Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][C:15]4=[O:22])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([O:21][CH2:20][C:17]2[CH:18]=[CH:19][N:14]([C:11]3[CH:12]=[CH:13][C:6]4[N:5]=[C:4]([CH:1]5[CH2:2][CH2:3]5)[N:8]([CH3:9])[C:7]=4[CH:10]=3)[C:15](=[O:22])[CH:16]=2)=[CH:26][CH:25]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(CO)cc3=O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(COc4ccc(Cl)cc4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 4 h
Yield: 21.8 %

Procedure:
To a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-(hydroxymethyl)pyridin-2(1H)-one (150 mg), 4-chlorophenol (130 mg) and tributylphosphine (514 mg) in THF (15 ml) was added 1,1′-(azodicarbonyl)dipiperidine (641 mg), and the mixture was stirred at 60° C. for 4 h. The mixture was concentrated in vacuo, and diluted with DCM. The mixture was washed with water and brine successively, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (MeOH/DCM) to afford the title compound (45 mg) as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]1[C:18]([O:20][CH2:21][CH3:22])=[O:19]>ClCCCl>[C:1]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[NH:9][C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)c1cc2cccc(C(C)=O)c2[nH]1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Acetyl chloride (0.76 ml) was added to a suspension of anhydrous aluminium (III) chloride (1.42 g) in 1,2-dichloroethane (20 ml) at 0° C. The reaction was stirred for 5 minutes then a solution of ethyl indole-2-carboxylate (1 g) in 1,2-dichloroethane (20 ml) was added dropwise over 10 minutes. The reaction was heated at reflux for 1 hour, cooled and poured into ice/water. The solution was partitioned between ethyl acetate and saturated aqueous sodium-hydrogen carbonate solution. Combined organic extracts were dried (MgSO4) and concentrated in vacuo and the residue purified by column chromatography using isohexane-10% ethyl acetate as eluent to give firstly ethyl 7-acetylindole-2-carboxylate as a white solid (0.1 8 g, 15%); NMR δ(CD3SOCD3) 1.35 (t, 3H), 2.7 (s, 3H), 4.4 (q, 2H), 7.3 (m, 2H), 8.05 (m, 2H), 10.7 (bs, 1H); M/z (+) 232 (MH+), followed by ethyl 3-acetylindole-2-carboxylate as a white solid (0.2 g, 16%); NMR δ(CD3SOCD3) 1.35 (t, 3H), 2.6 (s, 3H), 4.4 (q, 2H), 7.2 (t, 1H), 7.3 (t, 1H), 7.5 (d, 1H), 7.9 (d, 1H), 12.4 (bs, 1H); M/z (+) 232 (MH+), followed by ethyl 5-acetylindole-2-carboxylate as a white solid (0.5 g, 42%); NMR δ(CD3SOCD3) 1.35 (t, 3H) 12.6 (s, 3H), 4.35 (q, 2H), 7.3 (s, 1H), 7.5 (d, 1H), 8.4 (s, 1H), 12.2 (bs, 1H); M/z (+) 232 (MH+).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:22])[C:17]=2[CH3:21])[CH:12]=1)C1C=CC=CC=1.Cl[C:25]1[C:34]2[C:29](=[CH:30][C:31]([O:37][CH3:38])=[C:32]([O:35][CH3:36])[CH:33]=2)[N:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.[OH-].[Na+].[Cu]>[CH3:36][O:35][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][C:31]=1[O:37][CH3:38])[N:28]=[CH:27][CH:26]=[C:25]2[O:22][C:16]1[C:17]([CH3:21])=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([NH2:10])[CH:20]=[CH:19]2
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1c(O)ccc2cc(NC(=O)OCc3ccccc3)ccc12
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc4cc(N)ccc4c3C)c2cc1OC

Procedure:
(6-Hydroxy-5-methyl-naphthalen-2-yl)-carbamic acid benzyl ester (Step a, 0.300 g, 0.9 mmol), 4-chloro-6,7-dimethoxy-quinoline (0.218 g, 0.9 mmol), K2CO3 (0.124 g, 0.9 mmol), and copper (4% by wt.) were added to a vial, then microwaved for 30 min at 120° C. with 150 watts of power (Powermax, CEM). The mixture was diluted with CH2Cl2 and 40 mL of 1N NaOH, then extracted the organics 3 times with CH2Cl2. The organics were combined, dried over Na2SO4, filtered, and concentrated in vacuo. The crude was crystallized from CH2Cl2/Hexanes to give a light brown solid, which was the titled compound. MS (ESI, pos. ion) m/z: 361 (M+1). Mass Calc'd for C22H20N2O3: 360.15.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:7]([O:9]CC)=O)[CH2:6][CH2:5][CH2:4]1.[C:12](#[N:14])[CH3:13]>>[CH:3]1([C:7](=[O:9])[CH2:13][C:12]#[N:14])[CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C1CCC1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Product: N#CCC(=O)C1CCC1
Temperature: 75 °C

