Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=1)#[CH:25]>>[F:33][C:32]([F:34])([F:35])[C:29]1[CH:28]=[CH:27][C:26]([C:24]2[N:3]=[N:2][N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[CH:25]=2)=[CH:31][CH:30]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1cc(-c3ccc(C(F)(F)F)cc3)nn1)CC2

Procedure:
The title compound was prepared using procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 1-ethynyl-4-(trifluoromethyl)benzene. MS (+ESI) m/z: 441.1.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([O:9][CH:10](C)[CH3:11])=[CH:7][CH:6]=1)[CH2:2][CH3:3].C(Cl)(=[O:17])C.C(Cl)(C)C>>[C:10]([O:9][C:8]1[CH:13]=[CH:14][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[CH:6][CH:7]=1)(=[O:17])[CH3:11]
Reactant: CCCOc1ccc(OC(C)C)cc1
Reactant: CC(=O)Cl
Agent: CC(C)Cl
Product: CCCOc1ccc(OC(C)=O)cc1
Yield: 98 %

Procedure:
Hydroquinone isopropyl n-propylether was reacted with acetyl chloride for 3 hours (RT) to give 4-n-propoxyphenyl acetate (yield >98%) together with isopropyl chloride.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].C(CC(O)=O)(CCC=C(C)C)(C=C)C.[C:23]([O:26][C:27]([CH3:36])([CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[CH:28]=[CH2:29])(=[O:25])[CH3:24].[CH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][C:38]=1[C:47](Cl)=[O:48]>C1COCC1>[CH:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][C:38]=1[C:47](=[O:48])[CH2:24][C:23]([O:26][C:27]([CH3:36])([CH2:30][CH2:31][CH:32]=[C:33]([CH3:35])[CH3:34])[CH:28]=[CH2:29])=[O:25]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: C=CC(C)(CCC=C(C)C)OC(C)=O
Agent: C=CC(C)(CCC=C(C)C)CC(=O)O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(C)(CCC=C(C)C)OC(=O)CC(=O)c1ccc2ccccc2c1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide (101.0 mL of a 2.0 M solution, 0.202 mol) is placed into a 500 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition funnel. The flask is placed in a dry ice-acetone bath. 3,7-Dimethyl-1,6-octadien-3-yl acetate (linalyl acetate) in the amount of (18.66 g, 0.095 mol) is dissolved in THF (5 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min before being treated with a solution of 2-naphthoyl chloride in the amount of (17.43 g, 0.090 mol) dissolved in THF (25 mL) over 30 min. The mixture is warmed to -20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (53 mL). The mixture is poured into a separatory funnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an orange/red oil. The oil is purified by column chromatography (elution with 5% ethyl acetate dissolved in petroleum ether) to give an oil. Purity of the product is determined by thin layer chromatography and GC analysis and the structure confirmed by mass spectrometry, 1H and 13C NMR.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]([O:20]CC)=[O:19])[C:9]2=[O:23])[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]([OH:20])=[O:19])[C:9]2=[O:23])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nc2ccccc2n(-c2cccc(C)n2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(-n2c(=O)c(C(=O)O)nc3ccccc32)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
27.2 g (88 mmol) of ethyl 1-(6-methylpyridine-2-yl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylate was dissolved in 1,4-dioxane (50 ml) and water (50 ml), and 18.3 g (0.13 mol) of potassium carbonate was added thereto, and the solution was stirred for 1 hour at 60° C. The solvent was distilled off under reduced pressure and the aqueous layer was adjusted to pH <4. The precipitated crystals were filtered to obtain 23.3 g (yield: 94%) of 1-(6-methylpyridine-2-yl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylic acid.
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH3:22])([CH3:21])[CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=1[O:26][CH2:27][CH:28]1[O:30][CH2:29]1>C(O)(C)C>[CH2:1]([N:8]([CH2:29][CH:28]([OH:30])[CH2:27][O:26][C:25]1[CH:31]=[CH:32][CH:33]=[CH:34][C:24]=1[CH3:23])[C:9]([CH3:22])([CH3:21])[CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](=[O:17])[NH2:18])=[CH:14][N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1OCC1CO1
Reactant: CC(C)(COc1ccc(C(N)=O)cn1)NCc1ccccc1
Solvent: CC(C)O
Product: Cc1ccccc1OCC(O)CN(Cc1ccccc1)C(C)(C)COc1ccc(C(N)=O)cn1

