Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)[CH3:7])[C:2]#[CH:3].[CH3:18][O:19][C:20](=[O:26])[C:21](Br)=[CH:22][O:23][CH3:24]>C(N(CC)CC)C.O1CCCC1.[Cu]I>[CH3:18][O:19][C:20](=[O:26])[C:21](=[CH:22][O:23][CH3:24])[C:3]#[C:2][CH2:1][O:4][N:5]=[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=1)[CH3:7]
Reactant: COC=C(Br)C(=O)OC
Reactant: C#CCON=C(C)c1cccc(C(F)(F)F)c1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC=C(C#CCON=C(C)c1cccc(C(F)(F)F)c1)C(=O)OC
Temperature: 70 °C
Reaction time: 14 h
Yield: 31.2 %

Procedure:
0.25 g of Pd(TPP)2Cl2 and also 0.1 g of copper(I) iodide are added, under an argon atmosphere, to a solution of 10.0 g of 1-(3-trifluoromethylphenyl)ethanone O-prop-2-ynyl-oxime in 150 ml of triethylamine and the mixture is heated to 70° C. 8.9 g of 2-bromo-3-methoxyacrylic acid methyl ester in 30 ml of tetrahydrofuran are then added and the mixture is stirred at 70° C. for 14 h and then filtered. The filtrate is concentrated by evaporation and chromatographed on silica gel (hexane/diethyl ether 2:1) to yield 4.6 g of the product having a melting point of 57-58° C.
Reaction SMILES: CO.[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:7][C:6](=[N:21]O)[C:5]1=[O:23]>[Ni]>[NH2:21][CH:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:4]([CH3:3])[C:5]1=[O:23]
Reactant: Cn1c(=O)c(=NO)nc(-c2ccccc2)c2ccccc21
Agent: [Ni]
Solvent: CO
Product: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reaction time: 30 h
Yield: 95 %

Procedure:
A solution of 150 ml of methanol containing 5 g (17.9 mmole) of 1,3-dihydro-1-methyl-3-oximino-5-phenyl-1,4-benzodiazepin-2-one was treated with a slurry of active Raney-nickel catalyst1 (10 g wet weight). The resulting suspension was hydrogenated on a Parr apparatus at 60 psi and 23° C. for 30 hours. The catalyst was removed by filtration and the filtrate was concentrated to afford the title compound in 95% yield.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[CH:11]=[C:12]([Cl:31])[C:13]([C:16]2([CH2:19][NH:20][C:21](=[O:30])[C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[CH2:18][CH2:17]2)=[N:14][CH:15]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].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:31][C:12]1[C:13]([C:16]2([CH2:19][NH:20][C:21](=[O:30])[C:22]3[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=3[F:29])[CH2:18][CH2:17]2)=[N:14][CH:15]=[C:10]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)[CH:11]=1
Reactant: O=C(NCC1(c2ncc(Br)cc2Cl)CC1)c1c(F)cccc1F
Reactant: OB(O)c1ccoc1
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: O
Solvent: Cc1ccccc1
Product: O=C(NCC1(c2ncc(-c3ccoc3)cc2Cl)CC1)c1c(F)cccc1F
Temperature: 90 °C
Reaction time: 16 h
Yield: 15.8 %

Procedure:
To a suspension of 3-furylboronic acid (80 μmol) in toluene (0.3 ml) was added successively a solution of N-[1-(5-bromo-3-chloro-pyridin-2-yl)-cyclopropylmethyl]-2,6-difluorobenzamide (40 μmol) (from step 4) in toluene (0.5 ml), aqueous sodium carbonate 2M (0.06 ml), water (0.4 ml) and a solution of tetrakis(triphenylphosphine)palladium (4 μmol) in toluene (0.2 ml). The reaction mixture was stirred at 90° C. for 16 hours under an atmosphere of Argon. The reaction mixture was evaporated. The crude mixture was extracted 3 times with ethyl acetate and water. The organic phases were combined and evaporated. The crude product was dissolved in N,N-dimethylformamide (1ml) and purified by HPLC to give 2.45 mg N-[1-(3-chloro-5-furan-3-yl-pyridin-2-yl)-cyclopropylmethyl]-2,6-difluoro-benzamide.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[CH2:9][C:10]([OH:12])=[O:11])=[CH:4][N:3]=1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21]2[NH:26][CH2:25][CH2:24][CH2:23][N:22]=2)[CH2:9][C:10]([OH:12])=[O:11])=[CH:6][N:7]=1
Reactant: [H][H]
Reactant: Cc1ncc(C(CCCCCCCNc2ncccn2)CC(=O)O)cn1
Agent: [Pd]
Solvent: CCO
Product: Cc1ncc(C(CCCCCCCNC2=NCCCN2)CC(=O)O)cn1
Yield: 78.1 %

