Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:4][N:5]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[C:14]([CH:22]=[O:23])=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1F)[CH:10]=2)[CH3:2].[F:37][C:38]([F:44])([CH:41]([F:43])[F:42])[CH2:39][OH:40].[OH-].[Na+]>N1C=CC=CC=1>[CH2:1]([CH:3]([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:4][N:5]1[C:17]2[C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[C:14]([CH:22]=[O:23])=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[C:9]([C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:40][CH2:39][C:38]([F:44])([F:37])[CH:41]([F:43])[F:42])[CH:10]=2)[CH3:2]
Reactant: OCC(F)(F)C(F)F
Reactant: CCCCC(CC)Cn1c2ccc(C(=O)c3ccccc3F)cc2c2cc(C=O)c3ccccc3c21
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CCCCC(CC)Cn1c2ccc(C(=O)c3ccccc3OCC(F)(F)C(F)F)cc2c2cc(C=O)c3ccccc3c21
Temperature: 70 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To 11-(2-ethylhexyl)-8-(2-fluorobenzoyl)-11H-benzo[a]carbazole-5-carbaldehyde (1.73 g, 3.60 mmol) in pyridine (18 ml) are added 2,2,3,3-tetrafluoropropanol (0.72 g, 5.48 mmol) and sodium hydroxide (0.24 g, 6.00 mmol) at room temperature. The reaction mixture is heated at 70° C. After stirring for 3 hours, the reaction mixture is poured into ice-water. The crude product is extracted with CH2Cl2 and washed with water and brine. After drying over MgSO4 and concentration, the product is reprecipitated from hexane and ethylacetate to obtain an off-white solid (1.91 g, 89%). The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 0.83-0.89 (m), 1.19-1.51 (m), 2.26 (m), 4.32 (t), 4.72 (m), 5.29 (t), 7.03 (d), 7.26 (t), 7.56-7.61 (m), 7.69-7.78 (m), 8.07 (d), 8.58 (d), 8.60 (s), 8.61 (s), 10.39 (s); 19F-NMR spectrum (CDCl3). δ [ppm] −140.92, −126.30.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[N:34]1[O:35][C:36]([C:43](O)=[O:44])=[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=12.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[O:21]=[C:15]1[CH:14]([N:7]2[C:6](=[O:22])[C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:43]([C:36]3[O:35][N:34]=[C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=34)=[O:44])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)c1onc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4onc5ccccc45)c3C2=O)C(=O)N1
Reaction time: 0.17 h
Yield: 78.3 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (1.8 g, 5.7 mmol) in DMF (20 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.9 g, 6.8 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.9 g, 6.8 mmol) and benzo[c]isoxazole-3-carboxylic acid (1.0 g, 6.3 mmol) were added, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.6 g, 8.5 mmol). The mixture was stirred at room temperature overnight and was concentrated in vacuo. The residue was dissolved in CH2Cl2 (50 mL), washed with water (2×30 mL) and brine (30 mL), and dried over MgSO4. Solvent was removed in vacuo, and the resulting oil was purified by ISCO silica gel flash chromatography (eluent: 3% MeOH in CH2Cl2) to afford benzo[c]isoxazole-3-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide as a yellow solid (1.93 g, 78%): mp, 253-255° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, gradient from 10/90 (CH3CN/H2O) to 95/5(CH3CN/H2O) in 10 minutes: tR=6.6 min (96%); 1H NMR (DMSO-d6): δ 2.08-2.13 (m, 1H), 2.53-2.65 (m, 2H), 2.86-2.94 (m, 1H), 5.02 (d, J=6.0 Hz, 2H), 5.19 (dd, J=6, 12 Hz, 1H), 7.27-7.97 (m, 5H), 9.90 (t, J=6 Hz, 1H), 11.16 (s, 1H). 13C NMR (DMSO-d6) δ: 21.98, 30.93, 40.33, 48.89, 115.15, 118.27, 120.74, 122.07, 127.24, 131.54, 131.96, 133.20, 134.88, 138.13, 156.43, 156.52, 156.97, 160.91, 166.93, 167.49, 169.82, 172.75. Anal Calcd for C22H16N4O6+0.2H2O: C, 60.61; H, 3.79; N, 12.85. Found: C, 60.38; H, 3.50; N, 12.80.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:11]([NH2:13])[CH3:12]>>[CH2:11]([NH:13][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[Cl:1])[CH3:12]
