Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([S:48]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)(=[O:50])=[O:49])[CH:45]=[N:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:47]=[N:46][CH:45]=[C:44]([S:48]([N:51]6[CH2:52][CH2:53][O:54][CH2:55][CH2:56]6)(=[O:50])=[O:49])[CH:43]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: O=S(=O)(c1cncc(Br)c1)N1CCOCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cncc(S(=O)(=O)N4CCOCC4)c3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and 4-(5-bromo-pyridine-3-sulfonyl)-morpholine (prepared from 5-bromo-pyridine-3-sulfonyl chloride and morpholine, 60 mg) instead of 4-bromobenzoic acid methyl ester used in Example 1-D-8, in the same manner as Example 1-D-07, a crude product of bis-(4-methoxy-benzyl)-(5-{7-[5-(morpholine-4-sulfonyl)-pyridin-3-yl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl)-amine was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-248) as an ivory powder (65 mg, 67%).
Reaction SMILES: [CH2:1]([C:17]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]=1[OH:31])[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[OH:16].CN1CCCC1=O.[P:39](Cl)(Cl)[Cl:40]>C1(C)C=CC=CC=1>[Cl:40][P:39]1[O:16][C:3]2[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][C:6]([C:8]([CH3:11])([CH3:9])[CH3:10])=[CH:7][C:2]=2[CH2:1][C:17]2[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[C:19]([C:27]([CH3:30])([CH3:29])[CH3:28])[C:18]=2[O:31]1
Reactant: ClP(Cl)Cl
Reactant: CC(C)(C)c1cc(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Product: CC(C)(C)c1cc2c(c(C(C)(C)C)c1)OP(Cl)Oc1c(cc(C(C)(C)C)cc1C(C)(C)C)C2
Temperature: 25 °C
Yield: 74.2 %

Procedure:
To a solution of 25.0 g (0.059 mol) of 2,2'-methylenebis(4,6-di-tert-butylphenol) and 0.57 mL (5.9 mmol) of 1-methyl-2-pyrrolidinone in 275 mL of toluene at ambient temperature is added dropwise 5.16 mL (0.059 mol) of phosphorus trichloride. After the addition is complete, the reaction mixture is refluxed for eight hours. After cooling the mixture to ambient temperature, the toluene is removed in vacuo and the reaction mass is re, crystallized twice from 250 mL of 98% acetonitrile and 2% toluene (% by volume) in acetonitrile. The recrystallization solvent is removed by decantation and the residue is dried under vacuum to give 21.4 g (79% yield) of the title compound as an off-white solid melting at 227°-230° C.
Reaction SMILES: C([N:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2OCCC)=[CH:8][C:7]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25](C(=O)C)[N:24]=[CH:23]3)=[N:6][C:5]1=[O:32])(=O)C.Cl>CO.O1CCOCC1>[NH:25]1[C:26]2[C:22](=[CH:21][C:20]([C:7]3[CH:8]=[C:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[NH:4][C:5](=[O:32])[N:6]=3)=[CH:28][CH:27]=2)[CH:23]=[N:24]1
Reactant: CCCOc1ccccc1-c1cc(-c2ccc3c(cnn3C(C)=O)c2)nc(=O)n1C(C)=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=c1nc(-c2ccc3[nH]ncc3c2)cc(-c2ccccc2)[nH]1
Yield: 117 %

