Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH:16][C:17]([CH:19]4[O:24][CH2:23][CH2:22][NH:21][CH2:20]4)=[O:18])[CH:14]=3)[NH:9][N:8]=2)=[CH:3][CH:2]=1.[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Na]>C(O)(=O)C.ClCCl>[F:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][N:21]1[CH2:22][CH2:23][O:24][CH:19]([C:17]([NH:16][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[NH:9][N:8]=[C:7]3[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[O:18])[CH2:20]1
Reactant: O=Cc1ccccc1F
Reactant: O=C(Nc1ccc2[nH]nc(-c3ccncc3)c2c1)C1CNCCO1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(Nc1ccc2[nH]nc(-c3ccncc3)c2c1)C1CN(Cc2ccccc2F)CCO1
Reaction time: 0.25 h

Procedure:
In a flask, dichloromethane (0.5 mL) and acetic acid (3drops) was added to N-(3-(pyridin-4-yl)-1H-indazol-5-yl)morpholine-2-carboxamide (0.014 g, 0.0443 mmol) and 2-fluorobenzaldehyde (0.0112 g, 0.09 mmol). The reaction was stirred for 15 minutes. Sodium triacetoxyborohydride (0.040 g, 0.177 mmol) was added in one portion. The reaction was stirred for an additional 16 hours. Saturated sodium bicarbarbonate (1 mL) was added. The reaction was stirred for an additional 5 minutes and was extracted with dichloromethane (3×1 mL). The extracts were combined, dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by prep LC/MS. LC-MS: 432.2 [M+H]. LC/MS RT0.869 min.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[C:7](/[CH:10]=[C:11]2\[NH:12][C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[Cl:39][CH2:40][C:41]1[C:42]([CH3:47])=[N:43][O:44][C:45]=1[CH3:46].Cl>CN(C=O)C.CCOCC>[ClH:39].[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:40][C:41]3[C:42]([CH3:47])=[N:43][O:44][C:45]=3[CH3:46])[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C2\NC(=O)N(CCCC)C2=O)n1Cc1ccc(C(=O)OC)cc1
Reactant: Cc1noc(C)c1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2Cc2c(C)noc2C)n1Cc1ccc(C(=O)OC)cc1
Reaction time: 24 h

Procedure:
To a solution of methyl Z-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene)methyl]-1H-imidazol-1-yl]methyl]benzoate (1.00 g, 2.281 mmol) in DMF (10 mL) is added K2CO3 (1.580 g, 0.011 moles). After stirring for 15 minutes 4-chloromethyl-3,5-dimethylisoxazole (0.35 g, 2.39 mmol) is added. The mixture is stirred for 24 hours. The solvents were removed under high vacuum. After diluting with ethyl acetate and washing with water and brine the solution is dried over MgSO4. Evaporation in vacuo affords a viscous oil which is dissolved in ether and treated with ethereal HCl to afford a foamy solid upon evaporation in vacuo. This solid is crystallized from ethyl acetate/hexane.
Reaction SMILES: [O:1]=[C:2]([N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)[CH2:3][O:4][C@@H:5]1[CH2:10][N:9]([C:11]([O:13][CH3:14])=[O:12])[C@H:8]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[O:16])[C@@H:7]([C:29](OC)=[O:30])[CH2:6]1.[OH:38][NH2:39].C[O-].[Na+].Cl>CO>[OH:38][NH:39][C:29]([C@H:7]1[CH2:6][C@H:5]([O:4][CH2:3][C:2](=[O:1])[N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:10][N:9]([C:11]([O:13][CH3:14])=[O:12])[C@@H:8]1[C:15]([N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:21][CH2:22]1)=[O:16])=[O:30]
Reactant: COC(=O)[C@H]1C[C@H](OCC(=O)N2CCCC2)CN(C(=O)OC)[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)N1C[C@@H](OCC(=O)N2CCCC2)C[C@H](C(=O)NO)[C@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
To the reaction mixture of dimethyl(2S,3S,5S)-5-(2-oxo-2-pyrrolidin-1-ylethoxy)-2-[(4-phenylpiperazin-1-yl)carbonyl]piperidine-1,3-dicarboxylate (64 mg, 0.00012 mol) in methanol (0.5018 mL, 0.01239 mol) was added 1.640 M of N-hydroxyamine in methanol solution (1.51 mL) made from the corresponding salt and sodium methoxide. After stirred at rt for 1 h, the mixture was acidified with 1N HCl. The resultant mixture was applied directly on RP-HPLC to afford the product as a TFA salt (14 mg, 18%). MS (ESI): (M+H)+=518.2.
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:23]([NH2:31])[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]>CO>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:23]([NH:31][CH2:12][C@H:10]([OH:11])[C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[N:2][N:1]=3)[CH:9]=2)[CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Reactant: COc1ccc(C(N)Cc2ccccc2)cc1OC
Solvent: CO
Product: COc1ccc(C(Cc2ccccc2)NC[C@H](O)c2ccc3nnnn3c2)cc1OC

