Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]12[C:10]([O:13][CH3:14])([O:11][CH3:12])[C:5]([Cl:15])([C:6]([Cl:9])=[C:7]1[Cl:8])[CH:4](O)[CH:3]2O.I([O-])(=O)(=O)=O.[Na+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.O>[Cl:15][C:5]12[C:10]([O:11][CH3:12])([O:13][CH3:14])[C:2]([Cl:1])([C:7]([Cl:8])=[C:6]1[Cl:9])[CH2:3][N:31]([CH2:30][C:29]1[CH:32]=[CH:33][C:26]([O:25][CH3:24])=[CH:27][CH:28]=1)[CH2:4]2
Reactant: COC1(OC)C2(Cl)C(Cl)=C(Cl)C1(Cl)C(O)C2O
Reactant: COc1ccc(CN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: ClCCCl
Product: COc1ccc(CN2CC3(Cl)C(Cl)=C(Cl)C(Cl)(C2)C3(OC)OC)cc1
Reaction time: 3 h
Yield: 81.3 %

Procedure:
1,4,5,6-Tetrachloro-7,7-dimethoxy-bicyclo[2.2.1]hept-5-ene-2,3-diol (1.23 g, 3.80 mmol) and sodium periodate (1.19 g, 3.80 mmol) were stirred vigorously for 1.5 h in DCE (10 mL) and water (10 mL). The di-aldehyde was extracted with DCE (2×15 mL), washed with water (5×10 mL, or until no reaction to starch iodide is observed in the aqueous wash), then filtered through a cotton plug under N2 into a slurry of p-methoxybenzylamine (0.52 mL, 3.99 mmol) and NaBH(OAc)3 (2.58 g, 12.16 mmol) in DCE (10 mL). After 3 h at room temperature the reaction was judged complete by TLC. The solvent was removed in vacuo, and the residue was quenched with saturated aqueous NaHCO3 solution. The product was extracted with EtOAc (3×30 mL), washed with saturated aqueous NaCl solution (1×30 mL), dried over Na2SO4, filtered through a silica pad (2×3 in), eluted with 100% EtOAc and concentrated to yield the title compound as a white solid (1.32 g, 82%). (TLC 30% EtOAc/hexanes Rf 0.65); 1H NMR (400 MHz, CDCl3) δ 7.12 (d, J=8.3 Hz, 2H), 6.81 (d, J=8.3 Hz, 2H), 3.77 (s, 3H), 3.61 (s, 2H), 3.59 (s, 3H), 3.56 (s, 3H), 2.76 (d, J=11.4 Hz, 2H), 2.71 (d, J=11.1 Hz, 2H); GCMS m/z 427 (M)+.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[Br:13][C:14]1[C:15]([F:23])=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17](O)=[O:18].C(N(CC)CC)C.Cl.[CH3:32][NH:33][O:34][CH3:35]>ClCCl>[Br:13][C:14]1[C:15]([F:23])=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([N:33]([O:34][CH3:35])[CH3:32])=[O:18]
Reactant: CNOC
Reactant: O=C(O)c1cccc(Br)c1F
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cccc(Br)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
Carbonyldiimidazole (7.76 g) was added portionwise to commercially available 3-bromo-2-fluorobenzoic acid [161957-56-8] (9.53 g) in dichloromethane (100 mL) over 30 min. The mixture was then heated at reflux for 30 min (until gas evolution ceased). The reaction was then cooled to room temperature and triethylamine (6.37 mL) followed by N,O-dimethylhydroxylamine hydrochloride (4.7 g) were added. The reaction was left to stir at room temperature for 16 h before being washed with 10% citric acid (2×100 mL) and sat. NaHCO3 (2×100 mL), and then dried over sodium sulfate. The solvent was removed by evaporation to yield the product as a brown oil (10.89 g, 95%). NMR (CDCl3): 3.20-3.80 (6H, m, ArCONCH3OCH3), 7.10 (1H, t, Ar), 7.35 (1H, td, Ar), 7.60 (1H, dt, Ar).
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([Br:58])=[CH:53][CH:54]=4)[O:49][C:48]=3[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:56](=[O:57])[C:55]4[C:50](=[CH:51][C:52]([Br:58])=[CH:53][CH:54]=4)[O:49][C:48]=3[C:59]3[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=3)=[CH:45][CH:46]=2)[CH2:38][CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(Br)ccc4c3=O)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(Br)ccc4c3=O)cc2)CCC1
Yield: 77 %

