Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:10](Cl)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:27]([NH:35][C:36]1[CH:41]=[C:40]([Cl:42])[C:39]([NH2:43])=[CH:38][C:37]=1[OH:44])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[C:27]([NH:35][C:36]1[CH:41]=[C:40]([Cl:42])[C:39]([NH:43][C:10](=[O:11])[CH:9]([O:8][C:7]2[CH:25]=[CH:26][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:38][C:37]=1[OH:44])(=[O:34])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Nc1cc(O)c(NC(=O)c2ccccc2)cc1Cl
Reactant: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)C(=O)Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(Oc1ccc([N+](=O)[O-])cc1)C(=O)Nc1cc(O)c(NC(=O)c2ccccc2)cc1Cl
Temperature: 5 °C

Procedure:
An amount of 843 g (2.1 mol) of 2-(p-nitrophenoxy]-myristoyl chloride is added dropwise in 60 min to a cooled (0°-5° C.) solution of 525 g (2 mol) of 2-benzamido-4-chloro-5-aminophenol in 6 l of tetrahydrofuran and 220 ml of quninoline. The temperature of the reaction mixture is kept below 10° C. The precipitate of quinoline hydrochloride is filtered off. The filtrate is concentrated by evaporation. The residual oil is poured out in 5 l of hot (50° C.) acetonitrile. Upon cooling to 5° C. a precipitate forms, whch is filtered, dried, and recrystallized from boiling isopropyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.[C:18]1([O:24][CH3:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([C:21]1[CH:22]=[CH:23][C:18]([O:24][CH3:25])=[CH:19][CH:20]=1)=[O:9]
Reactant: COc1ccccc1
Reactant: Cc1ccc(Br)cc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cc(Br)ccc2C)cc1
Reaction time: 6 h
Yield: 90.1 %

Procedure:
To a stirred suspension of Part A 5-bromo-2-methylbenzoic acid (43 g, 200 mmol) in 200 mL of CH2Cl2 containing oxalyl chloride (140 mL of a 2M CH2Cl2 solution) was added 0.25 mL of DMF. Once the vigorous evolution of gas ceased, the reaction was stirred 6 hr prior to removal of the volatiles using a rotary evaporator. After dissolving the crude 5-bromo-2-methylbenzoyl chloride in 150 ml of CS2, the resulting solution was cooled to 4° while stirring with an overhead stirrer prior to addition of anisole (21.6 g, 200 mmol) followed by AlCl3 (29.3 g, 220 mmol) in portions. The reaction, after warming to 20° over 1 hr, was stirred for 15 hr prior to quenching by pouring over ice/conc HCl. Subsequently, the suspension was diluted with 500 ml H2O and stirred until all solids were dissolved. The mixture was extracted 3× with EtOAc. The combined organic extracts were washed 1× with 1N HCl, H2O, aq NaHCO3, and brine prior to drying over Na2SO4. After removal of the volatiles, the resulting tan solid was recrystallized from 95% EtOH to yield 55 g of 5-bromo-2-methyl-4′-methoxybenzophenone.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7](O)=[N:8]2.[C:14](=O)([O-])[O-:15].[K+].[K+].CI.O>CN(C=O)C>[OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:10]([O:15][CH3:14])=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2
Reactant: O=C([O-])[O-]
Reactant: OCc1cccc2nc(O)ccc12
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CO)c2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
5-(Hydroxymethyl) quinolinol (6.7 g, 38 mmol) was dissolved in DMF (38 mL) and treated with potassium carbonate (16 g, 116 mmol) followed by methyl iodide (2.9 mL, 6.8 g, 48 mmol). The mixture was allowed to stir overnight at RT, then poured into a separatory funnel with water and extracted 3× DCM. The organic layer was dried over Na2SO4, and concentrated to give solid 5-hydroxymethyl-8-methoxyquinoline (6.5 g). 1H NMR (CDCl3) δ 8.97 (d, 1H), 8.51 (d, 1H) 7.49 (m, 2H), 6.99 (d, 1H), 5.05 (s, 2H), 4.09 (s, 3H).
Reaction SMILES: CO[C:3]([C:5]1([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)=[O:4].[OH-].[K+].CCN=C=NCCCN(C)C.[C:42]([C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=1)([CH3:45])([CH3:44])[CH3:43]>CO.CN(C1C=CN=CC=1)C.C(O)(=O)C.O.C1COCC1>[C:25]([O:24][C:22](=[O:23])[NH:21][C:5]1([C:3](=[O:4])[NH:50][C:49]2[CH:51]=[CH:52][C:46]([C:42]([CH3:45])([CH3:44])[CH3:43])=[CH:47][CH:48]=2)[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH2:7][CH2:6]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: COC(=O)C1(NC(=O)OC(C)(C)C)CCN(S(=O)(=O)c2ccc(C)cc2)CC1
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)(C(=O)Nc3ccc(C(C)(C)C)cc3)CC2)cc1
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
A mixture of 0.493 g (1.195 mmol) 4-tert-Butoxycarbonylamino-1-(toluene-4-sulfonyl)-piperidine-4-carboxylic acid methyl ester and 0.478 mL KOH 5N aq. in a mixture of methanol, THF and water was stirred for 1.5 h at 45° C. The mixture was acidified with acetic acid and evaporated to dryness. The residue was taken up in 2 mL DMF, 28.7 mg (0.154 mmol) EDCI, 18.8 mg (0.309 mmol) DMAP and 23 mg (0.154 mmol) 4-tert.-butyl aniline was added and the mixture was shaken for 24 h at room temperature. The mixture was evaporated to dryness and subjected to purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid to yield after evaporation of the product containing fractions 7.9 mg (10%) of the title compound. MS (m/e): 530.2 [(M+H)+].
Reaction SMILES: C([O:5][C:6](=[O:32])[CH2:7][C@H:8]([C:17]([N:19]1[C@@H:23]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:22][O:21][C:20]1=[O:31])=[O:18])[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>O>[CH2:24]([C@H:23]1[CH2:22][O:21][C:20](=[O:31])[N:19]1[C:17]([C@H:8]([CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)[CH2:7][C:6]([OH:32])=[O:5])=[O:18])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCC1CCCCC1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@@H](CCC1CCCCC1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 1 h

