Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH:15]=O>C1(C)C=CC=CC=1.N1CCCCC1.C(O)(=O)C>[Cl:12][C:13]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:14]=1[CH:15]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1ccc(Cl)cc1Cl)C(=O)OCC
Temperature: 70 °C
Yield: 101 %

Procedure:
To a stirred solution of diethyl malonate (0.92 g, 5.71 mmol) in toluene (10 mL) was added 2,4-dichlorobenzaldehyde (1 g, 5.71 mmol), piperidine (23 μL, 0.23 mmol), acetic acid (13 μL, 0.23 mmol) and molecular sieves (3 Å). The reaction was heated to 70° C. for 2 days and was concentrated under reduced pressure. The residue was filtered through a pad of silica flushing with EtOAc/hexane (1:1) solution. The filtrate was concentrated to give diethyl 2-(2,4-dichlorobenzylidene)malonate (1.83 g, 97%) as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:17]([C:7]1[N:8]([CH2:12][C:13]2[N:16]=[C:29]([C:28]3[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=3)[O:15][N:14]=2)[C:9]2[C:5]([CH:6]=1)=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)[CH2:18][CH3:19]
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1
Temperature: 150 °C
Yield: 41.4 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (3.0 mL) under N2, was added 3-(trifluoromethyl)benzoyl chloride (0.256 g, 1.23 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.061 g (41% yield) of pure product: MS (ES) m/z 478 (M+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:21][C:20]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][C:23]=4[F:32])=[N:19][C:18]=3[CH:33]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(Cl)Cl.[OH2:37]>C(Cl)Cl>[F:32][C:23]1[CH:24]=[C:25]([S:28]([CH3:31])(=[O:29])=[O:30])[CH:26]=[CH:27][C:22]=1[C:20]1[O:21][C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH2:12][CH2:13][N:8]([C:1]([O:21][CH:17]([CH3:18])[CH3:16])=[O:37])[CH2:9][CH2:10]3)=[CH:33][C:18]=2[N:19]=1
Reactant: O
Reactant: CS(=O)(=O)c1ccc(-c2nc3cc(N4CCN(Cc5ccccc5)CC4)ccc3o2)c(F)c1
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCN(c2ccc3oc(-c4ccc(S(C)(=O)=O)cc4F)nc3c2)CC1

