Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9][C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[CH3:21][O:22]/[N:23]=[C:24](/[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)\[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][OH:34])=[CH:29][CH:28]=1>>[CH3:21][O:22]/[N:23]=[C:24](/[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)\[CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][O:34][C:18]2[CH:17]=[CH:16][C:15]([CH:8]([C:5]3[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=3)[CH2:9][C:10]([OH:12])=[O:11])=[CH:20][CH:19]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)CC(c1ccccc1)c1ccc(O)cc1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Product: CO/N=C(\COc1ccc(COc2ccc(C(CC(=O)O)c3ccccc3)cc2)cc1)c1ccccc1
Yield: 18.2 %

Procedure:
Compound 112 was synthesized from ethyl 3-(4-hydroxyphenyl)-3-phenylpropanoate (0.6 g, 2.2 mmol) and (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol (0.6 g, 2.2 mmol) by following the procedure described in scheme 36. (0.2 g, yield: 18.2%); purity: 98.55%.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH2:13][C:14]([OH:16])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:20])=O.CN(C)C=O>ClCCl>[C:1]1([C@H:7]2[CH2:11][O:10][C:9](=[O:12])[N:8]2[CH2:13][C:14]([Cl:20])=[O:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CN1C(=O)OC[C@@H]1c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CN1C(=O)OC[C@@H]1c1ccccc1
Reaction time: 0.75 h

Procedure:
A solution of 1.0 equivalent of (4(S)-phenyloxazolidin-2-on-3-yl)acetic acid (Evans, U.S. Pat. No. 4,665,171) and 1.3 equivalent of oxalyl chloride in 200 mL dichloromethane was treated with a catalytic amount of anhydrous dimethylformamide (85 mL/milliequivalent of acetic acid derivative) resulting in vigorous gas evolution. After 45 minutes all gas evolution had ceased and the reaction mixture was concentrated under reduced pressure to provide the title compound as an off-white solid after drying for 2 h under vacuum.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:14][O:13][C:12]3[CH:15]=[C:16]4[C:20](=[CH:21][C:11]2=3)[CH2:19][CH2:18][O:17]4)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1.[N-:31]=[N+:32]=[N-:33].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[NH:31]1[C:27]([C:26]2[CH:25]=[CH:24][C:23]([CH2:22][N:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:10]4([CH2:14][O:13][C:12]5[CH:15]=[C:16]6[C:20](=[CH:21][C:11]4=5)[CH2:19][CH2:18][O:17]6)[C:2]3=[O:1])=[CH:30][CH:29]=2)=[N:28][N:33]=[N:32]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1N(Cc2ccc(-c3nnn[nH]3)cc2)c2ccccc2C12COc1cc3c(cc12)CCO3
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A round bottom flask was charged with 4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzonitrile (0.50 g, 1.27 mmol), sodium azide (0.21 g, 3.17 mmol), and triethylamine hydrochloride (0.45 g, 3.17 mmol) in toluene (20 mL). The reaction mixture was refluxed under argon for 24 h. After cooling to ambient temperature, the product was extracted with water. 36% hydrochloric acid was added dropwise to the aqueous layer. The solid was filtrated and dried under reduced pressure to afford 1′-[4-(1H-tetrazol-5-yl)benzyl]-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.38 g, 58%); 1H NMR (300 MHz, CDCl3) δ8.02 (d, J=8.0 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 7.22 (t, J=7.6 Hz, 1H), 7.16 (d, J=7.6 Hz, 1H), 7.05-6.94 (m, 2H), 6.47 (s, 1H), 6.40 (s, 1H), 5.01 (ABq, 2H), 4.79 (ABq, 2H), 4.53-4.38 (m, 2H), 3.03-2.82 (m, 2H); 13C NMR (75 MHz, CD3OD) δ177.6, 161.6, 161.2, 142.5, 140.1, 132.6, 129.1, 128.6, 127.9, 124.2, 123.6, 120.8, 120.4, 119.4, 109.8, 92.9, 80.3, 72.5, 57.4, 43.3, 28.8; MS (ES+) m/z 437.9 (M+1).
Reaction SMILES: I[C:2]1[C:10]2[C:9]([NH2:11])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[C:18]1([C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][C:28](B4OC(C)(C)C(C)(C)O4)=[CH:29][CH:30]=3)[N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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>[C:12]1([N:4]2[C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH2:11])[C:10]=3[C:2]([C:28]3[CH:27]=[C:26]4[C:31]([CH:32]=[CH:33][C:24]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)=[N:25]4)=[CH:30][CH:29]=3)=[CH:3]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ncnc2c1c(I)cn2-c1ccccc1
Reactant: CC1(C)OB(c2ccc3ccc(-c4ccccc4)nc3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(-c1ccc3ccc(-c4ccccc4)nc3c1)cn2-c1ccccc1

