Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[O:9][CH3:10].Cl.[N:12]1([CH2:16][CH2:17][N:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[N:20]=[C:19]2[CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:15][CH2:14][CH2:13]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[N:12]1([CH2:16][CH2:17][N:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([C:29]([F:32])([F:30])[F:31])[CH:24]=3)[N:20]=[C:19]2[CH:33]2[CH2:34][CH2:35][N:36]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=3[O:9][CH3:10])[CH2:37][CH2:38]2)[CH2:13][CH2:14][CH2:15]1
Reactant: FC(F)(F)c1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccn1
Reactant: COc1c(N)ncnc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COc1c(N)ncnc1N1CCC(c2nc(-c3ccnc(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Temperature: 120 °C
Reaction time: 48 h

Procedure:
A reaction mixture of 6-Chloro-5-methoxy-pyrimidin-4-ylamine (45.00 mg; 0.28 mmol; 1.00 eq.), 4-[1-(2-Azetidin-1-yl-ethyl)-2-piperidin-4-yl-1H-imidazol-4-yl]-2-trifluoromethyl-pyridine hydrochloride (4) (148.13 mg; 0.28 mmol; 1.00 eq.), and Cs2CO3 (367.53 mg; 1.13 mmol; 4.00 eq.) in DMSO 1.0 ml was stirred at 120° C. for 2 days, purified by HPLC collected title compound 17 mg. LC-MS: (M+1=503, obsd.=503).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1(B(O)O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:16]([O:18][C:19]([C:21]1[CH:22]=[N:23][N:24]([C:26]2[N:35]([CH2:36][O:37][CH2:38][CH2:39][O:40][CH3:41])[C:34](=[O:42])[C:33]3[C:28](=[CH:29][C:30](I)=[CH:31][CH:32]=3)[N:27]=2)[CH:25]=1)=[O:20])[CH3:17].C1COCC1>C(Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[CH2:16]([O:18][C:19]([C:21]1[CH:22]=[N:23][N:24]([C:26]2[N:35]([CH2:36][O:37][CH2:38][CH2:39][O:40][CH3:41])[C:34](=[O:42])[C:33]3[C:28](=[CH:29][C:30]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[CH:31][CH:32]=3)[N:27]=2)[CH:25]=1)=[O:20])[CH3:17]
Reactant: CCOC(=O)c1cnn(-c2nc3cc(I)ccc3c(=O)n2COCCOC)c1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2nc3cc(-c4ccccc4)ccc3c(=O)n2COCCOC)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 85.3 %

Procedure:
A mixture of potassium carbonate (210 mg 1.52 mmol), phenylboronic acid (156 mg, 1.28 mmol), 1-[7-iodo-3-(2-methoxy-ethoxymethyl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (250 mg, 0.502 mmol), and THF (4.4 ml) was degassed with nitrogen for 10 min in a sealable tube. The dichloromethane adduct of 1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium (48.9 mg, 0.0610 mmol) was added to the reaction mixture and the pressure tube was sealed. The reaction mixture was stirred at 80° C. for 18 h. The reaction mixture was cooled to 23° C., diluted with DCM (15 mL), and filtered. The filtrate was concentrated. The residue was purified by FCC (5-45% EtOAc/hexanes) to yield the titled compound (192 mg, 85%). MS (ESI): mass calcd. for C24H24N4O5, 448.2; m/z found, 449.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 8.88 (d, J=0.6 Hz, 1H), 8.30 (d, J=0.6 Hz, 1H), 8.04 (d, J=1.5 Hz, 1H), 8.00 (dd, J=8.3, 1.8 Hz, 1H), 7.88-7.84 (m, 2H), 7.78 (dd, J=8.0, 1.5 Hz, 1H), 7.58-7.52 (m, 2H), 7.51-7.46 (m, 1H), 5.67 (s, 2H), 4.30 (q, J=7.1 Hz, 2H), 3.54-3.50 (m, 2H), 3.29-3.25 (m, 2H), 3.08 (s, 3H), 1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=3)[CH2:16][C:15]2=[O:25])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[ClH:26].O1CCOCC1>ClCCl>[ClH:26].[C:23]([C:20]1[CH:21]=[C:22]2[C:17]([CH2:16][C:15](=[O:25])[N:14]2[CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:18][CH:19]=1)#[N:24]
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)Cc3ccc(C#N)cc32)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)N(C1CCNCC1)C(=O)C2
Reaction time: 4 h
Yield: 83 %

