Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1.[NH2:32][C@@H:33]([CH2:37][OH:38])[C@H:34]([CH3:36])[OH:35].C1C=CC2N(O)N=NC=2C=1.O.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.[Cl-].[Na+].O>[OH:35][C@@H:34]([CH3:36])[C@@H:33]([NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:30])[CH2:37][OH:38]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: C[C@H](O)[C@@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)N[C@@H](CO)[C@H](C)O)[nH]2)c1
Reaction time: 20 h
Yield: 86.4 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (1.20 g, 2.69 mmol) synthesized in Example (78k), commercially available D-threoninol (0.34 g, 3.23 mmol), HOBT.H2O (0.40 g, 3.23 mmol) and N-methylmorpholine (0.59 mL, 5.38 mmol) were dissolved in N,N-dimethylformamide (20 mL), and WSCI.HCl (0.62 g, 3.23 mmol) was added at room temperature, followed by stirring for 20 hours under nitrogen atmosphere. To the reaction solution, saturated brine (30 mL) was added, and extraction was carried out with ethyl acetate (60 mL). After washing with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, drying was carried out over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-7%) to afford the desired compound (1.24 g, 86%) as a white solid.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].[H-].[Na+].[Na+].[I-].Cl[CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:3][C:2]([F:5])([F:4])[CH2:1][O:6][CH2:12][C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: OCC(F)(F)F
Reactant: CCOC(=O)CC(=O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)COCC(F)(F)F
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
A solution of 5.00 g of trifluoroethanol (50.0 mmol) in 5 mL of dry THF was added dropwise, over a period of 0.5 hr, to a stirred mixture of 4.00 g of 60% dispersion of NaH (100 mmol), 1.61 g of tetrabutylammonium bromide (5.0 mmol), and 830 mg of NaI (5.0 mmol) in 20 mL of dry THF (water bath). The resulting mixture was stirred for 0.5 hrs, cooled to −30° C., and a solution of 8.23 g of ethyl 4-chloro-3-oxobutanoate (50.0 mmol) in 10 mL of dry THF was added dropwise, over a period of 15 min, to the reaction mixture. The reaction mixture was warmed to 0° C. over a period of 2 hrs, and stirred at room temperature for 36 hrs. The reaction mixture was quenched with 5 mL of ethanol, partioned between 100 mL of EtOAc and 100 mL of 10% aqueous HCl solution, separated, extracted with 2×40 mL of EtOAc, the combined organic extracts were dried (Na2SO4), and the solvent was removed in vacuo. The crude product was chromatographed on 400 g of silica packed with 5% EtOAc-hexane. The column was eluted with 5 to 25% EtOAc-hexane (1 L/5% change) to afford 8.75 g (77%) of ethyl 4-(2,2,2-trifluoroethyl)oxy-3-oxobutanoate as a slightly yellow oil. The product was used in the next step after spectral characterization.