Procedure:
3-[4-(1-Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(7-bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted to give the title compound as a pale yellow solid (22 mg, 77%). 1H NMR (400 MHz, DMSO-d6): δ 8.09 (d, J=2 Hz, 1H), 8.03 (d, J=8 Hz, 1H), 7.71 (dd, J=2 and 8 Hz, 1H), 7.45-31 (m, 7H), 7.15-7.11 (m, 2H), 2.40-2.32 (m, 2H), 2.12-2.04 (m, 2H), 2.04-1.94 (m, 1H), 1.69-1.60 (m, 1H). LCMS (Method F): RT=10.10 min, [M+H]+=446/448.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][S:6]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:21])(=[O:8])=[O:7].[CH3:22][O:23]C(Cl)Cl>C(Cl)Cl>[CH3:5][S:6]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[C:16]([CH:22]=[O:23])[CH:17]=2)[CH2:12][CH2:11][C:10]1=[O:21])(=[O:8])=[O:7]
Reactant: COc1ccc2c(c1)CCC(=O)N2S(C)(=O)=O
Reactant: COC(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2c(cc1C=O)N(S(C)(=O)=O)C(=O)CC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66 %

Procedure:
To a flame dried round bottom flask equipped with a nitrogen cap was added 180 mg (1.35 mmol) aluminum chloride and 10 ml of methylene chloride. The mixture was stirred at ambient temperature for 0.25 hour and then cooled to 0° C. followed by the addition of 177 mg (0.69 mmol) 1-methanesulfonyl-6-methoxy-3,4-dihydro-1H-quinolin-2-one. The reaction mixture was stirred for 10 minutes at this temperature and was then treated with 171 μl (1.89 mmol) of α,α-dichloromethyl methyl ether before allowing the reaction to slowly warm to room temperature over 16 hours. The reaction mixture was quenched with 30 ml of 2M HCl and extracted with ethyl acetate (3×30 ml). The combined organics were then washed with saturated aqueous bicarbonate solution and brine followed by drying over sodium sulfate and evaporation in vacuo. The crude residue was purified on silica gel eluting with 95/5 methylene chloride/methanol to afford an off white solid in 66% yield (130 mg). Mass spectrum APCI m/e 284 (p+1).
Reaction SMILES: [CH3:1][Si:2]([CH3:28])([CH3:27])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH3:26])[CH2:22][CH:23]=[O:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1.CO.[BH4-].[Na+]>O>[CH3:27][Si:2]([CH3:1])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]2[N:12]=[CH:13][N:14]=[C:15]([C:16]3[CH:17]=[N:18][N:19]([CH:21]([CH2:25][CH3:26])[CH2:22][CH2:23][OH:24])[CH:20]=3)[C:10]=2[CH:9]=[CH:8]1
Reactant: CCC(CC=O)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(CCO)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of [3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]pentanal (50 mg, 0.0001 mol) in methanol (2 mL, 0.05 mol) was treated with sodium tetrahydroborate (8 mg, 0.0002 mol). The mixture was stirred at room temperature for 1 h, and then water was added and the product was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to give the desired product as an oil. LC/MS (M+H)+: m/z=402.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][C:20]([CH3:22])=[O:21])=[C:9]([O:12][CH2:13][CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[F:31])[NH2:27]>C(O)(C)C>[Cl:23][C:24]1[CH:25]=[C:26]([NH:27][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:19][C:20]([CH3:22])=[O:21])=[C:9]([O:12][CH2:13][CH:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:28]=[CH:29][C:30]=1[F:31]
Reactant: CC(=O)Oc1cc2ncnc(Cl)c2cc1OCC1CCCC1
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: CC(C)O
Product: CC(=O)Oc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCC1CCCC1
Temperature: 25 °C