Procedure:
A solution of 12 g of 6-(2-benzylamino-2,2-dimethylethoxy)-nicotinic acid amide and 12 g of 1-(2-methylphenoxy)2,3-epoxy-propane in 150 ml of isopropanol is boiled for 28 hours under reflux. After working up analogously to Example 1(c), crude 1-[N-benzyl-N-[2-(5-carbamoyl-2-pyridyloxy)-1,1-dimethyl-ethyl]-amino]-3-(2-methyl-phenoxy)-2-propanol is obtained, which is used further without additional purification.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([CH:20]=[CH2:21])[CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15].Br[CH:23]([C:28]1[CH:33]=[C:32]([Cl:34])[CH:31]=[C:30]([Cl:35])[CH:29]=1)[C:24]([F:27])([F:26])[F:25].N1C=CC=CC=1C1C=CC=CN=1>ClC1C=CC=CC=1Cl.Cl[Cu]>[Cl:1][C:2]1[CH:19]=[C:18](/[CH:20]=[CH:21]/[CH:23]([C:28]2[CH:29]=[C:30]([Cl:35])[CH:31]=[C:32]([Cl:34])[CH:33]=2)[C:24]([F:27])([F:26])[F:25])[CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:15]
Reactant: FC(F)(F)C(Br)c1cc(Cl)cc(Cl)c1
Reactant: C=Cc1ccc(CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Agent: Cl[Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: Clc1ccccc1Cl
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 180 °C
Reaction time: 24 h
Yield: 38.1 %

Procedure:
To a stirred solution of 2-(2-chloro-4-vinylbenzyl)isoindoline-1,3-dione (2.0 g, 6.51 mmol) in 1,2-dichlorobenzene (25 mL) were added 1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (3.48 g, 11.36 mmol), CuCl (112 mg, 1.13 mmol) and 2,2-bipyridyl (0.35 g). The resultant reaction mixture was degassed with argon for 30 min and then was stirred at 180° C. for 24 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in n-hexane) to afford the title compound as solid (1.3 g, 50%): mp 141-143° C.; 1H NMR (400 MHz, CDCl3) δ 7.92 (m, 2H), 7.79 (m, 2H), 7.42 (m, 2H), 7.24 (m, 2H), 7.20 (m, 2H), 6.54 (d, J=16.0 Hz, 1H), 6.34 (dd, J=16.0, 8.0 Hz, 1H), 5.00 (s, 2H), 4.10 (m, 1H); ESIMS m/z 524.07 ([M+H]+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[N+:22]([O-])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-:27].[NH4+]>C(O)C.O.[Fe]>[ClH:27].[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:15]=2[NH2:22])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [Cl-]
Reactant: COc1ccc(Oc2ccc(OCc3ccccc3)cc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1ccc(Oc2ccc(OCc3ccccc3)cc2)c(N)c1
Product: Cl
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
To a solution of 4-[4-(benzyloxy)phenoxy]-3-nitroanisole (1.23 g, 3.5 mmol) in ethanol (20 ml) were added an iron powder (0.90 g, 16.1 mg-atom) and a solution of ammonium chloride (0.11 g, 2.1 mmol) in water (2 ml), followed by reflux for 3 hours. The insoluble matter was filtered, and the filtrate was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with water, then with a saturated aqueous sodium chloride solution and dried, and thereafter the solvent was evaporated under reduced pressure. The residue was dissolved in a small amount of ethyl acetate, and the resulting solution was, after addition of 4N-hydrogen chloride/acetic acid solution (2 ml), stirred for 30 minutes. The precipitating crystals were collected by filtration and dried under reduced pressure to give the title compound (0.65 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([C:12]2[N:13]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:55]([CH2:63][CH2:64][CH2:65]O)[Si:56]([C:59]([CH3:62])([CH3:61])[CH3:60])([CH3:58])[CH3:57].CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[C:10]([O:11][CH2:65][CH2:64][CH2:63][O:55][Si:56]([C:59]([CH3:60])([CH3:62])[CH3:61])([CH3:57])[CH3:58])=[CH:9][C:8]([C:12]2[N:13]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:35]
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(O)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1c(-c2cc(OCCCO[Si](C)(C)C(C)(C)C)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 64 %

