Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]1(O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.S(=O)(=O)(O)O>>[CH:10]1([O:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: OC1CCCCC1
Reactant: OCCc1ccccc1
Agent: O=S(=O)(O)O
Product: c1ccc(CCOC2CCCCC2)cc1
Temperature: 115 °C
Reaction time: 3 h

Procedure:
Into a 2 liter reaction vessel equipped with stirrer, thermometer, heating mantle and overhead condenser with azeotrope takeoff apparatus is placed 488 grams of betaphenylethyl alcohol; 440 grams of cyclohexanol and 100 grams of concentrated sulfuric acid. The reaction mass is then heated to a temperature of 115° C. and maintained at a temperature in the range of 104°-127° C. at reflux while azeotropically removing 80 ml water, for a period of 3 hours. At the end of the 3 hour period, a sample is analyzed by means of GLC analysis (conditions: 180° C. isothermal using an SE-30 packed column). FIG. 1A is the GLC profile of the reaction product at this point.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@H:4](/[CH:5]=[C:6](\[CH3:9])/[CH:7]=O)[C@H:3]1[C:10]([O:12][CH3:13])=[O:11].Cl.[CH2:16]([O:18][NH2:19])[CH3:17].N1C=CC=CC=1>C(OCC)(=O)C>[CH2:16]([O:18][N:19]=[CH:7]/[C:6](/[CH3:9])=[CH:5]/[C@@H:4]1[C@@H:3]([C:10]([O:12][CH3:13])=[O:11])[C:2]1([CH3:14])[CH3:1])[CH3:17]
Reactant: COC(=O)[C@@H]1[C@@H](/C=C(\C)C=O)C1(C)C
Reactant: CCON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCON=C/C(C)=C/[C@@H]1[C@@H](C(=O)OC)C1(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.3 %

Procedure:
Under nitrogen atmosphere, a mixture of 0.94 g of methyl (1R)-trans-2,2-dimethyl-3-[(E)-2-methyl-3-oxo-1-propenyl]cyclopropanecarboxylate, 0.47 g of O-ethylhydroxylamine hydrochloride and 2 ml of pyridine was stirred at room temperature for 4 hours. Then, ethyl acetate was added to the reaction mixture, and the mixture was washed with 1 mol/L hydrochloric acid and saturated brine respectively. The organic layer was dried over anhydrous magnesium sulfate, then, filtrated, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.92 g of methyl (1R)-trans-3-[(E)-3-ethoxyimino-2-methyl-1-propenyl]-2,2-dimethylcyclopropanecarboxylate:
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:33]=[CH:32][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:31]=[CH:30][C:19]([O:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=O)=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl.[CH2:41]([O:43][NH2:44])[CH3:42]>C(O)C>[ClH:1].[Br:2][C:3]1[CH:4]=[CH:5][C:6](/[C:7](=[N:44]\[O:43][CH2:41][CH3:42])/[CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:20][C:21]4[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=4)=[CH:30][CH:31]=3)[CH2:11][CH2:10]2)=[CH:32][CH:33]=1
Reactant: CCON
Reactant: O=C(O)c1ccc(Oc2ccc(CN3CCC(C(=O)c4ccc(Br)cc4)CC3)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCO/N=C(\c1ccc(Br)cc1)C1CCN(Cc2ccc(Oc3ccc(C(=O)O)cc3)cc2)CC1

Procedure:
To a solution of the compound prepared in Example 5(15) (912 mg) in ethanol (10 mL) were added pyridine (5 mL) and O-ethylhydroxyamine hydrochloride (340 mg) and the solution was refluxed for 3 hours. After finishing the reaction, the reaction solution was concentrated. Water and 2N hydrochloric acid were added thereto and the solution was extracted with ethyl acetate. The organic layer was washed with brine and concentrated. The obtained residue was purified by column chromatography on silica gel (ethyl acetate:methanol=25:1) and 4N hydrogen chloride/ethyl acetate solution was added to the obtained residue, which was concentrated to give the compound of the present invention (E-form: 409 mg, Z-form: 500 mg) having the following physical data.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([OH:11])=[O:10].[C:16]1(C)C=CC=CC=1>>[CH3:16][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:14]([CH3:15])=[C:6]([F:5])[CH:7]=1
Reactant: Cc1ccccc1
Reactant: Cc1ccc(C(=O)O)cc1F
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C)c(F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83 %

