Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]2[C:3]=1[C:4]([CH2:17][CH2:18][C:19]([O:21]CC)=[O:20])=[C:5]([C:12]([O:14]CC)=[O:13])[NH:6]2.O.O.O.[OH-].[Li+].C(O)C.C(OCC)(=O)C>O1CCCC1.O.CO.CCCCCC>[C:19]([CH2:18][CH2:17][C:4]1[C:3]2[C:7](=[CH:8][C:9]([Br:11])=[CH:10][C:2]=2[Br:1])[NH:6][C:5]=1[C:12]([OH:14])=[O:13])([OH:21])=[O:20]
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c2cc(Br)cc(Br)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: O=C(O)CCc1c(C(=O)O)[nH]c2cc(Br)cc(Br)c12
Temperature: 25 °C
Yield: 95 %

Procedure:
Ethyl 4,6-dibromo-3-(3-ethoxy-3-oxopropyl)-1H-indole-2-carboxylate (4.47 g, 10 mmol) was dissolved in 25 ml tetrahydrofurane (THF) with stirring at rt. Then a solution of 1.26 g of lithium hydroxide trihydrate (3 equiv.) in 25 ml water was added and the resulting mixture was let to stir at rt for 24 h. After completion of the reaction THF was removed under reduced pressure and the pH was adjusted to 4-5, and the product was extracted with diethyl ether (3×30 ml). The organic layers were dried over magnesium sulfate, filtered, and evaporated to dryness to yield a light-beige-colored solid in 95-100% yield. mp. 259° C.; well soluble in methanol, ethanol and ethyl acetate; slightly soluble in petrol ether, water, hexane. 1H-NMR (MeOH-d4): δ 2.67 (t, 2H, 3J=8.4 Hz, CH2); 3.71 (t, 2H, 3J=8.4 Hz, CH2); 7.42 (d, 1H, 4J=1.6 Hz, C7-H); 7.62 (d, 1H, 4J=1.6 Hz, C5-H). 13C-NMR (MeOH-d4): δ 21.4 (C-2′); 37.9 (C-1′); 115.9 (C-7); 117.0 (C-4); 118.8 (C-6); 123.9 (C-3); 125.5 (C-2); 127.9 (C-3a); 128.2 (C-5); 139.6 (C-7a); 164.6 (2′-CO2H); 170.1 (2-CO2H). LC-MS (m/z): 392.0 [M]+; 390.0 [M]−. Purity (LC-MS): 99%.
Reaction SMILES: [CH3:1][N:2]([C:12](=[O:14])[CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[CH:4]=1>CO.O1CCOCC1.[C].[Pd]>[NH2:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[N:2]([CH3:1])[C:12](=[O:14])[CH3:13]
Reactant: CC(=O)N(C)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)N(C)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.6 %

Procedure:
A mixture of N-methyl-3′-nitroacetanilide (5.13 g) and 10% palladium carbon (0.6 g) in methanol (50 ml) and 1,4-dioxane (50 ml) and stirred under hydrogen (3 atm) at room temperature for 2 hours. The catalyst was removed by filtration and the solvent was evaporated. The resultant solid was collected and washed with isopropyl ether to give 3′-amino-N-methylacetanilide (4.06 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@H:14]2[C@@H:19]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:21])[CH2:18][CH2:17][NH:16][CH2:15]2)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:33]1[CH2:35][C@@H:34]1[CH2:36][O:37][C:38]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:39]=1[CH:40]=[CH:41][CH:42]=[N:43]2>C(O)(C)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C@H:14]2[C@@H:19]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:21])[CH2:18][CH2:17][N:16]([CH2:35][C@@H:34]([OH:33])[CH2:36][O:37][C:38]3[CH:47]=[CH:46][CH:45]=[C:44]4[C:39]=3[CH:40]=[CH:41][CH:42]=[N:43]4)[CH2:15]2)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Reactant: O=C(NCCCCc1ccccc1)[C@H]1CCNC[C@H]1C(=O)NCCCCc1ccccc1
Solvent: CC(C)O
Product: O=C(NCCCCc1ccccc1)[C@H]1CCN(C[C@@H](O)COc2cccc3ncccc23)C[C@H]1C(=O)NCCCCc1ccccc1
Temperature: 70 °C
Yield: 82.8 %

