Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=1>ClCCl>[Br:10][C:11]1[CH:7]=[CH:6][C:5]([OH:8])=[C:13]([C:14](=[O:17])[CH2:15][CH3:16])[CH:12]=1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred mixture of aluminium trichloride (2.5 kg) in dichloromethane (5000 ml) at room temperature was added propanoyl chloride (864 g) over a 5 minute period. The mixture was stirred for 45 minutes at room temperature and then a solution of 4-bromoanisole (875 g) in dichloromethane (1000 ml) was added over 15 minutes. The reaction was heated under reflux for 6 hours then cooled and stirred at room temperature overnight.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH:13]2[O:15][CH2:14]2)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39].[NH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1.O>CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH:13]([OH:15])[CH2:14][N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OCC3CO3)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: C1CCNCC1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)n1c(-c2cc(OCC(O)CN3CCCCC3)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 60 °C
Reaction time: 72 h
Yield: 70.3 %

Procedure:
4-Chloro-5-(2,3-epoxypropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (44.9 mg, 0.081 mmol) was dissolved in N,N-dimethylacetoamide (1.0 mL), and the solution was added with piperidine (0.160 mL, 1.61 mmol), followed by stirring at 60° C. for 72 hours. The reaction mixture was added with water. The obtained solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-chloro-5-[2-hydroxy-3-(piperidin-1-yl)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (36.3 mg, yield 70%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])[CH2:16][CH2:15]2)=[O:13])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[H-].[Na+].[CH3:30]I>CN(C)C=O>[CH3:1][C:2]1[N:3]=[C:4]([N:11]([CH3:30])[C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])[CH2:16][CH2:15]2)=[O:13])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8]
Reactant: CI
Reactant: COc1ccccc1N1CCN(C(=O)Nc2nc(C)c(C)nc2OC)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(C(=O)N(C)c2nc(C)c(C)nc2OC)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.5 %

Procedure:
1-[(5,6-Dimethyl-2-methoxypyrazin-3-yl)aminocarbonyl]-4-(2-methoxyphenyl)piperazine (200 mg, 0.54 mmol) was dissolved in dimethylformamide (15 ml) and thereto 60% sodium hydride (21.5 mg, 0.54 mmol) was added. The resulting mixture was stirred at room temperature for 15 minutes, and thereto methyl iodide (76.6 mg, 0.54 mmol) was added. The resulting mixture was stirred at room temperature for 6 hours, concentrated under the reduced pressure to remove the solvent, and purified by column chromatography to obtain the titled compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([N:9]1[CH:13]=[C:12]([NH:14][C:15](=[O:39])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:34]([OH:36])=O)[CH:32]=4)[N:27]=[CH:26][CH:25]=3)=[CH:19][C:18]=2[O:37][CH3:38])[CH:11]=[N:10]1)[CH3:8].C(OCC)C.[CH3:45][NH2:46]>C(Cl)Cl>[CH2:7]([N:9]1[CH:13]=[C:12]([NH:14][C:15](=[O:39])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:34](=[O:36])[NH:46][CH3:45])[CH:32]=4)[N:27]=[CH:26][CH:25]=3)=[CH:19][C:18]=2[O:37][CH3:38])[CH:11]=[N:10]1)[CH3:8]
Reactant: CCn1cc(NC(=O)Cc2ccc(Oc3ccnc4ccc(C(=O)O)cc34)cc2OC)cn1
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CCn1cc(NC(=O)Cc2ccc(Oc3ccnc4ccc(C(=O)NC)cc34)cc2OC)cn1