Procedure:
A solution of N-Boc 4-(6-cyano-2-oxo-2,3-dihydro-1H-indol-1-yl)-piperidine (D136, 400 mg, 1.172 mmol) in dichloromethane (5 mL) was treated with 4M HCl in dioxane (5 mL, 20.00 mmol). After 4 h at room temperature, evaporation and crystallisation from diethyl ether gave white crystals of 4-(6-cyano-2-oxo-2,3-dihydro-1H-indol-1-yl)-piperidine hydrochloride (270 mg, 0.972 mmol, 83% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][OH:10].[OH-].[K+]>CN(C=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:10][CH3:9])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CO
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc(Br)cn1
Temperature: 100 °C

Procedure:
To a solution of 2,5-dibromopyridine (1.4 g, 5.9 mmol) in DMF (10 mL) was added MeOH (4 mL), and 8N aqueous KOH (1 mL). The solution was heated to 100° C. for 2 h, then cooled and partitioned between Et2O and H2O. The organic layer was washed with brine, dried over MgSO4 and concentrated to provide 840 mg of the title compound, which was used in the next step without further purification.
Reaction SMILES: [C:1]([NH:4][C:5]1[O:6][CH:7]=[C:8]([C:10]([OH:12])=O)[N:9]=1)(=[O:3])[CH3:2].Cl.[CH2:14]([O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([C@@H:35]([NH2:37])[CH3:36])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[CH:19][CH:18]=1)[CH3:15].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:14]([O:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:30]=[CH:31][C:32]([C@@H:35]([NH:37][C:10]([C:8]4[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[O:6][CH:7]=4)=[O:12])[CH3:36])=[CH:33][CH:34]=3)[CH2:27][CH2:28]2)=[CH:21][CH:22]=1)[CH3:15]
Reactant: CC(=O)Nc1nc(C(=O)O)co1
Reactant: CCOc1ccc(C2CCN(c3ccc([C@H](C)N)cc3)CC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ccc(C2CCN(c3ccc([C@H](C)NC(=O)c4coc(NC(C)=O)n4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 2.0 mg (0.012 mmol) 2-acetylamino-oxazole-4-carboxylic acid, 3.6 mg (S)-1-{4-[4-(4-ethoxy-phenyl)-piperidin-1-yl]-phenyl}-ethylamine hydrochloride (XII.1) and 3.54 (0.02 mmol) DIPEA in 0.27 mL DMF are added 3.9 mg (0.012 mmol) TBTU. The mixture is shaken at rt for 12 h. 25 μl K2CO3 solution (3 M) is added, the mixture is filtered through basic alumina, washed with DMF/MeOH (9:1) and concentrated to yield the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.CC1(C)C(C)(C)OB([C:28]2[C:29]([C:35]([F:38])([F:37])[F:36])=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=2)O1>ClCCl.CO>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:28]3[C:29]([C:35]([F:38])([F:37])[F:36])=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=3)[N:3]=2)[CH2:15][CH2:16]1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2cnc(N)cc2C(F)(F)F)OC1(C)C
Solvent: ClCCl
Solvent: CO
Product: Nc1cc(C(F)(F)F)c(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cn1

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)pyridin-2-amine with reaction time of 15 h. Chromatography (dichlormethane/methanol 97:3) gave the title compound as an colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6](Cl)=[O:7].[NH2:15][CH2:16][C@H:17]1[O:21][C@@H:20]([N:22]2[CH:29]=[C:28]([CH2:30][CH3:31])[C:26](=[O:27])[NH:25][C:23]2=[O:24])[CH2:19][C@@H:18]1[O:32][CH2:33][CH3:34]>>[Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([NH:15][CH2:16][C@H:17]1[O:21][C@@H:20]([N:22]2[CH:29]=[C:28]([CH2:30][CH3:31])[C:26](=[O:27])[NH:25][C:23]2=[O:24])[CH2:19][C@@H:18]1[O:32][CH2:33][CH3:34])=[O:7]
Reactant: CC(Oc1ccc(Cl)cc1Cl)C(=O)Cl
Reactant: CCO[C@H]1C[C@H](n2cc(CC)c(=O)[nH]c2=O)O[C@@H]1CN
Product: CCO[C@H]1C[C@H](n2cc(CC)c(=O)[nH]c2=O)O[C@@H]1CNC(=O)C(C)Oc1ccc(Cl)cc1Cl