Procedure:
To a solution of 1-acetyl-4-(1-acetyl-1H-indazol-5-yl)-6-[2-(propyloxy)phenyl]pyrimidin-2(1H)-one (1.06 g, 2.46 mmol) in methanol (100 mL) was added hydrogen chloride in dioxane 4.0 N (1.0 mL) and then refluxed for 30 min. The solution was evaporated in vacuo to afford the title compound (0.83 g, 98%) as the di-hydrochloride salt. 1H NMR (400 MHz, d6-DMSO): 8.74 (s, 1H), 8.37 (s, 1H), 8.05 (d, 1H), 7.78 (t, 2H), 7.64 (t, 1H), 7.58 (s, 1H), 7.28 (d, 1H), 7.19 (t, 1H), 4.08 (t, 2H), 1.78 (m, 2H), 0.98 (t, 3H); MS (EI) for C20H18N4O2: 347 (MH+).
Reaction SMILES: C(O/[CH:4]=[CH:5]\[C:6]1[C:11]([C:12]#[N:13])=[CH:10][N:9]=[C:8]([S:14][CH3:15])[N:7]=1)C.BrN1C(=O)CCC1=O.[CH2:24]([C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1)[CH3:25].C(=O)([O-])O.[Na+]>O1CCOCC1.O>[CH2:24]([C:26]1[C:27]2[N:28]([C:5]([C:6]3[C:11]([C:12]#[N:13])=[CH:10][N:9]=[C:8]([S:14][CH3:15])[N:7]=3)=[CH:4][N:32]=2)[CH:29]=[CH:30][CH:31]=1)[CH3:25]
Reactant: CCc1cccnc1N
Reactant: CCO/C=C\c1nc(SC)ncc1C#N
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1cccn2c(-c3nc(SC)ncc3C#N)cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
4.89 g of 4-[(Z)-2-ethoxyvinyl]-2-(methylthio)-5-pyrimidinecarbonitrile (synthesized according to the method disclosed in International Publication WO2006/025567, page 90 to 91) was dissolved in a mixed solvent of 50 mL of 1,4-dioxane and 5 mL of water, then 3.93 g of N-bromosuccinimide was added under an ice-cold condition, and the mixture was stirred for 1 hour at room temperature. To the reaction solution was added 2.7 g of 3-ethylpyridine-2-amine (synthesized according to the method disclosed in International Publication WO2006/025567, page 142), and the solution was stirred overnight at room temperature. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, the solution was extracted with chloroform, and the resulting organic layer was dried over anhydrous sodium sulfate. The insolubles were filtered, and the filtrate was concentrated under reduced pressure. Diethylether was added to the resulting residue, and the resultant solution was stirred for 3 hours. Thus produced solid was taken by filtration and dried under reduced pressure to obtain 4.46 g of 4-(8-ethylimidazo[1,2-a]pyridin-3-yl)-2-(methylthio)pyrimidine-5-carbonitrile [5-6] (hereinafter, referred to as the compound [5-6]) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=O)[CH:3]=1.O=P(Cl)(Cl)[Cl:15]>C1(C)C=CC=CC=1>[Cl:15][C:4]1[CH:3]=[C:2]([CH3:1])[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(=O)[nH]c2ncccc12
Solvent: Cc1ccccc1
Product: Cc1cc(Cl)nc2ncccc12
Temperature: 120 °C
Yield: 67 %

Procedure:
To a solution of 4-methyl-1,8-naphthyridin-2(1H)-one (440 mg, 2.75 mmol) in toluene was added 302 uL of POCl3 (1.2 eq). The resulting mixture was refluxed at 120° C. for 3 hours. After cooling to room temperature the reaction mixture was quenched into ice-H2O and extracted with EtOAc (3×10 mL). The combined organic extracts was washed with H2O (2×15 mL), brine (1×20 mL), and then dried over MgSO4. Concentration and purification by MPLC gave the desired 2-chloro-4-methyl-1,8-naphthyridine (330 mg, 67%). Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ ppm 2.72 (s, 3 H) 7.35 (d, J=1.17 Hz, 1 H) 7.53 (dd, J=8.20, 4.40 Hz, 1 H) 8.36 (dd, J=8.35, 1.90 Hz, 1 H) 9.10 (dd, 1 H).
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[OH-].[Na+:16]>O.C(O)C>[CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O-:14])=[O:13])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[Na+:16]
Reactant: C=CCNc1ccc(CC(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCNc1ccc(CC(=O)[O-])cc1