Procedure:
A stirred suspension of sodium hydride (12 g of a 60% dispersion in mineral oil, 0.30 mol, which was washed with petroleum ether twice in dry THF) was heated to 75° C. To this was added a mixture of ethyl cyclobutanecarboxylate (25.64 g, 0.20 mol) and dry acetonitrile (12.32 g, 0.30 mol), dropwise, and the resulting colorless suspension was heated at 70° C. for 24 h. After cooling to rt the reaction mixture was concentrated under reduced pressure and the residue poured into water (100 mL) and extracted with ethyl acetate (100 mL). The aqueous layer was separated, acidified to pH 2 with aqueous 2 M HCl and extracted with diethyl ether (2×200 mL). The combined diethyl ether layers were dried over magnesium sulfate then concentrated under reduced pressure to afford 3-cyclobutyl-3-oxopropanenitrile as yellow oil which was used in the next step without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][CH2:9][CH3:10])[NH2:6].[F:12][C:13]1[CH:14]=[C:15]([NH:20][CH:21]([C:23](O)=[O:24])[CH3:22])[CH:16]=[C:17]([F:19])[CH:18]=1>>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([NH:6][C:23](=[O:24])[CH:21]([CH3:22])[NH:20][C:15]1[CH:16]=[C:17]([F:19])[CH:18]=[C:13]([F:12])[CH:14]=1)[CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(Nc1cc(F)cc(F)c1)C(=O)O
Reactant: CCCC[C@H](N)C(=O)OC
Agent: Cl
Product: CCCC[C@H](NC(=O)C(C)Nc1cc(F)cc(F)c1)C(=O)OC

Procedure:
Following General Procedure E and using L-norleucine methyl ester hydrochloride (Sigma) and N-(3,5-difluorophenyl)-D,L-alanine, the title compound was prepared as a solid (mp=93-95° C.). The reaction was monitored by tlc (Rf=0.6 in 3% methanol/methylene chloride) and purification of this compound was by flash chromatography with 3% methanol/methylene chloride.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[C:16](=[O:18])=[O:17]>CCOCC.CCCCCC>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:16]([OH:18])=[O:17])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C=O
Reactant: c1ccc2c(c1)CCCO2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(O)c1cccc2c1OCCC2
Temperature: 0 °C

Procedure:
At RT a solution of chroman (17.7 mmol) in ether (15 mL) is added over 10 min to a solution of n-BuLi (19.5 mmol) in a mixture of hexane (12.2 mL) and ether (15 mL). The mixture is stirred at reflux for 150 min, allowed to reach RT and poured into a mixture of dry ice and ether. Ice water is added and the layers are separated. The aq. layer is made acidic and extracted with a mixture of ether and EtOAc. The combined organic layers are washed with water, dried over Na2SO4 and concentrated in vacuo to give a crude product which is purified by CC (heptane/EtOAc 9/1 to EtOAc). LC-MS: tR=0.76 min; [M+CH3CN+H]+=220.1.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)(=O)=O.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>CN1CCCC1=O.O>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=3)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=2)=[CH:29][CH:28]=1
Reactant: COc1ccc(CN)cc1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(CNc2nc(-c3ccc(S(C)(=O)=O)cc3)cc(C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (1 g, 2.629 mmol) in N-methylpyrrolidone (10 ml) was treated with 4-methoxybenzylamine (0.69 ml). The mixture was stirred at room temperature for 18 h and was then diluted with water (50 ml). This gave a cream solid, which was triturated with diethyl ether giving the title compound as a colourless solid (0.98 g).
Reaction SMILES: [F:1][C:2]([F:16])([O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=O)[CH:3]([F:5])[F:4].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:28][C:29]1[CH:30]=[C:31]([CH:48]=[CH:49][CH:50]=1)[O:32][C:33]1[CH:34]=[CH:35][C:36]2[N:37]([CH:39]=[C:40]([NH:42][C:43]([CH:45]3[CH2:47][CH2:46]3)=[O:44])[N:41]=2)[N:38]=1>CN(C)C=O.CN1CCCC1=O>[CH:45]1([C:43]([NH:42][C:40]2[N:41]=[C:36]3[CH:35]=[CH:34][C:33]([O:32][C:31]4[CH:30]=[C:29]([NH:28][C:10](=[O:12])[C:9]5[CH:13]=[CH:14][CH:15]=[C:7]([O:6][C:2]([F:1])([F:16])[CH:3]([F:4])[F:5])[CH:8]=5)[CH:50]=[CH:49][CH:48]=4)=[N:38][N:37]3[CH:39]=2)=[O:44])[CH2:46][CH2:47]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(O)c1cccc(OC(F)(F)C(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cccc(OC(F)(F)C(F)F)c1
Yield: 33.4 %