Procedure:
A solution of 24-9 (47 mg, 0.131 mmol) in ethanol (1 mL) was treated with 10% palladium on carbon (7 mg) and hydrogen gas at one atmosphere (6 days). The reaction mixture was filtered through celite and the filtrate evaporated in vacuo. PCTLC (SiO2, 1 mm, 2% AcOH; 18% MeOH; 80% CHCl3) afforded 24-10 (37 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:27][CH2:28]C#N)[C:25](=[O:31])[CH2:24][O:23][C:22]=4[N:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[O:40]=C1COC2N=C(C3C=CC(C4(NC(=O)OC(C)(C)C)CCC4)=CC=3)C(C3C=CC=CC=3)=CC=2N1.BrCCO>>[C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:27][CH2:28][OH:40])[C:25](=[O:31])[CH2:24][O:23][C:22]=4[N:32]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCC#N)C(=O)CO4)cc2)CCC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Agent: OCCBr
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCO)C(=O)CO4)cc2)CCC1

Procedure:
Following the procedure for tert-butyl(1-(4-(1-(2-cyanoethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate, tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (100 mg, 0.212 mmol) was reacted with 2-bromoethanol (80 mg, 0.636 mmol) to afford the title compound (75 mg. 1H NMR (500 MHz, CDCl3): 7.47 (s, 1H), 7.23-7.29 (m, 7H), 7.16-7.19 (m, 2H), 5.04 (br, 1H), 4.89 (s, 2H), 4.12 (m, 2H), 3.94 (m, 2H), 2.37-2.48 (m, 4H), 2.37 (t, 1H), 2.05 (m, 1H), 1.81 (m, 1H), 1.2-1.43 (br, 9H).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[O:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1.CN(C)P(=O)(N(C)C)N(C)C.C([C:29]([O:31][CH2:32][CH3:33])=[O:30])#N>O1CCCC1>[O:15]=[C:12]1[CH2:13][CH2:14][O:9][CH2:10][CH:11]1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)C#N
Reactant: O=C1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1COCCC1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Lithium diisopropylamide (1.14 mol/l solution in n-hexane/tetrahydrofuran, 2.5 ml) was added dropwise to a solution of tetrahydro-4H-pyran-4-one (260 mg) in tetrahydrofuran (13 ml) at −78° C., and the mixture was stirred for one hour while warming to 0° C. The reaction solution was cooled to −78° C. again, hexamethylphosphoric triamide (452 μl) was added and subsequently ethyl cyanoformate (280 μl) was added at the same temperature. The mixture was stirred over one hour while warming to 0° C. The reaction solution was separated by adding distilled water and ethyl acetate. The resulting organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (210 mg).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH:25]=[O:26])[CH2:23][CH2:22][C:21]([C:27]([OH:29])=O)=[CH:20][C:19]=3[CH:30]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH2:53][C:54]1[CH:59]=[CH:58][C:57]([C@H:60]([C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=2)[OH:61])=[CH:56][CH:55]=1>CN(C=O)C.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH:25]=[O:26])[CH2:23][CH2:22][C:21]([C:27]([NH:53][C:54]4[CH:59]=[CH:58][C:57]([C@@H:60]([OH:61])[C:62]5[CH:67]=[CH:66][CH:65]=[CH:64][N:63]=5)=[CH:56][CH:55]=4)=[O:29])=[CH:20][C:19]=3[CH:30]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C=O)cc1
Reactant: Nc1ccc([C@@H](O)c2ccccn2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@@H](O)c4ccccn4)cc2)CCN3C=O)cc1
Reaction time: 0.5 h
Yield: 38.2 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (280 mg) and 1-hydroxybenzotriazole (0.14 g) in DMF (10 ml), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.20 g) was added at room temperature, and the mixture was stirred for 0.5 hour. To the reaction solution, a solution of (R)-(4-aminophenyl)-(2-pyridyl) methanol (150 mg) and triethylamine (0.28 ml) in DMF (10 ml) was added dropwise. The mixture was stirred for 3 days at room temperature, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified with column chromatography (ethyl acetate) and recrystallized from ethyl acetate-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-1-formyl-N-[4-[(R)-hydroxy(2-pyridyl)methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 76) (154.5 mg) as pale yellow crystals.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:16]3=[CH:17][C:18]4[O:19][CH2:20][CH2:21][O:22][C:23]=4[CH:24]=[C:15]3[O:14][CH2:13]1)[C:5](=[O:12])[N:6]2[CH3:11].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1.CC(C)([O-])C.[K+].CN1CCCC1=O>[Cu]Br.O>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4]2([C:16]4[C:15](=[CH:24][C:23]5[O:22][CH2:21][CH2:20][O:19][C:18]=5[CH:17]=4)[O:14][CH2:13]2)[C:5](=[O:12])[N:6]3[CH3:11])=[CH:29][CH:28]=1
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(Br)cccc21
Reactant: COc1ccc(O)cc1
Agent: [Cu]Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(Oc2cccc3c2C2(COc4cc5c(cc42)OCCO5)C(=O)N3C)cc1
Temperature: 25 °C
Yield: 38.9 %