Procedure:
In a similar manner to Step 1 of Example 149, 4-chloro-5-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (65.7 mg, 0.136 mmol) was dissolved in THF (3.5 mL), and the solution was treated with triphenylphosphine (178 mg, 0.680 mmol), 3-(tert-butyldimethylsiloxy)-1-propanol (0.145 mL, 0.680 mmol) and 40% DEAD-toluene solution (0.310 mL, 0.680 mmol), followed by purification by preparative thin-layer chromatography (chloroform/methanol=6/1) to obtain 4-chloro-5-[3-(tert-butyldimethylsiloxy)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (58.2 mg, yield 64%).
Reaction SMILES: [OH:1][C:2]12[CH2:16][CH:15]([CH3:17])[CH2:14][C:13](=[O:18])[CH:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2.[CH:19]([O:21][CH:22]=[CH2:23])=[CH2:20].F[C:25](F)(F)[C:26](O)=O>C1COCC1.CCCCC.CCOC(C)=O>[CH2:19]([O:21][CH:22]([O:1][C:2]12[CH2:16][CH:15]([CH3:17])[CH2:14][C:13](=[O:18])[CH:12]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH3:23])[CH2:20][CH2:25][CH3:26]
Reactant: O=C(O)C(F)(F)F
Reactant: CC1CC(=O)C2CCCCCCCCCC2(O)C1
Reactant: C=COC=C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCC
Product: CCCCOC(C)OC12CCCCCCCCCC1C(=O)CC(C)C2
Yield: 82 %

Procedure:
A mixture of 2 g (7.9 mmol) of (16) and 0.84 ml (8.7 mmol) buthyl vinyl ether in 2 ml THF was stirred at room temperature in the presence of 20 μl (0.32 mmol) trifluoroacetic acid for 1 day. Flash chromatography of the reaction mixture, using SiO2 (80 g) and pentane/EtOAc=9:1 as eluent, afforded 2.3 g (82%) of (27) as a ˜1:1 mixture of diastereomers.
Reaction SMILES: CC(C)([O-])C.[Na+].Cl[C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH2:23])[N:9]=1.[CH2:24]([OH:28])[CH2:25][CH2:26][CH3:27]>>[CH2:24]([O:28][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)=[C:10]([NH2:23])[N:9]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCO
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CCCCOc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 100 °C

Procedure:
To butan-1-ol (commercially available, for example, from Aldrich) (76 mL) was added portion wise sodium tert-butoxide (15.2 g) (Note: reaction mixture gets warm). The above was stirred until homogeneous (˜15 min) before 2-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (for example, as prepared for Intermediate 2) (10.0 g) was then added to the resultant pale yellow solution. The reaction mixture was then heated to 100° C., overnight. The reaction mixture was stripped to remove as much butan-1-ol as possible before being partitioned between diethyl ether and water. The diethyl ether phase was separated and the aqueous re-extracted further with diethyl ether. Combined organic layers dried over magnesium sulphate (anhydrous). Magnesium sulphate was filtered off and filtrate stripped to give brown viscous oil which was azeotroped with toluene (3 times) and placed under high vacuum overnight, transferred to new flask with dichloromethane and stripped, placed under high vacuum to give the title compound as a brown glass (9.45 g).
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][CH:7]([CH2:15][CH2:16][C@H:17]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:4][CH:3]=1.[CH2:35]([O:42][CH2:43][CH:44]=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>ClCCCl>[CH2:35]([O:42][CH2:43][CH2:44][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]([CH2:15][CH2:16][C@H:17]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])=[CH:33][CH:34]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=CCOCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(N)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCC(Cc1ccc(NCCOCc2ccccc2)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
Di-tert-butyl (5S)-2-(4-aminobenzyl)-5-[(tert-butoxycarbonyl)amino]hexanedioate (670 mg, 1.40 mmol) was dissolved in 1,2-dichloroethane (10 ml) and benzyloxyacetaldehyde (210 mg, 1.40 mmol) and sodium triacetoxyborohydride (415 mg, 1.96 mmol) were added. The mixture was stirred at room temperature for 4 h and than poured on 10 ml 1N aqueous sodium hydrogen carbonate solution. The aqueous phase was extracted with dichloromethane (2×10 ml) and the organic phases were washed with water (30 ml), dried over magnesium sulfate and concentrated in vacuo. Flash chromatography on silica gel (hexane, ethyl acetate) gave the product as slightly yellow oil (853 mg, 99%).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)(O)[O-].[Na+]>C(N(CC)CC)C.C(Cl)Cl>[C:11]([O:15][C:16]([NH:18][CH:19]1[CH2:20][CH2:21][C:22](=[O:25])[CH2:23][CH2:24]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
0.494 ml of DMSO was slowly added dropwise to 10 ml of a methylene chloride solution containing 0.526 ml of oxalyl chloride under argon gas atmosphere at −78° C. After 15 minutes from the completion of the addition, 30 ml of a methylene chloride suspension containing trans-4-tert-butoxycarbonylaminocyclohexanol in was added dropwise, and further 30 minutes later, 2.52 ml of triethylamine was added thereto and the mixture was stirred at −78° C. for 30 minutes and at 0° C. for 15 minutes. An aqueous sodium bicarbonate solution was added to the reaction mixture and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and then, the solvent was removed under reduced pressure. The resulting residue was suspended in a hexane-isopropyl ether mixed solvent and collected by filtration to obtain 0.903 g of 4-(tert-butoxycarbonylamino)cyclohexanone.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[O:10][C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[C:6]=2[N:7]=1.[NH:21]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[C:24]=2[CH:23]=[CH:22]1.C(=O)([O-])O.[Na+].C(O)C>O.C1(C)C=CC=CC=1>[NH:21]1[C:29]2[C:24](=[C:25]([C:2]3[N:3]=[C:4]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:5]4[O:10][C:9]5[N:11]=[CH:12][CH:13]=[CH:14][C:8]=5[C:6]=4[N:7]=3)[CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22]1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: Clc1nc(N2CCOCC2)c2oc3ncccc3c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1cc(-c2nc(N3CCOCC3)c3oc4ncccc4c3n2)c2cc[nH]c2c1
Temperature: 120 °C