Procedure:
Oxalyl chloride (0.142 ml) was added to a mixture of N-(1-ethylpyrazol-4-yl)-2-[4-(6-carboxyquinolin-4-yloxy)-2-methoxyphenyl]acetamide (0.15 g) and methylene chloride (6 ml) and the resultant mixture was stirred at ambient temperature for 10 minutes. Diethyl ether (10 ml) was added and the resultant precipitate was recovered and dried under vacuum. The material so obtained was suspended in methylene chloride and methylamine gas was passed into the suspension until a clear solution was obtained. The solvent was evaporated and the residue was purified by column chromatography on silica using a gradient of 100:0 to 19:1 of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.102 g); 1H NMR: (DMSOd6) 1.33 (t, 3H), 2.85 (d, 3H), 3.61 (s, 2H), 3.78 (s, 3H), 4.07 (q, 2H), 6.7 (d, 1H), 6.87 (m, 1H), 7.01 (d, 1H), 7.37 (d, 1H), 7.42 (s, 1H), 7.88 (s, 1H), 8.08 (d, 1H), 8.24 (m, 1H), 8.77 (d, 1H), 8.82 (q, 1H), 8.87 (d, 1H), 10.06 (s, 1H); Mass Spectrum: M+H+ 460.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[CH2:3][C:4]([NH:6][C@H:7]([C:10]([NH:12][C@H:13]([C:16]([N:18](CNC(=O)C)[CH2:19][C:20]([OH:22])=[O:21])=[O:17])[CH2:14][SH:15])=[O:11])[CH2:8][OH:9])=[O:5].O>C(O)(=O)C>[CH3:1][N:2]([CH3:28])[CH2:3][C:4]([NH:6][C@H:7]([C:10]([NH:12][C@H:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[CH2:14][SH:15])=[O:11])[CH2:8][OH:9])=[O:5]
Reactant: CC(=O)NCN(CC(=O)O)C(=O)[C@H](CS)NC(=O)[C@H](CO)NC(=O)CN(C)C
Solvent: O
Solvent: CC(=O)O
Product: CN(C)CC(=O)N[C@@H](CO)C(=O)N[C@@H](CS)C(=O)NCC(=O)O

Procedure:
A solution of dimethylglycylserinylcysteinyl(Acetomidomethyl)glycine (RP414) (50 mg) and mercuric acetate (75 mg) in 30% acetic acid (2 mL) was stirred at room temperature for 3 h. Distilled water (2 mL) was added and H2S gas was slowly bubbled through the solution for 3 min causing a black precipitate (mercury sulfide). The solution was filtered through a 0.2 micron filter diluted with a further 2 mL of distilled water and lyophilised.
Reaction SMILES: [C:1]([C:3]1[S:4][CH:5]=[C:6]([CH3:18])[C:7]=1OS(C1C=CC=CC=1)(=O)=O)#[N:2].[C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)#[CH:20]>CCCCCCC.CCOC(C)=O>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([C:19]#[C:20][C:7]2[C:6]([CH3:18])=[CH:5][S:4][C:3]=2[C:1]#[N:2])=[CH:22][CH:23]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: Cc1csc(C#N)c1OS(=O)(=O)c1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(C#Cc2c(C)csc2C#N)cc1

Procedure:
This product was prepared from benzenesulfonic acid 2-cyano-4-methyl-thiophen-3-yl ester and 1-ethynyl-4-methoxy-benzene following the general procedure for the Sonogashira cross-coupling reaction described above. Chromatography eluent: heptane/EtOAc 9:1; yield (110 mg, 87%); 1H NMR δ (CDCl3): 7.51 (d, J=8.52 Hz, 2H), 6.88 (d, J=8.60 Hz, 2H), 6.81 (s, 1H), 3.84 (s, 3H), 2.51 (s, 3H); LCMS m/z: 253.
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17](B(O)O)=[CH:18]4)=[CH:13][C:12]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[C:33]1[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=1>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:33]5[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=5)=[CH:18]4)=[CH:13][C:12]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: OB(O)c1ccc2cc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)cc2c1
Product: COC(=O)c1ccc(-c2ccc3cc(OCc4ccccc4)c(C45CC6CC(CC(C6)C4)C5)cc3c2)cc1
Yield: 72.3 %

Procedure:
Following the procedure of Example 1(c), but reacting 2.8 g (6.7 mmol) of 7-(1-adamantyl)-6-benzyloxy-2-naphthylboronic acid with 950 mg (4.4 mmol) of methyl 4-bromobenzoate, 1.6 g (72%) of the expected compound were obtained.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([F:18])[C:10]=1[F:19])C1C=CC=CC=1>CO.C1COCC1.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([F:19])[C:11]=1[F:18]
Reactant: O=[N+]([O-])c1ccc(OCc2ccccc2)c(F)c1F
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(O)c(F)c1F
Temperature: 32 °C
Reaction time: 13 h
Yield: 840.2 %