Procedure:
A solution of 0.178 g (1 mmol) of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane (see Fisher and Wyvratt, EP 0 318 092 A2 for the synthesis of this compound) and 0.518 g (2 mmol) of α-(3,4-dimethoxyphenyl) benzeneethanamine in dry methanol (10 mL) was heated at reflux in a gas tight vessel for 14 hours. The reaction mixture was concentrated and the residue was chromatographed on silica gel (5% methaol in methylene chloride) to give the product as a white solid: 1H NMR (500 MHz, CDCl3)δ 8.76 (d, 1H, J=15 Hz), 7.91 (dd, 1H, J=9, 3 Hz), 7.41 (t, 1H, J=11 Hz), 7.10-7.32 (m, 5H), 6.77-6.83 (m, 3H), 4.51-4.73 (m, 1H), 3.89 (s, 3H. OCH3), 3.88 and 3.86 (s, 3H, OCH3), 3.74-3.89 (m, 1H), 2.96-3.0 (m, 1H), 2.84-2.92 (m, 2H), 2.94-2.61 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH2:9])=[S:8])([O-:3])=[O:2].Cl[CH:14]([C:20]([CH3:22])=O)[C:15]([O:17]CC)=[O:16]>C(O)C>[CH3:22][C:20]1[N:9]=[C:7]([C:6]2[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[S:8][C:14]=1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NC(=S)c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: Cc1nc(-c2cccc([N+](=O)[O-])c2)sc1C(=O)O
Temperature: 70 °C
Yield: 52.9 %