Procedure:
Following the general procedure for the Suzuki coupling, 5-iodo-7-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (27 mg, 0.080 mmol) was reacted with 2-phenyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-quinoline (26.5 mg, 0.080 mmol), Na2CO3 (22 mg, 0.21 mmol) and Pd(PPh3)4 (6 mg, 0.005 mmol) in DMF (2.5 mL)/water (0.5 mL). The crude material was purified by chromatography on an SCX column (1 g/6 mL barrel) followed by column chromatography on silica gel [Jones Flashmaster, 5 g/25 mL cartridge, eluting with CH2Cl2 (1-12) 1% MeOH in CH2Cl2 (13-33)→2% MeOH in CH2Cl2 (34-40)], yielding the title compound as an off-white solid. 1H NMR (CDCl3, 400 MHz): δ=5.31 (brs, 2H), 7.38-7.42 (m, 1H), 7.43 (s, 1H), 7.47-7.52 (m, 1H), 7.53-7.59 (m, 4H), 7.75 (dd, J=2.0, 8.4 Hz, 1H), 7.75-7.79 (m, 2H), 7.94 (d, J=8.4 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 8.18-8.22 (m, 2H), 8.26 (d, J=8.4 Hz, 1H), 8.35-8.37 (m, 1H), 8.44 (s, 1H). MS (ES+): m/z 414.0 (25) [MH+]. HPLC: tR=3.4 min (OpenLynx, polar—5 min).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)OC)#[N:2].[N+]([O-])(O)=O.[O:21]([CH2:25][CH2:26][NH2:27])[N+:22]([O-:24])=[O:23].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:27][CH2:26][CH2:25][O:21][N+:22]([O-:24])=[O:23])#[N:2]
Reactant: NCCO[N+](=O)[O-]
Reactant: COC(=NC#N)c1cnc2ccccc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: O=[N+]([O-])O
Solvent: CO
Product: N#CNC(=NCCO[N+](=O)[O-])c1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 53.3 %

Procedure:
Methyl N-cyano-3-quinolinecarboximidate (0.32 g, 1.5 mmol) was dissolved in methanol (3 ml), 2-nitroxyethylamine nitrate (0.42 g, 2.5 mmol) and sodium methoxide (0.12 g, 2.2 mmol) were added. The mixture was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with dichloromethane-methanol (50:1). The eluted fractions were concentrated under reduced pressure and crystallized from dichloromethane-diethyl ether to give the title compound (0.23 g, 0.80 mmol, yield: 54%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:15]=1[NH2:16]>>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=1[C:7]([NH:16][C:15]1[CH:17]=[C:18]([C:21]([F:23])([F:24])[F:22])[CH:19]=[CH:20][C:14]=1[O:13][CH3:12])=[O:9]
Reactant: Cc1ccc(O)c(C(=O)O)c1
Reactant: COc1ccc(C(F)(F)F)cc1N
Product: COc1ccc(C(F)(F)F)cc1NC(=O)c1cc(C)ccc1O
Yield: 77.9 %

Procedure:
Using 5-methylsalicylic acid and 2-methoxy-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[O:8][C:7](=[O:9])[NH:6][CH2:5]1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33]>CC(O)C.CO>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]1[CH2:22][CH2:21][N:20]([CH2:2][CH2:3][CH:4]2[O:8][C:7](=[O:9])[NH:6][CH2:5]2)[CH2:19][CH2:18]1
Reactant: O=C1NCC(CCCl)O1
Reactant: Clc1ccccc1N1CCNCC1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)O
Product: O=C1NCC(CCN2CCN(c3ccccc3Cl)CC2)O1
Yield: 24.3 %