Procedure:
Intermediate 28 (490 mg, 1.32 mmol), N-Benzylpiprazine (280 mg, 1.6 mmol), K2CO3 (190 mg, 1.4 mmol), CuCl (6.5 mg, 0.05 mmol), acetyl acetone (17 mg, 0.12 mmol) were dissolved in NMP (2 ml). This reaction mixture was stirred at 130° C. for 15 h under N2 atmosphere. Work up (EtOAc/H2O) followed by column purification on 60-120 mesh silica gel using a gradient mixture of EtOAc and Petether (1:1) as eluent afforded 5-(4-benzylpiperazin-1-yl)-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazole (250 mg) as a yellow solid. 5-(4-Benzylpiperazin-1-yl)-2-[2-fluoro-4-(methylsulfonyl)phenyl]benzo[d]oxazole (130 mg, 0.28 mmol) dissolved in DCM (15 ml) and added isopropylchloro formate (102 mg, 0.84 mmol). This mixture was stirred at reflux for 18 h. Work up (DCM/H2O) followed by purification of the crude by column chromatography on 230-400 mesh silica gel using a gradient mixture of EtOAc and Petether (30:70) as eluent afforded the titled compound (25 mg) as a pale-yellow solid. M.P.: 231-234° C. 1H-NMR (δ ppm, CDCl3, 400 MHz): 8.28 (d, J 8.7, 1H), 7.96 (d, J 1.6, 1H), 7.68-7.64 (m, 2H), 7.57-7.47 (m, 2H), 4.95 (septet, J 6.2, 1H), 3.71-3.63 (m, 4H), 3.12-3.06 (m, 4H), 1.26 (d, J 6.2, 6H).
Reaction SMILES: [CH:1]1([NH:5][CH2:6][C:7]2[N:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:4][CH2:3][CH2:2]1.Br[C:15]1[C:16](=[O:23])[N:17]([CH3:22])[N:18]=[C:19]([Cl:21])[CH:20]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[Cl:21][C:19]1[CH:20]=[C:15]([NH:13][C:10]2[CH:9]=[N:8][C:7]([CH2:6][NH:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)=[CH:12][N:11]=2)[C:16](=[O:23])[N:17]([CH3:22])[N:18]=1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: Nc1cnc(CNC2CCC2)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1nc(Cl)cc(Nc2cnc(CNC3CCC3)cn2)c1=O
Temperature: 105 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
In a 15 mL microwave reaction vial was added a solution of 5-((cyclobutylamino)methyl)pyrazin-2-amine (280 mg, 1.57 mmol, Eq: 1.00) in dioxane (7 ml) under argon bubbling. To the solution was added 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (456 mg, 2.04 mmol, Eq: 1.3), Cs2CO3 (1.3 g, 3.99 mmol, Eq: 2.54), xantphos (136 mg, 236 μmol, Eq: 0.15) and bis(dibenzylideneacetone)palladium (67.7 mg, 118 μmol, Eq: 0.075). The reaction tube was sealed and heated in oil bath at 105° C. (bath temp) for 7 hrs then stirred at room temperature overnight. The crude reaction mixture was filtered and the solid was washed with dioxane (20 mL) and DCM (5 mL). The combined filtrate and washes were concentrated and absorbed on silica gel. The mixture was purified by LC chromatography (silica gel, 60 g) and eluted with 0-10% (10% NH4OH in MeOH) in (1/1) EtOAc/Heptane to afford 197 mg (39%) of the title compound.
Reaction SMILES: [CH:1]([S:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)[CH3:6])([CH3:3])[CH3:2].[H][H]>C(O)C.[Ni]>[CH:1]([S:4][CH:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)SC(C)c1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CC(C)SC(C)c1ccccc1N
Yield: 87.1 %

Procedure:
44 g (0.188 mol) 1-[1-(isopropylthio)ethyl]-2-nitrobenzene (VII-1) are dissolved in 250 ml ethanol, mixed with 3 g Raney nickel and hydrogenated in the autoclave for 6 hours at room temperature with 3 bar of hydrogen. After 6 hours another 3 g Raney nickel are added and hydrogenation is continued for another 16 hours at room temperature with 3 bar hydrogen. The catalyst is then removed by filtration and the solvent removed under vacuum. The crude product is purified by column chromatography (silica gel, 3:1 hexane/methyl t-butyl ether). 32 g (97.3% purity by HPLC, 84.4% theoretical yield) of 2-[1-(isopropylthio)ethyl]aniline are obtained as a yellow oil [logP (pH 2.3)=2.45].
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-:3])=[O:2].[H-].[Na+].S(O[CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]1)(C1C=CC(C)=CC=1)(=O)=O>CC(N(C)C)=O.O>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][N:8]2[CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:28]1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCN(C(=O)OC(C)(C)C)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(Cn2ncc3c([N+](=O)[O-])cccc32)C1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 39.7 %

Procedure:
To a solution of 4-nitro-1H-indazole (0.200 g, 1.23 mmol) in DMA (3 mL) was added 60% sodium hydride (0.074 g, 1.84 mmol) at ambient temperature. After 30 minutes, tert-butyl 3-(tosyloxymethyl)piperidine-1-carboxylate (0.544 g, 1.47 mmol) was added. The mixture was heated at 100° C. overnight, diluted with water, extracted with DCM, dried (phase separator silicone treated filter paper), concentrated and the residue purified on silica gel (10-50% EtOAc in DCM) to provide tert-butyl 3-((4-nitro-1H-indazol-1-yl)methyl)piperidine-1-carboxylate (0.176 g, 40% yield) as a yellow gum.
Reaction SMILES: Br[CH2:2][C:3]#[N:4].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([F:13])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:2][C:3]#[N:4])=[C:8]([F:13])[CH:7]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1ccc(Br)cc1F
Reaction time: 12 h