Procedure:
A 10 mL microwave reaction vessel was charged with 4′-bromo-1′-methyl-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one (0.19 g, 0.5 mmol), 4-methoxyphenol (0.12 g, 1.0 mmol), potassium tert-butoxide (0.11 g, 1.0 mmol), copper (I) bromide (0.012 g, 0.08 mmol) and anhydrous 1-methylpyrrolidin-2-one (2 mL). The reaction mixture was irradiated at 250° C. for 75 min in a microwave reactor and was allowed to cool to ambient temperature. The reaction mixture was poured into water (15 mL) and extracted with ethyl acetate (50 mL). The combined organic extracts were washed with water (3×50 mL) and brine (50 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography and eluted with a 15% to 50% gradient of ethyl acetate in hexanes afforded 4′-(4-methoxyphenoxy)-1′-methyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.084 g, 39%) as an off-white solid: mp 55-58° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ7.27-7.14 (m, 1H), 6.78-6.59 (m, 5H), 6.44 (d, J=8.48 Hz, 1H), 6.31 (d, J=1.08 Hz, 1H), 6.22 (d, J=1.08 Hz, 1H), 4.86 (ABq, 2H), 4.16-4.03 (m, 4H), 3.74 (s, 3H), 3.26 (s, 3H); 13C NMR (75 MHz, CDCl3) δ177.6, 155.8, 155.6, 154.3, 149.6, 144.8, 144.3, 137.7, 130.0, 120.2, 120.1, 119.5, 114.5, 112.7, 111.0, 103.1, 99.1, 64.4, 63.9, 57.4, 55.6, 27.0; MS (ES+) m/z 432.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([CH:9]=[CH:10][C:11]2[N:20]=[C:19](NC3C=CC(O)=CC=3)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.C(N)(=[O:38])C1C(=CC=CC=1)N.CC1NC(=O)C2C(=CC=CC=2)N=1.C(OC(OC(=O)C)C1OC([N+]([O-])=O)=CC=1)(=O)C.[N+](C1OC(C=O)=CC=1)([O-])=O>>[N+:1]([C:4]1[O:8][C:7]([CH:9]=[CH:10][C:11]2[NH:20][C:19](=[O:38])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: NC(=O)c1ccccc1N
Reactant: O=[N+]([O-])c1ccc(C=Cc2nc(Nc3ccc(O)cc3)c3ccccc3n2)o1
Agent: CC(=O)OC(OC(C)=O)c1ccc([N+](=O)[O-])o1
Agent: Cc1nc2ccccc2c(=O)[nH]1
Agent: Cl
Product: O=c1[nH]c(C=Cc2ccc([N+](=O)[O-])o2)nc2ccccc12