Procedure:
To a suspension of 1-(benzyloxy)-2,3-difluoro-4-nitrobenzene (1.93 g, 0.73 mmol) in CH3OH (45 mL) and THF (9 mL) was added Pd/C (333 mg, 6% Pd content, 53%˜55% water content). The mixture was stirred at 32° C. for 13 hours under H2 atmosphere. The mixture was filtered through a CELITE® pad, which was washed with 50 mL of EtOAc. The filtrate was concentrated in vacuo, washed with 30 mL of CH2Cl2 to give the title compound as a dark brown solid (0.89 g, 84%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:23][CH2:24][CH2:25][OH:26])[CH:12]=[C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]Br>>[Br:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:26][CH2:25][CH2:24][CH2:23][C:11]1[CH:10]=[C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:12]=1
Reactant: BrCCCCCBr
Reactant: OCCCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Product: BrCCCCCOCCCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1

Procedure:
(4.98 g) as a colourless oil, from 3,5-bis(phenylmethoxy)benzenepropanol (5.0 g) and 1,5-dibromopentane (5.9 ml) with stirring at room temperature for 16 h. T.l.c. (ER-CX 1:19) Rf 0.13.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]=[C:9]([CH:12]([F:14])[F:13])[N:10]([OH:11])[C:3]=12.[F-:15].[Na+]>>[F:15][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]=[C:9]([CH:12]([F:14])[F:13])[N:10]([OH:11])[C:3]=12
Reactant: [F-]
Reactant: On1c(C(F)F)nc2nccc(Cl)c21
Agent: [Na+]
Product: On1c(C(F)F)nc2nccc(F)c21

Procedure:
7-Chloro-1-hydroxy-2-(difluoromethyl)-1H-imidazo(4,5-b)-pyridine is reacted with sodium fluoride to obtain 7-fluoro-1-hydroxy-2-(difluoromethyl)-1H-imidazo(4,5-b)pyridine, which is then converted to its calcium salt.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9](Cl)[N:8]=1.[NH2:25][CH2:26][CH2:27][C:28]#N.C(N(C(C)C)CC)(C)C.C([O-])([O-])=O.[Na+].[Na+]>CN1C(=O)CCC1>[Br:1][C:2]1[N:3]=[C:4]([CH:22]2[CH2:24][CH2:23]2)[N:5]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:28][CH2:27][C:26]#[N:25])[N:8]=1
Reactant: N#CCCN
Reactant: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1c(C2CC2)nc(Br)c1-c1ccnc(CCC#N)n1
Temperature: 90 °C
Yield: 77.1 %

Procedure:
A mixture of 4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-2-chloropyrimidine (I-1a, step 5, 3.50 g, 8.14 mmol), 3-aminopropionitrile (1.79 mL, 24.4 mmol), diisopropylethylamine (2.84 ml, 16.3 mmol) and Na2CO3 (1.73 g, 16.3 mmol) in dry NMP (4 mL) was heated at 90° C. for 8 hours. The reaction was cooled to room temperature, and then partitioned between EtOAc (100 mL) and water (100 mL), and the layers separated. The organic portion was washed with water (100 mL), saturated aqueous NaHCO3 solution (100 ml), brine (100 mL), dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (SiO2, 0-50% EtOAc in heptane) to furnish 3-(4-(4-bromo-2-cyclopropyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)pyrimidin-2-yl)propanenitrile as a pale yellow foam (2.91 g, 6.28 mmol). LCMS (m/z) 463.1 (MH+), tR=0.98 minute, 1H NMR (CDCl3) δ ppm −0.09 (s, 9H) 0.73-0.85 (m, 2H) 0.99-1.11 (m, 2H) 1.12-1.21 (m, 2H) 1.90-2.05 (m, 1H) 2.75 (t, J=6.7 Hz, 2H) 3.36-3.48 (m, 2H) 3.76 (q, J=6.5 Hz, 3H) 5.50 (br s, 1H) 5.85 (s, 2H) 7.20 (d, J=5.1 Hz, 1H) 8.37 (d, J=5.1 Hz, 1H).
Reaction SMILES: C([O:5][C:6](=[O:17])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)(C)(C)C.Br[CH2:19][CH2:20]Br>>[N+:14]([C:10]1[CH:9]=[C:8]([C:7]2([C:6]([OH:5])=[O:17])[CH2:20][CH2:19]2)[CH:13]=[CH:12][CH:11]=1)([O-:16])=[O:15]
Reactant: CC(C)(C)OC(=O)Cc1cccc([N+](=O)[O-])c1
Reactant: BrCCBr
Product: O=C(O)C1(c2cccc([N+](=O)[O-])c2)CC1