Reactant: CCN
Reactant: O=C(Cl)c1ccccc1Cl
Product: CCNC(=O)c1ccccc1Cl

Procedure:
2-Chlorobenzoyl chloride is reacted with ethyl amine using General Method E1 or E2, to produce the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH3:19].C(OCC)(=O)C>CC(C)=O.CCCCCC>[CH2:18]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2)[CH3:19]
Reactant: CCI
Reactant: Oc1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOc1ccc2[nH]ncc2c1

Procedure:
A solution of 5-hydroxy-1H-indazole[0.5 g, Reference Example 38] in acetone (10 ml) was treated with potassium carbonate (2.56 g) then with iodoethane (0.296 ml). The mixture was refluxed for 4 hours then cooled and then evaporated. The residue was partitioned between ethyl acetate and water and the aqueous layer was further extracted twice with ethyl acetate. The combined organic fractions were dried over magnesium sulfate and then evaporated to yield a brown residue which was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (1:1, v/v) to give 5-ethoxy-1H-indazole (0.38 g) as an off-white solid. LC-MS (METHOD B): RT=2.68 minutes; 163 (M+H)+.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][CH:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.ClC1C=CC=CC=1C(OC1CNC1)C1C=CC(Cl)=CC=1>>[ClH:26].[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH:19]([O:18][CH:16]1[CH2:17][NH:14][CH2:15]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:26]
Reactant: Clc1ccccc1C(OC1CN(C(c2ccccc2)c2ccccc2)C1)c1ccccc1Cl
Agent: Cl
Agent: Clc1ccc(C(OC2CNC2)c2ccccc2Cl)cc1
Product: Clc1ccccc1C(OC1CNC1)c1ccccc1Cl

Procedure:
This material was prepared from compound (67) (12.7 mmol) using the procedure described for compound (9) (1.58 g, 48%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:35])[N:13]([CH2:25][C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[CH:14]2[CH2:19][CH2:18][C:17]3([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:16][CH2:15]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Cl.CN(C)CCCN=C=NCC.[NH2:48][C:49]1[NH:53][N:52]=[N:51][N:50]=1.O>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:35])[N:13]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]([NH:48][C:49]3[N:50]=[N:51][NH:52][N:53]=3)=[O:31])=[CH:33][CH:34]=2)[CH:14]2[CH2:15][CH2:16][C:17]3([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:18][CH2:19]2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: Nc1nnn[nH]1
Reactant: CS(=O)(=O)c1cccc(NC(=O)N(Cc2ccc(C(=O)O)cc2)C2CCC3(CCCCC3)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1cccc(NC(=O)N(Cc2ccc(C(=O)Nc3nn[nH]n3)cc2)C2CCC3(CCCCC3)CC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-[3-(3-Methylsulfonylphenyl)-1-spiro[5.5]undec-3-yl-ureidomethyl]benzoic acid (32.2 mg, 64.6 μmol) was dissolved in DMF (1 mL) and added N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (EDAC) (16.5 mg, 86 μmol) and 5-aminotetrazole.H2O (16,5 mg, 160 μmol). The mixture was stirred at 25° C. for 1 day and concentrated in vacuo. Brine (5 mL) was added to the residue followed by a mixture of ethanol and chloroform (1:2, 10 mL). The phases were separated and the aqueous layer was extracted with a mixture of ethanol and chloroform (1:2, 2×10 mL). The combined organic extracts were dried over MgSO4 and evaporated. The residue was purified by preparative HPLC affording the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[C:6](=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].S(=O)(=O)(O)O>>[CH2:1]([O:3][C:4]([C:5]1[O:13][C:14]2[CH:15]=[C:16]([F:20])[CH:17]=[CH:18][C:19]=2[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:21])[CH3:2]