Reaction SMILES: [CH2:1]([Sn](CCCC)(CCCC)CCCC)[CH:2]=[CH2:3].I[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1.[F-].[K+]>O1CCOCC1.C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH2:3]([C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)[CH:2]=[CH2:1]
Reactant: N#Cc1ccc(I)cc1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Solvent: CCOCC
Solvent: C1COCCO1
Product: C=CCc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
Add allyl tri-n-butylstannane (39.3 mmol, 12.18 ml) dropwise to a stirred solution of 4-iodo-benzonitrile (6 g, 26.2 mmol), tetrakis(triphenylphosphine)palladium(0) (1.31 g, 1.5 mmol) and copper (I) iodide (399 mg, 2.09 mmol) in 30 ml of dry 1,4-dioxane under argon atmosphere. Reflux the mixture for 24 hours and then cool to room temperature. Dilute with 40 ml of diethyl ether and add 20 ml of saturated solution of KF and stir for 2 hours. Filter the mixture and wash the organic layer with water (20 ml), brine (20 ml) and dry over sodium sulfate. Evaporate in vacuo and purify by flash chromatography in silica using hexane-ethyl acetate as eluent (20:1) to afford 2.66 g (70%) of 4-allylbenzonitrile
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[NH:2]=[C:1]([N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C1COCCN1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCOCC1
Yield: 38 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2 equivalents of morpholine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[N:4][C:3]=1[OH:9].C([O-])([O-])=O.[K+].[K+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[CH2:16]([N:4]1[C:3](=[O:9])[C:2]([Cl:1])=[C:7]([Cl:8])[CH:6]=[N:5]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Oc1nncc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(Cl)c(Cl)cnn1Cc1ccccc1
Yield: 96.4 %

Procedure:
To a stirring suspension of 4,5-dichloro-3-hydroxypyridazine (33 g, 200 mmol) in DMF (260 mL) at room temperature under argon was added K2CO3 (55 g, 400 mmol), followed by benzyl bromide (41 g, 505.8 mmol). After 16 h the reaction mixture was poured into a flask containing water (500 mL) with stirring. After 15 min stirring, the precipitated product was collected by filtration and washed thoroughly with water. The solid was dried in a vacuum oven at 50° C. for 16 h to obtain the title compound, 2-benzyl-4,5-dichloropyridazin-3(2H)-one, (49.2 g, 96%) as an off-white solid. MS [M+H]+ 255; HPLC retention time=3.02 min.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.BrBr.O>C(O)(=O)C>[C:4]1([C:3]#[C:2][C:1]([OH:11])=[O:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(O)C=Cc1ccccc1
Agent: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C#Cc1ccccc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 75.3 %

Procedure:
Cinnamic acid (29.6 g) was dissolved in acetic acid (80 ml) under heating and then bromine (32 g) was added dropwise. After stirring at 50° C. for 15 minutes, the resulting mixture was allowed to cool under standing and water (100 ml) was gradually added. The white crystals formed were filtered, washed with water and dried (yield: 56 g). Potassium hydroxide (56 g) was dissolved into methanol (20 ml) and then the above crystals were added in small portions to this solution. The methanol was removed under stirring with heating over a water bath. The residue was dissolved into 200 ml of water and neutralized with a diluted sulfuric acid under ice cooling. Freed pale yellow oil rapidly solidified. The solidified crystals were filtered and recrystallized from water to afford phenylpropiolic acid (22 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])C=CC=CC=1.[CH:26]([C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1)=O.C(Cl)(Cl)Cl>CS(C)=O>[O:13]=[C:9]1[C:8](=[CH:26][C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:12][CH2:11][O:10]1
Reactant: O=C1OCCC1=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: COC(=O)c1ccc(C=C2CCOC2=O)cc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A mixture of 40.00 g (0.12 mol) of 3-(triphenylphosphoranylidene)dihydro-2(3H)-furanone and 20.85 g (0.13 mol) of methyl 4-formylbenzoate in 240 ml of dimethyl sulfoxide is stirred at 80° C. for 18 hours. After cooling, 400 ml of chloroform are added, and the mixture is extracted five times with 200 ml of water. The organic phase is dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue is stirred with diethyl ether and dried under reduced pressure at 40° C.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([O:18]CC)=[O:17])=[CH:14][C:15]=3[N:7]2[CH2:6][C:5]2([CH2:23][CH2:22][CH2:21]2)[CH2:4][NH:3]1.[OH-].[Na+].C(O)(=O)C>C(O)C.O>[O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][C:15]=3[N:7]2[CH2:6][C:5]2([CH2:21][CH2:22][CH2:23]2)[CH2:4][NH:3]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)CC1(CCC1)CNC3=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1ccc2cc3n(c2c1)CC1(CCC1)CNC3=O
Temperature: 80 °C
Yield: 62.8 %

Procedure:
To a solution of ethyl 1′-oxo-2′,3′-dihydro-1′H-spiro[cyclobutane-1,4′-[1,4]diazepino[1,2-a]indole]-8′-carboxylate (7 g, 22.4 mmol) in ethanol (240 mL) is added a solution of NaOH (2.24 g, 56 mmol) in water (56 mL). The reaction mixture is heated at 80° C. for 2 h. Acetic acid (35.8 mL) and water (314 mL) are added and the resulting solid is filtered, rinsed with water and dried to afford the title compound (4 g, 64%) as a white solid.