Procedure:
cis-Piperidine-3,4-dicarboxylic acid bis[(4-phenyl-butyl)-amide] (9) (70.9 mg; 0.163 mmol) is dissolved in isopropanol (10 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (32.8 mg; 0.163 mmol) is added then the mixture is heated to 70° C. and maintained for 18 hours. After cooling to ambient temperature the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (0%→50% methanol in methylene chloride) affording the desired product (86.0 mg) as an oil. ESMS:MH+ 637.4 (base).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1.C1(=O)O[CH2:21][CH2:20][O:19]1.C(=O)=O>[Cl-].C[N+](C)(C)C.O>[OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:21][CH2:20][OH:19])[CH:5]=[CH:4][C:3]=1[N:9]1[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]2=[N:10]1
Reactant: Oc1ccc(-n2nc3ccccc3n2)c(O)c1
Reactant: O=C1OCCO1
Agent: C[N+](C)(C)C
Agent: O=C=O
Agent: [Cl-]
Solvent: O
Product: OCCOc1ccc(-n2nc3ccccc3n2)c(O)c1
Temperature: 155 °C

Procedure:
A mixture of 45.4 g (0.2 mole) of 2-(2',4'-dihydroxyphenyl)benzotriazole, 19.8 g (0.225 mole) of ethylene carbonate and 0.55 g (0.005 mole) of tetramethylammonium chloride was heated under argon while stirring in an oil bath. The mixture changed to a brown melt as the temperature rose to 140° C. The argon gas flow was stopped at this point and the temperature was raised to 155° C. After the evolution of carbon dioxide stopped (7-8 hours), the reaction mixture was cooled to about 100° C. and then within 5 minutes 150 mL of water was added while stirring. The mixture was cooled to room temperature while stirring, at which point the semi-solid looking product crystallized. After suctioning off the solid, washing with water, and drying; 2-[2'-hydroxy, 4'-(2"-hydroxyethoxy)phenyl]benzotriazole was obtained having purity of 98% (HPLC). Yield: 51.5 g (95% of the theoretical).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].C(=O)([O-])[O-].[Li+:18].[Li+].[Li].C(O)(=O)C(C)O.C(O)(=O)C(O)=O.C(O)(=O)CC(CC(O)=O)C(O)=O>O>[C:1]([O-:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([O-:11])=[O:10])([C:5]([O-:7])=[O:6])[OH:4].[Li+:18].[Li+:18].[Li+:18]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: CC(O)C(=O)O
Agent: O=C(O)C(=O)O
Agent: O=C(O)CC(CC(=O)O)C(=O)O
Solvent: O
Product: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]

Procedure:
A 3N solution of lithium citrate was prepared by slowly adding 384.3 grams of Miles Laboratories 50% w/w citric acid to a stirred aqueous slurry of reagent grade lithium carbonate and, after complete additional of the citric acid, adding sufficient water to bring the total volume to one liter. 3N solutions of lithium neutralized lactic acid, oxalic acid, and tricarballylic acid were similarly prepared.
Reaction SMILES: C(O[CH2:5][C:6]([C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]([O:17][CH3:18])=[C:10]([O:19][CH3:20])[CH:9]=1)=O)(=O)C.[C:21]([C:24]1[C:25]([C:31]([F:34])([F:33])[F:32])=[N+:26]([O-:30])[CH:27]=[CH:28][CH:29]=1)(=[O:23])[NH2:22].B(F)(F)F.CCOCC>C1(C)C(C)=CC=CC=1>[CH3:20][O:19][C:10]1[CH:9]=[C:8]([C:6]2[N:22]=[C:21]([C:24]3[C:25]([C:31]([F:32])([F:34])[F:33])=[N+:26]([O-:30])[CH:27]=[CH:28][CH:29]=3)[O:23][CH:5]=2)[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[C:11]=1[O:17][CH3:18]
Reactant: COc1cc(C(=O)COC(C)=O)cc([N+](=O)[O-])c1OC
Reactant: NC(=O)c1ccc[n+]([O-])c1C(F)(F)F
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: COc1cc(-c2coc(-c3ccc[n+]([O-])c3C(F)(F)F)n2)cc([N+](=O)[O-])c1OC
Temperature: 25 °C