Procedure:
4.03 g of 4-chloro-6-cyclopentylmethoxy-7-methylcarbonyloxy-quinazoline are suspended in 70 ml of isopropanol and 1.95 g of 3-chloro-4-fluoro-aniline are added. The reaction mixture is refluxed for two hours under a nitrogen atmosphere. After cooling to ambient temperature the light-coloured precipitate formed is suction filtered, washed with a little isopropanol and dried in the air.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:24]([NH2:25])=[CH:23][CH:22]=[CH:21][N:20]=1.Cl.CN(C)CCCN=C=NCC.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]([NH:25][C:24]2[C:19]([Cl:18])=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:17])[CH2:13][CH2:14]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cccnc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)Nc2cccnc2Cl)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture comprising 10 g of trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid, 7.93 g of 2-chloro-3-aminopyridine, 10.2 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 6.5 g of 4-dimethylaminopyridine, and 180 mL of N,N-dimethylformamide was stirred at room temperature for 15 hours. To the reaction mixture was added an aqueous sodium hydrogencarbonate solution to make the solution alkaline, and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain trans-4-tert-butoxycarbonylamino-N-(2-chloro-3-pyridyl)-cyclohexanecarboxamide.
Reaction SMILES: [CH3:1][O:2][NH:3][C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][O:20][CH2:21][C:22]#[CH:23].O>C(#N)C>[CH3:1][O:2][N:3]([CH2:19][O:20][CH2:21][C:22]#[CH:23])[C:4](=[O:11])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CONC(=O)c1ccccc1
Reactant: C#CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: C#CCOCN(OC)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
0.6 g of N-methoxybenzamide was dissolved in 10 ml of acetonitrile, and 0.55 g of potassium carbonate and 0.42 g of chloromethylpropargyl ether were added thereto in this order. The mixture was stirred at room temperature for 3 hours. After completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried, concentrated and purified by silica gel column chromatography to obtain 0.8 g of N-methoxy-N-propargyloxymethylbenzamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8](O)[C:7]([CH3:12])([CH3:11])[C:6]=2[CH:13]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:12])[C:6]=2[CH:13]=1
Reactant: CC1(C)c2cc(Br)ccc2OC1O
Agent: CC[SiH](CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)COc2ccc(Br)cc21

Procedure:
A solution of 5-Bromo-3,3-dimethyl-2,3-dihydro-benzofuran-2-ol (813 mg, 3.36 mmol), Triethylsilane (805 □L, 5.04 mmol), and 30% TFA/CH2Cl2 (15 mL), were stirred at room temperature for 1 h. The solution was then diluted with Toluene (15 mL), stripped of all solvents, and chromatographed on silica eluted with a gradient 5–25% Ethyl acetate/Hexanes. Yield 549 mg, 72%.
Reaction SMILES: [S:1]([N:11]1[C:15]2=[N:16][CH:17]=[C:18]([C:20]#[N:21])[N:19]=[C:14]2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([Mg]Br)=[CH:26][CH:25]=1>C1COCC1>[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([C:20]([C:18]2[N:19]=[C:14]3[CH:13]=[CH:12][N:11]([S:1]([C:4]4[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=4)(=[O:2])=[O:3])[C:15]3=[N:16][CH:17]=2)=[NH:21])=[CH:26][CH:25]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(C#N)cnc32)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=N)c2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbonitrile (0.500 g, 1.68 mmol) in anhydrous THF (3.35 mL) was added molecular sieves (4A, beads, 8-12 mesh, 0.643 g). The mixture was stirred at rt for about 40 min. A solution of (4-methoxyphenyl)magnesium bromide (0.5 M in THF, 4.12 mL, 2.01 mmol,) was added dropwise over about 3 min. The mixture was stirred at rt for about 2 h. The mixture was concentrated in vacuo to give (4-methoxyphenyl)(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)methanimine which was assumed to be quantitative and used immediately in the next step: LC/MS (Table 2, Method b) Rt=2.25 min; MS m/z: 407 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]2[CH:13]=[N:14][NH:15][C:7]=12.[C:16](Cl)(=[O:18])[CH3:17].[OH-].[Na+]>O>[C:16]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]2[CH:13]=[N:14][NH:15][C:7]=12)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: Cc1cc(NCCCO)c2[nH]ncc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)OCCCNc1cc(C)nc2cn[nH]c12