Reaction SMILES: C([O:4][P:5]([CH2:11][O:12][C@@H:13]([CH2:26][OH:27])[CH2:14][N:15]1[CH:23]=[N:22][C:21]2[C:20](=[O:24])[NH:19][C:18]([NH2:25])=[N:17][C:16]1=2)([O:7]C(C)C)=[O:6])(C)C.C[Si](Br)(C)C>C(#N)C>[OH:27][CH2:26][C@H:13]([O:12][CH2:11][P:5]([OH:6])([OH:7])=[O:4])[CH2:14][N:15]1[CH:23]=[N:22][C:21]2[C:20](=[O:24])[NH:19][C:18]([NH2:25])=[N:17][C:16]1=2
Reactant: CC(C)OP(=O)(CO[C@@H](CO)Cn1cnc2c(=O)[nH]c(N)nc21)OC(C)C
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: Nc1nc2c(ncn2C[C@H](CO)OCP(=O)(O)O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79.6 %

Procedure:
A solution of (R)9-[2-[(diisopropylphosphono)methoxy]3-hydroxypropyl]guanine (0.20 g, 0.50 mmol) in 5 mL of dry acetonitrile was treated with trimethylsilylbromide (0.99 g, 6.45 mmol) under nitrogen atmosphere. The resulting solution was protected from light and stirred at room temperature for 14 hours. The solvent was removed under reduced pressure, and the residue was dried under vacuum. To the residue, water (1 mL) and acetone (4 mL) were added. The mixture was stirred at room temperature overnight and then the solvent removed. The residue was triturated with methylene chloride and filtered. The collected solid was recrystallized from water-methanol to give 127 mg (80% yield) of the title compound as white crystals: mp 249° C. (dec.).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][NH2:5].C(N(CC)CC)C.[CH:19]1[C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([S:29](Cl)(=[O:31])=[O:30])[C:23]=2[CH:22]=[CH:21][N:20]=1.CO.C(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[NH2:1][CH2:2][CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][NH:5][S:29]([C:24]1[C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:28]=2[CH:27]=[CH:26][CH:25]=1)(=[O:30])=[O:31]
Reactant: NCC(CN)c1ccccc1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: NCC(CNS(=O)(=O)c1cccc2cnccc12)c1ccccc1
Reaction time: 4 h
Yield: 61 %

Procedure:
In 50 ml of a chloroform solution containing 11.55 g of 1,3-diamino-2-phenylpropane and 1.33 g of triethylamine was added dropwise 30 ml of a chloroform solution containing 3.5 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the chloroform solution, the mixed solution was stirred at a temperature of 10° C. to 20° C. for four hours, and the reaction mixture solution was washed with water and dried with anhydrous potassium carbonate. After the chloroform was distilled therefrom, the residue thus obtained was subjected to a silica gel column chromatography (silica gel: 90 g; solvent: 5% methanol/chloroform (volume ratio)) to give 3.20 g of N-(3-amino-2-phenylpropyl)-5-isoquinolinesulfonamide in a yield of 61%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6](O)=[O:7].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:9]=[CH:10][N:11]=1
Reactant: COc1cc(C(=O)O)ccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CO)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of 2-methoxyisonicotinic acid (V1) (490 mg, 3.20 mmol) in anhydrous THF (15 ml) was added dropwise lithium aluminum hydride (3.20 ml, 6.40 mmol) (2.0 N in Et2O), and the mixture was stirred at room temperature for overnight. The reaction mixture was cooled back to 0° C. 0.28 ml H2O, 0.21 ml of 20% NaOH solution, 0.98 ml H2O were added drop-wise sequentially and stirred for 1 h. The solid was filtered and wash with THF and the filtrate was concentrated to give (2-methoxypyridin-4-yl)methanol (V2) as a clear oil. It was carried over to next step without further purifications. ES-MS [M+1]1: 140.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5](/[CH:11]=[CH:10]/[C:9]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Product: COC(=O)/C=C/c1ccc(N)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