Procedure:
In an analogous manner, from 2(RS)-(2,4-dichlorophenoxy)propionyl chloride (prepared from the acid) and 5'-amino-2',5'-dideoxy-3'-O-ethyl-5-ethyluridine, there was obtained 5'-[2(RS)-(2,4-dichlorophenoxy)propionamido]-2',5'-dideoxy-3'-O-ethyl-5-ethyluridine of melting point 121°-124° C.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[CH:17][C:5]=1[O:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10])([O-])=O>C(O)(=O)C.[Cl-].[Cl-].[Cl-].[Ti+3]>[NH2:1][C:4]1[CH:20]=[C:19]([Cl:21])[C:18]([Cl:22])=[CH:17][C:5]=1[O:6][C:7]1[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccccc1Oc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [Ti+3]
Agent: [Cl-]
Solvent: CC(=O)O
Product: COC(=O)c1ccccc1Oc1cc(Cl)c(Cl)cc1N

Procedure:
A solution of methyl 2-(2-nitro-4,5-dichlorophenoxy)benzoate (2 g, 5.86 mmol) in acetic acid (50 mL) was treated with 20% aqueous titanium trichloride (22 mL, 36 mmol). The solvent was evaporated, and the aqueous residue was made basic with aqueous sodium hydroxide. The crude product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and evaporated. Flash chromatography (silica gel, ethyl acetate/hexane), followed by recrystallization from-ethyl acetate/hexane gave the title compound. 1H NMR (400 MHz, CDCl3) δ7.90 (dd, 1H), 7.46-7.50 (m, 1H), 7.18-7.26 (m, 1H), 6.93 (dd, 1H), 6.89 (s, 1H), 6.83 (s, 1H), 4.08 (br s, 2H), 3.87 (s, 3H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[CH3:12][O:13][N:14]([CH3:24])[C:15](=[O:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:5][CH2:6][CH2:7][CH2:8][C:9]([C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C:15]([N:14]([O:13][CH3:12])[CH3:24])=[O:23])=[CH:22][CH:21]=1)=[O:10]
Reactant: O=C(Cl)CCCCl
Reactant: CON(C)C(=O)Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CON(C)C(=O)Cc1ccc(C(=O)CCCCl)cc1
Temperature: 25 °C

Procedure:
Cool a slurry of aluminum chloride (87 g, 650 mmol) in methylene chloride (100 mL) with an ice bath. Add 4-chlorobutyryl chloride (51 g, 360 mL) dropwise over 0.5 hours. Add N-methoxy-N-methyl-benzeneacetamide (53 g; 300 mmol) over 0.5 hours. Allow the resultant solution to warm to room temperature. Then heat at reflux for 6 hours. Cool the solution to room temperature. Pour the solution into ice (1 L) and add methylene chloride (1 L). Separate the organic phase. Extract the aqueous phase with methylene chloride (2×500 mL). Dry the combined organics over anhydrous magnesium sulfate and concentrate to provide a solid which contains a ca. 1:1 mixture of the title compound and the meta isomer.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11](Br)[CH:10]=[CH:9][C:8]2=[O:14])=[CH:4][CH:3]=1.[OH:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>O1CCOCC1.CCOC(C)=O.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>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH:12]=[C:11]([C:24]3[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][CH2:18][OH:17])=[CH:22][CH:23]=3)[CH:10]=[CH:9][C:8]2=[O:14])=[CH:4][CH:3]=1
Reactant: OCCCc1ccc(B(O)O)cc1
Reactant: O=c1ccc(Br)cn1Cc1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=c1ccc(-c2ccc(CCCO)cc2)cn1Cc1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 4.5 h
Yield: 66.7 %