Procedure:
Bromoacetonitrile (1.81 ml, 0.026M) was added to a solution of 4-bromo-2-fluorophenol (5.0 g, 0.026M) and potassium carbonate (3.54 g, 0.026M) in DMF (50 ml). The reaction was stirred for 12 hours and then partitioned between diethyl ether (200 ml) and water (200 ml). The organics were separated, dried over magnesium sulfate, filtered and concentrated in vacuuo to afford the title compound as a yellow oil (6.0 g). 1H NMR (CDCl3): δ 4.84 (s, 2H), 7.03-7.10 (m, 2H), 7.21 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([OH:11])[C:5]2=[C:4]([CH3:12])[CH:3]=1.[N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[C:14]=[O:15]>C1COCC1>[CH2:16]([NH:13][C:14]([N:9]1[C:10](=[O:11])[C:5]2[C:6](=[N:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:12])[NH:8]1)=[O:15])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCN=C=O
Reactant: Cc1cc(Cl)nc2[nH]nc(O)c12
Solvent: C1CCOC1
Product: CCCCCCNC(=O)n1[nH]c2nc(Cl)cc(C)c2c1=O

Procedure:
In analogy to example 1c, 500 mg (2.72 mmol) of 6-chloro-4-methyl-1H-pyrazolo-[3,4-b]pyridin-3-ol were reacted with 346.3 mg (2.72 mmol) of 1-isocyanatohexane in THF at 60° C. Yield: 428 mg (51%), M+H+: 311.27.
Reaction SMILES: FC(F)(F)C1C=CC(COC2C=C(CO)C=CC=2)=CC=1.C[O:22][C:23](=[O:55])[CH2:24][O:25][C:26]1[CH:34]=[CH:33][C:32]([S:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=3)[CH:38]=2)=[C:31]2[C:27]=1[CH2:28][CH2:29][CH2:30]2>>[F:53][C:51]([F:52])([F:54])[C:48]1[CH:49]=[CH:50][C:45]([CH2:44][O:43][C:39]2[CH:38]=[C:37]([CH:42]=[CH:41][CH:40]=2)[CH2:36][S:35][C:32]2[CH:33]=[CH:34][C:26]([O:25][CH2:24][C:23]([OH:55])=[O:22])=[C:27]3[C:31]=2[CH2:30][CH2:29][CH2:28]3)=[CH:46][CH:47]=1
Reactant: COC(=O)COc1ccc(SCc2cccc(OCc3ccc(C(F)(F)F)cc3)c2)c2c1CCC2
Agent: OCc1cccc(OCc2ccc(C(F)(F)F)cc2)c1
Product: O=C(O)COc1ccc(SCc2cccc(OCc3ccc(C(F)(F)F)cc3)c2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 3B using 79A. MS m/z 265 (M-Cl). Step 3. Preparation of {7-[3-(4-Trifluoromethyl-benzyloxy)-benzylsulfanyl]-indan-4-yloxy}-acetic acid methyl ester (Compound 79C)
Reaction SMILES: [CH3:1][O:2][C:3]1([C:14](=[O:16])[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:4]1[CH:5]([OH:9])[C:6]([OH:8])=O.S(Cl)(Cl)=O.[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C=O)C.C(Cl)Cl.O.C1(C)C=CC=CC=1>[CH3:21][N:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:6](=[O:8])[CH:5]([CH:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]1([O:2][CH3:1])[C:14](=[O:16])[CH3:15])[OH:9]
Reactant: COC1(C(C)=O)C=CC=CC1C(O)C(=O)O
Reactant: CNc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1(C(C)=O)C=CC=CC1C(O)C(=O)N(C)c1ccccc1
Reaction time: 8 h
Yield: 95.4 %