2-Amino-5-bromopyridine (13.5 g, 78.0 mmol), methyl acrylate (10.1 g, 117 mmol) and tris(2-methylphenyl)phosphine (4.75 g, 15.6 mmol) were dissolved in acetonitrile (200 mL), palladium(II) acetate (1.75 g, 7.8 mmol) was added and the mixture was stirred overnight under an argon atmosphere at 100° C. After cooling the reaction mixture, the insoluble material was removed by filtering through celite and the solvent was evaporated under reduced pressure. The residue was dissolved in saturated aqueous sodium hydrogencarbonate and chloroform, and he mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform, then 0%-5% methanol/ethyl acetate), and recrystallized from ethyl acetate-hexane to give the title compound (3.81 g, yield 27%) as yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14](S(C3C=CC(C)=CC=3)(=O)=O)[CH:13]=2)[C:8]([CH3:43])=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([C:27]5[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=5)=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:43])=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(-c5ccncc5)cc4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(-c4ccncc4)cc3)cc12
Yield: 24.5 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(4-(pyridin-4-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (120 mg, 0.19 mmol) was hydrolyzed by lithium hydroxide (36.7 mg, 0.27 mmol), in THF/Methanol/water (2/2/1 ml) to afford 22 mg 24.3% yield of pure compound after purification by preparative TLC (SiO2) using 5% methanol in chloroform as eluent. 1H NMR (DMSO-d6, 300 MHz): δ 8.44-8.3 (b, 1H), 7.899-7.877 (d, 1H), 7.767-7.743 (s, 1H), 7.44 (m, 1H), 7.34-7.30 (m, 1H), 7.02-6.99 (m, 1H), 6.87-6.84 (m, 1H), 5.32 (s, 1H), 2.16 (s, 6H). MS: 453.2 m/z=(M+1), HPLC: 93.5% in method A.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[O:15]([CH2:23][CH2:24][O:25][C:26]1[C:33]([CH3:34])=[CH:32][C:29]([CH:30]=O)=[CH:28][C:27]=1[CH3:35])[Si](C(C)(C)C)(C)C.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CN(C)C(=O)C.C1COCC1.O>[OH:15][CH2:23][CH2:24][O:25][C:26]1[C:33]([CH3:34])=[CH:32][C:29]([C:30]2[NH:6][C:4](=[O:5])[C:3]3[C:7]([O:13][CH3:14])=[CH:8][C:9]([O:11][CH3:12])=[N:10][C:2]=3[N:1]=2)=[CH:28][C:27]=1[CH3:35]
Reactant: COc1cc(OC)c(C(N)=O)c(N)n1
Reactant: Cc1cc(C=O)cc(C)c1OCCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCO)c(C)c3)nc2n1
Temperature: 150 °C
Reaction time: 1 h
Yield: 6.6 %

Procedure:
To a solution of 2-amino-4,6-dimethoxy-nicotinamide (1.07 g, 5.42 mmol) and 4-[2-(tert-butyldimethylsilanoxy) ethoxy]-3,5-dimethylbenzaldehyde (1.67 g, 5.42 mmol) in N,N-dimethyl acetamide (25 mL), NaHSO3 (1.06 g, 5.97 mmol) and p-TSA (1.14 g, 5.97 mmol) were added and the reaction mixture was heated at 150° C. for 16 h, cooled to room temperature and poured into water. The solid was collected to give 3.25 g of crude product. To a solution of the crude product (3.25 g, 6.70 mmol) in THF (50 mL), TBAF (3.5 g, 13.4 mmol) was added at 0° C. and the mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. The solvent was removed, and the crude was purified by column chromatography (silica gel 230-400 mesh; 2% methanol in CH2Cl2 as eluent) to give 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxypyrido[2,3-d]pyrimidin-4(3H)-one (132 mg, 6%). Selected data: MS (ES) m/z: 371.99; MP 