Procedure:
According to Scheme 3 Method A: To a solution of 1-(4-chlorobenzyl)-5-bromopyridin-2(1H)-one (1 eq, 0.33 mmol, 0.10 g) in dioxane/saturated aqueous NaHCO3 (1:1, 6 mL) was added Pd(PPh3)4 (0.15 eq, 0.05 mmol, 58 mg) and 4-(3-hydroxypropyl)phenylboronic acid (1.5 eq, 0.50 mmol, 90.0 mg). The reaction was then stirred at 90° C. for 4.5 hours. The reaction was allowed to cool and diluted with AcOEt. The reaction washed with saturated NH4Cl solution, brine and the organic phase extracted (×3). The combined organic fractions were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 15 g SiO2) using pure AcOEt as the eluent to afford 1-(4-chlorobenzyl)-5-(4-(3-hydroxypropyl)phenyl)pyridin-2(1H)-one (0.22 mmol, 78 mg, 66%) as a white solid. M.p.: 165° C.; Rf=0.05 (CH2Cl2/AcOEt 80/20); LC (XTerra RP18, 3.5 μm, 3.0×50 mm Column): RT=3.78 min; MS m/z (CI) [MH]+=354, 356; 1H NMR (300 MHz, DMSO-d6) δ 1.64-1.77 (m, 2H), 2.61 (t, J=7.3 Hz, 2H), 3.32-3.46 (m, 2H), 4.48 (t, J=5.1 Hz, 1H), 5.15 (s, 2H), 6.52 (d, J=9.5 Hz, 1H), 7.24 (d, J=8.1 Hz, 2H), 7.35-7.44 (4H), 7.47 (d, J=8.1 Hz, 2H), 7.83 (dd, J=2.6 Hz, 9.5 Hz, 1H), 8.23 (d, J=2.6 Hz, 1H).
Reaction SMILES: [C:1]([C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][CH:5]([N:6]3C(OC(C)(C)C)=O)[CH2:4]1)[CH2:10]2)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH:7]12[CH2:12][C:3]3([C:1]#[N:2])[CH2:10][CH:9]([CH2:11][CH:5]([CH2:4]3)[NH:6]1)[CH2:8]2
Reactant: CC(C)(C)OC(=O)N1C2CC3CC1CC(C#N)(C3)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC12CC3CC(C1)NC(C3)C2
Temperature: 0 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
A 50 mL RB flask fitted with magnetic stirrer was charged with tert-butyl 5-cyano-2-azatricyclo[3.3.1.13,7]decane-2-carboxylate, Intermediate-13 (0.5 g, 1.98 mmol) in DCM (5 mL). Then reaction mixture was cooled to 0° C. and trifluoroacetic acid (1.1 g, 9.54 mmol) was added and stirred for 4 hours. After completion of the reaction (reaction was monitored by LCMS) the reaction mixture was concentrated followed by the process of trituration with mixture of hexane:ether (1:1) to give Intermediate-14 (0.5 g, yield=97%).
Reaction SMILES: [ClH:1].[C:2]1([CH2:18]N[C@@](C)([C@@H](O)C)CO)[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1.C1(C=O)C2C3=C4C(=CC=2)C=CC=C4C=CC3=CC=1.C([O:48][CH2:49][C:50]([NH2:56])([CH:53]([CH3:55])[CH3:54])[CH2:51][OH:52])(=O)C>>[ClH:1].[CH:53]([C:50]([NH:56][CH2:18][C:2]1[C:15]2[C:16]3=[C:17]4[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[C:8]4[CH:7]=[CH:6][C:5]3=[CH:4][CH:3]=1)([CH2:49][OH:48])[CH2:51][OH:52])([CH3:54])[CH3:55]
Reactant: CC(=O)OCC(N)(CO)C(C)C
Reactant: C[C@H](O)[C@@](C)(CO)NCc1ccc2ccc3cccc4ccc1c2c34
Agent: Cl
Agent: O=Cc1ccc2ccc3cccc4ccc1c2c34
Product: CC(C)C(CO)(CO)NCc1ccc2ccc3cccc4ccc1c2c34

Procedure:
Using the reductive amination procedure described for 20G, pyrene-1-carbaldehyde (Aldrich) and 2-amino-2-isopropyl-1,3-propanediol acetate (24B) gave 2-isopropyl-2-((1-pyrenylmethyl)amino)-1,3-propanediol hydrochloride mp 244°-245° (dec), (CH3OH/Et2O), (C, H, N, Cl).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].I.[CH:18]1([NH:21][C:22](=[NH:25])SC)[CH2:20][CH2:19]1>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:22]([NH2:25])=[N:21][CH:18]2[CH2:20][CH2:19]2)=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CSC(=N)NC1CC1
Reactant: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Agent: I
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCc1ccc(NC(N)=NC2CC2)cc1
Yield: 11.1 %