Procedure:
A mixture of 3.62 g. of 4-(allylamino)phenylacetic acid and 25 ml. of ethanol water (9:1) containing 0.400 g. of sodium hydroxide is stirred for 4 hours. The mixture is filtered and the residue washed with 10 ml. of ethanol-water (9:1) and dried in vacuo for 24 hours to yield sodium 4-(allylamino)phenylacetate as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[NH:15][C:14]=1[CH:22]=O.N1CCCCC1>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:22][C:14]1[NH:15][C:16]2[C:21]([C:13]=1[CH3:12])=[CH:20][CH:19]=[CH:18][CH:17]=2
Reactant: O=C1Cc2cc(Br)ccc2N1
Reactant: Cc1c(C=O)[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C=C2C(=O)Nc3ccc(Br)cc32)[nH]c2ccccc12
Temperature: 95 °C

Procedure:
A mixture of 5-bromo-2-oxindole (212 mg) (prepared as described in Compound IN-014), 3-methyl-indole-2-carbaldehyde (190 mg) (prepared according to Synthetic Communications, 1986, 16, 1799) and piperidine (10 mg) in ethanol was heated in a sealed tube at 95° C. for 4 hours. The mixture was cooled to room temperature. The solid was collected by vacuum filtration, washed with cold ethanol and dried in vacuum oven for overnight to give 5-bromo-3-(3-methyl-1H-indol-2-ylmethylene)-1,3-dihydro-indol-2-one.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:12]=[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[NH:14][N:15]=2)(=O)=O)C=CC=CC=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1/[CH:28]=[CH:29]\[C:30]#[N:31]>>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:13]1[N:12]=[C:11]2[CH:10]=[C:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=3)[CH:29]=[C:30]([NH2:31])[N:15]2[N:14]=1
Reactant: N#C/C=C\c1ccccn1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccccn2)n1)c1ccccc1
Product: Nc1cc(-c2ccccn2)cc2nc(-c3ccccn3)nn12

Procedure:
The title compound, MS m/e (%):289 (M+H+,100), was prepared in accordance with the general method of example 1 from 2-(5-benzenesulfonylmethyl-2H-[1,2,4]triazol-3-yl)-pyridine and (E)/(Z)-3-pyridin-2-yl-acrylonitrile.
Reaction SMILES: [CH2:1]([C@@H:8]([NH:22][C:23](=[O:32])[C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26](Br)[CH:25]=1)[C@H:9]([OH:21])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(Cl)(Cl)Cl.C1(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)C=CC=CC=1>[CH2:1]([C@H:8]([NH:22][C:23](=[O:32])[C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([C:34]2[O:33][CH:37]=[CH:36][CH:35]=2)[CH:25]=1)[C@H:9]([OH:21])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccco1
Reactant: COc1cccc(CNC[C@@H](O)[C@@H](Cc2ccccc2)NC(=O)c2cc(C)cc(Br)c2)c1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1cccc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)c2cc(C)cc(-c3ccco3)c2)c1
Temperature: 100 °C

Procedure:
N-{(1R,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-bromo-5-methylbenzamide (X, EXAMLE 761, 295 mg, 0.59 mmol), 2-furanylboronic acid (133 mg 1.19 mmol) and sodium carbonate (366 mg, 2.95 mmol) are combined in dimethylformamide (5 ml) and sparged under a flow of nitrogen for 15 minutes. Tetrakis(triphenylphosphino) palladium (136 mg, 0.12 mmol) is added and the mixture heated to 100 degrees C. overnight. The mixture is cooled to 20–25 degrees C., diluted with chloroform (50 ml) and extracted with water (3×100 ml). The organic phase is separated and washed with saturated sodium bicarbonate (2×100 ml) and saline (100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressue. The residue is chouromatographed (silica gel; methanol/methylene chloride, 8/92) to give the title compound, MS [M+H]+=485.3.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[N+:2]=[N-:3].[NH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].C([O-])([O-])=O.[Na+].[Na+].C(O)C>O>[N:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[N+:2]=[N-:3]
Reactant: NCCC(=O)O
Reactant: [N-]=[N+]=Nc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: [N-]=[N+]=Nc1ccc(NCCC(=O)O)c([N+](=O)[O-])c1
Temperature: 55 °C