Procedure:
This example shows preparation of 2-[2-(5-nitro-2-furyl)vinyl]-4-(p-hydroxyanilino)quinazoline, (V). In this preparation, anthranilamide hydrochloride was converted to 2-methyl-4-(3H)quinazolinone (I) and 5-nitrofurfurylidene diacetate to 5-nitro-2-furancarboxaldehyde (II); (I) and (II) were then reacted to obtain 2-[2-(5-nitro-2-furyl)vinyl]-4-(3H) quinazolinone (III); (III) was then chlorinated to obtain 2-[2-(5-nitro-2-furyl)vinyl]-4-chloroquinazoline (IV) which was reacted with p-aminophenol to obtain the desired product, 2-[2-(5-nitro-2-furyl)vinyl]-4-(p-hydroxyanilino)quinazoline (V) and referred to in subsequent examples as the product of Example I. The procedure in this preparation is as follows:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]=[C:10]3[N:16](S(C4C=CC=CC=4)(=O)=O)[C:17]([I:19])=[CH:18][C:9]=23)[CH:7]=1.[OH-].[Li+].Cl>O1CCCC1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:29][CH3:30])=[C:6]([C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]=[C:10]3[NH:16][C:17]([I:19])=[CH:18][C:9]=23)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1c(C#N)cnc2c1cc(I)n2S(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(F)cc1-c1c(C#N)cnc2[nH]c(I)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of Example 236C (3 g, 5.63 mmol) in 20 mL tetrahydrofuran and 20 mL methanol was added 2N lithium hydroxide (8.44 mL, 16.88 mmol) and the mixture was stirred at room temperature for 4 hours. The mixture was neutralized with 2N aqueous hydrochloric acid, extracted with ethyl acetate and purified by flash chromatography eluting with 0-50% ethyl acetate in heptane to afford the title compound. MS (ESI(+)) m/e 394 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C:12]3[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=[C:16]([C:17]4[CH:18]=[N:19][C:20]([N:23]([CH2:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=5)[CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)=[N:21][CH:22]=4)[C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[NH2:48][CH2:49][CH2:50][CH2:51][N:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:20]2[N:19]=[CH:18][C:17]([C:16]3[C:11]4[CH2:10][CH2:9][N:8]([C:6]5[CH:5]=[CH:4][N:3]=[C:2]([NH:48][CH2:49][CH2:50][CH2:51][N:52]6[CH2:57][CH2:56][O:55][CH2:54][CH2:53]6)[CH:7]=5)[C:12]=4[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=3)=[CH:22][N:21]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(Cl)c3)cn2)cc1
Reactant: NCCCN1CCOCC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(NCCCN4CCOCC4)c3)cn2)cc1
Yield: 42.5 %

Procedure:
Using {5-[7-(2-chloro-pyridin-4-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine (200 mg, 0.31 mmol) obtained in Step A instead of {5-[7-(6-chloro-pyridin-3-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine, and N-(3-aminopropyl)morpholine (54 μl, 0.37 mmol) instead of N,N,N′-trimethyl ethylenediamine, in the same manner as Step B in Example 1-D-48, amination was carried out, to obtain a crude product of bis-(4-methoxy-benzyl)-(5-{2-morpholin-4-yl-7-[2-(3-morpholin-4-yl-propylamino)-pyridin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl)-amine as a yellow solid (100 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-69) as a yellow powder (27 mg, 17%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19](C(OC(C)(C)C)=O)[N:18]=[C:17]3[C:30]#[C:31][Si](C)(C)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CCO>[C:30]([C:17]1[C:16]2[C:20](=[CH:21][CH:22]=[C:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[CH:15]=2)[NH:19][N:18]=1)#[CH:31]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3c(c2)c(C#C[Si](C)(C)C)nn3C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C#Cc1n[nH]c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc12
Yield: 95.4 %