Procedure:
The compound (0.946 g) obtained in Example 82 was added to a mixture of N-cyclopropyl-S-methylisothiourea hydroiodide (1.0 g) and pyridine (10 ml) and heated under reflux for 2 days. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:1) to give 0.131 g of the titled compound (yield, 12%).
Reaction SMILES: [CH:1]([C:4]1[C:12]2[O:11][CH2:10][C:9]([CH3:14])([CH3:13])[C:8]=2[CH:7]=[C:6]([N:15]([CH:24]([CH3:26])[CH3:25])[C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)[C:5]=1[CH3:27])([CH3:3])[CH3:2].IB1C2CCCC1CCC2>ClCCl>[CH:1]([C:4]1[C:12]2[O:11][CH2:10][C:9]([CH3:13])([CH3:14])[C:8]=2[CH:7]=[C:6]([N:15]([CH:24]([CH3:26])[CH3:25])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:5]=1[CH3:27])([CH3:3])[CH3:2]
Reactant: COc1ccc(N(c2cc3c(c(C(C)C)c2C)OCC3(C)C)C(C)C)cc1
Agent: IB1C2CCCC1CCC2
Solvent: ClCCl
Product: Cc1c(N(c2ccc(O)cc2)C(C)C)cc2c(c1C(C)C)OCC2(C)C
Yield: 80.8 %

Procedure:
Following general procedure M and using 7-isopropyl-5-[isopropyl-(4-methoxy-phenyl)-amino]-3,3,6-trimethyl-2,3-dihydro-benzofuran (Compound 55, 0.077 g, 0.21 mmol) and 1M solution of 9-iodo-9-borabicyclo[3.3.1]nonane (B-iodo-9-BBN) in hexanes (0.25 mL, 0.25 mmol) in 2 mL of anhydrous dichloromethane, the title compound (0.06 g, 77%) was obtained as a brown oil that was used in the next step without further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:8][C:7](=O)[C:6]2=[CH:10][CH:11]=[CH:12][N:5]2[N:4]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:7]1[C:6]2=[CH:10][CH:11]=[CH:12][N:5]2[N:4]=[C:3]([S:2][CH3:1])[N:8]=1
Reactant: CSc1nn2cccc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1nc(Cl)c2cccn2n1
Temperature: 75 °C

Procedure:
2-Methylsulfanyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one (23.25 g, 0.1283 mol) was dissolved in Phosphoryl chloride (114 mL, 1.22 mol) and the reaction was then heated at 75° C. until HPLC showed consumption of starting material. The mixture was reduced and the solution was poured over ice. The solid was then filtered and washed with water to afford the desired product. The product was then allowed to dry under vacuum overnight to provide 25.47 grams of 4-Chloro-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid. 1H NMR (400 MHz, DMSO, d6) δ 8.16 (s, 1H), 7.05 (m, 1H), 6.98 (m, 1H), 2.55 (s, 3H).
Reaction SMILES: Br[C:2]1[C:15]2=[N:16][O:17][C:13]3=[C:14]2[C:5]([C:6](=[O:18])[C:7]2[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:4]([NH:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH:3]=1.[CH:29]1([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.CC(OC)(C)C.CO>CS(C)=O>[CH:29]1([N:35]2[CH2:40][CH2:39][N:38]([C:2]3[C:15]4=[N:16][O:17][C:13]5=[C:14]4[C:5]([C:6](=[O:18])[C:7]4[C:12]5=[CH:11][CH:10]=[CH:9][CH:8]=4)=[C:4]([NH:19][C:20]4[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=4)[CH:3]=3)[CH2:37][CH2:36]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(O)c1ccc(Nc2cc(Br)c3noc4c3c2C(=O)c2ccccc2-4)cc1
Reactant: C1CCC(N2CCNCC2)CC1
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Solvent: CO
Product: O=C(O)c1ccc(Nc2cc(N3CCN(C4CCCCC4)CC3)c3noc4c3c2C(=O)c2ccccc2-4)cc1
Temperature: 65 °C
Reaction time: 2.5 h
Yield: 91 %

