C)NS(=O)(=O)c1cnn2c(Nc3cccc(Cl)c3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 77.8 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(2,3-dichlorophenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (4.56 g, 9.38 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (2.31 g, 12.9 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (4.52 g, 85%) was obtained.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=O.[CH3:24][NH:25][CH3:26].O>CCO>[CH3:24][N:25]([CH3:26])[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:2]
Reactant: CNC
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Solvent: O
Solvent: CCO
Product: CN(C)C(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 80 °C
Yield: 28.5 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (40 mg, 0.13 mmol) and dimethylamine (0.23 mL, 1.3 mmol, 5.6 M in EtOH) in 2 mL of EtOH was heated in a sealed tube at 80° C. for 4 h. After cooling to r.t., water (3 mL) was added. The resulting suspension was filtered dried under high vacuum to afford a crude solid, which was purified by silica gel chromatography (5-40% EtOAc/hexanes+2% AcOH) to give 12 mg of the title compound. MS: (+) m/z 324.03 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20])[OH:12]
Reactant: Fc1ccccc1Br
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Product: O=C1Nc2ccc(Cl)cc2C1(O)c1ccccc1F
Yield: 70.8 %

Procedure:
With 5.00 g of 5-chloroisatin and 6.92 g of 1-bromo-2-fluorobenzene as starting materials, 5.41 g of the title compound (yellow solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:30][C:31](=[O:34])[CH2:32][CH3:33]>C(Cl)Cl>[O:34]=[C:31]([CH2:32][CH3:33])[CH2:30][S:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CCC(=O)CBr
Reactant: Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)CSc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Temperature: 25 °C

Procedure:
To an ice bath cooled solution containing 1.0 g (3.4 mmole) of 2-(4-mercaptophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a]imidazole prepared as in Example 16 and 0.5 ml (3.6 mmole) of triethylamine in 10 ml of methylene chloride is added 0.36 ml (3.5 mmole) of 1-bromo-2-butanone. The reaction is allowed to warm to room temperature and stirred at room temperature for several hours. Workup and chromatography in a manner analogous to that outlined in Example 18 affords the desired titled compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:17]1([C:23]2[O:27][CH:26]=[N:25][C:24]=2[C:28](O)=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][S:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[N:15]=[C:14]([NH:16][C:28]([C:24]3[N:25]=[CH:26][O:27][C:23]=3[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[O:29])[CH:13]=[N:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CS(=O)(=O)c1ccc(Cn2ncc(N)n2)o1
Product: CS(=O)(=O)c1ccc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)o1

Procedure:
Following general procedure A, starting from 2-(5-methanesulfonyl-furan-2-ylmethyl)-2H-[1,2,3]triazol-4-ylamine and 5-phenyl-oxazole-4-carboxylic acid.
Reaction SMILES: O=[C:2]([CH2:6][CH3:7])[CH2:3][C:4]#[N:5].[C:8]1([NH:14][NH2:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)C>[CH2:6]([C:2]1[CH:3]=[C:4]([NH2:5])[N:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:15]=1)[CH3:7]
Reactant: NNc1ccccc1
Reactant: CCC(=O)CC#N
Solvent: CCO
Product: CCc1cc(N)n(-c2ccccc2)n1
Temperature: 90 °C
Yield: 37.4 %

Procedure:
A stirred mixture of 3-oxopentanenitrile (19.42 g, 0.20 mol) and phenylhydrazine (23.62 g, 0.20 mol) in ethanol (200 mL) was heated at 90° C. for 15 h. The reaction mixture was quenched with water and extracted with dichloromethane. The combined dichloromethane layers were dried over magnesium sulfate, concentrated under reduced pressure, and dried under vacuum to afford the light yellow oil which was purified by silica gel flash column chromatography (eluting with a mixture of 20% ethyl acetate in petroleum ether). The obtained solid was recrystallized from a mixture of 10% petroleum ether in ethyl acetate, to afford 3-ethyl-1-phenyl-1H-pyrazol-5-amine (14 g, 37% over two steps) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ7.57-7.59 (m, 2H), 7.43-7.46 (m, 2H), 7.27 (m, 1H), 5.36 (s, 1H), 5.26 (s, 2H), 2.45 (q, J=7.6 Hz, 2H), 1.15 (t, J=7.6 Hz, 3H); LC-MS (ESI) m/z 188 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]([F:13])([F:12])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[CH2:10][NH2:11].CCN(C(C)C)C(C)C.Cl[C:24]1[N:29]=[C:28]([Cl:30])[C:27]([C:31]#[N:32])=[CH:26][N:25]=1>CN(C=O)C>[Cl:30][C:28]1[C:27]([C:31]#[N:32])=[CH:26][N:25]=[C:24]([NH:11][CH2:10][C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:4]=2[C:3]([F:12])([F:2])[F:13])[N:29]=1
Reactant: N#Cc1cnc(Cl)nc1Cl
Reactant: NCc1cnccc1C(F)(F)F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cnc(NCc2cnccc2C(F)(F)F)nc1Cl
Reaction time: 0.17 h
Yield: 43 %

