Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]2[NH:15][C:16]([C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=3)=[CH:17][N:18]=2)[CH:12]2C[CH:9]1[CH2:10]C2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O:31]C(N1CCOCC1)=O)(C)(C)C.C(OC(N1CC2CC1CC2)=O)(C)(C)C.COC(=O)NC(C(N1CCOCC1C1NC(C2C=CC(Br)=CC=2)=CN=1)=O)C(C)C.COC(=O)NC(C(N1CCCC1C(=O)NC1C=CC(C2C=CC(Br)=CC=2)=CC=1)=O)C(C)C.C(OC(N1CCCC1C(=O)NC1C=CC(C2C=CC(Br)=CC=2)=CC=1)=O)(C)(C)C.COC(=O)NC(C(N1CCCC1C1NC(C2C=CC(C#CC3C=CC(C4NC(C5COCCN5C(=O)C(NC(OC)=O)C(C)C)=NC=4)=CC=3)=CC=2)=CN=1)=O)C(C)C.COC(=O)N.COC(=O)NC(C(N1CCCC1C1NC(C#CC2C=CC(Br)=CC=2)=CN=1)=O)C(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][O:31][CH2:12][CH:13]1[C:14]1[NH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][CH:20]=2)=[CH:17][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc(Br)cc2)[nH]1
Reactant: CC(C)(C)OC(=O)N1CCOCC1
Agent: CC(C)(C)OC(=O)N1CC2CCC1C2
Agent: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(-c2ccc(Br)cc2)cc1
Agent: COC(=O)NC(C(=O)N1CCCC1C(=O)Nc1ccc(-c2ccc(Br)cc2)cc1)C(C)C
Product: CC(C)(C)OC(=O)N1CCOCC1c1ncc(-c2ccc(Br)cc2)[nH]1

Procedure:
Title compound was prepared according to the method employed to prepare 3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (Example AS), substituting 342-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-morpholine-4-carboxylic acid tert-butyl ester for 342-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester. (1-{3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-morpholine-4-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare {1-[2-(4′-Bromo-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (Example CY), substituting 345-(4-Bromo-phenyl)-1H-imidazol-2-yl]-morpholine-4-carboxylic acid tert-butyl ester for 2-(4′-Bromo-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester. [1-(2-{5-[4-(4-{2-[4-(2-Methoxycarbonylamino-3-methyl-butyryl)-morpholin-3-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-ylethynyl}-phenylethynyl)-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example CT), substituting (1-{3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-morpholine-4-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester for (1-{2-[5-(4-bromo-phenylethynyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester. 1H-NMR: 400 MHz, (DMSO-d6) δ 12.05 (s, 1H), 11.84 (s, 1H), 7.81-7.74 (m, 4H), 7.69 (s, 1H), 7.56 (s, 1H), 7.50-7.47 (m, 4H), 7.32-7.27 (m, 2H), 4.42-4.34 (m, 2H), 4.08-3.95 (m, 2H), 3.85-3.79 (m, 3H), 3.72-3.68 (m, 2H), 3.56 (d, J=7.6 Hz, 5H), 3.46-3.40 (m, 2H), 2.2-2.07 (m, 3H), 2.01-1.90 (m, 4H), 1.02-1.00 (d, J=6.4 Hz, 2H), 0.953-0.837 (m, 12H); MS (ESI) m/z 779 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=3)[CH2:9][CH2:8][C:6]=2[N:7]=1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.[OH-].[Na+]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:11][N:10]([C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:17])=[CH:14][CH:13]=3)[CH2:9][CH2:8][C:6]=2[N:7]=1
Reactant: Nc1ccccc1
Reactant: Nc1ncc2c(n1)CCN(c1ccc(C(=O)O)cc1)C2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ncc2c(n1)CCN(c1ccc(C(=O)Nc3ccccc3)cc1)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.6 %

