Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:34]=[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([NH:19][C@@H:20]4[CH2:25][CH2:24][C@H:23]([NH:26]C(=O)OC(C)(C)C)[CH2:22][CH2:21]4)[N:13]3[N:12]=2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].C(C1C=CC(NC2N=C3C=CC=C(N[C@@H]4CC[C@H](NC(=O)OC(C)(C)C)CC4)N3N=2)=CC=1)#N.C(=O)([O-])[O-].[Na+].[Na+].OO>C(O)C.[Cl-].[Na+].O>[NH2:26][C@@H:23]1[CH2:24][CH2:25][C@H:20]([NH:19][C:18]2[N:13]3[N:12]=[C:11]([NH:10][C:7]4[CH:6]=[CH:5][C:4]([C:1]([NH2:2])=[O:3])=[CH:9][CH:8]=4)[N:34]=[C:14]3[CH:15]=[CH:16][CH:17]=2)[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Nc2cccc3nc(Nc4ccc(C(N)=O)cc4)nn23)CC1
Agent: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Nc2cccc3nc(Nc4ccc(C#N)cc4)nn23)CC1
Agent: O=C([O-])[O-]
Agent: OO
Solvent: CCO
Solvent: O
Product: NC(=O)c1ccc(Nc2nc3cccc(N[C@H]4CC[C@@H](N)CC4)n3n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl cis-4-(2-(4-carbamoylphenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexylcarbamate. To a pale yellow solution of tert-butyl cis-4-(2-(4-cyanophenylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-ylamino)cyclohexylcarbamate (0.078 g, 0.174 mmol) in ethanol (10 mL) (heated with a heat gun to get the starting material in solution) was added 3 N sodium carbonate (4 mL) and 30% w/w hydrogen peroxide (4 mL) at room temperature. The reaction mixture was stirred overnight at room temperature. Upon completion of the reaction as indicated by LCMS, the reaction mixture was poured into brine, and extracted with ethyl acetate several times. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated. The crude mixture was purified by column chromatography (eluting with 0-10% saturated methanolic ammonia in chloroform) to give the title compound as a pale pink solid (0.066 g, 81% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 9.86 (s, 1H), 7.84 (d, 2H, J=8 Hz), 7.76 (d, 3H, J=8 Hz), 7.44 (t, 1H, J=8 Hz), 7.12 (s, 1H), 6.78 (d, 1H, J=8 Hz), 6.22 (d, 1H, J=8 Hz), 5.96 (d, 1H, J=8 Hz), 3.73-3.65 (m, 1H), 3.58-3.51 (m, 1H), 1.91-1.82 (m, 2H), 1.81-1.73 (m, 2H), 1.69-1.58 (m, 4H), 1.40 (s, 9H); MS (ESI) m/z 466.55 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:13])=[C:4]([CH3:12])[C:5]2[O:9][CH2:8][S:7][C:6]=2[C:10]=1[CH3:11].N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C)C=O>[Si:19]([O:1][C:2]1[C:3]([CH3:13])=[C:4]([CH3:12])[C:5]2[O:9][CH2:8][S:7][C:6]=2[C:10]=1[CH3:11])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1c(C)c2c(c(C)c1O)SCO2
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)SCO2
Temperature: 50 °C
Reaction time: 7 h
Yield: 94.8 %

Procedure:
0.84 g of 5-hydroxy-4,6,7-trimethyl-1,3-benzoxathiole (prepared as described in Example 64) was dissolved in 5 ml of dimethylformamide, and then 0.58 g of imidazole and 1.29 g of t-butyldimethylsilyl chloride were added to the resulting solution. The mixture was then stirred for 7 hours at 50° C., after which it was allowed to stand overnight at room temperature. The solvent was then distilled off under reduced pressure, and the residue was extracted with benzene. The extract was washed with a saturated aqueous solution of sodium bicarbonate and with water, and then dried over anhydrous sodium sulfate. The solvent was then distilled off. The resulting residue was subjected to column chromatography through 40 g of silica gel eluted with hexane and with mixtures of hexane and benzene ranging from 10:1 to 2:1 by volume, to yield 1.26 g of the title compound as a colorless oily substance.