Procedure:
Thionyl chloride (9.62 g, 81 mmol) was added to a solution of 3-fluoro-4-methylbenzoic acid (5.0 g, 32.4 mmol) in toluene (50 ml). The mixture was stirred at room temperature for 1.5 h and heated at reflux for 3 h. The sol-vent was removed in vacuo and the residue was taken up in methanol (30 ml) and CH2Cl2 (30 ml) and stirred for 18 h. The mixture was evaporated in vacuo and the residue was taken up in EtOAc (50 ml), washed with saturated NaHCO3 solution (3×75 ml), dried and evaporated in vacuo to yield the title compound (4.5 g, 83%).
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:6]=1/[CH:7]=[CH:8]/[C:9](O)=[O:10].C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl.CN(C=O)C>[CH3:3][O:4][C:5]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:6]=1/[CH:7]=[CH:8]/[C:9]([Cl:23])=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(/C=C/C(=O)O)c(OC)c1OC
Agent: N#N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(/C=C/C(=O)Cl)c(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Dissolve trans-2,3,4-Trimethoxycinnamic acid (50) (200 mg, 0.84 mmol) in anhydrous DCM (4.4 mL) at it and add anhydrous DMF (3 drops, cat. amount). Then add slowly oxalyl chloride (96 μL, 1.09 mmol) stir the turbid mixture for additional 2 h at rt. Remove solvent and dry the residue in oil pump vacuum to obtain trans-2,3,4-Trimethoxycinnamic acid chloride (51) (ca. 0.84 mmol) as an yellow solid. Dissolve acid chloride (51) (108 mg, 0.42 mmol) in anhydrous DCM (4.0 mL) and add it to an ice cooled solution of Methyl 3-amino-4-methylbenzoate (52) (69 mg, 0.42 mmol) in anhydrous DCM (2.0 mL) and anhydrous pyridine (1.2 mL). Stir the resulting reaction mixture at rt overnight. Pour the reaction mixture into ice cooled 1M aqu. HCl, extract with EtOAc (3×), wash the combined organic layer with brine and dry it with Na2SO4. Purify the crude product by filtration through a short pad of silica gel with EtOAc and remove solvent to obtain 4-Methyl-3-[3-(2,3,4-trimethoxy-phenyl)-acryloylamino]-benzoic acid methyl ester (53) (99 mg, 61%) as a light yellow solid. 1H NMR (400 MHz, CDCl3): 2.35 (s, 3H); 3.87 (s, 3H); 3.88 (s, 6H); 3.91 (br.s, 3H); 6.59 (d, 1H, J=15.6 Hz); 6.68 (d, 1H, J=8.6 Hz); 7.08 (br.s, 1H); 7.20-7.29 (m, 2H); 7.77 (br.d, 1H, J=8.6 Hz); 7.90 (d, 1H, J=15.6 Hz); 8.55 (br.s 1H).
Reaction SMILES: [NH3:1].[N+:2]([C:5]1[CH:6]=[C:7]([N:11]=[C:12]=[O:13])[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3]>>[N+:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH2:1])=[O:13])[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: N
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Product: NC(=O)Nc1cccc([N+](=O)[O-])c1

Procedure:
Ammonia was bubbled into a solution of 3-nitrophenylisocyanate (1.5 g, 9.1 mmol) for ten minutes. The reaction mixture was then concentrated and the resulting yellow solid was washed with ether (200 mL) to afford N-(3-nitrophenyl)-urea (1.35 g, 7.5 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]([OH:16])=[O:15])[CH:8]=[N:7]2)([O-:3])=[O:2].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:28](O)[CH3:29]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([C:14]([O:16][CH2:28][CH3:29])=[O:15])[CH:8]=[N:7]2)([O-:3])=[O:2]
Reactant: CCO
Reactant: O=C(O)c1cnc2cc([N+](=O)[O-])ccc2n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1cnc2cc([N+](=O)[O-])ccc2n1
Temperature: 25 °C
Yield: 67 %