Reactant: CCOC(=O)C(=O)C(Oc1cccc(F)c1)C(=O)OCC
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1oc2cc(F)ccc2c1C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
108 (66 g, 221.3 mmol) is dissolved in 245 ml of cooled (−15° C.) conc. sulfuric acid and stirred for 3 h whereas the reaction mixture slowly warmed up to room temperature. Then the mixture is poured onto 1 kg of ice and extracted with diethyl ether. The organic layers are washed with brine, dried over sodium sulfate, filtrated and evaporated. The crude product is used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:45]=[C:35]5[CH2:36][N:37]([CH2:40][C:41]([F:44])([F:43])[F:42])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:46])[N:27]([CH3:47])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.ClCCl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:45]=[C:35]5[CH2:36][N:37]([CH2:40][C:41]([F:44])([F:43])[F:42])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:46])[N:27]([CH3:47])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2C=O)cc(Nc2cc3n(n2)CCN(CC(F)(F)F)C3)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2cc3n(n2)CCN(CC(F)(F)F)C3)c1=O
Reaction time: 1 h
Yield: 45.3 %

Procedure:
To a solution of 134e (110 mg, 0.169 mmol) in methanol/dichloromethane (4/4 mL) was added NaBH4 (19 mg, 0.51 mmol) at room temperature. After the reaction was stirred for 1 h, LCMS indicated the reaction was complete. The mixture was quenched with water (20 mL) and extracted with dichloromethane (3×30 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 134 (50 mg, 45%) as a white solid. MS-ESI: [M+H]+ 653.3. 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J=5.0 Hz, 1H), 8.35 (d, J=2.5 Hz s, 1H), 8.00 (d, J=2.5 Hz, 1H), 7.59-7.58 (m, 1H), 7.56-7.55 (m, 1H), 7.53-7.52 (m, 2H), 7.45 (s, 1H), 5.73 (s, 1H), 4.51-4.49 (m, 2H), 4.11-4.08 (m, 2H), 4.05-4.03 (m, 1H), 3.94 (s, 2H), 3.73 (s, 3H), 3.24-3.18 (m, 4H), 1.45 (s, 9H).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[C@@H]1(N)CCCC[C@H]1N.I[C:18]1[CH:19]=[C:20]([CH3:25])[CH:21]=[C:22]([CH3:24])[CH:23]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31].CCCCCCCCCCCC>[Cu]I.O1CCOCC1>[CH3:24][C:22]1[CH:23]=[C:18]([N:26]2[CH2:30][CH2:29][CH2:28][C:27]2=[O:31])[CH:19]=[C:20]([CH3:25])[CH:21]=1
Reactant: O=C1CCCN1
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: CCCCCCCCCCCC
Solvent: C1COCCO1
Product: Cc1cc(C)cc(N2CCCC2=O)c1
Temperature: 110 °C
Reaction time: 23 h
Yield: 99 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (2.0 mg, 0.0105 mmol, 1.0 mol %), K3PO4 (450 mg, 2.12 mmol), evacuated and backfilled with nitrogen. trans-1,2-Cyclohexanediamine (13 μL, 0.108 mmol, 10 mol %), 5-iodo-m-xylene (150 μL, 1.04 mmol), 2-pyrrolidinone (94 μL, 1.24 mmol) and dioxane (1.0 mL) were added under nitrogen. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 23 h. The resulting pale brown suspension was cooled to room temperature, dodecane (235 μL, GC standard) was added, and the mixture was filtered through a Celite pad eluting with ethyl acetate. The GC analysis of the filtrate indicated a 99% yield of the product.