Procedure:
3-(R)-(4-(S)-Benzyl-2-oxo-oxazolidine-3-carbonyl)-5-cyclohexyl-pentanoic acid tert-butyl ester (2.01 g, 4.53 mmol, 1.0 eq) was treated with a 45:50:5 CH2Cl2:TFA:H2O solution. The reaction was monitored by LC/MS and complete after 1 hour. The solution was evaporated and provided a quantitative yield of 3-(R)-(4-(S)-Benzyl-2-oxo-oxazolidine-3-carbonyl)-5-cyclohexyl-pentanoic acid as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 0.80-0.91 (m, 2H), 1.09-1.27 (m, 6H), 1.44-1.53 (m, 1H), 1.61-1.73 (m, 6H), 2.12 (s, 2H), 2.35 (dd, 1H, J=17.2, 4.0 Hz), 2.49 (dd, 1H, J=13.6, 9.6 Hz), 2.71 (dd, 1H, J=17.6, 10.8 Hz), 3.03 (dd, 1H, J=13.6, 3.2 Hz), 3.87-3.97 (m, 3H), 4.43 (m, 1H), 6.90-7.10 (m, 5H).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:8](=[O:11])[C:9]=1[OH:10])(=[O:3])[CH3:2].[C:18](=O)([O-])[O-].[K+].[K+].IC.CN(C=O)C>O>[C:1]([C:4]1[O:5][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:8](=[O:11])[C:9]=1[O:10][CH3:18])(=[O:3])[CH3:2]
Reactant: CC(=O)c1oc(-c2ccccc2)cc(=O)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1c(C(C)=O)oc(-c2ccccc2)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
A mixture of 2-acetyl-3-hydroxy-6-phenyl-4H-pyran-4-one (200 mg), potassium carbonate (150 mg), iodomethane (0.0600 mL) and DMF (5.0 mL) was stirred at room temperature overnight. The reaction mixture was diluted with water and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (90.0 mg).
Reaction SMILES: [OH:1][N:2]1[CH:5]([CH2:6][OH:7])[CH:4]([N:8]2[CH:23]=[CH:22][C:12]([NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:9]2=[O:10])[C:3]1=[O:24].[CH3:25][O:26][C:27]1[CH:48]=[CH:47][C:30]([C:31](Cl)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[CH:29][CH:28]=1>N1C=CC=CC=1>[OH:1][N:2]1[CH:5]([CH2:6][O:7][C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:30]2[CH:29]=[CH:28][C:27]([O:26][CH3:25])=[CH:48][CH:47]=2)[CH:4]([N:8]2[CH:23]=[CH:22][C:12]([NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:9]2=[O:10])[C:3]1=[O:24]
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C(Nc1ccn(C2C(=O)N(O)C2CO)c(=O)n1)c1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(C(OCC2C(n3ccc(NC(=O)c4ccccc4)nc3=O)C(=O)N2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 8 h