Procedure:
The title compound was prepared from 7(3-hydroxypropylamino)-5-methyl-1H-pyrazolo[4,3-b]pyridine (1.125 g) and acetyl chloride by the general method of Example 4 with the following addition. After removal of solvents under reduced pressure the crude reaction mixture was dissolved in water and brought to pH 9 with 10% sodium hydroxide. The resulting solid was collected and dried before purifying by column chromatography under the conditions used for Example 4. A clear gum was obtained which on trituration with ether gave the title compound as a white solid, m.p. 115°-119° C.
Reaction SMILES: [C:1]1(=[N:6][NH:7][C:8]([NH2:10])=S)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(NC(C)C)(C)C.[Li].Cl.S.[OH-].[Na+]>O1CCCC1>[NH:6]1[C:1]2[CH2:5][CH2:4][CH2:3][C:2]=2[C:8]([NH2:10])=[N:7]1
Reactant: NC(=S)NN=C1CCCC1
Agent: Cl
Agent: S
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Nc1n[nH]c2c1CCC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
5.3 g of cyclopentanone thiosemicarbazone is carefully added at 0° C. to a solution of lithium diisopropylamine in 200 ml of tetrahydrofuran (from 29 ml of diisopropylamine and 81 ml of 1.6 M n-butyllithium), whereby the temperature rises to 30° C. Then, it is stirred for 2 hours at room temperature. Then, 150 ml of 4N hydrochloric acid is carefully added in drops (exothermic, H2S development), and the mixture is refluxed for 30 minutes. Then, it is cooled to 5° C. and set at pH 14 with sodium hydroxide solution. The aqueous phase is extracted three times with tetrahydrofuran/ethyl acetate 95:5. The crude product is purified by column chromatography on silica gel with 1 l of ethyl acetate and 1 l of ethyl acetate/methanol 9:1 with the addition of 3% triethylamine. 2.58 g of 1,4,5,6-tetrahydro-cyclopentapyrazol-3-yl-amine with a melting point of 116-120° C. is obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[N+:8]([C:4]1[CH:3]=[C:2]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: C1CCNC1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(N2CCCC2)c1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 78 %

Procedure:
To a solution of 3-bromonitrobenzene (2.02 g, 10 mmol) in toluene (33 mL) and pyrrolidine (1.0 mL, 12 mmol) was added sodium t-butoxide (1.92 g, 20 mmol) and the solution was deoxygenated by passing a nitrogen through the solution at room temperature for 15 minutes. BINAP and tris(dibenzylideneacetone)dipalladium(0) complex were subsequently added as a solid and the nitrogen bubbling was continued for an additional 5 minutes. The mixture was heated at 100° C. overnight. The reaction mixture was then cooled and partitioned between water and ethyl acetate. The organic layer was washed once with brine solution and dried over anhydrous sodium sulfate. The ethyl acetate was decanted and evaporated under reduced pressure to give the desired 1-(3-nitrophenyl)pyrrolidine as a red oil (1.5 g, 79%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[C:31]([OH:32])=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[C:26]([CH3:33])[NH:27]2.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:32][C:31]3[C:23]([F:22])=[C:24]4[C:28](=[CH:29][CH:30]=3)[NH:27][C:26]([CH3:33])=[CH:25]4)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCc1ccccc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 57.5 %