Procedure:
To a solution of 6-nitroquinoxaline-2-carboxylic acid (6) (5.00 g, 22.8 mmol) (Higashida, S.; Sakurai, M.; Yabe, Y.; Nishihgaki, T.; Komai, T.; Handa, H. Preparation of peptide inhibitors of HIV protease, peptides capable of inhibiting the activity of HIV protease, their preparation and their therapeutic use. European Patent, EP 0 587 311, 1994) in dry ethanol (50 mL), was added under argon, concentrated sulfuric acid (750 μL). After being stirred at reflux for 7 h, the reaction mixture was cooled to room temperature and a saturated aqueous sodium carbonate solution (50 mL) was added. The solution was extracted with dichloromethane (3×30 mL) and the combined organic layers were dried on magnesium sulfate, filtered and evaporated to dryness to afford ester 7 (3.79 g, 15.3 mmol) as a brown solid. Yield 67%; mp 221-223° C.; IR (KBr) ν 1282, 1347, 1531, 1741 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.58 (t, 3H, J=7 Hz), 4.68 (q, 2H, J=7 Hz), 8.53 (d, 1H, J=9 Hz), 8.68 (dd, 1H, J=2.5, 9 Hz), 9.14 (d, 1H, J=2.5 Hz), 9.72 (s, 1H); MS m/z 248 (M+1, 4), 203 (36), 175 (100), 128 (23), 101 (32), 75 (24).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][NH:18]3)=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:10])(=[O:9])[N:8]=1.C(N(CC)CC)C.[CH3:30][CH:31]([CH3:36])[CH2:32][C:33](O)=[O:34].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:2][C:3]1[C:4]2[C:14]([O:15][CH2:16][C@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][N:18]3[C:33](=[O:34])[CH2:32][CH:31]([CH3:36])[CH3:30])=[CH:13][CH:12]=[CH:11][C:5]=2[NH:6][S:7](=[O:9])(=[O:10])[N:8]=1
Reactant: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCCN3)c21
Reactant: CC(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CC(=O)N1CCCC[C@@H]1COc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 25 °C
Reaction time: 18 h
Yield: 12.9 %

Procedure:
To a solution of (R)-4-amino-5-(piperidin-2-ylmethoxy)-1H-benzo[c][1,2,6]thiadiazine 2,2-dioxide hydrochloride (Example 15a, 500 mg, 1.44 mmol) in DMF (12 mL) was added triethylamine (399 uL, 2.88 mmol), 3-methylbutanoic acid (159 uL, 1.44 mmol), EDCI-HCl (276 mg, 1.44 mmol), and HOBt (220 mg, 1.44 mmol). The reaction mixture was stirred at room temperature, under nitrogen for 18 hrs, then was filtered and purified by HPLC (10-90% acetonitrile in water). The pure fractions were combined, concentrated and crystallized from ethanol and water to give the title compound as a white solid (73 mg, 13% yield). 1H NMR (400 MHz, DMSO-d6, 80° C.) δ 0.89 (d, J=6.8 Hz, 6H), 1.37 (m, 1H), 1.51-1.70 (m, 4H), 1.78 (d, J=12.8 Hz, 1H), 2.01 (m, 1H), 2.13-2.27 (m, 2H), 3.02 (br s, 1H), 3.89 (br s, 1H), 4.18 (br s, 1H), 4.48 (t, J=9.2 Hz, 1H), 5.02 (br s, 1H), 6.63 (d, J=8.0 Hz, 1H), 6.83 (d, J=8.8 Hz, 1H), 7.42 (t, J=8.4 Hz, 1H), 7.82 (br s, 2H), 10.63 (s, 1H). MS 395 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[NH:23]1[CH2:27][C@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]1.Cl>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:23]1[CH2:27][C@H:26]([OH:28])[C@@H:25]([OH:29])[CH2:24]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6]
Reactant: O[C@H]1CNC[C@@H]1O
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(F)c(Br)c1
Agent: Cl
Solvent: CS(C)=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1ccc(N2C[C@H](O)[C@@H](O)C2)c(Br)c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A solution of 3-bromo-4-fluoro-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.2, 500 mg, 1.322 mmol), (3S,4S)-pyrrolidine-3,4-diol (205 mg, 1.984 mmol) and TEA (553 μL, 3.97 mmol) in DMSO (994 μL) was stirred at 90° C. for 24 h. Additional (3S,4S)-pyrrolidine-3,4-diol, (68.2 mg, 0.661 mmol) and TEA (183 μL, 1.322 mmol) were added and mixture was stirred at 100° C. for 16 h. The cooled treated with 0.5 M HCl (20 mL) and extracted with TBME/EtOAc (1:1). The combined extracts were washed with 0.5 M HCl (20 mL) and brine, dried over MgSO4 and the solvent was evaporated off under reduced pressure to give a residue which was crystallised from cyclohexane/EtOAc to afford the title compound as an off-white solid. UPLC-MS (condition 1) tR=2.41 min, m/z=460.9/462.9 [M+H]+, m/z=459.0/461.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.24 (d, J=10.76 Hz, 2H) 3.88 (dd, J=10.51, 3.67 Hz, 2H) 4.02 (br. s, 2H) 5.15 (d, J=3.18 Hz, 2H) 6.89 (d, J=8.80 Hz, 1H) 7.34 (d, J=8.31 Hz, 2H) 7.84 (dd, J=8.68, 2.08 Hz, 1H) 7.85-7.89 (m, 2H) 8.13 (d, J=2.20 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:10][CH:11]=[N:12][N:13]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:14]1[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[O:20])[CH2:15]1>>[OH:1][C:2]1([C:9]2[S:10][CH:11]=[N:12][N:13]=2)[CH2:7][CH2:6][CH:5]([N:14]2[CH2:17][CH:16]([NH:18][C:19]([CH2:21][NH:22][C:23](=[O:34])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=3)=[O:20])[CH2:15]2)[CH2:4][CH2:3]1
Reactant: O=C1CCC(O)(c2nncs2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3nncs3)CC2)C1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-[1,3,4]thiadiazol-2-yl-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](=[N:18][OH:19])[NH2:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:23][CH2:24][C:25](OC(=O)CCl)=O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]3[CH2:21][CH2:20][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:17]=[C:25]([CH2:24][Cl:23])[O:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Cl)cccc1-2
Reactant: O=C(CCl)OC(=O)CCl
Solvent: CN(C)C=O
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Yield: 74.2 %