Procedure:
730 mg of 3-Nitrothiobenzamide was dissolved in 5 ml of ethanol, 725 mg of ethyl 2-chloroacetoacetate was added to the solution, and the mixture was heated under reflux for 18 hours. After the reaction mixture was cooled, the precipitated crystal was collected by filtration and recrystallized from a mixed solvent consisting of 10 ml of ethanol and 5 ml of ethyl acetate. 800 mg out of 898 mg of the resulting crystal was suspended in 10 ml of ethanol, 10 ml of an aqueous 1N sodium hydroxide solution was added to the suspension, and the mixture was heated at 70° C. for 2 hours. After the completion of the reaction, ethanol was removed by distillation, and the residue was neutralized with 1N hydrochloric acid. The precipitated crystal was collected by filtration and recrystallized from an aqueous 50% ethanol solution to give 560 mg of 4-methyl-2-(3-nitrophenyl)-5-thiazolecarboxylic acid (yield: 59%).
Reaction SMILES: [Si]([O:8][CH2:9][C@:10]1([CH3:36])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[N:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO.O1CCOCC1>[CH3:36][C@@:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:24]=[CH:25][C:26]([C:29]5[N:34]=[CH:33][C:32]([CH3:35])=[CH:31][N:30]=5)=[CH:27][CH:28]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: Cc1cnc(-c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cnc(-c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO)C5)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
The compound (348 mg, 0.67 mmol) obtained in Example 52-3) was dissolved in methanol (3 mL). A 4 N solution (1.67 mL) of hydrochloric acid in dioxane was added to the solution, and the mixture was stirred at room temperature for 1 h. The solvent was distilled off, the residue was dissolved in a mixed solvent of methylene chloride (50 mL) and methanol (2 mL), and the mixture was separated into organic and aqueous layers by the addition of saturated aqueous sodium hydrogencarbonate (20 mL). The organic layer was washed with saturated sodium chloride solution and then dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent: methanol/ethyl acetate=10% to 60%) to obtain the title compound (216 mg, 79%) in a white solid form.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8]O)[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]=1.S(Cl)([Cl:16])=O>C(Cl)Cl>[Cl:16][CH2:8][CH2:7][N:6]1[C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N:3]=[C:2]1[CH3:1]
Reactant: Cc1nc2ccccc2n1CCO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1nc2ccccc2n1CCCl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 2-(2-methyl-1H-benzoimidazol-1-yl)ethanol (4.00 g, 22.70 mmol) in DCM (80 mL) at 0° C., thionylchloride (3.5 mL, 48.25 mmol) was added. The reaction mixture was allowed to warm to rt and stirred for 5 h at this temperature, then the reaction mixture was quenched with aq. sat. NaHCO3-solution (gas evolution) and extracted with DCM (3×). The org. layers was dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield 1-(2-chloroethyl)-2-methyl-1H-benzoimidazole which was used without further prufication in the next step. LC-MS conditions B: tR=0.37 min, [M+H]+=195.09.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22])([O:13][CH3:14])=[O:12]>C(Cl)Cl>[C:8]([C:6]1[CH:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:25]([NH:24][S:21]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:11]([O:13][CH3:14])=[O:12])(=[O:23])=[O:22])=[O:26])[N:7]=1)#[N:9]
Reactant: Cc1cc(C#N)nc(N)n1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(C#N)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Amino-4-cyano-6-methylpyrimidine, 0.2 g, was mixed with 2-carbomethoxybenzenesulfonyl isocyanate, 0.7 g, in 8 ml of dry methylene chloride. After five minutes a thick precipitate formed and the reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered and the filtrate stripped to give 0.3 g of the title compound as a solid, m.p. 208°-213° C. (dec). NMR (CF3CO2D): δ2.95 (s, 3H), 4.05 (s, 3H), 7.85 (s, 1H), 7.88-8.15 (m), 8.25-8.65 (m).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH:16]4[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH3:22])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C(Cl)(Cl)Cl>[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([CH:16]4[CH2:21][CH2:20][N:19]([C:30](=[O:32])[CH3:31])[CH2:18][CH2:17]4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH3:22])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1[nH]n(C2CCCC2)c2nc(C3CCNCC3)nc(=O)c1-2
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(c2nc3n(C4CCCC4)[nH]c(C)c-3c(=O)n2)CC1
Reaction time: 3 h
Yield: 89.6 %

Procedure:
To a mixture of 1-cyclopentyl-3-methyl-6-(4-piperidinyl)pyrazolo[3,4-d]pyrimidin-4-one (0.79 g, 2.6 mmol), triethylamine (2.0 ml), and chloroform (25 ml) was added acetic anhydride (2.0 ml 0.02 mol) The mixture was stirred for 3 hours and the solvent was removed in vacuo. The residue was treated with water and the product was collected by filtration to afford 0.8 g (90%) of 1-cyclopentyl-3-methyl-6-(1-acetyl-4-piperidinyl)pyrazolo[3,4-d]pyrimidin-4-one as white needles, m.p. 176°-178° C. when recrystallized from cyclohexane.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>S(=O)(=O)(O)O.Cl>[C:12]([O:8][C:7](=[O:9])[C:6]1[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=1)[OH:11])(=[O:14])[CH3:13]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: CC(=O)OC(C)=O
Agent: Cl
Agent: O=S(=O)(O)O
Product: CC(=O)OC(=O)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.7 %