Procedure:
To a mixture of 4-(2-amino-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)benzoic acid (54 mg, 0.20 mmol), aniline (0.027 mL, 0.30 mmol), and N,N-diisopropylethylamine (0.174 mL, 1.0 mmol) in 1.5 mL DMF at room temperature was added HBTU (83 mg, 0.22 mmol). The reaction was stirred at room temperature for 1.5 hours, but also briefly warmed to approx. 60° C. three times during this time. At 2 hours additional 0.025 mL aniline was added and the reaction briefly warmed to approx. 60° C. three times. After 22 hours, the reaction was stored in the freezer for 3 days, then warmed to room temperature, 8 drops 1.0 M NaOH added, and the mixture stirred for 5 minutes. The reaction was partitioned between EtOAc and aqueous Na2CO3 solution, the EtOAc layer washed with H2O, brine, dried with anhydrous Na2SO4 and rotary evaporated. The resulting solid was triturated with EtOAc to give the title compound as an off-white solid (37 mg, 53%). 1H NMR (DMSO-d6) δ: 9.92 (s, 1H), 8.13 (s, 1H), 7.86-7.92 (m, 2H), 7.73-7.78 (m, 2H), 7.28-7.35 (m, 2H), 7.02-7.10 (m, 3H), 6.43 (s, 2H), 4.36 (s, 2H), 3.71 (t, J=6.0 Hz, 2H), 2.75 (t, J=5.9 Hz, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:13]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:32])[C@@H:28]([NH:30][CH3:31])[CH3:29])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)#[N:2].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.Cl.[CH3:48][N:49]([CH3:56])[CH2:50]/[CH:51]=[CH:52]/[C:53](O)=[O:54]>CN(C)C=O.CN1CCOCC1.ClC(OCC(C)C)=O.C(=O)([O-])O.[Na+]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:13]([C:21]#[C:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:32])[C@@H:28]([N:30]([CH3:31])[C:53](=[O:54])/[CH:52]=[CH:51]/[CH2:50][N:49]([CH3:56])[CH3:48])[CH3:29])=[CH:12][N:11]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CN(C)C/C=C/C(=O)O
Reactant: CN[C@@H](C)C(=O)NCCCC#Cc1cnc(Nc2ccc(C#N)cc2)nc1N1CCCC1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@@H](C(=O)NCCCC#Cc1cnc(Nc2ccc(C#N)cc2)nc1N1CCCC1)N(C)C(=O)/C=C/CN(C)C
Reaction time: 1 h

Procedure:
To a solution of (S)—N-(5-(2-((4-cyanophenyl)amino)-4-(pyrrolidin-1-yl)pyrimidin-5-yl)-4-pentyn-1-yl)-2-(methylamino)propanamide (H6) dihydrochloride (252 mg) and 4-dimethylaminocrotonic acid hydrochloride (331 mg) in N,N-dimethylformamide (8 mL), N-methylmorpholine (660 μL) and isobutyl chloroformate were added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture, saturated aqueous sodium hydrogencarbonate (5 drop) was added, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent, 100 to 90% ethyl acetate in methanol). The obtained solid matter was washed with a mixed solvent of ethyl acetate and hexane, and then dried under reduced pressure to obtain (S,E)-N-(1-((5-(2-((4-cyanophenyl)amino)-4-(pyrrolidin-1-yl)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)-4-(dimethylamino)-N-methyl-2-butenamide (9-1, 132 mg) as white solid.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][CH:7]([CH3:16])[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[CH:4][CH:3]=1.[CH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O)=[O:20].C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH3:16][CH:7]([O:6][C:5]1[CH:17]=[CH:18][C:2]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[CH:19]=[O:20])=[CH:3][CH:4]=1)[CH2:8][NH:9][S:10]([CH:13]([CH3:15])[CH3:14])(=[O:12])=[O:11]
Reactant: O=Cc1ccccc1B(O)O
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccccc2C=O)cc1
Yield: 21.1 %

Procedure:
The title compound (68 mg, 21%, white foam) was prepared from [2-(4-bromophenoxy)propyl][(methylethyl)sulfonyl]amine (300 mg, 0.892 mmol, prepared in example 1), 2-formylbenzeneboronic acid (180 mg, 1.085 mmol), dichlorobis(triphenylphosphine)palladium(II) (25 mg, 0.036 mmol), 2 M sodium carbonate (320 mg in 1.5 mL water), and 1,2-dimethoxyethane (6 mL) in a manner analogous to the procedure described in Example 8. The crude material was purified utilizing a Chromatotron® with a 2000 μm rotor in a 1:1 hexane:ethyl acetate solvent system, yielding 280 mg of a co-eluting mixture of unreacted starting material and title compound. This mixture was further purified by reverse phase chromatography on a Vydac C-18 column on a gradient of 5 to 70% of 0.1% trifluoroacetic acid/acetonitrile in water over 45 minutes at 200 mL/min elution rate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:38])[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][CH:27]([C:30]([NH:32][CH2:33][C:34]([O:36]C)=[O:35])=[O:31])[CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.[OH-].[Li+].S([O-])(O)(=O)=O.[K+].[Cl-].[NH4+]>O1CCCC1.CO>[CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:38])[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:25][CH2:26][CH:27]([C:30]([NH:32][CH2:33][C:34]([OH:36])=[O:35])=[O:31])[CH2:28][CH2:29]3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)CNC(=O)C1CCN(c2ccc([C@@H](CC(=O)c3ccnc(C)c3)c3ccccc3C)cc2)CC1
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)C[C@H](c2ccc(N3CCC(C(=O)NCC(=O)O)CC3)cc2)c2ccccc2C)ccn1