Procedure:
Using 3-nitrophenylacetic acid t-butyl ester as a starting material and also using 1,2-dibromoethane (1 eq.) as a reagent, the same procedures of Examples 1a and 1b gave 1-(3-nitrophenyl)cyclopropanecarboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1.C(N(CC)CC)C.O[C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=3)=[O:13])[CH:10]=2)[S:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC1(C)CCSc2ccc(C(=O)O)cc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(C)(C)CCS3)cc1
Reaction time: 0.5 h

Procedure:
A solution of 280 mg (1.26 mmol) of 4,4-dimethyl-6-carboxythiochroman and 252 mg (2.52 mmol) of triethylamine in 15 ml of chloroform was stirred at room temperature for 0.5 hours and then treated with 481 mg (1.26 mmol) of bias(2-oxo-3-oxazolidinyl)phosphinic chloride. The reaction mixture was stirred for 0.5 h, treated with 209 mg (1.26 mmol) of ethyl 4-hydroxybenzoate and then stirred at room temperature for a further 12 hours. The reaction mixture was washed successively with dilute HCl and saturated sodium bicarbonate solutions. The organic layer was concentrated in-vacuo and the resultant crude product purified by flash chromatography (silica; 10% ethyl acetate in hexane) followed by reversed-phase high pressure liquid chromatography (Whatman Partisil M20 10/50 ODS-2; 10% water in acetonitrile) to give the title compound as a colorless oil. PMR (CDCl3): δ1.38 (6H, s), 1.42 (3H, t, J~7.0 Hz), 1.98 (2H, m), 3.07 (2H, m), 4.39 (2H, q, J~7.0 Hz), 7.20 (1H, d, J~9.0 Hz), 7.28 (2H, d, J~8.1 Hz), 7.82 (1H, dd, J~9.0, 1.8 Hz), 8.12 (2H, d, J~8.1 Hz), 8.17 (1H, d, J~1.8 Hz).
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][CH2:23][CH2:24][N:25]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[NH2:25][CH2:24][CH2:23][CH2:22][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:2]1=[O:1]
Reactant: O=C1c2ccccc2C(=O)N1CCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 108.7 %