Procedure:
Under Ar(g), to a mixture of compound 5 (25 mg, 0.086 mmol), indole-4-boronic acid (15.2 mg, 0.095 mmol), dichloro-bis(triphenylphosphine)palladium (II) (3 mg, 0.004 mmol) and sodium hydrogen carbonate (22 mg, 0.26 mmol) was added ethanol (1 mL) followed by toluene (1.6 mL) and then water (0.5 mL). The reaction mixture was then heated in a microwave at 120° C. (300 W) for 45 min, and was subsequently cooled to rt; the mixture was then partitioned between CH2Cl2 and water, and the organic layer was separated, dried (MgSO4) and concentrated in vacuo. Purification by flash column chromatography on silica (eluant 30-60% EtOAc/Hex) furnished B (24.5 mg, 0.067 mol, 77%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[CH:10]=[C:11]([C:13]([N:15]2[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[O:14])[N:12]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([Mg]Br)=[CH:32][CH:31]=1.[NH4+].[Cl-].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[CH:10]=[C:11]([C:13]([N:15]2[CH2:16][CH2:17][C:18]([C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)([OH:21])[CH2:19][CH2:20]2)=[O:14])[N:12]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C1CCN(C(=O)c2cn(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)n2)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1cn(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)n1)N1CCC(O)(c2ccc(F)cc2)CC1
Temperature: -78 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A solution of 1-{[2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-yl]carbonyl}-4-piperidinone (0.1 g, 0.24 mmol, prepared as described in Example 13) in THF (4 mL) was added dropwise to a solution of 4-fluorophenylmagnesium bromide (0.6 mL, 0.60 mL) at −78° C. The mixture was stirred at −78° C. for 2 h then allowed to warm up to 30° C. Saturated NH4Cl (3 mL) was added slowly followed by water (3 mL). The mixture was extracted with ethyl acetate (3×20 mL) and dried over MgSO4. The product (0.056 g, 46%) was isolated by column (50% ethyl acetate in hexane). MS (Electrospray) 510.1 (M)+; 1H NMR (300 MHz, CD2Cl2) δ 7.81 (s, 1H), 7.50-7.24 (m, 8H), 7.10-6.98 (m, 4H), 5.33-5.17 (m, 1H), 4.74-4.57 (m, 1H), 3.68 (t, 1H), 3.31 (t, 1H), 2.15 (br, 2H), 1.83 (d, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:10]2[CH2:15][CH2:14][NH:13][C@H:12]([CH3:16])[CH2:11]2)=[C:6]([CH3:9])[C:7]=1[CH3:8].[Br-].[CH2:18]([Zn+])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>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>[CH2:18]([C:2]1[N:3]=[N:4][C:5]([N:10]2[CH2:15][CH2:14][NH:13][C@H:12]([CH3:16])[CH2:11]2)=[C:6]([CH3:9])[C:7]=1[CH3:8])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1c(Cl)nnc(N2CCN[C@H](C)C2)c1C
Reactant: [Zn+]Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: Cc1c(Cc2ccccc2)nnc(N2CCN[C@H](C)C2)c1C
Yield: 65.8 %