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C@H:16]3[CH2:21][CH2:20][C@H:19]([CH2:22][C:23](O)=[O:24])[CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[C:7]([CH3:26])=[N:6][C:5]=1[CH3:27])(=[O:3])[NH2:2].CCN=C=NCCCN(C)C.[CH3:39][S:40]([NH2:43])(=[O:42])=[O:41]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:27][C:5]1[C:4]([C:1]([NH2:2])=[O:3])=[N:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]([C@H:16]3[CH2:17][CH2:18][C@H:19]([CH2:22][C:23]([NH:43][S:40]([CH3:39])(=[O:42])=[O:41])=[O:24])[CH2:20][CH2:21]3)=[CH:14][CH:15]=2)=[C:7]([CH3:26])[N:6]=1
Reactant: Cc1nc(C)c(-c2ccc([C@H]3CC[C@H](CC(=O)O)CC3)cc2)nc1C(N)=O
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1nc(C)c(-c2ccc([C@H]3CC[C@H](CC(=O)NS(C)(=O)=O)CC3)cc2)nc1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 1 (30 mg, 0.082 mmol) in DCM was added DMAP (2 mg, 0.02 mmol), TEA (16 μL, 0.122 mmol), EDCI (20 mg, 0.11 mmol) and finally methanesulfonamide (11 mg, 0.11 mmol, CAS 3144-09-0). The solution was stirred at RT overnight. The crude was concentrated and purified by HPLC (acidic). Evaporation and co-evaporation with toluene gave title compound (22 mg, 60%).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[F:17][C:18]1[C:26]2[C:22](=[CH:23][N:24]([CH3:27])[N:25]=2)[C:21]([CH:28]=O)=[CH:20][CH:19]=1.O>O1CCCC1>[F:17][C:18]1[C:26]2[C:22](=[CH:23][N:24]([CH3:27])[N:25]=2)[C:21](/[CH:28]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:20][CH:19]=1
Reactant: Cn1cc2c(C=O)ccc(F)c2n1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(F)c2nn(C)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
To a suspension of sodium hydride (0.467 g, 11.7 mmol) in tetrahydrofuran (10 mL) was added a solution of ethyl diethylphosphonoacetate (2.34 mL, 11.7 mmol) in tetrahydrofuran (3 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 7-fluoro-2-methyl-2H-indazole-4-carbaldehyde (1.60 g, 8.98 mmol) in tetrahydrofuran (5 mL), and the mixture was warmed to room temperature over 4 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue is was purified by silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (1.85 g, yield 83%).
Reaction SMILES: [F:1][C:2]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>ClCCl>[F:1][C:2]1([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[N+:20]([O-:22])=[O:21])[CH2:7][CH2:6][N:5]([S:24]([CH3:23])(=[O:26])=[O:25])[CH2:4][CH2:3]1
Reactant: CS(=O)(=O)Cl
Reactant: NS(=O)(=O)c1ccc(OCC2(F)CCNCC2)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(F)(COc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])CC1

Procedure:
A mixture of EXAMPLE 173A (0.4 g), methanesulfonyl chloride (0.113 g), and triethylamine (0.64 mL) in dichloromethane (5 mL) was stirred overnight. The reaction mixture was loaded onto a silica gel column and eluted with 100:1 ethyl acetate:methanol to give the clean product.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:17][C:18]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[O:19])[CH:13]=2)[CH:8]=1)(=O)=O.[CH:27]1[C:36]2[C:31](=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(Cl)Cl.O>[CH:27]1[C:36]2[C:31](=[C:32]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[CH:13]=[C:12]([NH:17][C:18]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)=[O:19])[CH:11]=[CH:10]4)[CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1
Reactant: OB(O)c1cccc2cnccc12
Reactant: O=C(Nc1ccc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1)c1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(Nc1ccc2cc(-c3cccc4cnccc34)ccc2c1)c1cccs1