Procedure:
A suspension of 7-benzyloxy-4-chloro-6-methoxyquinazoline free base (10 g, 33.2 mmol), 4-fluoro-5-hydroxy-2-methylindole (5.9 g, 35.7 mmol), (prepared as described for the starting material in Example 1), and potassium carbonate (9.2 g, 66.6 mmol) in NMP (100 ml) was stirred at 95° C. for 1 hour. After cooling, the mixture was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate. The organic layer was separated, washed with brine and dried over magnesium sulphate and evaporated under vacuum. The residue was triturated under acetonitrile and the suspension was cooled. The precipitate was filtered and dried under vacuum to give 7-benzyloxy-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline (8.2 g, 57%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:17](=[CH:18][CH:19]=2)[CH:16]2[CH2:20][CH2:21][CH:12]3[CH2:13][N:14]([CH2:22][C:23]#C)[CH2:15]2)=[N:6][CH:7]=1.BrCC#[N:39]>>[Cl:1][C:2]1[C:3]([NH:25][C:26]2[CH:35]=[CH:34][CH:33]=[CH:32][C:27]=2[C:28]([NH:30][CH3:31])=[O:29])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]3[C:17](=[CH:18][CH:19]=2)[CH:16]2[CH2:20][CH2:21][CH:12]3[CH2:13][N:14]([CH2:22][C:23]#[N:39])[CH2:15]2)=[N:6][CH:7]=1
Reactant: N#CCBr
Reactant: C#CCN1CC2CCC(C1)c1cc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NC)n3)ccc12
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C2CCC3CN(CC#N)C2)ncc1Cl

Procedure:
2-[5-Chloro-2-(10-cyanomethyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide was prepared from 2-[5-chloro-2-(10-prop-2-ynyl-10-aza-tricyclo[6.3.2.0*2,7*]trideca-2,4,6-trien-4-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide and bromo-acetonitrile in an analogous manner to Example 279. Product isolated as a yellow foam (83 mg, 76%). LCMS (m/e) 488 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 11.02 (s, 1H), 8.64 (d, 1H, J=7.8 Hz), 8.09 (s, 1H), 7.52-7.40 (m, 2H), 7.39 (d, 1H, J=2.2 Hz), 7.32-7.25 (m, 1H), 7.11-7.00 (m, 2H), 6.92 (s, 1H), 6.21 (bs, 1H), 3.54 (s, 2H), 3.03 (d, 3H, J=4.9 Hz), 3.39-2.95 (m, 2H), 2.90-2.81 (m, 2H), 2.61-2.56 (m, 2H), 2.16-2.12 (m, 2H), 1.72-1.65 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8](=[C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=4)[NH:15][C:14]3=[O:23])[O:9][CH:10]([CH2:11][CH3:12])[C:4]=2[CH:3]=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH2:11]([CH:10]1[C:4]2[CH:3]=[CH:2][N:7]=[CH:6][C:5]=2[C:8](=[C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=3)[NH:15][C:14]2=[O:23])[O:9]1)[CH3:12]
Reactant: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2cnc(Cl)cc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2cnccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 40.5 %