Procedure:
To a solution of 2-(3,4-dimethoxy-5-nitrophenyl)-2-oxoethyl acetate (4.24 g, 15 mmol) in xylene (30 mL) were added 3-carbamoyl-2-(trifluoromethyl)pyridine 1-oxide (3.40 g, 16.5 mmol) and boron trifluoride etherate (0.18 mL, 15 mmol). The resulting yellow solution was heated to reflux for 18 hours and then cooled to room temperature. After evaporation of the solvent, the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was separated, washed with brine and the dried over anhydrous magnesium sulphate, filtered and evaporated. The pure 3-(4-(3,4-dimethoxy-5-nitrophenyl)oxazol-2-yl)-2-(trifluoromethyl)pyridine 1-oxide was obtained by column chromatography over silica gel (petroleum ether/ethylacetate 2:1) as a pale yellow solid, 2.58 g (42%).
Reaction SMILES: [K].[CH3:2][O:3][CH2:4][C:5]([CH:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C:8]1=[O:22])=O.Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1.C(=O)(O)[O-].[Na+]>C1CCCCC1.C1(C)C=CC=CC=1>[F:36][C:37]1[CH:43]=[CH:42][C:40]([NH:41][C:5](=[C:7]2[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C:8]2=[O:22])[CH2:4][O:3][CH3:2])=[CH:39][CH:38]=1
Reactant: Nc1ccc(F)cc1
Reactant: COCC(=O)C1CCN(C(=O)OCc2ccccc2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: COCC(Nc1ccc(F)cc1)=C1CCN(C(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 74.8 %

Procedure:
Into a 100 mL eggplant-shaped flask were added benzyl 3-(2-methoxyacetyl)-2-oxopyrrolidine-1-carboxylate potassium salt (2.93 g) [mw. 329.39, 8.9 mmol], 1 mol/L hydrochloric acid (16 mL) [16 mmol] and toluene (32 mL), and the mixture was stirred for 20 min. After partitioning, the organic layer was concentrated under reduced pressure, and to the concentrate were added toluene (12 mL), cyclohexane (36 mL), p-toluenesulfonic acid monohydrate (18.0 mg) [mw. 190.22, 0.09 mmol] and p-fluoroaniline (0.99 g) [mw. 111.12, 8.9 mmol]. Dean-Stark trap was set, and the mixture was subjected to dehydration reflux for 2 hr. After cooling to 25° C., 5 w/w % aqueous sodium bicarbonate solution (10 mL) was added and the mixture was partitioned. The organic layer was washed with water (10 mL), dried over magnesium sulfate and, after filtration, concentrated under reduced pressure. To the concentrate were added toluene (20 mL) and 10 w/w % aqueous citric acid solution, and the mixture was stirred and partitioned. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. Yellow candy-like product, 2.56 g, yield 74.8%. 1H-NMR (500 MHz, CDCl3, TMS) δ 2.77 (s, 1H), 3.31 (s, 3H), 3.81 (t, J=5.0 Hz, 2H), 3.96 (s, 2H), 5.30 (s, 2H), 6.90-7.12 (m, 5H), 7.22-7.49 (m, 5H), 10.44 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[O:5][C:6]1[C:7]2[S:28][CH:27]=[CH:26][C:8]=2[N:9]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:11]=1.[Cl:32]/[CH:33]=[CH:34]\[C:35](O)=[O:36].Cl.CN(C)CCCN=C=NCC.C(Cl)(Cl)Cl>N1C=CC=CC=1.CC(O)C>[Cl:32]/[CH:33]=[CH:34]\[C:35]([NH:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:4]([O:5][C:6]2[C:7]3[S:28][CH:27]=[CH:26][C:8]=3[N:9]=[C:10]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH2:20][CH2:21][N:22]([CH3:25])[CH2:23][CH2:24]4)=[CH:17][CH:18]=3)[N:11]=2)[CH:3]=1)=[O:36]
Reactant: CN1CCN(c2ccc(Nc3nc(Oc4cccc(N)c4)c4sccc4n3)cc2)CC1
Reactant: O=C(O)/C=C\Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Product: CN1CCN(c2ccc(Nc3nc(Oc4cccc(NC(=O)/C=C\Cl)c4)c4sccc4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
The compound (50 mg, 0.12 mmol) obtained in Step 5 of Example 1 was dissolved in pyridine (1.5 mL), and cis-3-chloroacrylic acid (18 mg, 0.17 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloric acid salt (44 mg, 0.23 mmol) were added thereto, followed by stirring at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with a mixed solvent (chloroform:2-propanol=3:1 (volume ratio)) and washed with sat. brine. The organic layer was dried with anhydrous sodium sulfate and then filtered and distilled under a reduced pressure. The residue was separated by column chromatography (dichloromethane:methanol=6:1 (volume ratio)) to obtain the title compound (yield: 15 mg, 24%).
Reaction SMILES: Br[C:2]1[C:3]([Cl:20])=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[O:5][C:6]1[C:14]2[N:13]=[N:12][NH:11][C:10]=2[CH:9]=[CH:8][C:7]=1[Cl:15].[CH3:21][N:22](C=O)C>CCOC(C)=O.[C-]#N.[Zn+2].[C-]#N>[Cl:20][C:3]1[C:4]([O:5][C:6]2[C:14]3[N:13]=[N:12][NH:11][C:10]=3[CH:9]=[CH:8][C:7]=2[Cl:15])=[CH:16][C:17]([Cl:19])=[CH:18][C:2]=1[C:21]#[N:22]
Reactant: CN(C)C=O
Reactant: Clc1cc(Br)c(Cl)c(Oc2c(Cl)ccc3[nH]nnc23)c1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc3[nH]nnc23)c1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-(3-bromo-2,5-dichlorophenoxy)-5-chloro-1H-1,2,3-benzotriazole (2.55 g, 6.49 mmol), tetrakis triphenylphosphine palladium(0) (2.25 g, 1.95 mmol) and zinc cyanide (0.915 g, 7.79 mmol) were suspended in dry DMF (50 mL) under N2 and placed in an oil bath at 90° C. for 24 hours, after which the reaction mixture was allowed to cool to room temperature. The cooled mixture was then diluted with EtOAc (200 mL) and washed with water (4×100 mL), the aqueous layer was extracted with EtOAc (100 mL) and then washed with water (4×50 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated with silica gel. The concentrate was purified by automated column chromatography on silica gel (40 g) eluting with 0-30% EtOAc/hexanes to afford the title compound. LRMS (M+1)=340.16.
Reaction SMILES: Br[C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[CH3:11][O:12][CH2:13][O:14][C:15]1[C:20]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:19][C:18]([CH2:25][CH3:26])=[CH:17][C:16]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:10][C:5]1[CH:4]=[CH:3][C:2]([C:16]2[CH:17]=[C:18]([CH2:25][CH3:26])[CH:19]=[C:20]([C:21]([CH3:24])([CH3:22])[CH3:23])[C:15]=2[O:14][CH2:13][O:12][CH3:11])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCc1cc(B(O)O)c(OCOC)c(C(C)(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCc1cc(-c2ccc(O)c(C=O)c2)c(OCOC)c(C(C)(C)C)c1
Yield: 76.9 %

