Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([O:8][CH:9]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH2:41][CH3:42])([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[C:27]([CH3:40])[CH:26]=2)[CH2:23][CH3:24])=[CH:18][C:17]=1[CH3:43])[C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[CH3:44][O:45][C:46](=[O:56])[CH:47]([C:49]1[CH:54]=[CH:53][C:52](Br)=[CH:51][CH:50]=1)[OH:48].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O>[CH3:44][O:45][C:46](=[O:56])[CH:47]([C:49]1[CH:54]=[CH:53][C:52]([C:28]2[CH:29]=[CH:30][C:25]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][CH:9]([O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:6])[CH3:7])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:17]([CH3:43])[CH:18]=3)([CH2:23][CH3:24])[CH2:41][CH3:42])=[CH:26][C:27]=2[CH3:40])=[CH:51][CH:50]=1)[OH:48]
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: COC(=O)C(O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(C(O)C(=O)OC)cc2)c(C)c1
Temperature: 90.5 °C
Reaction time: 4 h
Yield: 37.5 %

Procedure:
Degassed N,N-dimethylformamide (0.60 mL) was added to t-butyl-(1-{2-[4-(1-ethyl-1-{4-[4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl]-3-methyl-phenyl}-propyl)-2-methyl-phenyl]-ethyl}-2,2-dimethyl-propoxy)dimethylsilane (Example 23-(1); 61.4 mg, 0.101 mmol), 4-bromo-phenyl-hydroxy-acetic acid methyl ester (Example 154-(1); 49.8 mg, 0.203 mmol), tetrakis(triphenylphosphine)palladium (0) (19 mg, 0.016 mmol) and potassium phosphate (65 mg, 0.31 mmol). After replacement with nitrogen, the mixture was heated while stirring at an external temperature of 86 to 95° C. for four hours. Water was added to the reaction mixture, followed by extraction with diethyl ether. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=7/1) to give the title compound (24.4 mg, 37%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[NH:13][N:12]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[S:17]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([CH2:36][NH2:37])[CH:34]=2)[CH:29]=[CH:28]1)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18].CCN(C(C)C)C(C)C>CCCCO>[CH:14]1([C:11]2[NH:12][N:13]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:37][CH2:36][C:33]4[CH:34]=[C:35]5[C:30]([CH:29]=[CH:28][N:27]5[S:17]([C:20]5[CH:21]=[CH:22][C:23]([CH3:24])=[CH:25][CH:26]=5)(=[O:19])=[O:18])=[CH:31][CH:32]=4)[N:7]=3)[CH:10]=2)[CH2:16][CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3ccc(CN)cc32)cc1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3ccc(CNc4nccc(Nc5cc(C6CC6)[nH]n5)n4)cc32)cc1
Yield: 96.4 %

Procedure:
A microwave vial was charged with 53 (80 mg, 0.34 mmol), 36 (80 mg, 0.27 mmol), DIPEA (0.2 mL) and n-BuOH (2.0 mL), sealed and irradiated in a microwave reactor at 180° C. for 80 min. The reaction mixture was concentrated and purified with a CombiFlash® to afford 130 mg (95%) of N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-((1-tosyl-1H-indol-6-yl)methyl)pyrimidine-2,4-diamine (38) as yellow solid; MS (ESI) m/z=500.1 [M+1]+.
Reaction SMILES: C([S:4][CH2:5][C:6]1[C@:7]2([CH2:24][CH2:23][C@H:22]3[C:12](=[CH:13][CH:14]=[C:15]4[C@:20]3([CH3:21])[C@@H:19]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:18][C@H:17]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH2:16]4)[C@@H:9]2[CH2:10][CH:11]=1)[CH3:8])(=O)C.Br[CH2:42][CH2:43][CH2:44][C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51])[CH2:46][CH3:47].CO.[OH-].[K+]>O1CCCC1>[Si:26]([O:25][C@@H:19]1[C@@:20]2([CH3:21])[C:15](=[CH:14][CH:13]=[C:12]3[C@@H:22]2[CH2:23][CH2:24][C@@:7]2([CH3:8])[C@H:9]3[CH2:10][CH:11]=[C:6]2[CH2:5][S:4][CH2:42][CH2:43][CH2:44][C:45]([CH2:56][CH3:57])([O:48][Si:49]([CH2:54][CH3:55])([CH2:52][CH3:53])[CH2:50][CH3:51])[CH2:46][CH3:47])[CH2:16][C@@H:17]([O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])[CH2:18]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC(=O)SCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCC(CC)(CCCBr)O[Si](CC)(CC)CC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(CCCSCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)O[Si](CC)(CC)CC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 91.3 %