Reaction SMILES: [C@H:1]12[CH2:24][C@H:4]([N:5]([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][N:19]=[N+]=[N-])[O:15][C:14]4=[O:22])=[CH:9][C:8]=3[F:23])[CH2:6]1)[CH2:3][O:2]2.N1C=CC=CC=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].O1CCNC1=O>CO.C(Cl)Cl.[Pd].CO.C(Cl)(Cl)Cl>[C@H:1]12[CH2:24][C@H:4]([N:5]([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:31](=[O:33])[CH3:32])[O:15][C:14]4=[O:22])=[CH:9][C:8]=3[F:23])[CH2:6]1)[CH2:3][O:2]2
Reactant: CC(=O)OC(C)=O
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(N3C[C@@H]4C[C@H]3CO4)c(F)c2)C(=O)O1
Agent: [Pd]
Agent: O=C1NCCO1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3C[C@@H]4C[C@H]3CO4)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (R)-[[3-[4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]azide (0.652 g, 1.96 mmol) in MeOH (20 mL) and CH2Cl2 (10 mL) was treated with 10% palladium/carbon (0.095 g) under a N2 stream. The atmosphere was then replaced with H2 (balloon) by repeated evacuation and filling and the mixture stirred at ambient temperature under H2. After 3 h, TLC analysis (5% MeOH/CHCl3) revealed the reduction to be complete. The reaction mixture was filtered through Celite® and the filtrate concentrated under reduced pressure. The crude 5-(aminomethyl)oxazolidinone was dissolved in CH2C2 (20 mL) and treated with pyridine (0.190 mL, 2.35 mmol) and then acetic anhydride (0.222 mL, 2.35 mmol). After 0.5 h, TLC analysis (5% MeOH/CHCl3) indicated the acetylation to be complete. The reaction mixture was washed with H2O and brine, dried over Na2SO4, filtered and concentrated in vacuo to give an off-white solid. Chromatography over silica gel (70 g), eluting with a gradient of 1-3% MeOH/CHCl3, afforded, after concentration of appropriate fractions, 0.517 g (76%) of the title oxazolidinone antibacterial agent as a white solid with mp 60-65° C. and MS(EI) 349 (M+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:5]=2[N:4]([CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24](OC)=[O:25])=[CH:22][CH:21]=2)[C:3]1=[N:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=1.[Li+].[OH-].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.O.[NH:68]1[C:72]([NH2:73])=[N:71][N:70]=[N:69]1>O1CCOCC1.O.CCOC(C)=O.CN(C=O)C>[CH3:1][N:2]1[C:6]2[C:7]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:8][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:10][C:5]=2[N:4]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:73][C:72]3[NH:71][N:70]=[N:69][N:68]=3)=[O:25])=[CH:28][CH:29]=2)[C:3]1=[N:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]([F:40])([F:39])[F:41])=[CH:33][CH:32]=1
Reactant: COC(=O)c1ccc(Cn2c(=Nc3ccc(OC(F)(F)F)cc3)n(C)c3c(S(C)(=O)=O)cc(C(F)(F)F)cc32)cc1
Reactant: Nc1nnn[nH]1
Agent: On1nnc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1c(=Nc2ccc(OC(F)(F)F)cc2)n(Cc2ccc(C(=O)Nc3nnn[nH]3)cc2)c2cc(C(F)(F)F)cc(S(C)(=O)=O)c21
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a solution of the crude product from Example 10, Step B in dioxane (1 mL) was added LiOH (9.5 mg, 0.04 mmol) in 0.5 mL H2O, and the reaction mixture was stirred at 40° C. After 1 h, the reaction mixture was diluted with EtOAc and washed with pH 7 phosphate buffer. The aqueous phase was extracted twice with EtOAc, and the combined organic phases were dried over Na2SO4 and concentrated. To the crude mixture of carboxylic acids were added EDC (113 mg, 0.59 mmol), HOBt (91 mg, 0.59 mmol), DMF (1 mL), DIEA (230 μL, 1.32 mmol) and 1H-tetraazol-5-amine monohydrate (68 mg, 0.66 mmol). The reaction mixture was stirred at 40° C. for 12 h, then concentrated under high vacuum. Purification by reverse-phase chromatography (20-80% CH3CN/H2O, both containing 0.1% TFA), followed by lyophilization, provided the product as a white solid: 1H NMR (500 MHz, d6-DMSO) δ 12.40 (s, 1H), 8.00 (d, J=8.5 Hz, 2H), 7.84 (s, 1H), 7.79 (s, 1H), 7.22 (d, J=8.5 Hz, 2H), 7.20 (br s, 1H), 7.12 (d, J=8.0 Hz, 2H), 6.87 (d, J=8.0 Hz, 2H), 5.24 (s, 2H), 3.66 (s, 3H), 3.56 (s, 3H); LCMS (ESI,) 1.97 min, m/z 655.2 (M+1).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22](=[O:24])C)=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].BrBr.[OH-].[Na+].Cl.S(S([O-])=O)([O-])(=O)=[O:31].[Na+].[Na+]>O1CCOCC1.O>[CH:1]([O:4][C:5]([C:7]1([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([OH:31])=[O:24])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:2])[CH3:3]