Procedure:
Using 3-(1,1,2,2-tetrafluoroethoxy)benzoic acid (74 mg, 0.31 mmol), oxalyl chloride (33 μL, 0.39 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (80 mg, 0.26 mmol) and N-methylpyrrolidone (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (46 mg, 34%) was obtained as a white powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]=1.[CH:11]1([CH2:21][NH2:22])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][O:12]1.C([O-])(O)=O.[Na+]>CCO.O>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]=[C:2]([NH:22][CH2:21][CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][O:12]2)[CH:7]=1
Reactant: COc1nc(Cl)cc(Cl)n1
Reactant: NCC1OCCc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1nc(Cl)cc(NCC2OCCc3ccccc32)n1
Yield: 109.9 %

Procedure:
A mixture of 4,6-dichloro-2-methoxy-pyrimidine (0.45 g, 2.5 mmol), C-isochroman-1-yl-methylamine (0.53 g, 3.2 mmol), and NaHCO3 (0.63 g, 7.5 mmol) in EtOH (5 mL) is heated to reflux for 4 h. The mixture is diluted with water, concentrated in vacuo. The residue is partitioned between EtOAc and water, and extracted with EtOAc. The extracts are dried (Na2SO4), and concentrated to afford (6-chloro-2-methoxy-pyrimidin-4-yl)-isochroman-1-ylmethyl-amine (0.84 g). LCMS: RT=2.94 minutes; MS: 306 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C(N(CC)CC)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:10]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: C#CCCCCCCCCC
Reactant: O=Cc1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCCCCC#Cc1cccc(C=O)c1
Temperature: 55 °C
Reaction time: 6 h
Yield: 109.1 %

Procedure:
To a solution of 3-bromobenzaldehyde (30.3 g) and 1-undecyne (29.5 g) in triethylamine (120 ml) was added bis(triphenylphosphine)palladium(II) chloride (1.9 g) followed by copper(I) iodide (0.25 g). The mixture was stirred in the dark at 55° C. for 6 hrs, under nitrogen. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated to yield 45.8 g of 3-(1-undecynyl)benzaldehyde, as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([CH2:55][O:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH3:74])([CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:9]=[CH:8][C:4]=1[CH:5]=[N:6]O.Cl>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH2:13][C:14]([CH2:55][O:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH3:74])([CH2:35][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH:9]=[CH:8][C:4]=1[CH2:5][NH2:6]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCCCC)(COCCCCCCCCCCCCCCCCCC)COc1ccc(C=NO)c(OC)c1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCCCC)(COCCCCCCCCCCCCCCCCCC)COc1ccc(CN)c(OC)c1
Reaction time: 2.5 h
Yield: 107.9 %