Procedure:
To a solution of 17-acetylthiomethyl-1α,3β-bis(tert-butyldimethylsilyloxy)androsta-5,7,16-triene (274 mg, 0.454 mmol) and 1-bromo-4-ethyl-4-(triethylsilyloxy)hexane (294 mg, 0.909 mmol) in tetrahydrofuran (2 ml), was added a 1M potassium hydroxide methanol solution (3 ml) under a nitrogen atmosphere, followed by stirring at room temperature for 5 min. The thus obtained reaction mixture was partitioned by adding ethyl acetate and water. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and evaporated to remove the solvent under reduced pressure. The thus obtained residue was purified by column chromatography (hexane:toluene=6:1) to give the titled compound (333 mg, 91%) as a colorless oil.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1)#[N:13]>>[C:12]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])=[CH:16][CH:15]=1)#[N:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N#Cc1ccc(CBr)cc1
Product: CCOC(=O)C(Cc1ccc(C#N)cc1)C(=O)OCC
Yield: 66.3 %

Procedure:
In the same manner as in Example 6 (1), a crude product was obtained using diethyl malonate (13.6 g) and 4-cyanobenzyl bromide (16.7 g). This was purified by silica gel column chromatography to give the title compound (15.5 g) as an oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:15])=[C:12]([CH:14]=1)[NH2:13]>>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:15])=[C:12]([NH:13][C:3](=[O:4])[CH:2]([CH3:6])[CH3:1])[CH:14]=1
Reactant: Cc1ccc(Br)cc1N
Reactant: CC(C)C(=O)Cl
Product: Cc1ccc(Br)cc1NC(=O)C(C)C

Procedure:
Prepared by Procedure Q1 using 2-methylpropanoyl chloride and 5-bromo-2-methylaniline: ESMS m/e: 255.9 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[CH:16]=[CH:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>[N+](C1C=CC=CC=1)([O-])=O.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][N:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[C:16]([S:30]([C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[CH:25]=2)(=[O:32])=[O:31])=[CH:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: c1ccc(CN2CCCC2Cn2ccc3cccnc32)cc1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O=[N+]([O-])c1ccccc1
Product: O=S(=O)(c1cccc(Cl)c1)c1cn(CC2CCCN2Cc2ccccc2)c2ncccc12
Temperature: 100 °C
Yield: 27 %