Procedure:
A solution of 3-(6-Chloro-1-ethyl-1H-furo[3,4-c]pyridin-3-ylidene)-5-fluoro-1,3-dihydro-indol-2-one (50 mg, 0.15 mmol) in 8 ml ethanol is treated with 50 mg of 5% Pd/C and ammonium formate (500 mg). The reaction mixture is stirred for 24 h at room temperature. The reaction mixture is concentrated and is then loaded onto silica gel and purified using 5% MeOH-EtOAc. The product containing fractions are concentrated to give the title compound (18 mg, 40%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.BrC1N=CC(N)=CC=1.CC1(C)C(C)(C)OB(C2CCC3(OCCO3)CC=2)O1.[NH:42]1[CH2:45][CH:44]([NH:46][C:47](=[O:64])[CH2:48][NH:49][C:50]2[C:59]3[C:54](=[CH:55][CH:56]=[C:57]([C:60]([F:63])([F:62])[F:61])[CH:58]=3)[N:53]=[CH:52][N:51]=2)[CH2:43]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][CH:11]([N:42]3[CH2:43][CH:44]([NH:46][C:47](=[O:64])[CH2:48][NH:49][C:50]4[C:59]5[C:54](=[CH:55][CH:56]=[C:57]([C:60]([F:61])([F:63])[F:62])[CH:58]=5)[N:53]=[CH:52][N:51]=4)[CH2:45]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: Nc1ccc(C2CCC(=O)CC2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Agent: Nc1ccc(Br)nc1
Product: Nc1ccc(C2CCC(N3CC(NC(=O)CNc4ncnc5ccc(C(F)(F)F)cc45)C3)CC2)nc1

Procedure:
Reaction of 4-(5-aminopyridin-2-yl)cyclohexanone (prepared by the reaction of 6-bromopyridin-3-amine with 8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,4-dioxa-spiro[4.5]dec-7-ene using the sequence described in Example 1 Step A-C) with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[C:31]#[N:32])O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[F:18][C:17]([F:20])([F:19])[C:15]1[CH:14]=[N:13][N:12]2[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:29]4[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=4[C:31]#[N:32])[CH:7]=3)=[CH:9][N:10]=[C:11]2[N:16]=1
Reactant: CC1(C)OB(c2ccccc2C#N)OC1(C)C
Reactant: FC(F)(F)c1cnn2c(-c3ccnc(Cl)c3)cnc2n1
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: COCCOC
Product: N#Cc1ccccc1-c1cc(-c2cnc3nc(C(F)(F)F)cnn23)ccn1
Yield: 4 %

Procedure:
7-(2-Chloropyridin-4-yl)-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine was coupled with 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)benzonitrile in the presence of tetrakis(triphenylphosphine)palladium(0) and sodium carbonate, at 80° C. in aqueous 1,2-dimethoxyethane, to give the title compound in 4% yield: 1H NMR (360 MHz, CDCl3) δ 7.60 (1H, td, J 1.1, 7.7), 7.78 (1H, td, J 1.1, 7.7), 7.89 (1H, dd, J 1.1, 7.7), 7.97 (1H, dd, J 7.0, 0.7), 8.13 (1H, dd, J 1.8, 5.3), 8.65 (1H, d, J 0.7), 8.84 (1H, s), 8.94 (1H, s), 8.99 (1H, dd, J 0.7, 5.3).
Reaction SMILES: C(OC([N:8]([C:40](OC(C)(C)C)=O)[C:9](=[O:39])[C:10]1[CH:15]=[C:14]([N:16]2[C:20](=[O:21])[CH2:19][CH2:18][CH:17]2[CH3:22])[CH:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([CH3:37])=[CH:35][C:34]([CH3:38])=[CH:33][N:32]=2)[CH2:27][CH2:26]1)=[O:24])=O)(C)(C)C.N1C[CH2:51][O:50][CH2:49][CH2:48]1>>[CH3:37][C:36]1[C:31]([N:28]2[CH2:27][CH2:26][N:25]([C:23]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH:17]([CH3:22])[CH2:18][CH2:19][C:20]4=[O:21])=[CH:15][C:10]=3[C:9]([N:8]3[CH2:48][CH2:49][O:50][CH2:51][CH2:40]3)=[O:39])=[O:24])[CH2:30][CH2:29]2)=[N:32][CH:33]=[C:34]([CH3:38])[CH:35]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Reactant: C1COCCN1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)CCC4C)cc3C(=O)N3CCOCC3)CC2)c(C)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-methyl-5-oxopyrrolidin-1-yl)benzamide (70 mg) described in Example 837 and morpholine (39 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (18 mg) was obtained.