Procedure:
31.7 g (100 mmol) of (S)-8-chloro-9-oxo-12,12a-dihydro-9H, 11H-azeto[2,1-c]imidazo[1,5-a][1,4]-benzodiazepine-1-carboxamidoxime were suspended in 200 ml of N,N-dimethylformamide and treated with 18.8 g (110 mmol) of chloroacetic anhydride. The reaction mixture was heated to 105° for 2 hours and evaporated. By chromatography of the residue on silica gel while eluting with chloroform/methanol 9/1 there were obtained 27.9 g (74%) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]-imidazo[1,5-a][1,4]benzodiazepin-9-one of m.p. 211°-212°.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH2:11])[CH3:10])=[C:5]([CH3:12])[CH:4]=1.C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:42]([C:38]2[CH:37]=[C:36]3[C:41](=[CH:40][CH:39]=2)[N:33]([CH2:32][C:29]2[CH:28]=[CH:27][C:26]([C:21]4[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:31][CH:30]=2)[C:34]([CH3:46])=[C:35]3[CH3:45])=[O:43])[CH3:10])=[C:5]([CH3:12])[CH:4]=1
Reactant: Cc1cc(Cl)ccc1[C@H](C)N
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Agent: Cl
Product: Cc1cc(Cl)ccc1[C@H](C)NC(=O)c1ccc2c(c1)c(C)c(C)n2Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(4-chloro-2-methylphenyl)ethanamine hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 551 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[OH:29][CH2:30][CH:31]([N:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38](B3OC(C)(C)C(C)(C)O3)[CH:39]=2)[C:34]1=[O:51])[CH3:32]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:38]3[CH:39]=[C:40]4[C:35](=[CH:36][CH:37]=3)[C:34](=[O:51])[N:33]([CH:31]([CH3:32])[CH2:30][OH:29])[CH2:41]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CC(CO)N1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc5c(c4)CN(C(C)CO)C5=O)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 2-(2-hydroxy-1-methylethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=481.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:17])=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([CH2:17][OH:26])=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccnc(C)c1OCc1ccccc1
Solvent: ClCCl
Product: COc1ccnc(CO)c1OCc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
3-Benzyloxy-4-methoxy-2-methylpyridine (23.0 g) was dissolved in 200 ml of dichloromethane. m-Chloroperbenzoic acid (20.7 g) was added to the solution under ice cooling, and a reaction was allowed to proceed at room temperature overnight. The reaction product was washed with an aqueous saturated sodium hydrogensulfite solution and an aqueous saturated sodium hydrogencarbonate solution, and the washed reaction product was dried over anhydrous sodium sulfate. The solvent was concentrated under the reduced pressure. Acetic anhydride (200 ml) was added to 35.5 g of the concentrate as a light yellow oil, and a reaction was allowed to proceed at 100° C. for one hr. Ethanol (100 ml) was then added thereto, and the mixture was further refluxed for one hr. The reaction solution was concentrated under the reduced pressure. A 2 M solution (200 ml) of sodium hydroxide in 50% methanol was added to the concentrate, and the mixture was stirred at 80° C. for one hr. The reaction solution was concentrated under the reduced pressure. The concentrate was extracted with chloroform. The extract was washed with saturated brine, and was then dried over anhydrous sodium sulfate, followed by concentration under the reduced pressure to give 19.6 g (yield 80%) of 3-benzyloxy-2-hydroxymethyl-4-methoxypyridine as a yellowish brown solid.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12]2=[O:27])[S:5]([CH3:8])(=[O:7])=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:48]>C(Cl)Cl>[Br:48][CH2:2][CH2:3][N:4]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:12]2=[O:27])[S:5]([CH3:8])(=[O:7])=[O:6]
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(N(CCO)S(C)(=O)=O)cc2C1=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccc(N(CCBr)S(C)(=O)=O)cc2C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
To a stirred solution of tert-butyl 2-(5-(N-(2-hydroxyethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (as obtained from Example 38, step 1, 1.12 g, 2.81 mmol) in DCM (20 ml), triphenylphosphine (0.958 g, 3.65 mmol) was added. After 10 minutes at room temperature under stirring, CBr4 (1.212 g, 3.65 mmol) was added, and the mixture was stirred at the same temperature for additional 14 hours. The volatiles were removed under vacuum and the crude was purified by chromatography on silica gel column (petroleum ether:ethyl acetate=7:3) affording tert-butyl 2-(5-(N-(2-bromoethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate that crystallized on standing (0.980 g, 2.124 mmol, 76% yield).
Reaction SMILES: Br.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[O:19][C:18]([NH2:20])=[N:17][N:16]=3)=[CH:11][CH:10]=2)[CH:3]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32]>N1C=CC=CC=1.CO>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:20][C:18]2[O:19][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][C:4]4[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=4)=[CH:14][CH:13]=3)=[N:16][N:17]=2)=[O:27])=[CH:24][C:23]=1[C:31]([F:32])([F:33])[F:34]
Reactant: O=C(Cl)c1ccc(F)c(C(F)(F)F)c1
Reactant: Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1
Agent: Br
Solvent: c1ccncc1
Solvent: CO
Product: O=C(Nc1nnc(-c2ccc(Oc3cccnc3)cc2)o1)c1ccc(F)c(C(F)(F)F)c1
Reaction time: 18 h
Yield: 47.3 %