Procedure:
A solution of (R)-methyl 2-(1-(4-(3-(2-methylpyridin-4-yl)-3-oxo-1-o-tolylpropyl)-phenyl)piperidine-4-carboxamido)acetate (116 mg, 226 μmol) in tetrahydrofuran (3 mL), 1 M aq. lithium hydroxide solution (2.26 mL, 2.26 mmol) and methanol (1 mL) was stirred for 2 h at room temperature, then after addition of 1 M aq. potassium hydrogensulfate solution (2.5 mL) and sat. aq. ammonium chloride solution (5 mL) the reaction mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to produce [(1-{4-[(R)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-phenyl}-piperidine-4-carbonyl)-amino]-acetic acid. This was reacted in analogy to example 132, step 6 with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to produce the title compound (42 mg, 36%). Yellow semisolid, MS (ESI+): m/z=515.6 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(O)(C(F)(F)F)=O.[C:20]([Si:22]([CH3:25])([CH3:24])[CH3:23])#[CH:21]>[Cu]I.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:12][C:9]1[CH:10]=[CH:11][C:2]([C:21]#[C:20][Si:22]([CH3:25])([CH3:24])[CH3:23])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)ccc1Br
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cl)ccc1C#C[Si](C)(C)C
Temperature: 50 °C
Reaction time: 20 h
Yield: 102.9 %

Procedure:
To a solution of methyl 2-bromo-5-chlorobenzoate (14.8 g, 59 mmol) in TFA (124 ml, 889.82 mmol) was added copper (I) iodide (338 mg, 1.78 mmol) and triphenylphosphine (778 mg, 2.97 mmol) at room temperature and under nitrogen. This mixture had nitrogen bubbled through it for 10 minutes before the addition of ethynyl(trimethyl)silane (12.45 ml, 89 mmol) and Pd(OAc)2 (266 mg, 1.19 mmol). The reaction mixture was stirred at 50° C. for 20 hours before being concentrated under reduced pressure. The residue was dissolved in deionized water (50 ml) and EtOAc (50 ml) and filtered through Celite. The filter cake was washed with EtOAc (50 ml) before the phases were separated and the aqueous layer was extracted with EtOAc (2×50 ml). The combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 99:1 Heptane:EtOAc to 85:15 Heptane:EtOAc) to give 16.2 g (102.4%) of methyl 5-chloro-2-[2-(trimethylsilyl)ethynyl]benzoate as an orange oil that solidified upon standing. Sample contained heptane. LC-MS 91%, 2.57 min (3 minute LC-MS method), m/z=267.4/268.9, 1H NMR (500 MHz, Chloroform-d) δ ppm 7.89 (d, J=2.2 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.41 (dd, J=8.3, 2.3 Hz, 1H), 3.92 (s, 3H), 0.27 (s, 9H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](B(O)O)[CH:8]=2)[CH:3]=[CH:2]1.I[C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1/[C:16](=[CH:24]/[C:25]1[NH:26][CH:27]=[CH:28][C:29]=1[O:30][CH3:31])/[C:17](=[O:23])[NH:18]2.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3/[C:16](=[CH:24]/[C:25]3[NH:26][CH:27]=[CH:28][C:29]=3[O:30][CH3:31])/[C:17](=[O:23])[NH:18]4)[CH:8]=2)[CH:3]=[CH:2]1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(-c3ccc4cc[nH]c4c3)c21
Temperature: 90 °C
Yield: 61.9 %