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a microwave vial containing 6-(thiophene-2-carboxamido)naphthalen-2-yl trifluoromethanesulfonate (0.100 g, 0.2 mmol), in 1,4-Dioxane (3 mL), was added isoquinolin-5-ylboronic acid (0.129 g, 0.8 mmol), Fibrecat catalyst (0.005 g, 5% by wt.), and Potassium Carbonate (2 M, 0.50 mL, 1 mmol). The vial was capped and placed into CEM Microwave for 10 minutes at 80° C., while supplying 50 Watts of power through power-max. The mixture was diluted with DCM (2 mL) and water (2 mL). The aqueous layer was extracted with DCM (3×10 mL). The combined organics was dried over sodium sulfate, filtered, and concentrated in-vacuo. The crude was purified from reverse-phase HPLC. This gave a yellow colored amorphous solid, which was titled product (0.078 g, 0.2 mmol). MS (ESI pos. ion) m/z: 381 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.Cl.[N:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[C:56]1[S:60][C:59]([S:61]([N:64]2[CH2:69][CH2:68][CH:67]([CH2:70][NH2:71])[CH2:66][CH2:65]2)(=[O:63])=[O:62])=[CH:58][CH:57]=1>CN(C)C=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:71][CH2:70][CH:67]2[CH2:66][CH2:65][N:64]([S:61]([C:59]3[S:60][C:56]([C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][N:50]=4)=[CH:57][CH:58]=3)(=[O:63])=[O:62])[CH2:69][CH2:68]2)=[O:15])[CH:3]=1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Reactant: NCC1CCN(S(=O)(=O)c2ccc(-c3ccccn3)s2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1nc(C(=O)NCC2CCN(S(=O)(=O)c3ccc(-c4ccccn4)s3)CC2)cc(N)c1C#N
Reaction time: 0.25 h
Yield: 42.4 %

Procedure:
A solution of 4-amino-5-cyano-6-ethoxypicolinic acid (0.038 g) in N,N-dimethylformamide (2 mL) was treated with 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.039 g), 1-hyroxybenzotriazole hydrate (0.031 g), followed by diisopropylethylamine (0.096 mL) at room temperature. After stirring for 15 minutes, the compound prepared in Example 244 (0.079 g) was added. Stirring was continued overnight, and the resulting mixture was washed with water, and the product extracted with ethyl acetate. The organic layer was separated, filtered, evaporated in vacuo and the residue triturated in 1:1 hexane-diethyl ether. The precipitated solids were collected by filtration to provide the title compound (0.041 g) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[C:6]([O:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH:5]=1>CO.[Cl-].[NH4+].C(OCC)(=O)C.[Zn]>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([O:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:18])[CH3:19])[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OCCCN(C)C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)c(OCCCN(C)C)c1
Reaction time: 12 h
Yield: 88 %

Procedure:
To a stirred, cooled (about 0° C.) solution of 3-(3-dimethylamino-propoxy)-4-nitro-benzoic acid methyl ester (282 mg, 1.0 mmol) in methanol (2 mL) and saturated aqueous ammonium chloride (1 mL) was added zinc dust (2.0 mmol). After stirring for 12 hours, the reaction was diluted with 30 mL of ethyl acetate and washed with 30 mL of 10% aqueous sodium carbonate (2×30 mL), brine (1×30 mL), then dried (MgSO4), and filtered. The filtered solution was concentrated under reduced pressure to yield the desired product as a tan solid (88% yield). 1H-NMR (400 MHz, CDCl3) δ7.52 (d, 1H), 7.48 (s, 1H), 7.25 (s, 1H), 6.65 (d, 1H), 4.29 (br s, 1H), 4.09 (t, 2H), 3.85 (s, 3H), 2.49 (t, 2H), 2.25 (s, 6H), 2.00 (m, 2H).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:5]([CH3:7])[N:6]=1.Cl[CH2:14][C:15]1[CH:16]=[C:17]([CH:32]=[CH:33][CH:34]=1)[O:18][CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:23][C:24]=1[CH3:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:7][C:5]1[N:6]=[C:2]([S:1][CH2:14][C:15]2[CH:34]=[CH:33][CH:32]=[C:17]([O:18][CH2:19][C:20]3[N:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:23][C:24]=3[CH3:25])[CH:16]=2)[S:3][C:4]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)Cc1sc(S)nc1C
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1sc(SCc2cccc(OCc3nc(-c4ccccc4)oc3C)c2)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
A mixture of methyl (2-mercapto-4-methylthiazol-5-yl)acetate (385 mg), 4-(3-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (600 mg), potassium carbonate (400 mg) and N,N-dimethylformamide (20 ml) was stirred at room temperature for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [4-methyl-2-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzylthio]thiazol-5-yl]acetate (665 mg, yield 72%) was obtained as an oil from a fraction eluted with ethyl acetate-hexane (1:3 volume ratio).