Procedure:
10 g (57.9 mmol) 5-chlorosalicylic acid was weighed in a 100-mL round-bottomed flask, followed by the addition of acetic anhydride (12.8 mL, 115.9 mmol). The mixture was stirred for 5 minutes before adding concentrated sulfuric acid (2 drops). The reaction was refluxed for 3 hours. Progress of the reaction was monitored by HPLC. The reaction mixture was cooled to room temperature and poured into a beaker containing 2N HCl (200 mL) to precipitate the product out. The product was collected via vacuum filtration. A purity check by HPLC revealed the presence of impurities. The precipitate was stirred in water (150 mL) overnight in a 200-mL round-bottomed flask. The insoluble solid was collected via vacuum filtration. An impurity check by HPLC revealed that the crude product was free of the impurities. The product was dried overnight in vacuo to yield 12 g of O-acetyl-5-chlorosalicylic acid (56 mmol, 97% yield)
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:13](=[O:34])[NH:14][CH:15]1[CH2:21][CH2:20][CH2:19][N:18]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:17][CH:16]1[OH:33])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.[ClH:36]>C(Cl)Cl.O1CCOCC1>[ClH:36].[OH:33][CH:16]1[CH:15]([NH:14][C:13](=[O:34])[C@@H:8]([NH2:7])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:21][CH2:20][CH2:19][N:18]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:17]1
Reactant: COc1ccc(S(=O)(=O)N2CCCC(NC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(O)C2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N2CCCC(NC(=O)[C@@H](N)CC(C)C)C(O)C2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
{(S)-1-[3-Hydroxy-1-(4-methoxy-benzenesulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-carbamic acid-tert-butyl ester (compound 207a, 0.59 g, 1.15 mmol) was dissolved in CH2Cl2 (8 ml), then a solution of 4 M HCl in dioxane (8 ml) was added and the reaction was stirred at RT for 4 h. The reaction mixture was concentrated in vacuo, azeotroped from toluene twice (10 ml) in vacuo, and was used in the next reaction without further purification: M+H+=413.8.
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1.CNCCNC.[I-:34].[Na+]>O1CCOCC1.ClCCl.[Cu]I>[I:34][C:2]1[N:10]=[CH:9][C:8]2[NH:7][C:6]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: Brc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Ic1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 110 °C
Yield: 99.6 %

Procedure:
A mixture of 6-bromo-3-(4-piperidin-1-ylmethyl-phenyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (250 mg, 0.6 mmol), copper (I) iodide (23 mg, 0.12 mmol), N,N′-dimethyl-1,2-ethanediamine (0.013 mL, 0.12 mmol), and sodium iodide (360 mg, 2.4 mmol) in 1,4-dioxane was heated at 110° C. for 3 days. The reaction was diluted with dichloromethane (20 mL), filtered, and concentrated to afford a residue that was purified by flash chromatography (silica, 10 g column, Biotage, 0-10% methanol in (DCM containing 1% 2M ammonia in methanol)) to afford the title compound as an orange solid (280 mg, 100%).
Reaction SMILES: [OH-].[Na+:2].[C:3]1([CH2:9][C:10](=[O:14])[C:11]([OH:13])=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:15]I>O1CCCC1>[O:14]=[C:10]([CH:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:15])[C:11]([O-:13])=[O:12].[Na+:2]
Reactant: O=C(O)C(=O)Cc1ccccc1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C(=O)C(=O)[O-])c1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 68 %