Procedure:
A stirred mixture of 8.3 g (0.056 mol) of 5-(2-chloroethyl)-2-oxazolidinone, 11 g (0.056 mol) of 1-(2-chlorophenyl)piperazine and 7.7 g (0.056 mol) of potassium carbonate in 150 ml of 2-propanol was heated at reflux temperature for 18 h. The mixture was filtered and the filtrate concentrated at reduced pressure. The residue was dissolved in 2-propanol and treated with a solution of 6.9 g (0.0595 mol) of maleic acid in warm methanol. The resulting maleic acid salt was collected and recrystallized several times from a 2-butanone/methanol mixture to obtain 5.8 g (25%) of solid, mp 166°-168.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[N:4][C:5]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([NH2:21])[N:13]=2)=[N:6][CH:7]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C1COCC1>[NH2:21][C:14]1[N:13]=[C:12]([NH:11][CH2:10][CH2:9][NH:8][C:5]2[N:4]=[C:3]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[C:2]([NH:1][C:30](=[O:32])[CH3:31])=[CH:7][N:6]=2)[CH:17]=[CH:16][C:15]=1[N+:18]([O-:20])=[O:19]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cnc(NCCNc2ccc([N+](=O)[O-])c(N)n2)nc1-c1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: CC(=O)Nc1cnc(NCCNc2ccc([N+](=O)[O-])c(N)n2)nc1-c1ccc(Cl)cc1Cl

Procedure:
1 mmol of [5-amino-4-(2,4-dichlorophenyl)pyrimidin-2-yl]{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amine and 1 mmol of acetic anhydride were stirred at room temperature for four hours in THF. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate, and purified by column chromatography eluting with 5-10% methanol/methylene chloride to obtain N-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl]acetamide.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C>[C:19]([Si:16]([CH3:18])([CH3:17])[O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 97.8 %

Procedure:
To a solution of 4-hydroxyacetophenone (10.0 g, 73.5 mmol) in DMF (74 mL) was added imidazole (12.0 g, 176.3 mmol) and tert-butyldimethylsilyl chloride (13.3 g, 88.1 mmol). The colorless solution was stirred for 0.75 h at rt then quenched with saturated aqueous NaHCO3. The aqueous phase was extracted with hexanes and the combined organic layers were washed with saturated NaHCO3. The organic layers were dried over sodium sulfate, filtered, and concentrated to provide 1-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-ethanone (18.0 g, 98%) as a white solid which was utilized without further purification. ESI MS (m/z 251, M+H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]12[CH2:17][CH2:16][C:15](=[O:18])[N:14]1[CH2:13][CH2:12][CH2:11][NH:10]2.[Cl:19][CH:20]([Cl:24])[C:21](Cl)=[O:22]>C1(C)C=CC=CC=1>[Cl:19][CH:20]([Cl:24])[C:21]([N:10]1[C:9]2([CH3:8])[N:14]([C:15](=[O:18])[CH2:16][CH2:17]2)[CH2:13][CH2:12][CH2:11]1)=[O:22]
Reactant: CC12CCC(=O)N1CCCN2
Reactant: O=C(Cl)C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC12CCC(=O)N1CCCN2C(=O)C(Cl)Cl
Temperature: -10 °C
Reaction time: 4 h
Yield: 66.8 %

Procedure:
10.5 g (0.105 mole) of triethylamine are added to a solution of 15.4 g (0.1 mole) of 6-methyl-9-oxo-1,5-diazabicyclo[4.3.0]nonane in 100 ml of toluene. The mixture is cooled to -10° C. and 14.8 g (0.1 mole) of dichloroacetyl chloride are added dropwise at from -10° to -5° C. The batch is stirred for a further 4 hours and the triethylamine hydrochloride which has precipitated is filtered off. After evaporating the toluene from the filtrate, crystals separate out, and these can be recrystallized from a 1:3 toluene/acetone mixture. 17.7 g of 5-dichloroacetyl-6-methyl-9-oxo-1,5-diazabicyclo[4.3.0]nonane, of melting point 144°-147° C., are obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:6][CH2:7][CH:8]([OH:11])[CH2:9][OH:10])[CH:4]=[CH2:5].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1C=CC=CC=1.[O-][Mo]([O-])(=O)=O>[CH2:3]([O:6][CH2:7][CH:8]([O:11][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:9][O:10][CH2:15][CH:14]=[CH2:13])[CH2:4][CH2:5][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: C=CCOCC(O)CO
Reactant: CCCCCCCCCCCCCCBr
Agent: O=[Mo](=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: C=CCOCC(COCCCCCCCCCCCCCC)OCCCCCCCCCCCCCC
Temperature: 25 °C
Yield: 57.2 %