Procedure:
To (4-(trifluoromethyl)pyridin-3-yl)methanamine hydrochloride (1.0 equiv.) in DMF (1.0 M) was added DIEA (2.5 equiv.). The reaction was cooled to −20° C. (ice/brine bath) then added 2,4-dichloropyrimidine-5-carbonitrile (1.0 equiv.). The reaction mixture was stirred for 10 min, then removed from the ice bath and allowed to stir for 30 min. The reaction mixture was diluted with ethyl acetate and partitioned with water. The organic layer was separated and volatile solvents were removed under reduced pressure. The residue was purified using silica gel chromatography (5-50% ethyl acetate in hexanes). The desired fractions were combined and volatile solvents were removed under reduced pressure. The residue was triturated in 10% ethyl acetate in hexanes, filtered, washed with hexanes, and dried in vacuo to afford 4-chloro-2-(((4-(trifluoromethyl)pyridin-3-yl)methyl)amino)pyrimidine-5-carbonitrile (43.0% yield) as a pale tan solid; MS (ESI) m/z 314.0 [M+1]+
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4].[CH2:21]([O:23][P:24]([O:28]CC)[O:25][CH2:26][CH3:27])[CH3:22]>>[CH2:21]([O:23][P:24]([CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4])([O:25][CH2:26][CH3:27])=[O:28])[CH3:22]
Reactant: O=C1Nc2ccccc2N(C(=O)CBr)c2ccccc21
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(CC(=O)N1c2ccccc2NC(=O)c2ccccc21)OCC
Temperature: 120 °C
Yield: 95 %

Procedure:
A mixture of 143 g (0.43 mol) of 5-bromoacetyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and 400 ml of triethylphosphite was refluxed for 2 hours at 120° C., with stirring. In the course of the reaction, the 5-bromoacetyl compound went fully into solution and a grey precipitate began to settle out. After cooling, this was suction filtered and washed with ethyl acetate and 159 g (95% of theory) of 5-diethylphosphonoacetyl-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one were obtained; m.p. 195°-197° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:25]1([N:30]2[CH2:40][C:39]([CH3:42])([CH3:41])[C:38](=[O:43])[N:37]([CH3:44])[C:36]3[C:31]2=[N:32][C:33]([NH:45][C:46]2[CH:54]=[CH:53][C:49]([C:50]([OH:52])=O)=[CH:48][C:47]=2[O:55][CH3:56])=[N:34][CH:35]=3)[CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.Cl.Cl.[NH2:68][CH:69]1[CH2:74][CH2:73][CH2:72][N:71]([CH3:75])[CH2:70]1>CC(N(C)C)=O>[CH:25]1([N:30]2[CH2:40][C:39]([CH3:41])([CH3:42])[C:38](=[O:43])[N:37]([CH3:44])[C:36]3[C:31]2=[N:32][C:33]([NH:45][C:46]2[CH:54]=[CH:53][C:49]([C:50]([NH:68][CH:69]4[CH2:74][CH2:73][CH2:72][N:71]([CH3:75])[CH2:70]4)=[O:52])=[CH:48][C:47]=2[O:55][CH3:56])=[N:34][CH:35]=3)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CN1CCCC(N)C1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(C(=O)NC2CCCN(C)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.4 %

Procedure:
A solution of HATU (126 mg, 0.33 mmol) in DMA (5 mL) was added to a mixture of the 4-[(2-cyclopentyl-4,4,6-trimethyl-5-oxo-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-10-yl)amino]-3-methoxy-benzoic acid (Example 242 132 mg, 0.3 mmol), DIPEA (261 uL, 1.5 mmol) and 3-amino N-methylpiperidine dihydrochloride (71 mg, 0.375 mmol) in DMA (5 mL). The resulting mixture was stirred at room temperature for 2 hours, then partially purified by SCX. The compound was eluted from the SCX column using 7N ammonia in methanol, then concentrated in vacuo, and further purified by column chromatography, eluting with 0-10% ammonia (7N in methanol) in DCM. The pure material was recovered as an orange oil, which foamed and solidified under high vacuum. Trituration under ether gave the title compound as a pale yellow amorphous solid (65 mg, 41%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.C(N(CC)CC)C.[Cl:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[Cl:22][C:23]1[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=1[S:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:12])([CH3:13])[C:6]=2[CH:14]=1)(=[O:32])=[O:31]
Reactant: CC1(C)OC(=O)Nc2ccc(N)cc21
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OC(=O)Nc2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)cc21
Reaction time: 0.17 h
Yield: 8.3 %

Procedure:
To a stirred solution of 6-amino-4,4-dimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (0.05 g, 0.24 mmol) in methylene chloride (2 mL) at 0° C. was added triethylamine (0.05 mL, 0.36 mmol). After 10 minutes, 2,3-dichlorobenzenesulfonyl chloride (0.06 g, 0.24 mmol) was added. The solution was stirred for 2 hours, then partitioned between ammonium chloride solution (sat.) and methylene chloride. The organic layer was dried over magnesium sulfate and concentrated. Flash silica gel column separation with 50% ethyl acetate/hexane followed by trituration with ether gave 2,3-dichloro-N-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)benzenesulfonamide as a white solid (0.008 g, 8%). 1H NMR (DMSO-d6): δ 10.57 (s, 1H), 10.16 (s, 1H), 7.97 (dd, J=7.9, 1.3 Hz, 1H), 7.92 (dd, J=8.0, 1.3 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 6.93 (m, 2H), 6.74 (d, J=8.4 Hz, 1H), 1.46 (s, 6H). MS (ESI) m/z 401/403/405 ([M+H]+); MS (ESI) m/z 399/401/403 ([M−H]−).