Procedure:
A 1N aqueous solution of sodium hydroxide (20 ml, 20 mmoles) and 30 ml of tetrahydrofuran were added to 1.64 g (10.0 mmoles) of phenylpyruvic acid to form a solution. Then, 2.0 ml of methyl iodide was added, and the mixture was stirred at room temperature for 10 hours. The reaction mixture was concentrated, and ether was added to the resulting pale yellowish white semi-solid. The precipitated sodium 2-oxo-3-phenylbutanoate as a white solid (0.68 g, yield 68 %) was isolated by filtration.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH:10]([O:24][CH3:25])[N:9]=1.[CH2:26]([N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][C:30]1=[O:39])[C:27]#[CH:28].C(O)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:28]#[C:27][CH2:26][N:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:32][CH2:31][C:30]3=[O:39])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH:10]([O:24][CH3:25])[N:9]=1
Reactant: C#CCN1C(=O)CCc2ccccc21
Reactant: COC1N=C(c2ccccc2F)c2cc(I)ccc2-n2c(C)nnc21
Solvent: CCO
Solvent: ClCCl
Product: COC1N=C(c2ccccc2F)c2cc(C#CCN3C(=O)CCc4ccccc43)ccc2-n2c(C)nnc21

Procedure:
The title compound was prepared by coupling rac-6-(2-fluorophenyl)-8-iodo-4-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][4,1]benzodiazepine with 3,4-dihydro-1-(2-propynyl)-2(1H)-quinolinone under the conditions used in Example 37. The product was isolated by chromatography over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride for elution. The combined clean fractions were evaporated and the residue was crystallized from ethyl acetate/ether to give colorless crystals of rac-1-{3-[6-(2-fluorophenyl)-4-methoxy-1-methyl-4H[1,2,4]triazolo[4,3-a][1,4] benzodiazepin-8-yl]-2-propynyl}-3,4-dihydro-2(1H)-quinolinone with m.p. 155°-160°. These crystals contained 0.33 molar equivalents of water.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=[O:16])=[CH:9][C:8]=1[F:20])=[O:6])[CH2:2][CH3:3].[C:21]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C.O>[CH2:1]([NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([CH3:19])([CH3:18])[C:15]([O:17][CH3:21])=[O:16])=[CH:9][C:8]=1[F:20])=[O:6])[CH2:2][CH3:3]
Reactant: CCCNC(=O)c1ccc(NC(C)(C)C(=O)O)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)c1ccc(NC(C)(C)C(=O)OC)cc1F
Temperature: 55 °C
Yield: 76.3 %

Procedure:
The title compound was prepared according to General Method 5. A solution of 2-(4-(propylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoic acid (1.0 g, 3.54 mmol) and K2CO3 (1.0 g, 7.2 mmol) in DMF (7 mL) was stirred at RT for 10 minutes. Methyl iodide (0.8 g, 5.6 mmol) was added and heated at 55° C. for 4 h. The solvent was removed and reaction mixture was poured in water, extracted with ethyl acetate, dried over Na2SO4, concentrated and purified with column chromatography to obtain 800 mg of methyl 2-(4-(propylcarbamoyl)-3-fluorophenylamino)-2-methylpropanoate.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[O:10][C@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][N:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:39]([O:44][CH2:45][CH2:46]O)(=[O:43])[C:40]([CH3:42])=[CH2:41].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:39]([O:44][CH2:45][CH2:46][O:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:9]2[O:10][C@H:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][N:13]=2)[C:2]=1[F:1])(=[O:43])[C:40]([CH3:42])=[CH2:41]
Reactant: Oc1cccc(C2=NC[C@@H](c3ccccc3)O2)c1F
Reactant: C=C(C)C(=O)OCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCOc1cccc(C2=NC[C@@H](c3ccccc3)O2)c1F
Reaction time: 24 h
Yield: 85.5 %