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:3].C([O:21][C@@H:22]1[C@H:26]([O:27]C(=O)C2C=CC=CC=2)[C@@H:25]([CH2:36][O:37]C(=O)C2C=CC=CC=2)[O:24][C@H:23]1[N:46]1[CH:54]=[N:53][C:52]2[C:47]1=[N:48][C:49]([Cl:56])=[N:50][C:51]=2Cl)(=O)C1C=CC=CC=1.C(N(CC)CC)C.N>O1CCOCC1>[Cl:56][C:49]1[N:50]=[C:51]([NH:3][N:2]([CH3:1])[CH2:4][CH2:5][O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:52]2[N:53]=[CH:54][N:46]([C:47]=2[N:48]=1)[C@@H:23]1[O:24][C@H:25]([CH2:36][OH:37])[C@@H:26]([OH:27])[C@H:22]1[OH:21]
Reactant: CN(N)CCOc1ccccc1
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN(CCOc1ccccc1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 47 %

Procedure:
The title compound was prepared according to method A by reacting 1-methyl-1-(2-phenoxyethyl)hydrazine (prepared by the general method described in example 1) (0.80 g, 4 mmol) and 9-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.53 g, 4 mmol) and triethylamine (1.11 ml, 8 mmol) in dioxan (25 ml), followed by debenzoylation of the purified product using methanolic ammonia to provide the title 2-chloro-N-(N-methyl-N-(2-phenoxyethyl)amino)adenosine (0.84 g, 47%) (after column chromatography) obtained as a solid, mp 166°-8° C., 1H NMR (DMSO-d6)γ 2.70 (3H, s, --CH3), 3.22 (2H, br t, --CH2 --), 3.51-3.58 (1H, m, H-5'a), 3.62-3.69 (1H, m, H-5'a), 3.95 (1H, q, H-4'), 4.05-4.15 (3H, m, --CH2 -- and H-3' ), 4.50 (1H, q, H-2'), 5.06 (1H, t, 5'-OH), 5.21, 5.49 (2H, 2d, 2'- and 3--OH), 5.81 (1H, H-1'), 6.79-7.25 (5H, m, Ar-H), 8.41 (1H, s, H-8), 9.41 (1H, br s, N-H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:23])=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([C:16](=[O:21])[NH:17][CH:18]3[CH2:20][CH2:19]3)[CH:13]=[CH:12][C:11]=2[CH3:22])=[O:8])[S:5][CH:6]=1.[F:24][C:25]1[N:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[CH:18]1([NH:17][C:16]([C:14]2[CH:13]=[CH:12][C:11]([CH3:22])=[C:10]([NH:9][C:7]([C:4]3[S:5][CH:6]=[C:2]([C:28]4[CH:29]=[N:30][C:25]([F:24])=[CH:26][CH:27]=4)[C:3]=3[CH3:23])=[O:8])[CH:15]=2)=[O:21])[CH2:20][CH2:19]1
Reactant: OB(O)c1ccc(F)nc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1scc(Br)c1C
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1scc(-c2ccc(F)nc2)c1C

Procedure:
The title compound was prepared by coupling 4-bromo-N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-3-methylthiophene-2-carboxamide with commercially available 6-fluoropyridin-3-ylboronic acid using the method described in Step B of Example 136 to afford a white solid (Example 199). HPLC Ret time=2.98 min. LCMS [M+H]+ 410.25.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([F:21])([F:20])[F:19])=[CH:15][CH:16]=3)[NH:11][N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:23][C:24]1[S:25][CH:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=1.O>CN(C)C=O>[C:3]1([C:9]2[C:17]3[C:12](=[CH:13][C:14]([C:18]([F:20])([F:21])[F:19])=[CH:15][CH:16]=3)[N:11]([CH2:23][C:24]3[S:25][CH:26]=[C:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:28]=3)[N:10]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1csc(CBr)n1