Procedure:
22.4 g (0.1 mol) of 2-methoxy-0-acetylmandelic acid were heated under reflux with 100 ml of toluene and 28.8 ml (0.4 mol) of thionyl chloride in the presence of 2 drops of DMF for 2.5 hours. The excess thionyl chloride and the solvent were removed by distillation in vacuo. The residue was dissolved in 25 ml of methylene chloride. To this solution of the acid chloride were added dropwise 10.7 g of N-methylaniline (0.1 mol) and 13.8 ml (0.1 mol) of triethylamine in 100 ml of methylene chloride within 30 minutes. The reaction mixture is left to stand overnight and then 100 ml of water are added. The phases are separated, and the organic phase is washed successively with 50 ml each of 1 N HCl, saturated NaHCO3 solution and water. After drying with anhydrous magnesium sulfate, the solvent is evaporated in vacuo, and the residue is triturated with diisopropyl ether and is filtered off with suction. 30.1 g of crystals of melting point 84°-86° C. are obtained. H NMR (CDCl3): δ=6.4-7.5 (m,9H), 6.23 (s,1H), 3.27 (s,3H), 3.2 (s,3H), 2.08 (s,3H).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C>O1CCCC1>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[S:3][C:4]=2[CH:10]=1
Reactant: COc1ccc2nc(Cl)sc2c1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2nc(N3CCNCC3)sc2c1
Temperature: 160 °C

Procedure:
A mixture of 1.50 mmol 2-chloro-6-methoxybenzothiazole (CA=[2605-14-3]), 4.51 mmol of piperazine and 4.51 mmol of triethylamine in 5 ml of tetrahydrofuran in a sealed tube was heated at 160° C. for 5 min under microwave irradiation. The reaction mixture was concentrated, and the residue was purified by chromatography (SiO2, methanol/dichloromethane) to yield the title compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:16]=[C:15]2[N:6]([C:7](=[O:17])[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=32)[N:5]=1)(=[O:3])[CH3:2].CC(C)=O.[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)C.[NH4+].[Cl-]>O1CCCC1>[OH:3][C:1]([C:4]1[CH:16]=[C:15]2[N:6]([C:7](=[O:17])[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=32)[N:5]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:2]
Reactant: CC(=O)c1cc2c3ccccc3[nH]c(=O)n2n1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC(O)(c1ccccc1)c1cc2c3ccccc3[nH]c(=O)n2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5.0 g (0.022 mole) of the methyl ketone 2-acetylpyrazolo[1,5-c]quinazolin-5(6H)-one prepared as in Example 4A is suspended under argon in dry distilled tetrahydrofuran (100 ml) and treated quickly with 7.0 ml (~1.0 equivalent) of 3 M C6H5MgBr/ethyl ether. The mixture is stirred for 5 minutes and another 15 ml (~2 equivalents) of the Grignard reagent is quickly added. The reaction mixture (dark brown) is stirred at room temperature for 30 minutes and then refluxed for another 30 minutes, cooled down to room temperature and the resulting reddish solution is treated with 8.0 ml of saturated NH4Cl solution. The mixture is diluted with 70 ml tetrahydrofuran and stirred at room temperature for ~1 hour. The inorganic salts are filtered off and washed well with tetrahydrofuran (30 ml) and CHCl3 (50 ml). The filtrates are combined and stripped to dryness. Yield: 8.4 g; 3 spots on TLC.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[N+:10]([O-])([OH:12])=[O:11]>C(Cl)Cl>[N+:10]([C:7]1[CH:8]=[C:3]([S:2][CH3:1])[CH:4]=[CH:5][C:6]=1[OH:9])([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: CSc1ccc(O)cc1
Solvent: ClCCl
Product: CSc1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(methylthio)phenol(5.0 g) in methylene chloride (100 mls) was added 30% nitric acid absorbed on silica (9.29 g) and the mixture stirred at room temperature for 3 hrs. The mixture was filtered and washed with methylene chloride. The solvent was evaporated and the residue was purified by flash chromatography eluting with ethyl acetate and hexane (15:85 v/v) to give 2-nitro-4-(methylthio)phenol as an orange solid (2.22 g); NMR (200 MHz, CDCl3): 2.50(3H,s), 7.10(1H,d,J=8 Hz), 7.51(1H,dd,J=8 Hz), 7.95(1H,d,J=3 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[C:14]([NH2:19])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:35][CH2:36][C:37](Cl)=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:20]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:37]([CH2:36][Cl:35])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cnc2cc(OCc3ccccc3)ccc2c1NCC1CCOCC1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ClCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC1CCOCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 190.4 %