Procedure:
To a solution of 4,5-dihydro-2-(2-fluoro-3-hydroxyphenyl)-5(R)-phenyloxazol e (0.97 g, 3.8 mmol), triphenylphosphine (1.0 g, 4.0 mmol) and 2-hydroxyethyl methacrylate (0.50 ml, 4.0 mmol) in THF (30 ml) was added dropwise a solution of diethyl azodicarboxylate (0.65 ml, 4.0 mmol) in THF (15 ml). After stirring for 1 day, volatiles were removed by evaporation. The residue was purified by column chromatography on silica gel eluting with hexane-ethyl acetate (2:1) to afford the title compound (1.2 g, 86%) as a pale yellow liquid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].Br[CH2:18][CH2:19][Cl:20]>CS(C)=O>[Cl:20][CH2:19][CH2:18][N:12]1[CH2:13][CH2:14][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=2)[CH2:10][CH2:11]1
Reactant: ClCCBr
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: ClCCN1CCN(c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.6 %

Procedure:
A mixture of (3-chloro-phenyl)-piperazine hydrochloride (51.5 mmol) and powdered sodium hydroxide (103 mmol) in DMSO (75 mL) was treated with 2-bromo-1-chloroethane (77.2 mmol) and stirred at ambient temperature for 4 h. The reaction was poured into ice cold water (200 mL) and stirred for 0.5 h. A solid mass formed and was separated by decanting the water. The aqueous layer was extracted with dichloromethane (100 mL). The solid mass was dissolved with dichloromethane (100 mL) and the combined organics were dried with sodium sulfate, filtered and the solvent removed under vacuum. Flash chromatography (chloroform:acetone 50:1 to 20:1) yielded an oil (7.95 g) as the titled compound.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].Cl.[CH:7]1([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[CH2:9][CH2:8]1.C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH:7]1([NH:10][C:11]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:3](=[O:4])[CH2:2][Br:1])=[O:12])[CH2:9][CH2:8]1
Reactant: O=C(NC1CC1)[C@@H]1CCCN1
Reactant: O=C(Br)CBr
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(NC1CC1)[C@@H]1CCCN1C(=O)CBr

Procedure:
To a solution of 1.2 g of bromo-acetyl bromide in 30 ml of DCM a solution of 1 g of (S)-Pyrrolidine-2-carboxylic acid cyclopropylamide hydrochloride, 0.6 g of triethylamine and 7 mg of DMAP in 10 ml of DCM was added drop-wise at 0° C. After 1 h the reaction mixture was diluted with ethyl acetate and the solids were filtered off. The organic phase was evaporated under reduced pressure and the residue was filtered over silica gel eluting with ethyl acetate/heptane (8/2). After evaporation of the solvent the obtained product was pure enough for the subsequent reaction step. Yield: 1.3 g.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH:19]([CH2:24]O)[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([CH3:23])[CH:19]([CH2:24][F:7])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CN1CCN(Cc2ccccc2)CC1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(Cc2ccccc2)CC1CF
Temperature: 0 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To an ice-cooled solution of diethylaminosulfur trifluoride (10.8 mL, 81.8 mmol) in methylene chloride under N2 was added 336b (9.0 g, 40.9 mmol) in methylene chloride dropwise. The yellow solution was stirred at 0° C. for 1 h and then room temperature for 15 h. The reaction mixture was then diluted with NaHCO3, and the organic layer was separated and dried over Na2SO4. The crude product was purified on silica gel column chromatography eluting with 50:1 methylene chloride/methanol to afford 336c as a yellow oil (3.0 g, 33%). MS: [M+H]+ 223. 1H NMR (500 MHz, DMSO) δ 7.28 (m, 5H), 4.50 (m, 0.5H), 4.43 (m, 1H), 4.35 (m, 0.5H), 3.45 (s, 2H), 2.67 (m, 2H), 2.60 (m, 1H), 2.29 (m, 1H), 2.24 (s, 3H), 2.20 (m, 1H), 2.11 (m, 1H), 1.94 (m, 1H).