Procedure:
1-N-Hydroxy-3-(N-benzoylcytosin-1-yl)-4-hydroxymethyl-2-azetidinone (10 mmole) is dissolved in pyridine (20 ml) and 4,4'-dimethoxytrityl chloride (12 mmole) is added and stirred under argon for 8 hours. The reaction mixture is concentrated under reduced pressure. The crude product is purified by flash chromatorgraphy using silica gel and ethyl acetate/dichloromethane/1% triethylamine as eluants to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:16][CH:17]=[CH2:18])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C(OC(=O)N[C@H]1C[CH:43]=[CH:42][C@@H:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:40](C)[C:39]1=O)(C)(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:39][N:40]([CH:41]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH:42]=[CH2:43])[C:13]([C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:16][CH:17]=[CH2:18])=[O:15]
Reactant: CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CC=C[C@H]1c1ccccc1
Reactant: C=CC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=CC[C@@H](NC(=O)OCc1ccccc1)C(=O)N(C)C(C=C)c1ccccc1
Temperature: -20 °C
Reaction time: 4 h
Yield: 133.8 %

Procedure:
To a solution of (2R)-2-{[(benzyloxy)carbonyl]amino}pent-4-enoic acid (3a) (1.1 g) in DCM (5 mL) at −20° C. under N2 was added a mixture of EDAC.HCl (1.02 g) and DMAP (12 mg) in DCM (8 mL) portionwise. Methyl(1-phenylprop-2-en-1-yl)amine (1d) (650 mg) in DCM (3 mL) was then added dropwise to the reaction mixture. The reaction mixture was stirred for 1.5 h at −20° C. and 4 h at RT, then diluted with DCM (100 mL) and washed with 0.2 N HCl, saturated NaHCO3, brine, dried (Na2SO4), filtered, and evaporated. The crude product was purified via flash chromatography (20% EtOAc/hexanes) to give the desired product as a viscous oil (1.04 g, 63%). 1H NMR (300 MHz, CDCl3) δ 2.38-2.47 (m, 1H), 2.50-2.59 (m, 1H), 2.66-2.82 (m, 3H-diastereomer/rotamer mixture), 4.77-4.80 (m, 1H), 5.08-5.17 (m, 4H), 5.22-5.48 (m, 2H), 5.69-5.82 (m, 2H), 6.03-6.14 (m, 1H), 6.39-6.43 (m, 1H), 7.25-7.35 (m, 10H). MS APCI, m/z=379 (M+1). LC/MS 2.72 min., Method A.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7](Br)[CH:6]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:52]([C:54]([OH:86])([CH2:84][CH3:85])/[CH:55]=[CH:56]/[C:57]1[CH:62]=[CH:61][C:60]([C:63]([CH2:81][CH3:82])([C:66]2[CH:71]=[CH:70][C:69](B3OC(C)(C)C(C)(C)O3)=[CH:68][CH:67]=2)[CH2:64][CH3:65])=[CH:59][C:58]=1[CH3:83])[CH3:53].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:6]=[C:7]([C:69]2[CH:68]=[CH:67][C:66]([C:63]([CH2:81][CH3:82])([C:60]3[CH:61]=[CH:62][C:57](/[CH:56]=[CH:55]/[C:54]([CH2:84][CH3:85])([OH:86])[CH2:52][CH3:53])=[C:58]([CH3:83])[CH:59]=3)[CH2:64][CH3:65])=[CH:71][CH:70]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: COC(=O)Cc1ccc(OC)c(Br)c1
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1C)CC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cc(CC(=O)OC)ccc3OC)cc2)cc1C)CC
Temperature: 100 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
(3-Bromo-4-methoxy-phenyl)-acetic acid methyl ester (Example 175-(1); 39 mg, 0.151 mmol), palladium acetate (2.2 mg, 0.010 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (8.2 mg, 0.020 mmol), potassium phosphate (64 mg, 0.303 mmol) and water (0.2 mL) were added to a solution of (E)-3-ethyl-1-(4-{1-ethyl-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1-penten-3-ol (Example 39-(5); 48 mg, 0.101 mmol) in toluene (2 mL). After replacement with nitrogen, the mixture was stirred at 100° C. for two hours. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give the target compound as a colorless oil (26.2 mg, 49%).
Reaction SMILES: C(OC([N:8]([CH:32]([CH3:34])[CH3:33])[C:9]1[S:10][C:11]([C:14]2[CH:15]=[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]3[N:18]([CH:20]=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)[CH:19]=2)=[CH:12][N:13]=1)=O)(C)(C)C>C(O)(C(F)(F)F)=O>[CH:32]([NH:8][C:9]1[S:10][C:11]([C:14]2[CH:15]=[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]3[N:18]([CH:20]=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)[CH:19]=2)=[CH:12][N:13]=1)([CH3:34])[CH3:33]
Reactant: CC(C)N(C(=O)OC(C)(C)C)c1ncc(-c2cc(-c3ccccc3)c3nc(C(=O)O)cn3c2)s1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1ncc(-c2cc(-c3ccccc3)c3nc(C(=O)O)cn3c2)s1
Yield: 52.8 %