Procedure:
A solution of 6-indoleboronic acid (36 mg, 0.22 mmol) (from Step A above), (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-indol-2-one (54 mg, 0.15 mmol) (Starting Material 3) and sodium carbonate (52 mg, 0.49 mmol) in 5 mL DME and 2.5 mL water was degassed for 15 min. by bubbling argon through the solution. Dichlorobis(triphenylphosphine)palladium (II) (10 mol %) (Aldrich) was then added and the reaction was heated at 90° C. for 2 days. The reaction was then poured into 100 mL water and the product was extracted with ethyl acetate (4×50 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The resulting product, (Z)-1,3-dihydro-4-(6-indolyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one), was purified via flash column chromatography (40% EtOAc/hex) to yield 33 mg (62%) orange powder.
Reaction SMILES: [CH2:1]([O:19][CH:20]1[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23][CH:22]([CH2:64][O:65][C:66]2[CH:78]=[CH:77][C:76]3[C:75]4[C:70](=[CH:71][CH:72]=[CH:73][CH:74]=4)[C:69](=[O:79])[C:68]=3[CH:67]=2)[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cl:80][C:81]1[CH:86]=[CH:85][C:84]([Mg]Br)=[CH:83][CH:82]=1>C1COCC1>[Cl:80][C:81]1[CH:86]=[CH:85][C:84]([C:69]2([OH:79])[C:68]3[CH:67]=[C:66]([O:65][CH2:64][CH:22]4[CH2:21][CH:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23]4)[CH:78]=[CH:77][C:76]=3[C:75]3[C:70]2=[CH:71][CH:72]=[CH:73][CH:74]=3)=[CH:83][CH:82]=1
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc3c(c2)C(=O)c2ccccc2-3)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOC1CC(COc2ccc3c(c2)C(O)(c2ccc(Cl)cc2)c2ccccc2-3)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Temperature: 40 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
2-(3,4,5-Tris(octadecyloxy)-cyclohexylmethoxy)-9-fluorenone (61.6 mg, 56.1 μmol) was dissolved in dehydrated THF (3 mL), 4-chlorophenyl-magnesium bromide (200 μmol) was added, and the mixture was stirred at 40° C. for 3 hours. After evaporation of the solvent, 0.5N hydrochloric acid (6 mL) was added to the residue to allow crystallization. The crystals were collected by filtration, washed well with hydrochloric acid, water and methanol in this order to give 9-(4-chloro-phenyl)-2-(3,4,5-tris(octadecyloxy)-cyclohexylmethoxy)-9-fluorenol (64.1 mg, 53.0 μmol, 94%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[N:19]=[CH:18][C:17]([CH:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH3:21])=[CH:16][C:15]=1[B:28]1[O:32]C(C)(C)C(C)(C)[O:29]1.B(OC(C)C)(OC(C)C)OC(C)C>C1COCC1>[F:13][C:14]1[C:15]([B:28]([OH:29])[OH:32])=[CH:16][C:17]([CH:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH3:21])=[CH:18][N:19]=1
Reactant: CC(c1cnc(F)c(B2OC(C)(C)C(C)(C)O2)c1)N1CCOCC1
Agent: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(c1cnc(F)c(B(O)O)c1)N1CCOCC1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 80.6 %

Procedure:
To a solution of diisopropylamine (Aldrich) (0.640 mL, 4.57 mmol) in THF (10 mL) at −40° C. in 100 mL 3-neck round-bottom flask was added butyllithium solution, 1.6 m in hexanes (Aldrich) (2.85 mL, 4.57 mmol) dropwise via the addition funnel. After the addition, it was continued to stir at −40° C. for 20 min then cooled to −78° C. To this reaction mixture was added 4-(1-(6-fluoropyridin-3-yl)ethyl)morpholine (Example 339 step 3) (0.800 g, 3.81 mmol) in THF (10 mL) dropwise via the addition funnel. It was continued to stir at −78° C. after the addition. After 1 h, triisopropyl borate (Aldrich) (1.309 mL, 5.71 mmol) was added into the reaction mixture dropwise via the addition funnel. After the addition, it was continued to stir at −78° C. for 20 min then removed the cooling bath and slowly warmed up to rt and stirred for 1 h. The reaction mixture was quenched with 1 N NaOH (15 mL). The aqueous layer was extracted with EtOAc (2×15 mL)—the organic layer was discard; the aqueous layer was acidified to a pH of about 5 to 6 using 5N HCl. The resulting mixture was extracted with EtOAc (2×15 mL) and CHCl3 (2×15 mL). The combined organic layers were dried over MgSO4 and concentrated to afford the product as a light brown amorphous solid (780 mg). MS (ESI pos. ion) m/z: 255.1. 1H NMR (400 MHz, CDCl3) δ ppm 1.38 (dd, J=11.44, 6.75 Hz, 3H) 2.36 (d, J=4.30 Hz, 2H) 2.45-2.60 (m, 2H) 3.35-3.47 (m, 1H) 3.63-3.77 (m, 4H) 8.15 (dd, J=9.00, 2.35 Hz, 1H) 8.19-8.27 (m, 2H) 8.33 (d, J=9.00 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[F:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][CH:42]([C:45]2[CH:51]=[CH:50][C:48]([NH2:49])=[C:47]([O:52][CH3:53])[CH:46]=2)[CH2:41][CH2:40]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:49][C:48]3[CH:50]=[CH:51][C:45]([CH:42]4[CH2:41][CH2:40][N:39]([CH2:38][CH2:37][F:36])[CH2:44][CH2:43]4)=[CH:46][C:47]=3[O:52][CH3:53])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(C2CCN(CCF)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: COc1cc(C2CCN(CCF)CC2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 175 °C
Reaction time: 72 h