Procedure:
A solution of tert-butyl 5-[1-(tert-butoxycarbonyl)piperidin-4-yl]-3-[(trimethylsilyl)ethynyl]-1H-indazole-1-carboxylate (189 mg; 0.38 mmol; 1.0 eq.) and potassium carbonate (5.3 mg; 0.04 mmol; 0.1 eq.) in EtOH (3.8 mL) was stirred at RT O/N. EtOH was removed under reduced pressure and the residue was diluted with ether, washed with water then brine, dried over magnesium sulfate, filtered and concentrated. The crude was purified by flash chromatography on silica (heptane/EtOAc, gradient from 90:10 to 60:40) to give the title compound as a beige solid (118 mg, 95%). 1H NMR (300 MHz, DMSO-d6) δ 13.35 (brs, 1H), 7.55-7.47 (m, 2H), 7.33 (dd, J=1.6, 8.6 Hz, 1H), 4.48 (s, 1H), 4.15-4.03 (m, 2H), 2.93-2.71 (m, 3H), 1.86-1.74 (m, 2H), 1.65-1.45 (m, 2H), 1.42 (s, 9H). HPLC (Condition A): Rt 4.78 min (purity 99.1%).
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH3:36])[NH:15][C:16]=2[C:17](=[O:29])[NH:18][C:19]23[CH2:28][CH:23]4[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]4)[CH2:20]2)[CH2:26]3)[CH:5]=1.[OH-].[Na+].Cl>C(O)C.O>[C:19]12([NH:18][C:17]([C:16]3[NH:15][C:14]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[CH3:36])=[N:13][C:12]=3[CH2:11][CH2:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:37])=[O:2])=[O:29])[CH2:28][CH:23]3[CH2:22][CH:21]([CH2:27][CH:25]([CH2:24]3)[CH2:26]1)[CH2:20]2
Reactant: COC(=O)c1cccc(CCc2nc(-c3ccccc3C)[nH]c2C(=O)NC23CC4CC(CC(C4)C2)C3)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1-c1nc(CCc2cccc(C(=O)O)c2)c(C(=O)NC23CC4CC(CC(C4)C2)C3)[nH]1
Yield: 86.2 %

Procedure:
To a solution of the product of step c (232 mg, 0.65 mmol) in ethanol (13 ml) was added 1M sodium hydroxide (1.3 ml, 1.3 mmol). The solution was refluxed for 2 h, diluted with water (10 ml), then acidified (pH=5, 0.01M HCl). The resulting precipitate was collected by filtration, washed with water and dried to give the title compound (271 mg, 86%). 1H NMR (300 MHz, d6-DMSO) 12.40 (1H, br s), 12.2 (1H, br s), 7.80-7.29 (8H, m), 6.98 (1H, br s), 3.23 (2H, m), 3.00 (2H, m), 2.44 (3H, s) 2.03 (9H, s), 1.65 (6H, s). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 58.98; H, 7.83; N, 7.40% C37H50N4O8.4H2O requires: C, 59.18 H, 7.79; N, 7.46%.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:16].[CH3:17][N:18]([CH3:29])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1>>[CH3:29][N:18]([CH3:17])[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:1][N:2]2[N:11]=[C:10]([C:12]([F:15])([F:13])[F:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:16])=[O:27])=[CH:21][CH:20]=1
Reactant: CN(C)c1ccc(CC(=O)O)cc1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Product: CN(C)c1ccc(CC(=O)Nn2nc(C(F)(F)F)c3ccccc3c2=O)cc1