Procedure:
A solution of 6-(2-(tert-butoxycarbonyl(isopropyl)-amino)thiazol-5-yl)-8-phenyl-imidazo[1,2-a]pyridine-2-carboxylic acid (100 mg, 0.2 mmol) in 3 ml of TFA was stirred at room temperature for 2 hours. The solvent was removed under vacuum and the residue purified by HPLC to give 40 mg of 6-(2-(isopropylamino)thiazol-5-yl)-8-phenylimidazo[1,2-a]pyridine-2-carboxylic acid. LCMS (Conditions C): 2.27 min (RT); (M+H)+=379.34 (100%). 1H NMR, 400 MHz, DMSO: δ 8.64 (s, 1 H), 8.52 (s, 1 H), 8.13 (d, J=7.3 Hz, 2 H), 7.83 (m, 2 H), 7.57-7.47 (m, 3 H), 3.87 (m, 1 H), 1.23 (d, J=6.5 Hz, 6 H).
Reaction SMILES: [CH:1]([N:4]([CH:19]([CH3:21])[CH3:20])[CH:5]([CH3:18])[CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].Cl.[NH2:23][NH:24][C:25]([NH2:27])=[O:26]>>[CH:1]([N:4]([CH:19]([CH3:21])[CH3:20])[CH:5]([CH3:18])[CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)/[C:10](=[N:23]\[NH:24][C:25]([NH2:27])=[O:26])/[C:8]1=[O:9])([CH3:3])[CH3:2]
Reactant: CC(C)N(C(C)C)C(C)CN1C(=O)C(=O)c2ccccc21
Reactant: NNC(N)=O
Agent: Cl
Product: CC(C)N(C(C)C)C(C)CN1C(=O)/C(=N/NC(N)=O)c2ccccc21
Yield: 77.6 %

Procedure:
By using 1-(2-diisopropylaminopropyl)isatin and semicarbazide hydrochloride, a method analogous to that described in Example 10 was carried out, and the reaction product was recrystallized from ethanol to obtain (E)-1-(2-diisopropylaminopropyl)isatin 3-semicarbazone having a melting point of 201°-204° C. (yield: 77.6%).
Reaction SMILES: [CH2:1]([CH:8]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[N:15]=2)[CH2:12][CH2:11][N:10]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([CH2:36][CH3:37])=[N:28][N:29]3[CH:32]3[CH2:35][CH2:34][CH2:33]3)=[CH:25][CH:24]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C1COCC1.O>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:23]2[CH:31]=[C:30]3[C:26]([C:27]([CH2:36][CH3:37])=[N:28][N:29]3[CH:32]3[CH2:35][CH2:34][CH2:33]3)=[CH:25][CH:24]=2)[CH2:11][CH2:12][N:13]1[C:14]1[N:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1nn(C2CCC2)c2cc(N3CCN(c4cccc([N+](=O)[O-])n4)C(Cc4ccccc4)C3)ccc12
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nn(C2CCC2)c2cc(N3CCN(c4cccc(N)n4)[C@@H](Cc4ccccc4)C3)ccc12
Yield: 2 %