Procedure:
To a mixture of 91 mg (0.078 mmol, 5%) of Pd(PPh3)4 and 252 mg (1.26 mmol) of 5-bromo salicylaldehyde in 10 mL of dry toluene was added 685 mmol (2.5 mmol, 2 equivalents) of 2-methoxymethoxy-3-tert-butyl-5-ethyl phenylboronic acid diluted in 5 mL of ethanol followed by 1.3 mL of a 2N aqueous solution of Na2CO3. The mixture was stirred at reflux for 3 hours and after cooling extracted with ethyl acetate. The organic layer was dried over MgSO4 and evaporated under reduced pressure. The residual oil was purified over silica gel (eluent: ethyl acetate/hexane: 10/90) to give 333 mg (0.969 mmol, yield: 77%) of 2-hydroxy-5-(5-ethyl-3-tert-butyl-2-methoxymethoxyphenyl)-benzaldehyde a pale brownb oil. 1H NMR (CDCl3), δ: 11.04 (s, 1H), 9.95 (s, 1H), 7.75 (dd, J=8.9, 2.1 Hz, 1H), 7.74 (d, J=2.1 Hz, 1H), 7.19 (d, J=2.1 Hz, 1H), 7.06 (d, J=8.9 Hz, 1H), 6.98 (d, J=1.9 Hz, 1H), 4.52 (s, 2H), 3.29 (s, 3H), 2.64 (dd, J=15.2, 7.6 Hz, 2H), 1.47 (s, 9H), 1.26 (t, J=7.4 Hz, 3H).
Reaction SMILES: Br[CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5].[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[CH:14]=[C:13]([CH:18]([CH3:22])[C:19]([OH:21])=[O:20])[CH:12]=[CH:11]2>>[CH3:22][CH:18]([C:13]1[CH:12]=[CH:11][C:10]2[C:15](=[CH:16][CH:17]=[C:8]([O:7][CH2:2][CH:3]=[C:4]([CH3:6])[CH3:5])[CH:9]=2)[CH:14]=1)[C:19]([OH:21])=[O:20]
Reactant: CC(C)=CCBr
Reactant: CC(C(=O)O)c1ccc2cc(O)ccc2c1
Product: CC(C)=CCOc1ccc2cc(C(C)C(=O)O)ccc2c1