Procedure:
To a solution of 2-[3-(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)propyl]-1H-isoindole-1,3(2H)-dione (3.20 g, 6.80 mmol) in ethanol (70.0 mL) was added hydrazine monohydrate (1.87 g, 37.0 mmol). The mixture was stirred at ambient temperature for 4 h. The solvent was removed under reduced pressure and the residue was re-dissolved in ethyl acetate. The solution was washed with sodium bicarbonate and brine solution, dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to dryness. The residue was crystallized from hexane to yield the title compound (2.50 g) in 75% yield: 1H NMR (300 MHz, CDCl3) δ 7.31-7.24 (m, 1H), 7.16-7.14 (m, 1H), 7.06-7.01 (m, 1H), 6.94-6.91 (m, 1H), 6.48 (s, 1H), 6.10 (s, 1H), 5.82 (m, 2H), 4.90-4.87 (m, 1H), 4.61 (d, 1H), 3.98-3.71 (m, 2H), 2.77-2.73 (m, 2H), 1.97 (br, 2H), 1.84-1.81 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 177.8, 155.9, 148.9, 142.3, 142.2, 132.4, 129.0, 124.0, 123.4, 119.4, 108.7, 103.0, 101.5, 93.6, 80.5, 58.2, 38.8, 37.5, 30.6; MS (ES+) m/z 339.3 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][O:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([NH:27][C:28]([NH:30][C:31]3[N:35]([C:36]4[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=4)[N:34]=[C:33]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:32]=3)=[O:29])=[CH:19][CH:18]=2)[CH:11]=[CH:10][N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][O:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]([NH:27][C:28]([NH:30][C:31]3[N:35]([C:36]4[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=4)[N:34]=[C:33]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:32]=3)=[O:29])=[CH:19][CH:18]=2)[CH:11]=[CH:10][N:9]=1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCc3ccnc(NC(=O)OC(C)(C)C)c3)c3ccccc23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCc3ccnc(N)c3)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
To a suspension of tert-butyl-4-(2-(4-(3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido) naphthalen-1-yloxy)ethyl)pyridin-2-ylcarbamate (14) (1.35 g, 2.20 mmol) in DCM (10 mL) was added TFA (10 mL). After stirring at RT for 2 hr, the volatiles were evaporated and the residue was taken up in EtOAc (50 mL) and extracted with saturated aq NaHCO3 (50 mL). The layers were separated; the organic was washed with brine (50 mL), dried and evaporated to give 1-(4-(2-(2-aminopyridin-4-yl)ethoxy)naphthalen-1-yl)-3-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)urea (Intermediate D) as a pale pink solid (1.20 g, 100%): m/z 535 (M+H)+ (ES+).
Reaction SMILES: [O:1]1[C:6]2=[CH:7][C:8]3[C:9](=[O:15])[C:10](=[O:14])[NH:11][C:12]=3[CH:13]=[C:5]2[O:4][CH2:3][CH2:2]1.Br[C:17]1C=CC=C2C=1C(=O)C(=O)N2>>[CH3:17][N:11]1[C:12]2[CH:13]=[C:5]3[O:4][CH2:3][CH2:2][O:1][C:6]3=[CH:7][C:8]=2[C:9](=[O:15])[C:10]1=[O:14]
Reactant: O=C1Nc2cccc(Br)c2C1=O
Reactant: O=C1Nc2cc3c(cc2C1=O)OCCO3
Product: CN1C(=O)C(=O)c2cc3c(cc21)OCCO3

Procedure:
Following the procedure as described in PREPARATION 79A, and making non-critical variations using 2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione to replace 4-bromoisatin, 6-methyl-2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione was obtained (68%): 1H NMR (300 MHz, CDCl3) δ 7.09 (s, 1H), 6.74 (s, 1H), 4.41-4.38 (m, 2H), 4.27-4.24 (m, 2H), 3.08 (s, 3H); 13C NMR (75 MHz, CDCl3)8; MS (ES+) m/z 220.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][N:12]([CH2:14][CH2:15][OH:16])[CH:13]=2)[O:3]1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([O:16][CH2:15][CH2:14][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:17])([CH3:1])[O:3]2)[CH:10]=[N:11]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OB(c2cnn(CCO)c2)OC1(C)C
Solvent: ClCCl
Product: CC1(C)OB(c2cnn(CCOS(C)(=O)=O)c2)OC1(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a solution of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol (0.150 g, 0.630 mmol) and TEA (0.132 mL, 0.945 mmol) in 5 mL of DCM was added methansulfonyl chloride (0.0536 mL, 0.693 mmol) with stirring at 0° C. The reaction was allowed to proceed at 0° C. for 30 minutes. The reaction was loaded directly onto a silica gel column pre-pre-wetted with and eluted with 50% ethyl acetate in hexanes to afford 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl methanesulfonate (0.169 g, 0.513 mmol, 81.4% yield) MS (apci) m/z=317.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[C:11]([N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[CH3:1])[CH2:7][CH2:8]1)(=[O:13])[CH3:12]
Reactant: Cc1cccc2c1NCC2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CCc2cccc(C)c21
Temperature: 0 °C