Procedure:
5-[4-(Pyridin-3-yloxy)phenyl]-1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. Neat 4-fluoro-3-trifluoromethylbenzoyl chloride (200 uL) was added directly into the solution. It was left to stir for 18 hours. The reaction mixture formed a red solution with a yellow precipitate. Then it was diluted with ca. 1 mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (105.1 mg). Yield 47.3%.
Reaction SMILES: [Si]([O:18][CH:19]1[CH2:24][CH:23]2[CH:21]([CH:22]2[C:25]2[N:29]([CH:30]([CH3:32])[CH3:31])[N:28]=[C:27]([I:33])[CH:26]=2)[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.F.F.F.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[I:33][C:27]1[CH:26]=[C:25]([CH:22]2[CH:21]3[CH:23]2[CH2:24][CH:19]([OH:18])[CH2:20]3)[N:29]([CH:30]([CH3:32])[CH3:31])[N:28]=1
Reactant: CC(C)n1nc(I)cc1C1C2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC21
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)n1nc(I)cc1C1C2CC(O)CC21
Yield: 100.9 %

Procedure:
A solution of 5-(3-((tert-butyldiphenylsilyl)oxy)bicyclo[3.1.0]hexan-6-yl)-3-iodo-1-isopropyl-1H-pyrazole (11.2 g, 19.7 mmol) and triethylamine trihydrofluoride (63 g, 391 mmol) in anhydrous tetrahydrofuran (100 mL) was heated at 70° C. for 6 h. Saturated aqueous sodium bicarbonate solution was added until the solution reached pH=7. The resulting aqueous mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (5:1 petroleum either/ethyl acetate) afforded crude 6-(3-iodo-1-isopropyl-1H-pyrazol-5-yl)bicyclo[3.1.0]hexan-3-ol as a pale yellow oil (6.6 g, 100%). LRMS: [M+H]+ 332.9.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:20]([O:21][CH3:22])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:23].O1CCOCC1>CO>[ClH:23].[ClH:23].[CH3:22][O:21][C:20]1[C:15]([N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1cccnc1N1CCCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COc1cccnc1N1CCCNCC1
Reaction time: 15 h

Procedure:
To 4-(3-methoxypyridin-2-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (335 mg, 1.1 mmol) was added MeOH (3 mL) followed by 4M HCl in dioxane (5 mL, 20 mmol). This was stirred for 15 hours, then concentrated to give the title compound. MS (ES) m/z 208 (M+H+).