Procedure:
2-Methoxy-4-[2′,2′,2′-tris(octadecyloxymethyl)ethoxy]benzaldoxime (40 mg, 0.038 mmol) was dissolved in THF (1 ml), diisobutylaluminum hydride (DIBAL)-toluene solution (127 μl, 0.13 mmol) was added dropwise, and the mixture was stirred for 2.5 hr. 1N Hydrochloric acid (2 ml) was added dropwise to the reaction mixture to quench the reaction, and the mixture was extracted with chloroform (2 ml) and washed with 10% aqueous sodium carbonate solution (1 ml). The solvent was evaporated, and acetonitrile (1 ml) was added to the residue. The precipitate was collected by filtration, and purified by silica gel chromatography to give 2-methoxy-4-[2′,2′,2′-tris(octadecyloxymethyl)ethoxy]benzylamine (43 mg, 0.041 mmol, 85%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[F:19][C:20]1[CH:21]=[CH:22][C:23]2=[C:24]([CH:45]=1)[O:25][CH2:26][C:27]1[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:28]=1/[C:29]/2=[CH:30]\B1OC(C)(C)C(C)(C)O1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C.[K+]>O1CCOCC1.O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]2=[C:24]([CH:45]=1)[O:25][CH2:26][C:27]1[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:28]=1/[C:29]/2=[CH:30]\[C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: CC1(C)OB(/C=C2/c3ccc(F)cc3OCc3c(F)cccc32)OC1(C)C
Reactant: CN1CCN(Nc2ccc(Br)cc2[N+](=O)[O-])CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCN(Nc2ccc(/C=C3/c4ccc(F)cc4OCc4c(F)cccc43)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Yield: 54.9 %

Procedure:
Degas three times a mixture of (4-bromo-2-nitro-phenyl)-(4-methyl-piperazin-1-yl)-amine (0.016 mol, 5.0 g), (E)-3,7-difluoro-11-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-ylmethylene)-6,11-dihydro-dibenzo[b,e]oxepine (0.017 mol, 6.4 g), triphenylphosphine (0.0028 mol, 0.74 g) and potassium acetate (0.0317 mol, 3.11 g) in dioxane/water (3:1) (200 mL) with nitrogen. Add palladium (II) acetate (0.5 mmol, 113 mg) to the reaction mixture and degas again three times with nitrogen. Heat the resulting reaction mixture at 85° C. for 16 h. Cool the reaction mixture to room temperature and dilute with water. Extract the mixture with ethyl acetate, combine organic layers, and wash with water and brine. Dry the organic phase over anhydrous sodium sulfate, filter, and concentrate. Crystallize the crude material from methanol, filter, and dry under vacuum to obtain the title compound (4.2 g, 55%) as an orange solid. ES-MS m/z 479 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.C(N(CC)CC)C.Cl.[NH2:19][CH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CCO.O>[I:8][C:7]1[C:2]([NH:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[N:3][C:4]([NH2:10])=[N:5][C:6]=1[CH3:9]
Reactant: Cc1nc(N)nc(Cl)c1I
Reactant: NC1CCOCC1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(NC2CCOCC2)c1I
Temperature: 25 °C
Reaction time: 72 h
Yield: 51.6 %

Procedure:
To a suspension of 4-chloro-5-iodo-6-methylpyrimidin-2-amine (16.0 g, 59.3 mmol) in EtOH (200 mL) and H2O (250 mL) was added triethylamine (30.0 mL, 207.5 mmol) and 4-aminotetrahydropyran HCl salt (9.75 g, 71.2 mmol) successively. The reaction was heated to reflux, stirred for 72 h, and then cooled to RT. About 80% of the solvent was evaporated under reduced pressure. The mixture was partitioned between ethyl acetate and H2O. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude product. The product was purified by a flash chromatography (50% ethyl acetate/hexanes to 100% ethyl acetate) to afford 5-iodo-6-methyl-N4-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4-diamine as a light yellow crystal (yield: 10.23 g, 51.7%). LC/MS: calculated for C10H15IN4O (334.03). found: 335.08 (MH+). HPLC analytical purity: >99.0%.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9](Cl)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>O>[C:10]1([CH2:9][O:2][C:1]2[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][CH:8]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1cccc(O)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Oc1cccc(OCc2ccccc2)c1
Yield: 27.1 %

Procedure:
36.6 g (332.40 mmol) of resorcinol and 42 g (331.78 mmol) of benzyl chloride are refluxed overnight in 250 ml of dry Me2CO in the presence of 46.6 g of K2CO3, with stirring. The mixture is cooled, filtered and evaporated. The residue obtained is diluted in 500 ml of water and extracted with ethanol. The organic layer is washed with 10% aqueous NaOH and extracted with ethanol. The red oil obtained is distilled with the aid of a bulb tube distillation apparatus to give 18 g of m-PhCH2OC6H4OH, b.p.15 240-245° C. (lit. b.p.11 202-210° C.). A solution of 3.3 g (16.5 mmol) of m-PhCH2OC6H4OH in 50 ml of DMF is treated with 0.8 g (16.5 mmol) of sodium hydride and the mixture is stirred for 15 minutes. After the addition of 13.75 ml (16.5 mmol) of epichlorohydrin, the mixture is stirred at 60° C. for one hour until alkylation is complete. The excess reagent and the solvent are evaporated off under reduced pressure and the residue is partitioned between the following two phases: ethyl acetate and water. The organic phase yields the epoxide, which is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:10]([O:17][CH2:18][C:19](N)=[NH:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:19]([CH2:18][O:17][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:20]=1
Reactant: N=C(N)COCc1ccccc1
Reactant: N#Cc1nccnc1N
Solvent: CCO
Product: Nc1nc(COCc2ccccc2)nc2nccnc12