Procedure:
Benzene (250 ml) was added to 95% sodium hydride (11.4 g, 450.0 mmol), and the flask was flushed with nitrogen and sealed. A solution of 3-allyloxy-1,2-propanediol (6.6 g, 50.0 mmol) in benzene (75 ml) was added to the flask. Using a syringe, 97% 1-bromotetradecane (36.7 ml, 120.0 mmol) was added to the flask and the reaction was left to reflux overnight under a constant stream of nitrogen. Once cooled to room temperature, the excess sodium hydride was slowly quenched with ethanol until no further effervescence was observed. The solution was transferred to a separatory funnel with benzene (250 ml) and washed with distilled water (3×200 ml). The organic layer was dried with magnesium sulfate and the solvent removed on the rotary evaporator to yield a colourless oil. TLC (5% ether-hexane, developed in Molybdate) indicated that most of the starting material had reacted to form product. This resulting product was further purified by flash column chromatography (1-5% ether-hexane) to yield 15.0 g (57.3%) of 1,2-dimyristyloxy-3-allyloxypropane 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[CH:16]=[C:17](Br)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>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.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[CH:16]=[C:17]([C:29]3[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)CCn1cc(Br)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(C)CCn1cc(-c2ccc(Cl)cc2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 77 %

Procedure:
Add 4-[4-bromo-1-(2-dimethylamino-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.0 g; 0.0024 mol; 1.0 equiv), 4-chloro phenyl boronic acid (0.58 g; 0.0037 mol; 1.5 equiv), 3M Na2CO3 solution (0.79 g; 0.0074 mol; 3.0 equiv) to ethanol (5 mL) and toluene (5 mL) and degas the reaction with argon. Add Pd(PPh3)4 (0.29 g; 0.00024 mol; 0.1 equiv) and microwave at 110° C. for 20 min. Add EA and filter through a Celite® bed. Add saturated NaHCO3 aqueous and extract with EA. Evaporate the organic layer, and purify the residue over a silica gel column with methanol in DCM to give the title compound (0.8 g; crude).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C=[C:48]3[C:43]([O:44]CC[O:47]3)=CC=2OC=1C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[CH:25]=[C:24]5[C:23]([O:44][CH2:43][CH2:48][O:47]5)=[CH:22][C:21]=4[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=c1c(I)c(-c2ccccc2)oc2cc3c(cc12)OCCO3
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc5c(cc4c3=O)OCCO5)cc2)CCC1
Yield: 55 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-iodo-6-phenyl-2,3-dihydro-1,4,5-trioxa-anthracen-8-one (91 mg, 0.225 mmol) was reacted to give the title compound (65 mg, 55%). 1H NMR (400 MHz, CDCl3): δ 7.72 (s, 1H), 7.43-7.14 (m, 9H), 7.00 (s, 1H), 5.03 (s, 1H), 4.43-4.30 (m, 4H), 2.64-2.43 (m, 4H), 2.14-1.98 (m, 1H), 1.91-1.63 (m, 1H), 1.50-1.14 (m, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=23)=[C:4]([F:20])[CH:3]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[N:25]=[C:24]([NH2:32])[N:23]=1.Cl.C(O)C>O>[NH2:32][C:24]1[N:23]=[C:22]([NH:1][C:2]2[CH:19]=[CH:18][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[NH:13][CH:14]=[C:15]([C:16]#[N:17])[C:8]=34)=[C:4]([F:20])[CH:3]=2)[CH:27]=[C:26]([C:28]([F:31])([F:29])[F:30])[N:25]=1
Reactant: N#Cc1c[nH]c2nccc(Oc3ccc(N)cc3F)c12
Reactant: Nc1nc(Cl)cc(C(F)(F)F)n1
Agent: Cl
Solvent: O
Solvent: CCO
Product: N#Cc1c[nH]c2nccc(Oc3ccc(Nc4cc(C(F)(F)F)nc(N)n4)cc3F)c12
Temperature: 100 °C
Reaction time: 6 h

Procedure:
19.0 mg (0.071 mmol) of 4-(4-amino-2-fluorophenoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile and 19.6 mg (0.099 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are suspended in 5 ml of water. 0.1 ml (0.1 mmol) of 1N hydrochloric acid is added, and the mixture is heated at reflux overnight. 3 ml of ethanol and a further 19.6 mg (0.099 mmol) of 4-chloro-6-(trifluoromethyl)pyrimidine-2-amine are then added. The mixture is stirred at 100° C. for another 6 hours. The mixture is concentrated slightly and the pH is adjusted to 10 using 1N aqueous sodium hydroxide solution, resulting in the precipitation of crystals. The crystals are filtered off with suction, washed with water and purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol (7N ammonia) 100:1 to 10:1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([N:22]([CH3:39])[C:23](=[O:38])[CH2:24][N:25]3[C:30]4[CH:31]=[C:32]([Cl:36])[C:33]([Cl:35])=[CH:34][C:29]=4[O:28][CH2:27][C:26]3=[O:37])[CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:40](Cl)(=[O:43])[CH2:41][CH3:42].C(N(CC)CC)C>ClCCl>[Cl:36][C:32]1[C:33]([Cl:35])=[CH:34][C:29]2[O:28][CH2:27][C:26](=[O:37])[N:25]([CH2:24][C:23]([N:22]([CH3:39])[CH:14]([C:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:40](=[O:43])[CH2:41][CH3:42])=[CH:7][CH:6]=4)=[CH:9][CH:10]=3)[CH2:15][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[O:38])[C:30]=2[CH:31]=1
Reactant: CCC(=O)Cl
Reactant: CN(C(=O)CN1C(=O)COc2cc(Cl)c(Cl)cc21)C(CN1CCOCC1)c1ccc(-c2ccc(N)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1ccc(-c2ccc(C(CN3CCOCC3)N(C)C(=O)CN3C(=O)COc4cc(Cl)c(Cl)cc43)cc2)cc1
Reaction time: 0.25 h
Yield: 16.7 %