Procedure:
The title compound is prepared according to the method of Example 7 using 1-bromo-3-methyl-2-butene and racemic 6-hydroxy-α-methyl-2-naphthalene acetic acid. White crystals are obtained having a melting point of 97°-100° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[CH:14]=[C:13]([NH:15][CH3:16])[O:12][N:11]=2)[CH3:9])[CH:5]=[CH:4][C:3]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:23]([N:31]=[C:32]=[S:33])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[C:23]([NH:31][C:32](=[S:33])[N:15]([C:13]1[O:12][N:11]=[C:10]([CH:8]([C:6]2[CH:5]=[CH:4][C:3]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[C:2]([F:1])[CH:7]=2)[CH3:9])[CH:14]=1)[CH3:16])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CNc1cc(C(C)c2ccc(-c3ccccc3)c(F)c2)no1
Solvent: c1ccncc1
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1cc(N(C)C(=S)NC(=O)c2ccccc2)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
A solution consisting of {3-[1-(2-fluoro-biphenyl-4-yl)-ethyl]-isoxazol-5-yl}-methyl-amine (4.06 g), pyridine (40 ml) and benzoyl isothiocyanate (2.5 g) was stirred overnight at room temperature. The solution was concentrated and the residue was purified by a silica gel column chromatography to obtain the desired compound (5.28 g).
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].C[O:7][C:8](=O)[C@@H:9]1[CH2:13][C@@H:12]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][N:10]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].Cl>C(O)C.O>[CH2:25]([O:24][C:22]([N:10]1[CH2:11][C@H:12]([O:14][Si:15]([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:17])[CH3:16])[CH2:13][C@H:9]1[CH2:8][OH:7])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: O
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CO)N(C(=O)OCc2ccccc2)C1
Reaction time: 2 h

Procedure:
To a suspension of calcium chloride (53.55 g) in dry ethanol (455 ml), sodium borohydride (26.6 g) was added under nitrogen stream while ice-cooling, and the resultant suspension was stirred at the same temperature for 1 hour. A solution of trans-1-benzyloxycarbonyl-4-t-butyldimethylsilyloxy-L-proline methyl ester (68.87 g) in dry ethanol (200 ml) was added thereto while ice-cooling, and the resulting mixture was stirred at the same temperature for 1 hour and at 25° to 30° C. for 2 hours. The reaction mixture was neutralized with 6N hydrochloric acid, poured into water, extracted with ethyl acetate, washed with aqueous sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gave (2S,4R)-1-benzyloxycarbonyl-2-hydroxymethyl-4-t-butyldimethylsilyloxypyrrolidine.
Reaction SMILES: [F:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:15]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[O:16])[CH:12]=3)[NH:7][C:6]=2[C:5]([C:23]([NH2:25])=[O:24])=[CH:4][CH:3]=1.C1C(=O)N([Br:33])C(=O)C1>CN(C=O)C>[Br:33][C:3]1[CH:4]=[C:5]([C:23]([NH2:25])=[O:24])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[F:1])=[CH:12][C:11]([C:15]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[O:16])=[CH:10][CH:9]=3
Reactant: O=C1CCC(=O)N1Br
Reactant: NC(=O)c1ccc(F)c2c1[nH]c1ccc(C(=O)N3CCOCC3)cc12
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Br)c(F)c2c1[nH]c1ccc(C(=O)N3CCOCC3)cc12
Temperature: 80 °C