Reactant: O=S([O-])S(=O)(=O)[O-]
Reactant: CC(=O)c1ccc(-c2ccc(C3(C(=O)OC(C)C)CC3)cc2)cc1
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)OC(=O)C1(c2ccc(-c3ccc(C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1-(4′-acetylbiphenyl-4-yl)cyclopropanecarboxylic acid isopropyl ester (11.6 g, 36 mmol) in dioxane (200 mL) at ˜10° C. was added a solution of bromine (28.8 g, 180 mmol), sodium hydroxide (24.5 g, 612 mmol) in water (150 mL). The solution was stirred at room temperature for 30 minutes poured into water (500 mL) and acidified with dilute hydrochloric acid. Sodium metabisulfite was added until the brown bromine color dissipated. The product was filtered and dried in a vacuum over overnight at 40° C. to yield 10 g of the title compound.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].[C:4](OCC)(=O)CC(OCC)=O.C(N(CC)CC)C.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:25]=1[C:26](Cl)=[O:27].Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C.CS(C)=O.O>[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:25]=1[C:26](=[O:27])[CH3:4]
Reactant: COc1ccc([N+](=O)[O-])cc1C(=O)Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])cc1C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
Anhydrous magnesium chloride (150 mg, 1.6 mmol) was added to a solution of diethyl malonate (440 mg, 2.76 mmol) and triethylamine (670 mg, 6.5 mmol) in dry toluene (10 ml) at room temperature under inert atmosphere. After stirring for 1 hr, the reaction was cooled to 0° C. and 2-methoxy-5-nitro benzoyl chloride (550 mg, 2.3 mmol) was added. The reaction mixture was allowed to attain room temperature then stirred for 30 min before adding 6N hydrochloric acid (15 ml). The organic layer was separated, washed with water and dried. Concentration under reduced pressure gave a residue to which was added 1:1 DMSO-water (10 ml). The mixture was heated to 140° C. for 2 hr, then cooled to RT and diluted with ethyl acetate (50 ml). The organic layer was washed successively with water, bicarbonate solution, and brine, then dried. Evaporation under reduced pressure gave 1-(2-Methoxy-5-nitro-phenyl)-ethanone (350 mg, 70%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][CH2:15][C:16]2([CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[O:21][C:20](=[O:22])[C:19]([CH2:23][C:24]3[N:34]=[C:27]4[N:28]=[C:29]([CH3:33])[CH:30]=[C:31]([CH3:32])[N:26]4[N:25]=3)=[C:18]([OH:35])[CH2:17]2)[CH:5]=[CH:6][C:7]=1[C:8]1([CH3:13])OCC[O:9]1>CC(C)=O>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([CH2:14][CH2:15][C:16]2([CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[O:21][C:20](=[O:22])[C:19]([CH2:23][C:24]3[N:34]=[C:27]4[N:28]=[C:29]([CH3:33])[CH:30]=[C:31]([CH3:32])[N:26]4[N:25]=3)=[C:18]([OH:35])[CH2:17]2)=[CH:3][C:2]=1[Cl:1])(=[O:9])[CH3:13]
Reactant: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc(C5(C)OCCO5)c(Cl)c4)(C4CCCC4)OC3=O)nc2n1
Solvent: CC(C)=O
Product: CC(=O)c1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)cc1Cl