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 12.0 g )0.10 mole) of 3-amino-2-pyrazinecarbonitrile and 25.0 g (0.15 mole) of 2-(benzyloxy)acetamidine [prepared according to W. J. Haggerty Jr. and W. J. Rost, J. Pharm. Sci. 1969, 58, 50] in 400 ml of absolute ethanol. Refluxing time: 4 hours. Yld: 15.4 g (58%), m.p. 112°-114° C. An analytical sample was obtained by recrystallization from ethanol, followed by washing with dilute hydrochloric acid and finally recrystallization from ethyl acetate. M.p. 131°-133° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[CH2:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[C:23](I)[C:24]([CH3:28])=[CH:25][CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1.[CH3:30][NH:31][C:32]1[N:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[CH:38]=2)[N:33]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[C:23]([C:37]5[CH:38]=[C:39]6[C:34](=[CH:35][CH:36]=5)[N:33]=[C:32]([NH:31][CH3:30])[N:41]=[CH:40]6)[C:24]([CH3:28])=[CH:25][CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CNc1ncc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Reactant: Cc1ccc2c(Nc3ccc4c(c3)CCC4)ncnc2c1I
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNc1ncc2cc(-c3c(C)ccc4c(Nc5ccc6c(c5)CCC6)ncnc34)ccc2n1
Temperature: 180 °C

Procedure:
2 M Aqueous sodium carbonate (857 μl, 1.7 mmol), tetrakis(triphenylphosphine)palladium (0) (99 mg, 86 μmol), N-(2,3-dihydro-1H-inden-5-yl)-8-iodo-7-methylquinazolin-4-amine hydrochloride (250 mg, 571 μmol), N-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-2-amine (326 mg, 1142 μmol) and dioxane (5 mL) were added to a microwave vial. The reaction mixture was heated in a microwave at 180° C. for 20 min. The solid residue was filtered off through Celite® and washed with methanol and DCM. The filtrate was concentrated and purified by flash chromatography (0-10% MeOH in DCM) to give 6-(4-(2,3-dihydro-1H-inden-5-ylamino)-7-methylquinazolin-8-yl)-N-methylquinazolin-2-amine as an off-white amorphous solid. MS (M+H)+ 433.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:19]([CH3:28])[CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1)#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([N:19]([CH3:28])[CH2:20][C:21]([OH:23])=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][N:11]=1)#[N:2]
Reactant: CN(CC(=O)OC(C)(C)C)c1ccc(Oc2ccc([N+](=O)[O-])cn2)c(C#N)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CC(=O)O)c1ccc(Oc2ccc([N+](=O)[O-])cn2)c(C#N)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of t-butyl 2-((3-cyano-4-(5-nitropyridin-2-yloxy)phenyl)(methyl)amino)acetate (1.2 g, 3.1 mmol) in dichloromethane (12 mL) was added trifluoroacetic acid (12 mL), and the resulting reaction solution was stirred at room temperature for 5 hours. The solvent was evaporated, and water was added to the residue, and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated, to thereby yield crude 2-((3-cyano-4-(5-nitropyridin-2-yloxy)phenyl)(methyl)amino)-acetic acid. To a solution of this compound in DMF (24 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (659 mg, 3.4 mmol), 1-hydroxybenzotriazole monohydrate (526 mg, 3.4 mmol) and 1-piperonylpiperazine (757 mg, 3.4 mmol), and the resulting reaction solution was stirred for 8 hours at room temperature. Water was added to the reaction solution and extracted with ethyl acetate. The ethyl acetate layer was then washed with, in order, saturated aqueous sodium bicarbonate solution, water and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel chromatography (ethyl acetate), to thereby yield 412 g of the title compound.