Reactant: FC(F)(F)c1ccc2c(-c3ccccc3)n[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1csc(Cn2nc(-c3ccccc3)c3ccc(C(F)(F)F)cc32)n1
Reaction time: 0.08 h
Yield: 10.9 %

Procedure:
Sodium hydride (added with 40% mineral oil, 20 mg, manufacture by Kanto Chemical Co., Inc.) was added to a solution of 3-phenyl-6-(trifluoromethyl)-1H-indazole (40 mg), which had been synthesized in Reference Example 18 according to the methods of Reference Examples 8 and 9, in N,N-dimethylformamide (1 mL, manufactured by Kanto Chemical Co., Inc.) under ice cooling, and the mixture was stirred for 5 minutes at the same temperature. Subsequently, ethyl 2-bromomethylthiazole-4-carboxylate (114 mg) synthesized according to the method of the literature (K. Benno, et al., Liebigs. Ann. Chem., 1981, 4, 623-632) was added thereto, and the mixture was stirred overnight at room temperature. Water (1 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×2 mL), washed with brine (10 mL), and dried (MgSO4). The solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1), to give 7.2 mg of the title compound. LC-MS: HPLC retention time 1.41 minutes, m/z 404 (M+H), condition C-1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[N:7]([CH2:9][CH2:10][CH2:11][C:12]#[C:13][C:14]1[CH:19]=[C:18]([C:20](=[O:32])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)[CH:17]=[CH:16][C:15]=1[NH2:33])[CH3:8])([CH3:4])([CH3:3])[CH3:2]>C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.CN(C)C=O>[CH3:31][O:30][C:24]1[CH:23]=[C:22]([NH:21][C:20]([C:18]2[CH:19]=[C:14]3[C:15](=[CH:16][CH:17]=2)[NH:33][C:12]([CH2:11][CH2:10][CH2:9][N:7]([CH3:8])[C:6](=[O:34])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:13]3)=[O:32])[CH:27]=[CH:26][C:25]=1[O:28][CH3:29]
Reactant: COc1ccc(NC(=O)c2ccc(N)c(C#CCCCN(C)C(=O)OC(C)(C)C)c2)cc1OC
Agent: Cl[Pd]Cl
Solvent: CN(C)C=O
Solvent: N#Cc1ccccc1
Product: COc1ccc(NC(=O)c2ccc3[nH]c(CCCN(C)C(=O)OC(C)(C)C)cc3c2)cc1OC
Temperature: 80 °C

Procedure:
A 500 mL round bottom flask was charged with {5-[2-amino-5-(3,4-dimethoxy-phenylcarbamoyl)-phenyl]-pent-4-ynyl}-methyl-carbamic acid tert-butyl ester (3.4 g, 7.27 mmol), dichlorobis(benzonitrile)palladium (II) (0.558 g, 1.45 mmol), and dimethylformamide (80 mL) and the resulting mixture heated to 80° C. for 24 h. The resulting mixture was then concentrated in-vacuo and the residue purified via flash silica gel chromatography (Analogix IF-280, SF25-40 g column, gradient 90:10-10:90 heptane:EtOAc) to yield tert-butyl 3-(5-(3,4-dimethoxyphenylcarbamoyl)-1H-indol-2-yl)propyl(methyl)carbamate. 1H NMR (300 MHz, CDCl3) δ 7.84 (s, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.57 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.00 (d, J=8.6 Hz, 1H), 6.85 (d, J=8.6 Hz, 1H), 6.32 (s, 1H), 3.93 (s, 3H), 3.89 (s, 3H), 3.31-3.41 (m, 2H), 2.89 (s, 3H), 2.66-2.77 (m, 2H), 1.83-1.94 (m, 2H), and 1.53 (s, 9H). MS (ES+) 468 (M+1).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:8]=[C:7]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([C:23]4[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=4)[CH:22]=3)[CH:6]=2)[CH2:3][CH2:2]1.