255-256° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:27][C:28]2[CH:33]=[CH:32][C:31](=[O:34])[N:30]([CH3:35])[CH:29]=2)[C:9]2[C:10]([C:24]([OH:26])=O)=[N:11][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9]3[C:10](=[N:11][N:12]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=4)[C:13]=3[CH3:14])[C:24](=[O:26])[N:27]2[C:28]2[CH:33]=[CH:32][C:31](=[O:34])[N:30]([CH3:35])[CH:29]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(Cn2nc(C(=O)O)c(C(Nc3ccc(=O)n(C)c3)c3ccc(Cl)cc3)c2C)cc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Product: COc1ccc(Cn2nc3c(c2C)C(c2ccc(Cl)cc2)N(c2ccc(=O)n(C)c2)C3=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a stirred solution of 4-((4-chlorophenyl)(1-methyl-6-oxo-1,6-dihydropyridin-3-ylamino)methyl)-1-(4-methoxybenzyl)-5-methyl-1H-pyrazole-3-carboxylic acid (Step 1.5) (125 mg, 0.254 mmol) in CH2Cl2 (2 mL) under Ar was added 1-chloro-N,N,2-trimethyl-1-propenylamine (0.047 mL, 0.355 mmol) at 0° C. The reaction mixture was stirred for 1 hr at 0° C., quenched with a saturated aqueous solution of NaHCO3 (75 mL), and extracted with CH2Cl2. The combined organic layers were washed with a saturated aqueous solution of NaHCO3 (100 mL), dried over Na2SO4 the solvent was and evaporated off under reduced pressure. The crude residue was purified by silica gel column chromatography (CH2Cl2/MeOH 0.5-3.5%) to afford the title product (92 mg, 0.194 mmol, 76% yield) as a greenish solid. tR: 4.32 min (HPLC 1); tR: 0.97 min (LC-MS 2); ESI-MS: 475 [M+H]+ (LC-MS 2); Rf=0.65 (CH2Cl2/MeOH 9:1).
Reaction SMILES: N1([CH2:10][NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][C:13]=2[F:26])C2C=CC=CC=2N=N1.[BH4-].[Na+].O.C(OCC)(=O)C.O1CCCC1>CN(C)C=O.CO.C(O)C>[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:14][C:13]=1[F:26]
Reactant: Fc1cc(OCc2ccccc2)ccc1NCn1nnc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNc1ccc(OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 64.9 %

Procedure:
After dissolving N-{1-(1H-benzotriazolyl)methyl}-4-benzyloxy-2-fluoroaniline (14.13 g, 40.56 mmol) in N,N-dimethylformamide (200 ml), methanol (150 ml) and ethanol (50 ml), there was added sodium borohydride (3.06 g, 81.12 mmol) and the mixture was stirred for 2.5 hours at room temperature. There was further added sodium borohydride (0.78 g, 20.28 mmol), and the mixture was stirred for 13.5 hours at room temperature. Water was added to the reaction solution, extraction was performed with ethyl acetate-tetrahydrofuran, the extract was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was adsorbed onto silica gel and purified by silica gel column chromatography (hexane-ethyl acetate system) to obtain the title compound (5.98 g, 26.31 mmol, 64.87%) as light yellow crystals.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[C:8]([NH2:13])[CH:9]=[CH:10][CH:11]=2)[CH:6]=[N:5][CH:4]=1)#[CH:2].I[C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:42])[C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[C:26]([C:38]([F:41])([F:40])[F:39])[CH:25]=2)[CH:18]=[CH:19][C:20]=1[CH3:21]>>[NH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[CH:6]=[N:5][CH:4]=[C:3]2[C:1]#[C:2][C:15]1[CH:16]=[C:17]([NH:22][C:23](=[O:42])[C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]3[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH2:36]3)=[C:26]([C:38]([F:39])([F:40])[F:41])[CH:25]=2)[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: C#Cc1cncc2c(N)cccc12
Reactant: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1cncc2c(N)cccc12

Procedure:
The title compound can be synthesized from 4-ethynylisoquinolin-8-amine and N-(3-iodo-4-methylphenyl)-4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide in a manner similar to that described for Example 1. 4-ethynylisoquinolin-8-amine is prepared from 4-bromoisoquinolin-8-amine and ethynyltrimethylsilane according to the 2 steps procedure described in example 1.