Procedure:
Prepared using the same procedure described in Example 410 from 6-(3-benzyl-piperazin-1-yl)-1-cyclobutyl-3-ethyl-1H-indazole and 2-chloro-6-nitro-pyridine to afford the intermediate 6-[3-benzyl-4-(6-nitro-pyridin-2-yl)-piperazin-1-yl]-1-cyclobutyl-3-ethyl-1H-indazole {20.5 mg; LC/MS (Method B) 5.09 min, [M+1]+ 497]}. The nitro-intermediate was reduced with sodium hydrosulfite (48 mg, 0.28 mmol) in 50:50 THF/water at room temperature to obtain the title compound as a tan solid (6 mg, 2% overall). LC/MS (Method B) 4.02 min, [M+1]+ 467.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]([C:17]([NH2:19])=[O:18])=[CH:12][CH:11]=1)[CH3:2].[CH3:20]N(C)C=O>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]([C:17]([NH2:19])=[O:18])=[CH:12][CH:11]=1)[CH:2]=[CH2:20]
Reactant: CCOc1ccccc1-c1ccc(C(N)=O)c(=O)[nH]1
Reactant: CN(C)C=O
Product: C=CCOc1ccccc1-c1ccc(C(N)=O)c(=O)[nH]1

Procedure:
In a similar manner to that of Example 47, the product of Example 47 (1.89 g) gave the title compound, 1.74 g, m.p. 210°-212° C. (from dimethylformamide).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)=O>ClCCCl.P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:7]2[N:12]3[CH:13]=[CH:14][N:15]=[CH:16][C:11]3=[CH:10][N:9]=2)[CH:17]=1
Reactant: O=C(NCc1cnccn1)c1cc(Cl)ccc1O
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: Oc1ccc(Cl)cc1-c1ncc2cnccn12
Temperature: 25 °C
Yield: 18 %

Procedure:
A suspension of 5-chloro-2-hydroxy-N-(pyrazin-2-ylmethyl)benzamide (0.38 g, 1.4 mmol) in a mixture of 1,2-dichloroethane (6 mL) and phosphoryl chloride (6 mL) was heated at reflux for 2 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was suspended in water (10 mL), and the pH was adjusted to 6-7 with 1 N aqueous sodium hydroxide. The aqueous phase was extracted with ethyl acetate (3×30 mL) followed by dichloromethane (3×40 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with a 0-10% gradient of methanol in dichloromethane to afford 4-chloro-2-(imidazo[1,5-a]pyrazin-3-yl)phenol as a pale yellow solid in 18% yield (0.064 g): MS (ES+) m/z 245.9 (M+1), 247.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[H-].[Na+].Cl[CH2:15][CH2:16][O:17][CH2:18][CH2:19]Cl>CS(C)=O>[C:10]([C:9]1([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)#[N:11]
Reactant: ClCCOCCCl
Reactant: COc1ccc(CC#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccc(C2(C#N)CCOCC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.6 %