Procedure:
To a stirred solution of 7-(benzyloxy)-N4-(tetrahydro-2H-pyran-4-ylmethyl)quinoline-3,4-diamine (51.2 g, 0.141 mol) and triethylamine (39.94 g, 0.395 mol) in dichloromethane (410 mL) at 0° C. was added a solution of chloroacetyl chloride (8.67 g, 76.80 mmol) in dichloromethane (40 mL) drop wise by addition funnel. The reaction was stirred at ambient temperature for 17 hours then heated to reflux for 6 hours. The crude mixture was cooled to ambient temperature and partitioned between water and dichloromethane (200 mL). The layers were separated and the aqueous layer extracted with dichloromethane (2×300 mL). The organic layers were combined, washed with brine (2×300 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide 7-(benzyloxy)-2-(chloromethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (61.7 g) as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:24](=[O:26])[CH3:25])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: CC(=O)OC(C)=O
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(C)=O)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-acetamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (300 mg, 0.97 mmol) and acetic anhydride. The title compound was obtained as light brown powder (93 mg).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22].[CH:23]([O:25][CH2:26][CH2:27][O:28][NH2:29])=[CH2:24]>>[F:1][C:2]1[C:7]2[N:8]=[CH:9][O:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:29][O:28][CH2:27][CH2:26][O:25][CH:23]=[CH2:24])=[O:13])[C:3]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=1[F:22]
Reactant: C=COCCON
Reactant: O=C(O)c1cc2ocnc2c(F)c1Nc1ccc(I)cc1F
Product: C=COCCONC(=O)c1cc2ocnc2c(F)c1Nc1ccc(I)cc1F

Procedure:
4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d]oxazole-6-carboxylic acid can be reacted with O-(2-(vinyloxy)ethyl)hydroxylamine in the presence of coupling reagent in appropriate solvent. The reaction is generally carried out at ambient temperature and normally complete within several hours (1-12 h, prefer 3-10 h). 4-Fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]oxazole-6-carboxamide is obtained after conventional workup.
Reaction SMILES: [NH2:1][C:2]1([C:5]#[N:6])[CH2:4][CH2:3]1.[C:7](Cl)(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[C:5]([C:2]1([NH:1][C:7](=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:4][CH2:3]1)#[N:6]
Reactant: N#CC1(N)CC1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)NC1(C#N)CC1
Yield: 73.8 %

Procedure:
General procedure F was used to 1.68 mmols of 1-amino-1-cyclopropanecarbonitrile to 2.184 mmols of oleoyl chloride. After standard purification techniques, 1.24 mmols (74%) of the title product was recovered. 1H NMR (500 MHz, CDCl3) δ 6.53 (s, 1H), 5.43-5.25 (m, 2H), 2.17 (t, J=7.6, 2H), 1.99 (dd, J=6.5, 12.5, 4H), 1.60 (d, J=7.2, 2H), 1.52 (dd, J=5.7, 8.3, 2H), 1.39-1.15 (m, 24H), 0.87 (t, J=6.9, 3H). 13C NMR (126 MHz, CDCl3) δ 174.09, 130.00, 129.66, 120.14, 97.26, 35.97, 31.88, 29.74, 29.68, 29.51, 29.30, 29.23, 29.14, 29.09, 27.20, 27.14, 25.22, 22.66, 20.39, 16.74, 14.11.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[NH:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]=[CH:6]1.[Cl:14][C:15]1[N:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1.CO>ClCCl>[Cl:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[NH:5][CH:6]=2)=[O:22])=[CH:17][CH:16]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: O=C(c1ccc(Cl)nc1)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 89.1 %