Procedure:
A mixture of 1-[(1-benzylpyrrolidin-2-yl)methyl]-1H-pyrrolo[2,3-b]pyridine (2.0 g, 6.86 mmol), 3-chlorophenylsulfonyl chloride (1.63 g, 7.55 mmol) and silver trifluoromethanesulfonate (AgOTf) (2.32 g, 8.92 mmol) in nitrobenzene is heated at 100° C. under a nitrogen atmosphere for 36 h, cooled to room temperature, quenched with 10% aqueous sodium carbonate, and extracted with CH2Cl2. The extracts are combined, washed sequentially with water and brine and concentrated in vacuo. The resultant residue is purified by flash column chromatography (0–5% methanol in CH2Cl2 as eluent) to afford the title compound as a semi-solid, 865 mg (27% yield), identified by HNMR and mass spectral analyses.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]3[N:18]=[C:17]([N:19](CC)[CH2:20][C:21]4C=CC(OC)=CC=4)[C:16]4=[N:31][CH:32]=[C:33]([C:34]#[N:35])[N:15]4[N:14]=3)[CH:10]=2)[N:5]([CH:36]2[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]2)[CH:4]=1)#[N:2].[C:49]1([O:55]C)[CH:54]=CC=C[CH:50]=1.C(O)(C(F)(F)F)=O>ClCCCl>[C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13]3[N:18]=[C:17]([NH:19][CH2:20][CH3:21])[C:16]4=[N:31][CH:32]=[C:33]([C:34]#[N:35])[N:15]4[N:14]=3)[CH:10]=2)[N:5]([CH:36]2[CH2:41][CH2:40][N:39]([CH2:50][C@@H:49]([OH:55])[CH3:54])[CH2:38][CH2:37]2)[CH:4]=1)#[N:2]
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2ccc3c(c2)c(C#N)cn3C2CCN(C(=O)OC(C)(C)C)CC2)nn2c(C#N)cnc12
Reactant: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCNc1nc(Nc2ccc3c(c2)c(C#N)cn3C2CCN(C[C@H](C)O)CC2)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
tert-butyl 4-(3-cyano-5-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)-1H-indol-1-yl)piperidine-1-carboxylate (500 mg, 0.503 mmol) was mixed with anisole (0.5 mL, 4.58 mmol) and DCE (5 mL). TFA (1 mL, 12.98 mmol) was added. The mixture was stirred at 25° C. for 24 hrs. LC/MS showed product formation. The mixture was concentrated to dryness, diluted with MeOH and applied onto a cartridge of Phenomenex Strata-X-C 33 um cation mixed-mode polymer. This was washed with methanol and product was eluted with 2 N solution of ammonia in methanol. Removal of the solvents left 2-((3-cyano-1-(piperidin-4-yl)-1H-indol-5-yl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (80 mg) as solid.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[C@H:14]1[C@@H:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:20])=[CH:10][C:11]=3[CH2:12][CH2:13]1)[CH2:4][CH2:3]2.N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27].O>ClCCl>[O:20]([C:9]1[CH:8]=[CH:7][C:6]2[C@@H:5]3[C@H:14]([C@H:15]4[C@@:2]([CH2:3][CH2:4]3)([CH3:1])[C:18](=[O:19])[CH2:17][CH2:16]4)[CH2:13][CH2:12][C:11]=2[CH:10]=1)[Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
To a solution of estrone (100 g, 0.37 mole) in 400 ml of dichloromethane, imidazole (50.36 g, 0.74 mole) and t-butyl-dimethylsilyl chloride (61.3 g, 0.41 mole) were added. The solution was stirred at room temperature for 24 hours. Then water (200 ml) was added. The organic layer was partially evaporated and diisopropyl ether added. The white solid formed was collected by filtration and dried. It weighed 135.2 g, yield 95%, mp 172° C.
Reaction SMILES: [NH2-].[Na+].[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[CH2:6][C:5]1=[O:16].[CH3:17]OS([O-])(=O)=O>C1(C)C(C)=CC=CC=1>[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([CH3:17])[C:7](=[O:15])[CH2:6][C:5]1=[O:16]
Reactant: COS(=O)(=O)[O-]
Reactant: CN1C(=O)CC(=O)Nc2ccccc21
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CN1C(=O)CC(=O)N(C)c2ccccc21
Reaction time: 3 h

Procedure:
2 g of sodium amide are added to a suspension of 9.5 g of 1-methyl 1,2,4,5-tetrahydro 2,4-diketo 3H-1,5-benzodiazepine, obtained in the example XIV, in 30 c.c. of xylene, and the whole is heated for about thirty minutes, while agitating, treated with 20 c.c. of methyl-sulfate and as soon as the exothermic reaction has ceased, this is heated and boiled for three hours. The solvent is evaporated under reduced presure, the residue is taken up in 200 c.c. of a 10% solution of caustic soda, and after agitation, suction filtered, and purified upon crystallisation in 90% ethanol. Yield 4.5 g; melting point: 240°-242° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH3:19])=[C:13]2[C:5]=1[CH:6]1[CH:11]([C:12]2=[O:20])[CH2:10][CH2:9][CH2:8][CH2:7]1>CO.O>[CH3:3][C:4]1[CH:16]=[C:15]([CH3:17])[C:14]([O:18][CH3:19])=[C:13]2[C:5]=1[CH:6]1[CH:11]([CH:12]2[OH:20])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COc1c(C)cc(C)c2c1C(=O)C1CCCCC21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(C)cc(C)c2c1C(O)C1CCCCC21
Yield: 106.5 %

Procedure:
6.0 Grams of sodium borohydride was added to a solution prepared by dissolving 15.0 g of 5,7-dimethyl-8-methoxy-1,2,3,4,4a,9a-hexahydro-9-fluorenone in 300 ml of methanol and 50 ml of water and reaction was effected under ice-cooling for 4 hours. The solvent was distilled off and the residue was extracted with dichloromethane and then the extract was washed twice with saturated sodium chloride solution. Then, this was dried with magnesium sulfate and the solvent was distilled off to obtain 16.1 g of 5,7-dimethyl-8-methoxy-9-hydroxy-1,2,3,4,4a,9a-hexahydrofluorene.
Reaction SMILES: Cl.[CH2:2]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[N:15]=[CH:16][N:17]3[CH:21]=[CH:20][S:19][C:18]=23)[CH2:11][C@@H:10]([O:22][Si](C(C)(C)C)(C)C)[CH2:9]1)=[O:7])[CH:3]=[CH2:4].C(=O)([O-])O.[Na+]>C(#N)C.C(OCC)(=O)C>[CH2:2]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[N:15]=[CH:16][N:17]3[CH:21]=[CH:20][S:19][C:18]=23)[CH2:11][C@@H:10]([OH:22])[CH2:9]1)=[O:7])[CH:3]=[CH2:4]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1Cc1ncn2ccsc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cc1ncn2ccsc12
Reaction time: 0.33 h
Yield: 107.9 %