Procedure:
About 70 g of 4-((3-bromo-6-oxo-6H-anthra[1,9-cd]isoxazol-5-yl)amino)benzoic acid was dissolved in 950 mL of DMSO. About 50 mL of TEA and 50 g of 1-cyclohexyl piperazine were added to the reaction. Temperature was raised to 60-70° C. After 2-3 hours, slowly added 500 mL of MTBE and MeOH (10:1) solution and adjusted the temperature to 40-50° C. The solid was centrifuged and washed by 100 mL of MTBE and MeOH solution and followed by 100 mL of MeOH. Solid was dried under reduced pressure at 25-30° C. for 12-24 hours to obtain the 4-((3-(4-cyclohexylpiperazin-1-yl)-6-oxo-6H-anthra[1,9-cd]isoxazol-5-yl)amino)benzoic acid at about 98% purity and about 91% yield.
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[NH:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[N:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C.[H-].[Na+].CI.N#N.[N+](CCCC)(CCCC)(CCCC)[CH2:40]CCC.[F-]>CC#N.C1COCC1.CCOC(C)=O>[CH3:40][N:26]1[C:22]([CH:9]([OH:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:23][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[N:25]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)[Si](C)(C)OC(CCCCCCc1ccccc1)c1nnc(-c2ccccn2)[nH]1
Agent: N#N
Agent: [F-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nc(-c2ccccn2)nc1C(O)CCCCCCc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 64 %

Procedure:
A sample of 2-(5-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)-4H-1,2,4-triazol-3-yl)-pyridine (S64, 6 mg, 0.01 mmol) was dissolved in MeCN (142 μL) and cooled to 0° C. NaH (60%, 0.4 mg, 0.01 mmol) was added as a solid. After 5 min, MeI (1 μL) was added. Upon completion of the reaction (1.5 h), the solvent was removed in vacuo. The residue was purified by preparative thin layer chromatography (SiO2, 50% EtOAc-hexanes) to afford two separate compounds, the N1 and N2 alkylated triazoles (4.5 mg, 68%) as colorless oils. The individual N2 alkylated TBS ether (15 mg, 0.032 mmol) was dissolved in THF (403 μL), treated with Bu4NF (1 M in THF, 42 μL) and stirred at room temperature for 4.5 h under Ar. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaCl and dried over Na2SO4. Evaporation in vacuo yielded the crude alcohol that was purified by preparative thin layer chromatography (SiO2, 100% EtOAc) to afford the title compound (7.2 mg, 64%) as a colorless oil (N2 determined by HMBC): 1H NMR (CDCl3, 600 MHz) δ 8.71 (d, 1H, J=4.7 Hz), 8.07 (d, 1H, J=7.9 Hz), 7.76 (dt, 1H, J=1.7, 7.8 Hz), 7.29 (dd, 1H, J=5.0, 7.4 Hz), 7.26 (dd, 2H, J=6.5, 8.7 Hz), 7.16 (m, 3H), 4.91 (dd, 1H, J=5.7, 7.9 Hz), 3.97 (s, 3H), 2.58 (t, 2H, J=7.7 Hz), 1.92 (m, 2H), 1.60 (m, 2H), 1.35 (m, 6H); 13C NMR (CDCl3, 150 MHz) δ 160.1, 158.5, 150.0, 149.7, 142.8, 136.9, 128.5, 128.4, 125.7, 123.9, 121.6, 66.8, 36.4, 36.2, 36.0, 31.5, 29.3, 29.2, 25.4; HRMS-ESI-TOF m/z 351.2181 ([M+H]+, C21H26N4O requires 351.2179).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14](S(C)=O)=[N:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>COCCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:30][C:27]4[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)=[N:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: COc1ccc(N)cc1
Reactant: COc1ccc(Cl)cc1-c1ccc2cnc(S(C)=O)nn12
Solvent: COCCO
Product: COc1ccc(Nc2ncc3ccc(-c4cc(Cl)ccc4OC)n3n2)cc1
Temperature: 180 °C
Yield: 14 %

Procedure:
7-(5-Chloro-2-methoxy-phenyl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine (75.0 mg, 0.000233 mol) and 4-Methoxybenzenamine (57.4 mg, 0.000466 mol) were dissolved in 2-Methoxyethanol (1.64 mL) and the reaction was heated at 180° C. until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 12.41 mg of [7-(5-Chloro-2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-methoxy-phenyl)-amine as a lyophilized powder. (M+H)=381.11. 1H NMR (400 MHz, DMSO, d6) δ 9.29 (s, 1H), 8.95 (s, 1H), 8.05 (m, 1H), 7.63 (d, 2H, J=9.09 Hz), 7.46 (m, 1H), 7.23 (d, 1H, J=8.84 Hz), 7.03 (d, 1H, J=4.55 Hz), 6.90 (d, 1H, J=4.55 Hz), 6.85 (m, 2H), 3.82 (s, 3H), 3.70 (s, 3H).