Procedure:
4-azido-1-fluoro-2-nitro-benzene (90 mg) is mixed with an aqueous solution (0.5 ml) containing 3-aminopropionic acid (53 mg) and Na2CO3 (106 mg). Following addition of 2 ml of ethanol and 0.5 ml of water, the solution is heated for 24 h at 55° C. After removal of the unreacted materials by several ether extractions, the product (3-(N-(4-azido-2-nitrophenyl)-amino)propionic acid) is obtained by ether extraction of the acidified (pH 2.0) aqueous phase.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:18])[C@@H:13]([NH2:17])[CH2:14][CH2:15][CH3:16])=[N:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2].[CH3:19][CH2:20][C:21](=O)[CH2:22][CH3:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH2:1]([CH:3]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:18])[C@@H:13]([NH:17][CH:21]([CH2:22][CH3:23])[CH2:20][CH3:19])[CH2:14][CH2:15][CH3:16])=[N:8][CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC[C@H](N)C(=O)Nc1ncc(C(CC)CC)s1
Reactant: CCC(=O)CC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCC[C@H](NC(CC)CC)C(=O)Nc1ncc(C(CC)CC)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(S)-amino-pentanoic acid [5-(1-ethyl-propyl)-thiazol-2-yl]-amide (107 mg, 0.4 mmol) and 3-pentanone (34 mg, 0.4 mmol)in 3 mL of methylene chloride and 5 drops of acetic acid was treated with sodium triacetoxyborohydride (131 mg, 0.62 mmol) and stirred at room temperature overnight. An additional sodium triacetoxyborohydride (167 mg)was added and the resulting mixture was stirred at room temperature for 4 hrs. The mixture was quenched with ammonium hydroxide/water and extracted with methylene chloride. The organic layer was separated, dried, filtered and concentrated to dryness to give a yellow oil. The oil was purified by Shimadzu HPLC to give 2-(S)-(1-Ethyl-propylamino)-pentanoic acid [5-(1-ethyl-propyl)-thiazol-2-yl]-amide as a colorless oil, RT=1.88 min, M+1=340.4.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][C:19]2[CH:23]=[C:22](OC(C)C)[NH:21][N:20]=2)=[N:4][C:5]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[CH3:10])=[N:6][CH:7]=1.Cl[C:29]1N=C(NC2C=C(C)NN=2)C(Cl)=CN=1.CCN(C(C)C)C(C)C>CCCCO>[Cl:1][C:2]1[C:3]([NH:18][C:19]2[CH:23]=[C:22]([CH3:29])[NH:21][N:20]=2)=[N:4][C:5]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)[CH3:10])=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)ncc2Cl)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)ncc2Cl)n[nH]1
Temperature: 160 °C
Yield: 135.2 %

Procedure:
A mixture of (S)-1-(5-fluoropyridin-2-yl)ethanamine (Method 6; 146 mg, 1.04 mmol), 2,5-dichloro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 38; 244 mg, 1.04 mmol) and DIEA (0.39 ml) in n-BuOH (3 ml) was charged into a microwave reaction vessel. The vessel was sealed and heated in microwave reactor at 160° C. for 6 hrs. The solvent was removed under reduced pressure and the residue was purified by Gilson (10-50% acetonitrile/H2O, 15 min) to give the title compound as solid (489 mg). 1H NMR: 12.02 (s, 1H), 8.50 (d, 1H), 7.87-7.97 (m, 114), 7.64 (ddd, 1H), 7.33-7.46 (m, 1H), 5.85 (s, 1H), 4.75-5.24 (m, 1H), 2.16-2.21 (m, 3H), 1.45 (d, 3H); m/z 349.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:24](=[O:25])[C:23]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[CH:22][NH:21][CH:20]=3)=[O:18])=[C:11]([F:33])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:34][N:35]1[CH:39]=[C:38](B(O)O)[CH:37]=[N:36]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:33][C:11]1[CH:10]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:38]3[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=3)[CH:7]=2)[C:14]([F:15])=[CH:13][C:12]=1[NH:16][C:17]([C:19]1[C:24](=[O:25])[C:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[CH:22][NH:21][CH:20]=1)=[O:18]
Reactant: Cn1cc(B(O)O)cn1
Reactant: O=C(Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F)c1c[nH]cc(-c2ccc(F)cc2)c1=O
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: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(Oc3cc(F)c(NC(=O)c4c[nH]cc(-c5ccc(F)cc5)c4=O)cc3F)ccn2)cn1
Temperature: 80 °C
Yield: 82 %