Procedure:
Concentrated hydrochloric acid (0.204 ml) is added dropwise to a solution of 206 mg of (3R,5R)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-(imidazo[5,1-b]thiazol-7-yl)methylpyrrolidine in 5 ml of dry acetonitrile under ice cooling, and the mixture is stirred at that temperature for 20 min. The reaction solution is diluted with 20 ml of ethyl acetate, saline is added to the diluted solution, the mixture is adjusted to pH 9 by addition of a saturated aqueous sodium hydrogencarbonate solution, and the mixture is extracted three times with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate and filtered, and the solvent is removed by evaporation under reduced pressure. The residue is purified by column chromatography on silica gel (chloroform:methanol=10:1) to give 162 mg of (3R,5R)-1-allyloxycarbonyl-3-hydroxy-5-(imidazo[5,1-b]thiazol-7-yl)methylpyrrolidine.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([F:6])([F:5])I.C[Li].[Br-].[Li+].[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]=[CH:21][C:22](N(OC)C)=[O:23])=[N:18][CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]=[CH:21][C:22](=[O:23])[C:3]([F:6])([F:5])[C:2]([F:8])([F:7])[F:1])=[N:18][CH:19]=1
Reactant: FC(F)(F)C(F)(F)I
Reactant: CON(C)C(=O)C=Cc1ccc(Br)cn1
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Product: O=C(C=Cc1ccc(Br)cn1)C(F)(F)C(F)(F)F
Reaction time: 0.33 h
Yield: 56.8 %

Procedure:
To a saturated solution of pentafluoroiodoethane (0.84 M, in diethyl ether) (17.1 mL, 14.3 mmol), was slowly added a solution of methyllithium/lithium bromide (1.5 M, in diethyl ether) (9.6 mL, 14.3 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 20 minutes and then a solution of 3-(5-bromo-pyridin-2-yl)-N-methoxy-N-methyl-acrylamide (1.3 g, 4.8 mmol, in tetrahydrofuran 12.0 mL) prepared in Step 2 was slowly added thereto at −78° C. The reaction mixture was stirred at room temperature for 2 hours, quenched with distilled water, acidified by a 10% potassium hydrogen sulfate solution (pH=5), and then extracted with ethyl acetate. The extract was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to give 0.9 g of the titled compound as a yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28]>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:23]3[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:21]([O:20][CH3:19])[CH:22]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cc(OC)c(OC)c(OC)c3)cccc2c1N
Yield: 88.7 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (100 mg, 0.33 mmol) and 3,4,5-trimethoxyphenyl boronic acid (206 mg, 0.97 mmol) were reacted to afford the title compound (116 mg, 91.5% yield) as a pale-yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.56 (br, 1H), 7.88 (d, J=8.2 Hz, 1H), 7.80 (dd, J=7.2 Hz, J′=1.4 Hz, 1H), 7.72 (t, J=7.7 Hz, 1H), 6.87 (s, 2H), 3.92 (s, 3H), 3.90 (s, 6H), 3.47 (q, J=6.5 Hz, 2H), 1.68 (m, J=7.2 Hz, 2H), 1.01 (t, J=7.4 Hz, 3H) MS APCI, m/z=397 (M+H) HPLC 1.83 min.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[N:6]=[N:7][C:8]([NH:11][CH2:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH3:15])[CH3:14])=[CH:9][CH:10]=1)=O.[C:23]([NH:26][C:27]([NH2:29])=[NH:28])(=[O:25])[CH3:24]>C(#N)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]([CH3:15])([CH3:14])[CH2:12][NH:11][C:8]2[N:7]=[N:6][C:5]([C:3]3[N:28]=[C:27]([NH:26][C:23](=[O:25])[CH3:24])[NH:29][CH:2]=3)=[CH:10][CH:9]=2)=[CH:17][CH:18]=1
Reactant: CC(=O)NC(=N)N
Reactant: CC(C)(CNc1ccc(C(=O)CBr)nn1)c1ccc(F)cc1
Solvent: CC#N
Product: CC(=O)Nc1nc(-c2ccc(NCC(C)(C)c3ccc(F)cc3)nn2)c[nH]1
Temperature: 100 °C
Yield: 63.3 %