Procedure:
To 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (238 mg, 0.50 mmol) and 4-[1-(2-fluoroethyl)-4-piperidinyl]-2-(methyloxy)aniline (140 mg, 0.50 mmol) in iPrOH (1 mL) in a microwave vial was added p-toluenesulfonic acid monohydrate (190 mg, 1.0 mmol). The reaction was heated in a microwave at 175° C. for 1000 seconds. After cooling to rt the material was transferred to another flask, rinsing with a solution of DCM/MeOH. Silica gel was added and the solvent removed on the rotovap. The preabsorbed solids were purified by flash chromatography. The desired fractions were combined and the solvent removed on the rotovap to give product contaminated with an impurity. The material was placed under vacuum for 3 days then triturated with diethyl ether. The desired product was obtained as a white solid (23 mg, 0.033 mmol, 6.6% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 9.35 (d, J=6.2 Hz, 1H), 8.47 (s, 1H), 8.22 (d, J=5.1 Hz, 1H), 8.08, (s, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.71-7.60 (m, 2H), 7.42 (dd, J=8.4, 7.3 Hz, 1H), 7.35 (dd, J=7.1, 6.6 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.15 (dd, J=8.1, 7.9 Hz, 2H), 6.97-6.90 (m, 2H), 6.77 (d, J=8.2 Hz, 1H), 6.56 (d, J=5.1 Hz, 1H), 4.51 (dt, J=48.0, 4.8 Hz, 2H), 3.95, (s, 3H), 3.80 (s, 3H), 2.97 (d, J=11.0 Hz, 2H), 2.60 (dt, J=28.2, 4.8 Hz, 2H), 2.08 (dd, J=11.5, 8.8 Hz, 2H), 1.77-1.59 (m, 4H). MS (ESI) m/z=708 [M+1].
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC=C)(=O)C>C(OC(C)C)(C)C>[C:1]([O:9][C@H:10]1[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC1CCC(O)CC1)c1ccccc1
Solvent: C=COC(C)=O
Solvent: CC(C)OC(C)C
Product: O=C(O[C@H]1CC[C@@H](O)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxycyclohexyl benzoate (81.5 g) and Lipase QLG (40 g) in diisopropyl ether (800 mL) was added vinyl acetate (120 mL) at room temperature. After being stirred at room temperature for 2 hr, Lipase QLG was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (37.5 g, 46%).
Reaction SMILES: [CH3:1][NH:2][NH2:3].Br[C:5]([CH3:12])([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7]>>[CH3:11][C:5]([N:2]([CH3:1])[NH2:3])([CH3:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CNN
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)N(C)N
Yield: 97 %

Procedure:
According to the procedure described in the synthesis method of Compound XIV-1, methylhydrazine (7.12 g, 150 mmol) was reacted with ethyl 2-bromo-2-methylpropanoate (19.51 g, 100 mmol) to obtain the title compound (15.54 g, 96%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6].[C:12]([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[C:9]2[O:10][CH2:12][O:11][C:8]=2[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1
Reactant: O=Cc1cc(O)c(O)c(F)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(F)c2c(c1)OCO2
Temperature: 60 °C
Reaction time: 8 h
Yield: 49.6 %

Procedure:
To a solution of 3-fluoro-4,5-dihydroxy-benzaldehyde (1.5 g, 9.6 mmol) and BrClCH2 (4.9 g, 38.5 mmol) in dry DMF (50 mL) was added Cs2CO3 (12.6 g, 39 mmol). The mixture was stirred at 60° C. overnight and was then poured into water. The resulting mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate=10/1) to afford 7-fluoro-benzo[1,3]dioxole-5-carbaldehyde (0.80 g, 49%). 1H NMR (300 MHz, CDCl3) δ 9.78 (d, J=0.9 Hz, 1H), 7.26 (dd, J=1.5, 9.3 Hz, 1H), 7.19 (d, J=1.2 Hz, 1H), 6.16 (s, 2H).