Procedure:
Into a round bottom flask was added aluminum trichloride (16.0 g, 0.12 mol) and dichloromethane (100.0 mL) under an atmosphere of nitrogen. Into the reaction mixture 1H-Pyrrolo[2,3-b]pyridine 1 (3.2 g, 0.027 mol) in dichloromethane (20.0 mL) was added. The reaction was stirred at room temperature for 70.0 minutes and 6-Chloropyridine-3-carbonyl chloride 8 (5.4 g, 0.031 mol) in dichloromethane (10.0 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. Methanol (10 mL) was added to the reaction mixture and the solvent was evaporated in vacuo. The residue was poured into water and the precipitated compound was removed by filtration. The aqueous layer was extracted with ethyl acetate and the organic layer was dried and concentrated and combined with the solid isolated by filtration to give 7 (6.2 g, yield=88.6%) as a white solid. MS (ESI) [M+H+]+=258.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[C:3]([CH:11]=[O:12])[N:2]=1.[CH3:13][Mg]Br.C(OCC)C>O1CCCC1>[OH:12][CH:11]([C:3]1[N:2]=[CH:1][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=1)[CH3:13]
Reactant: O=Cc1cc2c(cn1)CCCC2
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)c1cc2c(cn1)CCCC2
Temperature: 25 °C
Yield: 99 %

Procedure:
5,6,7,8,-Tetrahydroisoquinoline-3-carbaldehyde (1.2 g, 7.44 mmole) is dissolved in 15 ml tetrahydrofuran at 0° C. in an oven dried 100 ml two neck round bottom flask under nitrogen. The solution is treated with methylmagnesium bromide in diethyl ether (3.7 ml, 11.2 mmole) followed by 10 ml diethyl ether. The reaction mixture is warmed to room temperature and then to reflux for 1 h. The mixture was cooled, is quenched with 20 ml 10% hydrochloric acid, and the pH is adjusted to 9 with 2N sodium hydroxide. The layers are separated, the aqueous layer is washed with 4×25 ml dichloromethane, and the combined organics are dried over potassium carbonate. The dried organics are concentrated in vacuo to give 1.30 g (99%) of the 3-(1-hydroxyethyl)-5,6,7,8-tetrahydroisoquinoline.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:5]2=[N:6][CH:7]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:52][CH2:53][N:54]1[CH2:58][CH2:57][CH2:56][C:55]1=[O:59]>O1CCCC1>[O:59]=[C:55]1[CH2:56][CH2:57][CH2:58][N:54]1[CH2:53][CH2:52][O:1][C:2]1[CH:3]=[C:4]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:5]2=[N:6][CH:7]=1
Reactant: O=C1c2ccccc2-c2ncc(O)cc21
Reactant: O=C1CCCN1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2-c2ncc(OCCN3CCCC3=O)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
3-Hydroxy-indeno[1,2-b]pyridin-5-one (0.0500 g), di-t-butyl azodicarboxylate (0.087 g) and triphenylphosphine (0.10 g) were mixed with tetrahydrofuran (1.0 ml), 1-(2-hydroxy-ethyl)-2-pyrrolidone (0.043 ml) was added thereto, and the mixture was stirred at room temperature for 1 day. The mixture was purified by preparative thin layer chromatography (silica gel, eluent: ethyl acetate/methanol=10/1) to give the title compound (0.0386 g, 49%).