Procedure:
To a 3 mL microwave reaction vial was added 2-bromo-1-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)ethanone (125 mg, 0.3 mmol, 1.0 equiv), acetyl guanidine (90 mg, 0.6 mmol, 2.0 equiv) and acetonitrile (2 mL). The reaction was heated in a microwave reactor at 100° C. for 13 min. The reaction was filtered and directly purified by reverse phase column chromatography to afford N-(4-(6-(2-(4-fluorophenyl)-2-methylpropylamino)pyridazin-3-yl)-1H-imidazol-2-yl)acetamide (70 mg) as an white solid. m/z=369.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:19]([O:21]C)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.C[Si](C)(C)[C:31]([F:34])([F:33])[F:32].[F-].[Cs+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[F:32][C:31]([F:34])([F:33])[C:19]([OH:20])([OH:21])[CH:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[N:9]=[CH:10]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OC(O)(C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1)C(F)(F)F
Reaction time: 4 h
Yield: 96 %

Procedure:
Methyl 2-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-2-phenylacetate (147d, 2.5 g, 6.6 mmol) was dissolved in THF (15 mL, dried over 4 Å MS) under Argon atmosphere and cooled in an ice-bath. Trimethyl(trifluoromethyl)silane (1.18 mL, 8 mmol) was added followed by Caesium fluoride (100 mg, 0.66 mmol). The cooling bath was removed and the stirring was continued at r.t. for 4 h. A solution of tetrabutylammonium fluoride in THF (1M, 7 mL, 7 mmol) followed by water (4 mL) was then added and the mixture was stirred for additional 1 h and then partitioned between ethyl acetate and water. The organic phase was washed twice with water, then brine and evaporated to afford 1,1,1-trifluoro-3-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-3-phenylpropane-2,2-diol (2.74 g, 95%)
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.C([O:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:22]([OH:23])[CH:21]=1)(=O)C.C(=O)([O-])O.[Na+]>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:22]([OH:23])[CH:21]=1
Reactant: CC(=O)Oc1cccc(O)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc2nccc(Oc3cccc(O)c3)c2cc1OC
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 9 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (300 mg) and commercially available resorcinol monoacetate (0.835 ml) were mixed and stirred at 180° C. for 30 minutes. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate and then partitioned between water and ethyl acetate, and the ethyl acetate layer was washed with brine and then dried with anhydrous sodium sulfate. After removing the solvent by reduced-pressure distillation, the resulting residue was crystallized with chloroform to obtain 37 mg of the title compound (yield: 9%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[C:6](=[O:20])[CH2:7][NH:8][C:9](=O)[C:10]1[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:12]([OH:14])=[O:13].S(=O)(=O)(O)O>>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([C:6]2[O:20][C:9]([C:10]3[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=3[C:12]([OH:14])=[O:13])=[N:8][CH:7]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(CNC(=O)c1ccccc1C(=O)O)c1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: O=C(O)c1ccccc1-c1ncc(-c2cccc(C(F)(F)F)c2)o1
Temperature: 0 °C
Yield: 91.1 %

Procedure:
N-(3-trifluoromethylphenacyl) phthalamic acid (9.4 g, 0.027 mol) was added portionwise to conc. sulfuric acid (30 ml) at <10° C. The resultant solution was stirred for 20 hours at room temperature and poured into 600 ml of ice-water to yield 8.2 g of crude 2-[5-(3-trifluoromethylphenyl)-1,3-oxazol-2-yl]benzoic acid as a brown solid; ir (CHCl3) 1720 cm-1. The crude acid was used for subsequent synthesis as obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.O>CN(C)C=O>[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][O:11][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=2[NH2:1])=[CH:20][CH:19]=1
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2cccc([N+](=O)[O-])c2N)cc1
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
To a solution of 2-amino-3-nitrophenoi (10 g) in dimethylformamide (100 ml) was added potassilum carbonate (17.9 g) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature. To the mixture was added 4-methoxybenzyl chloride (10.7 g) at ambient temperature, and the mixture was stirred for 30 minutes under ice-cooling and then overnight at ambient temperature. To the reaction mixture was added water, and the mixture was extracted with dichloromethane, and purified by silica gel column chromatography (ethyl acetate—n-hexane). The residue was crystallized with ethanol to give 2-(4-methoxybenzyloxy)-6-nitroaniline (13.6 mg) as yellow needles.