Procedure:
To a solution of N-[1-(4′-amino-4-biphenylyl)-2-(4-morpholinyl)ethyl]-2-(6,7-dichloro-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)-N-methylacetamide (85 mg, 0.15 mmol) in dichloromethane (2 mL) was added propanoyl chloride (15.6 mg, 0.17 mmol). Triethylamine (30 mg, 0.30 mmol) was added, and the resultant mixture was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure and the residue was purified by Gilson preparative HPLC (Xterra Prep RP, 30×100 mm, 45 mL/min, A: acetonitrile with 0.1% TFA B: water with 0.1% TFA, A: 25 to 55% over 15 min, UV detection at 214 nm) to give 15.7 mg (17%) of the title compound as an off white solid. MS (ES) m/e 625.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH:13]([CH3:16])[CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Br:24]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH2:12][CH:13]([CH3:16])[CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:24])[N:6]2[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: BrBr
Reactant: CCC(C)CSc1nc(N)c2ncn(Cc3ccccc3)c2n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCC(C)CSc1nc(N)c2nc(Br)n(Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 53 %

Procedure:
6-Amino-9-benzyl-2-(2-methylbutyl)thiopurine (60 mg, 0.18 mmol) and bromine (0.4 ml) were dissolved in 90 ml of methylene chloride and the solution was stirred at room temperature for 7 hours. Aqueous sodium thiosulfate was added to the reaction mixture. The organic layer was separated, dried on magnesium sulfate and filtered. The solvent in the filtrate was evaporated in vacuo. The residue was purified with silica gel chromatography (1% methanol/chloroform) to give the subject compound (39 mg, yield 53%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>C1COCC1>[Br:8][C:5]1[CH:4]=[N:3][C:2]([NH:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:7][CH:6]=1
Reactant: Clc1ncc(Br)cn1
Reactant: NCCN1CCOCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Brc1cnc(NCCN2CCOCC2)nc1
Temperature: 85 °C

Procedure:
A resealable tube was charged with a solution of 2-chloro-5-bromopyrimidine (1.00 g, 5.17 mmol), N-(2-aminoethyl)morpholine (0.808 g, 6.20 mmol), diisopropylethylamine (0.801 g, 1.1 mL, 6.20 mmol), and THF (40 mL). The mixture was heated at 85° C. for 20 h. The reaction mixture was concentrated and then purified via column chromatography on silica gel (gradient elution with 0-100% (90:10:1, dichloromethane/methanol/ammonium hydroxide)-dichloromethane) to afford 5-bromo-N-(2-morpholinoethyl)pyrimidin-2-amine as a light yellow solid. MS m/z=288 [M+H]+. Calc'd for C10H15BrN4O: 287.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:3]=1[C:4]#N.[N+:13]([C:16]1C=C(C=CC=1)CN)([O-])=O>C(O)C>[NH2:10][C:7]1[CH:6]=[C:3]2[C:2](=[CH:9][CH:8]=1)[NH:13][CH:16]=[CH:4]2
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Solvent: CCO
Product: Nc1ccc2[nH]ccc2c1

Procedure:
Compound 84 was prepared using methods shown in Example 1, wherein 2-fluoro-5-nitrobenzonitrile was reacted with 3-nitrobenzyl amine in Step A. Following steps B through E, the 3-nitrobenzyl intermediate was reduced using stannous chloride in ethanol to provide the corresponding 5-amino indole intermediate. Dimethylation of the 5-amino group was carried out using aqueous formaldehyde solution (37% w/w, 10 eq.) and MP-cyanoborohydride resion (2.42 mmol/g, 1.5 eq.) in methanol:acetic acid (9:1, v/v) at room temperature for about 15 hours.