Procedure:
To a solution of 4-methoxyphenylacetonitrile (5 g, 34 mmol) and NaH (2.8 g, 71 mmol) in DMSO (50 ml) was added 2-chloroethyl ether (5.3 g, 37 mmol) with cooling. The mixture was stirred at room temperature for 3 h, quenched with water, and extracted with CH2Cl2. The combined extracts were dried (Na2SO4) and concentrated in vacuo to give an oil which was purified by a column chromatography to give Compound 88 (5.3 g, 24 mmol, 71%) as a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:30](O)(=[O:33])[CH:31]=[CH2:32]>>[C:30]([O:12][C:10]1[CH:11]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:7])=[C:8]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:9]=1)(=[O:33])[CH:31]=[CH2:32]
Reactant: C=CC(=O)O
Reactant: CC(C)(C)c1cc(O)cc(C(C)(C)C)c1O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: C=CC(=O)Oc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
3,5-di tert.butyl-4-hydroxyphenyl acrylate was prepared by stirring a mixture of 22 grams of 2,6-di tert.butyl hydroquinone, 25.2 grams of trifluoroacetic acid anhydride, and 9.4 grams of acrylic acid for 4 hours at room temperature. The product was precipitated by adding 100 milliliters of water to the reaction mixture and was then filtered off and dried. After recrystallizing twice from hexane, there was obtained 13.3 grams of product of melting point 100° C. to 102° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[NH2:17])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.NC1C2C(=CC=C(O[Si](C(C)(C)C)(C)C)C=2)C(Br)=CC=1.[C:43]([O:47][C:48]([NH:50][C@H:51]([C:56](O)=[O:57])[CH2:52][CH2:53]SC)=[O:49])([CH3:46])([CH3:45])[CH3:44].C(OC(N[C@@H](C(O)=O)CCSC)=O)(C)(C)C>>[C:43]([O:47][C:48]([NH:50][C@H:51]1[CH2:52][CH2:53][N:17]([C:16]2[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:10]=3)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:56]1=[O:57])=[O:49])([CH3:45])([CH3:46])[CH3:44]
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(-c2ccccc2N)c1
Agent: CC(C)(C)[Si](C)(C)Oc1ccc2c(Br)ccc(N)c2c1
Agent: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccccc2-c2cccc(O[Si](C)(C)C(C)(C)C)c2)C1=O

Procedure:
Following the procedures described in Example 24, Steps F-H, but using 2-(3-tert-butyldimethylsilyloxyphenyl)aniline rather than 1-amino-4-bromo-7-(tert-butyldimethylsilyloxy)naphthalene hydrochloride, and (S)-N-(tert-butoxycarbonyl) methionine rather than (R)-N-(tert-butoxycarbonyl)methionine, the above-titled compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:12])[CH:3]=1.Cl.[F:14][C:15]([F:20])([F:19])[C@@H:16]([NH2:18])[CH3:17].C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH:18][C@@H:16]([CH3:17])[C:15]([F:20])([F:19])[F:14])=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: C[C@H](N)C(F)(F)F
Reactant: O=C(Cl)c1cc(F)c(Cl)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)c1cc(F)c(Cl)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Chloro-2,5-difluorobenzoyl chloride (29.6 mg, 0.140 mmol) (Oakwood, Cat. #: 001628) was added to a mixture of (2S)-1,1,1-trifluoropropan-2-amine hydrochloride (20.0 mg, 0.134 mmol) (SynQuest Lab, Cat. #: 3130-7-S1) and diisopropylethylamine (58 μL, 0.33 mmol) in dichloromethylene (4.0 mL) at 0° C. The reaction mixture was stirred at room temperature for 30 min., worked up with saturated aqueous NaHCO3, and extracted with dichloromethylene (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=288.0/290.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11](OCC)=[O:12])=[C:7]2[C:16]([O:18]CC)=O.O.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[C:10]2[NH:9][C:8]3[C:11](=[O:12])[N:22]=[N:23][C:16](=[O:18])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1[nH]c2c(Cl)cccc2c1C(=O)OCC
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C1N=NC(=O)c2c1[nH]c1c(Cl)cccc21
Temperature: 25 °C
Yield: 23 %

Procedure:
To a stirred solution of diethyl 7-chloroindole-2,3-dicarboxylate (0.6 g, 2.0 mM) in ethanol (4 mL) was added hydrazine hydrate (2 mL, 40 mM). The resulting solution was heated to reflux for 3 hrs during which time a white precipitate formed. The solid was filtered, suspended in acetic acid (2 mL), and warmed to reflux for several minutes. The mixture was then cooled to room temperature and the solid filtered and dried. This provided the titled compound as a white solid (0.11 g, 23%), mp >250° C. NMR (d6 -DMSO): 12.92 (s, 1H), 11.66 (s, 2H), 8.08 (d, J=8 Hz, 1H), 7.56 (d, J=8 Hz), 7.32 (t, J=8 Hz). MS(CI): 236(M+1).