Procedure:
The product from Example 11B and 2-[4-(dimethylamino)phenyl]acetic acid were treated using a method similar to that described in Example 57 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.43 (dd, J=7.9, 1.3 Hz, 1H), 8.13-8.17 (m, 1H), 8.04-8.08 (m, 2H), 7.38-7.40 (m, 2H), 7.19-7.21 (m, 2H), 3.70 (s, 2H), 3.05 (s, 6H); MS (ESI−) M/Z 389 (M−H)−.
Reaction SMILES: I[Si](C)(C)C.[C:6]([N:9]([CH:16]([P:25](=[O:32])([O:29]CC)[O:26]CC)[P:17](=[O:24])([O:21]CC)[O:18]CC)[C:10]1[CH:14]=[C:13]([CH3:15])[O:12][N:11]=1)(=[O:8])[CH3:7]>C(Cl)(Cl)(Cl)Cl>[C:6]([N:9]([CH:16]([P:25](=[O:26])([OH:29])[OH:32])[P:17](=[O:18])([OH:24])[OH:21])[C:10]1[CH:14]=[C:13]([CH3:15])[O:12][N:11]=1)(=[O:8])[CH3:7]
Reactant: CCOP(=O)(OCC)C(N(C(C)=O)c1cc(C)on1)P(=O)(OCC)OCC
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)N(c1cc(C)on1)C(P(=O)(O)O)P(=O)(O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
Iodotrimethylsilane (2.68 ml) was added to an ice-cooled solution of 2 g of tetraethyl [N-acetyl(5-methyl-3-isoxazolyl)amino]methylene-bis(phosphonate) in 20 ml of carbon tetrachloride. Then the temperature was allowed to rise to room temperature, and the mixture was stirred for 1 hour. The reaction mixture was concentrated, methanol was then added, and the mixture was again concentrated. The residue thus obtained was washed with ether, hexane and acetone to give a solid which was recrystallized from acetone-hexane to give 0.5 g of [N-acetyl(5-methyl-3-isoxazolyl)amino]methylene-bis(phosphonic acid) as crystals.
Reaction SMILES: [CH2:1]([N:4]([CH2:22][CH2:23][CH3:24])[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[C:14]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)[CH:15]=1)[C:10]([OH:12])=O)=[O:6])[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[ClH:68].Cl.[NH2:70][C@@H:71]([CH2:85][C:86]1[CH:91]=[C:90]([F:92])[CH:89]=[C:88]([F:93])[CH:87]=1)[C@H:72]([OH:84])[CH2:73][NH:74][CH2:75][C:76]1[CH:81]=[CH:80][CH:79]=[C:78]([CH2:82][CH3:83])[CH:77]=1>C(Cl)Cl>[ClH:68].[F:92][C:90]1[CH:91]=[C:86]([CH:87]=[C:88]([F:93])[CH:89]=1)[CH2:85][C@H:71]([NH:70][C:10](=[O:12])[C:9]1[CH:13]=[C:14]([C:16]2[N:20]=[C:19]([CH3:21])[O:18][N:17]=2)[CH:15]=[C:7]([C:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:22][CH2:23][CH3:24])=[O:6])[CH:8]=1)[C@H:72]([OH:84])[CH2:73][NH:74][CH2:75][C:76]1[CH:81]=[CH:80][CH:79]=[C:78]([CH2:82][CH3:83])[CH:77]=1
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2noc(C)n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CCC)C(=O)c1cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)cc(-c2noc(C)n2)c1
Reaction time: 8 h

Procedure:
A solution of 3-[(dipropylamino)carbonyl]-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid (209 mg, 0.63 mmol), HATU (359 mg, 0.95 mmol), HOBt (128 mg, 0.95 mmol), and diisopropylethylamine (165 μL, 0.95 mmol) is stirred in methylene chloride (2.0 mL) for 15 min. A solution of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method in Example SP-272 (257 mg, 0.63 mmol) and diisopropylethylamine (165 μL, 0.95 mmol) in methylene chloride (2.0 mL) is added and the reaction mixture is stirred overnight. The reaction mixture is diluted with methylene chloride, washed with 1 N hydrochloric acid (25 mL), saturated sodium bicarbonate (25 mL), and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 1:9 methanol/chloroform) provides the title compound as the free base. The solid is dissolved in methanol (1 mL), and treated with hydrochloric acid (0.3 mL of a 1.0 M solution in diethyl ether, 0.3 mmol). The resulting precipitate is collected by filtration to provide the title compound. APCI MS m/z 648.4 [M+H]+.