Procedure:
3-Chloro-4,5-dimethyl-6-((R)-3-methyl-piperazin-1-yl)-pyridazine (400 mg, 1.66 mmol, 1 eq) is added to a solution of benzylzinc bromide (12.3 mL 0.5 M in THF, 6.64 mmol, 4 eq) and tetrakis(triphenylphosphine)palladium (100 mg, 0.08 mmol, 0.05 eq) in a microwave vial. The vial is sealed and irradiated in the microwave at 100° C. (high absorption setting) for 40 min. The reaction mixture is concentrated and purified by silica gel chromatography (5-20% EtOAc/heptane) to yield the desired compound (324 mg, 66%).
Reaction SMILES: Cl.[OH:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[Br:8].[N:9]1([C:15](Cl)=[O:16])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[Br:8][C:4]1[N:3]([O:2][C:15]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[O:16])[CH:7]=[CH:6][N:5]=1
Reactant: On1ccnc1Br
Reactant: O=C(Cl)N1CCOCC1
Agent: Cl
Product: O=C(On1ccnc1Br)N1CCOCC1

Procedure:
The title compound was prepared from 1-hydroxy-2-bromoimidazole, hydrochloride and 4-morpholine carbonyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc) (98%, crystals).
Reaction SMILES: [C:1]1([CH:7]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([CH2:19][NH:20][S:21]([CH2:24][CH:25]([CH3:27])[CH3:26])(=[O:23])=[O:22])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3C2CCCCO2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:40]>C(O)C>[ClH:40].[C:34]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([CH2:19][NH:20][S:21]([CH2:24][CH:25]([CH3:27])[CH3:26])(=[O:22])=[O:23])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)CS(=O)(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Agent: Cl
Solvent: CCO
Product: CC(C)CS(=O)(=O)NCc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Reaction time: 18 h

Procedure:
A solution of N-({6-[(2,2-diphenylethyl)amino]-9-tetrahydro-2H-pyran-2-yl-9H-purin-2-yl}methyl)-2-methyl-1-propanesulfonamide (4.30 g, 7.84 mmol) (Preparation 7) in ethanol (100 ml) was heated to 37° C. and then treated with hydrochloric acid (2N, 15 ml). The mixture was left to stand at room temperature for 18 hours, after which time a crystalline precipitate was filtered off, washed with ethanol (10 ml) and dried to afford the title compound as a solid (3.0 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]2[N:7]=[C:8]([N:11]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22]C(OC(C)(C)C)=O)[CH:17]=4)[C:13]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)=[N:12]3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C(OC(NC1C=C(C2C(C3C=CC=CC=3)=NN(C3C=CC4N(C=NN=4)N=3)C=2)C=CN=1)=O)(C)(C)C>>[NH2:22][C:18]1[CH:17]=[C:16]([C:14]2[C:13]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[N:12][N:11]([C:8]3[CH:9]=[CH:10][C:5]4[N:6]([C:2]([NH2:1])=[N:3][N:4]=4)[N:7]=3)[CH:15]=2)[CH:21]=[CH:20][N:19]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2cn(-c3ccc4nnc(N)n4n3)nc2-c2ccc(F)cc2)ccn1
Agent: CC(C)(C)OC(=O)Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccccc2)ccn1
Product: Nc1cc(-c2cn(-c3ccc4nnc(N)n4n3)nc2-c2ccc(F)cc2)ccn1
Yield: 56.7 %

Procedure:
The reaction was carried out in the same manner as in Example 37-2) except for using 40.0 mg (0.082 mmol) of 1-(3-amino-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)-4-(2-t-butoxycarbonylaminopyridin-4-yl)-3-(4-fluorophenyl)-1H-pyrazole obtained in Example 48-1) in place of 4-(2-t-butoxycarbonylaminopyridin-4-yl)-3-phenyl-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole to obtain 18.0 mg of the title compound as a yellow powder. (Yield: 57%)