[C:31]([O:35][C:36](=[O:43])[NH:37][C@@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1)([CH3:34])([CH3:33])[CH3:32].CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:31]([O:35][C:36](=[O:43])[NH:37][C@@H:38]1[CH2:42][CH2:41][N:40]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([C:21]3[CH:22]=[C:17]([C:7]4[CH:6]=[C:5]([NH:4][CH:1]5[CH2:2][CH2:3]5)[N:10]=[C:9]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=5)[CH:8]=4)[CH:18]=[N:19][CH:20]=3)=[CH:30][CH:29]=2)[CH2:39]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: O=Cc1ccc(-c2cncc(-c3cc(NC4CC4)nc(-c4ccccn4)c3)c2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H]1CCN(Cc2ccc(-c3cncc(-c4cc(NC5CC5)nc(-c5ccccn5)c4)c3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4-(6′-cyclopropylamino-[2,2′;4′,3″]terpyridin-5″-yl)-benzaldehyde (Example 2.64)(1 eq, 0.204 mmol, 80 mg) in DCM (3 ml) is treated with (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester (2.2 eq, 0.448 mmol, 83.2 mg) followed by AcOH (1.2 eq, 0.245 mmol, 0.14 ml) and sodium triacetoxyborohydride (3.1 eq, 0.632 mmol, 134 mg). The reaction mixture is stirred at room temperature overnight and then extracted with DCM. The organic portion is washed with water, dried (MgSO4) and concentrated in vacuo to afford the title compound which is used in the next step without further purification; [M+H]+ 563.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:23])[C:4](=[O:22])[C:5]([C:14]2[CH:15]=[C:16]([C:20]#[N:21])[N:17]([CH3:19])[CH:18]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9](Br)[CH:8]=2)[N:6]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[N:32][CH:31]=1.CO.C(Cl)(Cl)Cl>CCOCC.CCCCCC.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>[NH2:1][C:2]1[N:3]([CH3:23])[C:4](=[O:22])[C:5]([C:14]2[CH:15]=[C:16]([C:20]#[N:21])[N:17]([CH3:19])[CH:18]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:34]3[CH:35]=[N:30][CH:31]=[N:32][CH:33]=3)[CH:8]=2)[N:6]=1
Reactant: OB(O)c1cncnc1
Reactant: CN1C(=O)C(c2cccc(Br)c2)(c2cc(C#N)n(C)c2)N=C1N
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: CO
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CN1C(=O)C(c2cccc(-c3cncnc3)c2)(c2cc(C#N)n(C)c2)N=C1N
Temperature: 100 °C

Procedure:
The toluene/ethanol (1/1) solvent mixture was deoxygenated vigorously with nitrogen gas prior to using in this reaction. A mixture of 4-[2-amino-4-(3-bromophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl]-1-methyl-1H-pyrrole-2-carbonitrile (173 mg, 0.465 mmol), sodium carbonate (148 mg, 1.394 mmol), pyrimidine-5-boronic acid (86.4 mg, 0.697 mmol) and tetrakis(triphenylphosphine)palladium(0) (27 mg, 0.023 mmol) in toluene/ethanol (1/1) solvent mixture (10 mL) was heated in a 100° C. oil bath for eight hours. TLC (5% methanol/chloroform) shows complete conversion to a new material. The solvent was removed by evaporation and the residue dissolved in chloroform and washed with water. The organic phase was dried (Na2SO4), filtered and evaporated. The resultant residue was purified by HPLC (Luna CN column, normal mobile phase). Crystallization from warm ethyl acetate/hexane afforded the title product as a pure crystalline material, mp 214-225° C.; MS (ES) m/z 370.1.