Procedure:
A solution of 7-methylindoline (10.2 g) in acetic anhydride (25 ml) was refluxed for 30 min. After cooling, the reaction solution was poured into ice water (250 ml) and the resulting crystal was filtered by means of suction, heated and vacuum dried to yield the end product (11.7 g).
Reaction SMILES: C(OC([N:11]1[C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:13]2([CH2:18][CH2:17][N:16]([C:19]([C@H:21]([NH:31][C:32](=[O:44])[C:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([CH3:35])[CH3:34])[CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:20])[CH2:15][CH2:14]2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[Pd+2].[OH-]>[N:16]1([C:19]([C@H:21]([NH:31][C:32](=[O:44])[C:33]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])([CH3:35])[CH3:34])[CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:20])[CH2:17][CH2:18][C:13]2([C:45]3[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=3)[NH:11][CH2:12]2)[CH2:14][CH2:15]1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCC2(CC1)CN(C(=O)OCc1ccccc1)c1ccccc12
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(C)(C)C(=O)N[C@H](COCc1ccccc1)C(=O)N1CCC2(CC1)CNc1ccccc12
Yield: 72 %

Procedure:
To a solution of 8.10 g of the intermediate obtained from Step A in 80 mL of ethanol was added 1 g of 20% palladium hydroxide/C and hydrogenated with hydrogen balloon for 1 h. The catalyst was filtered off through a pad of celite and washed with ethyl acetate. The filtrate was concentrated to give 4.69 g of the product as a colorless foam.
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[N:37][CH:38]=1>>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([C:18]2[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=2)[CH:36]=[N:37][CH:38]=1
Reactant: COc1cncc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Product: COc1cncc(C2=COCCN2C(=O)OC(C)(C)C)c1
Yield: 45 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and 5-methoxypyridin-3-ylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a white solid (45% yield); 1H-NMR (d6-DMSO) 1.07 (9H, s), 3.70 (2H, t), 3.81 (3H, s), 4.12 (2H, t), 6.57 (1H, s), 7.14 (1H, m), 8.02 (1H, d), 8.11 (1H, d); MS ES(+) 293.3 (M++1); HRMS m/z calcd for C15H20N20O4+H+ 293.1501 [M+H+]. Found 293.1519. IR λmax=1701 cm−1.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([O:16][CH2:17][O:18][CH3:19])[CH:13]=[CH:12][C:11]=1[CH3:20])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[C:21]1(=[O:25])[CH2:24][CH2:23][CH2:22]1>CCCCCC.[Li]CCCC.C1COCC1>[Si:5]([O:8][CH2:9][C:10]1[C:11]([CH3:20])=[CH:12][CH:13]=[C:14]([O:16][CH2:17][O:18][CH3:19])[C:15]=1[C:21]1([OH:25])[CH2:24][CH2:23][CH2:22]1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: O=C1CCC1
Reactant: COCOc1ccc(C)c(CO[Si](C)(C)C(C)(C)C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOc1ccc(C)c(CO[Si](C)(C)C(C)(C)C)c1C1(O)CCC1
Reaction time: 2 h
Yield: 13.7 %

Procedure:
To a solution of tert-butyl-[[5-(methoxymethoxy)-2-methyl-phenyl]methoxy]-dimethyl-silane (Intermediate 174, 0.3 g, 1 mmol) in hexane (5 ml), BuLi (1.6M in hexane, 0.9 ml, 1.4 mmoli) was added at room temperature. The reaction mixture was stirred for 2 h and then added dropwise at −30° C. to a suspension of CeCl3 (0.37 g, 1.5 mmoli) in dry THF (5 ml) that was previously stirred at room temperature overnight. After 45 min at −30° C., cyclobutanone (0.07 g, 1 mmoli) dissolved in THF (1 ml) was added. The reaction was stirred at the same temperature for and then quenched with ammonium chloride (20 ml) and extracted with Ethyl Acetate (2×20 ml). Combined organic layers were dried over Na2SO4 and evaporated under vacuum to afford a colorless oil that was purified by flash chromatography (Biotage system) on silica gel using a 25 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 75:25 as eluents affording the title compound (0.05 g) as a colorless oil.