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The title compound was prepared in the following way: Example B(122) 6-{2-[3-Chloro-4-(2-methyl-[1,3]dioxolan-2-yl)-phenyl]-ethyl}-6-cyclopentyl-3-(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-ylmethyl)-4-hydroxy-5,6-dihydro-pyran-2-one (0.138 g, 0.24 mmol), was dissolved in acetone (8 mL). Amberlyst-13 (0.23 g) was added from top and reaction was stirred under nitrogen for 72 hours at room temperature. The resulting reaction mixture was filtered through fritted funnel to remove the amberlyst and the resultant filtrate was diluted with EtOAC and washed with water (10 mL) and brine (10 mL) then dried over Na2SO4, filtered and concentrated. The resultant solid was recrystallized from MeOH to yield the product as a white solid (0.05 g, 41%). 1H NMR (400 MHz, DMSO-d6): δ 1.5-1.7 (m, 9H) 2.20-2.22 (m, 2H), 2.49-2.90 (m, 10H), 3.39 (s, 3H), 3.78 (d, J=16 Hz, 1H), 3.90 (d, J=16 Hz, 1H), 7.13 (s, 1H), 7.32 (s, 1H), 7.36 (d, J=8 Hz, 1H), 7.61 (d, J=8 Hz, 1H), 10.9 (s, 1H). MS (ESI): 523 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:16][CH2:15][O:14][C@H:13]([CH2:17][N:18]3[C:22]4=[N:23][C:24]([C:27]5[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=5)=[CH:25][N:26]=[C:21]4[N:20]=[N:19]3)[CH2:12]2)=[N:9][CH:10]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>CN(C=O)C>[CH3:32][N:30]1[CH:31]=[C:27]([C:24]2[N:23]=[C:22]3[N:18]([CH2:17][C@H:13]4[O:14][CH2:15][CH2:16][N:11]([C:8]5[N:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][N:37]6[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]6)=[CH:10][N:9]=5)[CH2:12]4)[N:19]=[N:20][C:21]3=[N:26][CH:25]=2)[CH:28]=[N:29]1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(OCCCl)cn5)CCO4)c3n2)cn1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: CN1CCN(CCOc2cnc(N3CCO[C@H](Cn4nnc5ncc(-c6cnn(C)c6)nc54)C3)nc2)CC1
Temperature: 75 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
(S)-4-(5-(2-chloroethoxy)pyrimidin-2-yl)-2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholine 9 mg (0.019 mmol) was dissolved in DMF 1 ml, and 1-methylpiperazine 4 μl (0.39 mmol) and KI 4 mg (0.022 mmol) were added. The mixture was stirred at 75° C. overnight. When the reaction was completed, the reaction mixture was extracted several times with ethyl acetate and brine, and the organic layer was dried over Na2SO4. Prep LC with 7% MeOH/MC gave a product 7.8 mg (76%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([NH2:14])=[N:10][CH:9]=2)=[CH:4][C:3]=1[F:15].Cl[CH:17]([CH:33]=O)[CH2:18][C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:22]=[CH:23][CH:24]=1>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([C:17]([CH2:18][C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH:22]=[CH:23][CH:24]=4)=[CH:33][N:14]=3)[N:13]=2)=[CH:4][C:3]=1[F:15]
Reactant: Nc1ncc(-c2ccc(Br)c(F)c2)nn1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CC(Cl)C=O)c1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1cccc(Cc2cnc3ncc(-c4ccc(Br)c(F)c4)nn23)c1
Temperature: 105 °C
Reaction time: 8 h

Procedure:
A mixture of 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (19 mg, 0.070 mmol) and tert-butyl [3-(2-chloro-3-oxopropyl)phenyl]carbamate (20 mg, 0.070 mmol) in ethanol (0.4 mL) was stirred overnight at 105° C. The reaction mixture was purified by RP-HPLC (pH 10) to afford the desired product. LCMS: (M+H)=498.0/500.0.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[Al]([C:13]#[N:14])(CC)CC>C1(C)C=CC=CC=1>[O:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:13]#[N:14])[CH2:2]1
Reactant: O=C1C=CCCC1
Reactant: CC[Al](C#N)CC
Solvent: Cc1ccccc1
Product: N#CC1CCCC(=O)C1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
To a solution of 2-cyclohexen-1-one (6 mL, 62 mmol) in hexanes (100 mL) was added 1M Et2AlCN (160 mL) in toluene with cooling at −15° C. After stirring for 30 min, the reaction mixture was poured into an ice-cold 2M HCl solution and extracted with CH2Cl2. The extracts were washed with cold 2M NaOH and water, dried and concentrated in vacuo. Distillation of the product yielded 1.7 g (22%) of 3-oxo-cyclohexanecarbonitrile, b.p. 145-146° C. (16 mmHg).