Procedure:
N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (0.100 g, 0.212 mmol), 1-methyl-pyrazole-4-boronic acid (0.055 g, 0.265 mmol) and K2CO3 (0.088 g, 0.636 mmol) were combined in dioxane (2 mL) and H2O (0.500 mL), sparged with argon, treated with Pd(PPh3)4 (0.012 g, 10.60 μmol) and heated at 80° C. for 22 h. Additional 1-methyl-pyrazole-4-boronic acid (0.055 g, 0.265 mmol) was added, the mixture sparged with argon, treated with additional Pd(PPh3)4 (0.012 g, 10.60 μmol) and heated at 100° C. overnight. The mixture was cooled to RT, diluted with EtOAc, filtered through diatomaceous earth and the filtrate washed with brine (2×), dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-5-(4-fluorophenyl)-4-oxo-1,4-dihydropyridine-3-carboxamide (90 mg, 82%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 13.48 (s, 1H), 12.72 (s, 1H), 8.63 (s, 1H), 8.57 (dd, J=12.6, 6.9 Hz, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.27 (s, 1H), 8.09 (s, 1H), 7.97 (s, 1H), 7.69 (m, 2H), 7.58 (dd, J=11.1, 7.6 Hz, 1H), 7.26 (m, 3H), 6.74 (d, J=5.6 Hz, 1H), 3.84 (s, 3H); MS (ESI) m/z: 518.2 (M+H+).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][C:13]([F:16])([F:15])[F:14])[C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C>[Pd].C(O)C>[F:16][C:13]([F:14])([F:15])[O:12][C:10]1[C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=[CH:2][CH:11]=1
Reactant: Nc1nc2c(OC(F)(F)F)cc(Br)cc2s1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1nc2c(OC(F)(F)F)cccc2s1
Yield: 72.4 %