Procedure:
4-Fluoro-6-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide (9 mg, 0.026 mmol) was mixed with NBS (5.5 mg, 0.031 mmol) in DMF (1.5 mL). The mixture was stirred at 80° C. for 20 mins More NBS (3 mg, 0.017 mmol) was added to the mixture and heated at 80° C. for another 20 mins. The mixture was concentrated and purified using preparative HPLC to give 3-bromo-4-fluoro-6-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide. MS (ESI) m/z 420 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.72 (s, 1H), 8.32 (d, 1H, J=6.5), 8.28 (bs, 1H), 8.13 (s, 1H), 7.85(d, 1H, J=8.3), 7.64 (bs, 1H), 7.58(dd, 1H, J=8.5, 1.6), 3.7-3.5 (bm, 8H).
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[CH:5]=[C:4](Cl)[N:3]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CS(C)=O>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[CH:5]=[C:4]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[N:3]=1
Reactant: Nc1nc(Cl)cc2nc(-c3ccco3)nn12
Reactant: C1CNCCN1
Solvent: CS(C)=O
Product: Nc1nc(N2CCNCC2)cc2nc(-c3ccco3)nn12
Temperature: 150 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
Into 180 mL of DMSO, 10.5 g (44.6 mmol) of Compound E and 19.2 g (223 mmol) of piperazine were dissolved, followed by stirring at 150° C. for about 2 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. After evaporation of the solvent, the resulting residue was purified by silica gel column chromatography (23% aqueous ammonia/methanol/chloroform=1/10/90) and then recrystallized from ethyl acetate to obtain 9.91 g of Compound F as a white solid (yield: 78%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[O:12])[N:7]([C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[N:27][N:28]3C(OC(C)(C)C)=O)=[CH:24][CH:23]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.CCO.Cl>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])=[O:12])[N:7]([C:22]2[CH:30]=[C:29]3[C:25]([CH:26]=[N:27][NH:28]3)=[CH:24][CH:23]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)n1ncc2ccc(-n3nc(C(C)(C)C)cc3NC(=O)Nc3cccc(Cl)c3Cl)cc21
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)n(-c2ccc3cn[nH]c3c2)n1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
A solution of yield of t-butyl 6-(3-t-butyl-5-(3-(2,3-dichlorophenyl)ureido)-1H-pyrazol-1-yl)-1H-indazole-1-carboxylate (0.13 g, 0.239 mmol, 1.00 eq) in satd. HCl/EtOH (5.00 ml) and stirred at 65° C. for 2 h until the reaction was clear and homogeneous. It was cooled to RT and evaporated. The syrupy residue was dissolved in MeCN/H2O, frozen and lyophilized to yield 1-(3-t-butyl-1-(1H-indazol-6-yl)-1H-pyrazol-5-yl)-3-(2,3-dichlorophenyl)urea (97.1 mg, 85% yield) as the HCl salt. 1H NMR (DMSO-d6): δ 9.32 (s, 1H), 8.81 (s, 1H), 8.17-8.16 (m, 1H), 8.13-8.12 (m, 1H), 8.10-8.07 (m, 1H), 7.92-7.82 (m, 1H), 7.65-7.59 (m, 1H), 7.24-7.25 (m, 2H), 6.44 (s, 1H), 1.30 (s, 9H); MS (ESI) m/z: 443.0 (M+H+), 445.0 (M+2+H+).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([C:11]2[CH:15]=[CH:14][NH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Cl:16][C:17]1[N:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>C(Cl)Cl.C(OCC)(=O)C>[Cl:16][C:17]1[C:18]([C:19]([C:12]2[NH:13][CH:14]=[CH:15][C:11]=2[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:20])=[CH:22][CH:23]=[CH:24][N:25]=1
Reactant: c1ccc(-c2cc[nH]c2)cc1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1cccnc1Cl)c1[nH]ccc1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
Aluminum chloride (1.33 g, 10 mmol) was added to a mixture of 3-phenyl-1H-pyrrole (1.35 g, 9.4 mmol, prepared as described in Journal of Organic Chemistry, 62: 2650 (1997) (incorporated herein by reference) and 2-chloronicotinoyl chloride (1.65 g, 9.4 mmol) in DCM (15 mL) at 0° C. The mixture was stirred at 0° C. for 30 mins and at room temperature for one hour. The reaction was diluted with ethyl acetate and washed with brine, 2N NaOH, brine, dried and concentrated. The residue was purified on silica gel column to give 0.682 g (26%) of (2-chloro-pyridin-3-yl)-(3-phenyl-1H-pyrrol-2-yl)-methanone.