Procedure:
6-Bromo-4-trifluoromethoxy-benzothiazol-2-ylamine (157 mg, 0.50 mg), triethylamine (0.21 ml, 1.5 mmol) and palladium on carbon (10%, 15 mg) are suspended in ethanol (12 ml) and hydrogenated at atmospheric pressure for 96 h. The catalyst was filtered off and the solution evaporated to dryness. The residue was dissolved in ethyl acetate, washed three times with water, dried and the solvent removed in vacuo. The product is obtained as brown solid (85 mg, 73%). MS: m/e=235 (M+H+).
Reaction SMILES: CN(C=O)C.CO[C:8](=[O:39])[N:9]=[C:10](SC)[C:11]([C:25]1[CH:26]=[C:27]([O:35][CH3:36])[C:28]2[O:33][CH2:32][O:31][CH2:30][C:29]=2[CH:34]=1)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[CH:15][CH:14]=1.Cl.[NH:41]([C:43]1[CH:51]=[CH:50][CH:49]=[CH:48][C:44]=1[C:45]([OH:47])=[O:46])[NH2:42]>C(N(CC)CC)C>[CH3:36][O:35][C:27]1[C:28]2[O:33][CH2:32][O:31][CH2:30][C:29]=2[CH:34]=[C:25]([CH:11]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:23]=[C:22]([CH3:24])[O:21][N:20]=3)=[CH:17][CH:18]=2)[C:10]2[NH:9][C:8](=[O:39])[N:41]([C:43]3[CH:51]=[CH:50][CH:49]=[CH:48][C:44]=3[C:45]([OH:47])=[O:46])[N:42]=2)[CH:26]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc2c(c(OC)c1)OCOC2
Reactant: NNc1ccccc1C(=O)O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)c2nn(-c3ccccc3C(=O)O)c(=O)[nH]2)cc2c1OCOC2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To 2 ml of a DMF solution containing 130 mg of [2-(8-methoxy-4H-benzo[1,3]dioxin-6-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (21h)), 46 mg of 2-hydrazinobenzoic acid hydrochloride and 0.200 ml of triethylamine were added. The resulting mixture was stirred at 80° C. for 8 hours under a nitrogen atmosphere, and then the reaction mixture was concentrated. The residue was dissolved in 3 ml of methanol and 0.3 ml of acetic acid, and 250 mg of sodium cyanotrihydroborate was added thereto. The mixture was stirred at room temperature overnight. To this reaction mixture, water was added and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give 2-(3-{(8-methoxy-4H-benzo[1,3]dioxin-6-yl)-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro[1,2,4]triazol-1-yl)benzoic acid.
Reaction SMILES: [NH2-].[Na+].O1CCCC1.[C:8]([CH:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)#[N:9].[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl>O>[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27][C:10]1([C:8]#[N:9])[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: CN(C)CCCCl
Reactant: N#CC1c2ccccc2-c2ccccc21
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCCC1(C#N)c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
To a stirred solution of 2.6 g. of sodium amide in 200 ml. of tetrahydrofuran was added dropwise over thirty minutes a solution of 12.7 g. of 9-cyanofluorene in 300 ml. of tetrahydrofuran. The reaction mixture was next heated to reflux for three hours, and then cooled to room temperature. While the reaction mixture was being stirred at room temperature, a solution of 14.2 g. of 3-dimethylaminopropyl chloride in 500 ml. of tetrahydrofuran was added dropwise over one hour. Following complete addition, the reaction mixture was again heated to reflux and stirred for sixteen hours. After cooling the mixture to room temperature, it was added to 500 ml. of water. The product was extracted into diethyl ether, and the ethereal extracts were combined, washed with water and dried. Removal of the solvent by evaporation under reduced pressure afforded, after distillation, 2.3 g. of 9-(3-dimethylaminopropyl)-9-cyanofluorene. B.P. 195°-201° C.at 0.1 torr.
Reaction SMILES: C[O-].[Na+].[Na].[CH3:5][SH:6].[CH2:7]1[O:16][C:10]([CH2:12][CH2:13][CH2:14]Cl)([CH3:11])[O:9][CH2:8]1>C1(C)C=CC=CC=1.CO>[CH2:7]1[O:16][C:10]([CH2:12][CH2:13][CH2:14][S:6][CH3:5])([CH3:11])[O:9][CH2:8]1
Reactant: CS
Reactant: CC1(CCCCl)OCCO1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: Cc1ccccc1
Product: CSCCCC1(C)OCCO1
Yield: 100.7 %

Procedure:
To a solution of sodium methoxide prepared by slowly adding 2.4 g (54 mmol) of sodium to 40 mL of methanol was added 4.8 g (48 mmol) of methylmercaptan followed by 6.6 g (40 mmol) of 5-chloro-2-pentanone ethylene ketal. The mixture was refluxed for 4 h and an additional 50 mmol each of sodium and methylmercaptan was added and then refluxed an additional 4 hours to complete the reaction. 50 mL of toluene was added and the mixture washed twice with 10 mL of 1N sodium hydroxide. The toluene layer was dried over magnesium sulfate and evaporated to give 7.1 g of 5-methylthio-2-pentanone ethylene ketal. This was stirred in 60 mL of 70% trifluoroacetic acid for 24 h at room temperature. The mixture was neutralized with sodium carbonate and extracted with 200 mL of ether. The ether extract was dried and evaporated to yield 3.5 g of the desired ketone as an oil.